serotonin and unipolar depression


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(Updated 7/19/04)

[See also Serotonergic Genes and Unipolar Depression / SSRI Response or 5-HT1B and Aggression/ Impulsivity] [Note that serotonin transporter research is not included on this page.]

Gibbons RD, Davis JM.
Consistent evidence for a biological subtype of depression characterized by low CSF monoamine levels.
Acta Psychiatr Scand 1986 Jul;74(1):8-12
"Analysis of previously published CSF monoamine data has revealed statistical evidence for a biological subtype of depression, characterized by abnormally low CSF-5HIAA and CSF HVA. Using maximum likelihood gaussian mixture analysis we were able to resolve the empirical frequency distributions of both CSF HVA and CSF 5-HIAA into two component normal mixtures. Simultaneous analysis of both CSF 5-HIAA and CSF HVA revealed a two component bivariate normal mixture distribution in which 35% of the depressed patient sample were classified in the low subgroup. No evidence for mixture distributions was found in controls. Analysis of CSF MHPG revealed a single component normal distribution with virtually identical mean and variance in both patients and controls. These results are shown to be virtually identical to parallel analyses conducted on CSF monoamine data collected as part of the NIMH collaborative study on the psychobiology of depression study." [Abstract]

Asberg M, Thoren P, Traskman L, Bertilsson L, Ringberger V.
"Serotonin depression"--a biochemical subgroup within the affective disorders?
Science 1976 Feb 6;191(4226):478-80
"The distribution of 5-hydroxyindoleacetic acid (5-HIAA) concentrations in the cerebrospinal fluid of 68 depressed patients was bimodal. Twenty-nine percent of the patients were in the lower mode, with a concentration of 5-HIAA below 15 nanograms per milliliter. Although there were no differences in overall severity of depression between the two modes, there was a significant correlation between the concnetration of 5-HIAA and severity of depression in the lower, but not in the upper, mode. The finding suggests the existence of a biochemical subgroup of depressive disorder, characterized by a disturbance of serotonin turnover." [Abstract]

Heninger GR, Delgado PL, Charney DS.
The revised monoamine theory of depression: a modulatory role for monoamines, based on new findings from monoamine depletion experiments in humans.
Pharmacopsychiatry 1996 Jan;29(1):2-11
"The new hypothesis most consistent with this new data is that the monoamine systems are only modulating "other" brain neurobiologic systems which have a more primary role in depression. The modulatory or "antidepressant" function of the monoamine systems appears to be only necessary during drug induced recovery and the maintenance of recovery after a prior episode. These clinical studies point to the need for more fundamental research on the interaction of monoamine systems with other brain neurobiologic mechanisms relevant to depression." [Abstract]

Pineyro, Graciela, Blier, Pierre
Autoregulation of Serotonin Neurons: Role in Antidepressant Drug Action
Pharmacol Rev 1999 51: 533-591 [Full Text]

Roy A.
CSF 5-HIAA correlates with neuroticism in depressed patients.
J Affect Disord 1999 Jan-Mar;52(1-3):247-9
"BACKGROUND: To examine for relationships between neurotransmitters and personality. METHOD: 27 depressed patients had cerebrospinal fluid (CSF) monoamine metabolites measured and completed the Eysenck Personality Questionnaire (EPQ). RESULT: CSF concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) correlated significantly with EPQ neuroticism scores. CONCLUSION: Central serotonin may play a role in neuroticism, a personality dimension predisposing to depression. LIMITATION: The positive correlation may partly reflect collinear relationships between both variables and anxiety/depression." [Abstract]

Nordin C.
Relationships between clinical symptoms and monoamine metabolite concentrations in biochemically defined subgroups of depressed patients.
Acta Psychiatr Scand 1988 Dec;78(6):720-9
"In 28 patients with primary depression, relationships were sought between rating scores on the Montgomery-Asberg Depression Rating Scale and the concentrations of the monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 4-hydroxy-3-methoxyphenylglycol (HMPG) in cerebrospinal fluid (CSF). Among the single items in the rating scale, reported sadness correlated negatively with HMPG. No other significant relationships were found in the total group of patients. However, in subgroups with low or high concentrations of monoamine metabolites, several significant relationships were found, such as a negative correlation between inner tension and concentration difficulties, respectively, and 5-HIAA in the low-HMPG subgroup. Curvilinear relationships were found between pessimistic thoughts and 5-HIAA in the high-5-HIAA subgroup and between apparent sadness and 5-HIAA in the low-HMPG subgroup. Suicidal thoughts tended to correlate in a curvilinear way with the ratio of HMPG/5-HIAA in the low-HVA and the high-HMPG subgroups, but the curves were mirrored. The results indicate that relationships between clinical symptoms and monoamine metabolite homeostasis in CSF are qualitatively and quantitatively different in defined high-and low-monoamine subgroups of depressed patients." [Abstract]

Cheetham SC, Crompton MR, Czudek C, Horton RW, Katona CL, Reynolds GP.
Serotonin concentrations and turnover in brains of depressed suicides.
Brain Res 1989 Nov 20;502(2):332-40
"5-Hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations and 5-HT turnover (5-HIAA/5-HT) were determined in 6 brain regions from 19 suicide victims in whom a retrospective diagnosis of depression was established, and 19 age- and sex-matched control subjects. Thirteen of the suicides were free of psychoactive drugs at the time of death; 5 were receiving antidepressant drugs. 5-HT, 5-HIAA and 5-HT turnover did not differ significantly between the total, drug-free and antidepressant-treated suicides and controls in frontal and temporal cortex, caudate and hippocampus. 5-HIAA concentration was significantly higher in amygdala of drug-free suicides than controls, whereas 5-HT and 5-HT turnover did not differ. 5-HT concentration was significantly lower in putamen of the total and antidepressant-treated suicides and a similar reduction was also apparent in the drug-free suicides. 5-HT turnover in putamen was significantly higher in the total and drug-free suicides compared to controls. 5-HT and 5-HIAA concentrations in putamen were significantly lower in drug-free suicides who died by non-violent means than in those who died by violent means. Differences between controls and suicides could not be attributed to age, sex or postmortem delay. These results offer no support for the view that 5-HT turnover is reduced in depressed subjects who commit suicide." [Abstract]

Owen F, Chambers DR, Cooper SJ, Crow TJ, Johnson JA, Lofthouse R, Poulter M.
Serotonergic mechanisms in brains of suicide victims.
Brain Res 1986 Jan 1;362(1):185-8
"Serotonergic mechanisms have been investigated in postmortem brain samples from controls and suicide victims. The concentrations of 5-hydroxytryptamine (serotonin; 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were determined in occipital cortex and hippocampus and the high-affinity binding of ligands to the 5-HT1, 5-HT2 and imipramine-binding sites was assessed in frontal cortex, occipital cortex and hippocampus. The only significant difference between the two groups was a modest increase in 5-HIAA levels in the hippocampus of suicide victims. There was no evidence to suggest that those suicide victims with a clinical history of depression represented a subgroup with altered metabolite levels or binding values. The storage conditions of the samples were not related to the metabolite levels or binding values. There was, however, a significant positive correlation between [3H]imipramine binding and age in some brain regions. The results do not provide any evidence of gross alterations in 5-HT mechanisms in suicide or depression." [Abstract]

Roy A, Pickar D, Linnoila M, Doran AR, Paul SM.
Cerebrospinal fluid monoamine and monoamine metabolite levels and the dexamethasone suppression test in depression. Relationship to life events.
Arch Gen Psychiatry 1986 Apr;43(4):356-60
"The cerebrospinal fluid levels of norepinephrine and six monoamine metabolites were measured in 23 patients meeting DSM-III criteria for major depressive episode, 15 of whom also met criteria for melancholia. Life events during the six-month period before the onset of depression were recorded using Paykel's method. There was no difference in Hamilton depression ratings between patients with life events and those without. However, depressed patients who did not have a life event in the six months before the onset of depression had significantly lower levels of the dopamine metabolite homovanillic acid and the serotonin metabolite 5-hydroxyindoleacetic acid than those with life events. The incidence of nonsuppression on the dexamethasone suppression test was also greater in patients with a major depressive episode who did not have an undesirable life event than in those who did. Thus, the presence or absence of life events led to a separation into biologically distinct groups." [Abstract]

Westrin A, Nimeus A.
The dexamethasone suppression test and CSF-5-HIAA in relation to suicidality and depression in suicide attempters.
Eur Psychiatry. 2003 Jun;18(4):166-71.
"This study tested suicidality in relation to cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and the dexamethasone suppression test. Patients with nonsuppression of cortisol had the highest scores of the Suicide Assessment Scale (SUAS) and the Montgomery Asberg Depression Rating Scale (MADRS), respectively (P < 0.05; P < 0.01). The results persisted when analysed for covariance with CSF-5-HIAA. We have previously noted an elevated suicide risk in suicide attempters with high SUAS-scores, why a large part of nonsuppressors may be at high risk for future suicide." [Abstract]

Geracioti TD Jr, Loosen PT, Ekhator NN, Schmidt D, Chambliss B, Baker DG, Kasckow JW, Richtand NM, Keck PE Jr, Ebert MH.
Uncoupling of serotonergic and noradrenergic systems in depression: preliminary evidence from continuous cerebrospinal fluid sampling.
Depress Anxiety 1997;6(3):89-94
"We used the technique of continuous cerebrospinal fluid (CSF) sampling to test the following hypotheses regarding CNS monoaminergic systems in depression: (1) absolute concentrations of the informational substances tryptophan and 5-hydroxyindoleacetic acid (5-HIAA) are altered in the CNS of depressed patients (2) abnormal rhythms of tryptophan and/or 5-HIAA, or defective conversion of tryptophan to serotonin (5HT), exist in the CNS of depressed patients, and (3) the relationship between the CNS 5HT and norepinephrine (NE) systems is disrupted in depressed patients. We obtained 6-h concentration time series of tryptophan, 5-HIAA, NE, and 3-methoxy-4-hydroxyphenylglycol (MHPG) in the CSF of 10 patients with major depression and in 10 normal volunteers. No significant differences in CSF tryptophan, 5-HIAA, NE, or MHPG concentrations or rhythms were observed between normal volunteers and depressed patients. Neither were there differences in the mean tryptophan-to-serotonin ratio. However, a negative linear relationship was observed between mean concentrations of 5-HIAA and NE in the CSF of the normal volunteers (r = 0.916 [r2 = 0.839], df = 9, P < 0.001) while, in contrast, depressed patients showed no such relationship (r = +0.094 [r2 = 0.00877], df = 9, n.s.). Furthermore, the correlation coefficients expressing the relationship between CSF MHPG and CSF 5-HIAA within the normal and depressed groups were significantly different. These data support the hypothesis that a disturbance in the interaction between the serotonergic and noradrenergic systems can exist in depressive illness in the absence of any simple 5HT or NE deficit or surplus." [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]

Koslow SH, Maas JW, Bowden CL, Davis JM, Hanin I, Javaid J.
CSF and urinary biogenic amines and metabolites in depression and mania. A controlled, univariate analysis.
Arch Gen Psychiatry 1983 Sep;40(9):999-1010
"Levels of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in the CSF, and norepinephrine (NE), epinephrine (E), vanillylmandelic acid, normetanephrine, metanephrine, and MHPG in the urine, were measured in 151 hospitalized patients with affective disorders and in 80 healthy controls following a two-week drug-free period. Unipolar and bipolar depressed subjects differed only in NE and E levels. Compared with controls, depressed subjects had higher CSF MHPG levels, women had higher 5-HIAA levels, and men had lower HVA levels. All urinary metabolites were elevated in depression and mania, with the exception of MHPG. The patterns of NE-E differences discriminated among the forms of affective disorders. These data suggest an imbalance of monoamine transmission in depression, characterized by the hyperactive sympathetic nervous system and adrenal medulla. However, MHPG may not be the measure of choice to reflect this imbalance, necessitating measurement of total body monoamine output." [Abstract]

Gjerris A, Sorensen AS, Rafaelsen OJ, Werdelin L, Alling C, Linnoila M.
5-HT and 5-HIAA in cerebrospinal fluid in depression.
J Affect Disord 1987 Jan-Feb;12(1):13-22
"CSF 5-HT and 5-HIAA were measured in endogenously depressed patients (ICD-9) (n = 23) and controls (n = 11). Distribution of sex, age and body height was similar in the two groups. Non-parametric statistics were used. In depressed patients CSF 5-HT concentrations were found to be higher (P less than or equal to 0.01) than in controls. A further classification of the depressed patients by the Newcastle Scale showed that the highest values were found in the endogenous group compared to the non-endogenous group (P less than or equal to 0.02). CSF 5-HIAA was found to be equal in the two groups, even when pairs matched for height were compared. No relation between clinical recovery due to drug treatment and changes in CSF 5-HT was seen." [Abstract]

Lykouras E, Markianos M, Malliaras D, Stefanis C.
Neurochemical variables in delusional depression.
Am J Psychiatry 1988 Feb;145(2):214-7
"The authors assayed plasma dopamine beta-hydroxylase activity, platelet monoamine oxidase (MAO) activity, plasma prolactin, the urinary monoamine metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA), and urinary cAMP from 18 delusional and 22 nondelusional depressed inpatients. No significant differences between the two groups were found." [Abstract]

Gjerris A, Werdelin L, Gjerris F, Sorensen PS, Rafaelsen OJ, Alling C.
CSF-amine metabolites in depression, dementia and in controls.
Acta Psychiatr Scand 1987 Jun;75(6):619-28
"Lumbar CSF concentration of 5-HIAA, MHPG, and HVA were measured in patients with depression, dementia due to normal pressure hydrocephalus (NPH) and in controls. Moreover, ventricular concentrations of the metabolites were measured in patients with NPH. It was aimed to match patients and controls for age, sex, and body height. Non-parametric statistics were used throughout the study. No differences in lumbar concentrations of CSF 5-HIAA, MHPG and HVA were found between the different diagnostic groups." [Abstract]

Reddy PL, Khanna S, Subhash MN, Channabasavanna SM, Rao BS.
CSF amine metabolites in depression.
Biol Psychiatry 1992 Jan 15;31(2):112-8
"The amine metabolites, namely homovanillic acid (HVA) and 5-hydroxy indoleacetic acid (5-HIAA) were measured in cerebrospinal fluid (CSF) of depressives (n = 30) and controls (n = 30). Depressed patients had significantly lower HVA levels than controls. No significant differences were noted between the two groups in 5-HIAA levels. However, the differences between the groups for the CSF HVA/5-HIAA ratio were larger than those for the CSF HVA alone (p less than 0.01 versus p less than 0.025, respectively). HVA levels correlated positively with monoamine oxidase activity and adenosine deaminase activity." [Abstract]

Peabody CA, Faull KF, King RJ, Whiteford HA, Barchas JD, Berger PA.
CSF amine metabolites and depression.
Psychiatry Res 1987 May;21(1):1-7
"Cerebrospinal fluid (CSF) amine metabolites were measured in 37 male subjects with major depressive disorder. Scores on the Hamilton Rating Scale for Depression (HRSD) correlated significantly with 5-hydroxyindoleacetic acid (5HIAA) and with homovanillic acid (HVA). In addition, the single suicide item of the HRSD correlated significantly with 5HIAA. Further, 5HIAA and HVA correlated significantly with each other. There was a significant positive correlation between HVA and two HRSD items, the depersonalization/derealization item and the paranoid item. Since lumbar CSF metabolite concentrations may reflect central nervous system activity of parent amines, these data suggest a relationship between depression and decreased dopaminergic and serotonergic activity." [Abstract]

Redmond DE Jr, Katz MM, Maas JW, Swann A, Casper R, Davis JM.
Cerebrospinal fluid amine metabolites. Relationships with behavioral measurements in depressed, manic, and healthy control subjects.
Arch Gen Psychiatry 1986 Oct;43(10):938-47
"We studied 99 hospitalized depressed, 14 manic, and 61 healthy control subjects and evaluated relationships during a drug-free baseline period between behavioral measures (postulated to be associated with brain norepinephrine, dopamine, and serotonin function) and metabolites of these neurotransmitters sampled from lumbar cerebrospinal fluid (CSF): 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid, and 5-hydroxyindoleacetic acid. Depressed subjects with increased anxiety, agitation, somatization, and sleep disturbance were found to have significantly elevated concentrations of CSF MHPG; this relationship was not found in the healthy controls. A correlation between CSF MHPG level and an anxiety/agitation dimension measured in all subjects was statistically significant but explained a modest portion of the total variance. No consistent relationships were found between CSF MHPG and depression/retardation, hostility/interpersonal sensitivity, and global severity, nor did any of these measures correlate significantly with the levels of the other monoamine metabolites, although some trends were found. Other factors did not account for the relationships between CSF MHPG and some behavioral measures, including diagnostic subgroup, motor movement, age, sex, and premenopausal or postmenopausal status in women. Suggested relationships among drug treatment modality, eventual treatment outcome, behavioral and mood state at baseline, and these metabolite levels will require further analyses." [Abstract]

Faustman WO, Faull KF, Whiteford HA, Borchert C, Csernansky JG.
CSF 5-HIAA, serum cortisol, and age differentially predict vegetative and cognitive symptoms in depression.
Biol Psychiatry 1990 Feb 1;27(3):311-8
"Prior studies have shown that both cerebrospinal fluid (CSF) concentrations of 5-hydroxyindolacetic acid (5-HIAA) and serum cortisol levels are related to overall symptom severity in depression. In the present study, 30 unmedicated inpatients meeting Research Diagnostic Criteria (RDC) criteria for depression participated in serum cortisol collection and a lumbar puncture for CSF. A multiple regression evaluated the ability of CSF 5-HIAA, serum cortisol, and age to predict cognitive and vegetative symptom clusters of the Hamilton Rating Scale for Depression. The multiple regression to predict the vegetative symptom cluster was highly significant overall (p = 0.002) and found that age and cortisol but not 5-HIAA predicted vegetative symptoms. The regression to predict the cognitive cluster narrowly missed overall significance (p = 0.06). Both CSF 5-HIAA and serum cortisol predicted cognitive symptoms and 5-HIAA predicted the cognitive cluster more strongly than cortisol. Age did not predict cognitive symptoms. The results suggest a dissociation between serum cortisol levels and CSF 5-HIAA in predicting vegetative and cognitive symptom clusters in depression." [Abstract]

Hasey GM, Stancer HC, Warsh JJ, Persad E.
Neurotransmitter metabolites and endocrine responses in depression.
Prog Neuropsychopharmacol Biol Psychiatry 1985;9(5-6):613-7
"Urinary 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), 3-4-dihydroxyphenylethyleneglycol (DHPG), 5-hydroxyindoleacetic acid (5-HIAA), plasma thyroid stimulating hormone (TSH), prolactin (PRL) and growth hormone (GH) were measured before and after the injection of thyrotropin releasing hormone (TRH) in healthy subjects and depressed patients with primary affective disorder. The TSH response to TRH did not differ in depressed compared with control subjects. A trend (.05 less than p less than .10) toward a lower PRL response appeared in male depressed compared with male control subjects. GH levels did not consistently change after TRH. In all subjects the TSH response correlated positively with pre- and post-TRH urinary MHPG. The PRL response correlated negatively with pre-TRH urinary 5-HIAA. Pre-TRH daytime urinary 5-HIAA levels were elevated in depressed subjects." [Abstract]

Secunda SK, Cross CK, Koslow S, Katz MM, Kocsis J, Maas JW, Landis H.
Biochemistry and suicidal behavior in depressed patients.
Biol Psychiatry 1986 Jul;21(8-9):756-67
"The present study was undertaken in order to further explore the relationship between monoamine levels and hypothalamic-pituitary-adrenocortical (HYPAC) functioning and suicidal behavior in depressed patients. One hundred and thirty-two depressed inpatients participated in the NIMH Collaborative Study on the Psychobiology of Depression. Similar to previous reports, our suicide attempters were younger, more likely to be bipolar, had an earlier age at onset, and displayed more psychotic features. No correlation between cortisol hypersecretion or Dexamethasone Suppression Test (DST) nonsuppression and suicide attempts were found. Only the pre-DST evening plasma cortisol distinguished the groups, being lower in the attempter group. We were unable to confirm the previously reported correlation between cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and suicide attempts. Of the monoamines examined, only urinary and plasma 3-methoxy-4-hydroxphenylglycol (MHPG) differed between suicide attempters and nonattempters, showing lower levels in the attempter group. There was a trend for CSF MHPG in the same direction. This latter reduction was restricted to the bipolar group." [Abstract]

Lambert G, Johansson M, Agren H, Friberg P.
Reduced brain norepinephrine and dopamine release in treatment-refractory depressive illness: evidence in support of the catecholamine hypothesis of mood disorders.
Arch Gen Psychiatry 2000 Aug;57(8):787-93
"BACKGROUND: The etiology of depressive illness has been linked with brain monoaminergic neuronal dysfunction, yet the development of sensitive markers of endogenous depression has proven difficult. METHODS: Using catheters placed in an internal jugular vein, we estimated the release of brain monoamine neurotransmitters in 19 healthy volunteers and in 9 patients with nonbipolar depressive illness refractory to medication at rest and following intravenous desipramine hydrochloride. Venoarterial plasma concentration gradients were used to quantify the amount of neurotransmitters stemming from the brain. Cerebral oxidative metabolism was assessed concurrently from measurements of oxygen and carbon dioxide gas exchange via the process of regional indirect calorimetry. RESULTS: The brains of these patients exhibited reduced venoarterial norepinephrine (4.0 +/- 2.7 nmol/L vs 0.7 +/- 1.3 nmol/L) and homovanillic acid concentration gradients (8.3 +/- 7.8 nmol/L vs 3.1 +/- 1.9 nmol/L), and used an energy source other than glucose. Internal jugular 5-hydroxyindoleacetic acid concentration gradients were not reduced in the patients with depressive illness. While both the reduction in norepinephrine turnover and the defect in cerebral metabolism were normalized following pharmacological blockade of the norepinephrine transporter with desipramine, paradoxically it was the brain's turnover of dopamine that bore a significant relation to the patients' clinical status (r(s) = 0.79, P =.02). The positive nature of this relationship remains difficult to reconcile. CONCLUSIONS: In accordance with the monoamine hypothesis, a deficit in brain norepinephrine and dopamine exists in patients with depressive illness. Moreover, the brains of these patients use an energy source other than glucose, a situation that is normalized following the acute pharmacological blockade of the norepinephrine transporter with the tricyclic antidepressant, desipramine." [Abstract]

Tapie M, Garnier JP, Tremine T, Bousquet B, Manet L, Dreux C, Lauzel JP.
[Determination of 3-methoxy-4-hydroxyphenyethylene-glycol and its urinary conjugates. Value in the diagnosis and therapeutic follow-up of depression]
Pathol Biol (Paris) 1988 Mar;36(3):217-23
"In psychiatric illness like depression, difference is essential between noradrenergic and serotoninergic sources. Therefore the measurement of urinary excretion of MHPG (3-methoxy-4-hydroxy-phenylethylene-glycol) is interesting, because MHPG seems to be the best reflect of central noradrenergic activity. Analytical assay of MHPG includes an enzymatic hydrolysis and an extraction by ethyl acetate. Separation is conducted by HPLC with fluorometric detection for MHPG and VMA, and electrochemical detection for 5-HIAA, which measurement is simultaneous. Quality control is evaluated (detection limit, linearity, precision, reproducibility, hydrolysis and extraction efficiency). Control values of 15 healthy subjects are 18.9 +/- 8.0 mumol/24 h of total MHPG, 1.5 +/- 1.0 of free MHPG, 8.5 +/- 2.0 of sulfate, and 10.7 +/- 4.4 of glucuronide MHPG (m +/- 2 sigma). In our study on depression, the best biological witness seems to be the sulfate-MHPG: in 16 depressed patients without treatment, its rate is very lowered (1.2 +/- 1.2 mumol/24 h). Total and glucuronide MHPG decrease weaker than sulfate (respectively -51% and -65%), while free MHPG increases (+ 193%) versus controls. Urinary VMA and 5-HIAA, peripheric catabolites of respectively adrenalin and serotonin are not significantly altered. There is no correlation neither between urinary sulfate-MHPG and scale evaluation before treatment, nor between urinary sulfate-MHPG and clinic improvement after antidepressive treatment." [Abstract]

Bondy B, Baghai TC, Minov C, Schule C, Schwarz MJ, Zwanzger P, Rupprecht R, Moller HJ.
Substance P serum levels are increased in major depression: preliminary results.
Biol Psychiatry. 2003 Mar 15;53(6):538-42.
"BACKGROUND: Substance P (SP) is thought to have an impact in the pathophysiology of depression and the mechanism of action of antidepressant drugs. The aim of this study was to analyze the serum SP levels in healthy control subjects and in depressed patients before and after antidepressant treatments. METHODS: Twenty-three patients with major depression and 33 control subjects participated in the study. Using an enzyme immunoassay, the SP serum levels were determined in patients at baseline (before treatment) and after 2 and 4 weeks of antidepressant therapy. Determinations of SP in control subjects were carried out twice, at baseline and after 4 weeks. RESULTS: The mean baseline SP serum concentration was significantly higher in depressed patients as compared with control subjects (p <.001). Repeated measurements in control subjects showed that SP remains relatively constant over a period of 4 weeks. Although in depressed patients there was no overall change in the mean SP levels between baseline and 4 weeks' treatment, 37% of them exhibited a decrease of SP (15%-50%), which can be correlated to a better drug response than an increase in SP concentration after treatment (p =.001). CONCLUSIONS: Our data show that serum SP levels are increased in a proportion of patients with major depression and might thus indicate a subgroup of the disorder in which neuropeptides have a key position. Future studies are needed to clarify whether the observed SP decrease in treatment responders can be attributed to a specific class of drugs." [Abstract]

Brown GL, Linnoila MI.
CSF serotonin metabolite (5-HIAA) studies in depression, impulsivity, and violence.
J Clin Psychiatry 1990 Apr;51 Suppl:31-41; discussion 42-3
"A neuroanatomical central nervous system (CNS) mechanism for the expression of emotions and behaviors in animals has now been proposed for over 50 years. More specifically, alterations in CNS serotonin associated with aggressive behavior in certain animal models have been among the most frequent, reliable, and replicable findings. Because alterations in CNS monoamines, i.e., catechols and indols, have been related to hypotheses for affective disorders and associated with both suicidal and aggressive behaviors, human clinical implications have emerged. The original studies, which reported an association between low cerebrospinal fluid 5-hydroxyindole-acetic acid concentration and impulsive, destructive behaviors, particularly where aggression and violence are involved, have now been replicated rather consistently in a number of countries and cultures." [Abstract]

Placidi GP, Oquendo MA, Malone KM, Huang YY, Ellis SP, Mann JJ.
Aggressivity, suicide attempts, and depression: relationship to cerebrospinal fluid monoamine metabolite levels.
Biol Psychiatry 2001 Nov 15;50(10):783-91
"BACKGROUND: We have proposed a stress-diathesis model for suicidal behavior, in which major depression is a stressor and the diathesis is shared with aggression. Neurotransmitter correlates of the stress or diathesis have not been adequately evaluated by previous studies, because they did not simultaneously examine the relationship of multiple neurotransmitters to all three psychopathologies in the same population. In the present study we investigated the relationship of monoamine metabolites to aggressivity, suicidal behavior, and depression in patients with mood disorders. METHODS: Ninety-three drug-free subjects with a major depressive episode underwent lumbar puncture and psychiatric evaluation. Cerebrospinal fluid CSF levels of 5hydroxyindolacetic acid (5-HIAA), homovanillic acid (HVA) and methoxy-hydroxy-phenylglycol (MHPG) were assayed. The relationships between monoamine metabolites and clinical variables were statistically evaluated. RESULTS: Higher lifetime aggressivity correlated significantly with lower CSF 5-HIAA. Lower CSF 5-HIAA and greater suicidal intent were found in high-lethality suicide attempters compared with low-lethality suicide attempters. Low-lethality attempters did not differ biologically from nonattempters. No correlation between CSF HVA and any of the psychopathological variables was found. Only aggression showed a trend statistically in correlating positively with CSF MHPG levels. CONCLUSIONS: Lower CSF 5-HIAA concentration was independently associated with severity of lifetime aggressivity and a history of a higher lethality suicide attempt and may be part of the diathesis for these behaviors. The dopamine and norepinephrine systems do not appear to be as significantly involved in suicidal acts, aggression, or depression. The biological correlates of suicide intent warrant further study." [Abstract]

Cremniter D, Jamain S, Kollenbach K, Alvarez JC, Lecrubier Y, Gilton A, Jullien P, Lesieur P, Bonnet F, Spreux-Varoquaux O.
CSF 5-HIAA levels are lower in impulsive as compared to nonimpulsive violent suicide attempters and control subjects.
Biol Psychiatry 1999 Jun 15;45(12):1572-9
"BACKGROUND: We studied CSF 5-HIAA and HVA concentrations in violent suicide attempters and examined their relationship with depression, anxiety, and impulsivity. METHODS: CSF 5-HIAA and HVA concentrations were determined very shortly after hospital admission and compared to those of a matched control population. Clinical evaluation was performed concomitantly; the level impulsivity was evaluated by the Impulsivity Rating Scale (IRS). RESULTS: Twenty-three patients and 23 control subjects were included. According to the IRS, 14 patients were classified as impulsive, including all patients suffering from personality disorders, and 9 as nonimpulsive, with a main DSM-IIIR diagnosis of melancholia. CSF 5-HIAA concentrations in the suicide group were significantly lower than in control subjects. This difference was entirely due to the impulsive suicide attempters. There was an inverse correlation between the IRS score and CSF 5-HIAA (r = -.47, p = .02) and only a trend for HVA (r = -.41, p = .078) levels in the suicide group. CONCLUSIONS: This study of a group of violent suicide attempters distinguished a subgroup of patients diagnosed with personality disorder with high impulsivity scores and a subgroup of patients with the main diagnosis of severe depression. CSF 5-HIAA was significantly lower in impulsive violent attempters than in nonimpulsive violent attempters, therefore desintangling violence from impulsivity and linking this biologic abnormality to impulsivity." [Abstract]

Asberg M, Traskman L, Thoren P.
5-HIAA in the cerebrospinal fluid. A biochemical suicide predictor?
Arch Gen Psychiatry 1976 Oct;33(10):1193-7
"The incidence of suicidal acts was studied in 68 depressed patients and related to the level of 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid. The distribution of 5-HIAA levels was bimodal. Patients in the low 5-HIAA mode (below 15 ng/ml) attempted suicide significantly more often than those in the high mode, and they used more violent means. Two of the 20 patients in the low mode, and none of the 48 patients in the high mode died from suicide." [Abstract]

Spreux-Varoquaux O, Alvarez JC, Berlin I, Batista G, Despierre PG, Gilton A, Cremniter D.
Differential abnormalities in plasma 5-HIAA and platelet serotonin concentrations in violent suicide attempters: relationships with impulsivity and depression.
Life Sci 2001 Jun 29;69(6):647-57
"Brain serotonergic systems may participate in the regulation of mood, impulsivity and aggressive behavior. Because some monoaminergic mechanisms seem to be similar in the central nervous system and peripheral tissues, we tested whether serotonergic or dopaminergic biochemical parameters in peripheral venous blood are related or not to violent suicide behavior.We simultaneously studied plasma serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and platelet 5-HT content in patients within 3 days following a violent suicide attempt and in matched healthy controls. We examined their relationship with depression and impulsivity. Twenty seven drug-free suicide attempters and controls were included. Plasma 5-HIAA and platelet 5-HT concentrations were lower in suicide attempters than in controls. Fifteen patients were classified as impulsive (I), including all patients suffering from personality disorder and alcohol abuse, and 12 as non impulsive (NI), mostly melancholics. MADRS scores were similar in both I and NI suicide attempters.When controlling for age, plasma 5-HIAA was lower in I than in NI suicide attempters or controls; these findings are similar to those we observed recently with CSF 5-HIAA in I and NI violent suicide attempters. Contrarily, platelet 5-HT levels were lower in NI than in I patients or controls. Plasma HVA was not associated with suicide behavior. Plasma 5-HIAA concentration was inversely associated with the degree of impulsivity and platelet 5-HT with the intensity of depression. This study indicates that each peripheral serotonergic index is specifically related to a distinct clinical feature and shows differential alteration according to the impulsivity group. In I and NI drug-free violent suicide attempters an inverse figure between plasma 5-HIAA and platelet 5-HT data was observed indicating a non parallelism between these two peripheral variables. Further prospective studies are needed to investigate whether these peripheral serotonergic parameters may be used as helpful early predictors of violent suicide behavior." [Abstract]

Mann JJ, Malone KM.
Cerebrospinal fluid amines and higher-lethality suicide attempts in depressed inpatients.
Biol Psychiatry 1997 Jan 15;41(2):162-71
"Previous studies have found that not all suicide attempters with major depression have reduced serotonergic activity based on low cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF- 5-HIAA) levels. In this study we hypothesized that serotonergic function is lower in depressed patients who have carried out high-lethality suicide attempts resulting in more medical damage, which might explain differences in serotonergic activity among depressed suicide attempters. We assessed the relationship of CSF 5-HIAA and other amine metabolites to the most lethal lifetime suicide attempt in 22 drug-free inpatients with major depression. CSF 5-HIAA levels were lower in depressed patients with a history of a high-lethality or well-planned suicide attempt compared to depressed patients with a history of only low-lethality suicide attempt(s). Other CSF monoamine metabolites did not correlate with suicidal behavior. Low serotonergic activity may correlate with a predisposition to more lethal suicide attempts in major depression." [Abstract]

Banki CM, Arato M, Kilts CD.
Aminergic studies and cerebrospinal fluid cations in suicide.
Ann N Y Acad Sci 1986;487:221-30
"Cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) measurements have been collected over six years from 275 drug-free, recently hospitalized psychiatric patients, almost exclusively females. In accord with other observations from various countries, patients who had attempted suicide shortly before admission had significantly lower mean CSF 5-HIAA concentration and this was particularly true for those using violent methods. This finding could be replicated in five subsequent samples of patients evaluated separately and using different assay procedures, and proved to be independent of the clinical diagnoses. CSF HVA also showed similar tendencies but it had much larger variance with respect to suicide attempts and therefore fell short of statistical significance. In two patient populations CSF calcium and magnesium measurements have been obtained. CSF calcium did not prove to be related to either suicidal behavior or the diagnosis of major depression; on the other hand, CSF magnesium was found to be significantly lower in the suicide attempters and also correlated with CSF 5-HIAA. Nonsuicidal depressives had comparable CSF calcium and magnesium levels to the controls." [Abstract]

Banki CM, Arato M.
Amine metabolites, neuroendocrine findings, and personality dimensions as correlates of suicidal behavior.
Psychiatry Res 1983 Dec;10(4):253-61
"Levels of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured in the cerebrospinal fluid (CSF) of 62 female inpatients with major depression (n = 19), schizophrenic disorder (n = 18), alcohol dependence (n = 13), and other disorders (n = 12). Nineteen patients had attempted suicide immediately before admission, and six had used violent methods. Fifty-three patients received a dexamethasone suppression test (DST) following lumbar puncture and all completed the Marke-Nyman Temperament Scale (Hungarian version) within 10 days. CSF 5-HIAA was significantly lower in patients who had made violent suicide attempts, but did not differ between suicide attempters who had taken drug overdoses and nonattempters. CSF HVA showed no significant differences. Dexamethasone nonsuppression occurred more frequently among attempters, but this difference did not reach statistical significance. Among the three personality dimensions of the Marke-Nyman Scale, validity was lower and stability higher in suicidal patients; both findings were more pronounced in the violent subgroup. CSF 5-HIAA and Marke-Nyman validity were inversely correlated to each other in all three subgroups, and violent attempters could be separated from the other two groups by their simultaneously low CSF 5-HIAA values and Marke-Nyman validity scores." [Abstract]

Banki CM, Arato M, Papp Z, Kurcz M.
Biochemical markers in suicidal patients. Investigations with cerebrospinal fluid amine metabolites and neuroendocrine tests.
J Affect Disord 1984 Jun;6(3-4):341-50
"141 female psychiatric patients, suffering from major depression, schizophrenia, alcohol dependence or adjustment disorder, were investigated for their 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and cortisol level in the cerebrospinal fluid (CSF). Dexamethasone suppression tests were also performed in 111 cases, and TRH/TSH tests in 40 subjects. Fifty-two patients were hospitalized following a recent suicide attempt, 18 of which were made using a violent method. The other 34 attempters took tranquilizer or sedative overdoses. CSF 5-HIAA was significantly lower in violent attempters in all 4 diagnostic categories. CSF HVA was higher in those taking drug overdoses, but only in depression (and less markedly in schizophrenia). CSF cortisol did not differ among either diagnostic or suicidal subgroups. Dexamethasone suppression was more frequently abnormal in suicidal patients than in nonattempters, and this difference was more important where the overall nonsuppression rate was lower. Maximal TSH response to TRH showed an inverse correlation with CSF 5-HIAA, and it was lowest in the nonattempter group. The difference between violent suicide attempters and nonattempters in their TSH response was significant. Since these biochemical changes were more or less independent of clinical diagnoses, it seems relevant to explore further the biological background of human aggression and suicide as a separate research direction." [Abstract]

Lopez-Ibor JJ Jr, Saiz-Ruiz J, Perez de los Cobos JC.
Biological correlations of suicide and aggressivity in major depressions (with melancholia): 5-hydroxyindoleacetic acid and cortisol in cerebral spinal fluid, dexamethasone suppression test and therapeutic response to 5-hydroxytryptophan.
Neuropsychobiology 1985;14(2):67-74
"5-Hydroxyindoleacetic acid (5-HIAA) and cortisol in cerebrospinal fluid (CSF), response of the dexamethasone suppression test (DST) and the clinical response to treatment with 5-hydroxytryptophan (5-HTp) plus carbidopa were studied in a group of 21 depressed inpatients (major depression with melancholia) in order to correlate biological findings with psychopathologicalones. A positive correlation was found between strong suicidal thoughts, suicidal attempts and self-aggressivity and low concentration of 5-HIAA in CSF and a less significant but still positive correlation with abnormal DST response and with clinical response to the treatment." [Abstract]

Faustman WO, King RJ, Faull KF, Moses JA Jr, Benson KL, Zarcone VP, Csernansky JG.
MMPI measures of impulsivity and depression correlate with CSF 5-HIAA and HVA in depression but not schizophrenia.
J Affect Disord 1991 Aug;22(4):235-9
"Recent studies have linked impulsivity with CSF concentrations of both 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA). One work found a negative correlation between the MMPI psychopathic deviate (Pd) scale and 5-HIAA in personality disordered men (Brown et al., 1982). We found that the 5-HIAA/Pd correlation extends (P less than 0.05) to unmedicated depressed patients (n = 21). A trend was found between HVA and Pd in depression. There was no relationship between either metabolite and the Pd scale in unmedicated schizophrenics (n = 24). A significant inverse correlation was found between the MMPI depression scale and CSF HVA but not 5-HIAA in the depressed patients." [Abstract]

Tuinier S, Verhoeven WM, van Praag HM.
Cerebrospinal fluid 5-hydroxyindolacetic acid and aggression: a critical reappraisal of the clinical data.
Int Clin Psychopharmacol 1995 Sep;10(3):147-56
"Over the past 15 years several clinical studies have been published dealing with the hypothesis that disturbances in central serotonergic functioning could be related to outward directed aggression and impulsivity. Close reading of the 22 relevant reports, however, raises doubt about the unequivocality of the results across diagnostic boundaries and in comparison with normal controls. Only eight of the studies are methodologically acceptable and seem to support the hypothesis. Taking all data together, it is concluded that some relationship exists between decreased serotonin metabolism, as reflected by lowered cerebrospinal fluid 5-hydroxyindolacetic acid, and certain aspects of aggressive behavior in a subgroup of young, male, personality-disordered subjects with seriously deviant behavior." [Abstract]

Prochazka H, Agren H.
Self-rated aggression and cerebral monoaminergic turnover. Sex differences in patients with persistent depressive disorder.
Eur Arch Psychiatry Clin Neurosci. 2003 Aug;253(4):185-92.
"OBJECTIVE: Outward-directed violence and impulsivity in humans and primates has frequently been related to abnormal brain monoaminergic turnover. Self-rated aggression is likely to be clinically relevant,and its psychobiological basis needs investigation. SUBJECTS: Sixty-six patients (40 women and 26 men) with persistent depressive disorder (PDD) were compared with 497 control subjects from the general Swedish population. METHODS: We administered the Aggression Questionnaire - Revised Swedish Version (AQ-RSV) to patients and control subjects. In patients, CSF 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-5-hydroxyphenylglycol (MHPG) in CSF were analyzed. Total Aggression score and Aggression subfactors 'Physical Aggression','Verbal Aggression','Anger', and 'Hostility'were correlated with CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA),and 3-methoxy-5-hydroxyphenylglycol (MHPG). RESULTS: Overall, Hostility was positively related to CSF MHPG (t=2.27, p=0.015). Split by sex,Hostility was related with 5-HIAA in males (r=0.62,p=0.003),and with MHPG in females (r=0.38, p=0.03). Comparing self rated aggression with age- and sex-matched data from the general Swedish population, the most prominent deviation was increased Hostility score among PDD patients. Among patients, all aggression factors were nominally higher in women than in men, with the most pronounced sex difference in Hostility (t=-1.89, p=0.04). CONCLUSIONS: Results suggest a clinically meaningful sex difference in a positive relationship between hostility and serotonergic/noradrenergic turnover in PDD patients." [Abstract]

van Praag HM.
Affective disorders and aggression disorders: evidence for a common biological mechanism.
Suicide Life Threat Behav 1986 Summer;16(2):103-32
"Ever since the discovery that the classical antidepressants--tricyclics and MA oxidase inhibitors--exert an influence on central 5-HT, this neurotransmitter has been studied in depression, particularly in those forms responsive to this type of treatment. This chapter reviews the evidence in favor of a relationship between depression and central 5-HT dysfunctions. Most of the findings have been derived from patients with depression as the principal diagnosis. Some data have originated from patients suffering from a somatic illness and from depression as well. Both peripheral and central data are discussed. Although no single 5-HT-related finding in depression has so far been unequivocally established, the available evidence, in balance, justifies the tentative conclusion that disturbances in 5-HT metabolism can occur in depression. Lowered CSF 5-HIAA, the major indicator of disturbed central 5-HT metabolism in depression, has also been reported in aggression disorders, both in patients who had committed suicidal acts and in those with outward-directed aggression. The finding can not be explained by a concomitant state of depression. Rather than to discard the classical 5-HT-depression hypothesis, in favor of a 5-HT-aggression hypothesis, the hypothesis is launched that disturbances in serotonergic regulation can give rise to both mood and aggression disorders. This would provide a biological explanation for the clinical observation that those disorders frequently go hand in hand." [Abstract]


Engstrom G, Alling C, Blennow K, Regnell G, Traskman-Bendz L.
Reduced cerebrospinal HVA concentrations and HVA/5-HIAA ratios in suicide attempters. Monoamine metabolites in 120 suicide attempters and 47 controls.
Eur Neuropsychopharmacol 1999 Sep;9(5):399-405
"Dysfunctions of central monoaminergic systems are important elements of the leading biological hypotheses of suicide and depression. The purpose of the present paper was to study the levels and the relationships between the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the dopamine metabolite homovanillic acid (HVA) and the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in the cerebrospinal fluid (CSF) in 120 hospitalised suicide attempters and 47 controls (healthy volunteers or patients admitted for minor surgery). The suicide attempters showed significantly lower HVA levels (174+/-82 vs. 216+/-96 nmol/L, P=0.004), HVA/5HIAA ratios (1.6+/-0.5 vs. 2.1+/-0.6, P=0.0001) and HVA/MHPG ratios (4.2+/-2.1 vs. 4.8+/-1.7, P=0.02) than the controls. The correlations between the monoamine metabolites were markedly lower in patients than in controls. CSF 5-HIAA showed no significant differences between patients and controls (107+/-40 vs. 108+/-51 nmol/L) or between violent and non-violent attempters (112+/-58 vs. 105+/-33 nmol/L). The monoamine metabolites showed no significant differences between survivors and patients who subsequently completed suicide, or between suicide attempters subgrouped by psychiatric diagnoses. The results suggest that low HVA levels and altered relationships between the monoamine metabolites are associated with suicidal behaviour." [Abstract]

Roy A, Karoum F, Pollack S.
Marked reduction in indexes of dopamine metabolism among patients with depression who attempt suicide.
Arch Gen Psychiatry 1992 Jun;49(6):447-50
"Cerebrospinal fluid studies have reported that low concentrations of the dopamine metabolite homovanillic acid are associated with suicidal behavior in depression. Although only a small proportion of homovanillic acid in the urine derives from the brain, we decided to examine 24-hour urinary outputs of homovanillic acid in relation to suicidal behavior in depression. Patients with depression who had attempted suicide had significantly smaller urinary outputs of homovanillic acid, dihydroxyphenylacetic acid, and total body output of dopamine (sum dopamine) than did patients with depression who had not attempted suicide. Patients with depression who reattempted suicide during 5-year follow-up had significantly smaller urinary outputs of homovanillic acid and sum dopamine than did patients who did not reattempt suicide, patients who never attempted suicide, and normal control subjects, and had significantly smaller outputs of dihydroxyphenylacetic acid than patients who never attempted suicide or control subjects. These data suggest that urinary outputs of homovanillic acid may be peripheral correlates of suicidality in depression. These data add to data on the low levels of homovanillic acid in cerebrospinal fluid in suggesting that diminished dopaminergic neurotransmission may play a part in suicidal behavior in depression." [Abstract]

Roy A.
Recent biologic studies on suicide.
Suicide Life Threat Behav 1994 Spring;24(1):10-4
"This paper selectively reviews the author's recent studies on suicidal behavior in depression. Data are reviewed from a study of depressed patients who had monoamine metabolites measured in both the cerebrospinal fluid (CSF) and urine. Depressed patients who had attempted suicide had significantly reduced CSF concentrations of the dopamine metabolite homovanillic acid (HVA) and significantly lower urinary outputs of HVA than patients who had not attempted suicide. Similarly, patients who went on to reattempt suicide over a 5-year follow-up period had both significantly reduced CSF concentrations of HVA and lower urinary outputs of HVA than patients who did not reattempt. These data suggest a role for diminished central dopaminergic neurotransmission in suicidal behavior in depression. Patients who had made a violent suicide attempt also showed evidence of dysregulation of the hypothalamic-pituitary-adrenal axis." [Abstract]

Traskman-Bendz L, Asberg M, Bertilsson L, Thoren P.
CSF monoamine metabolites of depressed patients during illness and after recovery.
Acta Psychiatr Scand 1984 Apr;69(4):333-42
"Repeated lumbar punctures in 16 healthy volunteers showed reproducible concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in cerebrospinal fluid (CSF). In seven depressed patients, studied during two or three illness periods, the metabolite concentrations were also fairly stable. In 11 patients CSF concentrations of 5-HIAA, but not of HVA, were higher after recovery than during depression. This increase of 5-HIAA after recovery was confined to patients whose initial serotonin metabolite levels were low. The finding constitutes further evidence of a biochemical heterogeneity within the depressive disorders, and suggests that patients whose CSF 5-HIAA is low during a depressive episode may have a less stable serotonin system than other patients with depressive illness." [Abstract]

Agren H.
Life at risk: markers of suicidality in depression.
Psychiatr Dev 1983 Spring;1(1):87-103
"One hundred and ten patients with Research Diagnostic Criteria (RDC) diagnoses of major depressive disorders were assessed for present or recent suicidal ideation and behavior and for suicidal acts earlier in life before current depression using the Schedule for Affective Disorders and Schizophrenia (SADS). Suicidal scores were correlated uni- and bivariately with levels of CSF monoamine metabolites (HVA, 5HIAA, MHPG), urinary MHPG, the proportion post-/predexamethasone plasma cortisol at 1100 h, and platelet MAO activity (all standardized to same sex, age, height and weight). Results indicate that all 3 monoamine metabolites and their interactions are involved in various aspects of suicidality, at least in unipolar patients. MHPG and 5HIAA (both low or both high) were involved in current or recent suicidal ideation, and low HVA was mainly associated with past potential lethality of suicidal acts. Current hypercortisolism was found in patients that earlier in life had tried to commit dangerous suicides. Bipolar patients (depressives with a history of manic or hypomanic episodes) had earlier in life significantly more, and more dangerous, suicidal attempts than the unipolars." [Abstract]

Botez MI, Young SN, Bachevalier J, Gauthier S.
Effect of folic acid and vitamin B12 deficiencies on 5-hydroxyindoleacetic acid in human cerebrospinal fluid.
Ann Neurol 1982 Nov;12(5):479-84
"Indoles were measured in cerebrospinal fluid (CSF) from control patients, from patients suffering from folate deficiency, and from patients with vitamin B12 deficiency. The folate-deficient patients were classified according to whether they exhibited a neuropsychiatric syndrome, consisting of organic mental changes, polyneuropathy, and depression, which responded to folate administration. CSF 5-hydroxyindoleacetic acid was low in the vitamin B12-deficient patients and in those folate-deficient patients whose symptoms were not related to folate deficiency. CSF 5-hydroxyindoleacetic acid returned to normal with folate treatment in the patients exhibiting folate-responsive neuropsychiatric signs. The data indicate a close association between folate-responsive neuropsychiatric symptoms and changes in 5-hydroxytryptamine metabolism in the central nervous system." [Abstract]

Young SN.
The use of diet and dietary components in the study of factors controlling affect in humans: a review.
J Psychiatry Neurosci 1993 Nov;18(5):235-44
"Although one of the first biological treatments of a major psychiatric disorder was the dietary treatment of pellagra, the use of diet and dietary components in the study of psychopathology has not aroused much interest. This article reviews three areas in which the dietary approach has provided interesting information. The tryptophan depletion strategy uses a mixture of amino acids devoid of tryptophan to lower brain tryptophan in order to study the symptoms that can be elicited. One effect of tryptophan depletion is a lowering of mood, the magnitude of which seems to depend on the baseline state of the subject. Therefore, recovered depressed patients often undergo an acute relapse, while normal subjects show more moderate changes of mood. Totally euthymic subjects show no lowering of mood, but subjects with high normal depression scale scores or subjects with a family history of depression show a moderate lowering of mood. These data indicate that low serotonin levels alone cannot cause depression. However, serotonin does have a direct effect on mood, and low levels of serotonin contribute to the etiology of depression in some depressed patients. Folic acid deficiency causes a lowering of brain serotonin in rats, and of cerebrospinal fluid 5-hydroxyindoleacetic acid in humans. There is a high incidence of folate deficiency in depression, and there are indications in the literature that some depressed patients who are folate deficient respond to folate administration. Folate deficiency is known to lower levels of S-adenosylmethionine, and S-adenosylmethionine is an antidepressant that raises brain serotonin levels. These data suggest that low levels of serotonin in some depressed patients may be a secondary consequence of low levels of S-adenosylmethionine. They also suggest that the dietary intake and psychopharmacological action of methionine, the precursor of S-adenosylmethionine, should be studied in patients with depression. Normal meals have definite effects on mood and performance in humans. The composition of the meal, in terms of protein and carbohydrate content, can influence these behaviors. Because protein and carbohydrate meals can influence brain serotonin in rats, these effects in humans have usually been interpreted in terms of altered serotonin functioning. However, the current balance of evidence is against the involvement of serotonin in the acute effects of protein and carbohydrate meals in humans. The underlying mechanisms involved are unknown, but there are a variety of possibilities." [Abstract]

Lima L, Urbina M.
Serotonin transporter modulation in blood lymphocytes from patients with major depression.
Cell Mol Neurobiol. 2002 Dec;22(5-6):797-804.
"1. Serotonin is a neurotransmitter in the central nervous system which has been implicated in the aetiology and pathogenesis of affective disorders. The serononergic system also plays several roles in the immune system through the expression of a number of its receptor subtypes in the immune cells. 2. Following release serotonin is inactivated by reuptake into neurons and other cells by a specific serotonin sodium and chloride-dependent transporter molecule, whose structure has been elucidated. 3. Measurement [3H]paroxetine binding showed that human lymphocytes contain a high-affinity serotonin transporter. 4. To assess the serotonin function in major depression, we investigated serotonin transporter density in blood lymphocytes from patients with this disorder and selected according to the interview of the American Psychiatric Association. 5. Patients were divided into two groups and treated with two different antidepressant drugs, one group receiving fluoxetine, a selective serotonin reuptake inhibitor, and another mirtazapine, an antagonist of alpha2-adrenergic auto and heteroreceptors, for a period of 6 weeks. 6. Blood samples were obtained before and after the treatment, lymphocytes were isolated by Ficoll/Hypaque gradient, subjected to differential adhesion to plastic, and cell membranes were prepared for binding assay of [3H]paroxetine. 7. Lymphocytes serotonin transporter number was significantly reduced, while the affinity was unchanged, in patients with major depression disorder as compare to controls. 8. In addition, there was a partial recovery in lymphocytes serotonin (5HT) transporter number in the period posterior to the antidepressants administration, accompanied with clinical and depression rating scales improvement. Serotonin was determined in platelet-poor plasma and in lymphocytes before and after drugs administration, showing a significant decrease in the patients treated compared to untreated and controls. 9. These results are evidence of the potential interaction between the nervous and immune systems. The mechanisms underlying this interaction are under study, and might be related to modifications in the expression or function of the serotonin transporters in lymphocytes of depressed patients." [Abstract]

Tafet GE, Idoyaga-Vargas VP, Abulafia DP, Calandria JM, Roffman SS, Chiovetta A, Shinitzky M.
Correlation between cortisol level and serotonin uptake in patients with chronic stress and depression.
Cogn Affect Behav Neurosci. 2001 Dec;1(4):388-93.
"In a recent study (Tafet, Toister-Achituv, & Shinitzky, 2001), we demonstrated that cortisol induces an increase in the expression of the gene coding for the serotonin transporter, associated with a subsequent elevation in the uptake of serotonin. This stimulatory effect, produced upon incubation with cortisol in vitro, was observed in peripheral blood lymphocytes from normal subjects. In the present work we investigated the cortisol-induced increase in serotonin uptake in lymphocytes from hypercortisolemic patients, including subjects with major depressive disorder (n = 8), and subjects with generalized anxiety disorder (n = 12), in comparison with a control group of normal healthy subjects (n = 8). A significant increase in serotonin uptake (+37% + 14, M + SD) was observed in the control group, whereas neither the generalized anxiety disorder nor the major depression group exhibited changes in serotonin uptake upon incubation with cortisol. It is likely that under chronic stress or depression, the capacity for increase in serotonin transporter has reached its limit due to the chronically elevated blood cortisol level. The physiological and diagnostic implications of this observation are discussed." [Abstract]

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Recent Serotonin in Unipolar Depression Research

1) Brown GW, Ban M, Craig TK, Harris TO, Herbert J, Uher R
SEROTONIN TRANSPORTER LENGTH POLYMORPHISM, CHILDHOOD MALTREATMENT, AND CHRONIC DEPRESSION: A SPECIFIC GENE-ENVIRONMENT INTERACTION.
Depress Anxiety. 2012 Jul 27;
BACKGROUND: Key questions about the interaction between the serotonin transporter length polymorphism (5-HTTLPR) and stress in the etiology of depression remain unresolved. We test the hypotheses that the interaction is restricted to childhood maltreatment (as opposed to stressful events in adulthood), and leads to chronic depressive episodes (as opposed to any onset of depression), using gold-standard assessments of childhood maltreatment, severe life events, chronic depression, and new depressive onsets. METHOD: In a risk-enriched sample of 273 unrelated women, childhood maltreatment was retrospectively assessed with the Childhood Experience of Care and Abuse (CECA) interview and 5-HTTLPR was genotyped. A subset of 220 women was followed prospectively for 12 months with life events assessed with the Life Events and Difficulties (LEDS) interview. Any chronic episode of depression (12 months or longer) during adulthood and onset of a major depressive episode during a 12-month follow-up were established with the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) interview. RESULTS: The short alleles of 5-HTTLPR moderated the relationship between childhood maltreatment and chronic depression in adulthood, reflected in a significant gene-environment interaction (RD = 0.226, 95% CI: 0.076-0.376, P = .0032). 5-HTTLPR did not moderate the effects of either childhood maltreatment or severe life events on new depressive onsets. CONCLUSIONS: The short variant of the serotonin transporter gene specifically sensitizes to the effect of early-life experience of abuse or neglect on whether an adult depressive episode takes a chronic course. This interaction may be responsible for a substantial proportion of cases of chronic depression in the general population. Depression and Anxiety 00:1-9, 2012. © 2012 Wiley Periodicals, Inc. [PubMed Citation] [Order full text from Infotrieve]


2) Owen RT
Glutamatergic approaches in major depressive disorder: focus on ketamine, memantine and riluzole.
Drugs Today (Barc). 2012 Jul;48(7):469-78.
The role of glutamate in modulating various mood states is being increasingly recognized and researched. Existing antidepressants have been shown to exert effects on various glutamatergic mechanisms, even if such agents are traditionally classified as working via other mechanisms, such as selective serotonin reuptake inhibitors. The NMDA receptor antagonist ketamine has been investigated in various mood disorders, especially major depressive disorder (MDD). It was found to produce a rapid, robust and persistent antidepressant effect. Although it can produce cognitive, dissociative and perceptual disturbances, these tend to be transient and do not outlast the antidepressant effect. Trials with memantine and riluzole, agents with actions broadly similar to and different from ketamine on the glutamatergic system, are also reviewed in MDD and prospects for future research in the area are discussed. Although preclinical studies are discussed, the main focus of the review is on clinical outcomes. [PubMed Citation] [Order full text from Infotrieve]


3) Vilar-Pereira G, da Silva AA, Pereira IR, Silva RR, Moreira OC, de Almeida LR, de Souza AS, Rocha MS, Lannes-Vieira J
Trypanosoma cruzi-induced depressive-like behavior is independent of meningoencephalitis but responsive to parasiticide and TNF-targeted therapeutic interventions.
Brain Behav Immun. 2012 Jul 25;
Inflammatory cytokines and microbe-borne immunostimulators have emerged as triggers of depressive behavior. Behavioral alterations affect patients chronically infected by the parasite Trypanosomacruzi. We have previously shown that C3H/He mice present acute phase-restricted meningoencephalitis with persistent central nervous system (CNS) parasitism, whereas C57BL/6 mice are resistant to T.cruzi-induced CNS inflammation. In the present study, we investigated whether depression is a long-term consequence of acute CNS inflammation and a contribution of the parasite strain that infects the host. C3H/He and C57BL/6 mice were infected with the Colombian (type I) and Y (type II) T. cruzi strains. Forced-swim and tail-suspension tests were used to assess depressive-like behavior. Independent of the mouse lineage, the Colombian-infected mice showed significant increases in immobility times during the acute and chronic phases of infection. Therefore, T.cruzi-induced depression is independent of active or prior CNS inflammation. Furthermore, chronic depressive-like behavior was triggered only by the type I Colombian T.cruzi strain. Acute and chronic T. cruzi infection increased indoleamine 2,3-dioxygenase (IDO) expression in the CNS. Treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine abrogated the T. cruzi-induced depressive-like behavior. Moreover, treatment with the parasiticide drug benznidazole abrogated depression. Chronic T. cruzi infection of C57BL/6 mice increased tumor necrosis factor (TNF) expression systemically but not in the CNS. Importantly, TNF modulators (anti-TNF and pentoxifylline) reduced immobility. Therefore, direct or indirect parasite-induced immune dysregulation may contribute to chronic depressive disorder in T.cruzi infection, which opens a new therapeutic pathway to be explored. [PubMed Citation] [Order full text from Infotrieve]


4) Yang SJ, Stewart R, Kang HJ, Kim SY, Bae KY, Kim JM, Jung SW, Lee MS, Yim HW, Jun TY
Response to antidepressants in major depressive disorder with melancholic features: the CRESCEND study.
J Affect Disord. 2012 Jul 25;
BACKGROUND: This study aimed to determine whether major depressive disorders with melancholic and without melancholic features differ with respect to their responses to treatment with antidepressants. METHODS: From a nationwide sample of 18 hospitals in South Korea, 559 presenting patients with major depressive disorder were recruited. The DSM-IV based Structured Clinical Interview was administered for confirmatory diagnoses and depression subtypes with/without melancholic features. After baseline evaluation, they received naturalistic clinician-determined antidepressant interventions. Assessment scales for evaluating depression (HAMD), anxiety (HAMA), global severity (CGI-s), and functioning (SOFAS) were administered at baseline and re-evaluated at 1, 2, 4, 8, and 12 weeks later. RESULTS: At baseline, the 243 (43.5%) participants with melancholic features were more likely to have a previous history of depression, and had higher HAMA and lower SOFAS scores. After adjustment for baseline status, participants with melancholic features were more likely to achieve and to experience shorter times to CGI-s remission and associated with an enhanced global symptomatic remission with any antidepressant treatment. They were more likely to achieve and to experience shorter times to CGI-s remission and this difference was strongest in those receiving selective serotonin reuptake inhibitor (SSRI) antidepressants treatment. LIMITATIONS: The study was observational, and the treatment modality was naturalistic. CONCLUSIONS: These findings suggest a faster and more evident global response to pharmacotherapy in melancholia compared to other depressive syndromes, particularly where SSRI agents are used. [PubMed Citation] [Order full text from Infotrieve]


5) Fisher HL, Cohen-Woods S, Hosang GM, Korszun A, Owen M, Craddock N, Craig IW, Farmer AE, McGuffin P, Uher R
Interaction between specific forms of childhood maltreatment and the serotonin transporter gene (5-HTT) in recurrent depressive disorder.
J Affect Disord. 2012 Jul 25;
BACKGROUND: There is inconsistent evidence of interaction between stressful events and a serotonin transporter promoter polymorphism (5-HTTLPR) in depression. Recent studies have indicated that the moderating effect of 5-HTTLPR may be strongest when adverse experiences have occurred in childhood and the depressive symptoms persist over time. However, it is unknown whether this gene-environment interaction is present for recurrent depressive disorder and different forms of maltreatment. Therefore, patients with recurrent clinically diagnosed depression and controls screened for the absence of depression were utilised to examine the moderating effect of 5-HTTLPR on associations between specific forms of childhood adversity and recurrent depression. METHOD: A sample of 227 recurrent unipolar depression cases and 228 never psychiatrically ill controls completed the Childhood Trauma Questionnaire to assess exposure to sexual, physical and emotional abuse, physical and emotional neglect in childhood. DNA extracted from blood or cheek swabs was genotyped for the short (s) and long (l) alleles of 5-HTTLPR. RESULTS: All forms of childhood maltreatment were reported as more severe by cases than controls. There was no direct association between 5-HTTLPR and depression. Significant interactions with additive and recessive 5-HTTLPR genetic models were found for overall severity of maltreatment, sexual abuse and to a lesser degree for physical neglect, but not other maltreatment types. LIMITATIONS: The cross-sectional design limits causal inference. Retrospective report of childhood adversity may have reduced the accuracy of the findings. CONCLUSIONS: This study provides support for the role of interplay between 5-HTTLPR and a specific early environmental risk in recurrent depressive disorder. [PubMed Citation] [Order full text from Infotrieve]


6) Wilkinson PO, Harris C, Kelvin R, Dubicka B, Goodyer IM
Associations between adolescent depression and parental mental health, before and after treatment of adolescent depression.
Eur Child Adolesc Psychiatry. 2012 Jul 27;
The negative impacts of parental mental health problems on children and adolescents are well known, but the relationship between a child's depression and their parents' health is not so well understood. Being a carer/parent of someone with mental illness can be associated with negative outcomes for the caregiver. This paper reports the associations between the mental health of adolescents with major depression and their parents, before and after treatment of the adolescent's depression. Data were collected as part of the Adolescent Depression Antidepressants and Psychotherapy Trial, a randomised controlled trial of selective serotonin reuptake inhibitors with and without cognitive behaviour therapy in 208 clinic-recruited adolescents with major depression. The baseline severity of depression in the adolescent was significantly associated with both maternal and paternal mental health (as rated by the General Health Questionnaire). This effect was not confounded by other psychiatric symptoms. The degree of improvement in parental and child mental health was positively correlated across time. Our results support the hypothesis that there is a significant association between parental mental health and adolescent depressive symptoms. This study was not able to establish the direction of this association. In clinical practice, the findings demonstrate the importance of considering the mental health of the parents when treating depressed adolescents. [PubMed Citation] [Order full text from Infotrieve]


7) 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]


8) Singh YS, Altieri SC, Gilman TL, Michael HM, Tomlinson ID, Rosenthal SJ, Swain GM, Murphey-Corb MA, Ferrell RE, Andrews AM
Differential serotonin transport is linked to the rh5-HTTLPR in peripheral blood cells.
Transl Psychiatry. 2012 Feb 21;2:e77.
The human serotonin transporter (SERT) gene possesses a 43-base pair (bp) insertion-deletion promoter polymorphism, the h5-HTTLPR. Genotype at this locus correlates with variation in anxiety-related personality traits and risk for major depressive disorder in many studies. Yet, the complex effects of the h5-HTTLPR, in combination with closely associated single-nucleotide polymorphisms (SNPs), continue to be debated. Moreover, although SERT is of high clinical significance, transporter function in vivo remains difficult to assess. Rhesus express a promoter polymorphism related to the h5-HTTLPR. The rh5-HTTLPR has been linked to differences in stress-related behavior and cognitive flexibility, although allelic variations in serotonin uptake have not been investigated. We studied the serotonin system as it relates to the 5-HTTLPR in rhesus peripheral blood cells. Sequencing of the rh5-HTTLPR revealed a 23-bp insertion, which is somewhat longer than originally reported. Consistent with previous reports, no SNPs in the rh5-HTTLPR and surrounding genomic regions were detected in the individuals studied. Reductions in serotonin uptake rates, cell surface SERT binding, and 5-hydroxyindoleacetic acid/serotonin ratios, but not SERT mRNA levels, were associated with the rh5-HTTLPR short allele. Thus, serotonin uptake rates are differentiable with respect to the 5-HTTLPR in an easily accessible native peripheral tissue. In light of these findings, we foresee that primary blood cells, in combination with high sensitivity functional measurements enabled by chronoamperometry, will be important for investigating alterations in serotonin uptake associated with genetic variability and antidepressant responsiveness in humans. [PubMed Citation] [Order full text from Infotrieve]


9) Lanzenberger R, Kranz GS, Haeusler D, Akimova E, Savli M, Hahn A, Mitterhauser M, Spindelegger C, Philippe C, Fink M, Wadsak W, Karanikas G, Kasper S
Prediction of SSRI treatment response in major depression based on serotonin transporter interplay between median raphe nucleus and projection areas.
Neuroimage. 2012 Jul 22;
Recent mathematical models suggest restored serotonergic burst-firing to underlie the antidepressant effect of selective serotonin reuptake inhibitors (SSRI), resulting from down-regulated serotonin transporters (SERT) in terminal regions. This mechanism possibly depends on the interregional balance between SERTs in the raphe nuclei and in terminal regions before treatment. To evaluate these hypotheses on a systems level in humans in vivo, we investigated SERT availability and occupancy longitudinally in patients with major depressive disorder using positron emission tomography (PET) and the radioligand [(11)C]DASB. Measurements were performed before and after a single oral dose, as well as after three weeks (mean 24.73±3.3days) of continuous oral treatment with either escitalopram (10mg/day) or citalopram (20mg/day). Data were analyzed using voxel-wise linear regression and ANOVA to evaluate SERT binding, occupancy and binding ratios (SERT binding of the entire brain compared to SERT binding in the dorsal and median raphe nuclei) in relation to treatment outcome. Regression analysis revealed that treatment response was predicted by pre-treatment SERT binding ratios, i.e., SERT binding in key regions of depression including bilateral habenula, amygdala-hippocampus complex and subgenual cingulate cortex in relation to SERT binding in the median but not dorsal raphe nucleus (p<0.05 FDR-corrected). Similar results were observed in the direct comparison of responders and non-responders. Our data provide a first proof-of-concept for recent modeling studies and further underlie the importance of the habenula and subgenual cingulate cortex in the etiology of and recovery from major depression. These findings may indicate a promising molecular predictor of treatment response and stimulate new treatment approaches based on regional differences in SERT binding. [PubMed Citation] [Order full text from Infotrieve]


10) Mitjans M, Gastó C, Catalán R, Fañanás L, Arias B
Genetic variability in the endocannabinoid system and 12-week clinical response to citalopram treatment: the role of the CNR1, CNR2 and FAAH genes.
J Psychopharmacol. 2012 Jul 23;
First line treatment of major depression is based on selective serotonin re-uptake inhibitors (SSRIs) that enhance serotonergic neurotransmission by blocking the serotonin transporter. However, clinical response is a complex phenomenon in which other systems such as the endocannabinoid system could be involved. Given the evidence for the role of the endocannabinoid system in the pathogenesis of depression as well as in the mediation of antidepressant drug effects, the aim of this study was to analyze genetic variability in the endocannabinoid system genes (CNR1, CNR2 and FAAH genes) and their role in clinical response (at week 4) and remission (at week 12) in SSRI (citalopram) treatment in a sample of 154 depressive outpatients, all of Spanish origin. All patients were treated with citalopram and followed over 12 weeks. Severity of depressive symptomatology was evaluated by means of the 21-item Hamilton Depression Rating Score (HDRS). No differences were found in any of the genotype distributions according to response or remission. The longitudinal study showed that (i) the CNR1 rs1049353-GG genotype conferred a better response to citalopram treatment in the subgroup of male patients and (ii) G allele carriers (CNR2 rs2501431) presented higher HDRS scores in the follow-up than AA homozygous allele carriers. Our results seem to suggest the involvement of CNR1 and CNR2 genes in clinical responses to citalopram treatment. [PubMed Citation] [Order full text from Infotrieve]


11) Albert PR
Transcriptional regulation of the 5-HT1A receptor: implications for mental illness.
Philos Trans R Soc Lond B Biol Sci. 2012 Sep 5;367(1601):2402-15.
The serotonin-1A (5-HT(1A)) receptor is an abundant post-synaptic 5-HT receptor (heteroreceptor) implicated in regulation of mood, emotion and stress responses and is the major somatodendritic autoreceptor that negatively regulates 5-HT neuronal activity. Based on animal models, an integrated model for opposing roles of pre- and post-synaptic 5-HT(1A) receptors in anxiety and depression phenotypes and response to antidepressants is proposed. Understanding differential transcriptional regulation of pre- versus post-synaptic 5-HT(1A) receptors could provide better tools for their selective regulation. This review examines the transcription factors that regulate brain region-specific basal and stress-induced expression of the 5-HT(1A) receptor gene (Htr1a). A functional polymorphism, rs6295 in the Htr1a promoter region, blocks the function of specific repressors Hes1, Hes5 and Deaf1, resulting in increased 5-HT(1A) autoreceptor expression in animal models and humans. Its association with altered 5-HT(1A) expression, depression, anxiety and antidepressant response are related to genotype frequency in different populations, sample homogeneity, disease outcome measures and severity. Preliminary evidence from gene × environment studies suggests the potential for synergistic interaction of stress-mediated repression of 5-HT(1A) heteroreceptors, and rs6295-induced upregulation of 5-HT(1A) autoreceptors. Targeted therapeutics to inhibit 5-HT(1A) autoreceptor expression and induce 5-HT(1A) heteroreceptor expression may ameliorate treatment of anxiety and major depression. [PubMed Citation] [Order full text from Infotrieve]


12) Levenson JC, Wallace ML, Fournier JC, Rucci P, Frank E
The Role of Personality Pathology in Depression Treatment Outcome With Psychotherapy and Pharmacotherapy.
J Consult Clin Psychol. 2012 Jul 23;
Background: Depressed patients with comorbid personality pathology may fare worse in treatment for depression than those without this additional pathology, and comorbid personality pathology may be associated with superior response in one form of treatment relative to another, though recent findings have been mixed. We aimed to evaluate the effect of personality pathology on time to remission of patients randomly assigned to 1 of 2 treatment strategies for depression and to determine whether personality pathology moderated the effect of treatment assignment on outcome. Method: Individuals undergoing an episode of unipolar major depression (n = 275) received interpersonal psychotherapy (Klerman, Weissman, Rounsaville, & Chevron, 1984) or selective serotonin reuptake inhibitor (SSRI) pharmacotherapy for depression. Depressive symptoms were measured with the HRSD-17. Remission was a mean HRSD-17 score of 7 or below over a period of 3 weeks. Personality disorders were measured according to SCID-II diagnoses, and personality pathology was measured dimensionally by summing the positive probes on the SCID-II. Results: The presence of at least 1 personality disorder was not a significant predictor of time to remission, but a higher level of dimensionally measured personality pathology and the presence of borderline personality disorder were associated with a longer time to remission. Personality pathology did not moderate the effect of treatment assignment on time to remission. Conclusions: The findings suggest that depressed individuals with comorbid personality pathology generally fare worse in treatment for depression, although in this report, the effect of personality pathology did not differ by the type of treatment received. (PsycINFO Database Record (c) 2012 APA, all rights reserved). [PubMed Citation] [Order full text from Infotrieve]


13) Coppola M, Mondola R
Methoxetamine: From drug of abuse to rapid-acting antidepressant.
Med Hypotheses. 2012 Jul 20;
Methoxetamine is a dissociative anaesthetic showing pharmacodynamic similarities with its analogue ketamine, a medication with demonstrated rapid-acting antidepressant effects. Like ketamine and other arylcyclohexylamine compounds, methoxetamine is thought to be both a noncompetitive NMDA receptor antagonist and a dopamine reuptake inhibitor. Furthermore, it acts as an agonist at dopamine D2, serotonin 5HT2, muscarinic cholinergic, sigma-1, opioid mu and k receptors. The hypothesis is that methoxetamine can produce rapid antidepressant effects in patients with resistant and non-resistant unipolar and bipolar depression. [PubMed Citation] [Order full text from Infotrieve]


14) Ara I, Bano S
Citalopram decreases tryptophan 2,3-dioxygenase activity and brain 5-HT turnover in swim stressed rats.
Pharmacol Rep. 2012 May;64(3):558-66.
Background: Selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed antidepressant class today and exert their effects by increasing synaptic concentrations of serotonin (5-HT). The forced swim test (FST) is the most widely used animal test predictive of antidepressant action. Rationale of the present study was to investigate the acute effects of citalopram on hepatic tryptophan metabolism and disposition in rats exposed to FST. Methods: We investigated the effects of acute citalopram (20 mg/kg, ip) administration on rat's behavioral responses in FST paradigm, hepatic tryptophan 2,3-dioxygenase (TDO) activity, serum corticosterone levels and brain regional 5-HT metabolism. Results: Citalopram administered to swim-stressed rats showed a decrease in FST-induced increases in plasma corticosterone concentration and 5-HT turnover in hypothalamus, amygdala and hippocampus. The drug also decreases immobility and increases swimming during the FST. Citalopram administration to unstressed rats increases plasma corticosterone concentration but decreases 5-HT turnover in all three brain areas examined. Conclusions: Our findings support the hypothesis that acute citalopram administration increases tryptophan (by inhibiting TDO activity) availability for 5-HT synthesis and activates serotonergic neurotransmission in limbic brain areas in rats exposed to FST paradigm. The mechanism of action of citalopram in ameliorating social stress related depressive disorder in humans is discussed. [PubMed Citation] [Order full text from Infotrieve]


15) Baharav E, Bar M, Taler M, Gil-Ad I, Karp L, Weinberger A, Weizman A
Immunomodulatory effect of sertraline in a rat model of rheumatoid arthritis.
Neuroimmunomodulation. 2012;19(5):309-18.
Objective: Previous studies suggest that selective serotonin reuptake inhibitors (SSRIs) modulate immune system functionality. SSRIs are the preferred treatment for major depressive disorder (MDD). A high rate of MDD is observed in rheumatoid arthritis (RA) patients. The aim of this study was to evaluate immunological effects of SSRIs in a rat model of RA. Methods: Adjuvant arthritis was induced in 8-week-old Lewis rats; in the first set of experiments following the induction, 15.3 or 30.6 mg/kg of sertraline was daily injected into the ankle joint of the left rear leg. Clinical disease activity was evaluated and the findings compared with the 3 untreated legs and with control groups given methotrexate (MTX) or vehicle only at the same site. In a second set of experiments, the effect of 5, 25 and 50 mg/kg daily oral sertraline was evaluated in the same rat model. Splenocyte viability and inflammatory mediators were evaluated. Results: The sertraline-treated rats showed a significant reduction in clinical arthritis compared to controls, at all doses given, accompanied by a significant increase in interleukin 10 and a decrease in tumor necrosis factor-? levels and cycloxygenase-2 production, without lymphotoxicity. There was no significant difference from MTX, the first-line treatment for RA patients. Oral sertraline had a significant anti-inflammatory effect at all doses. There was no treatment × time effect. Conclusion: The beneficial effects of sertraline in this rat model of arthritis have clinical implications for its use in humans. Large-scale clinical efficacy trials are needed. [PubMed Citation] [Order full text from Infotrieve]


16) Alevizos B, Alevizos E, Leonardou A, Zervas I
Low dosage lithium augmentation in venlafaxine resistant depression: An open-label study.
Psychiatrike. 2012 Apr-Jun;23(2):143-8.
Lithium augmentation is one of the best studied strategies for resistant depression. The lithium dosage usually given is around 900 mg/day and plasma level is maintained in the range of 0.5-0.8 mEq/L. However, the administration of lithium in this dosage necessitates monitoring of plasma concentration and increases the risk of toxicity and side effects. Since it has been shown that low lithium levels increase serotonin turnover and enhance serotonin neurotransmission, we thought it of interest to assess the efficacy of low dosage lithium augmentation for patients with resistant depression. Fifty one patients suffering from severe unipolar or bipolar depression who had failed to respond to treatment with venlafaxine 300-375 mg/day were included in the study and treated as outpatients. Patients had previously been exposed to unsuccessful treatment with various antidepressants, mostly SSRIs. After a washout period for previously administered antidepressants of one week, the dosage of venlafaxine was rapidly titrated to 300 or 375 mg/day, corresponding to about 5 mg/kg. The dose remained stable during the next six weeks. Additional antipsychotic medication was allowed to treat psychotic symptoms. Forty seven severely depressed patients who failed to respond to 300-375 mg/day venlafaxine were, in addition, given lithium carbonate in low dosage (300-450 mg/day). The Clinical Global Impression Improvement scale was used as the treatment outcome. A score of 1 or 2 was considered as non-response. All patients gave informed consent to participate in the study. Ratings were performed at baseline and after 1,2 and 5 weeks. Lithium plasma concentration measurements were performed after 1 and 4 weeks. After 5 weeks of augmentation, 51% of the patients were rated as "much" or "very much" improved. Bipolar patients showed a better response than unipolar (64.3% vs 45.5%, p<0.038). Most patients (76%) showed a rapid response (up tp 7 days), and only 2 patients (4.6%) responded after more than 2 weeks The mean lithium plasma level was 0.33±0.09 mEq/L. No significant differences were found in treatment response with regard to sex, family history, psychotic symptomatology and suicidal ideation. No troublesome side effects were reported. Our results show that treatment augmentation with low lithium dosage may be as effective as augmentation with higher dosage, is well tolerated and does not necessitate monitoring of plasma level. Hence, an initial trial of ugmentation at low dosage lithium may be the preferred first choice in non-emergent situations. The low dosage also minimizes the risk of side effects and drug-drug interactions. Prospective controlled studies to confirm our findings are needed as are larger scale comparisons with therapeutic dose lithium augmentation. [PubMed Citation] [Order full text from Infotrieve]


17) Wang Y, Liu X, Yu Y, Han Y, Wei J, Collier D, Li T, Ma X
The role of single nucleotide polymorphism of D(2) dopamine receptor gene on major depressive disorder and response to antidepressant treatment.
Psychiatry Res. 2012 Jul 13;
The study analyzed the effect of dopamine 2 receptor gene (DRD2) polymorphism on the risk for major depressive disorder (MDD) and the response to selective serotonin reuptake inhibitors (SSRIs). The results suggest that the DRD2 gene may play a role on MDD susceptibility and the onset-time of antidepressant response. [PubMed Citation] [Order full text from Infotrieve]


18) Cipriani A, Purgato M, Furukawa TA, Trespidi C, Imperadore G, Signoretti A, Churchill R, Watanabe N, Barbui C
Citalopram versus other anti-depressive agents for depression.
Cochrane Database Syst Rev. 2012;7:CD006534.
[PubMed Citation] [Order full text from Infotrieve]


19) Lagus M, Gass N, Saharinen J, Savelyev S, Porkka-Heiskanen T, Paunio T
Inter-tissue Networks Between the Basal Forebrain, Hippocampus, and Prefrontal Cortex in a Model for Depression Caused by Disturbed Sleep.
J Neurogenet. 2012 Jul 11;
Disturbances in sleep are encountered in the majority of patients with depressive disorder. To elucidate the molecular mechanisms behind this relationship, we examined gene expression changes in a rodent model for disturbed sleep and depression. The animals were treated with daily injections of clomipramine to affect their sleep during early infancy. This early interference with sleep is known to induce depression-like behavior in adult animals. After 2 weeks of treatment, the change in gene expression was examined using the Affymetrix Rat 230.2 chip. We studied the gene expression in the basal forebrain, hippocampus, and frontal cortex and combined the results to reveal the otherwise indissectible networks between and around the tissues. The major disrupted pathways between the three brain areas were related to synaptic transmission, regulation of translation, and ubiquitinylation. The involved pathways were within the cellular components of the axons, growth cones, melanosomes, and pigment granules. A network analysis allowing for additional interactors, in the form of chemicals or gene products, revealed a disturbed communicational network between the different brain areas. This disturbed network is centered around serotonin, Mn(II), and Rhoa. The findings elucidate inter-tissue pathways and networks in the brain that are involved in sleep and mood regulation. The findings are of uttermost interest, some are quite predictable and obvious, but some are novel or have only been proposed by rare theoretical speculations (such as the melanosome and Mn(II) involvement). Equally important as the findings are the methods described in this article. In this study, we present two novel simple ways to perform system biological analysis based on gene expression array data. We used two already existing tools in a new way, and by careful planning of the input data, managed to extrapolate intricate hidden inter-tissue networks to build a molecular picture of disease. [PubMed Citation] [Order full text from Infotrieve]


20) Kishi T, Ichinose H, Yoshimura R, Fukuo Y, Kitajima T, Inada T, Kunugi H, Kato T, Yoshikawa T, Ujike H, Musso GM, Umene-Nakano W, Nakamura J, Ozaki N, Iwata N
GTP cyclohydrolase 1 gene haplotypes as predictors of SSRI response in Japanese patients with major depressive disorder.
J Affect Disord. 2012 Jul 5;
BACKGROUND: Tetrahydrobiopterin (BH4) plays an important role in the biosynthesis of serotonin, melatonin and catecholamines, all of which are implicated in the pathophysiology of mood disorders (MDs), including major depressive disorder (MDD) and bipolar disorder (BP). Production of BH4 is regulated by GTP cyclohydrolase transcription and activity. Thus, we considered the GTP cyclohydrolase gene (GCH1) to be a good candidate gene in the pathophysiology of MDs and of the serotonin selective reuptake inhibitors (SSRIs) response in MDD, and conducted a case-control study utilizing three SNPs (rs8007267, rs3783641 and rs841) and moderate sample sizes (405 MDD patients, including 262 patients treated by SSRIs, 1022 BP patients and 1805 controls). METHOD: A multiple logistic regression analysis was carried out to compare the frequencies of each SNP genotype for the target phenotype across patients and controls in several genetic models, while adjusting for possible confounding factors. A clinical response was defined as a decrease of more than 50% from the baseline score on the Structured Interview Guide for Hamilton Rating Scale for Depression (SIGH-D) within 8 weeks, and clinical remission as a SIGH-D score of less than 7 at 8 weeks. RESULT: No associations between three SNPs in GCH1 and MDD or BP were observed; however, GCH1 was associated with SSRI therapeutic response in MDD in all the marker's haplotype analysis (Global P value=0.0379). CONCLUSIONS: Results suggest that GCH1 may predict response to SSRI in MDD in the Japanese population. Nevertheless, a replication study using larger samples may be required for conclusive results, since our sample size was small. [PubMed Citation] [Order full text from Infotrieve]