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Brain regional serotonin synthesis can be estimated in vivo using positron emission tomography (PET) and α-[(11)C]methyl-L-tryptophan (11C-AMT) trapping (K*) as a proxy. Recently, we reported evidence of lower normalized 11C-AMT trapping in the orbitofrontal cortex (OBFC) of subjects meeting the criteria for an impulsive and/or aggressive behavioral phenotype. In this study, we examined whether part of the variance in OBFC serotonin synthesis is related to polymorphisms of the gene that encodes for the indoleamine's rate-limiting enzyme in the brain, tryptophan hydroxylase-2 (TPH2). In all, 46 healthy controls had PET 11C-AMT scans and were genotyped for 11 single-nucleotide polymorphisms (SNPs) distributed across the TPH2 gene and its 5′ upstream region. Several TPH2 SNPs were associated with lower normalized blood-to-brain clearance of 11C-AMT in the OBFC. Dose-effect relationships were found for two variants (rs6582071 and rs4641527, respectively, located in the 5′ upstream region and intron 1) that have previously been associated with suicide. Associations in the OBFC remained statistically significant in a mixed larger sample of patients and controls. These results suggest that in humans, genetic factors might partly account for variations in serotonin synthesis in the OBFC. [ABSTRACT FROM AUTHOR]

The limbic system has consistently been associated with the control of emotions and with mood disorders. The goal of this study was to identify new molecular targets associated with suicide and with major depression using oligonucleotide microarrays in the limbic system (amygdala, hippocampus, anterior cingulate gryus (BA24) and posterior cingulate gyrus (BA29)). A total of 39 subjects were included in this study. They were all male subjects and comprised 26 suicides (depressed suicides=18, non depressed suicides=8) and 13 matched controls. Brain gene expression analysis was carried out on human brain samples using the Affymetrix HG U133 chip set. Differential expression in each of the limbic regions showed group-specific patterns of expression, supporting particular neurobiological mechanisms implicated in suicide and depression. Confirmation of genes selected based on their significance and the interest of their function with reverse transcriptase-polymerase chain reaction showed consistently correlated signals with the results obtained in the microarray analysis. Gene ontology analysis with differentially expressed genes revealed an overrepresentation of transcription and metabolism-related genes in the hippocampus and amygdala, whereas differentially expressed genes in BA24 and BA29 were more generally related to RNA-binding, regulation of enzymatic activity and protein metabolism. Limbic expression patterns were most extensively altered in the hippocampus, where processes related to major depression were associated with altered expression of factors involved with transcription and cellular metabolism. Additionally, our results confirm previous evidence pointing to global alteration of gabaergic neurotransmission in suicide and major depression, offering new avenues in the study and possibly treatment of such complex disorders. Overall, these data suggest that specific patterns of expression in the limbic system contribute to the etiology of depression and suicidal behaviors and highlight the role of the hippocampus in major depression.Molecular Psychiatry (2007) 12, 640–655; doi:10.1038/sj.mp.4001969; published online 13 March 2007 [ABSTRACT FROM AUTHOR]

OBJECTIVE: Midbrain dopamine transmission is thought to regulate responses to rewarding drugs and drug-paired stimuli; however, the exact contribution, particularly in humans, remains unclear. In the present study, we tested whether decreasing dopamine synthesis, as produced by acute phenylalanine/tyrosine depletion (APTD), would alter responses to the stimulant drug, d-amphetamine. METHODS: On 3 separate days, 14 healthy men received d-amphetamine (0.3 mg/kg, given orally) plus a nutritionally balanced amino acid mixture, the phenylalanine/tyrosine-deficient mixture or the phenylalanine/tyrosine-deficient mixture followed by the immediate dopamine precursor, L-DOPA (Sinemet, 2 x 100 mg/25 mg). Responses to these treatments were assessed with visual analog scales, the Profile of Mood States, and a computerized Go/No-Go task. RESULTS: d-Amphetamine elicited its prototypical subjective effects, but these were not altered by APTD. In comparison, APTD significantly increased commission errors on the Go/No-Go task and did so uniquely in conditions where subjects were rewarded for making correct responses; this effect of APTD was prevented by L-DOPA. CONCLUSIONS: Together these results support the hypothesis that, in healthy men, dopamine is not closely linked to euphorogenic effects of abused substances but does affect the salience of reward-related cues and the ability to respond to them preferentially. [ABSTRACT FROM AUTHOR]

Objective: Major depression is a major risk factor for suicide. However, not all individuals with major depression commit suicide. Impulsive and aggressive behaviors have been proposed as risk factors for suicide, but it remains unclear whether their effect on the risk of suicide is at least partly explained by axis I disorders commonly associated with suicide, such as major depression. With a case-control design, a comparison of the level of impulsive and aggressive behaviors and the prevalence of associated psychopathology was carried out with control for the presence of primary psychopathology. Method: One hundred and four male suicide completers who died during an episode of major depression and 74 living depressed male comparison subjects were investigated with proxy-based interviews by using structured diagnostic instruments and personality trait assessments. Results: The authors found that current (6-month prevalence) alcohol abuse/dependence, current drug abuse/dependence, and cluster B personality disorders increased the risk of suicide in individuals with major depression. Also, higher levels of impulsivity and aggression were associated with suicide. An analysis by age showed that these risk factors were more specific to younger suicide victims (ages 18-40). A multivariate analysis indicated that current alcohol abuse/dependence and cluster B personality disorder were two independent predictors of suicide. Conclusions: Impulsive-aggressive personality disorders and alcohol abuse/dependence were two independent predictors of suicide in major depression, and impulsive and aggressive behaviors seem to underlie these risk factors. A developmental hypothesis of suicidal behavior, with impulsive and aggressive behaviors as the starting point, is discussed. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The administration of amino acid (AA) mixtures that are selectively deficient either in tryptophan or phenylalanine plus tyrosine can decrease serotonin or catecholamine synthesis, respectively. In the present study, we assessed whether a mixture that was simultaneously deficient in tryptophan, phenylalanine and tyrosine could induce sufficient protein synthesis that plasma levels of all 3 monoamine precursors would decrease. DESIGN: Ten healthy volunteers (5 male, 5 female) were administered a tryptophan/phenylalanine/tyrosine-deficient AA mixture in an open-label study. Plasma concentrations of large neutral AAs were measured before and 5 hours after mixture ingestion. RESULTS: The tryptophan/phenylalanine/tyrosine-deficient mixture lowered plasma concentrations of the 3 AAs by 67;, 78% and 77%, respectively (p < or = 0.001); their ratio to other large neutral AAs was decreased more, namely, by 87%, 90% and 90% (p < or = 0.001). Mood lowering was seen on 3 subscales of the bipolar Profile of Mood States, that is, elated-depressed, composed-anxious and clearheaded-confused, as well as 2 visual analog scales, bored and irritated (p < or = 0.05). CONCLUSIONS: Acute tryptophan/phenylalanine/tyrosine depletion may be a suitable new method for rapidly decreasing serotonin and catecholamine transmission simultaneously. [ABSTRACT FROM AUTHOR]

The different serotonin (5-HT) receptors, including the serotonin transporter (5-HTT), are excellent candidate genes for suicide and suicidal behavior, and thus, they have been investigated in a large number of allelic association studies. The individual results of these studies have been inconsistent and definite conclusions are difficult to establish. A reliable method for assessing individual studies and generating combined results is provided by systematic reviews using meta-analytical techniques. In this study, we carried out a systematic review of studies investigating 5-HT receptors and the 5-HTT in suicidal behavior. Studies were identified by means of MEDLINE database searches and by scanning reference lists. More than 190 articles were reviewed and 26 met the inclusion criteria. In all, 14 studies investigated six different 5-HT receptor loci and 12 studies investigated the 5-HTT promoter 44 bp insertion/ deletion polymorphism. Two specific meta-analyses were carried out, pooling studies investigating the 5-HT2A 102 T/C and the 5-HTT promoter loci that included, respectively, a total of 1599 and 2539 subjects. The combined evidence was significant for association with the 5-HTT locus (Mantel-Haenszel weighted odds ratio (M-H[sub w] OR) = 1.17 C1:1.04-1.32, P = 0.009), but not for the 5-HT2A 102 TlC variant (M-H[sub w] OR) = 1.09 CI: 0.93-1.27, P = 0.319). The 5-HTT result was robust and remained significant following sensitivity analysis, suggesting that 5-HTT may play a role in the predisposition to suicide. [ABSTRACT FROM AUTHOR]

The different 5-HT (serotonin) receptors including the serotonin transporter (5-HTT) are candidate genes for affective disorders such as major depressive disorder (MDD) and bipolar disorder (BD). They have been investigated in a number of allelic association studies where the individual results have been inconsistent, and therefore, definite conclusions are difficult to make. Systematic reviews using meta-analytical techniques are a reliable method for objectively and reproducibly assessing individual studies and generating combined result. This study aimed at reviewing published studies investigating the association between affective disorders (MDD and BD) and variation at genes coding for serotonin receptors and the serotonin transporter. We performed National Library of Medicine database searches to identify potential studies. More than 430 articles were reviewed and 86 studies met the inclusion criteria for participation in our review. Of these, 41 studies investigated 45 different 5-HT receptor variants and 45 studies investigated at least one of two commonly studied 5-HTT polymorphisms in MDD. Many studies investigated the association between MDD and BD with the 5-HT2A 102 T/C, the 5-HTT promoter 44 bp insertion/deletion and the intron 2 VNTR polymorphisms, and thus, these could be pooled using meta-analytic techniques. The overall odds ratio (OR) for the combined individual results was significant for BD and the two 5-HTT polymorphisms: Mantel-Haenszel weighted OR = 1.14, CI: 1.03-1.26, P = 0.015 for the promoter locus (N = 3467) and Mantel-Haenszel Weighted odds ratio OR = 1.18, CI: 1.05-1.32, P = 0.004 for the VNTR locus (N = 3620). However, sensitivity analysis indicated that, in each case, the overall positive association could be mostly attributed to the large effect of one individual study. Therefore, these results suggest that, although promising, further studies are required to assess appropriately the evidence suggesting an association between... [ABSTRACT FROM AUTHOR]

Investigates the link between tryptophan hydroxylase (TPH) and suicide completion. Association between the gene that codes TPH and suicidal behavior; Genotyping of a sample of suicide completers; Public-health problem of suicidal behavior; Evidence that subjects with suicidal behavior have reduced serotonergic neuro-transmission.

Acute tryptophan depletion (ATD) lowers serotonin synthesis and elicits depressive symptoms in some, though not all, remitted patients with major depressive disorder (MDD). In the present study, eight medication-free remitted patients with MDD, seasonal pattern, were tested twice, once following the ingestion of a tryptophan-containing mixture, once following ATD. ATD significantly increased Hamilton depression scores (p < 0.001). Four of the patients had a family history of psychiatric disorders: substance abuse (n = 4), mood disorders (n = 3) or Cluster B personality disorders (n = 3). The mood-lowering response to ATD was significantly greater in those patients with, than without, affected relatives (p < 0.001). These preliminary findings (1) support the hypothesis that depressed states are related to disturbed serotonin neurotransmission and (2) suggest that depressive symptoms following ATD might identify a subgroup of patients at high genetic risk for disorders associated with affective lability and dysregulated impulse-control, conditions thought to be related to low serotonin neurotransmission. [ABSTRACT FROM AUTHOR]

The schizophrenia phenotype is heterogeneous with respect to clinical presentation, long-term response to medication, and outcome, possibly reflecting genetic heterogeneity and/or the presence of modifier genes. Compared to non-responders, schizophrenic patients who are responders to neuroleptic medications are characterized by a high female/male ratio, a better longterm outcome and more frequently disturbed dopamine neurotransmission. In this study, we compared two groups of schizophrenic patients selected on the basis of their long-term response to neuroleptics (excellent responders and non-responders) and a group of healthy volunteers, with regard to a missense mutation (677C→T) in the methylenetetrahydrofolate reductase (MTHFR) gene. This polymorphism was chosen because it is functional5 and was previously associated with schizophrenia. The present study revealed a significant association between schizophrenia and allele T of this gene. This association was entirely due to an over-representation of allele T in responder patients compared to controls; nonresponder patients did not differ from controls. Genotype TT was more frequent in responder patients compared to controls, thus replicating the findings of Arinami et al. These results strongly suggest that the MTHFR gene is involved in the pathogenesis of schizophrenia characterized by a rapid and sustained therapeutic response to typical neuroleptics and/or a good long-term prognosis/favorable therapeutic outcome. [ABSTRACT FROM AUTHOR]

Background: Recently we reported that, in vervet monkeys, ingestion of an amino acid mixture deficient in the catecholamine precursors, phenylalanine and tyrosine, produced a decrease in alcohol self-administration. We now report the results of a similar study in humans. Methods: Three groups of healthy female social drinkers were administered a nutritionally balanced amino acid mixture (B, n= 13), a mixture deficient in the serotonin precursor, tryptophan (Trp-free, n= 14), or a phenylalanine/tyrosine deficient mixture (Phe/Tyr-free, n= 12). Six hours after administration of the amino acid mixture, alcohol ingestion was measured during a free-choice 'Taste Test.' Results: Compared to the B mixture, Phe/Tyr-free, but not Trp-free, significantly decreased the ingestion of alcohol [ p < 0.02]. Neither Phe/Tyr-free nor Trp-free significantly decreased orange juice ingestion or the self-reported 'Liking' of either substance. Some subjects experienced transient nausea and/or regurgitated the amino acid mixtures, but excluding these subjects did not change the results. Conclusions: The results suggest that (a) Phe/Tyr-free may be a suitable method for investigating the role of catecholamines in the self-administration and subjective effects of alcohol, (b) acutely decreased catecholamine neurotransmission might disrupt mechanisms mediating alcohol self-administration, and (c) acutely decreased serotonin neurotransmission seems not to alter alcohol self-administration. [ABSTRACT FROM AUTHOR]

Genetic anticipation, manifested by increased severity and earlier age-at-onset of the disease over successive generations, is reported in schizophrenia. The molecular basis of anticipation in several neurodegenerative diseases is unstable coding CAG repeat expansions. Anticipation was reported in schizophrenia. Recently, studies suggested that enlarged CAG/CTG repeats are over represented in schizophrenic patients compared to normal controls. Together, these observations suggest that unstable CAG repeats may play a role in the etiology of schizophrenia. The purpose of this study is to test for the presence of polyglutamineexpanded tracts, encoded by CAG repeats, in total protein extracts derived from lymphoblastoid cell lines of schizophrenic patients. Proteins from schizophrenic patients (n = 59) and normal controls (n = 73) were separated by means of SDS-polyacrylamide gel electrophoresis, wet blotted onto nitrocellulose membrane and probed with a monoclonal antibody (mab lC2) recognizing expanded polyglutamine arrays. Three abnormal bands corresponding to protein(s) of molecular weight of approximately 50 kDa were identified in two unrelated schizophrenic patients and in a sibling of one of these patients. None of the normal controls tested positive for this abnormal band. These results suggest that expanded polyglutamine-containing proteins, though rare, may play a role in the pathogenesis of schizophrenia. [ABSTRACT FROM AUTHOR]

The potential value of pretreatment urinary 3-methoxy, 4-hydroxyphenylethyleneglycol (MHPG) levels to predict the therapeutic response to antidepressants was studied by measuring urinary MHPG output in 42 depressed inpatients treated with a selective inhibitor of serotonin (Indalpine) or noradrenaline (Maprotiline) reuptake. Among the 42 depressed inpatients there were 33 cases of major depressive episode. Patients were treated for at least 3 weeks, firstly with intravenous infusions of maprotiline or indalpine which have been administered at random. No difference in pretreatment urinary MHPG levels was found between the responders to indalpine (1.08±0.48 μg/24 h/mg of creatinine) and the responders to maprotiline (1.15±0.62 μg/24 h/mg of creatinine). However, there was a difference in the pretreatment levels of urinary MHPG between the non-responders to indalpine (0.56±0.28 μg/24 h/mg of creatinine) and the non-responders to maprotiline (1.37±0.68 μg/24 h/mg of creatinine). No correlation between this biochemical parameter and HDRS score was found. These results indicate that, in this study, there is no obvious relationship between the pretreatment urinary MHPG levels in depressed patients and their therapeutic response to specific inhibitors of noradrenaline or serotonin reuptake. However, there was a positive trend towards a lower pretreatment MHPG level to be associated with lack of response to indalpine. [ABSTRACT FROM AUTHOR]

Involvement of the brain serotonin (5-HI) neurotransrnitter system in obsessive-compulsive disorder (OCD) was originally suggested on the basis of therapeutic effects found with the semi-selective serotonin uptake inhibitor, clomipramine. More recent studies directly comparing clomipramine with non-selective or norepinephrine-selective uptake inhibitors, such as desipramine or nortriptyline, as well as studies with new, more selective serotonin uptake inhibitors, including fluvoxamine and fluoxetine, have supported that hypothesis. Clomipramine's antiobsessional effect has been augmented with the serotonin precursor, L-tryptophan, or with lithium, which has prominent serotonergic effects. Patients whose OCD symptoms improved on clomipramine worsened when the drug was discontinued (regardless of duration of therapy) and improved when clomipramine was reinstituted. OCD symptoms also worsened when metergoline, a 5-HT antagonist, was given to patients who had improved with clomipramine. Metergoline given alone had no effect. Administration of m-chlorophenylpiperazine (m-CPP), a 5-HT receptor agonist, to untreated OCD patients increased their anxiety, depression, and dysphoria, and exacerbated their OC symptoms. After 4 months of clomipramine therapy, m- CPP failed to produce the same behavioural effects, suggesting an alteration of a 5-HT subsystem (possibly downregulation of some 5-HT receptors). The data reviewed suggest an important role for an abnormal brain 5-HT subsystem in patients with OCD. [ABSTRACT FROM AUTHOR]

Reports on the in vivo measurements of serotonin synthesis in the brain of healthy human volunteers and determines sex differences. Selection of subjects; Acute tryptophan depletion; Scanning by emission tomography (PET) and magnetic resonance imaging (MRI).

Aims to test the prediction of temporal cortex activation during experimentally induced anxiety by using positron emission tomography and the [15 O]H2O bolussubtraction method to determine regional cerebral blood flow (CBF) changes in normal volunteers challenged with a bolus injection of cholecystokinin tetrapeptide. Possibility of a vascular/or mascular origin.

Verifies evidence that a genetic component may increase the predisposition to suicide and that deficiencies of the serotonin system play a significant role. Effort to replicate findings reported by Bondy and associates; Investigation of a large sample of suicide completers.

Comments on an article about the use of alpha-methyl-L-tryptophan (alpha-MTrp) as tracer for measuring the rate of hydroxytryptamine synthesis in the brain. Overview of a study on alpha-MTrp; Information on the alpha-MTrp model; Regional differences in lumped constant.

The effects of 400-600 mg trazodone on the sleep patterns of ten depressed in-patients treated for 5 weeks were studied during the initial (days 1-3) and terminal (days 26-28) treatment periods. The sleep parameters were compared to those obtained from three sleep recordings performed just prior to the initiation of the treatment and after 2 adaptation nights at the end of a 2-week drug-free period. At the same time, the clinical evolution of patients was evaluated weekly using MADRS and Hamilton-Anxiety scales for anxiety-depression symptomatology and Spiegel and Norris sleep scales. Weekly blood samples were collected to measure plasma levels of trazodone and, at the end of the study, the elimination half-life at steady state was calculated by repeated measurements of plasma levels. Clinical improvement, as assessed by a reduction of more than 60% in MADRS scale scores, was accompanied by evidence of the definitely beneficial effects of trazodone on the disturbed sleep of these depressed patients. From the beginning of treatment, there was a hypnotic-like effect (increase in total duration of sleep and stage II, decrease in sleep latency and intrasleep awakenings). In addition, records at the end of the study showed an increase in delta sleep and an increase in REM latency, an effect classically associated with an antidepressant action. These particularly valuable effects of trazodone on sleep would suggest that this drug should especially be given in cases of depression with major insomnia. [ABSTRACT FROM AUTHOR]