bipolar disorder neuroanatomy


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(Updated 1/12/04)

Neuroanatomical studies on bipolar disorder
Br J Psychiatry 2001 178: 142-147
"There are few post-mortem studies on bipolar disorder, and definite conclusions can hardly be drawn owing to the small and selective nature of the samples, which in particular might produce false-negative results. Moreover, problems sometimes arise from effects of medication or agonal and post-mortem changes. Data obtained from neuroimaging in mood disorders showing structural abnormalities in the frontal and temporal cortices as well as in subcortical regions are widely confirmed, and also extended and specified, by results from neurohistological investigations. Basal ganglia, preferentially those closely associated with the limbic system, have smaller volumes in patients with depressive illness irrespective of diagnostic polarity. Higher neuron numbers in the locus caeruleus of patients with bipolar disorder than in that of patients with major depressive disorder are in agreement with neuroimaging data indicating a ‘hypernormal’ structural pattern in bipolar disorder that does not appear to exist in major depression. Post-mortem studies showed no differences between the two types of disorder for noradrenalin and serotonin synthesis in the locus caeruleus and the dorsal raphe. Our data suggest a regionally reduced synthesis of these neurotransmitters, which have a major role in the pathogenesis of mood disorders." [Full Text]

Kruger S, Seminowicz D, Goldapple K, Kennedy SH, Mayberg HS.
State and trait influences on mood regulation in bipolar disorder: blood flow differences with an acute mood challenge.
Biol Psychiatry. 2003 Dec 1;54(11):1274-83.
"BACKGROUND: Even in remission, patients with bipolar disorder (BD) remain sensitive to external stressors that can trigger new episodes. Imitating such stressors by the controlled transient exposure to an emotional stimulus may help to identify brain regions modulating this sensitivity. METHODS: Transient sadness was induced in 9 euthymic and in 11 depressed subjects with BD. Regional blood flow (rCBF) changes were measured using (15)O-water positron emission tomography. RESULTS: Common changes in both groups were increased rCBF in anterior insula and cerebellum and decreased rCBF in dorsal-ventral-medial frontal cortex, posterior cingulate, inferior parietal, and temporal cortices. Decreases in dorsal ventral medial frontal cortices occurred in both groups, but subjects in remission showed a greater magnitude of change. Unique to remitted subjects with BD were rCBF increases in dorsal anterior cingulate and in premotor cortex. Lateral prefrontal rCBF decreases were unique to depressed subjects with BD. At baseline, remitted subjects showed a unique increase in dorsal anterior cingulate and orbitofrontal cortex. CONCLUSIONS: Common rCBF changes in remitted and depressed subjects identifies potential sites of disease vulnerability. Unique cingulate and orbitofrontal changes both at baseline and with induced sadness seen in the absence of prefrontal rCBF decreases may identify regional interactions important to the euthymic state in this population." [Abstract]

Rubinsztein, Judy S., Fletcher, Paul C., Rogers, Robert D., Ho, Luk W., Aigbirhio, Franklin I., Paykel, Eugene S., Robbins, Trevor W., Sahakian, Barbara J.
Decision-making in mania: a PET study
Brain 2001 124: 2550-2563
"Poor decision-making is often observed clinically in the manic syndrome. In normal volunteers, decision-making has been associated with activation in the ventral prefrontal cortex and the anterior cingulate gyrus. The aim of this study was to evaluate task-related activation in bipolar manic patients in these regions of the prefrontal cortex using PET. Six subjects with mania, 10 controls and six subjects with unipolar depression (an affective patient control group) were scanned using the bolus H(2)(15)O method while they were performing a decision-making task. Activations associated with the decision-making task were observed at two levels of difficulty. Task-related activation was increased in the manic patients compared with the control patients in the left dorsal anterior cingulate [Brodmann area (BA) 32] but decreased in the right frontal polar region (BA 10). In addition, controls showed greater task-related activation in the inferior frontal gyrus (BA 47) than manic patients. A positive correlation (r(s) = 0.88) between task-related activation in the anterior cingulate and increasing severity of manic symptoms was found. Depressed patients did not show significant task-related differences in activation compared with control subjects in the regions of interest. In conclusion, these patterns of activation point to abnormal task-related responses in specific frontal regions in manic patients. Moreover, they are consistent with neuropsychological observations in patients with lesions in the ventromedial prefrontal cortex, who show similar difficulties with decision-making and provide early evidence for context-specific neural correlates of mania." [Abstract]

Deicken RF, Pegues MP, Anzalone S, Feiwell R, Soher B.
Lower concentration of hippocampal N-acetylaspartate in familial bipolar I disorder.
Am J Psychiatry. 2003 May;160(5):873-82.
"OBJECTIVE: Previous studies attempting to identify neuropathological alterations in the hippocampus in bipolar disorder have been inconclusive. The objective of this study was to determine if the concentration of N-acetylaspartate, a neuronal and axonal marker, was lower in subjects with familial bipolar I disorder than in healthy comparison subjects, suggesting possible neuronal loss, neuronal dysfunction, or neuropil reduction in bipolar I disorder. METHOD: N-acetylaspartate, choline, and creatine in the right and left hippocampus were measured in 15 euthymic male patients with familial bipolar I disorder and 20 healthy male comparison subjects by using proton magnetic resonance spectroscopy ((1)H-MRS). RESULTS: Relative to the comparison group, the patients with bipolar I disorder demonstrated significantly lower concentrations of N-acetylaspartate and creatine but normal choline concentration in both the right and left hippocampus. There were no group or lateralized differences in the percentages of different tissue types within the MRS voxels, suggesting that the hippocampal N-acetylaspartate and creatine alterations were not an artifact of variations in tissue types represented in the voxels. There was also a significant negative correlation between N-acetylaspartate concentration in the right hippocampus and illness duration, after adjustment for the effects of age. CONCLUSIONS: This preliminary study provides support for the existence of neuronal loss, neuronal metabolic dysfunction, or interneuronal neuropil reduction in the hippocampal region in male patients with familial bipolar I disorder. The finding of normal hippocampal choline levels in these patients does not provide support for ongoing myelin breakdown or glial cell proliferation in this brain region in familial bipolar I disorder. The significant association between illness duration and N-acetylaspartate concentration in the right hippocampus supports the idea that neuronal pathology may increase with disease progression and that this effect may be lateralized, involving the right but not the left hippocampus." [Abstract]

Bertolino A, Frye M, Callicott JH, Mattay VS, Rakow R, Shelton-Repella J, Post R, Weinberger DR.
Neuronal pathology in the hippocampal area of patients with bipolar disorder: a study with proton magnetic resonance spectroscopic imaging.
Biol Psychiatry. 2003 May 15;53(10):906-13.
"BACKGROUND: The brain regions involved in the pathophysiology of bipolar disorder have not been definitively determined. Previous studies have suggested possible involvement of the hippocampus and of prefrontal regions. Proton magnetic resonance spectroscopic imaging ((1)H-MRSI) allows measurement of N-acetylaspartate (NAA, marker of neuronal integrity), choline-containing compounds (CHO), and creatine+phosphocreatine (CRE) in multiple brain regions. The objective of this study was to assess possible NAA reductions in hippocampus and prefrontal regions in patients with bipolar disorder. METHODS: We studied 17 patients with bipolar disorder and 17 age- and gender-matched healthy subjects on a 1.5-T nuclear magnetic resonance (NMR) machine. With (1)H-MRSI we measured ratios of areas under the metabolite peaks of the proton spectra (i.e., NAA/CRE, NAA/CHO, CHO/CRE) for multiple cortical and subcortical regions. RESULTS: Patients showed significant reductions of NAA/CRE bilaterally in the hippocampus. There were no significant changes in CHO/CRE or in NAA ratios in any other area sampled. CONCLUSIONS: This study shows that patients with bipolar disorder have a regional reduction of NAA relative signals, suggesting neuronal damage or malfunction of the hippocampus. As suggested by other studies, neuronal pathology in the hippocampus may be involved in the pathophysiology of bipolar disorder and in susceptibility to psychosis." [Abstract]

Strakowski, Stephen M., DelBello, Melissa P., Zimmerman, Molly E., Getz, Glen E., Mills, Neil P., Ret, Jennifer, Shear, Paula, Adler, Caleb M.
Ventricular and Periventricular Structural Volumes in First- Versus Multiple-Episode Bipolar Disorder
Am J Psychiatry 2002 159: 1841-1847
"OBJECTIVE: Ventriculomegaly has been reported in bipolar disorder, although whether it occurs at illness onset or progresses during the course of the disorder is unknown. In addition, it is unknown whether ventriculomegaly in bipolar disorder reflects acquired volume loss or underdevelopment of periventricular structures. METHOD: Magnetic resonance imaging was used to measure the volumes of the lateral and third ventricles and periventricular structures (caudate, putamen, thalamus, hippocampus). Patients with DSM-IV bipolar disorder, 18 who were having a first episode and 17 with multiple episodes, were compared with 32 healthy subjects. RESULTS: The lateral ventricles were significantly larger in the patients with multiple-episode bipolar disorder than in the first-episode patients or the healthy subjects, even after periventricular and total cerebral volumes were taken into account. Having larger lateral ventricles was associated with a higher number of prior manic episodes. The multiple-episode patients had a smaller total cerebral volume than the healthy subjects but not the first-episode patients. The putamen was significantly larger in the first-episode patients (and nearly so in the multiple-episode patients) than in the healthy subjects, although there was no difference between patient groups. CONCLUSIONS: Lateral ventriculomegaly was greater in bipolar disorder patients who had had repeated manic episodes, but it does not appear to be secondary to small critical periventricular structures. A larger than normal striatum, which has been reported in previous studies, was observed in first-episode patients. These results support the importance of prospectively studying neuroanatomic changes in bipolar disorder." [Abstract]

Dean B, Scarr E, Pavey G, Copolov D.
Studies on serotonergic markers in the human hippocampus: changes in subjects with bipolar disorder.
J Affect Disord. 2003 Jun;75(1):65-9.
"BACKGROUND: Various studies suggest the hippocampus and serotonergic systems are important in the pathology of bipolar disorder (BD). We therefore measured hippocampal serotonergic markers in post-mortem tissue from BD and control subjects. METHODS: The density and affinity of [3H]citalopram binding to the serotonin transporter (SERT), as well as the density of the 5HT(2A), 5HT(1A), 5HT(1D) and 5HT(1F) receptors were measured. RESULTS: The density of SERT and 5HT receptors was no different in BD. There was a significant decrease in the affinity of [3H]citalopram binding to SERT in the stratum lacunosum-moleculare (S(lac)) in BD (K(d) mean+/-S.E.M.=4.3+/-0.8 vs. 1.9+/-0.3 nM). LIMITATIONS: This study was completed using relatively small cohorts. CONCLUSIONS: There are no generalised changes in hippocampal serotonergic markers in the hippocampus from subjects with BD. There is a decreased affinity of radioligand binding to S(lac) SERT in subjects with BD." [Abstract]

Beasley C, Cotter D, Everall I.
An investigation of the Wnt-signalling pathway in the prefrontal cortex in schizophrenia, bipolar disorder and major depressive disorder.
Schizophr Res 2002 Nov 1;58(1):63
"The Wnt-signalling pathway has been implicated in a variety of processes including cortical development and plasticity. We have previously demonstrated a reduction in glycogen synthase kinase-3beta (GSK-3beta) levels in the prefrontal cortex in schizophrenia and aimed to further elucidate the abnormalities of the Wnt-signalling pathway in this and other psychiatric disorders. Immunoblotting was performed to quantify the levels of three members of the Wnt-signalling pathway, GSK-3beta, beta-catenin and dishevelled-2 (Dvl-2), in the prefrontal cortex in schizophrenia, bipolar disorder and major depressive disorder and in matched controls. We found no significant differences between the disease and control groups for any of the proteins studied, and therefore, cannot confirm our earlier findings of abnormalities of GSK-3beta in schizophrenia." [Abstract]

Sun Y, Zhang L, Johnston NL, Torrey EF, Yolken RH.
Serial analysis of gene expression in the frontal cortex of patients with bipolar disorder.
Br J Psychiatry Suppl 2001 Jun;41:s137-41
"BACKGROUND: Bipolar disorder is a serious brain disease affecting more than a million individuals living in the USA. Epidemiological studies indicate a role for both genetic and environmental factors in the pathogenesis of this disorder. AIM: To identify RNA transcripts that are up- or down-regulated in the frontal cortex regions of individuals with bipolar disorder. METHOD: Serial analysis of gene expression (SAGE) and reverse transcriptase-polymerase chain reaction were used to identify RNA transcripts which are differentially expressed in the frontal cortex of brains obtained postmortem from individuals with bipolar disorder compared with other psychiatric and control conditions. RESULTS: Levels of RNA transcripts encoding the serotonin transporter protein and components of the NF-kappa B transcription factor complex are significantly increased in individuals with bipolar disorder compared with unaffected controls. Increased levels of expression of these RNA transcripts were also detected in the brains of some individuals with schizophrenia and unipolar depression. CONCLUSION: The SAGE technique offers promise for the characterisation of complex human brain diseases." [Abstract]

Cotter D, Mackay D, Landau S, Kerwin R, Everall I.
Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder.
Arch Gen Psychiatry 2001 Jun;58(6):545-53
"BACKGROUND: Glial cells are more numerous than neurons in the cortex and are crucial to neuronal function. There is evidence for reduced neuronal size in schizophrenia, with suggestive evidence for reduced glial cell density in mood disorders. In this investigation, we have simultaneously assessed glial cell density and neuronal density and size in the anterior cingulate cortex in schizophrenia, major depressive disorder, and bipolar disorder. METHODS: We examined tissue from area 24b of the supracallosal anterior cingulate cortex in 60 postmortem brain specimens from 4 groups of 15 subjects, as follows: major depressive disorder, schizophrenia, bipolar disorder, and normal controls. Glial cell density and neuronal size and density were examined in all subjects using the nucleator and the optical disector. RESULTS: Glial cell density (22%) (P =.004) and neuronal size (23%) (P =.01) were reduced in layer 6 in major depressive disorder compared with controls. There was some evidence for reduced glial density in layer 6 (20%) (P =.02) in schizophrenia compared with controls, before adjusting for multiple layerwise comparisons, but there were no significant changes in neuronal size. There was no evidence for differences in glial density or neuronal size in bipolar disorder compared with controls. Neuronal density was similar in all groups to that found in controls. CONCLUSION: These findings suggest that there is reduced frontal cortical glial cell density and neuronal size in major depressive disorder." [Abstract]

Young, LT, Li, PP, Kamble, A, Siu, KP, Warsh, JJ
Mononuclear leukocyte levels of G proteins in depressed patients with bipolar disorder or major depressive disorder
Am J Psychiatry 1994 151: 594-596
"The levels of Gs alpha and G(i) alpha were significantly higher (160% and 114%, respectively) in the bipolar patients, but not the patients with major depressive disorder, than in the healthy subjects." [Abstract]

Okamoto Y, Kagaya A, Shinno H, Motohashi N, Yamawaki S.
Serotonin-induced platelet calcium mobilization is enhanced in mania.
Life Sci 1995;56(5):327-32
"Not only peak amplitude but also plateau phase were more significantly enhanced in the platelets of untreated manic patients than in those of normal controls. These results suggest that the serotonergic neural transmission by means of intracellular Ca2+ was enhanced by the prolonged plateau phase as well as by increased peak amplitude in platelets of mania." [Abstract]

Friedman E, Hoau-Yan-Wang, Levinson D, Connell TA, Singh H.
Altered platelet protein kinase C activity in bipolar affective disorder, manic episode.
Biol Psychiatry 1993 Apr 1;33(7):520-5
"Protein kinase C (PKC) activity and PKC translocation in response to serotonin were investigated in platelets obtained from bipolar affective disorder subjects before and during lithium treatment. Ratios of platelet membrane-bound to cytosolic PKC activities were elevated in the manic subjects. In addition, serotonin-elicited platelet PKC translocation was found to be enhanced in those subjects. Lithium treatment for up to 2 weeks resulted in a reduction in cytosolic and membrane-associated PKC activities and in an attenuated PKC translocation in response to serotonin. These preliminary results suggest that alteration in platelet PKC is associated with the manic phase of bipolar illness. The results also suggest that lithium treatment reduces the sensitivity of platelets to PKC translocation induced by activation of serotonin-2 receptors." [Abstract]

Friedman, E, Wang, HY
Receptor-mediated activation of G proteins is increased in postmortem brains of bipolar affective disorder subjects
J Neurochem 1996 67: 1145-1152 [Abstract]

Young, LT, Li, PP, Kish, SJ, Siu, KP, Kamble, A, Hornykiewicz, O, Warsh, JJ
Cerebral cortex Gs alpha protein levels and forskolin-stimulated cyclic AMP formation are increased in bipolar affective disorder
J Neurochem 1993 61: 890-898 [Abstract]

Wang HY, Friedman E.
Enhanced protein kinase C activity and translocation in bipolar affective disorder brains.
Biol Psychiatry 1996 Oct 1;40(7):568-75
"Brain membrane-associated PKC activity was higher in bipolar vs. control tissue. An examination of the specific PKC isozymes in cortical homogenates revealed that cytosolic alpha- and membrane-associated gamma- and zeta PKC isozymes were elevated in cortices of bipolar affective disorder subjects, whereas cytosolic epsilon PKC was found to be reduced. In control brain slices, incubation with 1 mumol/L phorbol 12-myristate 13-acetate (PMA) caused an increase in membrane PKC activity, whereas cytosolic enzyme activity was decreased. This redistribution of the enzyme by PMA was markedly potentiated in brain slices of bipolar subjects. The results suggest that PKC-mediated phosphorylation is increased in brains of subjects with bipolar affective illness." [Abstract]

Friedman E, Hoau-Yan-Wang, Levinson D, Connell TA, Singh H.
Altered platelet protein kinase C activity in bipolar affective disorder, manic episode.
Biol Psychiatry 1993 Apr 1;33(7):520-5
"Protein kinase C (PKC) activity and PKC translocation in response to serotonin were investigated in platelets obtained from bipolar affective disorder subjects before and during lithium treatment. Ratios of platelet membrane-bound to cytosolic PKC activities were elevated in the manic subjects. In addition, serotonin-elicited platelet PKC translocation was found to be enhanced in those subjects. Lithium treatment for up to 2 weeks resulted in a reduction in cytosolic and membrane-associated PKC activities and in an attenuated PKC translocation in response to serotonin. These preliminary results suggest that alteration in platelet PKC is associated with the manic phase of bipolar illness. The results also suggest that lithium treatment reduces the sensitivity of platelets to PKC translocation induced by activation of serotonin-2 receptors." [Abstract]

Pandey GN, Dwivedi Y, SridharaRao J, Ren X, Janicak PG, Sharma R.
Protein kinase C and phospholipase C activity and expression of their specific isozymes is decreased and expression of MARCKS is increased in platelets of bipolar but not in unipolar patients.
Neuropsychopharmacology 2002 Feb;26(2):216-28
"Phospholipase C (PLC) and protein kinase C (PKC) are important components of the phosphoinositide (PI) signaling system. To examine if the abnormalities observed in the PI signaling system of patients with affective disorders, reported in previous studies, are related to abnormalities in one or more of its components, we studied PKC, PI-PLC activity, the expression of their specific isozymes, and expression of myristoylated alanine-rich C-kinase substrate (MARCKS) in platelets obtained from 15 drug-free hospitalized patients with bipolar disorder and 15 with major depressive disorder (unipolar) and from 15 nonhospitalized normal control subjects. We observed a significant decrease in PI-PLC and PKC activity and the expression of selective PKC alpha, betaI, betaII, and PLC delta(1) isozymes in membrane and cytosol fraction of platelets from bipolar but not unipolar patients. On the other hand, the level of MARCKS was significantly increased in membrane and cytosol fraction of platelets from patients with bipolar but not unipolar disorders. These results suggest that alterations in PKC, PLC, and MARCKS may be involved in the pathophysiology of bipolar illness." [Abstract]

Kuloglu M, Ustundag B, Atmaca M, Canatan H, Tezcan AE, Cinkilinc N.
Lipid peroxidation and antioxidant enzyme levels in patients with schizophrenia and bipolar disorder.
Cell Biochem Funct 2002 Jun;20(2):171-5 [Abstract]

Rao U, Dahl RE, Ryan ND, Birmaher B, Williamson DE, Rao R, Kaufman J.
Heterogeneity in EEG sleep findings in adolescent depression: unipolar versus bipolar clinical course.
J Affect Disord 2002 Aug;70(3):273-80
"BACKGROUND: EEG sleep measures in child and adolescent subjects with depression have shown considerable variability regarding group differences between depressed and control subjects. This investigation was designed to assess whether some of the observed variability is related to undifferentiated unipolar and bipolar disorders in a sample that was reported previously. METHODS: Twenty-eight adolescents who met criteria for unipolar major depression and 35 controls with no lifetime psychiatric disorder participated in a cross-sectional sleep polysomnography study. Approximately 7 years later, follow-up clinical evaluations were conducted in 94% of the original cohort. Clinical course during the interval period was assessed without knowledge of subjects' initial diagnostic and psychobiological status. Re-analysis of the original sleep data were performed with the added information of longitudinal clinical course. RESULTS: Depressed subjects who had a unipolar course showed reduced REM latency, higher REM density, and more REM sleep (specifically in the early part of the night) compared with depressed adolescents who converted to bipolar disorder and controls who remained free from psychopathology at follow-up. In contrast to the unipolar group, depressed subjects who would later switch to bipolar disorder had demonstrated more stage 1 sleep and diminished stage 4 sleep. CONCLUSIONS: These preliminary results indicate that some of the observed variability in EEG sleep measures in adolescent depression appear to be confounded by latent bipolar illness. The findings also suggest that sleep regulatory changes associated with unipolar versus bipolar mood disorders may be different. Copright 2002 Elsevier Science BV." [Abstract]

Xing G, Russell S, Hough C, O'Grady J, Zhang L, Yang S, Zhang LX, Post R.
Decreased prefrontal CaMKII alpha mRNA in bipolar illness.
Neuroreport 2002 Mar 25;13(4):501-5
"Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays critical roles in neurotransmission, synaptic plasticity, learning and memory. The aim of this study was to examine, by in situ hybridization, prefrontal cortical expression of CaMKII alpha mRNA in postmortem brains of unipolar, bipolar, schizophrenic, and control subjects. Compared to controls, bipolar patients had significantly lower levels of CaMKII alpha mRNA in laminae I-VI of Brodmann's area 9 and laminae I-III and VI of area 46. Unipolar patients also exhibited significantly lower levels of CaMKII alpha mRNA in laminae I-IV of area 9 than did controls. The significant decrease in CaMKII alpha mRNA in bipolar patients could be associated with some of the affective and cognitive alterations that have been linked to prefrontal cortical dysfunction in bipolar disorder, although this requires further direct examination." [Abstract]

Pillai JJ, Friedman L, Stuve TA, Trinidad S, Jesberger JA, Lewin JS, Findling RL, Swales TP, Schulz SC.
Increased presence of white matter hyperintensities in adolescent patients with bipolar disorder.
Psychiatry Res 2002 Feb 15;114(1):51-6
"Several reports have noted an increase in white matter hyperintensities (WMH) on MRI scans of adult patients with bipolar disorder. We investigated whether this increase was also evident in a group of adolescent patients with bipolar disorder. The sample consisted of 15 bipolar patients, 19 patients with schizophrenia and 16 healthy comparison subjects. All subjects were adolescents. WMH were blindly rated on T2-weighted and PD-weighted MRI scans using our own scale with documented inter-rater reliability. WMH were present in 10 of 15 bipolar patients (67%), seven of 19 patients with schizophrenia (37%) and five of 16 comparison subjects (31%). The bipolar adolescent group had a statistically significant increased presence of WMH compared both with healthy comparison subjects and the schizophrenic group. The association between WMH and bipolar disorder appears to extend to the adolescent years." [Abstract]

Berns, Gregory S., Martin, Megan, Proper, Shawnette M.
Limbic Hyperreactivity in Bipolar II Disorder
Am J Psychiatry 2002 159: 304-306
"OBJECTIVE: The authors’ goal was to determine whether patients with bipolar II disorder had altered regional brain responses to novel motor sequences. METHOD: Regional cerebral blood flow was measured with positron emission tomography in 13 patients with bipolar II disorder and 14 healthy comparison subjects. Participants performed a serial reaction time task in which they were visually cued to press one of four buttons at a time. The order of button presses was determined by a complex sequence that was changed in the latter half of the study. RESULTS: In the comparison subjects a spatial attention circuit in the superior parietal lobe and supplementary motor area was activated in response to the introduction of the new sequence. Patients did not display this activation pattern; instead, a widespread limbic network was activated in response to the new sequence. CONCLUSIONS: The attentional resources of patients with bipolar II disorder are not reallocated when they are confronted with a nonemotional motor task; rather, their performance is altered through activation of limbic circuitry." [Abstract]

Pandey GN, Dwivedi Y, SridharaRao J, Ren X, Janicak PG, Sharma R.
Protein kinase C and phospholipase C activity and expression of their specific isozymes is decreased and expression of MARCKS is increased in platelets of bipolar but not in unipolar patients.
Neuropsychopharmacology 2002 Feb;26(2):216-28
"Phospholipase C (PLC) and protein kinase C (PKC) are important components of the phosphoinositide (PI) signaling system. To examine if the abnormalities observed in the PI signaling system of patients with affective disorders, reported in previous studies, are related to abnormalities in one or more of its components, we studied PKC, PI-PLC activity, the expression of their specific isozymes, and expression of myristoylated alanine-rich C-kinase substrate (MARCKS) in platelets obtained from 15 drug-free hospitalized patients with bipolar disorder and 15 with major depressive disorder (unipolar) and from 15 nonhospitalized normal control subjects. We observed a significant decrease in PI-PLC and PKC activity and the expression of selective PKC alpha, betaI, betaII, and PLC delta(1) isozymes in membrane and cytosol fraction of platelets from bipolar but not unipolar patients. On the other hand, the level of MARCKS was significantly increased in membrane and cytosol fraction of platelets from patients with bipolar but not unipolar disorders. These results suggest that alterations in PKC, PLC, and MARCKS may be involved in the pathophysiology of bipolar illness." [Abstract]

Hurd YL.
Subjects with major depression or bipolar disorder show reduction of prodynorphin mRNA expression in discrete nuclei of the amygdaloid complex.
Mol Psychiatry 2002;7(1):75-81
"The dynorphin system has been associated with the regulation of mood. The expression of the prodynorphin mRNA was currently studied in the amygdaloid complex, a brain region critical for emotional processing, in subjects (14-15 per group) diagnosed with major depression, bipolar disorder, or schizophrenia and compared to normal controls. In situ hybridization histochemistry was used to characterize the anatomical distribution and expression levels of the prodynorphin mRNA within the amygdaloid complex. High prodynorphin mRNA levels were expressed in the parvicellular division of the accessory basal, posterior cortical, periamygdaloid cortex, and amygdalohippocampal area in normal subjects. Individuals with major depression had significantly reduced (41-68%) expression of the prodynorphin mRNA in the accessory basal (both parvicellular and magnocellular divisions; P < 0.01) and amygdalohippocampal area (P < 0.001) as compared to controls. The bipolar disorder group also showed a significant reduction (37-38%, P < 0.01) of the mRNA expression levels in the amygdalohippocampal area and in the parvicellular division of the accessory basal. No other amygdala nuclei studied showed any significant differences for the prodynorphin mRNA levels measured in the major depression and bipolar disorder subjects. Additionally, the prodynorphin mRNA expression levels did not differ significantly between the schizophrenic and normal control subjects in any of the amygdala areas examined. These findings indicate specific prodynorphin amygdala impairment in association with mood disorder." [Abstract]

Benes FM, Vincent SL, Todtenkopf M.
The density of pyramidal and nonpyramidal neurons in anterior cingulate cortex of schizophrenic and bipolar subjects.
Biol Psychiatry 2001 Sep 15;50(6):395-406
"BACKGROUND: A recent study reported a decreased density of nonpyramidal neurons (NPs) in layer II of the anterior cingulate (ACCx) and prefrontal (PFCx) cortices of schizophrenic brain that was most pronounced in schizoaffective subjects. Our study assessed whether a decrease of NPs in ACCx may show a stronger covariation with affective disorder. A cohort consisting of 12 normal control (CONs), 11 schizophrenic, and 10 bipolar subjects matched for age and postmortem interval (PMI) has been analyzed. METHODS: A two-dimensional technique was employed for counting cells in a large x,y sampling column that extended across layers I through VI of ACCx. RESULTS: There was a 27% reduction in the density of NPs in layer II of the bipolar group, whereas in the schizophrenic group, this density was 16.2% lower. There were no differences in NPs in layers III through VI of either the schizophrenic or bipolar group. Both groups also showed modest decreases of PNs in the deeper laminae; however, these differences were only significant in layer IV of the schizophrenic subjects. The density of glial cells was similar across the control, schizophrenic, and bipolar groups. An Abercrombie correction for cell size did not alter the nature of the results. Subjects both with and without neuroleptic exposure showed a lower density of NPs in layer II of bipolar subjects or PNS in deeper laminae of schizophrenic subjects. CONCLUSIONS: Overall, the findings reported here suggest that local circuit cells in layer II of ACCx may be decreased in bipolar disorder, whereas projection neurons in deeper laminae are decreased in schizophrenia." [Abstract]

Ali SO, Denicoff KD, Altshuler LL, Hauser P, Li X, Conrad AJ, Smith-Jackson EE, Leverich GS, Post RM.
Relationship between prior course of illness and neuroanatomic structures in bipolar disorder: a preliminary study.
Neuropsychiatry Neuropsychol Behav Neurol 2001 Oct-Dec;14(4):227-32
"OBJECTIVE: In this preliminary study, we examined the relationships between prior course and severity of illness and size of the hippocampus, temporal lobes, and third and lateral ventricles in patients with bipolar disorder. BACKGROUND: The few studies that have investigated relationships between course of illness measures and neuroanatomic structures in patients with bipolar disorder found divergent results. METHOD: Twenty-six outpatients, who met Diagnostic and Statistical Manual, Third Edition - Revised (DSM-III-R) criteria for bipolar disorder, received a magnetic resonance imaging (MRI) scan, from which volumes of the temporal lobes, hippocampi, third ventricle, and areas of the lateral ventricles were calculated. Prior course of illness variables were determined using the NIMH Life-Chart Method and were correlated to the volumetric measures of neuroanatomic structures using multiple regression analyses. RESULTS: A longer duration of illness was paradoxically associated with a larger left temporal lobe volume whether patients with a history of substance abuse were removed from the analyses. CONCLUSIONS: Additional studies are needed to both replicate and further examine the association of prior course of illness and larger hippocampal and ventricular volumes in bipolar disorder." [Abstract]

Kasai K, Shenton ME, Salisbury DF, Onitsuka T, Toner SK, Yurgelun-Todd D, Kikinis R, Jolesz FA, McCarley RW.
Differences and similarities in insular and temporal pole MRI gray matter volume abnormalities in first-episode schizophrenia and affective psychosis.
Arch Gen Psychiatry. 2003 Nov;60(11):1069-77.
"CONTEXT: Whether psychoses associated with schizophrenia and affective disorder represent manifestations of different disorders or the same disorder is an important but unresolved question in psychiatry. Results of previous volumetric magnetic resonance imaging investigations indicate that gray matter volume reductions in neocortical regions may be specific to schizophrenia. OBJECTIVE: To simultaneously evaluate multiple olfactocentric paralimbic regions, which play crucial roles in human emotion and motivation, in first-episode patients with schizophrenia and affective psychosis. DESIGN: A cross-sectional study using high-spatial resolution magnetic resonance imaging in patients with schizophrenia and affective psychosis at their first hospitalization. SETTING: Inpatient units at a private psychiatric hospital. PARTICIPANTS: Fifty-three first-episode patients, 27 with schizophrenia and 26 with affective (mainly manic) psychosis, and 29 control subjects. MAIN OUTCOME MEASURES: Using high-spatial resolution magnetic resonance imaging, the gray matter volumes of 2 olfactocentric paralimbic regions of interest, the insular cortex and the temporal pole, were evaluated. RESULTS: A bilateral volume reduction in insular cortex gray matter was specific to first-episode patients with schizophrenia. In contrast, both first-episode psychosis groups showed a volume reduction in left temporal pole gray matter and an absence of normal left-greater-than-right asymmetry. Region of interest correlations showed that only patients with schizophrenia lacked a positive correlation between left temporal pole and left anterior amygdala-hippocampal complex gray matter volumes, whereas both psychosis groups were similar in lacking normal positive correlations between left temporal pole and left anterior superior temporal gyrus gray matter volumes. CONCLUSIONS: These partially different and partially similar patterns of structural abnormalities in olfactocentric paralimbic regions and their associated abnormalities in other temporolimbic regions may be important factors in the differential and common manifestations of the 2 psychoses." [Abstract]

Fatemi SH, Kroll JL, Stary JM.
Altered levels of Reelin and its isoforms in schizophrenia and mood disorders.
Neuroreport 2001 Oct 29;12(15):3209-15
"Reelin is a secreted extracellular matrix protein approximately 410 kDa mol. wt that is reduced in brains of patients with schizophrenia, autism, bipolar disorder and major depression. Recent reports also indicate its near absence in sera of some patients with an autosomal recessive form of lissencephaly. Moreover, Reelin is involved not only in normal cortical lamination of the brain during mammalian embryogenesis but is also implicated in cell signaling systems subserving cognition in adult brain. Here, we show that blood levels of Reelin and its isoforms are altered in three psychiatric disorders, namely, schizophrenia, bipolar disorder and major depression. The changes include significant increases in 410 kDa Reelin moiety of 49% in schizophrenic patients (p < 0.022) of four ethnic compositions (Caucasian, Vietnamese, Hmong and Laotian) and non-significant increases in depressed patients by 34% vs control blood. In contrast, 410 kDa Reelin levels decreased by 33% in bipolar blood, albeit non-signficantly, vs. controls. There was a significant increase of 90% (p < 0.0061) in 330 kDa Reelin in Caucasian schizophrenics; the depressed value was elevated by 30% vs. control but non-significantly. Again, in contrast, bipolar 330 kDa value decreased by 31% vs control (p < 0.0480). Finally, all 180 kDa Reelin values varied minimally in schizophrenics vs controls. In contrast, the 180 kDa Reelin values dropped significantly by 49% (p < 0.0117) and 29% (p < 0.0424) in bipolar and depressed patients, respectively, compared with controls. The alterations in blood Reelin values appear to be specific since levels of two other blood proteins, ceruloplasmin and albumin did not vary significantly between all psychiatric subjects and controls. These findings suggest that blood Reelin levels and its isoforms may be used as potential peripheral markers to diagnose presence of several psychiatric disorders and may also serve as targets for future therapeutic interventions." [Abstract]

Knable MB, Barci BM, Webster MJ, Meador-Woodruff J, Torrey EF.
Molecular abnormalities of the hippocampus in severe psychiatric illness: postmortem findings from the Stanley Neuropathology Consortium.
Mol Psychiatry. 2004 Jan 6 [Epub ahead of print].
"Between 1997 and 2002, 48 data sets from the hippocampus were produced on samples from the Stanley Neuropathology Consortium. From these data sets, 224 total measures were available from the various subdivisions of the hippocampus. An integrative analysis of these measures was performed using a multivariate, nonparametric analysis of variance (ANOVA). ANOVA with correction for multiple comparisons indicated that parvalbumin-containing cells in CA2 were reduced in schizophrenia and bipolar disorder. In addition, reelin protein in the molecular layer of the dentate gyrus was decreased in schizophrenia, bipolar disorder, and depression at the trend level of statistical significance (P=0.065). These results strongly suggest a dysfunction of inhibitory GABA-ergic interneurons in severe mental illness. Without correction for multiple comparisons, 31 measures were abnormal in at least one disease, whereas 11 measures would be expected to appear abnormal by chance. Abnormal molecules included measures of synaptic density or neuronal plasticity (reelin, SNAP-25, BDNF, Complexin I and II), as well as parvalbumin, tyrosine receptor kinase A, glucocorticoid receptors, glutamate NR1 receptor subunits, serotonin 5HT2(A) and 5HT1(B) receptors, and dopamine D(5) receptors." [Abstract]

Fatemi SH, Earle JA, Stary JM, Lee S, Sedgewick J.
Altered levels of the synaptosomal associated protein SNAP-25 in hippocampus of subjects with mood disorders and schizophrenia.
Neuroreport 2001 Oct 29;12(15):3257-62
"SNAP-25 levels were measured in ventral hippocampus in subjects with unipolar depression (n = 12), bipolar disorder (n = 13), schizophrenia (n = 15) and controls (n = 15) using quantitative immunocytochemistry. SNAP-25 levels were reduced significantly in stratum oriens of bipolar patients compared with controls (p < 0.05); they were also reduced significantly in st. oriens (p < 0.01 vs schizophrenia), in alveous (p < 0.01 vs schizophrenia) and in presubiculum (p < 0.05 vs depressed). SNAP-25 levels were also reduced in several layers of schizophrenics, only significantly so in st. granulosum (p < 0.05 vs controls). In contrast, depressed SNAP-25 levels increased in st. moleculare (p < 0.01 vs schizophrenics) and presubiculum (p < 0.05 vs controls and bipolars; p < 0.01 vs schizophrenics). SNAP-25 values were not affected by age, sex, race, post-mortem interval, brain pH, side of brain, age of onset of disease, family history of psychiatric disease, drug or alcohol use, antipsychotic drug treatment, or mode of death. The reported changes in SNAP-25 levels appear to be disease specific, separating synaptic pathology in unipolar depression from that observed in schizophrenia and bipolar disorders." [Abstract]

Tkachev D, Mimmack ML, Ryan MM, Wayland M, Freeman T, Jones PB, Starkey M, Webster MJ, Yolken RH, Bahn S.
Oligodendrocyte dysfunction in schizophrenia and bipolar disorder.
Lancet. 2003 Sep 6;362(9386):798-805.
"BACKGROUND: Results of array studies have suggested abnormalities in expression of lipid and myelin-related genes in schizophrenia. Here, we investigated oligodendrocyte-specific and myelination-associated gene expression in schizophrenia and bipolar affective disorder. METHODS: We used samples from the Stanley brain collection, consisting of 15 schizophrenia, 15 bipolar affective disorder, and 15 control brains. Indexing-based differential display PCR was done to screen for differences in gene expression in schizophrenia patients versus controls. Results were cross-validated with quantitative PCR, which was also used to investigate expression profiles of 16 other oligodendrocyte and myelin genes in schizophrenia and bipolar disorder. These genes were further investigated with an ongoing microarray analysis. FINDINGS: Results of differential display and quantitative PCR analysis showed a reduction of key oligodendrocyte-related and myelin-related genes in schizophrenia and bipolar patients; expression changes for both disorders showed a high degree of overlap. Microarray results of the same genes investigated by quantitative PCR correlated well overall. INTERPRETATION: Schizophrenia and bipolar brains showed downregulation of key oligodendrocyte and myelination genes, including transcription factors that regulate these genes, compared with control brains. These results lend support to and extend observations from other microarray investigations. Our study also showed similar expression changes to the schizophrenia group in bipolar brains, which thus lends support to the notion that the disorders share common causative and pathophysiological pathways." [Abstract]

Brambilla P, Harenski K, Nicoletti M, Mallinger AG, Frank E, Kupfer DJ, Keshavan MS, Soares JC.
MRI study of posterior fossa structures and brain ventricles in bipolar patients.
J Psychiatr Res 2001 Nov-Dec;35(6):313-22
"Previous brain imaging studies have suggested anatomical abnormalities in posterior fossa structures and brain ventricles in bipolar patients. Such abnormalities could possibly be implicated in the pathophysiology of bipolar disorder. Twenty-two DSM-IV bipolar outpatients (mean age+/-S.D.=36+/-10 years) and 22 healthy controls (mean age+/-S.D.=38+/-10 years) underwent an 1.5T MRI (3D-gradient echo-imaging SPGR), performed in the coronal plane (TR=25 ms, TE=5 ms, slice thickness=1.5 mm). The brain structures of interest were traced blindly with a semi-automated software. No significant differences were found between bipolar patients and healthy controls for any posterior fossa measures, or for measures of third or lateral ventricles (MANOVA, age covariate, P>0.05). Age was directly correlated with 3rd ventricle volumes in bipolar patients (Pearson correlation coefficient=0.458, P=0.032), but not in healthy controls (Pearson correlation coefficient=0.313, P=0.155). There was a significant direct correlation between the number of prior illness episodes and right lateral ventricle volumes (Partial correlation coefficient=0.658, P=0.011). Familial patients had smaller left and right cerebellar hemispheres and total vermis volumes, and larger left lateral ventricle volumes compared with non-familial ones (MANOVA, age covariate, P<0.05). In this preliminary study, we were not able to replicate previous findings of abnormalities in cerebellum or brain ventricles in bipolar individuals. However, there were suggestions that abnormalities in cerebellum, vermis, and lateral ventricle sizes may be present in familial cases of the disorder, which should be further examined in future studies with larger patient samples." [Abstract]

Caetano SC, Sassi R, Brambilla P, Harenski K, Nicoletti M, Mallinger AG, Frank E, Kupfer DJ, Keshavan MS, Soares JC.
MRI study of thalamic volumes in bipolar and unipolar patients and healthy individuals.
Psychiatry Res 2001 Dec 30;108(3):161-8
"The thalamus is a key structure in brain anatomic circuits potentially involved in the pathophysiology of mood disorders. Available findings from studies that examined this brain region in mood disorder patients have been conflicting. To examine the hypothesis of anatomical abnormalities in the thalamus in patients with mood disorders, we conducted a magnetic resonance imaging (MRI) study in 25 bipolar patients (mean age+/-S.D.=34.4+/-9.8 years), 17 unipolar patients (mean age+/-S.D.=42.8+/-9.2 years), and 39 healthy control subjects (mean age+/-S.D.=36.6+/-9.7 years). Thalamic volumes Gray Matter were measured blindly with a semi-automated technique. Multivariate analysis of variance, with age and gender as covariates, revealed no significant differences in left or right thalamic volumes among bipolar patients, unipolar patients and healthy individuals. There were no significant effects of gender, age at illness onset, episode type, number of episodes, length of illness, or family history of mood disorders on thalamic measurements. Although functional abnormalities in the thalamus are likely to be implicated in the pathophysiology of mood disorders, no abnormalities in thalamic size appear present in bipolar or unipolar individuals." [Abstract]

Serial analysis of gene expression in the frontal cortex of patients with bipolar disorder
Br J Psychiatry 2001 178: 137-141
"Levels of RNA transcripts encoding the serotonin transporter protein and components of the NF-kappaB transcription factor complex are significantly increased in individuals with bipolar disorder compared with unaffected controls. Increased levels of expression of these RNA transcripts were also detected in the brains of some individuals with schizophrenia and unipolar depression." [Full Text]

Benes FM, Berretta S.
GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder.
Neuropsychopharmacology 2001 Jul;25(1):1-27
"A core component to corticolimbic circuitry is the GABAergic interneuron. Neuroanatomic studies conducted over the past century have demonstrated several subtypes of interneuron defined by characteristic morphological appearances in Golgi-stained preparations. More recently, both cytochemical and electrophysiological techniques have defined various subtypes of GABA neuron according to synaptic connections, electrophysiological properties and neuropeptide content. These cells provide both inhibitory and disinhibitory modulation of cortical and hippocampal circuits and contribute to the generation of oscillatory rhythms, discriminative information processing and gating of sensory information within the corticolimbic system. All of these functions are abnormal in schizophrenia. Recent postmortem studies have provided consistent evidence that a defect of GABAergic neurotransmission probably plays a role in both schizophrenia and bipolar disorder. Many now believe that such a disturbance may be related to a perturbation of early development, one that may result in a disturbance of cell migration and the formation of normal lamination. The ingrowth of extrinsic afferents, such as the mesocortical dopamine projections, may "trigger" the appearance of a defective GABA system, particularly under stressful conditions when the modulation of the dopamine system is likely to be altered. Based on the regional and subregional distribution of changes in GABA cells in schizophrenia and bipolar disorder, it has been postulated that the basolateral nucleus of the amygdala may contribute to these abnormalities through an increased flow of excitatory activity. By using "partial" modeling, changes in the GABA system remarkably similar to those seen in schizophrenia and bipolar disorder have been induced in rat hippocampus. In the years to come, continued investigations of the GABA system in rodent, primate and human brain and the characterization of changes in specific phenotypic subclasses of interneurons in schizophrenia and bipolar disorder will undoubtedly provide important new insights into how the integration of this transmitter system may be altered in neuropsychiatric disease." [Abstract]

Brambilla P, Harenski K, Nicoletti MA, Mallinger AG, Frank E, Kupfer DJ, Keshavan MS, Soares JC.
Anatomical MRI study of basal ganglia in bipolar disorder patients.
Psychiatry Res 2001 Apr 10;106(2):65-80
"This study examined possible anatomical abnormalities in basal ganglia structures in bipolar disorder patients. Caudate and putamen gray matter volumes, and globus pallidus total volume were measured with magnetic resonance imaging (MRI) in 22 DSM-IV bipolar patients (age+/-S.D.=36+/-10 years; eight drug-free and 14 lithium monotherapy patients) and 22 matched healthy control subjects (age+/-S.D.=38+/-10 years). No significant differences were found between bipolar patients and healthy control subjects for any of the basal ganglia measures (t-tests, P>0.05). Age was inversely correlated with left putamen volumes in patients (R=-0.44, P=0.04), but not in healthy control subjects (R=-0.33, P=0.14). Older patients (>36 years old) had a significantly larger left globus pallidus than younger ones (< or =36 years old) (ANOVA, P=0.01). In a multiple regression analysis, after entering age as independent variable, the length of illness predicted smaller left putamen volumes, explaining 10.4% of the variance (F=4.07, d.f.=2, P=0.03). No significant effects of episode type, number of prior episodes, or gender were found in any basal ganglia measurements (ANOVA, P>0.05). In conclusion, our findings indicate that the basal ganglia may be anatomically preserved in bipolar patients. This is in contrast to available findings for unipolar disorder. However, our findings also suggest that age and length of illness may have significant effects on basal ganglia structures in bipolar patients, which may be more pronounced among bipolar I patients, and of relevance for the pathophysiology of the disorder." [Abstract]

Caligiuri MP, Brown GG, Meloy MJ, Eberson SC, Kindermann SS, Frank LR, Zorrilla LE, Lohr JB.
An fMRI study of affective state and medication on cortical and subcortical brain regions during motor performance in bipolar disorder.
Psychiatry Res. 2003 Jul 30;123(3):171-82.
"Structural neuroimaging studies have identified abnormalities in the basal ganglia in patients with bipolar disorder. Findings have been mixed with regard to affective state and have not elaborated on the role of medication on functional brain activity. The aims of the present study were to use functional magnetic resonance imaging (fMRI) to test whether depressed and manic bipolar disorder patients differ in terms of activity in cortical and subcortical brain areas and to examine the effects of psychotropic medication. Twenty-four bipolar disorder subjects and 13 healthy comparison subjects participated in an fMRI study of manual reaction time. Both manic and depressed subjects exhibited abnormally elevated blood oxygen level dependent BOLD responses in cortical and subcortical areas. Manic bipolar subjects had significantly higher BOLD responses in the left globus pallidus and significantly lower BOLD responses in the right globus pallidus compared with depressed bipolar patients. Correlational analyses revealed significant relationships between the severity of mania and activity within the globus pallidus and caudate. Patients off antipsychotic or mood-stabilizing medication exhibited significantly higher BOLD responses throughout the motor cortex, basal ganglia and thalamus compared with patients on these medications. These results suggest that affective state in bipolar disorder may be related to a disturbance of inhibitory regulation within the basal ganglia and that antipsychotics and/or mood stabilizers normalize cortical and subcortical hyperactivity." [Abstract]

Chang A, Li PP, Warsh JJ.
cAMP-Dependent protein kinase (PKA) subunit mRNA levels in postmortem brain from patients with bipolar affective disorder (BD).
Brain Res Mol Brain Res. 2003 Aug 19;116(1-2):27-37.
"Earlier findings of elevated basal and stimulated PKA activities, and increased immunoreactive levels of PKA regulatory and catalytic subunits in discrete postmortem brain regions from bipolar disorder (BD) patients suggest that disturbances in PKA are involved in the pathophysiology of BD. PKA subunit mRNA levels were measured using SYBR Green real-time RT-PCR to determine if previously observed differences in immunoreactive levels of PKA RIIbeta and Calpha subunits were associated with corresponding changes in mRNA levels in temporal and frontal cortices from the same BD patients and matched controls. In distinct contrast to the higher immunolabeling levels of the PKA subunits previously reported in the BD brain, there were no significant differences in RIIbeta and Calpha subunit mRNA levels in the temporal and frontal cortices of BD patients compared with controls. These findings infer that the elevated PKA immunolabeling and activity found in the selected cerebral cortical regions of BD postmortem brain were due to a posttranscriptional mechanism, rather than changes in regulation of gene transcription and/or mRNA stability of the PKA subunits." [Abstract]

Chang A, Li PP, Warsh JJ.
Altered cAMP-dependent protein kinase subunit immunolabeling in post-mortem brain from patients with bipolar affective disorder.
J Neurochem. 2003 Feb;84(4):781-91.
"Previous findings of reduced [3H]cAMP binding and increased activities of cAMP-dependent protein kinase (PKA) in discrete post-mortem brain regions from patients with bipolar affective disorder (BD) suggest that PKA, the major downstream target of cAMP, is also affected in this illness. As prolonged elevation of intracellular cAMP levels can modify PKA regulatory (R) and catalytic (C) subunit levels, we sought to determine whether these PKA abnormalities are related to changes in the abundance of PKA subunits in BD brain. Using immunoblotting techniques along with PKA subunit isoform-specific polyclonal antisera, levels of PKA RIalpha, RIbeta, RIIalpha, RIIbeta and Calpha subunits were measured in cytosolic and particulate fractions of temporal, frontal and parietal cortices of post-mortem brain from BD patients and matched, non-neurological, non-psychiatric controls. Immunoreactive levels of cytosolic Calpha in temporal and frontal cortices, as well as that of cytosolic RIIbeta in temporal cortex, were significantly higher in the BD compared with the matched control brains. These changes were independent of age, post-mortem interval or pH and unrelated to ante-mortem lithium treatment or suicide. These findings strengthen further the notion that the cAMP/PKA signaling system is up-regulated in discrete cerebral cortical regions in BD." [Abstract]

Jensen JB, Shimon H, Mork A.
Abnormal protein phosphorylation in post-mortem brain tissue from bipolar patients.
J Neural Transm 2000;107(4):501-9
"Abnormal phosphorylation has been proposed to be involved in the pathogenesis of affective disorders. The present study investigated basal and cAMP-stimulated endogenous protein phosphorylation in human post-mortem brain tissue from bipolar and schizophrenic patients. Furthermore, basal kinase activity and stimulated protein kinase A activity were measured. The frontal and occipital cortex were analysed. Using [gamma-32P]ATP as phosphate donor, basal and cAMP-stimulated phosphorylation of endogenous proteins was measured in the absence or presence of 8-Br-cAMP, respectively. The proteins were separated on SDS-gels and the radioactivity in the individual bands was measured. We observed a significant reduction of 32P incorporation in three protein substrates (15, 16 and 21 kD) in frontal cortex of bipolar patients. However, there were no differences in the PKA activity between any of the groups. The present study demonstrates abnormal phosphorylation of specific proteins in brain tissue obtained from bipolar patients in comparison to schizophrenics and controls." [Abstract]

Tardito D, Mori S, Racagni G, Smeraldi E, Zanardi R, Perez J.
Protein kinase A activity in platelets from patients with bipolar disorder.
J Affect Disord. 2003 Sep;76(1-3):249-53.
"BACKGROUND: Abnormal levels of protein kinase A (PKA) were found in patients with bipolar disorder (BD). Since altered levels are generally accompanied by functional modifications, the purpose of this study was to investigate PKA activity in patients with BD. METHODS: PKA activity was assessed in platelets from 20 drug-free bipolar patients and 19 controls. RESULTS: The cAMP-stimulated PKA activity was significantly increased in bipolar patients compared with controls. LIMITATIONS: This study made use of platelets, which may not fully represent changes occurring in specific brain regions. CONCLUSION: This study adds to the growing evidence suggesting that abnormalities of PKA are associated with BD." [Abstract]

Ketter TA, Kimbrell TA, George MS, Dunn RT, Speer AM, Benson BE, Willis MW, Danielson A, Frye MA, Herscovitch P, Post RM.
Effects of mood and subtype on cerebral glucose metabolism in treatment-resistant bipolar disorder.
Biol Psychiatry 2001 Jan 15;49(2):97-109
"BACKGROUND: Functional brain imaging studies in unipolar and secondary depression have generally found decreased prefrontal cortical activity, but in bipolar disorders findings have been more variable. METHODS: Forty-three medication-free, treatment-resistant, predominantly rapid-cycling bipolar disorder patients and 43 age- and gender-matched healthy control subjects had cerebral glucose metabolism assessed using positron emission tomography and fluorine-18-deoxyglucose. RESULTS: Depressed bipolar disorder patients compared to control subjects had decreased global, absolute prefrontal and anterior paralimbic cortical, and increased normalized subcortical (ventral striatum, thalamus, right amygdala) metabolism. Degree of depression correlated negatively with absolute prefrontal and paralimbic cortical, and positively with normalized anterior paralimbic subcortical metabolism. Increased normalized cerebello-posterior cortical metabolism was seen in all patient subgroups compared to control subjects, independent of mood state, disorder subtype, or cycle frequency. CONCLUSIONS: In bipolar depression, we observed a pattern of prefrontal hypometabolism, consistent with observations in primary unipolar and secondary depression, suggesting this is part of a common neural substrate for depression independent of etiology. In contrast, the cerebello-posterior cortical normalized hypermetabolism seen in all bipolar subgroups (including euthymic) suggests a possible congenital or acquired trait abnormality. The degree to which these findings in treatment-resistant, predominantly rapid-cycling patients pertain to community samples remains to be established."[Abstract]

Soares JC, Dippold CS, Wells KF, Frank E, Kupfer DJ, Mallinger AG.
Increased platelet membrane phosphatidylinositol-4,5-bisphosphate in drug-free depressed bipolar patients.
Neurosci Lett 2001 Feb 16;299(1-2):150-2
"Prior investigations in bipolar disorder patients have suggested abnormalities in the cellular phosphoinositide second messenger system. This study was conducted to examine the levels of platelet membrane phosphoinositides in drug-free bipolar patients in the depressed state (n=9) and healthy controls (n=19). Bipolar patients had significantly increased levels of platelet membrane phosphatidylinositol-4,5-bisphosphate (PIP(2)) compared to healthy individuals (0.67+/-0.14 and 0.44+/-0.17%, respectively, t-test=3.71, d.f.=26, P=0.001). No significant differences in the levels of phosphatidylinositol-4-phosphate (PIP) (0.65+/-0.17 and 0.58+/-0.20%, respectively, t-test=1.02; d.f.=26; P=0.32) or phosphatidylinositol (PI) (5.92+/-1.23 and 5.56+/-1.45%, respectively, t-test=0.68; d.f.=26; P=0.51) were found. These findings provide the first demonstration of increased PIP(2) platelet levels in bipolar patients in the depressed state, and provide additional evidence that the phosphoinositide second messenger system may be a site of abnormality in bipolar disorder." [Abstract]

Cerebral white matter lesions in bipolar affective disorder: relationship to outcome
Br J Psychiatry 2001 178: 172-176
"BACKGROUND: Twenty per cent of patients with bipolar affective disorder suffer an illness that responds inadequately to treatment and has a poor outcome. Many patients, but not all, with bipolar disorder show white matter abnormalities on T(2)-weighted magnetic resonance imaging (MRI). AIMS: To explore the hypothesis that white matter abnormalities on MRI are seen more frequently in subjects whose illness has a poor outcome compared with those with a good outcome or controls. METHOD: Two groups of age- and gender-matched patients with bipolar disorder (14 with a good outcome and 15 with a poor outcome) and 15 controls, aged 20-65 years, were studied. Axial T(2)-weighted MRI scans were examined for the presence and severity of white matter abnormalities. RESULTS: Significantly more poor outcome group members had deep subcortical punctate, but not periventricular, white matter hyperintensities than the good outcome group (P:=0.035) or controls (P:=0.003) and these abnormalities were of greater severity (P:=0.030 and P:<0.014, respectively). CONCLUSIONS: Subcortical white matter lesions are associated with poor outcome bipolar disorder." [Full Text]

Vawter MP, Freed WJ, Kleinman JE.
Neuropathology of bipolar disorder.
Biol Psychiatry 2000 Sep 15;48(6):486-504
"The literature on the neuropathology of bipolar disorder (BD) is reviewed. Postmortem findings in the areas of pathomorphology, signal transduction, neuropeptides, neurotransmitters, cell adhesion molecules, and synaptic proteins are considered. Decreased glial numbers and density in both BD and major depressive disorder (MDD) have been reported, whereas cortical neuron counts were not different in BD (in Brodmann's areas [BAs] 9 and 24). In contrast, MDD patients showed reductions in neuronal size and density (BA 9, BA 47). There are a number of findings of alterations in neuropeptides and monoamines in BD brains. Norepinephrine turnover was increased in several cortical regions and thalamus, whereas the serotonin metabolite, 5-hydroxyindoleacetic acid, and the serotonin transporter were reduced in the cortex. Several reports further implicated both cyclic adenosine monophosphate and phosphatidylinositol (PI) cascade abnormalities. G protein concentrations and activity increases were found in the occipital, prefrontal, and temporal cortices in BD. In the PI signal cascade, alterations in PKC activity were found in the prefrontal cortex. In the occipital cortex, PI hydrolysis was decreased. Two isoforms of the neural cell adhesion molecules were increased in the hippocampus of BD, whereas the synaptic protein marker, synaptophysin, was not changed. The findings of glial reduction, excess signal activity, neuropeptide abnormalities, and monoamine alterations suggest distinct imbalances in neurochemical regulation. Possible alterations in pathways involving ascending projections from the brain stem are considered. Larger numbers of BD brains are needed to further refine the conceptual models that have been proposed, and to develop coherent models of the pathophysiology of BD." [Abstract]

Sokolski KN, DeMet EM.
Cholinergic sensitivity predicts severity of mania.
Psychiatry Res 2000 Sep 11;95(3):195-200
"Our laboratory and others have reported that pupillary constrictions following application of the cholinergic agonist pilocarpine are increased in depressed patients. Moreover, mood improvements in manic patients, given lithium or Depakote, are also correlated with increases in pupil sensitivity. The present report describes the relationship between symptom severity and cholinergic sensitivity in a larger group (N=20) of manic patients (bipolar I; 296.4x). Pupil responses to pilocarpine eye drops (0-2%) were recorded using infrared pupillometry. The results were compared with pupil sizes measured under conditions of cholinergic blockade (0.5% tropicamide). Pupil responses were computed as percentages of the maximal range of areas measured under saturating agonist and antagonist conditions. Dose response curves were subjected to a log-logit transformation and ED(50) values were determined by weighted least squares regression. Bech-Rafaelsen mania ratings were found to be linearly related to ED(50) values (r=0.48). Patients with more severe mania required higher concentrations of pilocarpine in order to elicit a 50% reduction in pupil size. The present findings support a putative cholinergic role in the regulation of mood state. Moreover, the results suggest that pupillary responses may provide a simple and non-invasive means to evaluate cholinergic sensitivity in patients with affective disorders." [Abstract]

Greenberg DB, Jonasch E, Gadd MA, Ryan BF, Everett JR, Sober AJ, Mihm MA, Tanabe KK, Ott M, Haluska FG.
Adjuvant therapy of melanoma with interferon-alpha-2b is associated with mania and bipolar syndromes.
Cancer 2000 Jul 15;89(2):356-62
"BACKGROUND: The use of a high dose regimen of interferon-alpha-2b (IFN) has recently been demonstrated to benefit patients with resected high risk melanoma. The incidence of melanoma is rising rapidly, and the use of this regimen is becoming increasingly common. IFN has been associated with numerous psychiatric side effects. METHODS: The authors describe four melanoma patients treated with adjuvant IFN who developed a manic-depressive syndrome or mood instability with therapy, and they review the literature on mania and the mixed affective syndromes associated with IFN. RESULTS: The authors suggest that IFN may induce a mixed affective instability, and that patients risk developing hypomania or mania as IFN doses fluctuate or as IFN-induced depression is treated with antidepressants alone. Mania is particularly associated with dose reductions or pauses in IFN treatment. The risk of mood fluctuation continues after treatment with IFN stops, and patients should be monitored for 6 months following completion of therapy. Gabapentin appeared effective as monotherapy for acute mania, as an antianxiety agent, as a hypnotic, and as a mood stabilizer in these individual cases. CONCLUSIONS: Mania and mood instability can occur in patients being treated with IFN therapy for melanoma. In this study, gabapentin was an effective mood-stabilizing agent for these patients. Copyright 2000 American Cancer Society." [Abstract]

Eastwood SL, Harrison PJ.
Hippocampal synaptic pathology in schizophrenia, bipolar disorder and major depression: a study of complexin mRNAs.
Mol Psychiatry 2000 Jul;5(4):425-32
"Complexin (cx) I and cx II are synaptic proteins preferentially expressed by inhibitory and excitatory hippocampal neurons respectively. We previously reported decreased hippocampal formation cx mRNA and protein expression in schizophrenia, with a greater loss of cx II than cx I. The present in situ hybridization study was both an attempt at replication, and an extension to include bipolar and unipolar mood disorders, using sections from the Stanley Foundation brain series. In schizophrenia, both mRNAs were decreased in some hippocampal subfields, especially CA4, but were preserved in subiculum. The cx II/cx I mRNA ratio was unchanged. In bipolar disorder, the mRNAs were reduced in CA4, subiculum and parahippocampal gyrus, with the deficit in subiculum being diagnostically specific. No alterations in cx mRNAs were found in major depression. Treatment of rats with antipsychotics (haloperidol or chlorpromazine) for 2 weeks had no effect on hippocampal cx mRNAs. These data replicate the finding of decreased cx I and cx II expression in the hippocampus in schizophrenia and show a similar or greater abnormality in bipolar disorder. Non-replication of the cx II > cx I mRNA loss in schizophrenia means that the hypothesis of a preferential involvement of excitatory connections was not supported. The results extend the emerging evidence that altered circuitry may be a component of the neuroanatomy of both schizophrenia and bipolar mood disorder." [Abstract]

Krabbendam L, Honig A, Wiersma J, Vuurman EF, Hofman PA, Derix MM, Nolen WA, Jolles J.
Cognitive dysfunctions and white matter lesions in patients with bipolar disorder in remission.
Acta Psychiatr Scand 2000 Apr;101(4):274-80
"OBJECTIVE: To compare cognitive functioning in relation to white matter lesions in bipolar disorder in remission and schizophrenia. METHOD: Cognitive performance and the occurrence of white matter lesions on MRI images of the brain were assessed in 22 patients with bipolar disorder in remission, 22 patients with schizophrenia and 22 healthy volunteers. RESULTS: Performance of tests of memory, speed and cognitive flexibility was significantly impaired in both patient groups. The frequency of white matter lesions did not differ significantly between the three groups. No differences in cognitive performance were found between patients with white matter lesions and patients without such lesions. CONCLUSION: White matter lesions apparently do not underlie cognitive deficits that are found in patients with bipolar disorder in remission and in patients with schizophrenia." [Abstract]

Burnet PW, Harrison PJ.
Substance P (NK1) receptors in the cingulate cortex in unipolar and bipolar mood disorder and schizophrenia.
Biol Psychiatry 2000 Jan 1;47(1):80-3
"BACKGROUND: The substance P receptor (neurokinin-1 receptor) has been implicated in stress responses and anxiety traits in the rodent, and neurokinin-1 receptor antagonism may have antidepressant and anxiolytic effects. This suggests that the function and/or expression of neurokinin-1 receptor might be affected in subjects with mood disorders. METHODS: We measured neurokinin-1 receptor densities in the anterior cingulate cortex in subjects with unipolar (major) depression (n = 13), bipolar disorder (n = 13), schizophrenia (n = 14), and controls (n = 14) using quantitative autoradiography with [125I]BH-substance P. The anterior cingulate cortex was chosen for initial analysis since recent positron emission tomography, magnetic resonance imaging, and neuropathological data suggest its involvement in mood disorders. RESULTS: Neurokinin-1 receptor densities were higher in superficial than in deep laminae. Neurokinin-1 receptor densities increased with age and declined with prolonged autopsy interval. No differences were seen between the four groups. However, the ratio of superficial to deep laminar binding was lower in the subjects with unipolar depression compared with all other groups (p < .01) Neurokinin-1 receptor binding and the laminar ratio were unaffected by sex, medication history, pH, suicide, comorbid substance abuse, or a family psychiatric history. CONCLUSIONS: No overall change in neurokinin-1 receptor densities occurs in the cingulate cortex in subjects with mood disorders or schizophrenia. However, the changed laminar ratio in unipolar depression may reflect alterations in specific neural circuits expressing neurokinin-1 receptor." [Abstract]

Lim KO, Rosenbloom MJ, Faustman WO, Sullivan EV, Pfefferbaum A.
Cortical gray matter deficit in patients with bipolar disorder.
Schizophr Res 1999 Dec 21;40(3):219-27
"BACKGROUND: cortical gray matter volume deficit and ventricular enlargement are well documented in schizophrenia, but their presence in bipolar disorder is less well established. METHODS: global cortical gray matter, white matter and sulcal CSF, as well as lateral and third ventricular volume measures, were derived from axial MRI brain images obtained on age-matched bipolar (n=9), schizophrenic (n=9), and control (n=16) subjects. All subjects were free of history of alcohol or other substance dependence. RESULTS: relative to controls, bipolar patients had widespread volume deficits of cortical gray matter but not of cortical white matter. Schizophrenic patients had an even more severe cortical gray matter deficit and greater sulcal and lateral ventricular enlargement than the bipolar patients. CONCLUSIONS: this group of patients with bipolar disorder had a widespread deficit of cortical gray matter similar to, but less pronounced than, that observed in patients with schizophrenia." [Abstract]

Dasari M, Friedman L, Jesberger J, Stuve TA, Findling RL, Swales TP, Schulz SC.
A magnetic resonance imaging study of thalamic area in adolescent patients with either schizophrenia or bipolar disorder as compared to healthy controls.
Psychiatry Res 1999 Oct 11;91(3):155-62
"The purpose of this study was to compare thalamic size in adolescent patients with either schizophrenia or bipolar disorder and healthy controls. T2-weighted axial magnetic resonance images were used to manually define the area of the thalamus for 20 schizophrenia patients, 15 bipolar patients and 16 normal control subjects, all of whom were adolescents. Two orthogonal planned contrasts were tested: Contrast 1, patients with schizophrenia vs. patients with bipolar disorder; and Contrast 2, both patient groups taken as a single group compared to controls. Contrast 1 was not statistically significant for right or left thalamic area. Contrast 2 was statistically significant and indicated reductions in thalamic area in the patients as compared to controls. The same pattern of results emerged after adjustment for total brain volume. Our results indicate that thalamic abnormalities reported in adult schizophrenic and bipolar patients are also observed in adolescent patients. Our findings also add to the evidence implicating the thalamus in the pathophysiology of schizophrenia and bipolar disorder." [Abstract]

Fields, Anat, Li, Peter P., Kish, Stephen J., Warsh, Jerry J.
Increased Cyclic AMP-Dependent Protein Kinase Activity in Postmortem Brain from Patients with Bipolar Affective Disorder
J Neurochem 1999 73: 1704-1710
"Previous observations of reduced [3H]cyclic AMP binding in postmortem brainregions frombipolar affective disorder subjects imply cyclic AMP-dependent proteinkinase functionmay be altered in this illness. To test this hypothesis, basal and stimulated cyclic AMP-dependent protein kinase activity was determined in cytosolic and particulate fractions of postmortem brain from bipolar disorder patients and matched controls. Maximal enzyme activity was significantly higher (104%) in temporal cortex cytosolic fractions from bipolar disorder brain compared with matched controls. In temporal cortex particulate fractions and in the cytosolic and particulate fractions of other brain regions, smaller but statistically nonsignificant increments in maximal enzyme activity were detected. Basal cyclic AMP-dependent protein kinase activity was also significantly higher (40%) in temporal cortex cytosolic fractions of bipolar disorder brain compared with controls. Estimated EC50 values for cyclic AMP activation of this kinase were significantly lower (70 and 58%, respectively) in both cytosolic and particulate fractions of temporal cortex from bipolar disorder subjects compared with controls. These findings suggest that higher cyclic AMP-dependent proteinkinase activity in bipolar disorder brain may be associated with a reduction of regulatory subunits of this enzyme, reflecting a possible adaptive response of this transducing enzyme to increased cyclic AMP signaling in this disorder." [Abstract]

Kupka RW, Nolen WA, Post RM, McElroy SL, Altshuler LL, Denicoff KD, Frye MA, Keck PE Jr, Leverich GS, Rush AJ, Suppes T, Pollio C, Drexhage HA.
High rate of autoimmune thyroiditis in bipolar disorder: lack of association with lithium exposure.
Biol Psychiatry 2002 Feb 15;51(4):305-11
"BACKGROUND: We assessed the prevalence of thyroperoxidase antibodies (TPO-Abs) and thyroid failure in outpatients with bipolar disorder compared with two control groups. METHODS: The TPO-Abs of outpatients with DSM-IV bipolar disorder (n = 226), a population control group (n = 252), and psychiatric inpatients of any diagnosis (n = 3190) were measured. Thyroid failure was defined as a raised thyroid stimulating hormone level, previously diagnosed hypothyroidism, or both. Subjects were compared with attention to age, gender, and exposure to lithium. RESULTS: The TPO-Abs were more prevalent in bipolar patients (28%) than population and psychiatric controls (3-18%). The presence of TPO-Abs in bipolar patients was associated with thyroid failure, but not with age, gender, mood state, rapid cycling, or lithium exposure. Thyroid failure was present in 17% of bipolar patients and more prevalent in women. It was associated with lithium exposure, especially in the presence of TPO-Abs, but not with current rapid cycling, although an association may have been masked by thyroid hormone replacement. CONCLUSIONS: Thyroid autoimmunity was highly prevalent in this sample of outpatients with bipolar disorder and not associated with lithium treatment. These variables appear to be independent risk factors for the development of hypothyroidism, especially in women with bipolar disorder." [Abstract]

Hornig M, Amsterdam JD, Kamoun M, Goodman DB.
Autoantibody disturbances in affective disorders: a function of age and gender?
J Affect Disord 1999 Sep;55(1):29-37
"BACKGROUND: Numerous investigators have reported increased autoantibodies to a wide variety of native antigens in patients with affective disorders. However, association of autoimmunity with affective subtypes, mood state, psychotropic medications, age, and gender has not been extensively explored. METHODS: The present study assessed 79 bipolar I, 24 bipolar II, and 46 unipolar major depression patients along with 22 healthy, nonpsychiatric controls for the presence of serum antinuclear (ANA), anti-double stranded DNA, antithyroid microsomal, antithyroglobulin, anticardiolipin (ACA) IgM, and ACA IgG antibodies. RESULTS: Consistent with their higher prevalence of autoimmune disease, women exhibited increased levels of ANA and ACA IgM compared to men. ACA IgG antibody titers also increased significantly with age. Contrary to prior reports of general, overall increases in autoantibodies and specific increases in ANA and antithyroid antibodies in depressed patients, we did not see a significant association between any of the autoantibodies and affective subtype, mood state, or psychotropic medications. LIMITATIONS: Affective subgroups were heterogeneous with respect to psychotropic medications, affective state, age, and gender in this retrospective analysis. Subgroup sample size was insufficient to determine whether interactions of these clinical variables may have influenced results. CONCLUSION: These results suggest that gender and age may have more influence on autoantibodies than affective diagnosis, affective state, or medications." [Abstract]

Grider G, El-Mallakh RS, Huff MO, Buss TJ, Miller J, Valdes R Jr.
Endogenous digoxin-like immunoreactive factor (DLIF) serum concentrations are decreased in manic bipolar patients compared to normal controls.
J Affect Disord 1999 Aug;54(3):261-7
"BACKGROUND: A decrease in sodium pump activity in erythrocytes has been associated with manic episodes of bipolar illness relative to euthymic moods. Since red blood cells are long-lived and lack a nucleus, it is likely that a plasma factor is responsible for the observed decrease in sodium pump activity. METHODS: Utilizing a radioimmunoassay, we examined the serum concentrations of the digoxin-like immunoreactive factor (DLIF) in ill and well bipolar patients and compared the values to those of normal controls. RESULTS: DLIF was significantly decreased in manic individuals as compared to normal controls (143.6+/-S.E.M. 20.94 vs. 296.6+/-12.76 pg digoxin equivalents/ml, respectively, F = 4.77, P<0.05), but not compared to euthymic bipolar subjects 213.8+/-86.92, P = 0.77). There were no significant differences in DLIF concentrations between manic and euthymic bipolar individuals (P = 0.8). Since relapse in bipolar patients appears to display a seasonal pattern, we also measured the plasma concentration of this factor over a 12-months period. Normal controls exhibited a seasonal pattern of change in serum DLIF concentrations with a nadir in the winter months. Plasma concentrations of DLIF in bipolar patients did not show a seasonal pattern and maintained low levels throughout the year. LIMITATIONS: Due to the nonspecificity of our antibody, we could measure only total DLIF. Furthermore, it is unclear what the role of circulating DLIF, if any, may be on brain function. CONCLUSION: DLIF may be involved in the pathophysiology of mania." [Abstract]

Hough C, Lu SJ, Davis CL, Chuang DM, Post RM.
Elevated basal and thapsigargin-stimulated intracellular calcium of platelets and lymphocytes from bipolar affective disorder patients measured by a fluorometric microassay.
Biol Psychiatry 1999 Jul 15;46(2):247-55
"BACKGROUND: A number of investigators have reported finding elevated basal and stimulated intracellular calcium levels in the platelets or lymphocytes of bipolar disorder patients. METHODS: Intracellular calcium was measured by a micro fura-2 fluorometric method in the platelets and lymphocytes of 30 affective disorder patients and 14 control subjects. RESULTS: We observed significantly elevated basal calcium concentrations in bipolar patient platelets and lymphocytes compared to control subjects. Bipolar patient platelet calcium responses to thrombin, serotonin, and thapsigargin were also significantly greater than control subjects. The peak calcium levels of lymphocytes of bipolar patients were greater than control subjects only when stimulated by thapsigargin. There were significant differences between bipolar and unipolar patients in basal and thapsigargin-stimulated calcium measures but not between bipolar I and bipolar II patients. Unmedicated versus medicated calcium measures were not significantly different. We also found little correlation between calcium measures and the severity of mood rating. CONCLUSIONS: Using this method, we were able to confirm and extend the work of others, indicating altered intracellular calcium homeostasis in the blood cells of bipolar disorder patients. In addition, our data suggest that storage operated calcium channels may be the source of the elevated intracellular calcium in platelets and lymphocytes of bipolar patients." [Abstract]

Hamakawa H, Kato T, Shioiri T, Inubushi T, Kato N.
Quantitative proton magnetic resonance spectroscopy of the bilateral frontal lobes in patients with bipolar disorder.
Psychol Med 1999 May;29(3):639-44
"BACKGROUND: Using 31P and 1H magnetic resonance spectroscopy (MRS) we previously reported that phosphocreatine was decreased in the left frontal lobe and choline-containing compounds were increased in the basal ganglia in the depressive state in patients with bipolar disorder. We applied quantitative 1H-MRS for further characterization of biochemical alteration in the frontal lobes of bipolar patients. METHODS: Twenty-three bipolar patients and 20 normal controls were examined by 1H-MRS with a 1.5T MR system. All patients were examined in the euthymic state, and eight patients were also examined in the depressive state. Volumes of interest of 2.5 x 2.5 x 2.5 cm were selected in the left and right frontal lobes. Absolute concentrations of N-acetyl-1-aspartate, creatine plus phosphocreatine, and choline-containing compounds were calculated from each metabolite peak. RESULTS: Creatine concentration in the left frontal lobe in bipolar patients in the depressive state was significantly lower than that in the euthymic state. Creatine concentration in the right frontal lobe in the male patients was significantly higher than that in the female patients and a similar trend was also found in the control subjects. CONCLUSIONS: We found a state-dependent change of creatine metabolism in the left frontal lobe of bipolar patients. The present results are compatible with our previous report of decreased phosphocreatine measured by 31P-MRS in the left frontal lobe in bipolar disorder. We also found an effect of gender on the creatine concentration. There may be a gender difference in creatine transport function into the brain." [Abstract]

Friedman L, Findling RL, Kenny JT, Swales TP, Stuve TA, Jesberger JA, Lewin JS, Schulz SC.
An MRI study of adolescent patients with either schizophrenia or bipolar disorder as compared to healthy control subjects.
Biol Psychiatry 1999 Jul 1;46(1):78-88
"BACKGROUND: There are few imaging studies in adolescent patients with either schizophrenia or bipolar disorder. Such studies are of interest because adolescents may have a more severe illness and neurodevelopmental events may have a greater role in their pathophysiology. METHODS: We compared 20 patients with schizophrenia and 15 patients with bipolar disorder (10 to 18 years) to 16 normal adolescents on magnetic resonance imaging (MRI) measures of intracranial volume and ventricular and sulcal enlargement. Two planned comparison contrasts were employed, one comparing the two patient groups to each other (contrast 1), and one comparing both patient groups combined to control subjects (contrast 2). RESULTS: None of the contrast 1 comparisons (schizophrenia vs bipolar) were statistically significant. Contrast 2 comparisons (control subjects vs patients) were statistically significant for intracranial volume (reduced in patients) as well as frontal and temporal sulcal size (increased in patients). CONCLUSIONS: The patient groups were not statistically significantly different from each other on any measure. The combined patient groups were different from control subjects on intracranial volume and frontal and temporal sulcal size. Also, there was evidence for ventricular enlargement, after removal of a control subject with an extreme value. These findings indicate that the same abnormalities noted in adult populations are present in adolescents."

Breunis MN, Kupka RW, Nolen WA, Suppes T, Denicoff KD, Leverich GS, Post RM, Drexhage HA.
High numbers of circulating activated T cells and raised levels of serum IL-2 receptor in bipolar disorder.
Biol Psychiatry. 2003 Jan 15;53(2):157-65.
"BACKGROUND: Previously, we found an increased prevalence of thyroid autoantibodies in patients with bipolar disorder. In the present study, we investigated other signs of immune activation in bipolar patients, in particular an activation of the T cell system. METHODS: Fluorescence activated cell scanning (FACS) analysis was performed on lymphocytes of 64 outpatients with DSM-IV bipolar disorder using the T cell marker CD3 in combination with the activation markers MHC-class II, CD25, CD69 or CD71. In 34 patients, these assays were repeated after an interval of 2 years. In addition, T cell activation was determined by measuring serum soluble IL-2 receptor (sIL-2R) in 172 bipolar outpatients. Outcomes were compared with a healthy control group. RESULTS: Significantly higher numbers of circulating activated T cells and raised sIL-2R levels were found in euthymic, manic, and depressed bipolar patients when compared with healthy controls. In general, these abnormalities were stable over time. Manic patients showed significantly higher levels of sIL-2R in comparison with depressed patients. CONCLUSION: The T cell system was found to be activated in both symptomatic and euthymic patients with bipolar disorder. The pathophysiological significance of these findings remains to be explored." [Abstract]

Tsai SY, Chen KP, Yang YY, Chen CC, Lee JC, Singh VK, Leu SJ.
Activation of indices of cell-mediated immunity in bipolar mania.
Biol Psychiatry 1999 Apr 15;45(8):989-94
"BACKGROUND: Evidence supports that macrophages as well as lymphocytes and their products may be involved in the pathophysiology of psychiatric disorders. Whether patients with bipolar disorder have activation or reduction of immunity during a manic episode remains unclear. METHODS: The purpose of this case-control study was to investigate the lymphocyte proliferation to phytohemagglutinin (PHA), concanavalin A, and pokeweed mitogen, and plasma levels of soluble interleukin-2 receptor (sIL-2R) and sIL-6R in patients with bipolar mania (DSM-III-R). The subjects were 23 physically healthy patients with Young Mania Rating Scale (YMRS) scores > or = 26 as well as aged < or = 45 years and 23 age- and gender-matched normal control subjects. The above immune variables were measured in acute mania and consequent remission (YMRS scores < or = 12) among bipolar patients. RESULTS: The lymphocyte proliferation to PHA and the plasma sIL-2R levels, but not sIL-6R, of bipolar patients were significantly higher in acute mania than in consequent remission. These elevations were not due to differences in medication status. Only in acute mania were the plasma sIL-2R levels of patients significantly higher than control subjects. A positive correlation between the changes of manic severity and plasma sIL-2R levels was observed. Remitted bipolar patients and normal control subjects did not differ in any of these measures. CONCLUSIONS: Cell-mediated immunity activation in bipolar mania was demonstrated and may be through a specifically state-dependent immune response." [Abstract]

Su KP, Leu SJ, Yang YY, Shen WW, Chou YM, Tsai SY.
Reduced production of interferon-gamma but not interleukin-10 in bipolar mania and subsequent remission.
J Affect Disord. 2002 Sep;71(1-3):205-9.
"BACKGROUND: Activation of inflammatory response system (IRS) is suggested by increased levels of plasma soluble interleukin-2 receptor (sIL-2R) in patients with bipolar mania. The reasons for changes in stimulated interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) production in bipolar mania along with subsequent remission remain unclear. METHODS: We measured phytohemagglutinin (PHA)-stimulated IFN-gamma and IL-10 production in 20 physically healthy inpatients aged between 18 and 45 years with bipolar mania (DSM-IV) using Young Mania Rating Scale (YMRS) scores > or = 26 and in subsequent remission (YMRS < or = 12), as well as in 15 age- and sex-matched healthy normal controls. RESULTS: The mean values of IFN-gamma production in patients in acute mania and in subsequent remission were significantly lower than those of healthy controls (P=0.0004, P=0.0005, respectively). There was no significant difference in IL-10 production between bipolar patients in acute mania as well as in subsequent remission and healthy controls. In acute mania, the mean values of IFN-gamma and IL-10 production in medicated patients (n = 13) did not differ from those of drug-free patients (n = 7). Other clinical variables had no effect on IFN-gamma and IL-10 production. LIMITATION: The uncontrolled medication, small sample size of the bipolar individuals, and some immune re-measurements prior to full remission periods, limit generalization from the data in this study. CONCLUSION: Reduced production of IFN-gamma without alternation of IL-10 in bipolar mania and subsequent remission suggest that the immune modulation may vary in patients with different major psychiatric disorders." [Abstract]

Wadee AA, Kuschke RH, Wood LA, Berk M, Ichim L, Maes M.
Serological observations in patients suffering from acute manic episodes.
Hum Psychopharmacol. 2002 Jun;17(4):175-9.
"Although abnormalities of the immune system have been described in depression, information on serological alteration in acutely manic patients has been scarce. The present study undertook to investigate the levels of C-reactive proteins, circulating immune complexes, total immunoglobulins and immunoglobulin subclasses, complement proteins C3, C4, C6 and Factor B in the sera of 45 patients suffering from an acute manic episode. The findings were compared with assessments on the sera of 45 controls. The results demonstrate a number of significant differences between patients and controls. Whilst levels of immunoglobulin D were significantly lower, the levels of total immunoglobulin and immunoglobulin G1, complement proteins C3, C6 and Factor B were raised in the patient group when compared with the controls. Our results suggest a relationship between acute mania and immunological parameters associated with acute phase responses." [Abstract]

McDonald WM, Tupler LA, Marsteller FA, Figiel GS, DiSouza S, Nemeroff CB, Krishnan KR.
Hyperintense lesions on magnetic resonance images in bipolar disorder.
Biol Psychiatry 1999 Apr 15;45(8):965-71
"BACKGROUND: To examine the magnetic resonance (MR) images of bipolar patients across a wide age range for the presence of hyperintense lesions compared to age- and gender-matched control subjects. METHODS: Consecutive admissions to a mood disorders unit over a 2-year period were evaluated retrospectively for the presence of bipolar disorder by DSM-III-R criteria and whether they received an MR scan. Bipolar patients (n = 70, mean age = 49.9 +/- 19.7 years) were age- and gender-matched to control subjects (n = 70, mean age = 53.2 +/- 18.1 years) and the MR scans were rated to assess for the presence of hyperintensites. RESULTS: Compared to control subjects, the bipolar patients demonstrated hyperintense lesions in the subependymal region, subcortical gray nuclei, and the deep white matter. CONCLUSIONS: Hyperintense lesions in bipolar patients are found in both the subcortical white matter and gray nuclei and may play an important role in the etiology of bipolar illness." [Abstract]

DelBello MP, Strakowski SM, Zimmerman ME, Hawkins JM, Sax KW.
MRI analysis of the cerebellum in bipolar disorder: a pilot study.
Neuropsychopharmacology 1999 Jul;21(1):63-8
"Since qualitative CT studies have suggested decreased cerebellar size in patients with bipolar disorder, we performed a quantitative analysis of the cerebellum in patients with bipolar disorder to determine whether high-resolution, thin slice magnetic resonance imaging (MRI) morphometry would reveal similar results. Bipolar patients hospitalized for a first manic episode (n = 16), bipolar patients with prior manic episodes hospitalized for a manic episode (n = 14), and normal volunteers (n = 15) matched for age, sex, race, and education were recruited and anatomic brain scans were acquired using a Picker 1.5 Tesla MRI scanner. Right and left cerebellar hemisphere volumes and vermal areas V1 (lobules I-V), V2 (lobules VI-VII), and V3 (lobules VIII-X) were measured. ANCOVA comparing each ROI, adjusting for race, sex, age, total cerebral volume, and substance abuse duration, revealed a significant group effect for vermal V3 area. Specifically, V3 area was significantly smaller in multiple-episode patients than in first-episode patients or healthy volunteers. Number of previous episodes of depression may contribute to this finding. These results suggest that cerebellar vermal atrophy may be a later neurodegenerative event in patients with bipolar disorder who have had multiple affective episodes. The confounding effects of medications are considered." [Abstract]

Hoge EA, Friedman L, Schulz SC.
Meta-analysis of brain size in bipolar disorder.
Schizophr Res 1999 May 25;37(2):177-81
"A recent meta-analysis concluded that patients with schizophrenia have reduced cerebral volume, and this finding has been used to implicate neurodevelopmental events in the etiology of this disorder. Since bipolar-disorder patients and schizophrenia patients have some similar brain abnormalities, it was of interest to meta-analytically review the literature on brain size in bipolar disorder. Only seven studies met the inclusion/exclusion criteria for our meta-analysis, but none reported the brain size differences between the bipolar patients and the controls to be statistically significant. The composite effect size was a negligible 0.04 (95% CI: -0.17 to 0.25) and statistically not significantly different from 0.0 (no effect). Thus, it appears that bipolar disorder is not associated with the same cerebral volume reductions noted in schizophrenia. Implications for hypotheses regarding the etiology of the two disorders are discussed." [Abstract]

Webster MJ, Vawter MP, Freed WJ.
Immunohistochemical localization of the cell adhesion molecules Thy-1 and L1 in the human prefrontal cortex patients with schizophrenia, bipolar disorder, and depression.
Mol Psychiatry 1999 Jan;4(1):46-52
"L1 and Thy-1 are members of the immunoglobulin (Ig) superfamily of cell adhesion molecules (CAMs) that are vital for normal neural development. Abnormalities in CAM expression could lead to the histological abnormalities that have previously been described in the frontal cortex of patients with schizophrenia. A postmortem immunohistochemical study of L1 and Thy-1 in the normal human prefrontal cortex revealed positive immunostaining of axons in all layers of the cortex. Quantifying the intensity of immunostaining in the prefrontal cortex of patients with schizophrenia, bipolar disorder and depression failed to reveal any significant differences when compared to that of normal controls." [Abstract]

Vawter MP, Hemperly JJ, Hyde TM, Bachus SE, VanderPutten DM, Howard AL, Cannon-Spoor HE, McCoy MT, Webster MJ, Kleinman JE, Freed WJ.
VASE-containing N-CAM isoforms are increased in the hippocampus in bipolar disorder but not schizophrenia.
Exp Neurol 1998 Nov;154(1):1-11
"The neural cell adhesion molecule (N-CAM) is a cell recognition molecule that is involved in cellular migration, synaptic plasticity, and CNS development. In schizophrenia, a 105- to 115-kDa N-CAM protein is increased in CSF and in the hippocampus and prefrontal cortex. The variable alternatively spliced exon (VASE) of N-CAM is developmentally regulated and can be spliced into any of the major 120-, 140-, and 180-kDa N-CAM isoforms. We determined that the variable alternative spliced exon of N-CAM (VASE) also is increased in bipolar disorder by quantitative Western immunoblot. VASE immunoreactive proteins (triplet bands around 140 kDa and a single band around 145 kDa) were identified in soluble and membrane brain extracts and quantified in the hippocampus. Soluble VASE 140 kDa was increased in the hippocampus of patients with bipolar disorder as compared to controls, patients with schizophrenia, and suicide cases. Membrane-extracted VASE 140 and 145 kDa were unchanged in the same groups. Multiple 145-kDa VASE-immunoreactive proteins that also reacted to an N-CAM antibody were separated by isoelectric focusing and electrophoresis followed by western immunoblotting; however, the VASE 140-kDa proteins were only weakly N-CAM immunoreactive. By immunohistochemistry, VASE colocalized with GFAP-positive astrocytes in the hippocampus. VASE immunostaining was also observed in the cytoplasm of CA4 pyramidal neurons that were positive for phosphorylated high molecular weight neurofilament and synaptophysin terminals. Thus no differences in VASE were found in patients with schizophrenia, but there was a marked increase of VASE immunoreactive proteins in bipolar disorder. It is possible that abnormal regulation of N-CAM proteins results in differing patterns of abnormal expression in neuropsychiatric disorders." [Abstract]

Perez J, Tardito D, Mori S, Racagni G, Smeraldi E, Zanardi R.
Abnormalities of cyclic adenosine monophosphate signaling in platelets from untreated patients with bipolar disorder.
Arch Gen Psychiatry 1999 Mar;56(3):248-53
"BACKGROUND: Abnormalities in the cyclic adenosine monophosphate (cAMP)-dependent phosphorylation system have been recently reported in patients with bipolar disorder. We evaluated the immunoreactivity of the regulatory and catalytic subunits of cAMP-dependent protein kinase (protein kinase A) and 1 of its substrates, Rap1, in platelets from untreated euthymic, manic, and depressed patients with bipolar disorder and healthy subjects. METHODS: Platelets were collected from 112 drug-free patients with bipolar disorder (52 euthymic, 29 depressed, and 31 manic) and 62 healthy subjects. The levels of cAMP-dependent protein kinase and Rap1 were assessed by Western blot analysis, immunostaining, and computer-assisted imaging. RESULTS: The immunolabeling of the catalytic subunit of cAMP-dependent protein kinase was significantly different among groups (P<.001), with higher values in untreated depressed and manic patients with bipolar disorder compared with untreated euthymic patients with bipolar disorder and healthy subjects. No significant differences were found in the immunolabeling of the regulatory subunits (type I and type II) of cAMP-dependent protein kinase. The immunolabeling of Rap1 was significantly higher (P<.001) in untreated euthymic, depressed, and manic patients than in healthy persons. CONCLUSIONS: Levels of Rap1 and the catalytic subunit of cAMP-dependent protein kinase are altered in the platelets of bipolar patients. These findings may provide clues toward understanding the involvement of cAMP signaling in the pathogenesis of bipolar disorder." [Abstract]

Kato T, Murashita J, Kamiya A, Shioiri T, Kato N, Inubushi T.
Decreased brain intracellular pH measured by 31P-MRS in bipolar disorder: a confirmation in drug-free patients and correlation with white matter hyperintensity.
Eur Arch Psychiatry Clin Neurosci 1998;248(6):301-6
"The authors have previously reported decreased intracellular pH (pHi) in the frontal lobes in euthymic bipolar patients treated with lithium using 31P-MRS. White matter hyperintensity (WMHI) is frequently seen in bipolar disorder. To examine a possible effect of lithium on pHi and the relationship between pHi and WMHI, seven drug-free euthymic bipolar patients were examined, and T2-weighted MRI were examined in 14 previously reported bipolar patients. Drug-free patients showed significantly lower pHi than controls. WMHI was associated with low pHi and increased phosphodiester peak. These results suggest that decrease of pHi is not an effect of lithium but is instead related to the pathophysiology of illness. Decrease of pHi and increase of the PDE peak may be the biochemical basis of WMHI in bipolar disorder." [Abstract]

Hamakawa H, Kato T, Murashita J, Kato N.
Quantitative proton magnetic resonance spectroscopy of the basal ganglia in patients with affective disorders.
Eur Arch Psychiatry Clin Neurosci 1998;248(1):53-8
"Proton magnetic resonance spectra were recorded from a subcortical region containing the basal ganglia in 40 patients with affective disorders (18 with bipolar disorder and 22 with major depression) and in 20 normal controls. The absolute concentration of the choline-containing compounds (Cho) in the patients with bipolar disorder in the depressive state was significantly higher than that in the normal controls. The patients with bipolar disorder had significantly higher levels of the Cho/creatine + phosphocreatine (Cr) and Cho/N-acetly-1-aspartate (NAA) peak ratio compared with the normal controls in both the depressive and euthymic states, with a tendency to higher levels in the depressive state. The Cho/NAA peak ratio was also significantly higher in the patients with major depression compared with the normal controls. These results suggest that the membrane phospholipid metabolism in the basal ganglia is altered in affective disorders." [Abstract]

Shimon H, Agam G, Belmaker RH, Hyde TM, Kleinman JE.
Reduced frontal cortex inositol levels in postmortem brain of suicide victims and patients with bipolar disorder.
Am J Psychiatry 1997 Aug;154(8):1148-50
"OBJECTIVE: This study aimed to evaluate aspects of second messenger function in the brain of suicide victims and patients with bipolar disorder. METHOD: Inositol and its synthetic enzyme, inositol monophosphatase, were measured in postmortem brain samples of 10 suicide victims, eight patients with bipolar affective disorder, and 10 normal comparison subjects. RESULTS: The frontal cortex inositol levels of the suicide victims and the patients with bipolar disorder were significantly less than those of the normal comparison group. No differences in cerebellum or occipital cortex inositol levels were found among the three groups. The groups also showed no differences in inositol monophosphatase activity in any brain area. CONCLUSIONS: These results could suggest a deficiency of second messenger precursor in patients with bipolar disorder and suicide victims." [Abstract]

Strakowski SM, Adler CM, DelBello MP.
Volumetric MRI studies of mood disorders: do they distinguish unipolar and bipolar disorder?
Bipolar Disord 2002 Apr;4(2):80-8
"The authors reviewed magnetic resonance imaging volumetric imaging results in major mood disorders, particularly comparing similarities and differences from studies of bipolar disorder and unipolar major depression. Abnormalities of cerebral brain regions appear inconsistently in mood disorders and, when present, typically consist of decreased frontal or prefrontal cortical volumes in both unipolar depression and bipolar disorder. In contrast, subcortical and medial temporal abnormalities are more commonly observed and are different between these two major classes of affective illness. Specifically, whereas structural enlargement of the basal ganglia and amygdala have been observed in bipolar disorder, in unipolar depression, these structures appear to be smaller in patients than healthy subjects. These findings suggest that affective illnesses may share in common an underdeveloped or atrophied prefrontal region, leading to loss of cortical modulation of limbic emotional networks. The effect of this loss results in unipolar depression or cycling (mania with depression) depending on the abnormalities of the subcortical structures involved. The cerebellum may also play a role in the presentation of mood disorders. This hypothesis remains speculative as much more research is needed to specifically examine how morphometric brain abnormalities translate into the neurophysiologic deficits that produce mood disorders." [Abstract]

Altshuler LL, Curran JG, Hauser P, Mintz J, Denicoff K, Post R.
T2 hyperintensities in bipolar disorder: magnetic resonance imaging comparison and literature meta-analysis.
Am J Psychiatry 1995 Aug;152(8):1139-44
"OBJECTIVE: Accumulating evidence suggests a greater number of T2 abnormalities in the brains of patients with bipolar I disorder. The authors sought to evaluate the presence of signal "hyperintensities" in both bipolar I and II subjects and systematically review the existing literature. METHOD: Magnetic resonance images of the brain were obtained prospectively for 29 patients with bipolar I disorder, 26 patients with bipolar II disorder, and 20 normal comparison subjects. The presence and location of signal hyperintensities in three brain regions (periventricular white matter, subcortical gray matter, and deep white matter) were evaluated. RESULTS: No significant differences were found between groups for the presence of subcortical gray or deep white matter hyperintensities. Periventricular hyperintensities were more common in bipolar I patients (62%) than in bipolar II patients (38%) and normal comparison subjects (30%). Within patient groups, medication use was not significantly different for those with or without the presence of white matter hyperintensities. The literature on bipolar disorder and signal hyperintensities is reviewed. A meta-analysis of the pooled data in the literature on bipolar illness and signal hyperintensities revealed that the odds of having a T2 hyperintensity are significantly greater for bipolar I than for normal comparison subjects. CONCLUSIONS: Having bipolar I disorder significantly increases the chance of having white matter changes in the brain. This study suggests that bipolar II patients may be more similar than bipolar I patients to comparison subjects on T2 measures. The possible pathophysiological significance of hyperintensities is discussed." [Abstract]

Sax KW, Strakowski SM, Zimmerman ME, DelBello MP, Keck PE Jr, Hawkins JM.
Frontosubcortical neuroanatomy and the continuous performance test in mania.
Am J Psychiatry 1999 Jan;156(1):139-41
"OBJECTIVE: The authors examined whether Continuous Performance Test scores correlate with frontosubcortical volumes in bipolar disorder. METHOD: The subjects were 17 patients hospitalized for an acute manic episode and 12 group-matched comparison subjects. They underwent magnetic resonance imaging and completed the Continuous Performance Test. RESULTS: The patients performed worse on the Continuous Performance Test and had smaller prefrontal cortical volumes than the comparison subjects. Within the patient group, Continuous Performance Test performance significantly correlated with prefrontal and hippocampal volumes. CONCLUSIONS: These results suggest that certain neuroanatomic structures may be associated with attentional dysfunction in mania." [Abstract]

Drevets WC, Price JL, Bardgett ME, Reich T, Todd RD, Raichle ME.
Glucose metabolism in the amygdala in depression: relationship to diagnostic subtype and plasma cortisol levels.
Pharmacol Biochem Behav 2002 Mar;71(3):431-47
"In a previous positron emission tomography (PET) study of major depression, we demonstrated that cerebral blood flow was increased in the left amygdala in unipolar depressives with familial pure depressive disease (FPDD) relative to healthy controls [J. Neurosci. 12 (1992) 3628.]. These measures were obtained from relatively low-resolution PET images using a stereotaxic method based upon skull X-ray landmarks. The current experiments aimed to replicate and extend these results using higher-resolution glucose metabolism images and magnetic resonance imaging (MRI)-based region-of-interest (ROI) analysis. The specificity of this finding to FPDD was also investigated by assessing depressed samples with bipolar disorder (BD-D) and depression spectrum disease (DSD). Finally, the relationship between amygdala metabolism and plasma cortisol levels obtained during the scanning procedure was assessed. Glucose metabolism was measured using PET and 18F-fluorodeoxyglucose (18FDG) in healthy control (n=12), FPDD (n=12), DSD (n=9) and BD-D (n=7) samples in the amygdala and the adjacent hippocampus. The left amygdala metabolism differed across groups (P<.001), being increased in both the FPDD and BD-D groups relative to the control group. The left amygdala metabolism was positively correlated with stressed plasma cortisol levels in both the unipolar (r=.69; P<.005) and the bipolar depressives (r=0.68;.1<P<.05). In contrast, neither significant main effects of diagnosis nor significant relationships with plasma cortisol were evident in post hoc analyses of metabolism in the right amygdala or the hippocampus. Preliminary assessment of BD subjects imaged during remission suggested that amygdala metabolism is also elevated in remitted subjects who are not taking mood-stabilizing drugs, but within the normal range in subjects taking mood stabilizers. These data confirm our previous finding that neurophysiological activity is abnormally increased in FPDD, and extend it to BD-D. These abnormalities were not accounted for by spilling in of radioactivity from the adjacent hippocampus. The correlation between left amygdala metabolism and stressed plasma cortisol levels may conceivably reflect either the effect of amygdala activity on corticotropin-releasing hormone (CRH) secretion or the effect of cortisol on amygdala function." [Abstract]

Soares JC, Mann JJ.
The functional neuroanatomy of mood disorders.
J Psychiatr Res 1997 Jul-Aug;31(4):393-432
"Mood disorders may be associated with global and regional changes in cerebral blood flow and metabolism. The accumulated functional neuroimaging findings in mood disorders were reviewed in order to examine a proposed neuroanatomic model of pathophysiology. Global cerebral blood flow and glucose metabolism appear normal, but may be decreased in late-life depression. Regional cerebral blood flow and glucose metabolism deficits are present, and may be indicators of brain regions participating in neuroanatomic circuits involved in mood disorders. Decreased pre-frontal cortex blood flow and metabolism in depressed unipolar and bipolar patients are the most consistently replicated findings, and correlate with severity of illness. Basal ganglia abnormalities have been found in depressed unipolar and bipolar patients, involving decreased blood flow and metabolism. Temporal lobe abnormalities are present in bipolar disorder patients, and perhaps unipolar depression. There is conflicting evidence of abnormalities in other limbic regions. Cognitive impairment may correlate with decreased metabolism in frontal and cerebellar areas. The relationship between functional neuroimaging findings and clinical course, and therefore state and trait characteristics, has not been systematically investigated." [Abstract]

Rohan M, Parow A, Stoll AL, Demopulos C, Friedman S, Dager S, Hennen J, Cohen BM, Renshaw PF.
Low-Field Magnetic Stimulation in Bipolar Depression Using an MRI-Based Stimulator.
Am J Psychiatry. 2004 Jan;161(1):93-8.
"OBJECTIVE: Anecdotal reports have suggested mood improvement in patients with bipolar disorder immediately after they underwent an echo-planar magnetic resonance spectroscopic imaging (EP-MRSI) procedure that can be performed within clinical MR system limits. This study evaluated possible mood improvement associated with this procedure. METHOD: The mood states of subjects in an ongoing EP-MRSI study of bipolar disorder were assessed by using the Brief Affect Scale, a structured mood rating scale, immediately before and after an EP-MRSI session. Sham EP-MRSI was administered to a comparison group of subjects with bipolar disorder, and actual EP-MRSI was administered to a comparison group of healthy subjects. The characteristics of the electric fields generated by the EP-MRSI scan were analyzed. RESULTS: Mood improvement was reported by 23 of 30 bipolar disorder subjects who received the actual EP-MRSI examination, by three of 10 bipolar disorder subjects who received sham EP-MRSI, and by four of 14 healthy comparison subjects who received actual EP-MRSI. Significant differences in mood improvement were found between the bipolar disorder subjects who received actual EP-MRSI and those who received sham EP-MRSI, and, among subjects who received actual EP-MRSI, between the healthy subjects and the bipolar disorder subjects and to a lesser extent between the unmedicated bipolar disorder subjects and the bipolar disorder subjects who were taking medication. The electric fields generated by the EP-MRSI scan were smaller (0.7 V/m) than fields used in repetitive transcranial magnetic stimulation (rTMS) treatment of depression (1-500 V/m) and also extended uniformly throughout the head, unlike the highly nonuniform fields used in rTMS. The EP-MRSI waveform, a 1-kHz train of monophasic trapezoidal gradient pulses, differed from that used in rTMS. CONCLUSIONS: These preliminary data suggest that the EP-MRSI scan induces electric fields that are associated with reported mood improvement in subjects with bipolar disorder. The findings are similar to those for rTMS depression treatments, although the waveform used in EP-MRSI differs from that used in rTMS. Further investigation of the mechanism of EP-MRSI is warranted." [Abstract]

Bearden CE, Hoffman KM, Cannon TD.
The neuropsychology and neuroanatomy of bipolar affective disorder: a critical review.
Bipolar Disord 2001 Jun;3(3):106-50; discussion 151-3
"OBJECTIVES: To present a comprehensive review of the existing neuropsychological and neuroimaging literature on bipolar affective disorder. This review critically evaluates two common conceptions regarding the neuropsychology of bipolar disorder: 1) that, in contrast to schizophrenia, bipolar affective disorder is not associated with general cognitive impairment independent of illness episodes, and 2) relative right hemisphere (RH) dysfunction is implicated in bipolar illness patients, supported by reports of relatively greater impairment in visuospatial functioning, lateralization abnormalities, and mania secondary to RH lesions. METHODS: The major computerized databases (Medline and PSYCInfo) were consulted in order to conduct a comprehensive, integrated review of the literature on the neuropsychology and neuroanatomy of bipolar disorder. Articles meeting specified criteria were included in this review. RESULTS: In a critical evaluation of the above notions, this paper determines that: 1) while there is little evidence for selective RH dysfunction, significant cognitive impairment may be present in bipolar illness, particularly in a subgroup of chronic, elderly or multiple-episode patients, suggesting a possible toxic disease process, and 2) the underlying functional correlate of these cognitive deficits may be white matter lesions ('signal hyperintensities') in the frontal lobes and basal ganglia, regions critical for executive function, attention, speeded information processing, learning and memory, and affect regulation. While this hypothesized neural correlate of cognitive impairment in bipolar disorder is speculative, preliminary functional neuroimaging evidence supports the notion of frontal and subcortical hypometabolism in bipolar illness. CONCLUSIONS: The etiology of the structural brain abnormalities commonly seen in bipolar illness, and their corresponding functional deficits, remains unknown. It is possible that neurodevelopmental anomalies may play a role, and it remains to be determined whether there is also some pathophysiological progression that occurs with repeated illness episodes. More research is needed on first-episode patients, relatives of bipolar probands, and within prospective longitudinal paradigms in order to isolate disease-specific impairments and genetic markers of neurocognitive function in bipolar disorder." [Abstract]

Sobczak S, Honig A, van Duinen MA, Riedel WJ.
Serotonergic dysregulation in bipolar disorders: a literature review of serotonergic challenge studies.
Bipolar Disord. 2002 Dec;4(6):347-56.
"OBJECTIVES: Serotonin (5-hydroxytryptamine; 5-HT) and endocrine abnormalities have been repeatedly reported in bipolar disorders (BD). Useful methods to investigate 5-HT responsivity, and the interaction with neuroendocrine functioning, are provided by acute 5-HT challenge and depletion paradigms. In this review 5-HT challenges are limited to paradigms that stimulate 5-HT activity in BD. METHODS: Literature was searched for in electronic libraries: MEDLINE and PSYCHLIT, period 1966-2001. Papers describing effects of an acute 5-HT challenge on neuroendocrine functioning in BD patients were selected. RESULTS: Review of the literature revealed 15 studies: five papers described the effects of 5-HT challenges in manic BD patients, four papers in euthymic BD and seven in depressed BD patients. The reviewed 5-HT challenge paradigms are acute administration of oral and intravenous (i.v.) dosage of d,l-fenfluramine, tryptophan, 5-hydroxytryptophan, ipsapirone and buspirone. There were no papers which investigated neuroendocrine effects of m-chlorophenylpiperazine, clomipramine and citalopram in BD patients and were therefore not reviewed. CONCLUSIONS: The literature on 5-HT challenge procedures in BD shows evidence for a blunted prolactin (PRL) in mania and depression as well as a blunted cortisol in euthymic BD patients. This suggests that in both mania and depression similar changes in the 5-HT system are involved. It is speculated that blunting of cortisol responses in euthymic BD patients may be a result of chronically altered 5-HT functioning, whereas changes in PRL release following 5-HT challenges reflect more state-dependent changes in 5-HT activity. The 5-HT responsivity in BD patients has also been associated with pharmacological treatment, suicidal behaviour, weight loss and age. Recommendations for future research are given." [Abstract]

Avissar S, Nechamkin Y, Barki-Harrington L, Roitman G, Schreiber G.
Differential G protein measures in mononuclear leukocytes of patients with bipolar mood disorder are state dependent.
J Affect Disord 1997 Apr;43(2):85-93
"While manic patients showed highly significant elevations in mononuclear leukocytes levels of G alpha s and G alpha i, evaluated through immunoblot analysis using specific polyclonal antibodies against the subunit proteins, mononuclear leukocytes of bipolar depressed patients show significant reductions in G alpha s and G alpha i immunoreactive levels. G beta subunit levels were found to be similar in all three groups. The changes in G protein measures observed in mononuclear leukocytes of mood disordered patients thus represent state characteristics of the disorder." [Abstract]

Jope, RS, Song, L, Li, PP, Young, LT, Kish, SJ, Pacheco, MA, Warsh, JJ
The phosphoinositide signal transduction system is impaired in bipolar affective disorder brain
J Neurochem 1996 66: 2402-2409
"Thus, among the three cortical regions examined there was a selective impairment in G protein-stimulated [3H]Pl hydrolysis in occipital cortical membranes from bipolar compared with control subjects. These results directly demonstrate decreased activity of the phosphoinositide signal transduction system in specific brain regions in bipolar affective disorder." [Abstract]

Bezchlibnyk, Yarema B., Wang, Jun-Feng, McQueen, Glenda M., Young, L. Trevor
Gene expression differences in bipolar disorder revealed by cDNA array analysis of post-mortem frontal cortex
J Neurochem 2001 79: 826-834
"Selected targets were analyzed by RT-PCR, which confirmed a decrease in transforming growth factor-beta1 (TGF-ß1), and an increase in both caspase-8 precursor (casp-8) and transducer of erbB2 (Tob) expression in BD." [Abstract]

Shaltiel G, Kozlovsky N, Belmaker RH, Agam G.
3'(2')-phosphoadenosine 5'-phosphate phosphatase is reduced in postmortem frontal cortex of bipolar patients.
Bipolar Disord 2002 Oct;4(5):302-6 [Abstract]

Hahn CG, Friedman E.
Abnormalities in protein kinase C signaling and the pathophysiology of bipolar disorder.
Bipolar Disord 1999 Dec;1(2):81-6
"In comparison to patients with major depressive disorder, schizophrenia, or healthy controls, PKC activity was significantly increased in manic patients, suggesting that changes in PKC may be an illness-specific marker. Interestingly, enhanced PKC activity during mania was suppressed following mood-stabilizer treatment as manic symptoms improved. In parallel to the findings in platelets, postmortem studies demonstrate that membrane-associated PKC and stimulation-induced translocation of cytosolic enzyme to the membrane were also increased in frontal cortex of bipolar patients." [Abstract]

Manji HK, Lenox RH.
Ziskind-Somerfeld Research Award. Protein kinase C signaling in the brain: molecular transduction of mood stabilization in the treatment of manic-depressive illness.
Biol Psychiatry 1999 Nov 15;46(10):1328-51
"In rats chronically treated with lithium, there is a reduction in the hippocampus of the expression of two protein kinase isozymes, alpha and epsilon, as well as a reduction in the expression of a major PKC substrate, MARCKS, which has been implicated in long-term neuroplastic events in the developing and adult brain. In addition, we have been investigating the down-stream impact of these mood stabilizers on another kinase system, GSK-3 beta and on the AP-1 family of transcription factors. Further studies have generated promising preliminary data in support of the antimanic action of tamoxifen, and antiestrogen that is also a PKC inhibitor." [Abstract]

K Suzuki
The mechanism of enhanced platelet intracellular calcium mobilization stimulated by serotonin--in the pathophysiology of mood disorders
"There was no correlation between Ca response to 5-HT and the Bmax of 5-HT2A receptors. Pretreatment with PKC activator (PMA) dose-dependently reduced the Ca response induced by 5-HT, while pretreatment with CaM antagonist (10-30 microM W-7), myosin light chain kinase inhibitor (30 microM ML-9) or Ca/CaM-dependent protein kinase II inhibitor (10 microM KN-93) increased the Ca response with no remarkable changes in basal Ca level. But PKC inhibitors (bisindolylmaleimide II and staurosporine) failed to increase the Ca response at every dose." [Abstract]

Webster MJ, Knable MB, O'Grady J, Orthmann J, Weickert CS.
Regional specificity of brain glucocorticoid receptor mRNA alterations in subjects with schizophrenia and mood disorders.
Mol Psychiatry 2002;7(9):985-94, 924
"Glucocorticoid receptors (GR) mediate the direct effects of glucocorticoids released in response to stress and the regulation of the hypothalamic-pituitary-adrenocortical (HPA) system through a negative feedback mechanism. Individuals with major mental illness, who often exhibit hypercortisolemia, may have down-regulated levels of GR mRNA. In situ hybridization for GR mRNA was performed on post-mortem specimens from patients suffering from depression, bipolar disorder, schizophrenia and from normal controls (n = 15 per group). In frontal cortex, GR mRNA levels were decreased in layers III-VI in the subjects with depression and schizophrenia. In inferior temporal cortex, GR mRNA levels were decreased in layer IV in all three diagnostic groups. In the entorhinal cortex, GR mRNA levels were decreased in layers III and VI in the bipolar group. In hippocampus, GR mRNA levels were reduced in the dentate gyrus, CA(4), CA(3) and CA(1) in the schizophrenia group. In the subiculum, GR mRNA levels were reduced in the bipolar group. These results suggest that GR dysregulation occurs in all three major psychiatric illnesses with variability according to anatomical site. The severity and heterogeneity of this reduction may underlie some of the clinical heterogeneity seen in these disorders." [Abstract]

Hamakawa H, Murashita J, Yamada N, Inubushi T, Kato N, Kato T.
Reduced intracellular pH in the basal ganglia and whole brain measured by 31P-MRS in bipolar disorder.
Psychiatry Clin Neurosci. 2004 Feb;58(1):82-88.
"The authors have previously reported that intracellular pH measured by phosphorus-31 magnetic resonance spectroscopy (31P-MRS) was decreased in the frontal lobes of patients with bipolar disorder. In the present study, phosphorus metabolism in the basal ganglia was examined in 13 patients with bipolar disorder and 10 matched controls by localized 31P-MRS. While no significant alteration of peak area ratios was found for all phosphorus metabolites, intracellular pH was significantly reduced in the basal ganglia in patients with bipolar disorder (7.014 +/- 0.045) compared with control subjects (7.066 +/- 0.047, P < 0.05). Unexpectedly, non-localized 31P-MR spectra also showed significantly lower levels of intracellular pH (6.970 +/- 0.025) than controls (6.986 +/- 0.024, P < 0.05). These results suggest that decreased intracellular pH in the brain of patients with bipolar disorder is not caused by dysfunction of the frontal lobes but reflect altered metabolism at the cellular level." [Abstract]

Kato T, Murashita J, Kamiya A, Shioiri T, Kato N, Inubushi T.
Decreased brain intracellular pH measured by 31P-MRS in bipolar disorder: a confirmation in drug-free patients and correlation with white matter hyperintensity.
Eur Arch Psychiatry Clin Neurosci 1998;248(6):301-
"The authors have previously reported decreased intracellular pH (pHi) in the frontal lobes in euthymic bipolar patients treated with lithium using 31P-MRS. White matter hyperintensity (WMHI) is frequently seen in bipolar disorder. To examine a possible effect of lithium on pHi and the relationship between pHi and WMHI, seven drug-free euthymic bipolar patients were examined, and T2-weighted MRI were examined in 14 previously reported bipolar patients. Drug-free patients showed significantly lower pHi than controls. WMHI was associated with low pHi and increased phosphodiester peak. These results suggest that decrease of pHi is not an effect of lithium but is instead related to the pathophysiology of illness. Decrease of pHi and increase of the PDE peak may be the biochemical basis of WMHI in bipolar disorder." [Abstract]

Lyoo IK, Lee HK, Jung JH, Noam GG, Renshaw PF.
White matter hyperintensities on magnetic resonance imaging of the brain in children with psychiatric disorders.
Compr Psychiatry 2002 Sep-Oct;43(5):361-8
"The current study sought to determine the prevalence, severity, and location of white matter signal hyperintensities (WMH) on brain magnetic resonance imaging assessments of children and adolescents with psychiatric disorders. Seventy-one percent (N = 934) of children admitted to the McLean Hospital Child and Adolescent inpatient treatment unit were evaluated with the Diagnostic Interview Schedule for Children (DISC) within 7 days of admission during the period 1988 to 1993 (total, 1,308 admissions). Four hundred eight of these subjects (43.7%) were referred for brain magnetic resonance imaging (MRI) scans and became our study subjects (mean age, 12.4 years [SD = 2.7]; male/female, 230/178). Study subjects were grouped according to a hierarchical diagnostic system as follows: schizophrenia (n = 42), bipolar disorder (n = 56), unipolar depression (n = 94), conduct disorder/attention deficit disorder (n = 103), and other neurotic disorders (n = 30). Subjects without any level 2 diagnosis on DISC (n = 83) constituted the comparison group. Bipolar disorder, unipolar depression, and conduct disorder/attention deficit disorder groups were significantly more likely to have severe levels of WMH than the comparison group (prevalence rates: 17.9%, 13.8%, 13.6% v 1.2%). In addition, the bipolar disorder group was significantly more likely to have severe levels of WMH than the schizophrenia group (prevalence rates: 17.9% v 2.4%). The frontal lobes were the predominant locations of WMH in the bipolar disorder and unipolar depression groups (76.9% and 60.0%, respectively) and also the most frequent location for the conduct disorder/attention deficit disorder group (35.7%). The current study reports an increased prevalence and severity of WMH in children with bipolar disorder, unipolar depression, and conduct disorder/attention deficit disorder relative to the comparison group and in children with bipolar disorder compared to those with schizophrenia. The development of brain WMH, especially in the frontal lobes, may play a role in the pathophysiology of affective disorders in children and adolescents." [Abstract]

Breeze JL, Hesdorffer DC, Hong X, Frazier JA, Renshaw PF.
Clinical significance of brain white matter hyperintensities in young adults with psychiatric illness.
Harv Rev Psychiatry. 2003 Sep-Oct;11(5):269-83.
"Magnetic resonance imaging (MRI) provides detailed images of brain anatomy, with especially clear definition of gray and white matter structures. Several brain MRI studies have suggested that adults with bipolar disorder (BD) are more likely to have "white matter hyperintensities" (WMH) than adults without BD. The disproportionately greater frequency of these lesions in otherwise physically healthy patients suggests that the illness itself, or treatments used to control the illness, may be risk factors for the development of white matter changes. Similarly, WMH may be an etiological factor for some types of BD. In addition to reviewing the relevant literature, this research study attempted to determine whether lithium treatment is associated with an increased prevalence of WMH in young adults with psychiatric illness. To test this hypothesis, we evaluated over 600 brain MRI scans from inpatients at McLean Hospital, Belmont, Massachusetts. We controlled for possible confounding variables such as age, vascular disease, substance abuse, and markers of illness severity. We found that individuals with BD were no more likely to have WMH than other psychiatric patients. Lithium use was nonsignificantly associated with the presence of WMH. A multivariate regression model for the presence of WMH showed that heart disease, female gender, and multiple psychiatric admissions were significant predictors of WMH. This study does not support previous findings that BD, compared to other psychiatric illnesses, was associated with increased risk of WMH. Lithium use may be subtly associated with WMH. Our results are consistent with previous research that found an association between cardiovascular disease, advanced age, and the presence of WMH, though our analysis appears to be unique in its inclusion of cardiovascular disease as a risk factor in young adults with psychiatric illness." [Abstract]

Kieseppa T, van Erp TG, Haukka J, Partonen T, Cannon TD, Poutanen VP, Kaprio J, Lonnqvist J.
Reduced left hemispheric white matter volume in twins with bipolar I disorder.
Biol Psychiatry. 2003 Nov 1;54(9):896-905.
"BACKGROUND: Although the heritability of bipolar I disorder (BPI) is high, few magnetic resonance imaging (MRI) studies of siblings of bipolar patients exist. We performed MRI brain scans on a nationwide sample of twins with BPI, as well as on their co-twins and a demographically balanced sample of control twin subjects, to detect any structural alterations related to the disorder and to the increased genetic risk. METHODS: The National Hospital Discharge Register, National Population Register, and Finnish Twin Cohorts were used to identify bipolar twins. Structured diagnostic interviews and MRI scans were obtained for 24 twins with BPI, 15 healthy co-twins, and 27 control twin subjects. RESULTS: Patients and co-twins showed a significant decrease in left hemispheric white matter volume. The disparity in patients was -16.1 cm(3) (95% confidence interval [CI] -26.6, -5.6) and in co-twins -11.3 cm(3) (95% CI -22.1, -0.4) compared with control twin subjects. No gray matter decrease was seen in patients or co-twins. CONCLUSIONS: The results of this first large-scale MRI study of twins with BPI, their co-twins, and appropriate control twin subjects, suggest that alterations of the left hemisphere white matter in BPI may reflect genetic factors predisposing to the disorder." [Abstract]

Silverstone T, McPherson H, Li Q, Doyle T.
Deep white matter hyperintensities in patients with bipolar depression, unipolar depression and age-matched control subjects.
Bipolar Disord. 2003 Feb;5(1):53-7.
"OBJECTIVE: Hyperintensities in the white matter of the brain (DWH) and in the periventricular area (PVH) seen on magnetic resonance imaging (MRI) have been reported to be more frequent in patients with bipolar disorder (BP) than in normal subjects. To examine this further we compared MRI of patients with BP with age-matched patients with major depressive disorder (unipolar depression, UP) and healthy control subjects. METHODS: T2 weighted axial and coronal brain MRI scans were obtained from 13 patients in the depressive phase of BP, 11 with current UP and 19 age-matched control subjects. The degree of DWH and PVH present in each scan was determined using a standardized scoring method. RESULTS: The PVH ratings were similar in the three groups of subjects. However, proportionately more BP patients had higher DWH scores than either UP patients or controls. Although this difference did attain statistical significant, a main effect of age was noted. Further, subjects over the age of 50 were under-represented in the UP group. CONCLUSIONS: Notwithstanding the small total sample size and relative lack of older subjects in the UP group, the fact that almost twice as many BP patients showed more severe DWH suggests that patients with BP may be more vulnerable to develop these changes than UP patients and healthy controls." [Abstract]

Lopez-Larson MP, DelBello MP, Zimmerman ME, Schwiers ML, Strakowski SM.
Regional prefrontal gray and white matter abnormalities in bipolar disorder.
Biol Psychiatry 2002 Jul 15;52(2):93-100
"BACKGROUND: Previous magnetic resonance imaging (MRI) studies indicate that compared with healthy volunteers, patients with bipolar disorder have structural and functional abnormalities in the prefrontal cortex. The aim of this study was to investigate differences in prefrontal subregions between bipolar patients and healthy subjects.METHODS: Bipolar patients hospitalized for a manic episode (n = 17), and demographically matched healthy volunteers (n = 12) were recruited. Contiguous 1-mm coronal T1-weighted MRI slices were obtained using a Picker 1.5 Tesla scanner. The gray and white matter volumes of five prefrontal subregions of interest were measured: superior, middle, inferior, cingulate, and orbital.RESULTS: Bipolar patients had smaller left prefrontal gray matter volumes, specifically in the middle and superior subregions and smaller right prefrontal gray matter volumes, specifically in the inferior and middle subregions. White matter differences were not observed in any of the prefrontal subregions.CONCLUSIONS: The results suggest that bipolar patients have subregion-specific gray matter volume reductions in the prefrontal cortex as compared to healthy subjects. Further investigations into the role of specific prefrontal subregions in bipolar disorder are warranted." [Abstract]

Belmaker RH, Shapiro J, Vainer E, Nemanov L, Ebstein RP, Agam G.
Reduced inositol content in lymphocyte-derived cell lines from bipolar patients.
Bipolar Disord 2002 Feb;4(1):67-9
"OBJECTIVES: The study aimed to determine whether low inositol content and uptake previously reported in brain and peripheral tissue of bipolar patients are also reflected in lymphocyte-derived cell lines from these patients. METHODS: Inositol content and uptake were studied in lymphocyte-derived cell lines grown in vitro for at least five generations to eliminate influences of drug treatment. Inositol content was studied gas chromatographically and inositol uptake by following 3H-inositol incorporation at various concentrations. RESULTS: Inositol levels of cell lines derived from bipolar patients were significantly lower than those of cell lines from controls. CONCLUSIONS: Low inositol content in lymphocyte-derived cell lines from bipolar patients corroborates previous findings in frontal cortex and in lymphoblastoid cell lines and are consistent with the notion that the phosphatidylinositol signaling system is involved in the pathophysiology of this disorder." [Abstract]

Bezchlibnyk Y, Young LT.
The neurobiology of bipolar disorder: focus on signal transduction pathways and the regulation of gene expression.
Can J Psychiatry 2002 Mar;47(2):135-48
"METHOD: We reviewed the published findings from studies of postmortem brain tissue and blood samples from patients with BD. RESULTS: Although the exact biochemical abnormalities have yet to be identified, the presented findings strongly suggest that BD may be due, at least in part, to abnormalities in signal transduction mechanisms. In particular, altered levels or function, or both, of G-protein alpha subunits and effector molecules such as protein kinase A (PKA) and protein kinase C (PKC) have consistently been associated with BD both in peripheral cells and in postmortem brain tissue, while more recent studies implicate disruption in novel second-messenger cascades, such as the ERK/MAPK pathway. CONCLUSIONS: Despite the difficulties inherent in biochemical studies of clinically relevant tissue samples, numerous investigations have illuminated the signal transduction mechanisms in patients with BD. These studies also suggest that BD may be due to the interaction of many abnormalities. In this context, novel techniques enabling the study of gene expression promise to assist in untangling these complex interactions, through visualizing the end result of these changes at the level of gene transcription." [Abstract]

Dunn RT, Kimbrell TA, Ketter TA, Frye MA, Willis MW, Luckenbaugh DA, Post RM.
Principal components of the Beck Depression Inventory and regional cerebral metabolism in unipolar and bipolar depression.
Biol Psychiatry 2002 Mar 1;51(5):387-99
"BACKGROUND: We determined clustering of depressive symptoms in a combined group of unipolar and patients with bipolar disorder using Principle Components Analysis of the Beck Depression Inventory. Then, comparing unipolars and bipolars, these symptom clusters were examined for interrelationships, and for relationships to regional cerebral metabolism for glucose measured by positron emission tomography. METHODS: [18F]-fluoro-deoxyglucose positron emission tomography scans and Beck Depression Inventory administered to 31 unipolars and 27 bipolars, all medication-free, mildly-to-severely depressed. BDI component and total scores were correlated with global cerebral metabolism for glucose, and voxel-by-voxel with cerebral metabolism for glucose corrected for multiple comparisons. RESULTS: In both unipolars and bipolars, the psychomotor-anhedonia symptom cluster correlated with lower absolute metabolism in right insula, claustrum, anteroventral caudate/putamen, and temporal cortex, and with higher normalized metabolism in anterior cingulate. In unipolars, the negative cognitions cluster correlated with lower absolute metabolism bilaterally in frontal poles, and in right dorsolateral frontal cortex and supracallosal cingulate. CONCLUSIONS: Psychomotor-anhedonia symptoms in unipolar and bipolar depression appear to have common, largely right-sided neural substrates, and these may be fundamental to the depressive syndrome in bipolars. In unipolars, but not bipolars, negative cognitions are associated with decreased frontal metabolism. Thus, different depressive symptom clusters may have different neural substrates in unipolars, but clusters and their substrates are convergent in bipolars." [Abstract]

Johnson L, El-Khoury A, Aberg-Wistedt A, Stain-Malmgren R, Mathe AA.
Tryptophan depletion in lithium-stabilized patients with affective disorder.
Int J Neuropsychopharmacol 2001 Dec;4(4):329-36
"Central serotonergic function abnormalities are thought to be associated with the pathogenesis of affective disorder. Reduced serotonergic function, induced by tryptophan depletion, has in several studies transiently reversed the antidepressant effect of SSRIs in depressed patients in remission. Serotonergic pathways are suggested to be of importance in the mechanisms of the action of lithium. The purpose of this study was to investigate whether the stabilizing effect of lithium is dependent on short-term availability of serotonin. Tryptophan depletion was induced in thirty patients with affective disorder (20 bipolar and 10 unipolar), all stabilized on lithium treatment for at least one year. The study was performed using a randomized, double-blind, controlled design. Plasma tryptophan was reduced by 80% in the experimental group and 16% in the control group. However, no clinically relevant mood changes were observed. Transient reduction in serotonergic function does not seem to affect mood in affective-disorder patients stabilized on lithium treatment." [Abstract]

Cervantes P, Gelber S, Kin FN, Nair VN, Schwartz G.
Circadian secretion of cortisol in bipolar disorder.
J Psychiatry Neurosci 2001 Nov;26(5):411-6
"OBJECTIVE: To compare the 24-h cortisol secretion profiles of normal control subjects and patients with bipolar disorder who were in the depressive, manic and euthymic phases of the disorder. PARTICIPANTS: Eighteen patients, 25-62 years of age, in depressed (n = 5), manic (n = 5) or euthymic (n = 8) phase of bipolar disorder recruited through a psychiatric outpatient clinic, and 5 control subjects, 24-41 years of age, recruited through advertisement or word of mouth. OUTCOME MEASURES: Subjects were interviewed and symptom ratings were obtained using the Hamilton Depression Rating Scale, Beck Depression Inventory and Young Mania Scale. Blood collection began at 0800 and continued at hourly intervals for 24 h. Serum cortisol levels were assayed using a validated commercial radioimmunoassay kit. RESULTS: An analysis of variance of the area under the cortisol 24-h time-concentration curve (AUC) revealed a significant difference between the control group and patient groups (F = 3.69, p = 0.03). the mean AUCs of the patients in the depressed (263.4 micrograms/dL) and hypomanic (262.2 micrograms/dL) phases were beyond the 95% confidence interval for the controls (120.9-253.3 micrograms/dL). There were no significant group differences in cosinor acrophase and no significant effects of sex, education, age of illness onset, duration of illness or duration of mood state at time of testing on the cortisol measures. Pearson correlations between symptom rating scores and cortisol secretion variables were not significant. CONCLUSION: The increases in cortisol secretion in patients in both the depressed and manic phases of bipolar disorder suggest that cortisol level is probably not a state marker in bipolar disorder." [Abstract]

Dean B, Pavey G, McLeod M, Opeskin K, Keks N, Copolov D.
A change in the density of [(3)H]flumazenil, but not [(3)H]muscimol binding, in Brodmann's Area 9 from subjects with bipolar disorder.
J Affect Disord 2001 Oct;66(2-3):147-58
"BACKGROUND: This study examines the hypothesis that there are changes in cortical serotonergic, GABAergic and glutamatergic systems in bipolar disorder and schizophrenia. METHODS: In situ radioligand binding and autoradiography were used to measure neurochemical markers in Brodmann's Area (BA) 9 from control subjects and subjects with bipolar disorder or schizophrenia (n=8 per group). RESULTS: Compared to tissue from schizophrenic (mean+/-S.E.M, 385+/-44 fmol/mg ETE) and control (383+/-44 fmol/mg ETE) subjects, there was an increase in the density of [(3)H]flumazenil binding to the benzodiazepine binding site on the GABA(A) receptor in subjects with bipolar disorder (451+/-17 fmol/mg ETE; P<0.05). There was no difference in the density of [(3)H]muscimol binding to the GABA(A) receptor or in the density of the serotonin(1A) receptor, serotonin(2A) receptor, ionotropic glutamate receptors or the serotonin transporter between the three cohorts. There was an age-related decrease in NMDA receptor density in control subjects that was absent in schizophrenia and bipolar disorder. An age-related increase in [(3)H]flumazenil binding in schizophrenia was absent in control and bipolar disorder subjects. LIMITATIONS: This study involved a relatively small number of individuals. CONCLUSIONS: An increase in the gamma2-receptor sub-unit in the GABA(A) receptor has been shown to increase benzodiazepine but not [(3)H]muscimol binding, this is the mismatch in binding we have shown in BA 9 from subjects with bipolar disorder. Thus, a change in the assembly of receptor subunits into GABA(A) receptors may be involved in the neuropathology of bipolar disorder. There may also be differences in age-related changes in cortical receptor density between bipolar disorder and schizophrenia." [Abstract]

Eastwood SL, Harrison PJ.
Synaptic pathology in the anterior cingulate cortex in schizophrenia and mood disorders. A review and a Western blot study of synaptophysin, GAP-43 and the complexins.
Brain Res Bull 2001 Jul 15;55(5):569-78
"There are several reports of ultrastructural and protein changes affecting synapses in the anterior cingulate cortex in schizophrenia. Altered cytoarchitecture has also been described in this region in schizophrenia as well as in mood disorders. In this paper we review the literature and present a new study investigating synaptic abnormalities in the anterior cingulate cortex (area 24) in the Stanley Foundation brain series. We used Western blotting to assess four synaptic proteins: synaptophysin, growth-associated protein-43 (GAP-43), complexin I and complexin II, which inform about somewhat different aspects of the synaptic circuitry. Synaptophysin, complexin II and GAP-43 were reduced in bipolar disorder. The decreases correlated with the duration of illness and tended to be greater in subjects without a family history. Complexin II was also reduced in major depression. Complexin I and the housekeeping protein beta-actin did not differ between groups. None of the proteins changed significantly in schizophrenia. The results indicate the presence of a synaptic pathology in the anterior cingulate cortex in mood disorders, especially bipolar disorder. The abnormalities may contribute to the dysfunction of cingulate neural circuits. The loss of synaptophysin is suggestive of decreased synaptic density whilst the decrease in GAP-43 may denote impaired synaptic plasticity and the reduction of complexin II but not complexin I implies that the alterations particularly affect excitatory connections. The reductions may be progressive." [Abstract]

Curtis VA, Dixon TA, Morris RG, Bullmore ET, Brammer MJ, Williams SC, Sharma T, Murray RM, McGuire PK.
Differential frontal activation in schizophrenia and bipolar illness during verbal fluency.
J Affect Disord 2001 Oct;66(2-3):111-21
"INTRODUCTION: The precise nature of frontal lobe dysfunction in schizophrenia remains unclear. We have previously demonstrated, using fMRI, a task-specific attenuation of frontal activation in schizophrenic patients. By using an identical methodology in matched bipolar subjects, we sought to determine whether this finding is specific to schizophrenia or a correlate of psychosis in general. METHOD: Five dextral male bipolar patients and matching groups of schizophrenic subjects and controls were studied using fMRI. Echoplanar images were acquired while subjects performed two paced tasks: covert verbal fluency and a semantic decision task. Generic brain activation maps were constructed from individual images by sinusoidal regression analysis. Between-group differences in the mean power of experimental response were identified on a voxel-wise basis by an analysis of variance (ANOVA). RESULTS: The bipolar patients showed extensive prefrontal activation during verbal fluency which was significantly greater than in controls. There was no difference in the prefrontal BOLD response during the semantic decision task. CONCLUSIONS: These data indicate that bipolar patients show a strikingly different pattern of frontal responses compared to those with schizophrenia and provide further evidence that abnormal frontal activation in psychotic disorders is more apparent during verbal fluency than semantic decision." [Abstract]

Stewart RJ, Chen B, Dowlatshahi D, MacQueen GM, Young LT.
Abnormalities in the cAMP signaling pathway in post-mortem brain tissue from the Stanley Neuropathology Consortium.
Brain Res Bull 2001 Jul 15;55(5):625-9
"There is an established relationship between the monoaminergic neurotransmitter system and mood disorders. In an attempt to define further the pathophysiology of mood disorders, research is focussing on intracellular second messenger systems, including cyclic adenosine 3',5'-monophosphate (cAMP) and the polyphosphoinositol generated second messengers. The availability of tissue from the Stanley Foundation Neuropathology Consortium has offered us the opportunity to make a number of observations with respect to these second messenger systems in tissue from patients with major depressive disorder and bipolar affective disorder. There is evidence that antidepressants stimulate components of the cAMP pathway in patients with depression while mood stabilizers blunt the same pathway in patients with bipolar disorder. Furthermore, downstream targets of this pathway appear to be altered in patients with mood disorders. The relations between changes in second messenger systems, gene transcription, and clinical effects of current therapeutic regimens has implications for development of novel treatments of mood disorders." [Abstract]

Sassi RB, Nicoletti M, Brambilla P, Harenski K, Mallinger AG, Frank E, Kupfer DJ, Keshavan MS, Soares JC.
Decreased pituitary volume in patients with bipolar disorder.
Biol Psychiatry 2001 Aug 15;50(4):271-80
"BACKGROUND: Neuroendocrinologic investigations in bipolar disorder have suggested abnormalities in pituitary function. However, few imaging studies have evaluated possible anatomical differences in this brain structure in mood disorder patients. Our aim was to examine potential abnormalities in pituitary volume in patients with bipolar and in a comparison group of patients with unipolar disorder. METHODS: We measured the volumes of the pituitary gland in 23 patients with bipolar disorder (mean +/- s.d. = 34.3 +/- 9.9 years) and 13 patients with unipolar disorder (41.2 +/- 9.6 years), and 34 healthy control subjects (36.6 +/- 9.6 years) using 1.5 mm thick T1-weighted coronal 1.5 T MRI images. All measurements were done blindly by a trained rater. RESULTS: Patients with bipolar disorder had significantly smaller pituitary volumes than healthy control subjects (mean volume +/- s.d. = 0.55 +/- 0.15 ml and 0.68 +/- 0.20 ml, respectively; ANCOVA, F = 8.66, p = 0.005), and than patients with unipolar disorder (0.70 +/- 0.12 ml, F = 5.98, p = 0.02). No differences were found between patients with unipolar disorder and healthy control subjects (F = 0.01, p = 0.91)." [Abstract]

Wang H, Friedman E.
Increased association of brain protein kinase C with the receptor for activated C kinase-1 (RACK1) in bipolar affective disorder.
Biol Psychiatry 2001 Sep 1;50(5):364-70
"BACKGROUND: Membrane protein kinase C (PKC) activity is increased in frontal cortex of subjects with bipolar affective disorder, and lithium was demonstrated to inhibit PKC translocation to membranes. Protein kinase C is anchored to the membrane via the receptor for activated C kinase-1 (RACK1), suggesting that interactions between these proteins may be altered in bipolar disease. METHODS: The levels of RACK1 coimmunoprecipitating with PKC isozymes were compared in homogenates of frontal cortex slices from postmortem bipolar subjects and matched control subjects. RESULTS: Receptor for activated C kinase-1 was located exclusively in membranes and, in control brains, the levels of RACK1 that coimmunoprecipitated with most PKC isozymes were increased by stimulation with the PKC activator, phorbol 12-myristate, 13-acetate (PMA). The association of RACK1 with membrane gammaPKC and zetaPKC was increased under basal conditions in bipolar relative to control brains. Stimulation with PMA increased the amount of RACK1 that coimmunoprecipitated with the alpha, beta, gamma, delta, and varepsilonPKC isozymes, but not zetaPKC, in bipolar tissues over that elicited in control tissues. CONCLUSIONS: These data suggest that the increased association of RACK1 with PKC isozymes may be responsible for the increases in membrane PKC and in its activation that were previously observed in frontal cortex of bipolar affective disorder brains." [Abstract]

Stanley JA.
In vivo magnetic resonance spectroscopy and its application to neuropsychiatric disorders.
Can J Psychiatry 2002 May;47(4):315-26
"In vivo magnetic resonance spectroscopy (MRS) is the only noninvasive imaging technique that can directly assess the living biochemistry in localized brain regions. In the past decade, spectroscopy studies have shown biochemical alterations in various neuropsychiatric disorders. These first-generation studies have, in most cases, been exploratory but have provided insightful biochemical information that has furthered our understanding of different brain disorders. This review provides a brief description of spectroscopy, followed by a literature review of key spectroscopy findings in schizophrenia, affective disorders, and autism. In schizophrenia, phosphorus spectroscopy studies have shown altered metabolism of membrane phospholipids (MPL) during the early course of the illness, which is consistent with a neurodevelopmental abnormality around the critical period of adolescence when the illness typically begins. Children and adolescents who are at increased genetic risk for schizophrenia show similar MPL alterations, suggesting that schizophrenia subjects with a genetic predisposition may have a premorbid neurodevelopmental abnormality. Independent of medication status, bipolar subjects in the depressive state tended to have higher MPL precursor levels and a deficit of high-energy phosphate metabolites, which also is consistent with major depression, though these results varied. Further bipolar studies are needed to investigate alterations at the early stage." [Abstract]

Yildiz A, Sachs GS, Dorer DJ, Renshaw PF.
31P Nuclear magnetic resonance spectroscopy findings in bipolar illness: a meta-analysis.
Psychiatry Res 2001 May 30;106(3):181-91
"Published literature comparing 31P MR brain spectra of bipolar patients to healthy controls was evaluated, focusing on phosphomonoester (PME)/phosphodiester (PDE) resonance areas because these metabolites are related to membrane phospholipids and membrane defects in bipolar disorder have been suggested. Studies comparing PME and/or PDE values of bipolar subjects to values observed in healthy controls were reviewed. Data from the studies meeting our inclusion criteria (8 reports involving 139 bipolar and 189 comparison subjects) were grouped according to the mood state of the subjects. Meta-analyses of data were performed to compare PME and PDE levels of euthymic bipolar patients to healthy controls, as well as comparing PME levels during euthymia in bipolar subjects to values observed during manic and depressed states. The PME values of euthymic bipolar patients were found to be significantly lower than PME values of healthy controls. Depressed bipolar patients had significantly higher PME values in comparison to euthymic bipolar patients. No significant difference could be detected between the PDE values of bipolars and controls. This meta-analysis found support for trait- and possibly state-dependent abnormalities of membrane phospholipid metabolism, which may reflect a dysregulation in brain-signal transduction systems of relevance in bipolar illness." [Abstract]

Brambilla P, Harenski K, Nicoletti M, Mallinger AG, Frank E, Kupfer DJ, Keshavan MS, Soares JC.
Differential effects of age on brain gray matter in bipolar patients and healthy individuals.
Neuropsychobiology 2001;43(4):242-7
"This study examined possible differences in total gray and white matter brain content in bipolar patients and healthy individuals, and their relationship with age. 22 DSM-IV bipolar patients and 22 healthy controls underwent a 1.5-tesla Spoiled Gradient Recalled Acquisition (SPGR) MRI. Evaluators blind to patients' identities measured total brain, gray and white matter volumes using a semi-automated software. No differences were found for total brain volume, gray matter or white matter volumes between bipolar patients and healthy controls (MANCOVA, age as covariate, p > 0.05). Age was inversely correlated with total gray matter volume in patients (r = -0.576, p = 0.005), but not in controls (r = -0.193, p = 0.388). Our findings suggest that any existing gray matter deficits in bipolar disorder are likely to be localized to specific brain regions, rather than generalized. The inverse correlation between age and brain gray matter volumes in bipolar patients, not present in healthy controls, in this sample of mostly middle-aged adults, could possibly indicate more pronounced age-related gray matter decline in bipolar patients, and may be of potential relevance for the pathophysiology of the disorder. Copyright 2001 S. Karger AG, Basel." [Abstract]

Rajkowska G, Halaris A, Selemon LD.
Reductions in neuronal and glial density characterize the dorsolateral prefrontal cortex in bipolar disorder.
Biol Psychiatry 2001 May 1;49(9):741-52
"BACKGROUND: Bipolar disorder (BPD) is a mental illness in which depression and mania typically alternate, and both phases can present with psychotic features. The symptomatology of BPD, therefore, resembles major depressive disorder (MDD) and schizophrenia (SCHZ), posing diagnostic dilemmas. Distinct alterations in cellular architecture of the dorsolateral prefrontal cortex distinguish SCHZ and MDD, whereas the cellular neuropathology of BPD has not been studied. METHODS: Dorsolateral prefrontal area 9 was analyzed using a three-dimensional morphometric method in postmortem brains from 10 BPD patients and 11 matched nonpsychiatric control subjects. RESULTS: Area 9 in BPD was characterized by reduced neuronal density in layer III (16%-22%) and reduced pyramidal cell density in layers III and V (17%-30%). A 19% reduction in glial density was found in sublayer IIIc coupled with enlargement and changes in shape of glial nuclei spanning multiple layers. CONCLUSIONS: The morphologic signature of BPD, i.e., decreased neuronal and glial density in association with glial hypertrophy, is distinct from previously described elevations in neuronal density in SCHZ, instead resembling the reductions in cell density found in MDD. Thus, the neuropathologic distinctions between BPD and SCHZ are indicative of separate mental illnesses, each with a unique morphologic disturbance of specific neural circuits." [Abstract]

Strakowski SM, DelBello MP, Adler C, Cecil DM, Sax KW.
Neuroimaging in bipolar disorder.
Bipolar Disord 2000 Sep;2(3 Pt 1):148-64
"OBJECTIVE: The authors reviewed neuroimaging studies of bipolar disorder in order to evaluate how this literature contributes to the current understanding of the neurophysiology of the illness. METHOD: Papers were reviewed as identified, using the NIMH PubMed literature search systems that reported results of neuroimaging studies involving a minimum of five bipolar disorder patients compared with healthy comparison subjects. RESULTS: Structural neuroimaging studies report mixed results for lateral and third ventriculomegaly. Recent studies suggest subcortical structural abnormalities in the striatum and amygdala, as well as the prefrontal cortex. Proton spectroscopic studies suggest that abnormalities in choline metabolism exist in bipolar disorder, particularly in the basal ganglia. Additionally, phosphorous MRS suggests that there may be abnormalities in frontal phospholipid metabolism in bipolar disorder. Functional studies have identified affective state-related changes in cerebral glucose metabolism and blood flow, particularly in the prefrontal cortex during depression, but no clear abnormalities specific to bipolar disorder have been consistently observed. CONCLUSIONS: The current literature examining the neurophysiology of bipolar disorder using neuroimaging is limited. Nonetheless, abnormalities in specific frontal-subcortical brain circuits seem likely. Additional targeted studies are needed to capitalize on this burgeoning technology to advance our understanding of the neurophysiology of bipolar disorder." [Abstract]

Yurgelun-Todd DA, Gruber SA, Kanayama G, Killgore WD, Baird AA, Young AD.
fMRI during affect discrimination in bipolar affective disorder.
Bipolar Disord 2000 Sep;2(3 Pt 2):237-48
"OBJECTIVE: It has been hypothesized that disturbances in affect may represent distinct etiologic factors for bipolar affective disorder. The neural mechanisms mediating affective processes and their relationship to brain development and the pathophysiology of bipolar affective disorder remain to be clarified. Recent advances in neuroimaging techniques have made possible the non-invasive examination of specific brain regions during cortical challenge paradigms. This study reports findings based on fMRI data acquired during fearful and happy affect recognition paradigms in patients with bipolar affective disorder and in healthy adult subjects. METHODS: Prior to the scan, subjects were instructed to view the stimuli and to identify the type of facial expression presented. Echo planar scanning was performed on a 1.5 Tesla scanner which had been retrofitted with a whole body echo planar coil, using a head coil. RESULTS: The data indicate that in adult subjects with bipolar affective disorder, there is a reduction in dorsolateral prefrontal cortex activation and an increase in amygdalar activation in response to fearful facial affect. In a healthy comparison group, signal intensity changes were not found in these regions. In addition, although the patients with bipolar affective disorder completed the task demands, they demonstrated an impaired ability to correctly identify fearful facial affect but not the happy facial affect displayed. CONCLUSION: These findings are consistent with the hypothesis that in some patients with bipolar affective disorder, there may be a reduction of frontal cortical function which may be associated with affective as well as attentional processing deficits." [Abstract]

Blumberg, Hilary P., Martin, Andres, Kaufman, Joan, Leung, Hoi-Chung, Skudlarski, Pawel, Lacadie, Cheryl, Fulbright, Robert K., Gore, John C., Charney, Dennis S., Krystal, John H., Peterson, Bradley S.
Frontostriatal Abnormalities in Adolescents With Bipolar Disorder: Preliminary Observations From Functional MRI
Am J Psychiatry 2003 160: 1345-1347
"OBJECTIVE: This study investigated whether the functional abnormalities in prefrontal systems observed in adult bipolar disorder are manifested in adolescents with this illness. METHOD: Ten adolescents with bipolar disorder and 10 healthy comparison subjects participated in a color-naming Stroop task during event-related functional magnetic resonance imaging. RESULTS: Signal increases in the left putamen and thalamus were significantly greater in the bipolar disorder group than in the healthy group. Age correlated positively with signal increases in the bilateral rostroventral prefrontal cortex and the striatum in the healthy group but not in the bipolar disorder group. In the bipolar disorder subjects, depressive symptoms correlated positively with signal increases in the ventral striatum. CONCLUSIONS: These findings suggest the presence of dysfunction in the subcortical portions of the frontostriatal circuits in adolescents with bipolar disorder. The absence of the prefrontal abnormalities that were observed previously in adults and the absence of the age-related increases in prefrontal activity observed in normal comparison subjects suggest that a developmental disturbance in prefrontal function may emerge in bipolar disorder over the course of adolescence." [Abstract]

Ghaemi SN, Shields GS, Hegarty JD, Goodwin FK.
Cholesterol levels in mood disorders: high or low?
Bipolar Disord 2000 Mar;2(1):60-4
"OBJECTIVES: To assess cholesterol levels in patients with mood disorders. METHODS: All consecutively admitted patients meeting inclusion criteria (n = 50) who were hospitalized in an affective disorders unit received assessments of cholesterol levels. Correlations were made with diagnosis using DSM-IV criteria, current mood states, and other clinical and demographic features of illness. Exclusion criteria included current alcohol abuse, medical illnesses that could influence cholesterol levels, eating disorders, and age greater than 70 years. RESULTS: Cholesterol levels did not differ based on diagnostic status of unipolar depression or bipolar disorder. In the total sample, cholesterol levels were lower in patients with current manic (170.2 +/- 38.9, p = 0.05) and depressive (182.0 +/- 42.0) than in mixed (226.4 +/- 43.3) episodes (p = 0.05). In subgroups of patients with bipolar disorder, manic episodes (169.9 +/- 38.8, n = 9) were associated with lower cholesterol levels than depressive (201.0 +/- 49.4) or mixed (226.4 +/- 44.4) episodes (p = 0.02 for comparison of manic and mixed episodes). Body mass index (BMI), age, alcohol use, and gender did not account for these findings. CONCLUSIONS: Cholesterol levels were lower in manic and depressive than in mixed episodes. No differences were found between diagnoses of unipolar or bipolar mood disorders. Cholesterol may be a state rather than a trait function, and may be influenced by the acute mood state." [Abstract]

Atmaca M, Kuloglu M, Tezcan E, Ustundag B, Bayik Y.
Serum leptin and cholesterol levels in patients with bipolar disorder.
Neuropsychobiology. 2002;46(4):176-9.
"Low cholesterol levels have been reported in patients with manic episodes. Leptin seems to be strongly associated with lipid metabolism. In the present study, therefore, serum total cholesterol and leptin levels were compared in 16 patients with manic episodes, 16 with bipolar I disorder in full remission and 16 healthy controls. The serum total cholesterol and leptin levels were measured and Young Mania Rating (YMRS) and Hamilton Depression Rating Scales (HAM-D) were administered for each subject. Both the patients with manic episodes and the patients with bipolar I disorder in full remission had markedly low serum cholesterol and leptin levels compared with controls, though the difference was more obvious in patients with manic episodes. In addition, there were negative correlations between YMRS scores and serum cholesterol or leptin levels in the patients with manic episodes. Our results suggest that the patients with manic episodes and those with bipolar I disorder in full remission seem to be associated with decreased serum cholesterol and leptin levels." [Abstract]

Thomas EA, Dean B, Scarr E, Copolov D, Sutcliffe JG.
Differences in neuroanatomical sites of apoD elevation discriminate between schizophrenia and bipolar disorder.
Mol Psychiatry. 2003 Feb;8(2):167-75.
"We previously demonstrated that apolipoprotein D (apoD) levels are elevated in the dorsolateral prefrontal cortex and caudate obtained postmortem from subjects with schizophrenia and bipolar disorder compared to controls, suggesting a focal compensatory response to neuropathology associated with psychiatric disorders. We have now extended those studies by measuring apoD protein levels in additional brain regions from post-mortem samples of schizophrenic and bipolar disorder subjects using an enzyme-linked immunosorbent assay. Increased apoD levels were observed in the lateral prefrontal cortex (Brodmann Area 46) in both schizophrenia (46%) and bipolar disorder (111%), and in the orbitofrontal cortex (Brodmann Area 11) (44.3 and 37.9% for schizophrenia and bipolar disorder, respectively). However, differences between the disease groups were observed in other brain regions. In subjects with schizophrenia, but not bipolar disorder, apoD levels were significantly elevated in the amygdala (42.8%) and thalamus (31.7%), while in bipolar disorder, but not schizophrenia, additional increases were detected in the parietal cortex (Brodmann Area 40; 123%) and the cingulate cortex (Brodmann Area 24; 57.7%). These data demonstrate that there is anatomical overlap in the pathophysiologies of schizophrenia and bipolar disorder, as well as areas of pathology that distinguish the two disorders." [Abstract]

Fatemi SH, Earle JA, McMenomy T.
Reduction in Reelin immunoreactivity in hippocampus of subjects with schizophrenia, bipolar disorder and major depression.
Mol Psychiatry 2000 Nov;5(6):654-63, 571
"Accumulation of neurobiological knowledge points to neurodevelopmental origins for certain psychotic and mood disorders. Recent landmark postmortem reports implicate Reelin, a secretory glycoprotein responsible for normal lamination of brain, in the pathology of schizophrenia and bipolar disorders. We employed quantitative immunocytochemistry to measure levels of Reelin protein in various compartments of hippocampal formation in subjects diagnosed with schizophrenia, bipolar disorder and major depression compared to normal controls. Significant reductions were observed in Reelin-positive adjusted cell densities in the dentate molecular layer (ANOVA, P < 0.001), CA4 area (ANOVA, P < 0.001), total hippocampal area (ANOVA, P < 0.038) and in Reelin-positive cell counts in CA4 (ANOVA, P < 0.042) of schizophrenics vs controls. Adjusted Reelin-positive cell densities were also reduced in CA4 areas of subjects with bipolar disorder (ANOVA, P < 0.001) and nonsignificantly in those with major depression. CA4 areas were also significantly reduced in schizophrenic (ANOVA, P < 0.009) patients. No significant effects of confounding variables were found. The exception was that family history of psychiatric illness correlated strongly with Reelin reductions in several areas of hippocampus (CA4, adjusted cell density, F = 13.77, P = 0.001). We present new immunocytochemical evidence showing reductions in Reelin expression in hippocampus of subjects with schizophrenia, bipolar disorder and major depression and confirm recent reports documenting a similar deficit involving Reelin expression in brains of subjects with schizophrenia and bipolar disorder." [Abstract]

Blumberg HP, Stern E, Martinez D, Ricketts S, de Asis J, White T, Epstein J, McBride PA, Eidelberg D, Kocsis JH, Silbersweig DA.
Increased anterior cingulate and caudate activity in bipolar mania.
Biol Psychiatry 2000 Dec 1;48(11):1045-52
"BACKGROUND: Executive control of cognition, emotion, and behavior are disrupted in the manic state of bipolar disorder. Whereas frontal systems are implicated in such dysfunction, the localization of functional brain abnormalities in the manic state is not well understood. METHODS: We utilized a high-sensitivity H(2)(15)0 positron emission tomography technique to investigate regions of increased brain activity in mania, compared to euthymia, in bipolar disorder. RESULTS: The principal findings were manic state-related increased activity in left dorsal anterior cingulate, and left head of caudate. CONCLUSIONS: The findings suggest that the manic state of bipolar disorder may be associated with heightened activity in a frontal cortical-subcortical neural system that includes the anterior cingulate and caudate." [Abstract]

Heckers S, Stone D, Walsh J, Shick J, Koul P, Benes FM.
Differential hippocampal expression of glutamic acid decarboxylase 65 and 67 messenger RNA in bipolar disorder and schizophrenia.
Arch Gen Psychiatry 2002 Jun;59(6):521-9
"BACKGROUND: Expression of messenger RNA (mRNA) for the gamma-aminobutyric acid (GABA)-synthesizing enzyme, glutamic acid decarboxylase (GAD), in the prefrontal cortex and the number of GABAergic neurons in the hippocampus are reduced in schizophrenia and bipolar disorder. We tested the hypothesis that the expression of the 2 isoforms, one 65 kd (GAD(65)) and the other 67 kd (GAD(67)), is differentially affected in the hippocampus in schizophrenia and bipolar disorder. METHODS: Hippocampal sections from 15 subjects in 3 groups (control subjects and subjects with schizophrenia and bipolar disorder) were studied using an in situ hybridization protocol with sulfur 35-labeled complementary riboprobes for GAD(65) and GAD(67) mRNA. Emulsion-dipped slides were analyzed for the density of GAD mRNA-positive neurons in 4 sectors of the hippocampus and for the cellular expression level of both GAD mRNAs. RESULTS: The density of GAD(65) and GAD(67) mRNA-positive neurons was decreased by 45% and 43%, respectively, in subjects with bipolar disorder, but only 14% and 4%, respectively, in subjects with schizophrenia. The decreased density of GAD(65) mRNA-positive neurons in subjects with bipolar disorder was significant in sectors CA2/3 and dentate gyrus, and that of GAD(67) mRNA-positive neurons was significant in CA4, but not other hippocampal sectors. Cellular GAD(65) mRNA expression was significantly decreased in subjects with bipolar disorder, particularly in CA4, but not in schizophrenic subjects. Cellular GAD(67) mRNA expression was normal in both groups. CONCLUSION: We have found a region-specific deficit of GAD(65) and GAD(67) mRNA expression in bipolar disorder." [Abstract]

Guidotti A, Auta J, Davis JM, Di-Giorgi-Gerevini V, Dwivedi Y, Grayson DR, Impagnatiello F, Pandey G, Pesold C, Sharma R, Uzunov D, Costa E, DiGiorgi Gerevini V.
Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study.
Arch Gen Psychiatry 2000 Nov;57(11):1061-9
"BACKGROUND: Reelin (RELN) is a glycoprotein secreted preferentially by cortical gamma-aminobutyric acid-ergic (GABAergic) interneurons (layers I and II) that binds to integrin receptors located on dendritic spines of pyramidal neurons or on GABAergic interneurons of layers III through V expressing the disabled-1 gene product (DAB1), a cytosolic adaptor protein that mediates RELN action. To replicate earlier findings that RELN and glutamic acid decarboxylase (GAD)(67), but not DAB1 expression, are down-regulated in schizophrenic brains, and to verify whether other psychiatric disorders express similar deficits, we analyzed, blind, an entirely new cohort of 60 postmortem brains, including equal numbers of patients matched for schizophrenia, unipolar depression, and bipolar disorder with nonpsychiatric subjects. METHODS: Reelin, GAD(65), GAD(67), DAB1, and neuron-specific-enolase messenger RNAs (mRNAs) and respective proteins were measured with quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) or Western blot analyses. Reelin-positive neurons were identified by immunohistochemistry using a monoclonal antibody. RESULTS: Prefrontal cortex and cerebellar expression of RELN mRNA, GAD(67) protein and mRNA, and prefrontal cortex RELN-positive cells was significantly decreased by 30% to 50% in patients with schizophrenia or bipolar disorder with psychosis, but not in those with unipolar depression without psychosis when compared with nonpsychiatric subjects. Group differences were absent for DAB1,GAD(65) and neuron-specific-enolase expression implying that RELN and GAD(67) down-regulations were unrelated to neuronal damage. Reelin and GAD(67) were also unrelated to postmortem intervals, dose, duration, or presence of antipsychotic medication. CONCLUSIONS: The selective down-regulation of RELN and GAD(67) in prefrontal cortex of patients with schizophrenia and bipolar disorder who have psychosis is consistent with the hypothesis that these parameters are vulnerability factors in psychosis; this plus the loss of the correlation between these 2 parameters that exists in nonpsychotic subjects support the hypothesis that these changes may be liability factors underlying psychosis." [Abstract]

Shapiro J, Belmaker RH, Biegon A, Seker A, Agam G.
Scyllo-inositol in post-mortem brain of bipolar, unipolar and schizophrenic patients.
J Neural Transm 2000;107(5):603-7
"Inositol levels measured in postmortem brain of unipolar, bipolar and schizophrenic patients, suicide victims and normal controls showed no difference in scyllo-inositol levels in frontal or occipital cortex between any of the groups. We could not replicate previous reports of low myo-inositol levels in the frontal cortex of unipolar, bipolar and schizophrenic patients and suicide victims. There was no correlation between myo-inositol levels and estimated chlorpromazine equivalents in neuroleptic-treated subjects, and no effect of chronic haloperidol treatment on rat brain myo-inositol levels." [Abstract]

Hauser P, Matochik J, Altshuler LL, Denicoff KD, Conrad A, Li X, Post RM.
MRI-based measurements of temporal lobe and ventricular structures in patients with bipolar I and bipolar II disorders.
J Affect Disord 2000 Oct;60(1):25-32
"OBJECTIVE: There have been relatively few quantitative MRI studies of temporal lobe structures and the lateral ventricles in bipolar patients and a lack of agreement across studies as to whether these structures differ significantly in size from control subjects. Also there have been no quantitative MRI studies of bipolar II patients. The present study measured temporal lobe and ventricular structures in both bipolar I and bipolar II patients, as well as control subjects. METHOD: Twenty-five bipolar I patients, 22 bipolar II patients and 19 control subjects underwent MRI brain scans. The 5 mm coronal slices of each subject were coded and measured by a rater who was blind with respect to subject diagnosis. Volume estimates of the temporal lobe and hippocampus were calculated for each hemisphere by measuring the area of the structure in each slice in which it appears, multiplying by 5 mm and summing. In addition to these volume estimates, the area of the lateral ventricle and the inferior horn of the lateral ventricle, the lateral ventricle to cerebrum area ratio (LV/C) and the temporal lobe to cerebrum area ratio (TL/C), were calculated for each hemisphere in one reference slice only. The area of the third ventricle was also measured. Volume estimates and area ratios were then compared among diagnostic groups. RESULTS: There were no significant differences in temporal lobe or hippocampal volume estimates, in the third ventricle and inferior horn of the lateral ventricle area measurements, and in the TL/C area ratio among diagnostic groups. The lateral ventricle area and LV/C area ratio were significantly larger in bipolar I patients than either bipolar II patients or control subjects only in the left hemisphere. Furthermore, these measures were approximately twice as large in the bipolar I patients as the other groups. CONCLUSIONS: The current study adds to a growing literature that bipolar I disorder, particularly in males, may show different neurobiological alterations compared to bipolar II patients or control subjects. The pathophysiologic implications of this accumulating evidence of increased left ventricular size in bipolar I disorder remains to be further elucidated." [Abstract]

Altshuler LL, Bartzokis G, Grieder T, Curran J, Jimenez T, Leight K, Wilkins J, Gerner R, Mintz J.
An MRI study of temporal lobe structures in men with bipolar disorder or schizophrenia.
Biol Psychiatry 2000 Jul 15;48(2):147-62
"BACKGROUND: Hippocampal atrophy has been described in postmortem and magnetic resonance imaging studies of schizophrenia. The specificity of this finding to schizophrenia remains to be determined. The neuropathology of bipolar disorder is understudied, and temporal lobe structures have only recently been evaluated. METHODS: Twenty-four bipolar, 20 schizophrenic, and 18 normal comparison subjects were evaluated using magnetic resonance brain imaging. Image data were acquired using a three-dimensional spoiled GRASS sequence, and brain images were reformatted in three planes. Temporal lobe structures including the amygdala, hippocampus, parahippocampus, and total temporal lobe were measured to obtain volumes for each structure in the three subject groups. Severity of symptoms in both patient groups was assessed at the time the magnetic resonance images were obtained. RESULTS: Hippocampal volumes were significantly smaller in the schizophrenic group than in both bipolar and normal comparison subjects. Further, amygdala volumes were significantly larger in the bipolar group than in both schizophrenic and normal comparison subjects. CONCLUSIONS: The results suggest differences in affected limbic structures in patients with schizophrenia and bipolar disorder. These specific neuroanatomic abnormalities may shed light on the underlying pathophysiology and presentation of the two disorders." [Abstract]

Carran MA, Kohler CG, O'Connor MJ, Bilker WB, Sperling MR.
Mania following temporal lobectomy.
Neurology. 2003 Sep 23;61(6):770-774.
"OBJECTIVE: To determine clinical and diagnostic variables that predict the development of mania after temporal lobectomy for treatment of refractory epilepsy. METHODS: From a large surgical database, 16 patients with new-onset mania after temporal lobectomy were identified. Mania patients were frequency matched for age, gender, and laterality of surgery to 16 temporal lobectomy patients with no postoperative mood disorder. These groups were compared on pre- and postoperative clinical and diagnostic data with each other and with 30 patients with depression after temporal lobectomy. Posthoc analyses compared mania and depression groups with the general surgical database matched for gender and laterality of surgery. RESULTS: Preoperative evaluations in postoperative mania patients, in particular EEG, were more likely to yield findings of brain dysfunction localizing to the hemisphere contralateral to temporal lobectomy. Right temporal lobectomy was more common in the postoperative mania group. Duration of manic episodes was usually transient, and all but one case remitted within 1 year after onset. In comparison with the control group, mania and depression groups had a higher likelihood for preoperative generalized tonic-clonic seizures and lack of seizure freedom following surgery. CONCLUSIONS: A limitation of this study was the relatively small number of patients. Despite this, clinical features that distinguish patients at risk for postoperative mania from those with depression and those with no psychiatric illness include bihemispheric abnormalities, in particular bitemporal EEG activity, and right temporal lobectomy." [Abstract]

Nurnberger JI Jr, Adkins S, Lahiri DK, Mayeda A, Hu K, Lewy A, Miller A, Bowman ES, Miller MJ, Rau L, Smiley C, Davis-Singh D.
Melatonin suppression by light in euthymic bipolar and unipolar patients.
Arch Gen Psychiatry 2000 Jun;57(6):572-9
"BACKGROUND: Previous studies have suggested that bipolar patients are supersensitive to light suppression of melatonin and that this may be a trait marker for genetic vulnerability. The present study was an attempt to replicate and extend this observation. Propranolol hydrochloride effects were compared with light effects because of the documented influence of beta-adrenergic receptors on melatonin production. Nighttime levels of corticotropin and cortisol were also examined as potential trait vulnerability markers. METHODS: Melatonin levels in euthymic bipolar patients (n= 29) were tested before and after 500-lux light was administered between 2 and 4 AM and on a separate night in the dark. Results were compared with those of a group of patients with unipolar depression (n= 24) and with those of a group of non-psychiatrically ill control subjects (n= 50). Lithium effects and propranolol effects were tested in subgroups. RESULTS: No group differences were seen in light suppression among bipolar patients, unipolar patients, and controls; an analysis of the whole group did not reveal differences in propranolol effect, differences in corticotropin or cortisol levels, or evidence for a lithium effect. However, patients with bipolar I affective disorder showed the following: (1) significantly lower melatonin levels on the light night, at baseline and following light exposure; and (2) a later peak time for melatonin on the dark night. CONCLUSIONS: The general hypothesis of increased light sensitivity in bipolar patients was not supported. However, melatonin secretion abnormalities were confirmed in the subgroup with bipolar I disorder. Further assessments of circadian rhythm disruption as a vulnerability marker in bipolar illness are indicated." [Abstract]

Perez J, Tardito D, Mori S, Racagni G, Smeraldi E, Zanardi R.
Altered Rap1 endogenous phosphorylation and levels in platelets from patients with bipolar disorder.
J Psychiatr Res 2000 Mar-Apr;34(2):99-104
"Previous studies have reported abnormalities either in the cAMP-dependent endogenous phosphorylation or in the levels of Rap1 in platelets from bipolar patients. One limitation of these findings was that they come from different groups of patients in independent studies. To overcome this limitation, we designed the present study in which both these biochemicals parameters were assessed in the same cohort of euthymic bipolar patients and healthy subjects. The results showed that the cAMP-dependent phosphorylation of Rap1 was significantly higher in platelets of bipolar patients with respect to healthy subjects. Furthermore, immunoblotting experiments revealed that also the levels of Rap1 were significantly higher in bipolar patients than in control subjects, thus supporting that the abnormal phosphorylation can be ascribed to the increased levels of Rap1. Taken together the results of the present study further support that downstream components of the cAMP signal cascade could be involved in the pathophysiology of bipolar disorders." [Abstract]

Lesort M, Greendorfer A, Stockmeier C, Johnson GV, Jope RS.
Glycogen synthase kinase-3beta, beta-catenin, and tau in postmortem bipolar brain.
J Neural Transm 1999;106(11-12):1217-22
"Therapeutic concentrations of the anti-bipolar drug lithium inhibit the activity of glycogen synthase kinase-3beta, which raises the possibility that this enzyme and its substrates may be altered in the brain of subjects with bipolar disorder. Therefore, in prefrontal cortical samples from subjects with bipolar disorder and age-matched control subjects, we examined the levels of glycogen synthase kinase 3beta and of two proteins modified by it, beta-catenin and the microtubule associated protein tau. There were no significant differences between subject groups among these measurements, but there was a tendency for the tau isoform profile to be modified in bipolar tissue. Thus, while there are no differences between bipolars and controls in prefrontal cortical levels of glycogen synthase kinase-3beta, beta-catenin, or tau, tau isoform levels or phosphorylation states may be modified in bipolar disorder." [Abstract]

Ali SO, Denicoff KD, Altshuler LL, Hauser P, Li X, Conrad AJ, Mirsky AF, Smith-Jackson EE, Post RM.
A preliminary study of the relation of neuropsychological performance to neuroanatomic structures in bipolar disorder.
Neuropsychiatry Neuropsychol Behav Neurol 2000 Jan;13(1):20-8
"OBJECTIVE: To investigate the relation between neuropsychological dysfunction and volumetric measures of neuroanatomic structures in patients with bipolar disorder. BACKGROUND: Previous research suggests that neuropsychological deficits are associated with neuroanatomic changes in patients with bipolar disorder. METHOD: Twenty-six outpatients who met Diagnostic and Statistical Manual, Third Edition-Revised criteria for bipolar disorder were administered a battery of neuropsychological tests that assessed memory, abstracting ability, psychomotor performance, sustained attention, and intelligence. Patients also received a magnetic resonance imaging scan, from which volumes of the temporal lobes, hippocampus, third ventricle, and areas of the lateral ventricles were calculated. Using multiple regression analyses, neuroanatomic structures were compared with neuropsychological test variables. RESULTS: Data suggest that a larger right hippocampal volume is associated with poorer neuropsychological functioning. CONCLUSIONS: Further studies are needed to both replicate and examine the relation between potential mechanisms of neuroanatomic alterations and neuropsychological dysfunction in patients with bipolar disorder." [Abstract]

Vawter MP, Howard AL, Hyde TM, Kleinman JE, Freed WJ.
Alterations of hippocampal secreted N-CAM in bipolar disorder and synaptophysin in schizophrenia.
Mol Psychiatry 1999 Sep;4(5):467-75
"Schizophrenia and bipolar disorder have both been linked to structural abnormalities of the hippocampus, which is consistent with a neurodevelopmental anomaly. One isoform of the neural cell adhesion molecule (N-CAM) protein, cytosolic N-CAM 105-115 kDa, was previously shown to be increased in schizophrenia in the hippocampus and prefrontal cortex. Another isoform of N-CAM, the variable alternative spliced exon of N-CAM, was also increased in the hippocampus and prefrontal cortex of bipolar disorder patients. In the present study, the secreted isoform of N-CAM (SEC N-CAM), synaptophysin, and actin proteins were measured in the hippocampus of controls, suicide victims, and patients with bipolar disorder or schizophrenia by quantitative Western immunoblotting. Previous measurements of cytosolic N-CAM (105-115 kDa) protein, from the same hippocampus samples, were used to calculate the N-CAM (105-115 kDa)/synaptophysin ratio. An affinity purified antibody to SEC N-CAM recognized SEC N-CAM (108 kDa and 115 kDa) in brain but SEC N-CAM was not detectable in CSF. In bipolar disorder, but not in schizophrenia, an increased SEC N-CAM 115 kDa/108 kDa ratio was found as compared to controls (P = 0.03). The synaptophysin/actin ratio was significantly decreased in schizophrenia (P = 0.014) as compared to controls. The cytosolic N-CAM 105-115 kDa/synaptophysin ratio was increased in patients with schizophrenia (P= 0.017), but not in bipolar disorder. Thus, bipolar disorder patients show altered expression of SEC N-CAM in the hippocampus. Patients with schizophrenia show a decrease in synaptophysin and an increase in the cytosolic N-CAM 105-115 kDa/synaptophysin ratio. The results offer further evidence of differences in protein expression between bipolar disorder and schizophrenia in the hippocampus, which is consistent with a distinct neuropathology for each neuropsychiatric disorder." [Abstract]

Grossman F, Potter WZ.
Catecholamines in depression: a cumulative study of urinary norepinephrine and its major metabolites in unipolar and bipolar depressed patients versus healthy volunteers at the NIMH.
Psychiatry Res 1999 Jul 30;87(1):21-7
"Studies comparing urinary norepinephrine (NE) and its metabolites in unipolar or bipolar depressed patients and healthy volunteers have not yielded consistent findings. However, in unipolar depressed patients, most studies in non-elderly populations consistently report elevated concentrations of plasma NE, at least following an orthostatic challenge. Expanding upon previous studies which showed elevated plasma NE in depression, we compared the urinary excretion of NE, normetanephrine (NMN), 3-methoxy-4-hydroxyphenylglycol (MHPG), and vanillylmandelic acid (VMA) in age- and sex-matched unipolar and bipolar depressed patients versus healthy volunteers hospitalized at an inpatient unit at the National Institute of Mental Health. Only depressed subjects with a minimum 4-week drug-free period were included. Total turnover (NE + NMN + MHPG + VMA) was reduced in this sample of unipolar and bipolar depressed patients. MHPG concentration did not distinguish unipolar from bipolar depressed patients and was not significantly different from that in healthy volunteers. A construct of the average fractional extraneuronal concentration of NE (NE + NMN/NE + NMN + MHPG + VMA) was significantly higher in unipolar and bipolar depressed patients than in healthy volunteers. This finding extends data suggesting that unmedicated unipolar and bipolar depressed patients have a 'hyperresponsive' noradrenergic system and provides a framework which ties together plasma and urinary findings." [Abstract]

Caberlotto L, Hurd YL.
Reduced neuropeptide Y mRNA expression in the prefrontal cortex of subjects with bipolar disorder.
Neuroreport 1999 Jun 3;10(8):1747-50
"In the present study, we compared neuropeptide Y mRNA expression levels in the prefrontal cortex (Brodmann area 9 and 46) of subjects diagnosed with major depression, bipolar disorder and schizophrenia with those in normal controls without a psychiatric history. No correlation was found regarding neuropeptide Y mRNA expression and postmortem interval, age, gender, hemisphere side, suicide as cause of death, or the history of use of substances such as alcohol, marihuana and cocaine/amphetamine. The only significant alteration found was related to the clinical diagnosis; neuropeptide Y mRNA expression was reduced in the group of bipolar subjects as compared to the controls. Overall, the present results confirm an involvement of neuropeptide Y in affective disorders, and show for the first time a specific association between NPY and bipolar disorder." [Abstract]

Andreopoulos S, Li PP, Siu KP, Kish SJ, Warsh JJ.
Altered CTX-catalyzed and endogenous [32P]ADP-ribosylation of stimulatory G protein alphas isoforms in postmortem bipolar affective disorder temporal cortex.
J Neurosci Res. 2003 Jun 1;72(5):638-45.
"Reports of elevated Gs alpha subunit (alpha(s)) immunolabeling and cAMP-mediated hyper-functionality in autopsied cerebral cortical brain regions from bipolar affective disorder (BD) patients suggest signal transduction abnormalities occur in this disorder. Because covalent modification of alpha(s) can affect its turnover and levels, we determined whether CTX-catalyzed and endogenous [(32)P] adenosine diphosphate (ADP)-ribosylation of alpha(s) isoforms are altered in temporal and occipital cortical regions, which show elevated alpha(s) levels in BD as compared to nonpsychiatric subjects. Reduced CTX-catalyzed [(32)P]ADP-ribosylated alpha(s-S) and endogenous [(32)P]ADP-ribosylation of a 39-kDa alpha(s)-like protein were found in BD temporal cortex compared to controls. These findings suggest that clearance of these alpha(s) isoforms through ADP-ribosylation may be decreased in BD temporal cortex. Although no differences were observed in mean levels of endogenous and CTX-catalyzed [(32)P]ADP-ribosylation of alpha(s-L) in BD temporal cortex, alpha(s-L) immunolabeling was elevated significantly and correlated inversely with the degree of endogenous [(32)P]ADP-ribosylation of this subunit. In addition, endogenous [(32)P]ADP-ribosylation of an exogenous substrate, myelin basic protein, was similar in BD and comparison subject temporal cortex. Taken together, these observations suggest that elevations of alpha(s) in BD brain are more likely related to factors affecting the disposition or availability of alpha(s) to this posttranslational enzymatic modification." [Abstract]

Dowlatshahi, Dar, MacQueen, Glenda M., Wang, Jun-Feng, Reiach, James S., Young, L. Trevor
G Protein-Coupled Cyclic AMP Signaling in Postmortem Brain of Subjects with Mood Disorders: Effects of Diagnosis, Suicide, and Treatment at the Time of Death
J Neurochem 1999 73: 1121-1126
"Components of cyclic AMP (cAMP) signaling were examined in postmortem cerebral cortex of a well characterized group of patients with mood disorders and nonpsychiatric control subjects. We measured G protein levels, adenylyl cyclase (AC) activity, and CREB levels in cerebral cortex of the subjects with respect to diagnosis, treatment, and suicide. There was no effect of diagnosis on any measure, except for a trend toward decreased stimulated AC activity in subjects with mood disorders relative to control subjects. We also detected a significant effect of suicide on temporal cortex CREB levels in subjects that died as a result of suicide relative to those that did not, which was more evident in patients with major depressive disorder. Bipolar disorder (BD) subjects treated with anticonvulsants at the time of death had decreased temporal cortex CREB levels relative to those not receiving anticonvulsants. Furthermore, we found a trend toward decreased occipital cortex G alpha(s) (short) levels in BD subjects treated with lithium. These results support the hypothesis of altered cAMP signaling in mood disorders and raise the possibility that factors other than diagnosis, such as treatment and suicide, may be relevant to cell-signaling abnormalities reported in the literature." [Abstract]

Drevets WC.
Prefrontal cortical-amygdalar metabolism in major depression.
Ann N Y Acad Sci 1999 Jun 29;877:614-37
"Functional neuroimaging studies of the anatomical correlates of familial major depressive disorder (MDD) and bipolar disorder (BD) have identified abnormalities of resting blood flow (BF) and glucose metabolism in depression in the amygdala and the orbital and medial prefrontal cortical (PFC) areas that are extensively connected with the amygdala. The amygdala metabolism in MDD and BD is positively correlated with both depression severity and "stressed" plasma cortisol concentrations measured during scanning. During antidepressant drug treatment, the mean amygdala metabolism decreases in treatment responders, and the persistence of elevated amygdala metabolism during remission is associated with a high risk for the development of depressive relapse. The orbital C metabolism is also abnormally elevated during depression, but is negatively correlated with both depression severity and amygdala metabolism, suggesting that this structure may be activated as a compensatory mechanism to modulate amygdala activity or amygdala-driven emotional responses. The posterior orbital C and anterior cingulate C ventral to the genu of the corpus callosum (subgenual PFC) have more recently been shown in morphometric MRI and/or post mortem histopathological studies to have reduced grey matter volume and reduced glial cell numbers (with no equivalent loss of neurons) in familial MDD and BD. These data suggest a neural model in which dysfunction of limbic PFC structures impairs the modulation of the amygdala, leading to abnormal processing of emotional stimuli." [Abstract]

Brambilla P, Nicoletti MA, Sassi RB, Mallinger AG, Frank E, Kupfer DJ, Keshavan MS, Soares JC.
Magnetic resonance imaging study of corpus callosum abnormalities in patients with bipolar disorder.
Biol Psychiatry. 2003 Dec 1;54(11):1294-7.
"BACKGROUND: This study was conducted to further examine the hypothesis of abnormalities in size of corpus callosum in subjects with bipolar disorder. METHODS: Sixteen right-handed DSM-IV bipolar I patients and 27 right-handed healthy control subjects were studied. A 1.5-T GE Signa magnet was used, and three-dimensional gradient echo imaging (spoiled gradient recall acquisition) was conducted. Area measurements of corpus callosum were obtained blindly, with a semi-automated software, by a well-trained rater. RESULTS: Right-handed bipolar I patients had significantly smaller total corpus callosum, genu, posterior body, and isthmus areas compared with right-handed healthy control subjects (analysis of covariance with age, gender, and intracranial volume as covariates, p <.05). Partial correlation analyses, controlled for intracranial volumes, found a significant inverse relationship between age and total callosal, genu, anterior body, isthmus, and circularity in healthy control subjects (p <.05) but not in bipolar patients (p >.05). CONCLUSIONS:Smaller callosal areas may lead to altered inter-hemispheric communication and be involved in the pathophysiology and cognitive impairment found in bipolar disorder." [Abstract]

Small JG, Milstein V, Malloy FW, Medlock CE, Klapper MH.
Clinical and quantitative EEG studies of mania.
J Affect Disord 1999 Jun;53(3):217-24
"BACKGROUND: Earlier EEG studies reported essentially normal findings during acute manic episodes but some atypical EEG characteristics and distinctions between familial and sporadic cases were described. Recently quantitative EEG (qEEG) studies differentiating mania from schizophrenia and depression have been published. METHODS: Clinical EEGs were obtained in 202 patients hospitalized for acute mania. EEGs were repeated in 75 patients rehospitalized for subsequent manic attacks. Quantitative EEGs were recorded in 37 patients who were able to cooperate after drug washout and again on completion of randomly assigned pharmacotherapy. RESULTS: Normal EEGs were obtained in most patients. Moderately abnormal EEGs in 16% were significantly associated with absent family histories of affective disorder. Left sided abnormalities were more common than right. "Small sharp spikes" and "microsleep" were encountered in 17% and 10% respectively of patients who drowsed. EEG findings during subsequent episodes did not suggest increasing CNS vulnerability. qEEGs showed significant differences between each of the therapeutic agents compared-lithium, carbamazepine, and lithium combined with carbamazepine, haloperidol or risperidone. Nonresponders at baseline had significantly more diffuse theta activity than responders. During pharmacotherapy nonresponders had higher amplitudes in the left temporoparietal areas. LIMITATION: Clinical EEG findings confirmed previous reports but did not contain original observations. Applications of qEEG were limited by requirements for patient cooperation." [Abstract]

Velayudhan A, Sunitha TA, Balachander S, Reddy JY, Khanna S.
A study of platelet serotonin receptor in mania.
Biol Psychiatry 1999 Apr 15;45(8):1059-62
"BACKGROUND: Serotonergic (5-HT) dysfunction has been hypothesized in mania; however platelet studies on the 5-HT uptake rate and the 5-HT transporter have revealed inconsistent results. To the best of our knowledge no studies have been conducted on the 5-HT2 receptor status in mania. METHODS: We determined density (Bmax) and dissociation constant (Kd) of 5-HT2 receptors in the platelets of 29 normal control and 29 manic subjects using 125I-ketanserin as the binding radioligand. The manic patients were assessed for the same after 14 days of treatment with lithium (n = 14) and after return to premorbid levels of functioning (n = 5). RESULTS: There were no significant differences in the Bmax (3.51 +/- 3.04 vs. 3.14 +/- 3.44 fmol/mg protein, p = ms) values between normal control and manic subjects. In comparison to the baseline values Bmax at day 14 (3.49 +/- 3.68 vs. 2.18 +/- 1.90 fmol/mg protein, p = ns) and following recovery (1.17 +/- 0.85 vs. 1.29 +/- 1.13 fmol/mg protein, p = ns) did not show any significant difference. CONCLUSIONS: Our findings preliminarily suggest that the platelet 5-HT2 receptor is neither a state marker nor a trait marker in mania; however studies on the 5-HT2 receptor using positron-emission tomography ligands will help in conclusively ruling out the involvement of this receptor in mania." [Abstract]

Swann AC, Katz MM, Bowden CL, Berman NG, Stokes PE.
Psychomotor performance and monoamine function in bipolar and unipolar affective disorders.
Biol Psychiatry 1999 Apr 15;45(8):979-88
"BACKGROUND: Affective disorders are associated with prominent psychomotor abnormalities that may be related to changes in arousal or motivation due to altered catecholamine function. METHODS: We investigated relationships between performance on psychomotor tests of motor speed (reaction time and tapping speed) and visual tracking (trail making and dot placement) and catecholamine system function including cerebrospinal fluid (CSF) or urinary concentrations of catecholamines or their metabolites. Subjects were medicine-free inpatients with unipolar depression or with manic, depressive, or mixed episodes of bipolar disorder, and healthy controls matched by gender and stratified by age. RESULTS: Unipolar and bipolar depressed patients were impaired in motor speed, dexterity, and visual tracking, whereas manic and mixed patients did not differ from controls. Tapping speed correlated positively with CSF 3-methoxy-4-hydroxyphenylglycol in healthy controls and with CSF homovanillic acid in bipolar depressed subjects. Increased catecholamine function correlated with slowing in all other measures for patients with bipolar disorder. Relationships between catecholamines and psychomotor function were weaker in unipolar depressed subjects. Psychomotor function was related to severity of depression in bipolar, but not in unipolar, patients. CONCLUSIONS: These data suggest that catecholamine systems are associated with increased arousal and psychomotor impairment in patients with bipolar disorder. Similar behavioral changes have different neurotransmitter relationships in unipolar disorder." [Abstract]

Anand A, Darnell A, Miller HL, Berman RM, Cappiello A, Oren DA, Woods SW, Charney DS.
Effect of catecholamine depletion on lithium-induced long-term remission of bipolar disorder.
Biol Psychiatry 1999 Apr 15;45(8):972-8
"BACKGROUND: This study investigated the effects of catecholamine depletion with alpha-methylparatyrosine (AMPT) on mood indices in patients with bipolar disorder who were in long-term remission with lithium therapy. METHODS: Eight subjects with DSM-IV bipolar disorder currently in remission for > 3 months on lithium were included in the study. Subjects were given either AMPT or placebo, in a randomized double-blind manner, in two test sessions of 4 days each. RESULTS: Subjects did not have any significant changes in mood during AMPT or placebo administration; however, 24-48 hours after the last active AMPT dose subjects had a transient relapse of hypomanic symptoms. Relapse of hypomanic symptoms did not correlate with increases in serum levels of homovanillic acid or 3-methoxy-4-hydroxyphenylglycol. CONCLUSIONS: These findings suggest that the mechanism of prevention of manic relapse by long-term lithium therapy may be dependent on stability of the catecholamine system." [Abstract]

Koek RJ, Yerevanian BI, Tachiki KH, Smith JC, Alcock J, Kopelowicz A.
Hemispheric asymmetry in depression and mania. A longitudinal QEEG study in bipolar disorder.
J Affect Disord 1999 May;53(2):109-22
"BACKGROUND: previous research has been inconclusive about the nature of hemispheric asymmetry in emotional processing. METHOD: 13 patients with DSM-IV bipolar disorder received repeated QEEGs over 2 years in different mood states. Z-score measures of asymmetry were assessed. RESULTS: asymmetry in frontotemporal slow-wave activity appeared to be in opposite directions in depression compared to mania/hypomania. CONCLUSIONS: mood change in bipolar disorder is associated with change in QEEG asymmetry. LIMITATIONS: study of larger numbers of more homogenous patients under similar conditions is needed. CLINICAL RELEVANCE: study of mood state-dependent asymmetry changes in bipolar disorder may lead to better understanding of hemispheric processing of emotion." [Abstract]

Helmkamp CE, Bigelow LB, Paltan-Ortiz JD, Torrey EF, Kleinman JE, Herman MM.
Evaluation of superior vermal Purkinje cell placement in mental illness.
Biol Psychiatry 1999 May 15;45(10):1370-5
"BACKGROUND: A number of neuroimaging and neuropathological studies have reported abnormalities in the cerebellar vermis in schizophrenia and bipolar disorder. In an effort to further understand vermal abnormalities in mental illness, we have analyzed ectopic placement of Purkinje-like cells. METHODS: The superior cerebellar vermis was evaluated in 39 cases of severe mental illness [schizophrenia (n = 12), bipolar disease (n = 12), and depression (n = 15)]. We also examined 9 subjects with polysubstance abuse and 15 normal controls. All normally placed Purkinje cells and displaced Purkinje-like cells (i.e., in the internal granule layer and intrafoliar white matter) were counted in the same foliar field. The ratio of displaced Purkinje-like cells to total Purkinje cells and Purkinje cell density were calculated. RESULTS: No significant difference in the ratio of displaced to normally placed Purkinje cells or in Purkinje cell density between groups of subjects was found. CONCLUSIONS: Our study does not support a hypothesis of abnormalities of Purkinje cell migration or other events related to their displacement as a basis for the vermal abnormalities reported previously in schizophrenia and bipolar disorder." [Abstract]

Loeber RT, Sherwood AR, Renshaw PF, Cohen BM, Yurgelun-Todd DA.
Differences in cerebellar blood volume in schizophrenia and bipolar disorder.
Schizophr Res 1999 May 4;37(1):81-9
"Brain morphometry has been studied extensively in schizophrenic patients, and among the cortical differences identified two consistent findings are decreased cerebellar vermal volume and increased volume of the fourth ventricle; although contradictory findings are reported as well. Recent cognitive activation studies utilizing PET, SPECT and fMRI have identified both decreased and increased activation in the cerebellum of schizophrenic patients compared with healthy controls. This study used DSC fMRI to map cerebellar blood volume in patients with schizophrenia or bipolar disorder and healthy controls. For all cerebellar regions analyzed, schizophrenic patients had the highest cerebellar blood volume, while bipolars had the lowest blood volume. Morphometric measurements were completed and indicated that the ratio of vermis to whole CBL tissue volume was 24% less for the schizophrenic population than controls, whereas the subjects with bipolar disorder had a ratio that was non-significantly smaller than controls by 19%. Comparison of morphometric data with blood volume data did not reveal any statistically significant correlations among the study groups." [Abstract]

Wang HY, Markowitz P, Levinson D, Undie AS, Friedman E.
Increased membrane-associated protein kinase C activity and translocation in blood platelets from bipolar affective disorder patients.
J Psychiatr Res 1999 Mar-Apr;33(2):171-9
"BACKGROUND: recent investigations have suggested that the phosphoinositide (PI) signal transduction system may be involved in the pathophysiology of bipolar affective disorders. Earlier studies in our laboratory have implicated altered PKC-mediated phosphorylation in bipolar affective disorder and in the clinical action of lithium. In the present study, we compared PKC activity and its translocation in platelets from subjects with bipolar affective disorder and three other groups. METHODS: subjects included 44 with bipolar disorder (acute manic episode), 25 with acute major depression, 23 with schizophrenia in acute exacerbation and 43 controls free of personal or family history of an Axis I disorder. Blood platelet membrane and cytosol PKC activity was measured before and after in vitro stimulation with serotonin (5-HT), thrombin and the direct PKC activator, PMA. In addition, we examined 5-HT-, thrombin- and PMA-elicited translocations of PKC isozymes from cytosol to the membrane in platelets of control subjects. RESULTS: in the basal state, manic subjects demonstrated higher membrane PKC activity than depressive and control subjects. The ratio of membrane to cytosol PKC activity was significantly higher in manic (1.10), as compared to control (0.84), depressed (0.93) or schizophrenic (0.93) subjects. Stimulation of platelets with 5-HT in vitro, resulted in greater membrane to cytosol ratio in the manic subjects compared to the three other groups. The responsiveness of platelets to PMA and thrombin was greater for manic subjects than for depressed and schizophrenic subjects, but not greater than the controls. In this measure both the schizophrenic and depressive groups were less active than controls. The results also demonstrate that platelets contain alpha-, beta-, delta- and zeta-PKC isozymes. While alpha- and beta-PKC isoforms were translocated from cytosol to membrane in response to serotonin, PMA and thrombin, serotonin also elicited the redistribution of delta-PKC and thrombin also activated zeta-PKC. CONCLUSION: the results demonstrate that a heightened PKC-mediated signal transduction is associated with acute mania and suggest a decreased transduction in patients with unipolar depression or schizophrenia." [Abstract]

Strakowski SM, DelBello MP, Sax KW, Zimmerman ME, Shear PK, Hawkins JM, Larson ER.
Brain magnetic resonance imaging of structural abnormalities in bipolar disorder.
Arch Gen Psychiatry 1999 Mar;56(3):254-60
"BACKGROUND: The neuropathogenesis of bipolar disorder remains poorly described. Previous work suggests that patients with bipolar disorder may have abnormalities in neural pathways that are hypothesized to modulate human mood states. We examined differences in brain structural volumes associated with these pathways between patients with bipolar disorder hospitalized with mania and healthy community volunteers. METHODS: Twenty-four patients with bipolar disorder and mania were recruited from hospital admission records. Twenty-two healthy volunteers were recruited from the community who were similar to the patients in age, sex, race, height, handedness, and education. All subjects were scanned using a 3-dimensional radio-frequency-spoiled Fourier acquired steady state acquisition sequence on a 1.5-T magnetic resonance imaging scanner. Scans were analyzed using commercial software. Prefrontal, thalamic, hippocampal, amygdala, pallidal, and striatal volumetric measurements were compared between the 2 groups. RESULTS: Patients with bipolar disorder demonstrated a significant (A = 0.64; F6,37 = 3.4; P = .009) overall difference in structural volumes in these regions compared with controls. In particular, the amygdala was enlarged in the patients. Brain structural volumes were not significantly associated with duration of illness, prior medication exposure, number of previous hospital admissions, or duration of substance abuse. Separating patients into first-episode (n = 12) and multiple-episode (n = 12) subgroups revealed no significant differences in any structure (P>.10). CONCLUSION: Patients with bipolar disorder exhibit structural abnormalities in neural pathways thought to modulate human mood." [Abstract]

Spleiss O, van Calker D, Scharer L, Adamovic K, Berger M, Gebicke-Haerter PJ.
Abnormal G protein alpha(s) - and alpha(i2)-subunit mRNA expression in bipolar affective disorder.
Mol Psychiatry 1998 Nov;3(6):512-20
"Disturbances of events associated with intracellular signaling pathways have been suspected of involvement in the development or progression of affective disorders. Often, heterotrimeric G proteins are located at the beginning of these pathways as modulators of extracellular messages. For this reason, messenger RNA expression of three G protein alpha-subunits and of phosphatidylinositol-3 kinase (PI-3 K) regulatory subunit p85 was examined in granulocytes from patients with bipolar or unipolar affective disorder and compared to healthy controls. Messenger RNA expression of the G protein subunit alpha(q) and of p85 was identical in unipolar and bipolar patients and in controls. Furthermore, mRNAs of G protein subunits alpha(s) and alpha(i2) were not different in unipolar patients as compared to healthy controls. Alpha(s) mRNA, however, was markedly increased in bipolar patients. This increase was observed in lithium-treated (more than 12 months) and in unmedicated patients. Elevated levels of alpha(i2) mRNA in unmedicated bipolar patients did not reach statistical significance, whereas mRNA in bipolar patients receiving lithium was significantly above controls. Finally, long-term medication of unipolar patients with lithium had no influence on alpha(i2) mRNA levels. The data reveal elevated mRNA levels of G alpha(s) as a robust feature of bipolar affective disorder. Moreover, despite responsiveness of alpha(i2) gene expression to cAMP-related events, no substantial upregulation of alpha(i2) mRNA was observed in bipolar patients. The lack of alpha(i2) mRNA upregulation, hence, could be an additional abnormality in these patients. Even though lithium was able to reinstate this upregulation, there was no feedback downregulation of alpha(s). This strongly supports the notion of major disturbances of the cAMP signaling system in bipolar illness." [Abstract]

Rose AM, Mellett BJ, Valdes R Jr, Kleinman JE, Herman MM, Li R, el-Mallakh RS.
Alpha 2 isoform of the Na,K-adenosine triphosphatase is reduced in temporal cortex of bipolar individuals.
Biol Psychiatry 1998 Nov 1;44(9):892-7
"BACKGROUND: The pathophysiology of bipolar illness has been associated with changes in transmembrane ion flux and redistribution of biologically active ions. The recent identification of multiple isoforms of Na,K-adenosine triphosphatase (ATPase) alpha and beta subunits raises the possibility of altered pump isoform expression. METHODS: We determined Na,K-ATPase alpha subunit expression in postmortem temporal cortex gray matter from individuals suffering from bipolar disorder, schizoaffective disorder, schizophrenia, and matched normal controls. Quantification of isoform expression was accomplished via densitometric scanning of Western blots utilizing isoform-specific antibodies. RESULTS: Bipolar individuals exhibited a significant reduction in the abundance of the alpha 2 isoform of Na,K-ATPase compared to normal controls. Schizophrenic and schizo-affective brains were not significantly different from normal controls. CONCLUSION: These data suggest that previously observed abnormalities in regulation and distribution of ions in bipolar illness may be related to specific alpha 2 dysregulation." [Abstract]

Dost Öngür, Wayne C. Drevets, and Joseph L. Price
Glial reduction in the subgenual prefrontal cortex in mood disorders
PNAS 95: 13290-13295, 1998.
"Mood disorders are among the most common neuropsychiatric illnesses, yet little is known about their neurobiology. Recent neuroimaging studies have found that the volume of the subgenual part of Brodmann's area 24 (sg24) is reduced in familial forms of major depressive disorder (MDD) and bipolar disorder (BD). In this histological study, we used unbiased stereological techniques to examine the cellular composition of area sg24 in two different sets of brains. There was no change in the number or size of neurons in area sg24 in mood disorders. In contrast, the numbers of glia were reduced markedly in both MDD and BD. The reduction in glial number was most prominent in subgroups of subjects with familial MDD (24%, P = 0.01) or BD (41%, P = 0.01). The glial reduction in subjects without a clear family history was lower in magnitude and not statistically significant. Consistent with neuroimaging findings, cortical volume was reduced in area sg24 in subjects with familial mood disorders. Schizophrenic brains studied as psychiatric controls had normal neuronal and glial numbers and cortical volume. Glial and neuronal numbers also were counted in area 3b of the somatosensory cortex in the same group of brains and were normal in all psychiatric groups. Glia affect several processes, including regulation of extracellular potassium, glucose storage and metabolism, and glutamate uptake, all of which are crucial for normal neuronal activity. We thus have identified a biological marker associated with familial mood disorders that may provide important clues regarding the pathogenesis of these common psychiatric conditions." [Full Text]

Roy PD, Zipursky RB, Saint-Cyr JA, Bury A, Langevin R, Seeman MV.
Temporal horn enlargement is present in schizophrenia and bipolar disorder.
Biol Psychiatry 1998 Sep 15;44(6):418-22
"BACKGROUND: Ventricular enlargement and temporal lobe volume deficits have been demonstrated in patients with affective disorder as well as those with schizophrenia. This study compares quantitative measures of temporal lobe, hemispheric, and ventricular volumes in a group of patients with chronic schizophrenia and bipolar disorder and seeks to determine if the groups can be differentiated on the basis of measured brain abnormalities. METHODS: A series of coronal magnetic resonance imaging sections were acquired and analyzed for each of 22 patients with chronic schizophrenia, 14 patients with bipolar disorder, and 15 community volunteers. Eleven regions of interest for each brain were defined, which included temporal lobe, superior temporal gyrus, hemisphere, lateral ventricle, third ventricle, and temporal horn measures. Tissue measures were obtained by tracing, and cerebrospinal fluid measures were obtained by fluid-tissue thresholding using specialized computer software. RESULTS: Both patient groups had significantly larger temporal horn volumes in comparison with the control group both before and after correction for intracranial volume. The two patient groups did not differ from each other or controls on any other tissue or fluid measure. CONCLUSIONS: This study confirms the findings of increased temporal horn volume in patients with schizophrenia and suggests that this structural abnormality does not differentiate the structural neuropathology of schizophrenia from that of bipolar disorder." [Abstract]

Hasanah CI, Khan UA, Musalmah M, Razali SM.
Reduced red-cell folate in mania.
J Affect Disord 1997 Nov;46(2):95-9
"Forty-five hospitalised patients with DSM-III-R diagnosis of mania, were found to have a mean red-cell folate level of 193 nmol/l, as compared to 896 nmol/l in the control group (P < 0.00001). Assessment of serum folate in both groups showed no significant differences in the levels. Furthermore the manic patients and the controls were matched by the socio-economic status. This indicated that the reduced red-cell folate in mania is associated with the illness and not due to reduced absorption or dietary deficiency of folate. Considering previous studies that showed reduced red-cell folate in depression, our findings suggest that reduced red-cell folate occurred in both phases of bipolar disorders." [Abstract]

Dowlatshahi D, MacQueen G, Wang JF, Chen B, Young LT.
Increased hippocampal supragranular Timm staining in subjects with bipolar disorder.
Neuroreport 2000 Nov 27;11(17):3775-8
"Biochemical and structural abnormalities have been reported in hippocampus of subjects with mood disorders. This study examined the organization of mossy fibers in anterior hippocampus of subjects obtained from the Stanley Neuropathology Consortium. Frozen postmortem hippocampal sections from subjects with major depression, bipolar disorder, schizophrenia and non-psychiatric controls were stained using the Neo-Timm procedure, which selectively stains mossy fibers. Increased Timm staining in the supragranular layer was found in subjects with bipolar disorder relative to control subjects. These results are suggestive of neuronal sprouting in hippocampus of subjects with bipolar disorder. There were no significant associations between supragranular Timm staining and suicide, length illness or drug treatment at the time of death." [Abstract]

Castillo M, Kwock L, Courvoisie H, Hooper SR.
Proton MR spectroscopy in children with bipolar affective disorder: preliminary observations.
AJNR Am J Neuroradiol 2000 May;21(5):832-8
"BACKGROUND AND PURPOSE: Bipolar affective disorder (BPAD) can have its onset during childhood, but the diagnosis may be difficult to establish on the basis of clinical findings alone. Our purpose was to determine whether proton MR spectroscopy can be used to identify abnormalities in the brain of children with BPAD. METHODS: Ten children, ages 6 to 12 years, underwent clinical testing to establish the diagnosis of BPAD. After a drug washout period, all patients underwent MR spectroscopy in which a TE of 135 was used along with a single-voxel placement in both frontal and temporal lobes during a single session. Peaks from N-acetylaspartate (NAA), choline (Cho), glutamate/ glutamine (Glu/Gln), and lipids were normalized with respect to the creatine (Cr) peak to obtain ratios of values of peak areas. These data were compared with those obtained in 10 non-age-matched control subjects. To corroborate our data, five children with BPAD also underwent 2D MR spectroscopic studies of the frontal lobes with parameters similar to those used in the single-volume studies. RESULTS: All children with BPAD had elevated levels of Glu/Gln in both frontal lobes and basal ganglia relative to the control group. Children with BPAD had elevated lipid levels in the frontal lobes but not in the temporal lobes. Levels of NAA and Cho were similar for all locations in both groups. Two-dimensional MR spectroscopic studies in five children with BPAD confirmed the presence of elevated lipids in the frontal lobes. CONCLUSION: Our preliminary observations suggest that MR spectroscopy may show abnormalities in children with BPAD not found in unaffected control subjects. It remains to be established whether these abnormalities are a signature of the disease and can be used as a screening test." [Abstract]

Blumberg HP, Stern E, Ricketts S, Martinez D, de Asis J, White T, Epstein J, Isenberg N, McBride PA, Kemperman I, Emmerich S, Dhawan V, Eidelberg D, Kocsis JH, Silbersweig DA.
Rostral and orbital prefrontal cortex dysfunction in the manic state of bipolar disorder.
Am J Psychiatry 1999 Dec;156(12):1986-8
"OBJECTIVE: This study investigated prefrontal cortex function in the manic state of bipolar disorder. METHOD: High-sensitivity [15O]H2O positron emission tomography and a word generation activation paradigm were used to study regional cerebral blood flow in five manic and six euthymic individuals with bipolar disorder and in five healthy individuals. RESULTS: Decreased right rostral and orbital prefrontal cortex activation during word generation and decreased orbitofrontal activity during rest were associated with mania. CONCLUSIONS: The data support the presence of rostral and orbital prefrontal dysfunction in primary mania. These findings, when seen in the context of the human brain lesion and the behavioral neuroanatomic literatures, may help to explain some of the neurobehavioral abnormalities characteristic of the manic state." [Abstract]

Pearlson GD, Barta PE, Powers RE, Menon RR, Richards SS, Aylward EH, Federman EB, Chase GA, Petty RG, Tien AY.
Ziskind-Somerfeld Research Award 1996. Medial and superior temporal gyral volumes and cerebral asymmetry in schizophrenia versus bipolar disorder.
Biol Psychiatry 1997 Jan 1;41(1):1-14
"Prior magnetic resonance imaging (MRI) studies report both medial and lateral cortical temporal changes and disturbed temporal lobe asymmetries in schizophrenic patients compared with healthy controls. The specificity of temporal lobe (TL) changes in schizophrenia is unknown. We determined the occurrence and specificity of these TL changes. Forty-six schizophrenic patients were compared to 60 normal controls and 27 bipolar subjects on MRI measures of bilateral volumes of anterior and posterior superior temporal gyrus (STG), amygdala, entorhinal cortex, and multiple medial temporal structures, as well as global brain measures. Several regional comparisons distinguished schizophrenia from bipolar disorder. Entorhinal cortex, not previously assessed using MRI in schizophrenia, was bilaterally smaller than normal in schizophrenia but not in bipolar disorder. Schizophrenic but not bipolar patients had an alteration of normal posterior STG asymmetry. Additionally, left anterior STG and right amygdala were smaller than predicted in schizophrenia but not bipolar disorder. Left amygdala was smaller and right anterior STG larger in bipolar disorder but not schizophrenia." [Abstract]

Chiu CC, Huang SY, Su KP, Lu ML, Huang MC, Chen CC, Shen WW.
Polyunsaturated fatty acid deficit in patients with bipolar mania.
Eur Neuropsychopharmacol. 2003 Mar;13(2):99-103.
"The aim of this study is to test the hypothesis that there is a depletion of polyunsaturated fatty acids of erythrocyte membranes in patients with bipolar disorder and to connect the previous therapeutic and psychoimmunological findings. Fatty acid compositions of erythrocyte membranes in 20 bipolar manic patients and 20 healthy controls were analyzed by thin-layer chromatography and gas chromatography. The major finding was significantly reduced arachidonic acid (20:4n-6) and docosahexaenoic acid (22:6n-3) compositions in bipolar patients as compared to normal controls with P values of 0.000 and 0.002, respectively. There were no differences in total omega-3 and omega-6 polyunsaturated fatty acids. This abnormality may be related to the mechanisms of action of mood stabilizers and the previous findings on the abnormal psychoimmunology of patients with bipolar disorder. Larger sample sizes of medicated patients or drug-free manic, well-controlled designs on the diet and smoking, and fatty acid composition measurements during full remission after the index episode are warranted in future studies." [Abstract]

Tsai SY, Lee HC, Chen CC, Lee CH.
Plasma levels of soluble transferrin receptors and Clara cell protein (CC16) during bipolar mania and subsequent remission.
J Psychiatr Res. 2003 May-Jun;37(3):229-35.
"Clara cell protein (CC16) and transferrin receptor (TfR) have been reported as possible biological markers for major depression and schizophrenia. However, the alternations of plasma TfR and CC16 levels and the influences of numerous clinical variables on them during bipolar mania are not sufficiently described. We investigated the immune function of 36 bipolar I, manic (DSM-IV) patients with Young Mania Rating Scale (YMRS) scores > or =26 as well as during the subsequent remission (YMRS < or =12) and age- and sex- matched healthy controls. The plasma TfR levels were increased during acute mania along with subsequent remission and were independent of medication status, individual variations, clinical and erythrocyte variables. Among inflammatory parameters and haematological variables, the plasma TfR levels merely had significant and negative relationship with the percentage of monocyte in circulating leukocyte counts despite of elevated plasma soluble interleukin-2 receptors levels during bipolar mania. The plasma levels of CC16 of bipolar patients did not significantly alter during acute mania, whereas smoking, body mass index, and co-existing psychotic features collectively contributed 42% of the plasma levels of CC16. We provide additional evidence to indicate the pathophysiological role of the immune systems in affective disorders. It is suggested that the elevation of plasma TfR levels might be a trait phenomenon in bipolar disorder." [Abstract]

Huang TL.
Lower serum albumin levels in patients with mood disorders.
Chang Gung Med J 2002 Aug;25(8):509-13
"BACKGROUND: Some physicians have reported lower serum albumin levels in patients with major depression in Western countries. In this study, the relationship between serum albumin levels and mood disorders (including mania and major depression) was investigated during the acute phases in Taiwanese psychiatric inpatients. METHODS: A review of medical charts during a 1-year period was carried out in a population of 213 Taiwanese psychiatric inpatients that included 61 patients with mood disorders (with or without suicide attempts). The collected data included age, body weight, height, serum albumin levels, and routine blood biochemistry examination results. These data were compared with data from a healthy control group (N = 32) drawn from the staff of the psychiatric ward. Statistical analysis was done using covariance after age adjustment. RESULTS: The mean serum albumin levels were 40.2 +/- 4.0 g/L in patients with mania (N = 25), 39.8 +/- 2.8 g/L in patients with major depression (N = 36), and 45.8 +/- 2.0 g/L in the control group. Patients with mania (F = 64.6, p = 0.000) and major depression (F = 68.9, p = 0.000), respectively, had significantly lower albumin levels than the control group after age adjustment. However, for the patients with major depression, no significant difference in serum albumin levels were found between patients who had attempted suicide and those who had not. CONCLUSION: Lower serum albumin levels were noted during the acute phases of mania and major depression in Taiwanese psychiatric inpatients." [Abstract]

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Recent Bipolar Disorder Neuroanatomy Research

1) Lee B, Liu CY, Apuzzo ML
Quantum Computing: A Prime Modality in Neurosurgery's Future.
World Neurosurg. 2012 Jul 27;
OBJECTIVE: With each significant development in the field of neurosurgery, our dependence upon computers, small and large, has continuously increased. From something as mundane as bipolar cautery to sophisticated intraoperative navigation with real-time MRI-assisted surgical guidance, both technologies, however simple or complex, require computational processing power to function. The next frontier for neurosurgery involves developing a greater understanding of the brain and furthering our capabilities as surgeons to directly affect brain circuitry and function. METHODS: This has come in the form of implantable devices which can electronically and nondestructively influence the cortex and nuclei with the purpose of restoring neuronal function and improving quality of life. RESULTS: We are now transitioning from devices that are turned on and left alone, such as vagus nerve stimulators (VNS) and deep brain stimulators (DBS), to "smart" devices that can listen and react to the body as the situation may dictate. CONCLUSION: The development of quantum computers and their potential to be thousands, if not millions of times faster than current "classical" computers, will significantly affect the neurosciences, especially the field of neurorehabilitation and neuromodulation. Quantum computers may advance our understanding of the neural code, and in turn, better develop and program implantable neural devices. When quantum computers reach the point where we can actually implant such devices in patients, the possibilities of what can be done to interface and restore neural function will be limitless. [PubMed Citation] [Order full text from Infotrieve]

2) Spears DA, Suszko AM, Dalvi R, Crean A, Ivanov J, Nanthakumar K, Downar E, Chauhan VS
Relationship of Bipolar and Unipolar Electrogram Voltage to Scar Transmurality and Composition Derived by Magnetic Resonance Imaging in Patients with Nonischemic Cardiomyopathy undergoing VT Ablation.
Heart Rhythm. 2012 Jul 27;
BACKGROUND: Bipolar voltage mapping has a role in defining endocardial-based scar in postinfarct patients undergoing VT catheter ablation. The utility of bipolar and unipolar voltages in characterizing scar has not been evaluated in patients with nonischemic cardiomyopathy. OBJECTIVE: We sought to relate LV endocardial bipolar and unipolar voltages in these patients to scar transmurality (endocardial vs. nonendocardial) and composition (homogeneous core vs. heterogeneous gray). METHODS: Ten consecutive cardiomyopathy patients undergoing endocardial LV VT ablation were included (48±14yrs, LVEF 43±15%). Preablation late gadolinium-enhanced MRI (LGE-MRI) was used to quantify core and gray scar using signal-intensity thresholding. Electroanatomic LV endocardial mapping provided bipolar and unipolar voltages. Electroanatomic maps and LGE-MRI were rigidly registered in order to relate voltage to scar (registration error 3.6±2.9mm). RESULTS: Bipolar voltage was lower in endocardial core compared to no scar (p<0.001). Unipolar voltage was lower in endocardial core and nonendocardial core than no scar (p<0.001). Endocardial and nonendocardial gray scar had a similar effect to core in reducing bipolar and unipolar voltages (p<0.001). The mass of healthy myocardium, and endocardial core scar independently predicted bipolar and unipolar voltages using GEE modeling. With ROC analysis, bipolar voltage >1.9 mV and unipolar voltage <6.7 mV had a high negative predictive value (91%) for detecting nonendocardial scar from either endocardial scar or no scar. CONCLUSIONS: In patients with nonischemic cardiomyopathy, LV endocardial bipolar voltage is dependent on endocardial core and gray scar, while unipolar voltage is influenced by core and gray scar across the LV wall as defined by LGE-MRI. [PubMed Citation] [Order full text from Infotrieve]

3) Garrett AS, Reiss AL, Howe ME, Kelley RG, Singh MK, Adleman NE, Karchemskiy A, Chang KD
Abnormal amygdala and prefrontal cortex activation to facial expressions in pediatric bipolar disorder.
J Am Acad Child Adolesc Psychiatry. 2012 Aug;51(8):821-31.
[PubMed Citation] [Order full text from Infotrieve]

4) Sprooten E, McIntosh AM, Lawrie SM, Hall J, Sussmann JE, Dahmen N, Konrad A, Bastin ME, Winterer G
An investigation of a genomewide supported psychosis variant in ZNF804A and white matter integrity in the human brain.
Magn Reson Imaging. 2012 Jul 25;
ZNF804A, a genomewide supported susceptibility gene for schizophrenia and bipolar disorder, has been associated with task-independent functional connectivity between the left and right dorsolateral prefrontal cortices. Several lines of evidence have converged on the hypothesis that this effect may be mediated by structural connectivity. We tested this hypothesis using diffusion tensor magnetic resonance imaging in three samples: one German sample of 50 healthy individuals, one Scottish sample of 83 healthy individuals and one Scottish sample of 84 unaffected relatives of bipolar patients. Voxel-based analysis and tract-based spatial statistics did not detect any fractional anisotropy (FA) differences between minor allele carriers and individuals homozygous for the major allele at rs1344706. Similarly, region-of-interest analyses and quantitative tractography of the genu of the corpus callosum revealed no significant FA differences between the genotype groups. Examination of effect sizes and confidence intervals indicated that this negative finding is very unlikely to be due to a lack of statistical power. In summary, despite using various analysis techniques in three different samples, our results were strikingly and consistently negative. These data therefore suggest that it is unlikely that the effects of genetic variation at rs1344706 on functional connectivity are mediated by structural integrity differences in large, long-range white matter fiber connections. [PubMed Citation] [Order full text from Infotrieve]

5) Gigante AD, Bond DJ, Lafer B, Lam RW, Young LT, Yatham LN
Brain glutamate levels measured by magnetic resonance spectroscopy in patients with bipolar disorder: a meta-analysis.
Bipolar Disord. 2012 Aug;14(5):478-87.
Gigante AD, Bond DJ, Lafer B, Lam RW, Young LT, Yatham LN. Brain glutamate levels measured by magnetic resonance spectroscopy in patients with bipolar disorder: a meta-analysis. Bipolar Disord 2012: 14: 478-487. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives:? Bipolar disorder (BD) is a common and highly disabling disease characterized by substantial cognitive and functional impairment. The exact neurobiological mechanisms underlying the expression of symptoms in this condition remain unknown but there is growing evidence that glutamate might play an important role. Using proton magnetic resonance spectroscopy ((1) H-MRS), a number of studies have examined brain glutamate/glutamine levels in patients with bipolar disorder, but they have produced conflicting results. The objective of this paper was to conduct a systematic review and meta-analysis of the literature on brain glutamate/glutamine in BD as measured by (1) H-MRS. Methods:? A Medline search for the period January 1980-April 2010 was conducted to identify published studies that used (1) H-MRS to measure glutamate?+?glutamine (Glx), the Glx/creatine (Cr) ratio, glutamate (Glu), or the Glu/Cr ratio in any brain region in adult or child/adolescent patients with BD and healthy subjects. A meta-analysis of the pooled data was conducted. Results:? BD patients were found to have increased Glx compared to healthy subjects when all brain areas were combined. This finding remained true in medicated and non-medicated patients, and in frontal brain areas in adults. There was a non-significant trend (p?=?0.09) for an increase in whole-brain Glx/Cr and Glu in patients compared with healthy subjects. No significant difference was found in Glu/Cr. Conclusions:? The results of this meta-analysis suggest that brain Glx levels are elevated in BD patients and support the idea that glutamate might play an important role in the pathophysiology of BD. [PubMed Citation] [Order full text from Infotrieve]

6) Sarubbo S, Latini F, Sette E, Milani P, Granieri E, Fainardi E, Cavallo MA
Is the resection of gliomas in Wernicke's area reliable? : Wernicke's area resection.
Acta Neurochir (Wien). 2012 Jul 26;
Wernicke's area was, for a long time, considered a non-removable area and patients affected by low-grade gliomas (LGGs) or high-grade gliomas (HGGs) in this region were considered inoperable. Several studies have demonstrated a large functional reshaping of language networks in patients affected by gliomas or acute stroke involving Wernicke's territories, and the complete resection of this region invaded by LGG has recently been reported. We report our experience in the removal of Wernicke's territories invaded by gliomas. Four patients underwent awake surgery, with neuropsychological and neurophysiological monitoring and direct cortico-subcortical bipolar stimulation, for resection of LGG (one case) and HGGs (three cases) invading Wernicke's territories. Resection rates were evaluated by means of magnetic resonance imaging (MRI) and computed tomography (CT) perfusion for LGG and HGGs, respectively. HGGs were totally resected and LGG was partially resected (67%), according to functional limits. No patients reported neurological deficit. The patient affected by LGG underwent postoperative chemotherapy. Two of the patients harbouring HGGs died 21 and 23 months after surgery and postoperative adjuvant treatment, respectively. The third one is still alive and progression-free 21 months after surgery. Awake surgery is a reliable and effective technique for resection of gliomas invading Wernicke's territories without postoperative permanent deficit. LGGs in this region can safely be removed, according to the functional subcortical boundaries, allowing postoperative adjuvant treatment, functional reshaping and multi-step surgery. HGGs, instead, can be completely removed without deficits and sometimes beyond the contrast enhancement area, allowing the best possible oncological prognosis for the patients. [PubMed Citation] [Order full text from Infotrieve]

7) Morris RW, Sparks A, Mitchell PB, Weickert CS, Green MJ
Lack of cortico-limbic coupling in bipolar disorder and schizophrenia during emotion regulation.
Transl Psychiatry. 2012 Feb 21;2:e90.
Bipolar disorder (BD) and schizophrenia (Sz) share dysfunction in prefrontal inhibitory brain systems, yet exhibit distinct forms of affective disturbance. We aimed to distinguish these disorders on the basis of differential activation in cortico-limbic pathways during voluntary emotion regulation. Patients with DSM-IV diagnosed Sz (12) or BD-I (13) and 15 healthy control (HC) participants performed a well-established emotion regulation task while undergoing functional magnetic resonance imaging. The task required participants to voluntarily upregulate or downregulate their subjective affect while viewing emotionally negative images or maintain their affective response as a comparison condition. In BD, abnormal overactivity (hyperactivation) occurred in the right ventrolateral prefrontal cortex (VLPFC) during up- and downregulation of negative affect, relative to HC. Among Sz, prefrontal hypoactivation of the right VLPFC occurred during downregulation (opposite to BD), whereas upregulation elicited hyperactivity in the right VLPFC similar to BD. Amygdala activity was significantly related to subjective negative affect in HC and BD, but not Sz. Furthermore, amygdala activity was inversely coupled with the activity in the left PFC during downregulation in HC (r=-0.76), while such coupling did not occur in BD or Sz. These preliminary results indicate that differential cortico-limbic activation can distinguish the clinical groups in line with affective disturbance: BD is characterized by ineffective cortical control over limbic regions during emotion regulation, while Sz is characterized by an apparent failure to engage cortical (hypofrontality) and limbic regions during downregulation. [PubMed Citation] [Order full text from Infotrieve]

8) Latapy C, Rioux V, Guitton MJ, Beaulieu JM
Selective deletion of forebrain glycogen synthase kinase 3β reveals a central role in serotonin-sensitive anxiety and social behaviour.
Philos Trans R Soc Lond B Biol Sci. 2012 Sep 5;367(1601):2460-74.
Serotonin (5-HT) neurotransmission is thought to underlie mental illnesses, such as bipolar disorder, depression, autism and schizophrenia. Independent studies have indicated that 5-HT or drugs acting on 5-HT neurotransmission regulate the serine/threonine kinase glycogen synthase kinase 3? (GSK3?). Furthermore, GSK3? inhibition rescues behavioural abnormalities in 5-HT-deficient mice with a loss-of-function mutation equivalent to the human variant (R441H) of tryptophan hydroxylase 2. In an effort to define neuroanatomical correlates of GSK3? activity in the regulation of behaviour, we generated CamKIIcre-floxGSK3? mice in which the gsk3b gene is postnatally inactivated in forebrain pyramidal neurons. Behavioural characterization showed that suppression of GSK3? in these brain areas has anxiolytic and pro-social effects. However, while a global reduction of GSK2? expression reduced responsiveness to amphetamine and increased resilience to social defeat, these behavioural effects were not found in CamKIIcre-floxGSK3? mice. These findings demonstrate a dissociation of behavioural effects related to GSK3 inhibition, with forebrain GSK3? being involved in the regulation of anxiety and sociability while social preference, resilience and responsiveness to psychostimulants would involve a function of this kinase in subcortical areas such as the hippocampus and striatum. [PubMed Citation] [Order full text from Infotrieve]

9) Hajek T, Cullis J, Novak T, Kopecek M, Blagdon R, Propper L, Stopkova P, Duffy A, Hoschl C, Uher R, Paus T, Young LT, Alda M
Brain Structural Signature of Familial Predisposition for Bipolar Disorder: Replicable Evidence For Involvement of the Right Inferior Frontal Gyrus.
Biol Psychiatry. 2012 Jul 19;
BACKGROUND: To translate our knowledge about neuroanatomy of bipolar disorder (BD) into a diagnostic tool, it is necessary to identify the neural signature of predisposition for BD and separate it from effects of long-standing illness and treatment. Thus, we examined the associations among genetic risk, illness burden, lithium treatment, and brain structure in BD. METHODS: This is a two-center, replication-design, structural magnetic resonance imaging study. First, we investigated neuroanatomic markers of familial predisposition by comparing 50 unaffected and 36 affected relatives of BD probands as well as 49 control subjects using modulated voxel-based morphometry. Second, we investigated effects of long-standing illness and treatment on the identified markers in 19 young participants early in the course of BD, 29 subjects with substantial burden of long-lasting BD and either minimal lifetime (n = 12), or long-term ongoing (n = 17) lithium treatment. RESULTS: Five groups, including the unaffected and affected relatives of BD probands from each center as well as participants early in the course of BD showed larger right inferior frontal gyrus (rIFG) volumes than control subjects (corrected p < .001). The rIFG volume correlated negatively with illness duration (corrected p < .01) and, relative to the controls, was smaller among BD individuals with long-term illness burden and minimal lifetime lithium exposure (corrected p < .001). Li-treated subjects had normal rIFG volumes despite substantial illness burden. CONCLUSIONS: Brain structural changes in BD may result from interplay between illness burden and compensatory processes, which may be enhanced by lithium treatment. The rIFG volume could aid in identification of subjects at risk for BD even before any behavioral manifestations. [PubMed Citation] [Order full text from Infotrieve]

10) Shi XF, Kondo DG, Sung YH, Hellem TL, Fiedler KK, Jeong EK, Huber RS, Renshaw PF
Frontal lobe bioenergetic metabolism in depressed adolescents with bipolar disorder: a phosphorus-31 magnetic resonance spectroscopy study.
Bipolar Disord. 2012 Jul 20;
Shi X-F, Kondo DG, Sung Y-H, Hellem TL, Fiedler KK, Jeong E-K, Huber RS, Renshaw PF. Frontal lobe bioenergetic metabolism in depressed adolescents with bipolar disorder: a phosphorus-31 magnetic resonance spectroscopy study. Bipolar Disord 2012: 00: 000-000. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives:? To compare the concentrations of high-energy phosphorus metabolites associated with mitochondrial function in the frontal lobe of depressed adolescents with bipolar disorder (BD) and healthy controls (HC). Methods:? We used in vivo phosphorus-31 magnetic resonance spectroscopy ((31) P-MRS) at 3 Tesla to measure phosphocreatine (PCr), beta-nucleoside triphosphate (?-NTP), inorganic phosphate (Pi), and other neurometabolites in the frontal lobe of eight unmedicated and six medicated adolescents with bipolar depression and 24 adolescent HCs. Results:? Analysis of covariance, including age as a covariate, revealed differences in PCr (p?=?0.037), Pi (p?=?0.017), and PCr/Pi (p?=?0.002) between participant groups. Percentage neurochemical differences were calculated with respect to mean metabolite concentrations in the HC group. Post-hoc Tukey-Kramer analysis showed that unmedicated BD participants had decreased Pi compared with both HC (17%; p?=?0.038) and medicated BD (24%; p?=?0.022). The unmedicated BD group had increased PCr compared with medicated BD (11%; p?=?0.032). The PCr/Pi ratio was increased in unmedicated BD compared with HC (24%; p?=?0.013) and with medicated BD (39%; p?=?0.002). No differences in ?-NTP or pH were observed. Conclusions:? Our results support the view that frontal lobe mitochondrial function is altered in adolescent BD and may have implications for the use of Pi as a biomarker. These findings join volumetric studies of the amygdala, and proton MRS studies of n-acetyl aspartate in pointing to potential differences in neurobiology between pediatric and adult BD. [PubMed Citation] [Order full text from Infotrieve]

11) Kähler AK, Rimol LM, Brown AA, Djurovic S, Hartberg CB, Melle I, Dale AM, Andreassen OA, Agartz I
Effect of DISC1 SNPs on brain structure in healthy controls and patients with a history of psychosis.
Am J Med Genet B Neuropsychiatr Genet. 2012 Jul 19;
Disrupted-in-Schizophrenia-1 (DISC1) has been suggested as a susceptibility locus for a broad spectrum of psychiatric disorders. Risk variants have been associated with brain structural changes, which overlap alterations reported in schizophrenia and bipolar disorder patients. We used genome-wide genotyping data for a Norwegian sample of healthy controls (n?=?171) and patients with a history of psychosis (n?=?184), to investigate 61 SNPs in the DISC1 region for putative association with structural magnetic resonance imaging (sMRI) measures (hippocampal volume; mean cortical thickness; and total surface area, as well as cortical thickness and area divided into four lobar measures). SNP rs821589 was associated with mean temporal and total brain cortical thickness in controls (P(adjusted) ?=?0.009 and 0.02, respectively), but not in patients. SNPs rs11122319 and rs1417584 were associated with mean temporal cortical thickness in patients (P(adjusted) ?=?0.04 and 0.03, respectively), but not in controls, and both SNPs have previously been highly associated with DISC1 gene expression. There were significant genotype?×? case-control interactions. There was no significant association between SNPs and cortical area or hippocampal volume in controls, or with any of the structural measures in cases, after correction for multiple comparisons. In conclusion, DISC1 SNPs might impact brain structural variation, possibly differently in psychosis patients versus controls, but independent replication will be needed to confirm our findings. © 2012 Wiley Periodicals, Inc. [PubMed Citation] [Order full text from Infotrieve]

12) Colombo RR, Schaufelberger MS, Santos LC, Duran FL, Menezes PR, Scazufca M, Busatto GF, Zanetti MV
Voxelwise evaluation of white matter volumes in first-episode psychosis.
Psychiatry Res. 2012 Jul 15;
The occurrence of white matter (WM) abnormalities in psychotic disorders has been suggested by several studies investigating brain pathology and diffusion tensor measures, but evidence assessing regional WM morphometry is still scarce and conflicting. In the present study, 122 individuals with first-episode psychosis (FEP) (62 fulfilling criteria for schizophrenia/schizophreniform disorder, 26 psychotic bipolar I disorder, and 20 psychotic major depressive disorder) underwent magnetic resonance imaging, as well as 94 epidemiologically recruited controls. Images were processed with the Statistical Parametric Mapping (SPM2) package, and voxel-based morphometry was used to compare groups (t-test) and subgroups (ANOVA). Initially, no regional WM abnormalities were observed when both groups (overall FEP group versus controls) and subgroups (i.e., schizophrenia/schizophreniform, psychotic bipolar I disorder, psychotic depression, and controls) were compared. However, when the voxelwise analyses were repeated excluding subjects with comorbid substance abuse or dependence, the resulting statistical maps revealed a focal volumetric reduction in right frontal WM, corresponding to the right middle frontal gyral WM/third subcomponent of the superior longitudinal fasciculus, in subjects with schizophrenia/schizophreniform disorder (n=40) relative to controls (n=89). Our results suggest that schizophrenia/schizophreniform disorder is associated with right frontal WM volume decrease at an early course of the illness. [PubMed Citation] [Order full text from Infotrieve]

13) Schneider MR, Adler CM, Whitsel R, Weber W, Mills NP, Bitter SM, Eliassen J, Strakowski SM, Delbello MP
The effects of ziprasidone on prefrontal and amygdalar activation in manic youth with bipolar disorder.
Isr J Psychiatry Relat Sci. 2012;49(2):112-20.
Background: Prior research has found that manic adolescents with bipolar disorder exhibit neurofunctional changes in the amygdala and prefrontal cortex following treatment with some pharmacological agents. We examined the neurofunctional effects of ziprasidone in manic adolescents. Method: Manic adolescents with bipolar disorder (n=23) participated in a placebo-controlled study of ziprasidone and underwent a functional magnetic resonance imaging scanning session while performing a task of sustained attention at baseline, prior to treatment as well as on days 7 and 28 (or early termination) of treatment. A comparison group of healthy adolescents (n=10) participated in a single scanning session. Region of interest analyses were performed to assess activation changes associated with treatment in Brodmann Areas (BA) 10, 11 and 47 and in the amygdala. Results: Compared with placebo, treatment with ziprasidone was associated with greater increases over time in right BA 11 and 47 activation. These effects were not associated with differences in symptom improvement between the treatment groups. Patients who subsequently responded to ziprasidone showed significantly greater deactivation in the right Brodmann area 47 at baseline than those who did not respond to ziprasidone. Similarly, among the bipolar adolescents who were treated with ziprasidone, baseline activation in right BA 47 was negatively correlated with improvement in Young Mania Rating Scale (YMRS) score. Limitations: The small sample size limits the ability to detect significant group differences in other regions of interest. Healthy comparison subjects were scanned only at a single timepoint, which limits the interpretation of the results. Ziprasidone is not currently approved by the United States Food and Drug Administration for the treatment of adolescents with mania, and, therefore, the clinical relevance of these results is limited. Conclusions: The increases in right BA 11 and 47 activation observed during sustained attention tasks following ziprasidone treatment and the association identified between lower baseline BA 47 activation and ziprasidone treatment response suggests that ziprasidone may correct prefrontal dysfunction in manic adolescents with bipolar disorder. [PubMed Citation] [Order full text from Infotrieve]

14) Vizueta N, Rudie JD, Townsend JD, Torrisi S, Moody TD, Bookheimer SY, Altshuler LL
Regional fMRI Hypoactivation and Altered Functional Connectivity During Emotion Processing in Nonmedicated Depressed Patients With Bipolar II Disorder.
Am J Psychiatry. 2012 Jul 6;
OBJECTIVE: Although the amygdala and ventrolateral prefrontal cortex have been implicated in the pathophysiology of bipolar I disorder, the neural mechanisms underlying bipolar II disorder remain unknown. The authors examined neural activity in response to negative emotional faces during an emotion perception task that reliably activates emotion regulatory regions. METHOD: Twenty-one nonmedicated depressed bipolar II patients and 21 healthy comparison subjects underwent functional MRI (fMRI) while performing an emotional face-matching task. Within- and between-group whole-brain fMRI activation and seed-based connectivity analyses were conducted. RESULTS: In depressed bipolar II patients, random-effects between-group fMRI analyses revealed a significant reduction in activation in several regions, including the left and right ventrolateral prefrontal cortices (Brodmann's area [BA] 47) and the right amygdala, a priori regions of interest. Additionally, bipolar patients exhibited significantly reduced negative functional connectivity between the right amygdala and the right orbitofrontal cortex (BA 10) as well as the right dorsolateral prefrontal cortex (BA 46) relative to healthy comparison subjects. CONCLUSIONS: These findings suggest that bipolar II depression is characterized by reduced regional orbitofrontal and limbic activation and altered connectivity in a fronto-temporal circuit implicated in working memory and emotional learning. While the amygdala hypoactivation observed in bipolar II depression is opposite to the direction seen in bipolar I mania and may therefore be state dependent, the observed orbitofrontal cortex hypoactivation is consistent with findings in bipolar I depression, mania, and euthymia, suggesting a physiologic trait marker of the disorder. [PubMed Citation] [Order full text from Infotrieve]

15) Rapoport SI
Translational studies on regulation of brain docosahexaenoic acid (DHA) metabolism in vivo.
Prostaglandins Leukot Essent Fatty Acids. 2012 Jul 4;
One goal in the field of brain polyunsaturated fatty acid (PUFA) metabolism is to translate the many studies that have been conducted in vitro and in animal models to the clinical setting. Doing so should elucidate the role of PUFAs in the human brain, and effects of diet, drugs, disease and genetics on this role. This review discusses new in vivo radiotracer kinetic and neuroimaging techniques that allow us to do this, with a focus on docosahexaenoic acid (DHA). We illustrate how brain PUFA metabolism is influenced by graded reductions in dietary n-3 PUFA content in unanesthetized rats. We also show how kinetic tracer techniques in rodents have helped to identify mechanisms of action of mood stabilizers used in bipolar disorder, how DHA participates in neurotransmission, and how brain DHA metabolism is regulated by calcium-independent iPLA(2)?. In humans, regional rates of brain DHA metabolism can be quantitatively imaged with positron emission tomography following intravenous injection of [1-(11)C]DHA. [PubMed Citation] [Order full text from Infotrieve]

16) Whalley HC, Papmeyer M, Sprooten E, Romaniuk L, Blackwood DH, Glahn DC, Hall J, Lawrie SM, Sussmann J, McIntosh AM
The influence of polygenic risk for bipolar disorder on neural activation assessed using fMRI.
Transl Psychiatry. 2012;2:e130.
Genome-wide association studies (GWAS) have demonstrated a significant polygenic contribution to bipolar disorder (BD) where disease risk is determined by the summation of many alleles of small individual magnitude. Modelling polygenic risk scores may be a powerful way of identifying disrupted brain regions whose genetic architecture is related to that of BD. We determined the extent to which common genetic variation underlying risk to BD affected neural activation during an executive processing/language task in individuals at familial risk of BD and healthy controls. Polygenic risk scores were calculated for each individual based on GWAS data from the Psychiatric GWAS Consortium Bipolar Disorder Working Group (PGC-BD) of over 16?000 subjects. The familial group had a significantly higher polygene score than the control group (P=0.04). There were no significant group by polygene interaction effects in terms of association with brain activation. However, we did find that an increasing polygenic risk allele load for BD was associated with increased activation in limbic regions previously implicated in BD, including the anterior cingulate cortex and amygdala, across both groups. The findings suggest that this novel polygenic approach to examine brain-imaging data may be a useful means of identifying genetically mediated traits mechanistically linked to the aetiology of BD. [PubMed Citation] [Order full text from Infotrieve]

17) Freidlin RZ, Kakareka JW, Pohida TJ, Komlosh ME, Basser PJ
A spin echo sequence with a single-sided bipolar diffusion gradient pulse to obtain snapshot diffusion weighted images in moving media.
J Magn Reson. 2012 Aug;221:24-31.
In vivo MRI data can be corrupted by motion. Motion artifacts are particularly troublesome in Diffusion Weighted MRI (DWI), since the MR signal attenuation due to Brownian motion can be much less than the signal loss due to dephasing from other types of complex tissue motion, which can significantly degrade the estimation of self-diffusion coefficients, diffusion tensors, etc. This paper describes a snapshot DWI sequence, which utilizes a novel single-sided bipolar diffusion sensitizing gradient pulse within a spin echo sequence. The proposed method shortens the diffusion time by applying a single refocused bipolar diffusion gradient on one side of a refocusing RF pulse, instead of a set of diffusion sensitizing gradients, separated by a refocusing RF pulse, while reducing the impact of magnetic field inhomogeneity by using a spin echo sequence. A novel MRI phantom that can exhibit a range of complex motions was designed to demonstrate the robustness of the proposed DWI sequence. [PubMed Citation] [Order full text from Infotrieve]

18) Jackowski AP, Filho GM, Almeida AG, Araújo CM, Reis M, Nery F, Batista IR, Silva I, Lacerda AL
The involvement of the orbitofrontal cortex in psychiatric disorders: an update of neuroimaging findings.
Rev Bras Psiquiatr. 2012 Jun;34(2):207-12.
[PubMed Citation] [Order full text from Infotrieve]

19) Savitz JB, Drevets WC
Neuroreceptor imaging in depression.
Neurobiol Dis. 2012 Jun 9;
The in vivo study of receptor binding potential in the human brain is made possible by positron emission tomography (PET) imaging. Here we review PET studies of neuroreceptor function in mood disorders - specifically, major depressive disorder (MDD) and bipolar disorder (BD). We concentrate on the most widely studied receptors of the serotonergic and dopaminergic systems. Specifically, the serotonin 1A (5-HT(1A)), serotonin 2A (5-HT(2A)), serotonin 1B (5-HT(1B)), dopamine 1 (D1), and dopamine 2/3 (D2/3) receptors. We also review PET studies of the serotonin transporter (5-HTT), the dopamine transporter (DAT), monoamine oxidase A (MAO-A), and the muscarinic 2 receptor (M2). On the basis of the PET literature as well as supporting genetic studies, postmortem data, and preclinical models of depression, and several models of how monoaminergic function is altered in mood disorders are discussed with respect to inflammation, endocrine dysfunction, depression subtypes, and altered neurocircuitry. [PubMed Citation] [Order full text from Infotrieve]

20) Bellani M, Perlini C, Ferro A, Cerruti S, Rambaldelli G, Isola M, Cerini R, Dusi N, Andreone N, Balestrieri M, Pozzi Mucelli R, Tansella M, Brambilla P
White matter microstructure alterations in bipolar disorder.
Funct Neurol. 2012 Jan-Mar;27(1):29-34.
Genetic, neuropathological and magnetic resonance imaging findings support the presence of diffuse white matter cytoarchitectural disruption in bipolar disorder. In this study, diffusion-weighted imaging (DWI) was applied to study cortical white matter microstructure organisation in 24 patients with DSM-IV bipolar disorder and 35 matched normal controls. DWI images were obtained using a 1.5 Tesla scanner and apparent diffusion coefficient (ADC) values were determined over regions of interest placed, bilaterally, in the frontal, temporal, parietal, and occipital white matter. Significantly increased ADC values were found in bipolar patients with respect to normal controls in the right temporal lobe, left parietal lobe and bilateral occipital lobes. ADC values did not associate significantly with age or with clinical variables (p>0.05). Diffuse cortical white matter alterations on DWI in bipolar disorder denote widespread disruption of white matter integrity and may be due to altered myelination and/or axonal integrity. [PubMed Citation] [Order full text from Infotrieve]