norepinephrine and bipolar disorder


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(Updated 8/25/04)

Laifenfeld, Daphna, Klein, Ehud, Ben-Shachar, Dorit
Norepinephrine alters the expression of genes involved in neuronal sprouting and differentiation: relevance for major depression and antidepressant mechanisms
J Neurochem 2002 83: 1054-1064
"Recent research into depression has focused on the involvement of long-term intracellular processes, leading to abnormal neuronal plasticity in brains of depressed patients, and reversed by antidepressant treatment. Given a suggested decrease in noradrenergic transmission in depression, and an antidepressant induced increase in norepinephrine (NE) level, a possible role for NE in mediating alterations in neuronal morphology and plasticity was examined. Human neuroblastoma SH-SY5Y cells treated with 10-5 m NE presented an elongated granule-rich cell-body and increased number of neurites, when compared with non-treated cells. Moreover, cell survival was enhanced in the presence of NE, while proliferation was inhibited. The above effects suggest a role for NE in cell differentiation. Indeed similar effects on cell survival and neurite outgrowth were induced in SH-SY5Y cells by retinoic acid (RA), an established differentiating agent. Finally, NE treatment resulted in a progressive decrease in the pluripotent marker Oct4 and an increase in the neuronal growth cone marker, growth-associated-protein 43 (GAP-43). Alongside these effects, NE-treated cells presented alterations in the expression of 44 genes as observed in a neurobiology cDNA microarray. Among the altered genes, an increase in the expression level of two neurite-outgrowth promoting genes, neural cell adhesion molecule L1 and laminin, was confirmed by RT-PCR. Taken together, the results support a role for NE in processes of synaptic connectivity, and may point to a role for this neurotransmitter in mediating the suggested neuronal plasticity in depression and in antidepressant treatment." [Abstract]

Post RM, Stoddard FJ, Gillin JC, Buchsbaum MS, Runkle DC, Black KE, Bunney WE Jr.
Alterations in motor activity, sleep, and biochemistry in a cycling manic-depressive patient.
Arch Gen Psychiatry 1977 Apr;34(4):470-7
"Biochemical and electrophysiological factors were studied longitudinally in a rapidly cycling manic-depressive patient. Slow changes in mood, motor activity, sleep, and urinary norepinephrine levels during the course of each depressed and manic episode are reported, as well as rapid alterations in many variables at the time of mood switch. Urinary concentrations of norepinephrine and its metabolite, 3-methoxy-4-hydroxyphenyl glycol (MHPG) were significantly lower in depression than in mania; norepinephrine but not MHPG excretion increased prior to the switch. We postulate that the slow behavioral and biological changes preceding switches in this patient are an important manifestation of the cyclic process in manic-depressive illness." [Abstract]

Ostrow D, Halaris A, Dysken M, DeMet E, Harrow M, Davis J.
State dependence of noradrenergic activity in a rapidly cycling bipolar patient.
J Clin Psychiatry 1984 Jul;45(7):306-9
"Plasma levels of the major norepinephrine (NE) metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), were measured in a rapidly cycling bipolar patient and her first-degree relatives. The mood state dependence and the reciprocal relationship between noradrenergic and cholinergic activity were investigated by assessing mood, thought disorder, and plasma MHPG following the infusion of physostigmine. A correlation was found between plasma MHPG and mood states, with exceedingly high levels during mania and hypomania. Levels were significantly decreased by ECT or combined lithium and chlorpromazine administration. A pathologic diurnal MHPG pattern was detected during periods of abnormal mood changes. Infusion of physostigmine led to a prompt reduction in MHPG release and a marked decline in mood-state measurements and the overall level of thought disorder. Muscarinic receptors exerting negative feedback control over the synthesis and/or release of NE may have become supersensitive as a consequence of alpha 2-adrenoceptor densensitization." [Abstract]

Joyce PR, Fergusson DM, Woollard G, Abbott RM, Horwood LJ, Upton J.
Urinary catecholamines and plasma hormones predict mood state in rapid cycling bipolar affective disorder.
J Affect Disord 1995 Apr 4;33(4):233-43
"Over the course of 1 year, a patient with a rapid cycling bipolar affective disorder was followed at weekly intervals to examine whether plasma hormones and urinary catecholamines could predict current or future mood. Higher cortisol levels were found to predict depressed mood 3 days after blood sampling, higher urinary dopamine predicted a manic mood 3 days after blood sampling, urinary norepinephrine was associated with severity of current mood and prolactin was lower with concurrent depressed mood. In multivariate analyses of mood against cortisol, prolactin and three urinary catecholamines, > 50% of the variance in mood state in 3 days was explained by combinations of these biologic measures, especially cortisol and urinary dopamine, while all five biologic variables contributed to explaining 50% of the variance in current mood state. Based on the interrelationships between urinary dopamine, norepinephrine and mood, we postulate the existence of an overcompensating mechanism which is reflected in opposing correlations between urinary dopamine and norepinephrine with mood, despite the two urinary catecholamines being positively correlated." [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]
[I include this to show that cortisol abnormalities may be different in non rapid cycling bipolar disorder than in rapid cycling bipolar disorder.]

Wehr TA, Muscettola G, Goodwin FK.
Urinary 3-methoxy-4-hydroxyphenylglycol circadian rhythm. Early timing (phase-advance) in manic-depressives compared with normal subjects.
Arch Gen Psychiatry 1980 Mar;37(3):257-63
"Twenty-four-hour (circadian) rhythms in urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) excretion, motor activity, and oral temperature were studied in 14 normal subjects and ten manic-depressive patients. In both groups, a daily rhythm in MHPG excretion was present, with daytime peaks and nighttime lows. This pattern of urinary MHPG excretion may reflect a rhythm in central noradrenergic function. The physiological changes in levels of MHPG excretion associated with the circadian rhythm were at least as great as pathological changes associated with manic-depressive illness. Compared with controls, the timing or phase of circadian rhythms in each variable was one to three hours earlier in the patients, whether depressed or manic. Although the presence of circadian rhythms complicates the task of designing clinical research procedures, their early timing in manic-depressives suggests that disturbances in central biological clocks may be an integral part of the pathophysiology of affective illness and may be related to disturbances of sleep and neuroendocrine function associated with depression." [Abstract]

Gonzalez-Maeso J, Rodriguez-Puertas R, Meana JJ, Garcia-Sevilla JA, Guimon J.
Neurotransmitter receptor-mediated activation of G-proteins in brains of suicide victims with mood disorders: selective supersensitivity of alpha(2A)-adrenoceptors.
Mol Psychiatry 2002;7(7):755-67
"Abnormalities in the density of neuroreceptors that regulate norepinephrine and serotonin release have been repeatedly reported in brains of suicide victims with mood disorders. Recently, the modulation of the [(35)S]GTPgammaS binding to G-proteins has been introduced as a suitable measure of receptor activity in postmortem human brain. The present study sought to evaluate the function of several G-protein coupled receptors in postmortem brain of suicide victims with mood disorders. Concentration-response curves of the [(35)S]GTPgammaS binding stimulation by selective agonists of alpha(2)-adrenoceptors, 5-HT(1A) serotonin, mu-opioid, GABA(B), and cholinergic muscarinic receptors were performed in frontal cortical membranes from 28 suicide victims with major depression or bipolar disorder and 28 subjects who were matched for gender, age and postmortem delay. The receptor-independent [(35)S]GTPgammaS binding stimulation by mastoparan and the G-protein density were also examined. The alpha(2A)-adrenoceptor-mediated stimulation of [(35)S]GTPgammaS binding with the agonist UK14304 displayed a 4.6-fold greater sensitivity in suicide victims than in controls, without changes in the maximal stimulation. No significant differences were found in parameters of 5-HT(1A) serotonin receptor and other receptor-mediated [(35)S]GTPgammaS binding stimulations. The receptor-independent activation of G-proteins was similar in both groups. Immunoreactive densities of G(alphai1/2)-, G(alphai3)-, G(alphao)-, and G(alphas)-proteins did not differ between suicide victims and controls. In conclusion, alpha(2A)-adrenoceptor sensitivity is increased in the frontal cortex of suicide victims with mood disorders. This receptor supersensitivity is not related to an increased amount or enhanced intrinsic activity of G-proteins. The new finding provides functional support to the involvement of alpha(2)-adrenoceptors in the pathogenesis of mood disorders." [Abstract]

Schildkraut JJ, Orsulak PJ, Schatzberg AF, Gudeman JE, Cole JO, Rohde WA, LaBrie RA.
Toward a biochemical classification of depressive disorders. I. Differences in urinary excretion of MHPG and other catecholamine metabolites in clinically defined subtypes of depressions.
Arch Gen Psychiatry 1978 Dec;35(12):1427-33
"The urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) and other catecholamine metabolites was measured in a series of 63 patients with various clinically defined subtypes of depressive disorders. MHPG excretion was significantly lower in patients with bipolar manic-depressive depressions and schizo-affective depressions than in patients with unipolar nonendogenous depressions. Patients with schizophrenia-related depressions also excreted reduced levels of MHPG when compared with patients with unipolar nonendogenous depressions. Moreover, levels of urinary epinephrine and metanephrine were significantly lower in patients with schizophrenia-related depressions. These data, coupled with our recent finding that patients with schizophrenia-related depressions had significantly higher levels of platelet monoamine oxidase activity than control subjects of patients with unipolar endogenous depressions, suggest that we can discriminate three biochemically discrete subgroups of depressive disorders corresponding to the following clinically defined subtypes: (1) the bipolar manic-depressive depressions plus the schizo-affective depressions; (2) the unipolar nonendogenous depressions; and (3) the schizophrenia-related depressions." [Abstract]

Schildkraut JJ, Orsulak PJ, LaBrie RA, Schatzberg AF, Gudeman JE, Cole JO, Rohde WA.
Toward a biochemical classification of depressive disorders. II. Application of multivariate discriminant function analysis to data on urinary catecholamines and metabolites.
Arch Gen Psychiatry 1978 Dec;35(12):1436-9
"The previous article in this series reported on the differences in urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) in patients with various clinically defined subtypes of depressive disorders. We now report that further biochemical discrimination among depressive subtypes is provided by the following equation, derived empirically by applying multivariate discriminant function analysis to data on urinary catecholamine metabolits: Depression-type (D-type) score = C1(MHPG) + C2(VMA) + C3(NE) +C4(NMN + MN)/VMA + C0. In the original derivation of this equation, low scores were related to bipolar manic-depressive depressions, and high scores were related to unipolar nonendogenous (chronic characterological) depressions. Findings from a series of depressed patients whose biochemical data had not been used to derive this equation confirmed these differences in D-type scores among subtypes of depressions. The findings presented in this report further suggest that we can discriminate three biochemically discrete subgroups of depressive disorders." [Abstract]

Deleon-Jones F, Maas JW, Dekirmenjian H, Sanchez J.
Diagnostic subgroups of affective disorders and their urinary excretion of catecholamine metabolities.
Am J Psychiatry 1975 Nov;132(11):1141-8
"Previous reports have indicated that some depressed patients excrete less than normal quantities of 3-methoxy-4-hydroxyphenyl glycol (MHPG). The authors present data indicating that a subgroup of depressed patients who excrete less than normal quantities of MHPG may be identified by the application of explicit clinical criteria. They found no significant difference in the excretion of normetanephrine (NM), metanephrine (M), and 3-methoxy-4-hydroxymandelic acid (VMA) among any of the diagnostic subgroups or between each patient group and a healthy comparison group. However, depressed patients diagnosed as having primary affective disorder and bipolar illness excreted significantly less MHPG than did the healthy comparison group." [Abstract]

Agren H.
Symptom patterns in unipolar and bipolar depression correlating with monoamine metabolites in the cerebrospinal fluid: II. Suicide.
Psychiatry Res 1980 Oct;3(2):225-36
"Suicidality scores from the Schedule for Affective Disorders and Schizophrenia on 21 unipolar and 12 bipolar depressives were correlated with monoamine metabolites in the cerebrospinal fluid using multiple regression analyses. The single item of Suicidal Tendencies Worst Week correlated highly significantly and negatively with 3-methoxy-4-hydroxyphenylglycol (MHPG) and only to a very slight degree with 5-hydroxyindoleacetic acid (5HIAA). Seriousness of Intent of Worst Suicide Attempt earlier in life correlated significantly and negatively with both MHPG and 5HIAA. Subjective Anger was positively and Overt Anger negatively associated with thoughts of suicide. The results support earlier reports that depressives with low 5HIAA are prone to violent suicides, but also point to the equal, if not even greater involvement of MHPG and noradrenergic neuronal systems in carrying out a wish for death." [Abstract]

Garfinkel PE, Warsh JJ, Stancer HC, Godse DD.
CNS monoamine metabolism in bipolar affective disorder. Evaluation using a peripheral decarboxylase inhibitor.
Arch Gen Psychiatry 1977 Jun;34(6):735-9
"Carbidopa, a decarboxylase inhibitor that does not cross the blood-brain barrier, inhibits the peripheral synthesis of nor-adrenaline, serotonin, and tryptamine. By reducing the peripheral component of end-products of these amines in urine, a more accurate assessment of central nervous system (CNS) amine metabolism is provided. Urinary 5-hydroxyindoleacetic acid (5-HIAA), tryptamine, and 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured over ten days in ten normal controls and eight bipolar depressives. After a three-day baseline period, carbidopa, 100 mg three times a day, was given for seven days. While the patients tended to excrete less MHPG in the baseline period, these differences became somewhat larger, and statistically significant when peripheral contributions were reduced with carbidopa. While carbidopa resulted in striking inhibition of tryptamine excretion, and smaller decreases in the excretion of 5-HIAA and MHPG, evidently from storage pools, there were no significant differences in degree of inhibition between patients and controls. Absolute values of 5-HIAA and tryptamine were similar for both groups, during the baseline and again with carbidopa. These results after carbidopa are compatible with a central catecholaminergic deficit in bipolar depressives and the use of urinary MHPG as an index of CNS catecholamine function." [Abstract]

Beckmann H, Goodwin FK.
Urinary MHPG in subgroups of depressed patients and normal controls.
Neuropsychobiology 1980;6(2):91-100
"3-Methoxy-4-hydroxyphenylglycol (MHPG), the urinary metabolite thought best to reflect brain norepinephrine metabolism, was studied in a large group of hospitalized depressed patients with primary affective disorder and in normal controls, as part of an ongoing effort to evaluate the role of central amine dysfunction in affective illness. Overall there was no difference in MHPG between the depressed patients and controls. Hosever, within the depressed population the bipolar patients excreted significantly less MHPG than the unipolars and, as a group, the male bipolar patients had significantly lower MHPG than male controls. MHPG correlated positively with age, age of onset, rating of anxiety and psychosis and, most importantly, with systolic blood pressure. These data support the concept of biological heterogeneity among individuals with major depressive disorders. However, the relationship between MHPG excretion and various psychological and physiological parameters is both intriguing and complex and warrants careful interpretation." [Abstract]

Rudorfer MV, Ross RJ, Linnoila M, Sherer MA, Potter WZ.
Exaggerated orthostatic responsivity of plasma norepinephrine in depression.
Arch Gen Psychiatry 1985 Dec;42(12):1186-92
"An orthostatic challenge paradigm was used to assess noradrenergic regulation in depressive disorders. Plasma norepinephrine (NE) concentrations and concurrent blood pressure and pulse were measured at rest and after five minutes of standing in groups of bipolar (N = 22) and unipolar (N = 19) depressives and in 12 partially age-matched healthy female volunteers. Supine plasma NE levels were significantly lower in bipolar patients than in either unipolar depressives or normal volunteers. Following the orthostatic challenge, the fractional NE increase in both patient groups--particularly the bipolar group--was greatly exaggerated, exceeding that in the controls by approximately 100%. Nonetheless, the postural cardiovascular changes--elevations of diastolic blood pressure and heart rate--failed to distinguish the three subject groups. Noradrenergic dysregulation in depression thus is characterized by inefficient hyperreactivity to physiologic stress." [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]

Zhou DF, Shen YC, Shu LN, Lo HC.
Dexamethasone suppression test and urinary MHPG X SO4 determination in depressive disorders.
Biol Psychiatry 1987 Jul;22(7):883-91
"The Dexamethasone Suppression Test (DST) was performed in 64 depressed inpatients, in 48 schizophrenics, and in 20 normal controls. Thirty-four percent of depressive inpatients were found to escape from dexamethasone suppression significantly higher than either schizophrenics (13%) or normal subjects (5%). Among subgroups, bipolar and unipolar endogenous depression patients had much higher abnormal rates for the DST (59% and 48%, respectively) than nonendogenous cases (8%). DST results were also found to be positively correlated with patients' Hamilton scores. These findings suggested that DST could be helpful in diagnosis, discrimination of subtypes, and in assessment of severity of symptoms. In 32 of the 64 depressed inpatients, urinary MHPG X SO4 excretion was determined and compared with 21 normal controls. Bipolar patients (n = 7) had less MHPG X SO4 excretion than unipolar endogenous patients (n = 16). Excretion was positively correlated with cortisol level at 17 hr after dexamethasone administration in 32 depressive inpatients, especially in the unipolar subgroup. A trend toward negative correlation, though not statistically significant, was found in bipolar depression between cortisol levels at 17 hr after dexamethasone administration and urinary MHPG X SO4 excretion. This may indicate that some differences in norepinephrine (NE) metabolism may exist between unipolar and bipolar depression, leading to differing correlations between deviation of central NE function and hypothalamus-pituitary-adrenal (HPA) axis in different subgroups of depression." [Abstract]

Scatton B, Loo H, Dennis T, Benkelfat C, Gay C, Poirier-Littre MF.
Decrease in plasma levels of 3,4-dihydroxyphenylethyleneglycol in major depression.
Psychopharmacology (Berl) 1986;88(2):220-5
"Plasma levels of free and sulfoconjugated 3,4-dihydroxyphenylethyleneglycol (DOPEG), the main deaminated metabolite of norepinephrine, were measured in a group of 45 hospitalized patients presenting a major depression and a group of 45 healthy subjects, matched for sex and age. Compared to healthy subjects, depressed patients had significantly lower plasma levels of free and sulfoconjugated DOPEG. The ratio of free over conjugated DOPEG was not statistically different in the two groups. The reduction of plasma DOPEG levels in the depressed patients did not appear to be related to the duration of drug-free period and was similar in males and females. There was no statistically significant correlation between plasma DOPEG levels and total score on the Hamilton Rating Scale for Depression. Finally, plasma DOPEG levels did not differ in uni or bipolar patients. The present data provides further evidence for a reduced CNS noradrenergic transmission in major depression." [Abstract]

Swann AC, Secunda S, Davis JM, Robins E, Hanin I, Koslow SH, Maas JW.
CSF monoamine metabolites in mania.
Am J Psychiatry 1983 Apr;140(4):396-400
"As part of the National Institute of Mental Health Clinical Research Branch Collaborative Program on the Psychobiology of Depression, the authors compared concentrations of CSF monoamine metabolites (the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol [MHPG], the dopamine metabolite homovanillic acid [HVA], and the serotonin metabolite 5-hydroxyindoleacetic acid [5-HIAA]) from 14 hospitalized manic patients with concentrations from 62 healthy comparison subjects. The manic patients had significantly higher levels of MHPG. Levels of 5-HIAA and HVA did not differ between the manic patients and the comparison male subjects, but they were elevated in the female manic patients. MHPG was the only metabolite that correlated significantly with mania symptom ratings. These data are consistent with findings that have shown abnormal, perhaps excessive, central noradrenergic activity in patients with mania, but not with those suggesting deficits in serotoninergic function." [Abstract]

Post RM, Rubinow DR, Uhde TW, Roy-Byrne PP, Linnoila M, Rosoff A, Cowdry R.
Dysphoric mania. Clinical and biological correlates.
Arch Gen Psychiatry 1989 Apr;46(4):353-8
"Patients studied at peak severity of a manic episode showed substantial degrees of depression (dysphoria) and anxiety. Compared with nondysphoric manics (n = 26), the dysphoric manics (n = 22) had a significantly greater number of previous hospitalizations, and they displayed less rapid cycling both in the year before and during the index hospitalization admission. The severity of manic dysphoria tended to correlate with the number of previous hospitalizations, a finding that was highly significant in women (n = 27). Medication-free manic patients (n = 22) had significant elevations in cerebrospinal fluid norepinephrine concentrations compared with depressed and euthymic patients and normal volunteers, and the degree of elevation correlated significantly with the degree of manic dysphoria, anger, and anxiety rated at the time of the lumbar puncture. Patients with dysphoric mania, recognized by Kraepelin to have poor prognoses, have been reported to respond poorly to lithium carbonate but may be among those who respond to carbamazepine. Clinical, biologic, and pharmacologic response characteristics of manic subgroups, particularly those with extreme dysphoric components to their illness, appear to be clinically meaningful and deserving of further investigation." [Abstract]

Swann AC, Secunda SK, Koslow SH, Katz MM, Bowden CL, Maas JW, Davis JM, Robins E.
Mania: sympathoadrenal function and clinical state.
Psychiatry Res 1991 May;37(2):195-205
"We investigated sympathoadrenal and sympathetic nervous system activity, catecholamine disposition, and clinical state in 19 hospitalized manic patients. Severity of the core manic syndrome, anxiety, and hostility correlated with 24-hour urinary excretion of epinephrine relative to its metabolites, but only weakly with norepinephrine. Agitation, however, correlated most strongly and significantly with norepinephrine. Eight of the patients had mixed states: concurrent manic and depressive syndromes. There were no differences between mixed and pure manic patients with respect to catecholamine or metabolite excretion or precursor/product ratios, but mixed manic patients tended to have higher excretion of norepinephrine and had increased variance with respect to catecholamine measures. These data suggest that the function of the adrenal medulla, whether directly or indirectly, is important in the symptoms of both mixed and pure mania." [Abstract]

Bhanji NH, Margolese HC, Saint-Laurent M, Chouinard G.
Dysphoric mania induced by high-dose mirtazapine: a case for 'norepinephrine syndrome'?
Int Clin Psychopharmacol 2002 Nov;17(6):319-22
"The antidepressant mirtazapine antagonizes central presynaptic alpha2-adrenergic auto- and heteroreceptors resulting in increased central norepinephrine and serotonin activity. Histamine H2 receptors are also antagonized, as are postsynaptic serotonin 5-HT2 and 5-HT3 receptors, leading to serotonergic activity primarily via 5-HT1A receptors. Based on the case report of a patient who developed mania with higher than recommended dosage of mirtazapine, we review the literature on the atypical nature of manic symptoms with mirtazapine. Eight subjects, including those in our study, were identified as having developed mirtazapine-induced mania with atypical features, consisting of dysphoria, irritability, insomnia, psychomotor agitation and abnormal gait. Predisposing features may have included the presence of underlying brain dysfunction and certain selective serotonin reuptake inhibitor-mirtazapine combinations. Dysphoric mania with atypical features may be induced by mirtazapine, providing support for a common hypothesis such as 'central norepinephrine hyperactivity' as the basis for development of mania with mirtazapine." [Abstract]

Swann AC, Stokes PE, Secunda SK, Maas JW, Bowden CL, Berman N, Koslow SH.
Depressive mania versus agitated depression: biogenic amine and hypothalamic-pituitary-adrenocortical function.
Biol Psychiatry 1994 May 15;35(10):803-13
"The existence of mixed affective states challenges the idea of specific biological abnormalities in depression and mania. We compared biogenic amines and hypothalamic-pituitary-adrenocortical (HPA) function in mixed manic (n = 8), pure manic (n = 11), agitated bipolar depressed (n = 20), and nonagitated bipolar depressed (n = 27) inpatients (Research Diagnostic Criteria). Mixed manics met Research Diagnostic Criteria for primary manic episodes and also met criteria for major depressive episodes except for duration. The norepinephrine metabolite methoxyhydroxy phenthylene glycol (MHPG) was higher in cerebrospinal fluid from mixed manic than from agitated depressed patients, consistent with differences previously reported between the overall samples of depressed and manic patients. Similarly, patients in a mixed state had higher urinary excretion of norepinephrine (NE) and elevated output of NE relative to its metabolites. HPA activity was similar in mixed manic and agitated depressed patients. These data suggest that mixed manics combine certain biological abnormalities considered to be characteristic of mania and of depression." [Abstract]

Adler LE, Gerhardt GA, Franks R, Baker N, Nagamoto H, Drebing C, Freedman R.
Sensory physiology and catecholamines in schizophrenia and mania.
Psychiatry Res 1990 Mar;31(3):297-309
"Hypersensitivity to sensory stimulation is a prominent characteristic of both schizophrenia and mania. Neurophysiological recordings suggest a common deficit in a central neuronal sensory gating mechanism which regulates sensitivity to repeated auditory stimuli. Dopamine and norepinephrine are hypothesized to have major roles in these illnesses, but their role in aberrant sensory processing has not yet been proved. Presumptive evidence for effects of catecholamines on sensory processing comes from psychophysiological studies of normal subjects challenged with stimulants who show decreased sensory gating, and studies of psychotic patients treated with neuroleptics who show improved function. Studies of similar phenomena in animals show comparable effects of catecholamines on sensory processing, both behaviorally and at the single neuron level. In this study, gating of auditory evoked potentials (EPs) during treatment of both illnesses was compared with plasma dopamine and norepinephrine metabolites. Comparisons of medicated and unmedicated states showed that schizophrenic patients have a fixed deficit in sensory gating, which is a familial trait, unchanged by medication. During acute illness, they have an additional transient hypersensitivity to stimuli, manifested as smaller EPs, which seems to be mediated by dopamine. Manic patients have only the deficit in sensory gating, which is transient and seems to be mediated by norepinephrine. Thus, similar neurophysiological deficits in the two psychoses are associated with different biochemical abnormalities, which may explain similarities in acute symptoms and differences in other aspects of the illnesses, such as their response to treatment." [Abstract]

Swann AC, Petty F, Bowden CL, Dilsaver SC, Calabrese JR, Morris DD.
Mania: gender, transmitter function, and response to treatment.
Psychiatry Res 1999 Oct 18;88(1):55-61
"Noradrenergic and GABA systems may be involved in mania, but there is little information about relationships between the function of these systems and response to specific antimanic treatments. We investigated relationships between indices of catecholamine or GABA system function, pretreatment mania severity and antimanic response to divalproex, lithium, or placebo. Plasma GABA and urinary excretion of catecholamine metabolites were measured before randomization to lithium, divalproex or placebo in patients hospitalized for manic episodes. Severity of mania was evaluated using the Manic Syndrome, Behavior and Ideation and Mania Rating Scale scores from the SADS-C. Multiple regression analysis showed that pretreatment plasma GABA was related to severity of manic symptoms. This relationship seemed stronger in women. Multiple regression analysis showed that pretreatment levels of urinary MHPG correlated with improvement in manic syndrome scores. These data suggest that GABA and norepinephrine may be related to different aspects of the manic state and to its pharmacologic sensitivity." [Abstract]

Swann AC, Berman N, Frazer A, Koslow SH, Secunda S.
Lithium distribution in mania: plasma and red blood cell lithium, clinical state, and monoamine metabolites during lithium treatment.
Psychiatry Res 1987 Jan;20(1):1-12
"We examined red blood cell (RBC) and plasma lithium concentrations and RBC/plasma lithium ratios in 14 manic patients during lithium treatment as part of the National Institute of Mental Health's Collaborative Program on the Psychobiology of Depression, Biological Studies. All of the lithium measures increased during treatment, especially RBC lithium. There were positive correlations between the RBC lithium concentration and the RBC/plasma lithium ratio and their maximal values in a single-dose pharmacokinetic experiment before treatment. After 5 and 16 days of treatment, patients with good subsequent outcome had higher RBC/plasma lithium ratios than did patients with poor outcome. Early in treatment, there was a negative correlation between lithium concentrations and severity of mania. During treatment, there was a negative correlation between RBC lithium and urinary MHPG excretion. There was a positive correlation between RBC or plasma lithium during the first few days of treatment and subsequent reduction in norepinephrine excretion during treatment. At 3 weeks, there were negative correlations between reductions in catecholamine measures and lithium concentrations. These data suggest that there are changes in the sensitivity of behavior and catecholamine function to lithium during treatment. RBC concentrations of lithium appear to be a potentially useful indicator of its behavioral and neurochemical effects." [Abstract]

Swann AC, Koslow SH, Katz MM, Maas JW, Javaid J, Secunda SK, Robins E.
Lithium carbonate treatment of mania. Cerebrospinal fluid and urinary monoamine metabolites and treatment outcome.
Arch Gen Psychiatry 1987 Apr;44(4):345-54
"Treatment of manic patients with lithium carbonate was associated with significant decreases in cerebrospinal fluid (CSF) 3-methoxy-4-hydroxyphenylglycol (MHPG) and urinary norepinephrine excretion. These measures, before treatment, were higher in manic patients than in either depressed or normal subjects and correlated significantly with severity of mania. Levels in CSF of homovanillic acid and 5-hydroxyindoleacetic acid did not correlate with severity or with change during lithium carbonate treatment. Responders (about 70% of the patients) did not differ from nonresponders in pretreatment mania ratings or neurotransmitter measures. The CSF MHPG and urinary norepinephrine excretion were reduced during lithium carbonate treatment in both responders and nonresponders. Unlike the case before treatment, urinary MHPG excretion was higher during treatment in nonresponders than in responders and correlated with several indexes of symptom severity. These results support a relationship between mania and increased noradrenergic function. Treatment outcome, however, was not related exclusively to the reduction of noradrenergic indexes by lithium carbonate since reductions were similar in both responders and nonresponders. Reduced noradrenergic activity may therefore be necessary but not sufficient for successful outcome during lithium carbonate treatment." [Abstract]

Beckmann H, ST-Laurent J, Goodwin FK.
The effect of lithium on urinary MHPG in unipolar and bipolar depressed patients.
Psychopharmacologia 1975 Jun 19;42(3):277-82
"Twenty-four hour urinary excretion of 3-methoxy-4-hydroxphaeylglycol (MHPG), the metabolite thought best to reflect brain norepinephrine metabolism, was studied longitudinally in ten depressed patients before and during the acute and chronic phases of lithium treatment. Five of the patients were identified as bipolar I (prior history of mania), 3 as bipolar II (history of hypomania) and 2 as unipolar (history of depression). During acute lithium administration (first week) there was no consistent pattern of change in MHPG. Comparing the predrug period with the third and fourth week of treatment, all of the responders showed an increase in MHPG, while the non-responders showed no change or a decrease. It is concluded that the change in clinical state is the most important variable contributing to MHPG changes in these patients. There was a tendency for the pretreatment MHPG excretion to be low in the patients who went on to show a clear-cut antidepressant response to lithium compared to those who were unequivocal non-responders. The predrug MHPG for the bipolar patients (prior history of mania) was significantly lower than the unipolar patients, a difference which apparently contributes to the lower MHPG in the lithium responders, all of whom were in the bipolar group." [Abstract]

Goodnick PJ, Dominguez RA, DeVane CL, Bowden CL.
Bupropion slow-release response in depression: diagnosis and biochemistry.
Biol Psychiatry 1998 Oct 1;44(7):629-32
"BACKGROUND: Bupropion has been previously shown to be particularly beneficial in bipolar and atypical depression. Previous research has supported a possible association of response to plasma levels and to changes in plasma homovanillic acid (HVA). These findings were here extended to bupropion slow-release (SR), a formulation with slower release kinetics. METHODS: Forty-one patients with major depressive disorder (DSM-III-R) completed 8 weeks of a fixed dose of 300 mg/day in two doses/day. Clinical outcome measures were the Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI). Biological parameters included plasma HVA and 3-methoxy-4-hydroxyphenyl-glycol (MHPG), as well as a final measurement of plasma bupropion and its metabolites. RESULTS: Response to bupropion SR differed among the three groups: results for change in HDRS and in BDI were greater in the bipolar and atypical than in the "typical" depressed patients. Mean change in HDRS was, respectively, of 15.6, 17.1, and 7.6 (F = 5.57, p < .01); mean change in the BDI, 21.1, 16.9, and 7.3 (F = 3.32, p < .05). Threobupropion levels correlated with HDRS scores (r = .47, p = .02, n = 23); plasma HVA and MHPG increased significantly (t = 2.31, p = .03; t = 2.15, p = .04, n = 17). Bipolar depressed patients' improvement in HDRS was related to increases in MHPG (r = .87, p = .01) and in HVA (r = .70, p = .08). CONCLUSIONS: This fixed-dose study indicates that there may be specific benefits for bupropion SR in atypical and bipolar depression, and that these benefits may be related also to plasma levels and biochemical changes in catecholamines. Due to the small sample size, replication is of key importance." [Abstract]

Bakchine S, Lacomblez L, Benoit N, Parisot D, Chain F, Lhermitte F.
Manic-like state after bilateral orbitofrontal and right temporoparietal injury: efficacy of clonidine.
Neurology 1989 Jun;39(6):777-81
"A manic-like state occurred in a 44-year-old right-handed woman with bilateral orbitofrontal and right temporoparietal traumatic contusions. In a brief trial, we assessed the effect of clonidine, carbamazepine, dopa therapy, and placebo on manic symptoms and cognitive functions. Clonidine rapidly reversed the manic syndrome. The patient's behavior did not change with carbamazepine and worsened with levodopa. We suggest that the manic-like syndrome was related to noradrenergic overactivity secondary to the fronto-orbital lesions." [Abstract]

Post RM.
Time course of clinical effects of carbamazepine: implications for mechanisms of action.
J Clin Psychiatry 1988 Apr;49 Suppl:35-48
"The relatively acute time course of antimanic efficacy may be related to the above-mentioned mechanisms or to other effects related to systems postulated to be altered in the manic syndrome. These effects might include carbamazepine's ability to increase acetylcholine in the striatum, decrease probenecid-induced levels of CSF homovanillic acid (HVA) in man and dopamine turnover in animals, decrease CSF norepinephrine in manic patients, inhibit adenylate cyclase activity (in response to norepinephrine, dopamine, adenosine, or ouabain), decrease GABA turnover, or act as a vasopressin agonist." [Abstract]

Swann AC, Secunda SK, Stokes PE, Croughan J, Davis JM, Koslow SH, Maas JW.
Stress, depression, and mania: relationship between perceived role of stressful events and clinical and biochemical characteristics.
Acta Psychiatr Scand 1990 Apr;81(4):389-97
"We investigated the perceived role of stressful events in episodes of major affective disorder in patients studied in the NIMH Clinical Research Branch Collaborative Program on the Psychobiology of Depression (Biological Studies). Using items from the Schedule for Affective Disorders and Schizophrenia (SADS), episodes were divided into environment-sensitive (high perceived role of stressful events) and autonomous (minimal or no perceived role of stressful events). Patients with environment-sensitive episodes had fewer previous episodes and a longer index episode. The groups did not differ with respect to age, gender, education, socioeconomic group, diagnosis, severity of illness, or eventual response to treatment. Unipolar depressed patients with environment-sensitive episodes had lower CSF 5-HIAA than those with autonomous episodes. Among bipolar depressed patients, those with autonomous episodes had elevated excretion of O-methylated catecholamine metabolites and of epinephrine, while those with environment-sensitive episodes had normal excretion of catecholamines and metabolites. Manic subjects with environment-sensitive episodes had elevated norepinephrine excretion, while this was normal in manics with autonomous episodes. Relationships between environmental sensitivity of affective episodes and neurotransmitter function therefore appear to be related to the type of episode." [Abstract]

Kosten TR, Mason JW, Giller EL, Ostroff RB, Harkness L.
Sustained urinary norepinephrine and epinephrine elevation in post-traumatic stress disorder.
Psychoneuroendocrinology 1987;12(1):13-20
"Urinary norepinephrine and epinephrine levels (microgram/day) were measured at two-week intervals during the course of hospitalization in the following patient groups: post-traumatic stress disorder (PTSD); major depressive disorder (MDD); bipolar I, manic (BP); paranoid schizophrenia (PS); and undifferentiated schizophrenia (US). The mean norepinephrine level during hospitalization was significantly higher in PTSD (76 +/- 10.4 micrograms/day) than in BP (60.6 +/- 8.4 micrograms/day), MDD (41.2 +/- 4.7 micrograms/day), PS (33.4 +/- 4.9 micrograms/day) and US (34.3 +/- 5.9 micrograms/day) groups, according to Duncan's multiple range test, (F(4,39) = 6.94, p less than 0.0003). The norepinephrine elevations in the PTSD group were sustained throughout hospitalization. The only other group to show mean levels in this range was the BP group in the first sample after hospital admission. This finding supports prior psychophysiological studies indicating increased sympathetic nervous system activity in PTSD patients. The mean epinephrine level during hospitalization was also significantly higher in PTSD (22.7 +/- 2.4 micrograms/day) than in MDD (13.6 +/- 1.7 micrograms/day), PS (14.7 +/- 2.4 micrograms/day), and US (18.9 +/- 1.8 micrograms/day), but not higher than in BP (21.5 +/- 2.7 micrograms/day). The relationship of epinephrine levels among diagnostic groups was sustained throughout hospitalization. It appears likely that the main underlying mechanisms for elevations of both hormones are psychological, but further work will be required to establish the exact nature of these mechanisms." [Abstract]

Young LT, Warsh JJ, Kish SJ, Shannak K, Hornykeiwicz O.
Reduced brain 5-HT and elevated NE turnover and metabolites in bipolar affective disorder.
Biol Psychiatry 1994 Jan 15;35(2):121-7
"Levels of norepinephrine (NE), serotonin (5-HT), dopamine (DA), and their major metabolites were determined in postmortem brain obtained from nine subjects with antemortem histories meeting DSM-III-R criteria for bipolar affective disorder. Compared with controls, no statistically significant differences were found in mean levels of NE, 5-HT, or DA in any brain area of bipolar subjects. NE turnover as estimated by the ratio of the major NE metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) to NE was increased in frontal (+107%), temporal (+103%), and occipital (+64%) cortex and thalamus (+83%). Significant decreases were found in the major 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA), in frontal (-54%) and parietal cortex (-64%), and in 5-HIAA/5-HT ratio in temporal cortex (-55%), with a trend for decreases in both measures in caudate nucleus. In addition, levels of the major DA metabolite, homovanillic acid (HVA) were significantly decreased (-46%) in parietal cortex and HVA/DA ratios were significantly reduced (-66%) in occipital cortex obtained from bipolar compared to control subjects. Our data, taken together with previous findings regarding monoamines in postmortem brain of depressed and suicide subjects, suggest that decreased 5-HT metabolite levels and turnover may be common to all mood disorders. Increased cortical NE turnover, however, may be a more important component in the pathophysiology of bipolar disorder." [Abstract] [Note that no information on the mood state of the subjects is given.]

Dilsaver SC, Minkus D, Swann AC.
Chronic treatment with valproate decreases the hypothermic response to clonidine.
Pharmacol Biochem Behav 1993 May;45(1):247-9
"Treatment with lithium (the prototype of an antimanic agent) attenuates responsiveness to the alpha 2-agonist clonidine in animal models. Valproate is now used to treat mania. The effect of treatment with this drug on responses mediated by an alpha 2-agonist have yet to be reported. The authors assessed the effect of a 14-day course of orally administered valproate on the rat's hypothermic response to clonidine. Treatment with valproate decreased this response." [Abstract]

Bauer M, London ED, Silverman DH, Rasgon N, Kirchheiner J, Whybrow PC.
Thyroid, brain and mood modulation in affective disorder: insights from molecular research and functional brain imaging.
Pharmacopsychiatry. 2003 Dec;36 Suppl 3:215-21.
"The efficacy resulting from adjunctive use of supraphysiological doses of levothyroxine has emerged as a promising approach to therapy and prophylaxis for refractory mood disorders. Most patients with mood disorders who receive treatment with supraphysiological doses of levothyroxine have normal peripheral thyroid hormone levels, and also respond differently to the hormone and tolerate it better than healthy individuals and patients with primary thyroid diseases. Progress in molecular and functional brain imaging techniques has provided a new understanding of these phenomena, illuminating the relationship between thyroid function, mood modulation and behavior. Thyroid hormones are widely distributed in the brain and have a multitude of effects on the central nervous system. Notably many of the limbic system structures where thyroid hormone receptors are prevalent have been implicated in the pathogenesis of mood disorders. The influence of the thyroid system on neurotransmitters (particularly serotonin and norepinephrine), which putatively play a major role in the regulation of mood and behavior, may contribute to the mechanisms of mood modulation. Recent functional brain imaging studies using positron emission tomography (PET) with [ (18)F]-fluorodeoxyglucose demonstrated that thyroid hormone treatment with levothyroxine affects regional brain metabolism in patients with hypothyroidism and bipolar disorder. Theses studies confirm that thyroid hormones are active in modulating metabolic function in the mature adult brain, and provide intriging neuroanatomic clues that may guide future research." [Abstract]

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Recent Bipolar Disorder & Norepinephrine Research

1) Bj÷rkholm C, Jardemark K, Marcus MM, Malmerfelt A, Nyberg S, Schilstr÷m B, Svensson TH
Role of concomitant inhibition of the norepinephrine transporter for the antipsychotic effect of quetiapine.
Eur Neuropsychopharmacol. 2012 Jun 23;
Quetiapine alleviates both positive and negative symptoms as well as certain cognitive impairments in schizophrenia despite a low D(2) receptor occupancy and may also be used as monotherapy in bipolar and major depressive disorder. The mechanisms underlying the broad clinical utility of quetiapine remain to be clarified, but may be related to the potent inhibition of the norepinephrine transporter (NET) by norquetiapine, the major metabolite of quetiapine in humans. Since norquetiapine is not formed in rodents we here investigated in rats whether NET-inhibition may, in principle, contribute to the clinical effectiveness of quetiapine and allow for its low D(2) receptor occupancy, by combining quetiapine with the selective NET-inhibitor reboxetine. Antipsychotic-like activity was assessed using the conditioned avoidance response (CAR) test, dopamine output in the medial prefrontal cortex (mPFC) and the nucleus accumbens was measured using in vivo microdialysis, and NMDA receptor-mediated transmission was measured using intracellular electrophysiological recordings in pyramidal cells of the mPFC in vitro. Adjunct reboxetine potentiated the suppression of CAR by quetiapine. Moreover, concomitant administration of quetiapine and reboxetine resulted in a synergistic increase in cortical, but not accumbal, dopamine output. The combination of low, clinically relevant concentrations of quetiapine (60nM) and reboxetine (20nM) markedly facilitated cortical NMDA receptor-mediated transmission in contrast to either drug alone, an effect that could be inhibited by the D(1) receptor antagonist SCH23390. We conclude that concomitant NET-inhibition by norquetiapine may contribute to the overall antipsychotic effectiveness of quetiapine in spite of its relatively low level of D(2) occupancy. [PubMed Citation] [Order full text from Infotrieve]

2) Chang JS, Ha K, Yoon IY, Yoo CS, Yi SH, Her JY, Ha TH, Park T
Patterns of cardiorespiratory coordination in young women with recurrent major depressive disorder treated with escitalopram or venlafaxine.
Prog Neuropsychopharmacol Biol Psychiatry. 2012 Jun 12;
Evidence from previous studies suggests autonomic dysregulation in patients with major depressive disorder (MDD). Antidepressant treatment may also affect central autonomic function. We investigated whether the type of antidepressant might be associated with the pattern of cardiorespiratory coordination in non-depressed women with recurrent MDD. Resting electrocardiograms and respiratory signals were simultaneously recorded from 38 euthymic women with recurrent MDD who were treated with either escitalopram (n=19) or venlafaxine (n=19) monotherapy and from 38 healthy women. Linear measures of heart rate variability were extracted to assess cardiac autonomic control. Sample entropy (SampEn) was computed to assess the complexity of heart rate and respiratory signals, and cross-SampEn was calculated to measure the nonlinear interaction of both signals. Significant decreases in the cardiovagal tone and cardiorespiratory coupling of women with recurrent MDD receiving venlafaxine, and tendencies toward lower cardiovagal tone and cardiorespiratory coupling in women with recurrent MDD receiving escitalopram were observed when compared with healthy controls. Effect sizes for these differences were large between women receiving venlafaxine and healthy controls. We found a positive association between cardiorespiratory decoupling and venlafaxine dose. Norepinephrine-enhancement, within a therapeutic dose range, seems to be closely associated with decreased vagal tone and reduced nonlinear coupling between heart rate and respiration in euthymic women with recurrent MDD. However, the effects of serotonin enhancement on cardiovagal tone should be considered. Our results suggest that the pharmacodynamic properties of antidepressants may affect autonomic regulation of women with recurrent MDD even in euthymic state. [PubMed Citation] [Order full text from Infotrieve]

3) Bielau H, Brisch R, Bernard-Mittelstaedt J, Dobrowolny H, Gos T, Baumann B, Mawrin C, Bernstein HG, Bogerts B, Steiner J
Immunohistochemical evidence for impaired nitric oxide signaling of the locus coeruleus in bipolar disorder.
Brain Res. 2012 Jun 12;1459:91-9.
Nitric oxide (NO) is an important messenger in brain signaling and influences the balance of monoaminergic and glutamatergic neurotransmission. Alterations of NO signaling are thought to play a crucial role in the pathophysiology of mood disorders. The locus coeruleus (LC) comprises the largest group of norepinephrine containing neurons in the mammalian brain. These norepinephrinergic LC neurons are able to generate NO. Immunohistochemical staining of neuronal nitric oxide synthase (nNOS)-immunoreactive (ir) neurons was performed in the LC of the brains of 10 patients with bipolar I disorder (BD), 8 patients with major depressive disorder (MDD) and 16 control cases (C). Analysis of variance (ANOVA) revealed significant differences between the groups, and post hoc tests indicated a lower nNOS-ir neuron number in bipolar patients than in controls (left -34%, right -17%). The total number of Nissl-stained LC neurons showed no changes between major depressive disorder patients, bipolar patients and controls. In the mood disorder patients, illness duration correlated negatively with nNOS-ir neuronal number (r=-0.74, p=0.002). A reduced relative amount of NO in the LC of bipolar patients is likely a result of a compensation for increased glutamatergic activity. The current data on nNOS suggest a dysregulation of the nitrergic system in bipolar disorder. Future studies may clarify the potential role of glial cells in the context of the described nNOS deficit. [PubMed Citation] [Order full text from Infotrieve]

4) McIntyre RS, Cha DS, Alsuwaidan M, McIntosh D, Powell AM, Jerrell JM
A review of published evidence reporting on the efficacy and pharmacology of lurasidone.
Expert Opin Pharmacother. 2012 Aug;13(11):1653-9.
Introduction: Lurasidone is a benzisothiazol derivative, approved by the US Food and Drug Administration for the acute treatment of adults with schizophrenia. Lurasidone's binding affinities are highest for the 5-HT(2A), 5-HT(7), and D(2) receptors; with lower and similar binding affinities for the norepinephrine ?(2C) and 5-HT(2C) receptor subtypes. It has demonstrated efficacy in fixed-dose studies across a variable dose range (i.e., 40 - 160 mg), with a recommended starting dose of 40 mg and a maximum recommended dose of 80 mg. Lurasidone's preclinical profile is predictive not only of efficacy against psychotic and negative symptoms but also of affective symptomatology and cognitive deficits. Controlled trials are currently underway to evaluate lurasidone's efficacy in bipolar depression as well as its procognitive effects in individuals with schizophrenia. Lurasidone is administered once a day with ? 350 calories of food, regardless of fat content. Lurasidone is not known to adversely affect body composition, anthropometrics, metabolic and/or electrocardiographic parameters. Although prolactin elevation might be observed, prolactin-related adverse events are rarely reported. Areas covered: This paper presents the pharmacodynamics and pharmacokinetics of lurasidone, and discusses its efficacy, safety and tolerability data. Expert opinion: Lurasidone's simplicity of use and favorable metabolic profile are distinct advantages relative to several other agents (e.g., olanzapine). Outcomes in cognitive data analyses are awaited to determine if there is a key differentiator between lurasidone and other atypical agents with respect to efficacy. Moreover, lurasidone's efficacy in bipolar depression is awaited to determine whether this agent can be considered as a treatment alternative for depressive symptoms in adults with bipolar disorder. [PubMed Citation] [Order full text from Infotrieve]

5) Chernoloz O, El Mansari M, Blier P
Effects of sustained administration of quetiapine alone and in combination with a serotonin reuptake inhibitor on norepinephrine and serotonin transmission.
Neuropsychopharmacology. 2012 Jun;37(7):1717-28.
Quetiapine is now used in the treatment of unipolar and bipolar disorders, both alone and in combination with other medications. In the current study, the sustained administration of quetiapine and N-Desalkyl quetiapine (NQuet) in rats in a 3?:?1 mixture (hQuetiapine (hQuet)) was used to mimic quetiapine exposure in patients because rats do not produce the latter important metabolite of quetiapine. Sustained administration of hQuet for 2 and 14 days, respectively, significantly enhanced the firing rate of norepinephrine (NE) neurons by blocking the cell body ??-adrenergic autoreceptors on NE neurons, whether it was given alone or with a serotonin (5-HT) reuptake inhibitor. The 14-day regimen of hQuet enhanced the tonic activation of postsynaptic ??- but not ??-adrenergic receptors in the hippocampus. This increase in NE transmission was attributable to increased firing of NE neurons, the inhibition of NE reuptake by NQuet, and the attenuated function of terminal ??-adrenergic receptors on NE terminals. Sustained administration of hQuet for 2 and 14 days, respectively, significantly inhibited the firing rate of 5-HT, whether it was given alone or with a 5-HT reuptake inhibitor, because of the blockade of excitatory ??-adrenergic receptors on 5-HT neurons. Nevertheless, the 14-day regimen of hQuet enhanced the tonic activation of postsynaptic 5-HT(1A) receptors in the hippocampus. This increase in 5-HT transmission was attributable to the attenuated inhibitory function of the ??-adrenergic receptors on 5-HT terminals and possibly to direct 5-HT(1A) receptor agonism by NQuet. The enhancement of NE and 5-HT transmission by hQuet may contribute to its antidepressant action in mood disorders. [PubMed Citation] [Order full text from Infotrieve]

6) Calandre EP, Rico-Villademoros F
The role of antipsychotics in the management of fibromyalgia.
CNS Drugs. 2012 Feb 1;26(2):135-53.
Fibromyalgia is a syndrome characterized by chronic generalized pain associated with different somatic symptoms, such as sleep disturbances, fatigue, stiffness, balance problems, hypersensitivity to physical and psychological environmental stimuli, depression and anxiety. It has been estimated to affect roughly the 2-4% of the general population in most countries studied, and it has been shown to be much more prevalent in women than in men. Although its pathophysiology is not yet fully understood, it is known that both genetic and environmental factors are involved in its development. Fibromyalgia shares a high degree of co-morbidity with other conditions, including chronic headache, temporomandibular disorder, irritable bowel syndrome, major depression, anxiety disorders and chronic fatigue syndrome. Therefore, this is a syndrome difficult to treat for which multimodal treatments including physical exercise, psychological therapies and pharmacological treatment are recommended. Although different kinds of drugs have been studied for the treatment of fibromyalgia, the most widely used drugs that have the higher degree of evidence for efficacy include the ?(2)? ligands pregabalin and gabapentin, and the tricyclic antidepressants (TCAs) and serotonin noradrenaline (norepinephrine) reuptake inhibitors (SNRIs). However, there is a need to look for newer additional therapeutic pharmacological options for the treatment of this complex and disabling disease. First- and second-generation antipsychotics have shown analgesic properties both in an experimental setting and in humans, although most of the available evidence for the treatment of human pain concerns older antipsychotics and involves clinical trials performed several decades ago. In addition, several second-generation antipsychotics, risperidone, olanzapine and quetiapine, have shown efficacy in the treatment of some anxiety disorders. Some second-generation antipsychotics, mainly quetiapine, aripiprazole and amisulpride, have demonstrated antidepressant activity, with quetiapine approved for the treatment of bipolar depression and refractory major depression, and aripiprazole approved as an adjunctive treatment for major depressive disorder. Finally, several old and new antipsychotics, including promethazine, levopromazine, olanzapine, quetiapine and ziprasidone, have been shown to improve sleep parameters in healthy subjects. Each of these properties suggests that antipsychotics could represent a new potential alternative for the treatment of fibromyalgia syndrome. To date, most of the published studies on the use of antipsychotics in the treatment of fibromyalgia syndrome have been uncontrolled, either case reports or case series, dealing with olanzapine, quetiapine, ziprasidone, levopromazine and amisulpride. The studies on olanzapine and quetiapine have suggested therapeutic efficacy although, in the case of olanzapine, hampered by tolerability problems. A double-blind controlled trial, published in 1980, showed that chlorpromazine increased slow-wave sleep and improved pain and mood disturbances. More recently, four double-blind controlled studies have explored the efficacy of quetiapine, either alone or as an add-on treatment, in fibromyalgia management. None of these trials has yet been published, although two of them have been presented as congress communications, both of them suggesting that quetiapine could be a potential alternative treatment for fibromyalgia. In summary, the current available evidence suggests that at least some antipsychotics, specifically quetiapine, could be useful for the treatment of fibromyalgia and that further studies on the efficacy of these compounds are worth pursuing. [PubMed Citation] [Order full text from Infotrieve]

7) Howland RH
The use of dopaminergic and stimulant drugs for the treatment of depression.
J Psychosoc Nurs Ment Health Serv. 2012 Feb;50(2):11-4.
The brain reward system consists of extensive neural pathways that mediate reward behavior such as pleasure and motivation. These pathways may be involved in the development of symptoms such as apathy, anhedonia, and cognitive dysfunction seen in patients with major depression. These pathways are served primarily, although not exclusively, by the chemical neurotransmitter dopamine, which has suggested a therapeutic role for drugs that influence dopamine activity. A small number of clinical trials using various dopaminergic and stimulant drugs for the treatment of major depression and bipolar depression have demonstrated some benefit when combined with standard antidepressant drugs. Based on this work, several ongoing trials are investigating the use of the stimulant drug lisdexamfetamine (Vyvanse«) as an adjunctive treatment for depression. [PubMed Citation] [Order full text from Infotrieve]

8) Han C, Pogwizd SM, Killingsworth CR, He B
Noninvasive reconstruction of the three-dimensional ventricular activation sequence during pacing and ventricular tachycardia in the rabbit heart.
Conf Proc IEEE Eng Med Biol Soc. 2011;2011:1684-7.
Ventricular arrhythmias represent one of leading causes for sudden cardiac death, a significant problem in public health. Noninvasive imaging of cardiac electric activities associated with ventricular arrhythmias plays an important role in better our understanding of the mechanisms and optimizing the treatment options. The present study aims to rigorously validate a novel three-dimensional (3-D) cardiac electrical imaging (3-DCEI) technique with the aid of 3-D intra-cardiac mapping during paced rhythm and ventricular tachycardia (VT) in the rabbit heart. Body surface potentials and intramural bipolar electrical recordings were simultaneously measured in a closed-chest condition in thirteen healthy rabbits. Single-site pacing and dual-site pacing were performed from ventricular walls and septum. VTs and premature ventricular complexes (PVCs) were induced by intravenous norepinephrine (NE). The non-invasively imaged activation sequence correlated well with invasively measured counterparts, with a correlation coefficient of 0.72 and a relative error of 0.30 averaged over all paced beats and NE-induced PVCs and VT beats. The averaged distance from imaged site of initial activation to measured site determined from intra-cardiac mapping was ?5mm. These promising results suggest that 3-DCEI is feasible to non-invasively localize the origins and image activation sequence of focal ventricular arrhythmias. [PubMed Citation] [Order full text from Infotrieve]

9) Sacchetti E, Galluzzo A, Valsecchi P
Oral ziprasidone in the treatment of patients with bipolar disorders: a critical review.
Expert Rev Clin Pharmacol. 2011 Mar;4(2):163-79.
Ziprasidone, a benzisothiazolyl piperazine derivative of tiospirone, is a second-generation antipsychotic with high-affinity antagonism for 5-hydroxytryptophan (5HT)(2A), 5HT(2C), 5HT(1D) and D(2) receptors, pre- and post-synaptic agonism for 5HT(1A) receptors, and inhibition of reuptake for serotonin and norepinephrine. Initially approved for the treatment of adults with schizophrenia, ziprasidone has more recently received supplementary indications for acute manic and mixed episodes and as maintenance therapy for people affected by bipolar disorder. Based on MEDLINE citations up to November 2010 and hand-searched references, this article relating to ziprasidone addresses its short- and long-term efficacy and safety, according to the results of randomized clinical trials, open-label studies and real-world experiences. Emerging evidence indicates that in patients with bipolar disorder, ziprasidone provides valid efficacy and remarkable safety when administered alone for the treatment of manic and mixed episodes. The same applies when ziprasidone is administered in combination with lithium or valproate for the prevention of affective relapses and recurrences. Any conclusion on the potential of ziprasidone as an antidepressant should be postponed because of insufficient evidence. [PubMed Citation] [Order full text from Infotrieve]

10) Chiesa A, Chierzi F, De Ronchi D, Serretti A
Quetiapine for bipolar depression: a systematic review and meta-analysis.
Int Clin Psychopharmacol. 2012 Mar;27(2):76-90.
Quetiapine has been proposed for depression in bipolar patients but a quantitative analysis is lacking. In the present paper, we review and meta-analyze available data about the short-term and long-term efficacy and tolerability of quetiapine for the depressive phase of bipolar disorder or bipolar depression. A literature research was carried out using three electronic databases. Studies providing measures of efficacy and tolerability of quetiapine, either as monotherapy or as augmentation, for bipolar depression were considered. Seven short-term studies and four maintenance studies were included. Short-term studies suggested that patients treated with quetiapine monotherapy were significantly more likely than patients treated with placebo and further active comparators to achieve higher response and remission rates as well as more clinical improvements at the endpoint. Such benefits were significant from the first weeks of treatment onward. Maintenance studies suggested that the combination of quetiapine and mood stabilizers was significantly better than placebo plus mood stabilizers for the prevention of both depressive and manic relapses. Quetiapine was generally well tolerated. Furthermore, several clinical variables moderated outcomes under investigation. In conclusion, quetiapine could have some advantages over traditional treatments for the treatment of bipolar depression. [PubMed Citation] [Order full text from Infotrieve]

11) Han C, Pogwizd SM, Killingsworth CR, He B
Noninvasive reconstruction of the three-dimensional ventricular activation sequence during pacing and ventricular tachycardia in the canine heart.
Am J Physiol Heart Circ Physiol. 2012 Jan 1;302(1):H244-52.
Single-beat imaging of myocardial activation promises to aid in both cardiovascular research and clinical medicine. In the present study we validate a three-dimensional (3D) cardiac electrical imaging (3DCEI) technique with the aid of simultaneous 3D intracardiac mapping to assess its capability to localize endocardial and epicardial initiation sites and image global activation sequences during pacing and ventricular tachycardia (VT) in the canine heart. Body surface potentials were measured simultaneously with bipolar electrical recordings in a closed-chest condition in healthy canines. Computed tomography images were obtained after the mapping study to construct realistic geometry models. Data analysis was performed on paced rhythms and VTs induced by norepinephrine (NE). The noninvasively reconstructed activation sequence was in good agreement with the simultaneous measurements from 3D cardiac mapping with a correlation coefficient of 0.74 ▒ 0.06, a relative error of 0.29 ▒ 0.05, and a root mean square error of 9 ▒ 3 ms averaged over 460 paced beats and 96 ectopic beats including premature ventricular complexes, couplets, and nonsustained monomorphic VTs and polymorphic VTs. Endocardial and epicardial origins of paced beats were successfully predicted in 72% and 86% of cases, respectively, during left ventricular pacing. The NE-induced ectopic beats initiated in the subendocardium by a focal mechanism. Sites of initial activation were estimated to be ?7 mm from the measured initiation sites for both the paced beats and ectopic beats. For the polymorphic VTs, beat-to-beat dynamic shifts of initiation site and activation pattern were characterized by the reconstruction. The present results suggest that 3DCEI can noninvasively image the 3D activation sequence and localize the origin of activation of paced beats and NE-induced VTs in the canine heart with good accuracy. This 3DCEI technique offers the potential to aid interventional therapeutic procedures for treating ventricular arrhythmias arising from epicardial or endocardial sites and to noninvasively assess the mechanisms of these arrhythmias. [PubMed Citation] [Order full text from Infotrieve]

12) Johansson J, Landgren M, Fernell E, Vumma R, ┼hlin A, Bjerkenstedt L, Venizelos N
Altered tryptophan and alanine transport in fibroblasts from boys with attention-deficit/hyperactivity disorder (ADHD): an in vitro study.
Behav Brain Funct. 2011;7:40.
[PubMed Citation] [Order full text from Infotrieve]

13) Jerrell JM, McIntyre RS, Tripathi A
Childhood treatment with psychotropic medication and development of comorbid medical conditions in adolescent-onset bipolar disorder.
Hum Psychopharmacol. 2011 Oct;26(7):451-9.
[PubMed Citation] [Order full text from Infotrieve]

14) Fountoulakis KN, Kelsoe JR, Akiskal H
Receptor targets for antidepressant therapy in bipolar disorder: an overview.
J Affect Disord. 2012 May;138(3):222-38.
The treatment of bipolar depression is one of the most challenging issues in contemporary psychiatry. Currently only quetiapine and the olanzapine-fluoxetine combination are officially approved by the FDA against this condition. The neurobiology of bipolar depression and the possible targets of bipolar antidepressant therapy remain relatively elusive. We performed a complete and systematic review to identify agents with definite positive or negative results concerning efficacy followed by a second systematic review to identify the pharmacodynamic properties of these agents. The comparison of properties suggests that the stronger predictors for antidepressant efficacy in bipolar depression were norepinephrine alpha-1, dopamine D1 and histamine antagonism, followed by 5-HT2A, muscarinic and dopamine D2 and D3 antagonism and eventually by norepinephrine reuptake inhibition and 5HT-1A agonism. Serotonin reuptake which constitutes the cornerstone in unipolar depression treatment does not seem to play a significant role for bipolar depression. Our exhaustive review is compatible with a complex model with multiple levels of interaction between the major neurotransmitter systems without a single target being either necessary or sufficient to elicit the antidepressant effect in bipolar depression. [PubMed Citation] [Order full text from Infotrieve]

15) Gamo NJ, Arnsten AF
Molecular modulation of prefrontal cortex: rational development of treatments for psychiatric disorders.
Behav Neurosci. 2011 Jun;125(3):282-96.
Dysfunction of the prefrontal cortex (PFC) is a central feature of many psychiatric disorders, such as attention deficit hyperactivity disorder (ADHD), posttraumatic stress disorder (PTSD), schizophrenia, and bipolar disorder. Thus, understanding molecular influences on PFC function through basic research in animals is essential to rational drug development. In this review, we discuss the molecular signaling events initiated by norepinephrine and dopamine that strengthen working memory function mediated by the dorsolateral PFC under optimal conditions, and weaken working memory function during uncontrollable stress. We also discuss how these intracellular mechanisms can be compromised in psychiatric disorders, and how novel treatments based on these findings may restore a molecular environment conducive to PFC regulation of behavior, thought and emotion. Examples of successful translation from animals to humans include guanfacine for the treatment of ADHD and related PFC disorders, and prazosin for the treatment of PTSD. [PubMed Citation] [Order full text from Infotrieve]

16) Flaherty AW
Brain illness and creativity: mechanisms and treatment risks.
Can J Psychiatry. 2011 Mar;56(3):132-43.
Brain diseases and their treatment may help or hurt creativity in ways that shape quality of life. Increased creative drive is associated with bipolar disorder, depression, psychosis, temporal lobe epilepsy, frontotemporal dementia, Parkinson disease treatments, and autism. Creativity depends on goal-driven approach motivation from midbrain dopaminergic systems. Fear-driven avoidance motivation is of less aid to creativity. When serotonin and norepinephrine lower motivation and flexible behaviour, they can inhibit creativity. Hemispheric lateralization and frontotemporal connections must interact to create new ideas and conceptual schemes. The right brain and temporal lobe contribute skill in novelty detection, while the left brain and frontal lobe foster approach motivation and more easily generate new patterns of action from the novel perceptions. Genes and phenotypes that increase plasticity and creativity in tolerant environments with relaxed selection pressure may confer risk in rigorous environments. Few papers substantively address this important but fraught topic. Antidepressants (ADs) that inhibit fear-driven motivation, such as selective serotonin reuptake inhibitors, sometimes inhibit goal-oriented motivation as well. ADs that boost goal-directed motivation, such as bupropion, may remediate this effect. Benzodiazepines and alcohol may be counterproductive. Although dopaminergic agonists sometimes stimulate creativity, their doing so may inappropriately disinhibit behaviour. Dopamine antagonists may suppress creative motivation; lithium and anticonvulsant mood stabilizers may do so less. Physical exercise and REM sleep may help creativity. Art therapy and psychotherapy are not well studied. Preserving creative motivation can help creativity and other aspects of well-being in all patients, not just artists or researchers. [PubMed Citation] [Order full text from Infotrieve]

17) ValentÝ M, Pacchiarotti I, Rosa AR, BonnÝn CM, Popovic D, Nivoli AM, Murru A, Grande I, Colom F, Vieta E
Bipolar mixed episodes and antidepressants: a cohort study of bipolar I disorder patients.
Bipolar Disord. 2011 Mar;13(2):145-54.
[PubMed Citation] [Order full text from Infotrieve]

18) Adida M, Jollant F, Clark L, Besnier N, Guillaume S, Kaladjian A, Mazzola-Pomietto P, Jeanningros R, Goodwin GM, Azorin JM, Courtet P
Trait-related decision-making impairment in the three phases of bipolar disorder.
Biol Psychiatry. 2011 Aug 15;70(4):357-65.
[PubMed Citation] [Order full text from Infotrieve]

19) Han C, Pogwizd SM, Killingsworth CR, He B
Noninvasive imaging of three-dimensional cardiac activation sequence during pacing and ventricular tachycardia.
Heart Rhythm. 2011 Aug;8(8):1266-72.
[PubMed Citation] [Order full text from Infotrieve]

20) Dell'Osso B, Palazzo MC, Oldani L, Altamura AC
The noradrenergic action in antidepressant treatments: pharmacological and clinical aspects.
CNS Neurosci Ther. 2011 Dec;17(6):723-32.
Even though noradrenaline has been recognized as one of the key neurotransmitters in the pathophysiology of major depression (MD), noradrenergic compounds have been less extensively utilized in clinical practice, compared to selective serotonin reuptake inhibitors (SSRIs). The development of the first selective noradrenergic reuptake inhibitor (NRI), Reboxetine, has not substantially changed the state of the art. In addition, Atomoxetine, a relatively pure NRI used for the treatment of ADHD, has shown mixed results when administered in augmentation to depressed subjects. Through a Medline search from 2000 to 2010, the present article provides an updated overview of the main pharmacological and clinical aspects of antidepressant classes that, partially or selectively, act on the noradrenergic systems. The noradrenergic action plays an important clinical effect in different antidepressant classes, as confirmed by the efficacy of dual action antidepressants such as the serotonin noradrenaline reuptake inhibitors (SNRIs), the noradrenergic and dopaminergic reuptake inhibitor (NDRI) Bupropion, and other compounds (e.g., Mianserin, Mirtazapine), which enhance the noradrenergic transmission. In addition, many tricyclics, such as Desipramine and Nortriptyline, have prevalent noradrenergic effect. Monoamine oxidase inhibitors (MAOIs), moreover, block the breakdown of serotonin, noradrenaline, dopamine and increase the availability of these monoamines. A novel class of antidepressants--the triple reuptake inhibitors--is under development to selectively act on serotonin, noradrenaline, and dopamine. Finally, the antidepressant effect of the atypical antipsychotic Quetiapine, indicated for the treatment of bipolar depression, is likely to be related to the noradrenergic action of its metabolite Norquetiapine. Even though a pure noradrenergic action might not be sufficient to obtain a full antidepressant effect, a pronoradrenergic action represents an important element for increasing the efficacy of mixed action antidepressants. In particular, the noradrenergic action seemed to be related to the motor activity, attention, and arousal. [PubMed Citation] [Order full text from Infotrieve]