norepinephrine, CRF, and unipolar depression


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On Site Link: CRF and Unipolar Depression

Gold PW, Chrousos GP.
Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states.
Mol Psychiatry 2002;7(3):254-75
"Stress precipitates depression and alters its natural history. Major depression and the stress response share similar phenomena, mediators and circuitries. Thus, many of the features of major depression potentially reflect dysregulations of the stress response. The stress response itself consists of alterations in levels of anxiety, a loss of cognitive and affective flexibility, activation of the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system, and inhibition of vegetative processes that are likely to impede survival during a life-threatening situation (eg sleep, sexual activity, and endocrine programs for growth and reproduction). Because depression is a heterogeneous illness, we studied two diagnostic subtypes, melancholic and atypical depression. In melancholia, the stress response seems hyperactive, and patients are anxious, dread the future, lose responsiveness to the environment, have insomnia, lose their appetite, and a diurnal variation with depression at its worst in the morning. They also have an activated CRH system and may have diminished activities of the growth hormone and reproductive axes. Patients with atypical depression present with a syndrome that seems the antithesis of melancholia. They are lethargic, fatigued, hyperphagic, hypersomnic, reactive to the environment, and show diurnal variation of depression that is at its best in the morning. In contrast to melancholia, we have advanced several lines of evidence of a down-regulated hypothalamic-pituitary adrenal axis and CRH deficiency in atypical depression, and our data show us that these are of central origin. Given the diversity of effects exerted by CRH and cortisol, the differences in melancholic and atypical depression suggest that studies of depression should examine each subtype separately. In the present paper, we shall first review the mediators and circuitries of the stress system to lay the groundwork for placing in context physiologic and structural alterations in depression that may occur as part of stress system dysfunction." [PDF] [Note that the authors use the atypical acronym CRH rather than the equivalent acronym CRF.]

Bissette G, Klimek V, Pan J, Stockmeier C, Ordway G.
Elevated concentrations of CRF in the locus coeruleus of depressed subjects.
Neuropsychopharmacology. 2003 Jul;28(7):1328-35. Epub 2003 May 21.
"Research evidence that corticotropin-releasing factor (CRF) plays a role in the pathophysiology of major depressive disorder (MDD) has accumulated over the past 20 years. The elevation of lumbar cerebrospinal fluid (CSF) concentrations of CRF decreased responsiveness of pituitary CRF receptors to challenge with synthetic CRF, and increased levels of serum cortisol in MDD subjects support the hypothesis that CRF is chronically hypersecreted in at least the endocrine circuits of the hypothalamic-pituitary-adrenal (HPA) axis and may also involve other CRF brain circuits mediating emotional responses and/or arousal. One such circuit includes the excitatory CRF input to the locus coeruleus (LC), the major source of norepinephrine in the brain. Furthermore, there are now reports of decreased levels of CRF in lumbar CSF from MDD patients after symptom relief from chronic treatment with antidepressant drugs or electroconvulsive therapy. Whether this normalization reflects therapeutic effects on both endocrine- and limbic-associated CRF circuits has not yet been effectively addressed. In this brief report, we describe increased concentrations of CRF-like immunoreactivity in micropunches of post-mortem LC from subjects with MDD symptoms as established by retrospective psychiatric diagnosis compared to nondepressed subjects matched for age and sex." [Abstract]

Austin MC, Janosky JE, Murphy HA.
Increased corticotropin-releasing hormone immunoreactivity in monoamine-containing pontine nuclei of depressed suicide men.
Mol Psychiatry. 2003 Mar;8(3):324-32.
"A number of clinical investigations and postmortem brain studies have provided evidence that excessive corticotropin-releasing hormone (CRH) secretion and neurotransmission is involved in the pathophysiology of depressive illness, and several studies have suggested that the hyperactivity in CRH neurotransmission extends beyond the hypothalamus involving several extra-hypothalamic brain regions. The present study was designed to test the hypothesis that CRH levels are increased in specific brainstem regions of suicide victims with a diagnosis of major depression. Frozen tissue sections of the pons containing the locus coeruleus and caudal raphe nuclei from 11 matched pairs of depressed suicide and control male subjects were processed for radioimmunocytochemistry using a primary antiserum to CRH and a ([125])I-IgG secondary antibody. The optical density corresponding to the level of CRH-immunoreactivity (IR) was quantified in specific pontine regions from the film autoradiographic images. The level of CRH-IR was increased by 30% in the locus coeruleus, 39% in the median raphe and 45% in the caudal dorsal raphe in the depressed suicide subjects compared to controls. No difference in CRH-IR was found in the dorsal tegmentum or medial parabrachial nucleus between the subject groups. These findings reveal that CRH-IR levels are specifically increased in norepinephrine- and serotonin-containing pontine nuclei of depressed suicide men, and thus they are consistent with the hypothesis that CRH neurotransmission is elevated in extra-hypothalamic brain regions of depressed subjects." [Abstract]

Bissette G, Klimek V, Pan J, Stockmeier C, Ordway G.
Elevated Concentrations of CRF in the Locus Coeruleus of Depressed Subjects.
Neuropsychopharmacology. 2003 Jul;28(7):1328-35.
"Research evidence that corticotropin-releasing factor (CRF) plays a role in the pathophysiology of major depressive disorder (MDD) has accumulated over the past 20 years. The elevation of lumbar cerebrospinal fluid (CSF) concentrations of CRF decreased responsiveness of pituitary CRF receptors to challenge with synthetic CRF, and increased levels of serum cortisol in MDD subjects support the hypothesis that CRF is chronically hypersecreted in at least the endocrine circuits of the hypothalamic-pituitary-adrenal (HPA) axis and may also involve other CRF brain circuits mediating emotional responses and/or arousal. One such circuit includes the excitatory CRF input to the locus coeruleus (LC), the major source of norepinephrine in the brain. Furthermore, there are now reports of decreased levels of CRF in lumbar CSF from MDD patients after symptom relief from chronic treatment with antidepressant drugs or electroconvulsive therapy. Whether this normalization reflects therapeutic effects on both endocrine- and limbic-associated CRF circuits has not yet been effectively addressed. In this brief report, we describe increased concentrations of CRF-like immunoreactivity in micropunches of post-mortem LC from subjects with MDD symptoms as established by retrospective psychiatric diagnosis compared to nondepressed subjects matched for age and sex." [Abstract]

Zhu MY, Klimek V, Dilley GE, Haycock JW, Stockmeier C, Overholser JC, Meltzer HY, Ordway GA.
Elevated levels of tyrosine hydroxylase in the locus coeruleus in major depression.
Biol Psychiatry. 1999 Nov 1;46(9):1275-86.
"BACKGROUND: Levels of tyrosine hydroxylase (TH) are regulated in the noradrenergic locus coeruleus (LC) in response to changes in the activity of LC neurons and in response to changes in brain levels of norepinephrine. To study the potential role of central noradrenergic neurons in the pathobiology of major depression, TH protein was measured in the LC from postmortem brains of 13 subjects with a diagnosis of major depression and 13 age-matched control subjects having no Axis I psychiatric diagnosis. Most of the major depressive subjects died as a result of suicide. METHODS: Protein from sections cut through multiple rostro-caudal levels of LC was transferred to Immobilon-P membrane, immunoblotted for TH, and quantified autoradiographically. RESULTS: The distribution of TH-immunoreactivity (TH-ir) along the rostro-caudal axis of the LC was uneven and was paralleled by a similar uneven distribution of neuromelanin-containing cells in both major depressive and psychiatrically normal control subjects. Amounts of TH-ir in the rostral, middle and caudal levels of the LC from major depressive subjects were significantly higher than that of matched control subjects. There were no significant differences in the number of noradrenergic cells at any particular level of the LC comparing major depressive subjects to control subjects. CONCLUSIONS: Elevated expression of TH in the LC in major depression implies a premortem overactivity of these neurons, or a deficiency of the cognate transmitter, norepinephrine." [Abstract]

Ordway GA, Smith KS, Haycock JW.
Elevated tyrosine hydroxylase in the locus coeruleus of suicide victims.
J Neurochem. 1994 Feb;62(2):680-5.
"The amounts of tyrosine hydroxylase protein in locus coeruleus from nine pairs of antidepressant-free suicide victims and age-matched, sudden-death control cases were determined by quantitative blot immunolabeling of cryostat-cut sections from the caudal portion of the nucleus. In each of the nine age-matched pairs, the concentration of tyrosine hydroxylase was greater in the sample from the suicide victim, with values ranging from 108 to 172% of the matched control value (mean = 136%). By contrast, there were no differences in the concentrations of neuron-specific enolase protein in the same set of samples. Similarly, the number of neuromelanin-containing cells, counted in sections of locus coeruleus adjacent to those taken for blot immunolabeling analyses, did not differ between the two groups. These data indicate that locus coeruleus neurons from suicide victims contain higher than normal concentrations of tyrosine hydroxylase, thus raising the possibility that the expression of tyrosine hydroxylase in locus coeruleus may be relevant in the pathophysiology of suicide." [Abstract]

Brady LS, Whitfield HJ Jr, Fox RJ, Gold PW, Herkenham M.
Long-term antidepressant administration alters corticotropin-releasing hormone, tyrosine hydroxylase, and mineralocorticoid receptor gene expression in rat brain. Therapeutic implications.
J Clin Invest. 1991 Mar;87(3):831-7.
"Imipramine is the prototypic tricyclic antidepressant utilized in the treatment of major depression and exerts its therapeutic efficacy only after prolonged administration. We report a study of the effects of short-term (2 wk) and long-term (8 wk) administration of imipramine on the expression of central nervous system genes among those thought to be dysregulated in imipramine-responsive major depression. As assessed by in situ hybridization, 8 wk of daily imipramine treatment (5 mg/kg, i.p.) in rats decreased corticotropin-releasing hormone (CRH) mRNA levels by 37% in the paraventricular nucleus (PVN) of the hypothalamus and decreased tyrosine hydroxylase (TH) mRNA levels by 40% in the locus coeruleus (LC). These changes were associated with a 70% increase in mRNA levels of the hippocampal mineralocorticoid receptor (MR, type I) that is thought to play an important role in mediating the negative feedback effects of low levels of steroids on the hypothalamic-pituitary-adrenal (HPA) axis. Imipramine also decreased proopiomelanocortin (POMC) mRNA levels by 38% and glucocorticoid receptor (GR, type II) mRNA levels by 51% in the anterior pituitary. With the exception of a 20% decrease in TH mRNA in the LC after 2 wk of imipramine administration, none of these changes in gene expression were evident as a consequence of short-term administration of the drug. In the light of data that major depression is associated with an activation of brain CRH and LC-NE systems, the time-dependent effect of long-term imipramine administration on decreasing the gene expression of CRH in the hypothalamus and TH in the LC may be relevant to the therapeutic efficacy of this agent in depression." [Abstract]

EJ Nestler, A McMahon, EL Sabban, JF Tallman, and RS Duman
Chronic Antidepressant Administration Decreases the Expression of Tyrosine Hydroxylase in the Rat Locus Coeruleus
PNAS 87: 7522-7526, 1990.
"Regulation of tyrosine hydroxylase expression by antidepressant treatments was investigated in the locus coeruleus (LC), the major noradrenergic nucleus in brain. Rats were treated chronically with various antidepressants, and tyrosine hydroxylase levels were measured in the LC by immunoblot analysis. Representatives of all major classes of antidepressant medication-including imipramine, nortriptyline, tranylcypromine, fluvoxamine, fluoxetine, bupropion, iprindole, and electroconvulsive seizures-were found to decrease levels of tyrosine hydroxylase immunoreactivity by 40-70% in the LC. Decreased levels of enzyme immunoreactivity were shown to be associated with equivalent decreases in enzyme mRNA levels. Antidepressant regulation of LC tyrosine hydroxylase appeared specific to these compounds, inasmuch as chronic treatment of rats with representatives of other classes of psychotropic drugs, including haloperidol, diazepam, clonidine, cocaine, and morphine, failed to decrease levels of this protein. The results demonstrate that chronic antidepressants dramatically downregulate the expression of tyrosine hydroxylase in the LC and raise the possibility that such regulation of the enzyme represents an adaptive response of LC neurons to antidepressants that mediates some of their therapeutic actions in depression and/or other psychiatric disturbances." [Abstract]

Melia KR, Nestler EJ, Duman RS.
Chronic imipramine treatment normalizes levels of tyrosine hydroxylase in the locus coeruleus of chronically stressed rats.
Psychopharmacology (Berl). 1992;108(1-2):23-6.
"Previous studies have demonstrated that chronic stress increases and antidepressant treatments decrease levels of tyrosine hydroxylase (TH) in locus coeruleus (LC). In the present study, the influence of chronic antidepressant treatment on the induction of TH immunoreactivity in response to cold stress is examined. It was found that chronic imipramine pretreatment (18 days) attenuated the induction of TH in response to cold stress, resulting in levels of TH immunoreactivity not different from control. In contrast, imipramine pretreatment for 1 or 7 days was not sufficient to normalize the stress-induced elevation of TH immunoreactivity. These findings raise the possibility that the therapeutic action of antidepressants may be derived, in part, from the ability of these treatments to normalize levels of TH and thereby the function of the NE neurotransmitter system under conditions of stress." [Abstract]

Butterweck V, Winterhoff H, Herkenham M.
Hyperforin-Containing Extracts of St John's Wort Fail to Alter Gene Transcription in Brain Areas Involved in HPA Axis Control in a Long-Term Treatment Regimen in Rats.
Neuropsychopharmacology. 2003 Jul 16 [Epub ahead of print].
"Fluoxetine (10 mg/kg) given daily for 8 weeks, but not 2 weeks, significantly decreased levels of corticotropin-releasing hormone (CRH) mRNA by 22% in the paraventricular nucleus (PVN) of the hypothalamus and tyrosine hydroxylase (TH) mRNA by 23% in the locus coeruleus. Fluoxetine increased levels of mineralocorticoid (MR) (17%), glucocorticoid (GR) (18%), and 5-HT(1A) receptor (21%) mRNAs in the hippocampus at 8, but not 2, weeks." [Abstract]

Zeng J, Kitayama I, Yoshizato H, Zhang K, Okazaki Y.
Increased expression of corticotropin-releasing factor receptor mRNA in the locus coeruleus of stress-induced rat model of depression.
Life Sci. 2003 Jul 18;73(9):1131-9.
"Hypersecretion of corticotropin-releasing factor (CRF) has been hypothesized to occur in depression. To investigate CRF receptor (CRFR) response to the increased production of CRF in chronically stressed rats, we measured by in situ hybridization the expression of CRFR mRNA in the locus coeruleus (LC) concomitant with measuring plasma adrenocorticotropin (ACTH). The expression of both CRFR mRNA in the LC and the plasma level of ACTH increased significantly in "depression-model rats" which exhibit reduced activity following exposure to 14 days forced walking stress (FWS), but not in "spontaneous recovery rats" whose activity was restored after the long-term stress. These results suggest that the LC neurons continue to be stimulated by CRF, and that the hypothalamic-pituitary-adrenal (HPA) axis is hyperfunctioning in the depression-model rats." [Abstract]

Jezova D, Ochedalski T, Glickman M, Kiss A, Aguilera G.
Central corticotropin-releasing hormone receptors modulate hypothalamic-pituitary-adrenocortical and sympathoadrenal activity during stress.
Neuroscience. 1999;94(3):797-802.
"The role of brain corticotropin-releasing hormone receptors in modulating hypothalamic-pituitary-adrenal and sympathoadrenal responses to acute immobilization stress was studied in conscious rats under central corticotropin-releasing hormone receptor blockade by intracerebroventricular injection of a peptide corticotropin-releasing hormone receptor antagonist. Blood for catecholamines, adrenocorticotropic hormone and corticosterone levels was collected through vascular catheters, and brains were removed at 3 h for in situ hybridization for tyrosine hydroxylase messenger RNA in the locus coeruleus, and corticotropin-releasing hormone and corticotropin-releasing hormone receptor messenger RNA in the hypothalamic paraventricular nucleus. Central corticotropin-releasing hormone receptor blockade reduced the early increases in plasma epinephrine and dopamine, but not norepinephrine, during stress. Immobilization stress increased tyrosine hydroxylase messenger RNA levels in the locus coeruleus by 36% in controls, but not in corticotropin-releasing hormone antagonist-injected rats. In control rats, corticotropin-releasing hormone messenger RNA and type 1 corticotropin-releasing hormone receptor messenger RNA in the paraventricular nucleus increased after stress (P<0.01), and these responses were attenuated by central corticotropin-releasing hormone receptor blockade. In contrast, central corticotropin-releasing hormone antagonist potentiated plasma adrenocorticotropic hormone responses, but slightly attenuated plasma corticosterone responses to stress. The inhibition of plasma catecholamine and locus coeruleus tyrosine hydroxylase messenger RNA responses to stress by central corticotropin-releasing hormone receptor blockade supports the notion that central corticotropin-releasing hormone regulates sympathoadrenal responses during stress. The attenuation of stress-induced corticotropin-releasing hormone and corticotropin-releasing hormone receptor messenger RNA responses by central corticotropin-releasing hormone receptor blockade suggests direct or indirect positive feedback effects of corticotropin-releasing hormone receptor ligands on corticotropin-releasing hormone expression, whereas additional mechanisms potentiate adrenocorticotropic hormone responses at the pituitary level. In addition, changes in neural activity by central corticotropin-releasing hormone are likely to modulate adrenocortical responsiveness during stress." [Abstract]

Roy A, Pickar D, Linnoila M, Chrousos GP, Gold PW.
Cerebrospinal fluid corticotropin-releasing hormone in depression: relationship to noradrenergic function.
Psychiatry Res 1987 Mar;20(3):229-37
"We investigated the neurotransmitter regulation of corticotropin-releasing hormone (CRH). Among 21 depressed patients cerebrospinal fluid (CSF) levels of CRH significantly correlated with urinary outputs of norepinephrine and its major metabolites, and there were trends for significant correlations with both CSF and plasma levels of norepinephrine. These results suggest that CRH may be associated with the dysregulation of the norepinephrine system that is found in [depression]." [Abstract]

Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB.
The role of corticotropin-releasing factor in depression and anxiety disorders.
J Endocrinol 1999 Jan;160(1):1-12
"In the present review, we describe the evidence suggesting that CRF is hypersecreted from hypothalamic as well as from extrahypothalamic neurons in depression, resulting in hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and elevations of cerebrospinal fluid (CSF) concentrations of CRF. This increase in CRF neuronal activity is also believed to mediate certain of the behavioral symptoms of depression involving sleep and appetite disturbances, reduced libido, and psychomotor changes. The hyperactivity of CRF neuronal systems appears to be a state marker for depression because HPA axis hyperactivity normalizes following successful antidepressant treatment. Similar biochemical and behavioral findings have been observed in adult rats and monkeys that have been subjected to early-life stress. In contrast, clinical studies have not revealed any consistent changes in CSF CRF concentrations in patients with anxiety disorders; however, preclinical findings strongly implicate a role for CRF in the pathophysiology of certain anxiety disorders, probably through its effects on central noradrenergic systems. The findings reviewed here support the hypothesis that CRF receptor antagonists may represent a novel class of antidepressants and/or anxiolytics." [Abstract]

Banki CM, Bissette G, Arato M, O'Connor L, Nemeroff CB.
CSF corticotropin-releasing factor-like immunoreactivity in depression and schizophrenia.
Am J Psychiatry 1987 Jul;144(7):873-7
"To further investigate the hypothesis that hyperactivity of the hypothalamic-pituitary-adrenal axis in patients with depression may be mediated by hypersecretion of corticotropin-releasing factor (CRF), the authors measured CRF-like immunoreactivity in CSF samples from 138 neurological control, 54 depressed, and 27 nondepressed (23 schizophrenic and four manic) subjects. The CSF CRF concentration was markedly higher (almost twofold) in depressed patients than in control subjects and nondepressed psychiatric patients. The concentration of CSF CRF was slightly but significantly higher in schizophrenic patients than in control subjects. These findings provide further support for the hypothesis that CRF hypersecretion occurs in major depression."

Schulz C, Lehnert H.
Activation of noradrenergic neurons in the locus coeruleus by corticotropin-releasing factor. A microdialysis study.
Neuroendocrinology 1996 May;63(5):454-8
"In the present study the effects of different doses of corticotropin-releasing factor (CRF) and the CRF antagonist alpha-helical CRF on locus coeruleus (LC) neurons were studied in anesthetized male Wistar rats. To monitor the release of noradrenaline (NA) and its metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), a microdialysis probe was implanted into the parietal cortex, a major projection area of the LC. Saline, 0.17, 0.51 nmol CRF and a combination of 5.1 nmol alpha-helical CRF and 0.51 nmol CRF were applied to the LC via a fused silica capillary. While both doses of CRF augmented NA in parietal cortex dialysates (0.51 nmol CRF: from 0.0206 to 0.0266 pmol/sample; 0.17 nmol CRF: from 0.0147 to 0.0170 pmol/sample), saline did not affect NA concentration. The metabolite MHPG also increased, but in a more prolonged time course. The antagonist alpha-helical CRF attenuated the CRF effects. The increase of extraneuronal NA concentration monitored in the cortical samples indicates an augmented depolarization rate of noradrenergic LC neurons. This clearly demonstrates the activation of these neurons by CRF, suggesting physiological interactions of CRF and noradrenergic neurons." [Abstract]

Emoto H, Tanaka M, Koga C, Yokoo H, Tsuda A, Yoshida M.
Corticotropin-releasing factor activates the noradrenergic neuron system in the rat brain.
Pharmacol Biochem Behav 1993 Jun;45(2):419-22
"The effect of corticotropin-releasing factor (CRF) on central noradrenaline (NA) metabolism was examined by measuring levels of the major metabolite of NA, 3-methoxy-4-hydroxy-phenylethyleneglycol sulfate (MHPG-SO4) in several rat brain regions. Various doses of CRF ranging from 0.5-10 micrograms injected ICV significantly increased MHPG-SO4 levels in several brain regions including the hypothalamus, amygdala, midbrain, locus coeruleus (LC) region, and pons + medulla oblongata excluding the LC region. Plasma corticosterone levels were also significantly increased after ICV CRF administration up to 0.5 micrograms. The present results that CRF not only elevates plasma corticosterone levels but also increases NA metabolism in many brain regions suggest its neurotransmitter and/or neuromodulator role exerting the excitatory action on central NA neurons." [Abstract]

Emoto H, Koga C, Ishii H, Yokoo H, Yoshida M, Tanaka M.
A CRF antagonist attenuates stress-induced increases in NA turnover in extended brain regions in rats.
Brain Res 1993 Nov 5;627(1):171-6
"We investigated the effects of intracerebroventricular (i.c.v.) administration of corticotropin-releasing factor (CRF) antagonist, alpha-helical CRF9-41 (ahCRF), on increases in noradrenaline (NA) turnover caused by immobilization stress in rat brain regions. Pretreatment with ahCRF (50 or 100 micrograms) significantly attenuated increases in levels of 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4), the major metabolite of NA in rat brain, in the locus coeruleus (LC) region, and attenuated the MHPG-SO4/NA ratio after immobilization stress for 50 min in the cerebral cortex, hippocampus, amygdala, midbrain and hypothalamus. However, stress-induced increases in plasma corticosterone levels were not decreased significantly by pretreatment with ahCRF. These results suggest that CRF, released during stress, causes increases in NA release in extended brain regions of stressed rats." [Abstract]

Valentino RJ, Foote SL, Page ME.
The locus coeruleus as a site for integrating corticotropin-releasing factor and noradrenergic mediation of stress responses.
Ann N Y Acad Sci 1993 Oct 29;697:173-88
"It could be predicted that the effects of CRF neurotransmission in the LC during stress would enhance information processing concerning the stressor or stimuli related to the stressor by LC target neurons. One consequence of this appears to be increased arousal. Although this may be adaptive in the response to an acute challenge, it could be predicted that chronic CRF release in the LC would result in persistently elevated LC discharge and norepinephrine release in targets. This could be associated with hyperarousal and loss of selective attention as occurs in certain psychiatric diseases. Manipulation of endogenous CRF systems may be a novel way in which to treat psychiatric diseases characterized by these maladaptive effects." [Abstract]

Curtis AL, Valentino RJ.
Corticotropin-releasing factor neurotransmission in locus coeruleus: a possible site of antidepressant action.
Brain Res Bull 1994;35(5-6):581-7
"Hypersecretion of corticotropin-releasing factor (CRF), has been hypothesized to occur in depression. Because CRF may serve as a neurotransmitter in the locus coeruleus (LC), it was proposed that CRF hypersecretion in the LC is responsible for some characteristics of depression, and that antidepressants act by interfering with CRF neurotransmission in the LC. To test this hypothesis, the acute and chronic effects of four antidepressants and cocaine were characterized on LC spontaneous and sensory-evoked discharge, LC activation by a stressor that requires CRF release, and LC activation by exogenously administered CRF. None of the antidepressants or cocaine altered LC activation by intracerebroventricularly administered CRF (3.0 microgram) after chronic administration. However, chronic administration of desmethylimipramine and mianserin inhibited LC activation by a hypotensive stress that requires endogenous CRF release, suggesting that they decrease CRF release in the LC. Chronic administration of sertraline and phenelzine altered LC responses to repeated sciatic nerve stimulation in a manner opposite to the effect produced by CRF, suggesting that these drugs may functionally antagonize CRF actions in the LC. Cocaine did not appear to interfere with CRF actions in the LC. In conclusion, chronic administration of antidepressants may have the potential to interfere with CRF neurotransmission in the LC." [Abstract]

Valentino RJ, Curtis AL.
Pharmacology of locus coeruleus spontaneous and sensory-evoked activity.
Prog Brain Res 1991;88:249-56
"Neuroendocrine and catecholamine dysfunctions in depression may be linked by corticotropin-releasing factor (CRF) effects on locus coeruleus (LC) neurons. One consequence of CRF hypersecretion in depression would be persistent elevated levels of LC discharge and diminished responses to phasic sensory stimuli. The hypothesis that antidepressants could reverse these changes was tested by characterizing effects of pharmacologically distinct antidepressants on LC sensory-evoked discharge, LC activation by stress, and LC activation by CRF. The most consistent effect of all of the antidepressants tested was a decrease in LC sensory-evoked discharge after acute administration. However, tolerance occurs to these effects after chronic administration. With chronic administration each of the antidepressants produced effects which could potentially interfere with CRF function in the LC. Desmethylimipramine and mianserin attenuated LC activation by a stressor which requires endogenous CRF, suggesting that these antidepressants attenuate stress-elicited release of CRF and perhaps the hypersecretion that occurs in depression. The serotonin reuptake inhibitor, sertraline (SER), enhanced the signal-to-noise ratio of the LC sensory response, an effect opposite to that of CRF. Thus, SER could serve as a functional antagonist of CRF that is hypersecreted in depression. The finding that three pharmacologically distinct antidepressants share the potential to interfere with CRF function in the LC implies that this may be an important common mechanism for antidepressant activity." [Abstract]

Curtis, Andre L., Pavcovich, Luis A., Valentino, Rita J.
Long-Term Regulation of Locus Ceruleus Sensitivity to Corticotropin-Releasing Factor by Swim Stress
J Pharmacol Exp Ther 1999 289: 1211-1219
"Corticotropin-releasing factor (CRF) acts as a putative neurotransmitter in the locus ceruleus (LC) to mediate its activation by certain stressors. In this study, we quantified LC sensitivity to CRF 24 h after swim stress, at a time when behavioral depression that is sensitive to antidepressants is apparent. Rats were placed in a tank with 30 cm (swim stress) or 4 cm water and 24 h later, either behavior was monitored in a forced swim test or LC discharge was recorded. Swim stress rats were more immobile than control animals in the swim test. LC neurons of swim stress rats were sensitized to low doses of CRF (0.1-0.3 µg i.c.v.) that were ineffective in control animals and were desensitized to higher doses. Swim stress selectively altered LC sensitivity to CRF because neither LC spontaneous discharge nor responses to other agents (e.g., carbachol, vasoactive intestinal peptide) were altered. Finally, the mechanism for sensitization was localized to the LC because neuronal activation by low doses of CRF was prevented by the intracerulear administration of a CRF antagonist. CRF dose-response curves were consistent with a two-site model with similar dissociation constants under control conditions but divergent dissociation constants after swim stress. The results suggest that swim stress (and perhaps other stressors) functionally alters CRF receptors that have an impact on LC activity. Stress-induced regulation of LC sensitivity to CRF may underlie behavioral aspects of stress-related psychiatric disorders." [Full Text]

Van Bockstaele EJ, Colago EE, Valentino RJ.
Corticotropin-releasing factor-containing axon terminals synapse onto catecholamine dendrites and may presynaptically modulate other afferents in the rostral pole of the nucleus locus coeruleus in the rat brain.
J Comp Neurol 1996 Jan 15;364(3):523-534 [Abstract]

Smagin GN, Swiergiel AH, Dunn AJ.
Corticotropin-releasing factor administered into the locus coeruleus, but not the parabrachial nucleus, stimulates norepinephrine release in the prefrontal cortex.
Brain Res Bull 1995;36(1):71-6 [Abstract]

Lamberts SW, Bons E, Zuiderwijk J.
High concentrations of catecholamines selectively diminish the sensitivity of CRF-stimulated ACTH release by cultured rat pituitary cells to the suppressive effects of dexamethasone.
Life Sci 1986 Jul 14;39(2):97-102
"ACTH-release by primary cultures of rat anterior pituitary cells in response to CRF, vasopressin, epinephrine, norepinephrine and VIP is readily suppressible by dexamethasone. Rat hypothalamic extract-induced ACTH release is less sensitive to the inhibitory effect of dexamethasone than that elicited by CRF and the other secretagogues mentioned above. In studying the additive and potentiating effect on ACTH release of CRF in combination with vasopressin, VIP and the catecholamines it became evident that only the combination of micromolar concentrations of epinephrine or norepinephrine together with nanomolar concentrations of CRF will make ACTH release significantly less sensitive to the suppressive effect of dexamethasone. Other combinations of CRF and vasopressin or CRF and VIP will render ACTH release as suppressible to dexamethasone, as that elicited by each of these compounds by itself. This observation in the rat might explain at least in part the observation that a diminished suppressibility of the pituitary-adrenal axis to dexamethasone can be found in patients with psychiatric disease, especially depression." [Abstract]

Maes M, Vandewoude M, Schotte C, Martin M, Blockx P.
Positive relationship between the catecholaminergic turnover and the DST results in depression.
Psychol Med. 1990 Aug;20(3):493-9.
"In the past some workers have reported positive relationships between indices of noradrenaline activity and measures of hypothalamic-pituitary-adrenal (HPA)-axis function. In order to investigate these relations, the authors measured noradrenaline, adrenaline and vanillylmandelic acid (VMA) in 24 h urine samples of 72 depressed females. Serum adrenocorticotrophic hormone (ACTH) and cortisol concentrations were determined before and after administration of 1 mg of dexamethasone. Cortisol non-suppressors exhibited a significantly higher noradrenaline, adrenaline and VMA excretion as compared to cortisol suppressors. We determined significantly positive correlations between the postdexamethasone cortisol values and the excretion rates of noradrenaline and VMA. These indices of noradrenaline activity correlated neither with the baseline cortisol and ACTH nor with the postdexamethasone ACTH values." [Abstract]

Roy A, Pickar D, De Jong J, Karoum F, Linnoila M.
Norepinephrine and its metabolites in cerebrospinal fluid, plasma, and urine. Relationship to hypothalamic-pituitary-adrenal axis function in depression.
Arch Gen Psychiatry 1988 Sep;45(9):849-57
"Among 140 depressed and control subjects, there were significant positive correlations between indexes of noradrenergic activity in cerebrospinal fluid (CSF), plasma, and urine. Among the depressed patients, CSF levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and urinary outputs of NE and its metabolites normetanephrine, MHPG, and vanillylmandelic acid correlated significantly with plasma cortisol levels in relation to dexamethasone administration. Also, CSF levels of MHPG were significantly higher among patients who were cortisol nonsuppressors than among either patients who were cortisol suppressors or controls. Urinary outputs of NE and normetanephrine were significantly higher among patients who were cortisol nonsuppressors than among controls. Patients who were cortisol suppressors had indexes of NE metabolism similar to those of controls. These results in the depressed patients extend recent observations suggesting that dysregulation of the noradrenergic system and hypothalamic-pituitary-adrenal axis occur together in a subgroup of depressed patients." [Abstract]

Golczynska A, Lenders JW, Goldstein DS.
Glucocorticoid-induced sympathoinhibition in humans.
Clin Pharmacol Ther. 1995 Jul;58(1):90-8.
"OBJECTIVE: To test whether glucocorticoids inhibit sympathetic nerve activity or norepinephrine release in humans, as has been suggested by results in laboratory animals. METHODS: This was a double-blind, placebo-controlled, randomized crossover study performed at the Clinical Center of the National Institutes of Health. Thirteen normal volunteers received 20 mg prednisone or placebo orally each morning for 1 week, followed by a washout period of 1 week and then by treatment with the other drug for 1 week. On the last day of each treatment week, blood samples were drawn for measurements of plasma levels of catecholamines and their metabolites, of cortisol, and of corticotropin at baseline and during reflexive sympathetic stimulation elicited by lower body negative pressure (-15 mm Hg). A 24-hour urine collection was obtained at the end of each week of treatment for measurement of urinary excretion of catechols. In eight subjects, directly recorded peroneal skeletal muscle sympathetic nerve activity was also measured after both treatments. RESULTS: Prednisone significantly decreased sympathetic nerve activity by 23% +/- 6%, plasma norepinephrine levels by 27% +/- 6%, and plasma corticotropin levels by 77%. Blood pressure, heart rate, body weight, and urinary excretion of catechols and electrolytes were unaffected. Prednisone did not alter proportionate increments in sympathetic nerve activity or plasma norepinephrine levels during lower body negative pressure. Relationships between sympathetic nerve activity and plasma norepinephrine levels were unchanged. CONCLUSIONS: Glucocorticoids decrease sympathoneural outflows in humans without affecting acute sympathoneural responses to decreased cardiac filling and probably without affecting presynaptic modulation of norepinephrine release." [Abstract]

Raucoules D, Levy C, Azorin JM, Bruno M, Valli M.
[Plasma levels of MHPG, HVA and total 5-HIAA in depression. Preliminary study]
Encephale 1992 Nov-Dec;18(6):611-6
"This study was aimed at assessing monoamine catabolites plasma levels in depressed patients and healthy volunteers. Plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) of 21 control subjects and 26 depressed patients (according to DSM III-R criteria) were measured at baseline (day 0) and day 4, day 7, day 30 of prescribed antidepressant treatment. The clinical assessment, at baseline as well as during treatment, used the Hamilton depression rating scale and the BPRS. Our data show the interest of these results in predicting response. The respondent patients showed a significant decrease in plasma MHPG level at J7, contrary to non-respondent patients. Moreover, a positive correlation between plasma levels of MHPG and HVA before any prescribed antidepressants was found only with respondent patients. The lack of correlation for non-respondent patients can suggest that the relationships between this monoamine systems should be disrupted in these patients." [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]

Roy A, Pickar D, Douillet P, Karoum F, Linnoila M.
Urinary monoamines and monoamine metabolites in subtypes of unipolar depressive disorder and normal controls.
Psychol Med 1986 Aug;16(3):541-6
"An examination was made of urinary catecholamine and metabolite outputs in 28 unipolar depressed patients and 25 normal controls. The total group of depressed patients had significantly higher urinary outputs of norepinephrine (NE) and its metabolite normetanephrine (NM), and significantly lower urinary outputs of the dopamine metabolite dihydroxyphenylacetic acid (DOPAC), than controls. Patients who met DSM-III criteria for a major depressive episode with melancholia (N = 8) had significantly higher urinary outputs of normetanephrine than controls, whereas patients with a major depressive episode without melancholia (N = 7) and dysthymic disorder patients (N = 8) had levels comparable with controls. We postulate that the higher urinary outputs of norepinephrine and its metabolite, normetanephrine, reflect dysregulation of the sympathetic nervous system in depression." [Abstract]

Roy A, Linnoila M, Karoum F, Pickar D.
Relative activity of metabolic pathways for norepinephrine in endogenous depression.
Acta Psychiatr Scand 1986 Jun;73(6):624-8
"Thirteen patients with endogenous depression, compared to 25 normal controls, had a significantly greater ratio of the urinary excretion of norepinephrine plus its metabolite normetanephrine to either the sum of the two urinary norepinephrine metabolites 3-methoxy-4-hydroxyphenylglycol plus vanillylmandelic acid or to the sum of urinary norepinephrine and all of its metabolites. As urinary levels of norepinephrine and normetanephrine are derived from an extraneuronal metabolic pathway, while levels of 3-methoxy-4-hydroxyphenylglycol and vanillylmandelic acid are more representative of total norepinephrine metabolism, these results suggest that there is a shift in endogenous depression to extraneuronal metabolic pathways for norepinephrine and its metabolites." [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]

Roy A, Pickar D, Linnoila M, Doran AR, Ninan P, Paul SM.
Cerebrospinal fluid monoamine and monoamine metabolite concentrations in melancholia.
Psychiatry Res 1985 Aug;15(4):281-92
"Cerebrospinal fluid levels of norepinephrine and six monoamine metabolites were measured in 28 medication-free depressed patients. Patients with a major depressive episode with melancholia (n = 15) had significantly lower levels of the three dopamine metabolites: homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC), and conjugated dihydroxyphenylacetic (CONJDOPAC), when compared with a combined group of patients with a major depressive episode or dysthymic disorder (n = 13). In patients with major depressive episode with melancholia, levels of HVA and of the serotonin metabolite 5-hydroxyindoleacetic acid significantly correlated with the severity of depression. In the total group of 28 depressed patients, cerebrospinal fluid (CSF) levels of norepinephrine significantly correlated with symptoms of anxiety. In both patients with major depressive episode and major depressive episode with melancholia, those who were non-suppressors on the dexamethasone suppression test had significantly higher CSF levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol compared to those who were suppressors." [Abstract]

Yazici O, Aricioglu F, Gurvit G, Ucok A, Tastaban Y, Canberk O, Ozguroglu M, Durat T, Sahin D.
Noradrenergic and serotoninergic depression?
J Affect Disord 1993 Feb;27(2):123-9
"The only significant finding in this study was the obvious decrease in MHPG excretion during the antidepressant treatment in the group with high pretreatment MHPG." [Abstract]

Potter WZ, Manji HK.
Catecholamines in depression: an update.
Clin Chem 1994 Feb;40(2):279-87
"Despite extensive research, the biochemical abnormalities underlying the predisposition to and the pathogenesis of affective disorders remain to be clearly established. Efforts to study norepinephrine (NE) output and function have utilized biochemical assays, neuroendocrine challenge strategies, and measures of peripheral blood cell receptors; the cumulative database points to a dysregulation of the noradrenergic system. Depressed patients (in particular, melancholic, unipolar subjects) excrete disproportionately greater amounts of NE and its major extraneuronal metabolite, normetanephrine, than do controls. Depressed patients also show subsensitive neuroendocrine (growth hormone) and biochemical (inhibition of adenylate cyclase) responses to alpha 2-adrenergic agonists, suggesting that subsensitivity of nerve terminal alpha 2 autoreceptors may underlie the exaggerated plasma NE observed in response to various challenges in affective disorders. Future advances in brain imaging techniques and in the molecular biology of adrenergic receptor-coupled signal transduction systems offer promise for meaningful advances in our understanding of the pathophysiology of affective disorders." [Abstract]

Backman J, Alling C, Alsen M, Regnell G, Traskman-Bendz L.
Changes of cerebrospinal fluid monoamine metabolites during long-term antidepressant treatment.
Eur Neuropsychopharmacol 2000 Sep;10(5):341-9
"This study describes the changes in cerebrospinal fluid (CSF) monoamine metabolites during antidepressant treatment for more than 6 months. Eight patients, who received antidepressant treatment after attempted suicide and then underwent lumbar punctures every 3 or 4 months, were included. Plasma drug concentrations and the clinical outcome were also measured. Consistent with previous reports about antidepressant treatment for between 3 and 6 weeks, both 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and 5-hydroxyindoleacetic acid (5-HIAA) were significantly decreased after treatment for a mean of 15 weeks compared to pretreatment. However, after continued treatment for a mean of 30 weeks the MHPG concentration remained significantly lower than at pretreatment while 5-HIAA had returned to the pretreatment level. The clinical outcome was significantly correlated to the pretreatment 5-HIAA/MHPG ratio. These results suggest that the frequently reported reduction in CSF 5-HIAA after antidepressant treatment does not remain during long-term treatment." [Abstract]

Mine K, Okada M, Mishima N, Fujiwara M, Nakagawa T.
Plasma-free and sulfoconjugated MHPG in major depressive disorders: differences between responders to treatment and nonresponders.
Biol Psychiatry 1993 Nov 1;34(9):654-60
"The plasma levels of free and sulfoconjugated forms of 3-methoxy-4-hydroxyphenylglycol (MHPG) were examined before and after treatment in 16 patients with unipolar major depressive disorders without melancholia. The patients were treated with intravenous administration of clomipramine for 4 weeks. Seven depressive disorder patients who showed marked improvement (the improvement group) revealed significant reduction in their plasma sulfoconjugated MHPG levels. In 6 depressive disorder patients who showed no improvement (the no-improvement group), the plasma sulfoconjugated MHPG levels showed no significant change after treatment. The remaining 3 patients, who showed ambiguous change after treatment, were excluded from the analysis. Levels of plasma-free MHPG showed significant change after treatment in neither the improvement group nor in the no-improvement group. It is suggested that levels of plasma sulfoconjugated MHPG may serve as an indicator of brain noradrenergic activity." [Abstract]

Karege F, Bovier P, Hilleret H, Gaillard JM.
Lack of effect of anxiety on total plasma MHPG in depressed patients.
J Affect Disord 1993 Jul;28(3):211-7
"This report was undertaken to test the noradrenergic deficiency hypothesis of depression and the postulated increase in noradrenergic activity associated to anxiety states. A possible dual effect of both depression and anxiety on total plasma MHPG levels was hypothesized and assessed in anxious and non-anxious depressed patients. The findings show a decrease in plasma MHPG levels in depressed patients whatever their degree of anxiety. There was no difference in total plasma MHPG levels either between anxious and non-anxious depressed patients or between low and high anxiety to depression ratio (ADR) depressed patients. Following antidepressant drug-treatment, a decrease in plasma MHPG was found. A positive correlation between the drug-induced decrease in NA activity and the severity of depression was observed, and suggested a relationship between the severity of depression and the instability of the NA system. No correlation between the drug-induced decrease in plasma MHPG and the degree of anxiety was found. The results do not suggest out an effect of anxiety on total plasma MHPG levels in depressed patients." [Abstract]

Correa H, Duval F, Claude MM, Bailey P, Tremeau F, Diep TS, Crocq MA, Castro JO, Macher JP.
Noradrenergic dysfunction and antidepressant treatment response.
Eur Neuropsychopharmacol 2001 Apr;11(2):163-8
"The purpose of this study was to investigate differences in outcome following treatment with two different antidepressants in depressed patients according to their pretreatment hormonal response to clonidine. In all, 62 drug-free DSM-IV recurrent major depressed patients and 20 normal controls were studied. Patients were subsequently treated for 4 weeks with fluoxetine (n=28), or amitriptyline (n=34), and were then classified as responders or nonresponders according to their final Hamilton depression scale score. Compared to controls, depressed patients showed lower GH response to CLO (DeltaGH) (P<0.0002). One control (5%) and 35 depressed patients (56%) had blunted DeltaGH values. The efficacy of the two antidepressants was not significantly different: 15 patients responded to AMI (44%), seven patients responded to FLUOX (25%) (P>0.15). However, in the subgroup of patients with blunted DeltaGH levels, the rate of responders was higher for AMI (11/21) compared to FLUOX (1/14) treated patients (P<0.01). These results suggest that in depressed patients a blunted GH response to CLO could predict antidepressant response." [Abstract]

Markianos M, Alevizos B, Hatzimanolis J, Stefanis C.
Effects of monoamine oxidase A inhibition on plasma biogenic amine metabolites in depressed patients.
Psychiatry Res 1994 Jun;52(3):259-64
"The main metabolites of noradrenalin, dopamine, and serotonin-3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), respectively--were estimated in plasma of 21 depressed patients before and after 2 and 4 weeks of treatment with the monoamine oxidase-type A (MAO-A) inhibitor moclobemide (mean final daily dose = 8.9 mg/kg body weight). The treatment caused significant mean reductions in plasma MHPG and HVA (46% and 30%, respectively), while plasma 5-HIAA was unchanged. Multiple regression analysis revealed associations between reductions in MHPG and changes on the anxiety-somatization factor of the Hamilton Rating Scale for Depression (HRSD), and between reductions in HVA and changes in the HRSD factors cognitive disturbance and retardation." [Abstract]

Stout SC, Owens MJ, Nemeroff CB.
Regulation of corticotropin-releasing factor neuronal systems and hypothalamic-pituitary-adrenal axis activity by stress and chronic antidepressant treatment.
J Pharmacol Exp Ther 2002 Mar;300(3):1085-92
"In a series of experiments, we tested the hypothesis that chronic antidepressant drug administration reduces the synaptic availability of corticotropin-releasing factor (CRF) through one or more effects on CRF gene expression or peptide synthesis. We also determined whether effects of acute or chronic stress on CRF gene expression or peptide concentration are influenced by antidepressant drug treatment. Four-week treatment with venlafaxine, a dual serotonin (5-HT)/norepinephrine (NE) reuptake inhibitor, and tranylcypromine, a monoamine oxidase inhibitor, resulted in an attenuation of acute stress-induced increases in CRF heteronuclear RNA (hnRNA) synthesis in the paraventricular nucleus (PVN). Trends toward the same effect were observed after treatment with the 5-HT reuptake inhibitor fluoxetine, or the NE reuptake inhibitor reboxetine. CRF mRNA accumulation in the PVN during exposure to chronic variable stress was attenuated by concurrent antidepressant administration. Basal CRF hnRNA and mRNA expression were not affected by antidepressant treatment in the PVN or in other brain regions examined. Chronic stress reduced CRF concentrations in the median eminence, but there were no consistent effects of antidepressant drug treatment on CRF, serum corticotropin, or corticosterone concentrations. CRF receptor expression and basal and stress-stimulated HPA axis activity were unchanged after antidepressant administration. These results suggest that chronic antidepressant administration diminishes the sensitivity of CRF neurons to stress rather than alters their basal activity. Additional studies are required to elucidate the functional consequences and mechanisms of this interaction." [Abstract]

Manier DH, Shelton RC, Sulser F.
Noradrenergic antidepressants: does chronic treatment increase or decrease nuclear CREB-P?
J Neural Transm 2002;109(1):91-9
"Chronic administration of noradrenergic antidepressants causes a desensitization of the beta adrenoceptor coupled adenylate cyclase system." [Abstract]

Widmaier EP, Lim AT, Vale W.
Secretion of corticotropin-releasing factor from cultured rat hypothalamic cells: effects of catecholamines.
Endocrinology 1989 Feb;124(2):583-90
"An understanding of the regulation of CRF secretion in rats is currently incomplete, in part due to the lack of sensitive in vitro models available for studying this neuropeptide. In particular, the effects of catecholamines on CRF secretion, and the receptor subtypes mediating these actions have long been the subject of much debate. A cultured cell model has been adapted for studying secretory responses of hypothalamic cells of 1-week-old rats. Between 7-16 days in monolayer culture the cells secreted detectable levels of immunoreactive CRF, and this release was paralleled by the appearance of punctate bead-like regions of immunoreactivity along fine cellular processes. CRF secretion was increased up to 4-fold by norepinephrine (EC50, approximately 0.5 microM). The increase in CRF secretion produced by norepinephrine was blocked by the beta-receptor antagonist propranolol, but not by the alpha-antagonist prazosin. Moreover, the beta-receptor agonist isoproterenol significantly elevated CRF secretion, whereas the alpha-agonist phenylephrine was without effect, except at high concentrations. Addition of phenylephrine, however, potentiated the effect of isoproterenol, but this response was still significantly less than that produced by norepinephrine. Forskolin (EC50, approximately 0.7 microM) and the active phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (EC50, approximately 40 nM) also increased CRF secretion by 3- to 4-fold. Inactive phorbol derivatives had no effect on CRF release from these cultures. The results indicate that cultured neonatal rat hypothalamic cells are a powerful model for the study of CRF release in vitro, and that norepinephrine acts directly at the isolated cell level to stimulate secretion of this peptide, primarily by activating beta-adrenoceptors. The results also suggest that at least two functional second messenger systems (adenylate cyclase and protein kinase-C) are involved in CRF secretion and are already functional in the neonatal hypothalamus." [Abstract]

Tilders FJ, Berkenbosch F, Vermes I, Linton EA, Smelik PG.
Role of epinephrine and vasopressin in the control of the pituitary-adrenal response to stress.
Fed Proc 1985 Jan;44(1 Pt 2):155-60
"In addition to corticotropin-releasing factor (CRF) and structurally related peptides, arginine vasopressin (AVP), oxytocin, angiotensin II, vasoactive intestinal polypeptide, peptide histidine isoleucinamide, epinephrine (E), and norepinephrine induce secretion of adrenocorticotropin (ACTH) from corticotropic cells in vitro. The apparent affinity and intrinsic ACTH-releasing activity of these substances are lower than those of CRF. These substances can also act synergistically with CRF. In this paper the role of catecholamines and AVP in the control of ACTH release is discussed. Infusion i.v. of E increases plasma ACTH and corticosterone to levels that are normally found during stress. E-induced stimulation of pituitary-adrenal activity is mediated by beta adrenoceptors and involves release of CRF, because it can be prevented by beta-adrenoceptor blockers and by destruction of CRF neurons (hypothalamic lesions), blockade of CRF release (chlorpromazine, morphine, and Nembutal), or administration of CRF antiserum. Although stress can cause a vast increase in plasma E, circulating E is not essential for the acute stress-induced release of ACTH because blockade of beta (or alpha) adrenoceptors, administration of chlorisondamine, or extirpation of the adrenal medulla and sympathectomy do not prevent the pituitary-adrenal response to stress. In contrast, circulating E plays a major role in the release of intermediate-lobe peptides during emotional stress. Studies of the role of AVP in pituitary-adrenal control by the use of pressor receptor (V1) antagonists are not valuable because of the ineffectiveness of such antagonists in blocking AVP-induced release of ACTH from corticotropic cells in vitro. Treatment of rats with an antiserum to AVP reduces the ACTH response to stress. We conclude that AVP has an important role in stress-induced activation of the pituitary-adrenal system, possibly by potentiating the effects of CRF." [Abstract]

Ordway GA, Gambarana C, Frazer A.
Quantitative autoradiography of central beta adrenoceptor subtypes: comparison of the effects of chronic treatment with desipramine or centrally administered l-isoproterenol.
J Pharmacol Exp Ther 1988 Oct;247(1):379-89
"This study compares the regulation of the subtypes of central beta adrenoceptors produced by treatment of rats with desipramine (10 mg/kg i.p. twice daily for 10 days) to that caused by central infusion of l-isoproterenol (5 micrograms/hr for 7 days). Beta adrenoceptors were measured by quantitative autoradiography of the binding of [125I]iodopindolol ([125I]IPIN) to coronal sections of rat brain as well as the binding of this radioligand to homogenates of certain areas of brain. Administration of desipramine caused significant reductions in the total specific binding of [125I]IPIN in many areas of the brain, including regions of the amygdala, cerebral cortex, hippocampus, hypothalamus and thalamus." [Abstract]

Ko HC, Lu RB, Shiah IS, Hwang CC.
Plasma free 3-methoxy-4-hydroxyphenylglycol predicts response to fluoxetine.
Biol Psychiatry 1997 Apr 1;41(7):774-81
"This study was designed to investigate the relationship between platelet serotonin (5-HT) and plasma free 3-methoxy-4-hydroxyphenylglycol (MHPG) measures in depressed outpatients obtained from the same patient with unipolar depression during the pretreatment period and subsequent response to 6 weeks of treatment with either fluoxetine or maprotiline. Compared to the nonresponder group, the fluoxetine responders showed significantly higher pretreatment levels of MHPG, but no difference in pretreatment 5-HT levels. There were no significant differences in either 5-HT or MHPG levels between maprotiline responders and nonresponders. As to posttreatment levels, there were no between-group differences in 5-HT or MHPG between responders and nonresponders to either fluoxetine or maprotiline. When the relationships between changes in 5-HT or MHPG levels and treatment response were examined, 5-HT values showed a marked decrease in both fluoxetine responders and nonresponders, but no significant changes were found in the maprotiline treatment groups. On the other hand, MHPG levels in the fluoxetine nonresponders tended to increase (borderline significance), whereas the MHPG levels for fluoxetine responders and maprotiline responders and nonresponders were unaffected from pre- to posttreatment. Pretreatment levels of plasma free MHPG appear to predict response to fluoxetine." [Abstract]

De Bellis MD, Geracioti TD Jr, Altemus M, Kling MA.
Cerebrospinal fluid monoamine metabolites in fluoxetine-treated patients with major depression and in healthy volunteers.
Biol Psychiatry 1993 Apr 15-May 1;33(8-9):636-41
"Cerebrospinal fluid (CSF) levels of the monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and homovanillic acid (HVA) were measured in three groups: 46 healthy volunteers; 9 medication-free patients with DSM III-R major depressive disorder, recurrent; and these same 9 patients following at least 4 weeks of fluoxetine treatment at 20 mg/day. CSF monoamine metabolite levels in medication-free patients did not differ from healthy volunteers; however, CSF 5-HIAA and MHPG decreased significantly from 95.9 +/- 24.6 (all values +/- SD) to 64.2 +/- 26.1 pmol/ml and from 46.7 +/- 14.2 to 42.6 +/- 11.6 pmol/ml, respectively, following fluoxetine treatment. Fluoxetine also significantly decreased mean Hamilton Depression Rating Scale scores from 23.2 +/- 6.5 to 17.4 +/- 5.0 and significantly increased the CSF HVA/5-HIAA ratio." [Abstract]

Sheline Y, Bardgett ME, Csernansky JG.
Correlated reductions in cerebrospinal fluid 5-HIAA and MHPG concentrations after treatment with selective serotonin reuptake inhibitors.
J Clin Psychopharmacol 1997 Feb;17(1):11-4
"We sought to determine whether fluvoxamine and fluoxetine, two different antidepressants with in vitro selectivity for the serotonin uptake transporter also demonstrated similar selectivity in vivo. To accomplish this, we measured cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and homovanillic acid (HVA) before and after 6 weeks of treatment with these two drugs. Twenty-four subjects who had major depression according to DSM-III-R criteria gave written, informed consent for the collection of CSF during a double-blind comparative treatment trial of fluvoxamine (50-150 mg/day) and fluoxetine (20-80 mg/day). The symptoms of subjects were assessed clinically on a weekly basis throughout the treatment trial. CSF samples were obtained after a 7- to 14-day washout period before treatment and again at the end of treatment. CSF samples were analyzed for 5-HIAA, HVA, and MHPG using high-pressure liquid chromatography coupled to electrochemical detection. Fluvoxamine- and fluoxetine-treated patients did not differ in clinical outcome or in the CSF concentrations of monoamine metabolite levels before or after treatment. Therefore, the CSF data were pooled. Drug treatment, overall, was associated with significant decreases in 5-HIAA and MHPG and a trend toward a reduction in HVA levels. Levels of 5-HIAA, MHPG, and HVA were reduced by 57%, 48%, and 17%, respectively. In addition, the magnitude of the decreases in 5-HIAA and MHPG appeared to be correlated (r = 0.83) across the subjects, although a Spearman rank correlation indicated that outlying values had an undue effect on this relationship. These results suggest that treatment with selective serotonin reuptake inhibitors, which are selective for serotonin uptake in vitro, does not show a similarly selective effect on serotonin in vivo during treatment of patients." [Abstract]

Widerlov E, Bissette G, Nemeroff CB.
Monoamine metabolites, corticotropin releasing factor and somatostatin as CSF markers in depressed patients.
J Affect Disord 1988 Mar-Apr;14(2):99-107
"CSF samples from ten healthy volunteers and 22 patients with major depression were collected by lumbar puncture at 9 a.m. and the content of monoamine metabolites, corticotropin releasing factor (CRF) and somatostatin (SRIF) was analyzed. Plasma concentrations of TSH following a TRH challenge test (200 micrograms) and plasma cortisol following dexamethasone (1 mg; DST) were also analyzed. No relationships were observed between the CRF or SRIF concentrations and either basal or post-dexamethasone cortisol concentrations. Fourteen of 21 depressed patients were DST nonsuppressors using a plasma cortisol concentration cut off point greater than or equal to 138 nmol/l. If a more conservative cut off point was used (greater than 290 nmol/l) seven out of 21 patients revealed a severity-related cortisol nonsuppression. No significant difference was observed between healthy volunteers and depressed patients with regard to TSH response to TRH. The CSF content of CRF was elevated and the content of SRIF reduced in the depressed patients. In the healthy volunteers an inverse relationship was observed between CSF concentrations of CRF and MHPG (r = -0.72; P = 0.019); no relationship was observed between the concentrations of CRF and 5-HIAA or HVA. In the depressed patients positive correlations were found between CSF concentrations of CRF and 5-HIAA (r = 0.59; P = 0.004) and between CRF and HVA (r = 0.44; P = 0.042). These data are concordant with the view that norepinephrine and serotonin may be involved in the regulation of CRF secretion." [Abstract]

Jorgensen H, Knigge U, Kjaer A, Moller M, Warberg J.
Serotonergic Stimulation of Corticotropin-Releasing Hormone and Pro-Opiomelanocortin Gene Expression.
J Neuroendocrinol 2002 Oct;14(10):788-795
"The neurotransmitter serotonin (5-HT) stimulates adrenocorticotropic hormone (ACTH) secretion from the anterior pituitary gland via activation of central 5-HT1 and 5-HT2 receptors. The effect of 5-HT is predominantly indirect and may be mediated via release of hypothalamic corticotropin-releasing hormone (CRH). We therefore investigated the possible involvement of CRH in the serotonergic stimulation of ACTH secretion in male rats. Increased neuronal 5-HT content induced by systemic administration of the precursor 5-hydroxytryptophan (5-HTP) in combination with the 5-HT reuptake inhibitor fluoxetine raised CRH mRNA expression in the paraventricular nucleus (PVN) by 64%, increased pro-opiomelanocortin (POMC) mRNA in the anterior pituitary lobe by 17% and stimulated ACTH secretion five-fold. Central administration of 5-HT agonists specific to 5-HT1A, 5-HT1B, 5-HT2A or 5-HT2C receptors increased CRH mRNA in the PVN by 15-50%, POMC mRNA in the anterior pituitary by 15-27% and ACTH secretion three- to five-fold, whereas a specific 5-HT3 agonist had no effect. Systemic administration of a specific anti-CRH antiserum inhibited the ACTH response to 5-HTP and fluoxetine and prevented the 5-HTP and fluoxetine-induced POMC mRNA response in the anterior pituitary lobe. Central or systemic infusion of 5-HT increased ACTH secretion seven- and eight-fold, respectively. Systemic pretreatment with the anti-CRH antiserum reduced the ACTH responses to 5-HT by 80% and 64%, respectively. It is concluded that 5-HT via activation of 5-HT1A, 5-HT2A, 5-HT2C and possibly also 5-HT1B receptors increases the synthesis of CRH in the PVN and POMC in the anterior pituitary lobe, which results in increased ACTH secretion. Furthermore, the results indicate that CRH is an important mediator of the ACTH response to 5-HT." [Abstract]

Contesse V, Lefebvre H, Lenglet S, Kuhn JM, Delarue C, Vaudry H.
Role of 5-HT in the regulation of the brain-pituitary-adrenal axis: effects of 5-HT on adrenocortical cells.
Can J Physiol Pharmacol. 2000 Dec;78(12):967-83. [Abstract]

Fuller RW.
Serotonin receptors and neuroendocrine responses.
Neuropsychopharmacology 1990 Oct-Dec;3(5-6):495-502
"There is extensive pharmacologic evidence that serotonin receptors in the brain can activate the hypothalamic-pituitary-adrenocortical (HPA) axis in rats. Direct-acting serotonin agonists, serotonin uptake inhibitors, serotonin releasers and the serotonin precursor L-5-hydroxytryptophan all increase adrenocorticotrophin (ACTH) and corticosterone release. Serotonin-containing nerve terminals make synaptic contact with corticotrophin-releasing factor (CRF)-containing cells in rat hypothalamus, and serotonin and serotonin agonists stimulate CRF release from isolated rat hypothalamus in vitro. Current evidence, based partly on the ability of selective serotonin receptor antagonists to prevent the increases in ACTH and corticosterone in rats in vivo, implicates 5-HT1A and 5-HT2/5-HT1C receptor subtypes in regulating CRF secretion." [Abstract] [Serotonin 5-HT1C receptors are now referred to as 5-HT2C receptors.]

Damjanoska KJ, Van de Kar LD, Kindel GH, Zhang Y, D'Souza DN, Garcia F, Battaglia G, Muma NA.
Chronic fluoxetine differentially affects 5-hydroxytryptamine (2A) receptor signaling in frontal cortex, oxytocin- and corticotropin-releasing factor-containing neurons in rat paraventricular nucleus.
J Pharmacol Exp Ther. 2003 Aug;306(2):563-71. Epub 2003 Apr 29.
"Differential adaptive changes in serotonin2A [5-hydroxytryptamine (5-HT)2A] receptor signaling during treatment may be one mechanism involved in the latency of therapeutic improvement with antidepressants, such as fluoxetine. We examined the effects of fluoxetine (2, 3, 7, 21, or 42 days) on hypothalamic 5-HT2A receptor signaling. The hormone responses to an injection of the 5-HT2A receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane HCl (DOI) were used as an index of hypothalamic 5-HT2A receptor function. Treatment with fluoxetine for 21 or 42 days produced diminished adrenocorticotropic hormone (ACTH) and oxytocin (but not corticosterone) responses to DOI injections (2.5 mg/kg i.p.; 15 min postinjection). Regulators of G protein signaling 4 and Galphaq protein levels in the hypothalamic paraventricular nucleus were not altered during fluoxetine treatment. Because previous studies indicate that treatment with fluoxetine for 21 days resulted in increased hormone responses to DOI when measured at 30 min after injection, we examined the effect of fluoxetine (21 days) on DOI-induced increase hormone levels at 15, 30, and 60 min after DOI injection. Fluoxetine decreased the oxytocin response at 15 but not at 30 min post-DOI injection, and potentiated the ACTH and corticosterone responses at 30 min post-DOI injection. For comparison, we examined the effect of fluoxetine on 5-HT2A receptor-mediated increase in phospholipase C (PLC) activity in the frontal cortex. 5-HT-stimulated, but not guanosine 5'-O-(3-thio)triphosphate-stimulated PLC activity was increased after 21 days of fluoxetine-treatment. Overall, these results indicate that chronic fluoxetine treatment can potentiate 5-HT2A receptor signaling in frontal cortex but differentially alters 5-HT2A receptor signaling in oxytocin-containing neurons and corticotropin-releasing factor-containing neurons in the paraventricular nucleus." [Abstract]

Owens MJ, Knight DL, Ritchie JC, Nemeroff CB.
The 5-hydroxytryptamine2 agonist, (+-)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane stimulates the hypothalamic-pituitary-adrenal (HPA) axis. II. Biochemical and physiological evidence for the development of tolerance after chronic administration.
J Pharmacol Exp Ther 1991 Feb;256(2):795-800
"In order to investigate the long term effects of the 5-hydroxytryptamine2 (5-HT2) receptor agonist, (+-)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB), on hypothalamic-pituitary-adrenal (HPA) axis activity, DOB (0.35 mg/kg/day) was administered via osmotic minipumps to rats for 7 days at which time plasma adrenocorticotrophic hormone (ACTH), corticosterone and regional brain corticotropin-releasing factor (CRF) concentrations were measured. In addition, anterior pituitary CRF and frontal cortical 5-HT2 receptor binding was measured. Seven-day infusion of DOB resulted in tolerance to the stimulatory actions of the drug on the HPA axis as evidenced by the return of plasma ACTH and corticosterone concentrations to base-line values. Moreover, rats treated chronically with DOB exhibited decreased numbers of both anterior pituitary CRF and cortical and hypothalamic 5-HT2 receptor. These receptor changes were physiologically significant as challenges doses of DOB or CRF resulted in blunted ACTH responses. Chronic DOB infusion was without effect on CRF concentrations in all hypothalamic and extrahypothalamic brain regions studied. A series of time course experiments revealed that DOB-induced increases in plasma corticosterone returned to base-line by 2-days postimplantation. This effect was apparently associated with down-regulation of the 5-HT2 receptor because high-affinity cortical [3H]DOB and hypothalamic (+-)-[125I]-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane binding were decreased at this time as well. Although median eminence CRF content was unchanged at all time points, anterior pituitary CRF receptor binding was significantly decreased 7 days postimplantation." [Abstract]

Moncek F, Duncko R, Jezova D.
Repeated citalopram treatment but not stress exposure attenuates hypothalamic-pituitary-adrenocortical axis response to acute citalopram injection.
Life Sci. 2003 Feb 7;72(12):1353-65.
"Many experimental, clinical and epidemiological studies have shown a direct connection between exposure to stress or adverse life events and disease, but little is known about the effect of stress on the action of drugs. The aim of this study was to test the hypothesis that previous exposure to stress changes the action of the antidepressant drug citalopram (10 mg/kg, i.p.) on hypothalamic-pituitary-adrenocortical (HPA) axis function, gene expression of selected neuropeptides and serotonin reuptake. Three different stress models were used, which included immobilization, restraint and unpredictable stress stimuli. Samples of plasma for hormone measurement were taken from conscious cannulated animals. Changes in corticotropin-releasing hormone (CRH) and proopiomelanocortin (POMC) gene expression in the paraventricular nucleus of the hypothalamus and the anterior pituitary, respectively, and the ability of citalopram to inhibit serotonin reuptake were investigated. The exposure to three different stress models did not influence citalopram action on individual parameters of HPA axis and on serotonin reuptake. On the other hand, repeated administration of the drug led to significant attenuation of ACTH and CRH mRNA responses. The present results allow to suggest that the stressors used did not influence serotonergic neurotransmission to the extent that would modify HPA axis response to citalopram challenge. Activation of HPA axis by acute citalopram treatment was found to be accompanied by increased CRH gene expression in the hypothalamus. Repeated administration of the drug led to the development of tolerance to activation of central and peripheral components of HPA axis, but not to serotonin reuptake inhibition." [Abstract]

Neuger J, Wistedt B, Sinner B, Aberg-Wistedt A, Stain-Malmgren R.
The effect of citalopram treatment on platelet serotonin function in panic disorders.
Int Clin Psychopharmacol 2000 Mar;15(2):83-91
"We investigated the effect of the selective serotonin reuptake inhibitor (SSRI) citalopram after 6-8 weeks and 6 months of treatment on clinical and peripheral indexes for central serotonergic function: platelet [14C]serotonin uptake and [3H]paroxetine- and [3H]LSD-binding to platelets membranes in 33 patients with panic disorder. Basal data from patients were compared with data from a control material consisting of 33 healthy volunteers. Bmax for platelet [3H]paroxetine binding was significantly lower in patients than in controls. There were no differences in serotonin uptake or [3H]LSD-binding between patients and controls. The degree of anxiety and depression was assessed using the Beck Anxiety Inventory (BAI) and Beck Depression Inventory self-assessment scales, and the Clinical Anxiety Scale and the Montgomery Asberg Depression Rating Scale for clinical evaluation. Complete remission was found in one third of the patients after 6-8 weeks and in two-thirds after 6 months of treatment. The reduction in assessment scores was parallelled with similar reductions in platelet 5-HT2-receptor density, [3H]LSD affinity variable (Kd) and Vmax for platelet [14C]5-HT uptake." [Abstract]

Peroutka, SJ, Snyder, SH
Regulation of serotonin2 (5-HT2) receptors labeled with [3H]spiroperidol by chronic treatment with the antidepressant amitriptyline
J Pharmacol Exp Ther 1980 215: 582-587
"The properties of 5-HT2 receptor reduction after chronic antidepressant treatment indicate that this alteration could be associated with therapeutic response." [Abstract]

Sibille, Etienne, Sarnyai, Zoltan, Benjamin, Daniel, Gal, Judit, Baker, Harriet, Toth, Miklos
Antisense Inhibition of 5-Hydroxytryptamine2a Receptor Induces an Antidepressant-Like Effect in Mice
Mol Pharmacol 1997 52: 1056-1063
"The antidepressant-like effect induced by AS oligonucleotide injection in mice is consistent with the beneficial effect of pharmacological blockade of the 5-HT2A receptor in dysthymic disorders." [Full Text]

Flugge G.
Effects of cortisol on brain alpha2-adrenoceptors: potential role in stress.
Neurosci Biobehav Rev 1999 Nov;23(7):949-56
"It has been proposed that behavioural changes induced by chronic psychosocial stress in male tree shrews might be related to alterations in the central nervous alpha2-adrenoceptor system. In the noradrenergic centres of the brain, alpha2-adrenoceptors function as autoreceptors regulating noradrenaline release. Chronic stress downregulates these receptors in several brain regions. Since during stress, the activity of the hypothalamus-pituitary-adrenal axis is increased leading to high concentrations of plasma glucocorticoids, we investigated whether the effects of chronic stress can be mimicked by cortisol treatments. Two experiments were performed: a short-term treatment (males were injected i.v. with 1.5 mg cortisol and brains were dissected 2 h later) and a long-term treatment (animals received the hormone in their drinking water for 5 days; daily uptake 3-7 mg). The short-term treatment (injection), similar to the stress effects, downregulated alpha2-adrenoceptors in several brain regions. In contrast, the long-term oral treatment induced regional receptor upregulation. These data show: (i) that glucocorticoids regulate alpha2-adrenoceptors in the brain; (ii) that the duration and/or the route of cortisol application determines the results: and (iii) that chronic stress effects are not only due to the long-term glucocorticoid exposure, but also to other elements of the stress response." [Abstract]

Ordway GA, Schenk J, Stockmeier CA, May W, Klimek V.
Elevated agonist binding to alpha2-adrenoceptors in the locus coeruleus in major depression.
Biol Psychiatry. 2003 Feb 15;53(4):315-23.
"BACKGROUND: Recent postmortem studies demonstrate disrupted neurochemistry of the noradrenergic locus coeruleus (LC) in major depression (MD). Increased levels of tyrosine hydroxylase and decreased levels of norepinephrine transporter implicate a norepinephrine deficiency in the LC in MD. Here we describe a study of alpha2-adrenoceptors in the LC and raphe nuclei of subjects with MD compared with psychiatrically normal control subjects. METHODS: The specific binding of p-[125I]iodoclonidine to alpha2-adrenoceptors was measured at multiple levels along the rostrocaudal extent of the LC in postmortem tissue from 14 control and 14 MD subjects. In addition, p-[125I]iodoclonidine binding was measured in the dorsal and median raphe nuclei in the same tissue sections. RESULTS: The specific binding of p-[125I]iodoclonidine to alpha2-adrenoceptors was significantly elevated throughout the LC from MD compared with matched control subjects. No significant differences were observed in p-[125I]iodoclonidine binding to alpha2-adrenoceptors in the raphe nuclei comparing MD and control subjects. CONCLUSIONS: Given that alpha2-adrenoceptors are upregulated in laboratory animals by treatment with drugs that deplete norepinephrine, our findings implicate a premortem deficiency of brain norepinephrine in the region of the locus coeruleus in subjects with MD." [Abstract]

Gurguis GN, Vo SP, Griffith JM, Rush AJ.
Platelet alpha2A-adrenoceptor function in major depression: Gi coupling, effects of imipramine and relationship to treatment outcome.
Psychiatry Res. 1999 Dec 20;89(2):73-95.
"Studies suggest alpha2A-adrenoceptors (alpha(2A)AR) dysregulation in major depressive disorder (MDD). Platelet alpha(2A)ARs exist in high- and low-conformational states that are regulated by Gi protein. Although alpha(2A)AR coupling to Gi protein plays an important role in signal transduction and is modulated by antidepressants, it has not been previously investigated. Alpha2AR density in the high- and low-conformational states, agonist affinity and coupling efficiency were investigated in 27 healthy control subjects, 23 drug-free MDD patients and 16 patients after imipramine treatment using [3H]yohimbine saturation and norepinephrine displacement of [3H]yohimbine binding experiments. Coupling measures were derived from NE-displacement experiments. Patients had significantly higher alpha(2A)AR density, particularly in the high-conformational state, than control subjects. Coupling indices were normal in patients. High pre-treatment agonist affinity to the receptor in the high-conformational state and normal coupling predicted positive treatment outcome. Decreased coupling to Gi predicted a negative treatment outcome. Imipramine induced uncoupling (-11%) and redistribution of receptor density in treatment responders only, but had no effect on alpha(2A)AR coupling or density in treatment non-responders. Increased alpha(2A)AR density may represent a trait marker in MDD. The results provide indirect evidence for abnormal protein kinase A (PKA) and protein kinase C (PKC) in MDD which may be pursued in future investigations." [Abstract]

Takeda T, Harada T, Otsuki S.
Platelet 3H-clonidine and 3H-imipramine binding and plasma cortisol level in depression.
Biol Psychiatry 1989 May;26(1):52-60
"Platelet 3H-clonidine (alpha 2-adrenergic agonist) binding and 3H-imipramine binding were measured and the Dexamethasone Suppression Test performed in 17 normal controls and 14 unmedicated depressed patients in order to clarify the relationship among these three biological markers. Increases in the Bmax and the Kd for 3H-clonidine binding and decreases in the Bmax for 3H-imipramine binding of the platelets from depressed patients were observed when compared with controls. There was a significant positive correlation among 3H-clonidine Bmax, the basal (predexamethasone) plasma cortisol levels, and the severity of depression, as indicated by the Hamilton Depression Rating Scale. On the other hand, no significant correlation was observed in 3H-imipramine binding between the Bmax and the severity of depression or between the Bmax and the basal plasma cortisol levels. There was no statistically significant correlation between the Bmax of 3H-clonidine binding and that of 3H-imipramine binding in depression, but there was a trend toward correlation in normal controls." [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]

Siever LJ, Uhde TW.
New studies and perspectives on the noradrenergic receptor system in depression: effects of the alpha 2-adrenergic agonist clonidine.
Biol Psychiatry 1984 Feb;19(2):131-56
"In an attempt to understand the dynamics of noradrenergic function in depression, we evaluated neuroendocrine, biochemical, cardiovascular, and behavioral responses to the acute intravenous administration of the alpha 2-adrenergic agonist, clonidine, in depressed patients and normal controls. Significantly more variance was observed in the depressed patients than the controls for most indices of basal noradrenergic output including plasma norepinephrine (NE) and 3-methoxy-4-hydroxyphenylglycol (MHPG). Growth hormone, plasma MHPG, and heart rate responses to clonidine were reduced in the depressed patients compared to the controls, all suggesting reduced responsiveness of alpha 2-adrenergic receptors in depression. Baseline levels of cortisol were elevated in the depressed patients compared to the controls. Clonidine decreased cortisol to normal levels in the depressed patients but had little effect in the controls. Thus the depressed patients manifested a significantly increased cortisol response to clonidine. These data raise the possibility that the hypercortisolemia of depression may be related to noradrenergic dysfunction. Clonidine also significantly reduced anxiety in the depressed patients, particularly those with elevated basal plasma MHPG, but not in controls. These results suggest that diminished alpha 2-adrenergic responsiveness as documented by decreased endocrine, biochemical, and physiological responses to clonidine may be related to the depressive and anxiety symptoms as well as the neuroendocrine disturbances characteristic of many depressed patients." [Abstract]

Mokrani MC, Duval F, Crocq MA, Bailey P, Macher JP.
HPA axis dysfunction in depression: correlation with monoamine system abnormalities.
Psychoneuroendocrinology 1997;22 Suppl 1:S63-8
"Abnormality of the hypothalamic-pituitary-adrenal (HPA) axis has been one of the most consistently demonstrated biological markers of depressive disorder. It has also been proposed that abnormality of monoamine function plays a role in the pathogenesis of the disorder. In order to examine the interrelationships of the HPA axis with the dopaminergic, noradrenergic, and serotoninergic systems, we studied, in 52 medication-free inpatients with DSM-IV nonpsychotic major depressive disorder, the relationship between dexamethasone suppression test (DST) status and a series of multihormonal responses to apomorphine (APO), clonidine (CLO), and D-fenfluramine (FEN) tests. DST nonsuppressors did not present any difference compared with suppressors in growth hormone (GH) and cortisol stimulation by APO suggesting that a chronic elevation of cortisol did not lead to an alteration of dopaminergic activity in this population of nonpsychotic depressed inpatients. Cortisol and prolactin responses to FEN were comparable in nonsuppressors and in suppressors. In contrast, GH response to CLO was lower in DST nonsuppressors than in suppressors (p < .03), suggesting that the HPA abnormality indicated by a positive DST may be related to alpha 2-adrenoreceptor dysfunction." [Abstract]

Price LH, Charney DS, Rubin AL, Heninger GR.
Alpha 2-adrenergic receptor function in depression. The cortisol response to yohimbine.
Arch Gen Psychiatry 1986 Sep;43(9):849-58
"There is evidence that the abnormalities in hypothalamic-pituitary-adrenal (HPA) axis function observed in patients with depression may be related to changes in central neurotransmitter receptor function. To evaluate this possibility further, the alpha 2-adrenergic receptor antagonist yohimbine hydrochloride, which increases brain norepinephrine turnover, was administered to 40 patients with DSM-III major depression (18 melancholic, 22 nonmelancholic) and 16 healthy controls. Plasma free 3-methoxy-4-hydroxyphenylglycol (MHPG) level was measured as an index of noradrenergic function, and plasma cortisol level was used to assess the HPA response. Baseline cortisol levels were elevated in melancholic depressed patients, but not in nonmelancholic patients, when compared with healthy controls. The cortisol response to yohimbine was significantly greater in depressed patients than in controls, despite similar MHPG responses between groups. Since there is evidence that stimulation of postsynaptic alpha 2-adrenergic receptors inhibits HPA axis function, the abnormally increased cortisol response to the alpha 2-antagonist yohimbine suggests a relative subsensitivity of postsynaptic alpha 2-adrenergic receptors in depression." [Abstract]


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Recent Norepinephrine and Depression Research

1) Vogelzangs N, Duivis HE, Beekman AT, Kluft C, Neuteboom J, Hoogendijk W, Smit JH, de Jonge P, Penninx BW
Association of depressive disorders, depression characteristics and antidepressant medication with inflammation.
Transl Psychiatry. 2012 Feb 21;2:e79.
Growing evidence suggests that immune dysregulation may be involved in depressive disorders, but the exact nature of this association is still unknown and may be restricted to specific subgroups. This study examines the association between depressive disorders, depression characteristics and antidepressant medication with inflammation in a large cohort of controls and depressed persons, taking possible sex differences and important confounding factors into account. Persons (18-65 years) with a current (N=1132) or remitted (N=789) depressive disorder according to DSM-IV criteria and healthy controls (N=494) were selected from the Netherlands Study of Depression and Anxiety. Assessments included clinical characteristics (severity, duration and age of onset), use of antidepressant medication and inflammatory markers (C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-?)). After adjustment for sociodemographics, currently depressed men, but not women, had higher levels of CRP (1.33 versus 0.92?mg?l(-1), P<0.001, Cohen's d=0.32) and IL-6 (0.88 versus 0.72?pg?ml(-1), P=0.01, Cohen's d=0.23) than non-depressed peers. Associations reduced after considering lifestyle and disease indicators - especially body mass index - but remained significant for CRP. After full adjustment, highest inflammation levels were found in depressed men with an older age of depression onset (CRP, TNF-?). Furthermore, inflammation was increased in men using serotonin-norepinephrine reuptake inhibitors (CRP, IL-6) and in men and women using tri- or tetracyclic antidepressants (CRP), but decreased among men using selective serotonin reuptake inhibitors (IL-6). In conclusion, elevated inflammation was confirmed in depressed men, especially those with a late-onset depression. Specific antidepressants may differ in their effects on inflammation. [PubMed Citation] [Order full text from Infotrieve]

2) Björkholm C, Jardemark K, Marcus MM, Malmerfelt A, Nyberg S, Schilström 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]

3) Martinotti G, Sepede G, Gambi F, Di Iorio G, De Berardis D, Di Nicola M, Onofrj M, Janiri L, Di Giannantonio M
Agomelatine Versus Venlafaxine XR in the Treatment of Anhedonia in Major Depressive Disorder: A Pilot Study.
J Clin Psychopharmacol. 2012 Aug;32(4):487-91.
ABSTRACT: The primary aim of the present study was to compare the effects of agomelatine (AGO) and venlafaxine XR (VLX) on anhedonia in patients with major depressive disorder. Secondary end points were to test its antidepressant and anxiolytic efficacy.Sixty patients were enrolled and randomly assigned to two different treatments: AGO (25-50 mg/d; n = 30 subjects) or VLX (75-150 mg/d, n = 30 subjects). Psychopathological assessment was performed at baseline and after 8 weeks of treatment with the Snaith Hamilton Rating Scale (SHAPS), the Hamilton Depression Rating Scale, the Hamilton Anxiety Rating Scale, and the Clinical Global Impression for anhedonia, depression, anxiety, and global improvement, respectively.Both groups showed a significant reduction in time for the SHAPS, the Hamilton Depression Rating Scale, and the Hamilton Anxiety Rating Scale. A significant between-group difference was observed for SHAPS scores: patients treated with AGO showed a more relevant reduction compared with that in VLX-treated patients. Moreover, only patients treated with AGO showed a statistically significant improvement in Clinical Global Impression scores.In this study, AGO showed significantly greater efficacy on anhedonia and similar antidepressant efficacy to the serotonin-norepinephrine reuptake inhibitor VLX in patients with major depressive disorder during an 8-week treatment period. Anhedonia has been considered a potential trait marker related to vulnerability for depression. Therefore, the efficacy of AGO on this dimension holds particular importance in the treatment of patients with anhedonic features. [PubMed Citation] [Order full text from Infotrieve]

4) Pergolizzi JV, Raffa RB, Taylor R, Rodriguez G, Nalamachu S, Langley P
A Review of Duloxetine 60 mg Once-Daily Dosing for the Management of Diabetic Peripheral Neuropathic Pain, Fibromyalgia, and Chronic Musculoskeletal Pain Due to Chronic Osteoarthritis Pain and Low Back Pain.
Pain Pract. 2012 Jun 21;
Background:? Duloxetine is a selective dual neuronal serotonin (5-Hydroxytryptamine, 5-HT) and norepinephrine reuptake inhibitor (SSNRI). It is indicated in the United States for treatment of major depressive disorder (MDD), generalized anxiety disorder (GAD), and several chronic pain conditions, including management of diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain due to chronic osteoarthritis (OA) pain and chronic low back pain (LBP). Its use for antidepressant and anxiolytic actions has been extensively reviewed previously. We here review the evidence for the efficacy of 60?mg once-daily dosing of duloxetine for chronic pain conditions. Method:? The literature was searched for clinical trials in humans conducted in the past 10?years involving duloxetine. Results:? There were 199 results in the initial search. Studies not in the English language were excluded. We then included only studies of diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain (OA and LBP). Studies of painful symptoms reported in mental health studies were excluded. This resulted in 32 studies. Articles that did not include a 60?mg/day daily dose as a study arm were excluded. This resulted in 30 studies, broken down as follows: 12 for diabetic peripheral neuropathy, 9 for fibromyalgia, 6 for LBP, and 3 for OA pain. Conclusions:? The studies reviewed report that duloxetine 60?mg once-daily dosing is an effective option for the management of diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain due to chronic OA pain and chronic LBP. As these pains are often comorbid with MDD or GAD, duloxetine might possess the pharmacologic properties to be a versatile agent able to address several symptoms in these patients. With adequate attention to FDA prescribing guidance regarding safety and drug-drug interactions, duloxetine 60?mg once-daily dosing appears to be an effective option in the appropriate pain patient population. [PubMed Citation] [Order full text from Infotrieve]

5) 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]

6) Johansson D, Falk A, Marcus MM, Svensson TH
Celecoxib enhances the effect of reboxetine and fluoxetine on cortical noradrenaline and serotonin output in the rat.
Prog Neuropsychopharmacol Biol Psychiatry. 2012 Jun 9;
A substantial number of patients with major depressive disorder (MDD) do not respond adequately to current antidepressant pharmacological treatments, which are all more or less based on a gradually increased enhancement of monoaminergic neurotransmission. Although a functional deficiency in monoaminergic neurotransmission may contribute to MDD, the etiology and pathophysiology are far from clarified. Recent studies suggest that inflammatory processes may contribute, since increased levels of pro-inflammatory cytokines and prostaglandin E(2) (PGE(2)) have repeatedly been observed in a subset of patients suffering from MDD. Interestingly, adjunct treatment with the anti-inflammatory drug celecoxib, a cyclo-oxygenase-2 (COX-2) inhibitor which blocks the PGE(2)-production, has shown to enhance the efficacy of both reboxetine, a selective noradrenaline reuptake inhibitor, as well as fluoxetine, a selective serotonin reuptake inhibitor, in treatment-resistant depression. To examine the neurobiological underpinnings to the clinical observations, we here studied the acute effects of a combined treatment with celecoxib and reboxetine on noradrenaline and dopamine output, as well as celecoxib and fluoxetine on 5-HT output in the medial prefrontal cortex, using in vivo microdialysis in awake freely moving rats. Celecoxib significantly potentiated the effects of reboxetine and fluoxetine on cortical noradrenaline and 5-HT output, respectively, but not the reboxetine-induced dopamine output. Moreover, celecoxib, when given alone, enhanced 5-HT output. These findings provide, in principle, novel experimental support for the clinical utility of combined treatment with antidepressant and anti-inflammatory drugs, such as COX-2 inhibitors, in MDD. [PubMed Citation] [Order full text from Infotrieve]

7) Torres-Sanchez S, Perez-Caballero L, Mico JA, Elorza J, Berrocoso E
Preclinical discovery of duloxetine for the treatment of depression.
Expert Opin Drug Discov. 2012 Aug;7(8):745-55.
Introduction: Affective disorders, including major depressive disorder (MDD), are among the most severely disabling mental disorders, and in many cases are associated with poor treatment outcomes. From the emergence of the monoamine hypothesis of depression, the first-line treatment for MDD had mainly acted by inhibiting monoamine reuptake, and thereby increasing these levels in the synaptic cleft. However, in recent years, several new antidepressant drugs have appeared, including duloxetine, a dual serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor recommended for the treatment of MDD. Areas covered: The article reviews and discusses the biochemical and functional profile of duloxetine splitting the review into acute and long-term treatment with this dual monoamine reuptake inhibitor. In addition, the authors summarize available preclinical behavioral research data, which have demonstrated among other effects, the antidepressant-like activity of duloxetine in several animal models. The authors focus on the most recent literature on synaptic neuroplasticity modulation of this antidepressant drug. Finally, the authors briefly mention other approved indications of duloxetine. Expert opinion: Duloxetine inhibits 5-HT and NA reuptake, effectively desensitizes various autoreceptors and promotes neuroplasticity. Clinically, duloxetine is an effective antidepressant that is well tolerated and has significant efficacy in the treatment of MDD. [PubMed Citation] [Order full text from Infotrieve]

8) Scapagnini G, Davinelli S, Drago F, De Lorenzo A, Oriani G
Antioxidants as antidepressants: fact or fiction?
CNS Drugs. 2012 Jun 1;26(6):477-90.
Depression is a medical condition with a complex biological pattern of aetiology, involving genetic and epigenetic factors, along with different environmental stressors. Recent evidence suggests that oxidative stress processes might play a relevant role in the pathogenic mechanism(s) underlying many major psychiatric disorders, including depression. Reactive oxygen and nitrogen species have been shown to modulate levels and activity of noradrenaline (norepinephrine), serotonin, dopamine and glutamate, the principal neurotransmitters involved in the neurobiology of depression. Major depression has been associated with lowered concentrations of several endogenous antioxidant compounds, such as vitamin E, zinc and coenzyme Q10, or enzymes, such as glutathione peroxidase, and with an impairment of the total antioxidant status. These observations introduce new potential targets for the development of therapeutic interventions based on antioxidant compounds. The present review focuses on the possible role of oxidative stress processes in the pathogenesis of depression. The therapeutic potential of antioxidant compounds as a co-adjuvant treatment to conventional antidepressants is discussed. For instance, N-acetyl-cysteine has been shown to have a significant benefit on depressive symptoms in a randomized placebo-controlled trial. Additionally, curcumin, the yellow pigment of curry, has been shown to strongly interfere with neuronal redox homeostasis in the CNS and to possess antidepressant activity in various animal models of depression, also thanks to its ability to inhibit monoamine oxidases. There is an urgent need to develop better tolerated and more effective treatments for depressive disorders and several antioxidant treatments appear promising and deserve further study. [PubMed Citation] [Order full text from Infotrieve]

9) Knörle R
Extracts of Sideritis scardica as triple monoamine reuptake inhibitors.
J Neural Transm. 2012 May 24;
Sideritis species are traditionally used within the Mediterranean area as teas, flavouring agents or for therapeutical purposes. The aim of this study was to investigate the effects of Sideritis scardica extracts on the monoamine transporters and to derive and explain possible medicinal applications from the pharmacological profile of the extracts. We have studied the effect of various S. scardica extracts on serotonin, noradrenaline and dopamine uptake in rat brain synaptosomes and serotonin uptake in human JAR cells. All extracts inhibited the uptake of all three monoamines into rat brain synaptosomes by their respective transporters, the alcoholic extracts being more effective than the water extract. EC(50) values were in the range of 30-40 ?g/ml. Inhibition of the human serotonin transporter by the methanol extract was even more effective (EC(50) 1.4 ?g/ml). Combining Sideritis ethanol extract and fluvoxamine resulted in a leftward shift of the fluvoxamine concentration-response curve. The pharmacological profile of S. scardica extracts as triple monoamine reuptake inhibitors suggests their use in the phytochemical therapy of mental disorders associated with a malfunctioning monoaminergic neurotransmission, such as anxiety disorders, major depression, attention-deficit hyperactivity disorder, mental impairment or neurodegenerative diseases. [PubMed Citation] [Order full text from Infotrieve]

10) Duric V, Duman RS
Depression and treatment response: dynamic interplay of signaling pathways and altered neural processes.
Cell Mol Life Sci. 2012 May 15;
Since the 1960s, when the first tricyclic and monoamine oxidase inhibitor antidepressant drugs were introduced, most of the ensuing agents were designed to target similar brain pathways that elevate serotonin and/or norepinephrine signaling. Fifty years later, the main goal of the current depression research is to develop faster-acting, more effective therapeutic agents with fewer side effects, as currently available antidepressants are plagued by delayed therapeutic onset and low response rates. Clinical and basic science research studies have made significant progress towards deciphering the pathophysiological events within the brain involved in development, maintenance, and treatment of major depressive disorder. Imaging and postmortem brain studies in depressed human subjects, in combination with animal behavioral models of depression, have identified a number of different cellular events, intracellular signaling pathways, proteins, and target genes that are modulated by stress and are potentially vital mediators of antidepressant action. In this review, we focus on several neural mechanisms, primarily within the hippocampus and prefrontal cortex, which have recently been implicated in depression and treatment response. [PubMed Citation] [Order full text from Infotrieve]

11) 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]

12) Wu CH, Farley JF, Gaynes BN
The association between antidepressant dosage titration and medication adherence among patients with depression.
Depress Anxiety. 2012 Jun;29(6):506-14.
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13) Thaler KJ, Morgan LC, Van Noord M, Gaynes BN, Hansen RA, Lux LJ, Krebs EE, Lohr KN, Gartlehner G
Comparative effectiveness of second-generation antidepressants for accompanying anxiety, insomnia, and pain in depressed patients: a systematic review.
Depress Anxiety. 2012 Jun;29(6):495-505.
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14) Ruengorn C, Sanichwankul K, Niwatananun W, Mahatnirunkul S, Pumpaisalchai W, Patumanond J
Factors related to suicide attempts among individuals with major depressive disorder.
Int J Gen Med. 2012;5:323-30.
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15) Singh M, Schwartz TL
Clinical utility of vilazodone for the treatment of adults with major depressive disorder and theoretical implications for future clinical use.
Neuropsychiatr Dis Treat. 2012;8:123-30.
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16) Sanford M, Keating GM
Quetiapine: a review of its use in the management of bipolar depression.
CNS Drugs. 2012 May 1;26(5):435-60.
Quetiapine (Seroquel®) is an orally administered atypical antipsychotic that is indicated for the treatment of schizophrenia and bipolar disorder, including bipolar depression. An extended-release (XR) formulation of quetiapine is also available. This review summarizes the pharmacological properties, efficacy and tolerability of quetiapine and quetiapine XR in patients with bipolar depression. Quetiapine is an antagonist at both serotonin 5-HT2 and dopamine D2 receptors, and its antipsychotic effects are thought to stem from interactions at these receptors. The antidepressant effects of quetiapine are poorly understood, but may be related to antagonism of 5-HT2A receptors in cortical regions, partial agonism of 5-HT1A in the prefrontal cortex in association with increased extracellular dopamine release in the region, or to reduced synaptic reuptake of noradrenaline resulting from inhibition of the noradrenaline reuptake transporter by the quetiapine metabolite norquetiapine. The efficacy and tolerability of quetiapine was evaluated in five 8-week, randomized, double-blind, placebo-controlled, multicentre or multinational trials in patients with a major depressive episode (MDE) associated with bipolar disorder. Across trials, monotherapy with oral quetiapine 300 or 600?mg/day (or quetiapine XR 300?mg/day) produced significantly greater improvements than placebo in depressive symptoms (primary endpoint), according to the change in the Montgomery-Asberg Depression Rating Scale total score. In general, quetiapine and quetiapine XR were also associated with significantly higher MDE response and remission rates than placebo. Across trials, quetiapine and quetiapine XR produced significantly greater improvements in global severity of illness scores than placebo, according to changes in the Clinical Global Impressions scale score. There were no differences in treatment outcomes between quetiapine 300?mg/day and 600?mg/day dosage groups. Patients with bipolar depression who responded to quetiapine during two 8-week acute treatment trials also benefited from continuing quetiapine therapy for up to 52 weeks. Compared with quetiapine responders randomized to placebo, quetiapine responders who continued quetiapine 300 or 600?mg/day had a significantly reduced risk of recurrence of any mood events and of depression mood events, but not of hypomanic/manic events. In a randomized, double-blind, placebo-controlled trial, quetiapine maintenance therapy for up to 104 weeks was more efficacious than placebo or lithium in prolonging the time to recurrence of any mood event (primary endpoint). Patients in this trial had bipolar I disorder with mania, depression or a mixed episode as the index episode, and the trial included only patients who were responsive to acute phase quetiapine, which may have introduced a positive bias in favour of quetiapine over lithium during maintenance therapy. Quetiapine 300 or 600?mg/day and quetiapine XR 300?mg/day was generally well tolerated in patients with bipolar depression, with most treatment-emergent adverse events being of mild to moderate severity. The most frequent adverse events occurring during the acute treatment phase were dry mouth, sedation, somnolence, dizziness (quetiapine and quetiapine XR), constipation (quetiapine) and increased appetite (quetiapine XR). Extrapyramidal symptoms (EPS) occurred across quetiapine and placebo groups, but there were no significant differences between quetiapine and placebo recipients on objective measures of EPS and akathisia. In some trials, quetiapine recipients experienced significantly greater weight gain than placebo recipients. Across trials, some quetiapine recipients had clinically relevant increases in blood glucose or lipid parameters, although these also occurred in patients from other treatment groups. The clinical significance of these changes is uncertain. In conclusion, quetiapine and quetiapine XR are valuable additions to the first-line treatments for bipolar depression. Further head-to-head trials of quetiapine versus other drug regimens that are effective in bipolar depression would be of considerable interest. [PubMed Citation] [Order full text from Infotrieve]

17) Richard IH, McDermott MP, Kurlan R, Lyness JM, Como PG, Pearson N, Factor SA, Juncos J, Serrano Ramos C, Brodsky M, Manning C, Marsh L, Shulman L, Fernandez HH, Black KJ, Panisset M, Christine CW, Jiang W, Singer C, Horn S, Pfeiffer R, Rottenberg D, Slevin J, Elmer L, Press D, Hyson HC, McDonald W
A randomized, double-blind, placebo-controlled trial of antidepressants in Parkinson disease.
Neurology. 2012 Apr 17;78(16):1229-36.
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18) Bangasser DA, Valentino RJ
Sex differences in molecular and cellular substrates of stress.
Cell Mol Neurobiol. 2012 Jul;32(5):709-23.
Women are twice as likely as men to suffer from stress-related psychiatric disorders, like unipolar depression and post-traumatic stress disorder. Although the underlying neural mechanisms are not well characterized, the pivotal role of stress in the onset and severity of these diseases has led to the idea that sex differences in stress responses account for this sex bias. Corticotropin-releasing factor (CRF) orchestrates stress responses by acting both as a neurohormone to initiate the hypothalamic-pituitary-adrenal (HPA) axis and as a neuromodulator in the brain. One target of CRF modulation is the locus coeruleus (LC)-norepinephrine system, which coordinates arousal components of the stress response. Hypersecretion of CRF and dysregulation of targets downstream from CRF, such as the HPA axis and LC-norepinephrine system, are characteristic features of many stress-related psychiatric diseases, suggesting a causal role for CRF and its targets in the development of these disorders. This review will describe sex differences in CRF and the LC-norepinephrine system that can increase stress sensitivity in females, making them vulnerable to stress-related disorders. Evidence for gonadal hormone regulation of hypothalamic CRF is discussed as an effect that can lead to increased HPA axis activity in females. Sex differences in the structure of LC neurons that create the potential for hyperarousal in response to emotional stimuli are described. Finally, sex differences at the molecular level of the CRF(1) receptor that make the LC-norepinephrine system more reactive in females are reviewed. The implications of these sex differences for the treatment of stress-related psychiatric disorders also will be discussed. [PubMed Citation] [Order full text from Infotrieve]

19) Houston JP, Lau K, Aris V, Liu W, Fijal BA, Heinloth AN, Perlis RH
Association of common variations in the norepinephrine transporter gene with response to olanzapine-fluoxetine combination versus continued-fluoxetine treatment in patients with treatment-resistant depression: a candidate gene analysis.
J Clin Psychiatry. 2012 Jun;73(6):878-85.
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20) Castro VM, Gallagher PJ, Clements CC, Murphy SN, Gainer VS, Fava M, Weilburg JB, Churchill SE, Kohane IS, Iosifescu DV, Smoller JW, Perlis RH
Incident user cohort study of risk for gastrointestinal bleed and stroke in individuals with major depressive disorder treated with antidepressants.
BMJ Open. 2012;2(2):e000544.
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