Early improvement and serum concentrations of citalopram to predict antidepressant drug response of patients with major depression.

INTRODUCTION: Post hoc analyses of clinical trials have shown that early improvement around day 14 is highly predictive for later response. More-over, evidence has been given that sufficiently high concentrations of antidepressant drugs in blood are required to attain response. In this study, we determined cut-off levels for citalopram serum concentrations and clinical improvement during the early phase of treatment to predict later response and the predictive power of these measures either alone or in combination. METHODS: Inpatients with depressive disorder according to ICD-10 who received citalopram were included. Psychopathology was assessed by the 17-item Hamilton Depression (HAMD-17) rating scale, and serum concentrations of citalopram were measured in weekly intervals. RESULTS: The analysis included 55 inpatients. Receiver operating characteristics analysis revealed for citalopram a serum concentration of 53 ng/ml on day 7 and a clinical improvement of 24% on the HAMD-17 scale on day 14 as significant cut-off values to predict response after 5 weeks of treatment. Both measures taken together predicted response on week 5 with 73% sensitivity and 85% specificity with an odds ratio of 14.6. DISCUSSION: It is concluded that treatment with citalopram should be guided by symptom rating at baseline and on day 14 and serum concentration determination on day 7.

The serotonin transporter promoter polymorphism (5-HTTLPR) affects the relation between antidepressant serum concentrations and effectiveness in major depression.

INTRODUCTION: Both the serotonin transporter promotor polymorphism (5-HTTLPR) and serum concentrations of SSRIs have been shown to affect response to SSRIs. Results, however, are inconsistent. The aim of this study was to investigate whether remission or response to SSRIs is influenced by an interaction of 5-HTTLPR and SSRI serum concentrations. METHODS: 49 patients with major depression and SSRI treatment were genotyped for the 5-HTTLPR locus including the rs25531. Drug serum concentrations and depression severity were measured weekly. RESULTS: Logistic regression analysis revealed a significant association between 5-HTTLPR, SSRI serum concentrations and response to treatment. A favourable treatment outcome correlated with SSRI serum concentration in 5-HTTLPR-L(A) allele carriers (r² = 34.3 %; p = 0.001), but not in S/L(G)-allele carriers (p = 0.31). DISCUSSION: In the group of L(A) allele carriers, those MDD patients with a high antidepressant serum concentrations responded better to treatment than patients with a low serum concentration. We conclude that the 5-HTTLPR might affect reponse to SRRI subject to serum concentrations. If replicated this might be a starting point for prospective clinical trials.

Is MAO-B activity in platelets associated with the occurrence of suicidality and behavioural personality traits in depressed patients?

OBJECTIVE: Low platelet monoaminoxidase B (MAO-B) activity has been associated with various forms of impulsive behaviour and suicidality. The present study investigated the relationship between MAO-B activity in platelets and aspects of suicidality in depressed patients and controls. METHOD: In 87 patients with affective spectrum disorders (58% suffering from a major depressive episode - MDE) the potential association between platelet MAO-B activity and suicidality was examined. Fifty-nine of the patients had committed suicide attempt recently (SA -'suicide attempters'), 28 patients were acutely depressed without having shown suicidal thoughts or suicidal behaviour in the past (NA -'non-suicide attempters'). RESULTS: The SA and NA were comparable as to their diagnoses and general demographic and psychopathological parameters. MAO-B activity did not differ between SA and NA. No systematic correlations existed between MAO-B activity and any dimensions of suicidal behaviour or psychopathology. As a single finding only a weak positive association of higher MAO-B activity in SA with a fatal intention of the SA was observed. CONCLUSION: Our findings do not support a consistent association of platelet MAO-B activity and suicidal behaviour in general, but specific facts of suicidality might be associated.

[Therapeutic drug monitoring (TDM) of psychotropic drugs: a consensus guideline of the AGNP-TDM group]. / Le dosage plasmatique des médicaments psychotropes a des fins thérapeutiques: recommandations du groupe d'experts AGNP-TDM.

In psychiatry, therapeutic drug monitoring (TDM) is an established procedure for most psychotropic drugs. However, as its use in everyday clinical practice is far from optimal, the AGNP-TDM group has worked out consensus guidelines to assist psychiatrists and laboratories involved in drug analysis. Based on a thorough analysis of available literature, 5 levels of recommendation were defined with regard to TDM of psychoactive drugs, from 1) (strongly recommended) to 5) (not recommended). A list of indications for TDM, alone or in combination with pharmacogenetic tests is presented. Instructions are given with regard to preparation of TDM, analytical procedures, reporting and interpretation of results and the use of information for patient treatment. Using the consensus guideline will help to ensure optimal clinical benefit of TDM.

Relationship between mirtazapine dose, plasma concentration, response, and side effects in clinical practice.

OBJECTIVE: The aim of this study was to evaluate the benefit of mirtazapine plasma concentration monitoring in a typical clinical setting. METHODS: The relationship between mirtazapine plasma concentration, dose, response, and side effects was studied in 65 inpatients presenting with a depressive episode according to ICD-10. Plasma concentrations, the 17-item Hamilton Depression Rating (HAMD), and the UKU side effect rating were performed weekly. A subgroup of 45 patients was evaluated for a concentration-response relationship. RESULTS: We found a low positive correlation between plasma concentration and dose. A low negative correlation between plasma concentration and increased duration of sleep was noted in the first week of mirtazapine treatment, but not during the entire observation time. Responders to mirtazapine treatment presented with higher plasma concentrations than non-responders, revealing a threshold concentration of 30 ng/mL. CONCLUSION: The mirtazapine dose is a weak predictor of mirtazapine plasma concentrations. Plasma concentration measurements may therefore be useful to adjust mirtazapine doses in non-responders with plasma concentrations below 30 ng/mL. Sedative effects appear temporary and require no plasma concentration control when standard doses are administered.

The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry.

Therapeutic Drug Monitoring (TDM) is a valid tool to optimise pharmacotherapy. It enables the clinician to adjust the dosage of drugs according to the characteristics of the individual patient. In psychiatry, TDM is an established procedure for lithium, some antidepressants and antipsychotics. In spite of its obvious advantages, however, the use of TDM in everyday clinical practice is far from optimal. The interdisciplinary TDM group of the Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) has therefore worked out consensus guidelines to assist psychiatrists and laboratories involved in psychotropic drug analysis to optimise the use of TDM of psychotropic drugs. Five research-based levels of recommendation were defined with regard to routine monitoring of plasma concentrations for dose titration of 65 psychoactive drugs: (1) strongly recommended, (2) recommended, (3) useful, (4) probably useful and (5) not recommended. A second approach defined indications to use TDM, e. g. control of compliance, lack of clinical response or adverse effects at recommended doses, drug interactions, pharmacovigilance programs, presence of a genetic particularity concerning the drug metabolism, children, adolescents and elderly patients. Indications for TDM are relevant for all drugs either with or without validated therapeutic ranges. When studies on therapeutic ranges are lacking, target ranges should be plasma concentrations that are normally observed at therapeutic doses of the drug. Therapeutic ranges of plasma concentrations that are considered to be optimal for treatment are proposed for those drugs, for which the evaluation of the literature demonstrated strong evidence. Moreover, situations are defined when pharmacogenetic (phenotyping or genotyping) tests are informative in addition to TDM. Finally, practical instructions are given how to use TDM. They consider preparation of TDM, analytical procedures, reporting and interpretation of results and the use of information for patient treatment. Using the consensus guideline will help to ensure optimal clinical benefit of TDM in psychiatry.

Neuroimaging and 5-HT2C receptor polymorphism: a HMPAO-SPECT study in healthy male probands using mCPP-challenge of the 5-HT2C receptor.

BACKGROUND: The human 5-HT (2C) receptor gene has been localized on the X chromosome and is expressed in two genetic variants. Whereas previous investigations have suggested that the 5-HT (2C) receptor gene polymorphism is critically involved in the pathogenesis of affective and eating disorders, as yet the functional consequences being associated with the rare serine variant of the 5-HT (2C) receptor in humans are unclear. METHODS: We explored by HMPAO-SPECT if a challenge with the serotonin agonist mCPP, that interacts mainly with the 5-HT (2C) receptor, provokes different patterns of regional cerebral bloodflow (rCBF) as a function of the genetic variant of the receptor. Thus we studied its action in 16 healthy male volunteers carrying the common 5-HT (2C)-cys-23 receptor gene and 16 healthy male volunteers carrying the less frequent 5-HT (2C)-ser-23 receptor gene. RESULTS: We found significant differences in rCBF between the two genotypes after mCPP infusion compared to placebo: In the cysteine group rCBF was increased in the left medial prefrontal cortex and decreased in the left anterior cingulate and right medio-temporal cortex, whereas the serine group showed an increase of rCBF in the left medio- and superior-temporal cortex and in cerebellum and a reduced rCBF in the right medial prefrontal cortex. In addition, there was a significant disordinal interaction of the genotype factors and challenge with an increase of rCBF in the serine group and a decrease in the cysteine group in the left motor cortex and calcarine cortex. Additionally, a decrease of rCBF in the serine-group and a simultaneous increase in the cysteine group was found in the right anterior and the left posterior cingulate cortex. CONCLUSION: These findings suggest that differences in the 5-HT (2C) receptor gene polymorphism has functional consequences due to a different responsiveness of the expressed 5-HT (2C) receptor variants.

Pharmacokinetics of m-chlorophenylpiperazine after intravenous and oral administration in healthy male volunteers: implication for the pharmacodynamic profile.

INTRODUCTION: Serotonin plays an important role in psychiatric diseases, most notably in depression and anxiety. Seven different major serotonin receptor subtypes have been described. Receptor-selective agonists and antagonists have been searched for to find a suitable drug to test the in vivo receptor sensitivity. Different serotonin receptor subtypes take part in the control of neuroendocrine function. m-Chlorophenylpiperazine (mCPP) acts as an agonist to serotonin 2C, 1A, 1B, and 1D receptor subtypes and is applied in challenge tests. The object of this study was to develop a pharmacokinetic-pharmacodynamic model to describe the effects of mCPP on pituitary hormone secretion. METHODS: The hormone and mCPP plasma concentrations were determined after intravenous and oral administration of mCPP to 12 healthy men. The kinetic parameters of mCPP were compared to the drug's effect on hormonal response. RESULTS: After mCPP treatment, ACTH, cortisol, and prolactin levels were significantly increased compared to placebo. There was also a significant increase in clinical response (anxiety, shivering, dizziness, heightened sensitivity toward light and noise, and fear of losing control). Maximum mCPP concentrations varied 2.3-fold after intravenous infusion and 8-fold after oral administration. The absolute bioavailability ranged from 12% to 84%. mCPP's elimination half-life ranged from 2.4 h to 6.8 h after intravenous infusion and from 2.6 h to 6.1 h after oral application. However, the kinetic data as well as the pharmacodynamic response varied to an extent that precluded pharmacokinetic-pharmacodynamic modeling. The wide interindividual variability in mCPP's disposition kinetics could not be fully explained by genetic variation of the mCPP-metabolizing enzyme cytochrome P4502D6, which was determined in all probands. DISCUSSION: Other factors contributing to the variability in disposition kinetics could not be ruled out in this study, suggesting that mCPP is not a suitable model drug to test serotonin 2C receptor activity in vivo.

Therapeutic monitoring of psychotropic drugs: an outline of the AGNP-TDM expert group consensus guideline.

TDM of psychotropic drugs is widely used, but there is little consensus regarding its optimal use in the clinical context. This prompted a multidisciplinary group comprised of clinical biochemists, clinical pharmacologists, and psychiatrists of the AGNP (Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie) to provide a consensus guideline. This will allow clinical psychiatrists, practitioners, and laboratory directors involved in psychopharmacotherapy to optimize TDM of antidepressants, antipsychotics, and opioid substituents. Recommendations are also given on the combined use of TDM and pharmacogenetic tests.

Polymorphism in the peroxisome proliferator-activated receptor alpha gene influences the risk for Alzheimer's disease.

The peroxisome proliferator-activated receptor alpha (PPAR-alpha) is a member of the steroid hormone super family of ligand-inducible transcription factors, involved in glucose and lipid metabolism. We screened for polymorphisms in the PPAR-alpha gene and detected two known polymorphisms located in exon 5 and intron 7. These polymorphisms were investigated for their possible association with Alzheimer's disease (AD) and for their effect in carriers of an insulin gene (INS) polymorphism. The PPAR-alpha C --> G polymorphism in exon 5 (L162V) was associated with AD, in that the V-allele was more frequent in AD patients than in healthy subjects. Further data analysis revealed that carriers of an PPAR-alpha L162V V-allele and an INS-1 allele presented with an increased risk for AD. Cerebrospinal fluid amyloid-beta levels were influenced by PPAR-alpha L162V genotype. These results suggest, that PPAR-alpha polymorphism may be a risk factor for AD.

Therapeutic drug monitoring of tricyclic antidepressants: how does it work under clinical conditions?

Therapeutic drug monitoring (TDM) of tricyclic antidepressants (TCA) is established in the treatment of depression to optimize outcome and safety. However, there are few reports on TDM under naturalistic clinical conditions. In the present study, we investigated a TDM group (TDM) and a randomly assigned parallel group without TDM (no-TDM) while on TCA treatment. Serum levels were analyzed in both cohorts, but feedback and dose recommendation were only provided for the TDM group. Serum levels of TCA were assessed by high-performance liquid chromatography (HPLC). The outcome was measured weekly using the Hamilton Depression Rating Scale (HAMD), the Clinical Global Impressions Scale (CGI), and the UKU side-effect scale. 84 patients with depressive disorder according to DSM-IV were recruited in three centers (TDM, n = 43; no-TDM, n = 41; mean age 49.9 +/- 13.2 years, 63.1 % female). Patients were treated with either amitriptyline (n = 69) or doxepin (n = 15); the mean dosage at endpoint was 126 +/- 35 mg and 155 +/- 47 mg, respectively. The mean study duration was 21 +/- 8 days. Both groups improved according to HAMD (from 25.2 +/- 8.4 at baseline to 12.0 +/- 7.4 at endpoint) and CGI scores (68 % responders). Moderately severe or severe side effects occurred in 16 % of patients. Adequate dose adjustment was significantly higher in the TDM group (60 % vs. 46 %, p < 0.05); this led to a significantly higher rate of therapeutic serum levels in the TDM group (58 % vs. 44 %, p < 0.05). Direct effects of TDM were not found for effectiveness. Therapeutic TCA serum levels over weeks one to three, however, were associated with significantly better outcome at endpoint (p < 0.05) as measured with changes in the HAMD or CGI response rates from baseline to endpoint. Finally, considerable side effects occurred significantly more often when serum levels were above the therapeutic range (27 % vs. 11 %; p < 0.01). We conclude that treating depression with TCA can be optimized by early TDM, which is superior to clinical judgment on its own. Since the psychiatrists in charge were less than completely "compliant" to the recommendations provided together with serum levels, the effect could be more pronounced than this study shows. The results encourage further studies in order to optimize antidepressant pharmacotherapy when using TDM appropriately.

CYP2D6 polymorphism and tardive dyskinesia in schizophrenic patients.

Antipsychotic drug-induced tardive dyskinesia (TD) is a serious problem during psychopharmacologic treatment of schizophrenic patients. In search of genetic factors contributing to TD, there is a lack of consensus regarding the role of the polymorphic isozyme cytochrome P450 CYP2D6, which is involved in the oxidative metabolism of antipsychotic drugs. In the present case-control study, we tested the putative influence of the CYP2D6 genotype on the development of TD. Out of 157 patients, 109 were retrospectively selected meeting DSM IV criteria for schizophrenia or schizoaffective disorder, and 50 of them persistently presenting with TD. Genotyping detected the functional allele CYP2D6 *1, the known major defective alleles CYP2D6 *3, *4, *5, *6, and gene duplication. According to their number of functional CYP2D6 alleles, subjects were divided into carriers of none, one, or at least two functional CYP2D6 alleles. The proportions of these categories did not differ between patients and an ethnically homogenous control population (n = 195, p = 0.99) or between patients with and without TD (p = 0.818). Schizophrenic patients were carriers of gene duplication more often than healthy probands, without revealing statistical significance (p = 0.10). Out of seven patients with gene duplication, three developed persistent TD. Furthermore, patients with and without TD were comparable according to age, age of onset, gender, and duration of illness, but subjects with TD had taken more lifetime chlorpromazine equivalents (CPZ) than had patients without TD (chi 2-test, Student's t-test). Forward as well as backward logistic regression analyses confirmed that the presence of TD was influenced by lifetime CPZ but not by age, age of onset, gender, duration of illness, or CYP2D6 genotype. In contrast to the relevance of lifetime CPZ, the lifetime dose of antipsychotic drugs known to be metabolized by CYP2D6 did not significantly influence the presence of TD. In conclusion, our results provide no evidence for the contribution of CYP2D6 genotype to the development of TD in schizophrenic patients receiving long-term antipsychotic medication.

Effects of estrogen on brain development and neuroprotection--implications for negative symptoms in schizophrenia.

Increasing evidence during the last few years suggests that there are gender-specific differences in schizophrenia, influencing the age of onset, treatment outcome and the prevalence of negative symptoms. With respect to the latter in postmortem brain and cerebrospinal fluid of schizophrenic patients with negative symptoms a reduction of dopaminergic activity became evident. Measures of noradrenergic activity, dopamine beta-hydroxylase and the metabolite MHPG, appear to decrease with brain atrophy seen in patients with negative symptoms. Serotonergic activity tends to be low in patients with impaired cognitive function as is seen in negative schizophrenia. In these patients ventricular enlargement is associated with the severity of negative symptoms, low monoamine activity and low cerebral glucose metabolism. On the other hand atypical antipsychotic drugs that modulate also glutamate receptor activity, suggest an additional alternative mechanism of antipsychotic action beyond aminergic neurotransmitters. These drugs improve glutamatergic transmission and decrease negative symptoms; this suggests a glutamatergic deficiency as an extension of the dopamine model. The glutamate-dopamine interaction illustrates the importance of cross-talk between projections to the cortex, striatum, and lower brainstem for the expression of negative symptomatology. On the other hand, estradiol-17beta the most potent female sex hormone influences not only primary and secondary sexual characteristics but also embryonal and fetal growth as well as development of the brain aminergic networks, which are involved in schizophrenia. Estradiol-l7beta possesses neuroprotective properties, which are relevant for the course of schizophrenia and this may explain the pronounced gender differences with respect to progression and therapeutic response of schizophrenia. The present review attempts an update and synthesis of the information about the hormonal influence on neuronal pathways in negative symptoms of schizophrenia. It shows that estradiol-l7beta influences transporters and receptors as well as the morphological appearance of neuronal systems and that it may be an integral part of the neuroprotective system ameliorating schizophrenia.

Polymorphism in the cholesterol 24S-hydroxylase gene is associated with Alzheimer's disease.

Cholesterol and 24S-hydroxycholesterol are involved in the pathogenesis of Alzheimer's disease (AD). Increased serum cholesterol concentrations have been detected in patients with AD. 24S-Hydroxycholesterol is the primary cholesterol elimination product of the brain and possesses neurotoxic properties in vitro. The enzyme catalyzing the conversion of cholesterol to 24S-hydroxycholesterol, cholesterol 24S-hydroxylase (CYP46), is mainly expressed in neurons. Concentrations of 24S-hydroxycholesterol in cerebrospinal fluid (CSF) and serum differ significantly between AD patients and non-demented subjects. To test the hypothesis if polymorphisms in the CYP46 gene might influence the function of the respective enzyme and thus cholesterol metabolism in the human brain, we screened for polymorphisms in 114 AD patients and 144 healthy controls. Two intronic single nucleotide polymorphisms were observed and their allelic distribution was investigated. In our study sample, carriers of the C allele of the IVS3+43C --> T polymorphism were more prevalent in the group of AD patients than in healthy controls, while another IVS2-150A --> G polymorphism did not show a significant association with AD. The CC genotype of the IVS3+43C --> T polymorphism was associated with an increased 24S-hydroxycholesterol/cholesterol ratio in the CSF of AD patients. Our results indicate that the CYP46 gene locus may predispose to AD by increasing the 24S-hydroxycholesterol/cholesterol ratio in the brain.

The insulin gene VNTR polymorphism in Alzheimer's disease: results of a pilot study.

Insulin (INS) and insulin-like growth factors include different polypeptides involved in growth and development. Possibly they play a role in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD). A variable number of tandem repeats (VNTR) polymorphism at the human INS 5'-flanking region consisting of three distinct allele classes has been shown to influence the tissue-specific expression of INS and the insulin-like growth factor 2 (IGF-2). Since alterations in the expression of INS or IGF-2 might be relevant in AD, we investigated the association between the INS VNTR polymorphism and the risk for AD. We found no association between the INS VNTR genotype and the risk for AD (p = 0.873). However, survival analysis revealed that class III homozygotes of the INS VNTR polymorphism had an earlier initial onset in patients suffering from early AD (p = 0.002). Our preliminary results suggest, that genetically determined alterations of the INS/IGF-2 metabolism might modify the course of AD. Further studies are warranted to confirm these data in larger study samples.

Initial serotonin transport into viable platelets and imipramine binding to platelet membranes.

Transport of serotonin into human platelets is a paradigm for neuronal reuptake to investigate putatively low neurotransmitter availability in certain psychiatric diseases. However, inconsistent results have been obtained on serotonin binding to platelet membranes at equilibrium and transport during initial phase into isolated platelets. In the present study we applied a rapid oil-centrifugation technique to study (14)C-serotonin transport for 15s into viable human platelets during the initial phase, compared to the binding of (3)H-imipramine at equilibrium (60 min) to membranes isolated from platelets of the same individuals and to their blood serotonin levels. Platelets were viable for two h after the isolation procedure; concomitant with the decrease in viability transport also decreased. Initial transport into viable cells was observed for two min. Across 19 healthy individuals blood serotonin levels correlated with the halfmaximal saturation constants of binding, K(D), for imipramine but not with any other transport or binding parameters, such as V(max) or B(max). Inhibition studies with psychoactive drugs showed good correlation between transport during the initial phase and binding at equilibrium (r = 0.83). It is speculated that changes in the V(max) of transport reflect problems with isolation, pretreatment with drugs, the energy load of the cell, and polymorphism of the serotonin transporter. The latter shows a polymorphism in the 5'regulatory region with a 44-bp insertion (l, long form) or deletion (s, short form). Results by Greenberg et al. indicate that in platelets from healthy men the l-variant was associated with increased initial serotonin uptake. Thus for genotyping, we suggest to subdivide patient and control groups in addition to psychopathology also according to their peripheral biochemical lesions.

A social approach to the validation of traditional veterinary remedies--the Anthra project.

Anthra, an organization of women veterinary scientists working in the field of livestock production and development, has been involved since 1996 in a research project to document and validate local ethnoveterinary and animal management practices carried out by livestock-rearing communities in different parts of the states of Andhra Pradesh and Maharashtra in India. Communal knowledge and innovation are an integral part of the day-to-day healing and management practices of farmers in all areas and over 80% of farmers continue to use these because they are easily and quickly available, especially in remote villages. However, this knowledge is today rapidly being lost. Farmers, both men and women, have expressed a keen desire to increase their own knowledge of these systems. This paper outlines the validation framework evolved by Anthra, wherein farmers using these medicines are actively participating in an evaluation process. Major findings are that local practices are effective, participating farmers use them confidently and other farmers are keen to use and increase their knowledge of them.

Neuroprotective effects of estradiol-17beta: implications for psychiatric disorders.

Estradiol-17beta is the most potent female sex hormone. In addition to its role in the control of primary and secondary sexual characteristics, it also influences the development of the brain. Furthermore, estradiol-17beta possesses neuroprotective properties that are mediated via receptor action and also independently of receptors. Several processes that are regulated by estradiol-17beta might influence the expression of Alzheimer's disease and schizophrenia. Differences between the sexes have been described in both disorders, and it has been suggested that these may be due to the action of oestrogens. Long-term oestrogen replacement has proved to be beneficial in the prevention and treatment of Alzheimer's disease and schizophrenia. The results, however, are controversial. Preliminary in vitro and in vivo findings, which are summarised in this review, encourage further studies with estradiol-17beta or its analogues as potential adjunctive interventions particularly in "negative syndrome" schizophrenia and in Alzheimer's disease.

Allelic variants of the serotonin(2C) receptor and neuroendocrinological responses to the serotonin(2C) receptor agonist m-chlorophenylpiperazine in healthy male volunteers.

The neurotransmitter serotonin (5-HT) possesses several receptors and their subtypes, some of which are polymorphic, such as the 5-HT(2C) receptor. The latter has been implicated in the control of neuroendocrine function, and has been discussed in the pathophysiology and pharmacotherapy of psychiatric disorders such as obsessive-compulsive disorder, panic disorder and bipolar affective disorder. To investigate whether the 5-HT(2C) receptor polymorphism contributes to the variation of neuroendocrinological responses elicited by activation of the hypothalamic-pituitary axis, we performed an m-chlorophenylpiperazine (m-CPP) challenge and monitored m-CPP and ACTH, cortisol and prolactin plasma levels in 16 healthy male volunteers carrying the common 5-HT(2C)-cys-23 receptor gene and 16 healthy male volunteers carrying the less frequent 5-HT(2C)-ser-23 receptor gene. The 5-HT(2C) polymorphism contributed little to the variation of the scores regarding hormonal responses of ACTH, cortisol and prolactin to the m-CPP challenge. The group carrying the rare 5-HT(2C)-ser-23 receptor gene showed a faster and stronger but not statistically significant ACTH response to the challenge. However, it is noteworthy that there is a 'medium' effect size of the ACTH response according to the conventions of Cohen, and thus comparable to other studies. Both groups show similar major scores in the Temperament and Character Inventory (TCI).