[Association between the violence in the community and the aggressive behaviors of psychotics during their hospitalizations]. / Relation entre la violence intra-hospitalière des patients avec psychoses et la violence dans la communauté.

BACKGROUND: Violence is a common issue in psychiatry and has multiple determiners. The aim of this study is to assess the psychotic inpatients' violence in association with the violence of the neighborhood from which the patients are drawn and to estimate the impact of this environmental factor with regard to other factors. METHOD: A prospective multicenter study was led in nine French cities. Eligible patients were psychotic involuntary patients hospitalized in the cities' psychiatric wards. During their treatments, any kind of aggressive behavior by the patients has been reported by the Overt Aggression Scale (OAS). RESULTS: From June 2010 to May 2011, 95 patients have been included. Seventy-nine per cent of the patients were violent during their hospitalizations. In a bivariate analysis, inpatient violence was significantly associated with different factors: male gender, patient violence history, substance abuse, manic or mixed disorder, the symptoms severity measured by the BPRS, the insight degree and the city crime rate. In a multivariate analysis, the only significant factors associated with the patients' violence were substance abuse, the symptoms severity and the crime rates from the different patients' cities. CONCLUSION: These results suggest that violence within the psychotic patients' neighborhood could represent a risk of violence during their treatments.

[Milnacipran and venlafaxine at flexible doses (up to 200 mg/d) in the outpatient treatment of adults with moderate-to-severe major depressive disorder: a 24-week randomised, double blind exploratory study]. / Milnacipran et venlafaxine à posologie flexible (jusqu'à 200 mg/j) dans le traitement ambulatoire des épisodes dépressifs majeurs modérés à sévères de l'adulte: étude exploratoire de 24 semaines, randomisée en double insu.

INTRODUCTION: Serotonin (HT) and noradrenaline (NA) reuptake inhibitors (SNRIs) are commonly used as first line treatment of major depressive disorders (MDD). As compared to tricyclic antidepressants, they have proved similar efficacy and better tolerability. Milnacipran (MLN) (Ixel) and venlafaxine (VLF) (Effexor) are two SNRIs pharmacologically differing by their NA/HT ratio of potency: 1:1 and 1:30, respectively. OBJECTIVES: To investigate the efficacy and safety/tolerability of MLN and VLF administered at flexible doses (100, 150 or 200 mg/day) for 24 weeks (including 4 weeks of up-titration) in the outpatient treatment of adults with moderate-to-severe MDD. DESIGN: Multicentre, randomised, double blind, 2-parallel-arm, 24-week exploratory trial conducted in France by 50 psychiatrists. DIAGNOSIS AND MAIN INCLUSION CRITERIA: Male or female outpatients, aged 18 to 70, meeting the DSM-IV-TR and related MINI criteria for recurrent, unipolar, moderate-to-severe MDD, with neither psychotic features nor severe suicidal risk. A Montgomery-Asberg depression rating scale (MADRS) score> or =23 was required at inclusion. TREATMENT SCHEDULE: Patients were randomised to receive either MLN or VLF (1:1 ratio) for 24 weeks in double-blind conditions. Regardless of the treatment received, the following dosing schedule was applied: during the initial 4-week up-titration phase, the dosage was progressively increased from 25 mg/day (qd administration) to 150 mg/day (bid administration). At week 4, the dosage was either maintained at 150 mg/day, or adapted to 100 or 200 mg/day, based on the investigator's clinical judgement. At any time during the 20 following treatment weeks, the dose could be lowered for safety concerns until a minimal threshold of 100 mg/day. From Week 24, the dosage was decreased by 50mg/day every five days. After randomisation, eight assessment visits were organised at 2, 4, 6, 8, 12, 18, 24 weeks, and at study end (after the 5-15 days of down-titration and 10 days free of treatment). Efficacy evaluation ratings included the MADRS and global disease severity (CGI-S) total scores. Rates of MADRS response (reduction of initial score> or =50%) and remission (score< or =10) were calculated at Week 8 and Week 24 in the full analysis set as well as in the subgroups of patients with depressive disorder of severe DSM-IV intensity and with a MINI evaluation of suicidal risk (rated as required 'moderate' at the worst). STATISTICAL ANALYSIS: Standard distribution statistics (including mean and standard deviation [S.D.]) of scores and their changes from baseline, were calculated using the observed-case (OC) approach at all assessment times for the MADRS score, and the last-observation-carried-forward (LOCF) at 8 and 24 weeks for both MADRS and CGI-S scores. MADRS response and remission rates at 8 and 24 weeks were calculated using the LOCF approach by normal approximation of the binomial distribution. Bilateral exploratory statistical tests at 5% significance level were performed for results at 8 and 24 weeks of: (i) MADRS score changes from baseline, based on the score progress at each visit (mixed model for repeated measurements [MMRM]), and (ii) global MADRS response and remission rates (Chi(2)). RESULTS AND PATIENTS: A total of 195 patients were randomly assigned MLN (n=97) or VLF (n=98) and 134 (68.7%: 61.9%/MLN and 75.5%/VLF) completed the trial. At the end of the up-titration, patients received 100 mg/day (11.4%/MLN, 10%/VLF), 150 mg/day (30.4%/MLN, 43.8%/VLF), or 200 mg/day (58.2%/MLN, 46.3%/VLF). Totals of 177 patients (90/MLN and 87/VLF) and 181 patients (90/MLN and 91/VLF) were analysed for efficacy and safety, respectively. Treatment groups were similar for baseline characteristics except a higher proportion of MLN patients with a severe depressive episode (63.3% versus 54%). RESULTS AND EFFICACY: MADRS score (mean [S.D.] initial score: 31 [4.5]) progressively decreased all along the treatment course and similarly in both groups (Week 8-OC : -18.8 [7.7]/MLN and -18.6 [7.3]/VLF, p(MMRM)=0.95 ; Week 24-OC : -23.1 [7.8]/MLN and -22.4 [7.3]/VLF, p(MMRM)=0.37 ). At week 8-LOCF, MADRS response rates were similar in both groups (64.4%/MLN, 65.5%/VLF, p(chi2)=0.88) as well as remission rates (42.2%/MLN, 42.5%/VLF p(chi2)=0.97). At week 24 they remained non clinically and statistically different between groups (response rates: 70%/MLN, 77%/VLF, p(chi2)=0.29; remission rates: 52.2%/MLN, 62.1%/VLF, p(chi2)=0.19). In both "severe depressive episode" and "MINI mild or moderate suicidal risk" subgroups (n=104 and 75, respectively), response and remission rates were non clinically different at both time points, however in the "MINI mild-to-moderate suicidal risk" subgroup, MLN tended to be more rapidly active (remission rate at week 8-LOCF: 44.7%/MLN, 35.1%/VLF). The changes in CGI-S were also indicative of a significant improvement of the global illness severity with both treatments. RESULTS AND SAFETY/TOLERABILITY: The tolerability profile of both drugs was in line with their pharmacological activity. About 70% of patients in both groups experienced at least one adverse event (AE). In both groups, the most common AEs were nausea, dizziness, headache and hyperhidrosis, and, in the male patients, genito-urinary problems: orgasmic disorders (VLF only) and dysuria (MLN only). These AEs were mostly responsible for definitive treatment discontinuation for tolerability concerns. None of the 6 serious adverse events (SAEs) on MLN and 4 of the 8 SAEs on VLF were related to the test drug. CONCLUSION: MLN and VLF at flexible doses up to 200 mg/day globally exhibited similar efficacy and tolerability profiles in the long-term treatment of adults with MDD.

[Assessment of metabolic impairments inducted by atypical antipsychotics among schizophrenic patients]. / Evaluation des troubles du métabolisme induits par les antipsychotiques atypiques chez les patients schizophrènes.

Conventional and atypical antipsychotics are known to induce weight gain, cause glucose and lipid impairments among schizophrenic patients. These impairments contribute to the intrinsic risk factors linked to the psychiatric pathology (sedentary state, nicotin addiction, diabetes) increasing numbers of cardiovascular complications. We propose to study ponderal modifications and presence of metabolic abnormalities in a population of schizophrenic patients treated by conventional or atypical antipsychotics, depending on the received treatment; 32 patients, whose schizophrenia diagnosis had been previously made, were consecutively included over a 4 months period. They were divided into three groups: patients treated by conventional antipsychotics (n = 6), by atypical antipsychotics (n = 16) or by a combination of both (n = 10); 6 patients (18%) display overweight problems, 4 patients (12.5%) got hypertriglyceridemia and 4 other patients (12.5%) have hypercholesterolemia. No particular drug could be directly targeted, partly because of the restricted size of our sample, but the patients presenting metabolism impairment were treated by atypical antipsychotic. The observance of these abnormalities is reflected in publications and lead to some antipsychotic treatments monitoring rules.

[Visuospatial context processing in untreated schizophrenic patients and relation to disorganization syndrome]. / Traitement du contexte visuospatial chez des patients schizophrènes non traités -- influence de la désorganisation.

AIM: Previous studies on schizophrenia have suggested that context-processing disturbances were one of the core cognitive deficits present in schizophrenia. Schizophrenic patients have a failure either of inhibition strategy and maintenance of visuospatial information (25) in condition of contextual interference. In the present study, we explored the performances of untreated schizophrenic patients with 2 tasks exploring detection and long term retention of complex visual features and field dependence-independence tasks were selected. These abilities involve temporary maintenance of visuospatial information and executive functioning of visual working memory system. Several studies have shown that cognitive deficit may depend on schizophrenic symptomatology. However results remain controversial in determining the specific influence of negative and positive symptomatologies as well as clinical disorganization. Our goal was to explore the processing of spatial context and its relation to disorganized syndrome. This study was approved by the local ethic committee. METHODOLOGY: Thirty-six schizophrenic patients were included according to DSM IV criteria (19 neuroleptic naïve, 17 unmedicated patients during more than 3 months). Thirty-six healthy controls were matched to patients for age, gender and level of education. Absence of axis 1 pathology was attested for controls with SCID-NP. Current symptomatology was evaluated by the Positive and Negative Syndrome Scale (PANSS) (14). Clinical disorganisation was evaluated with the disorganisation score established upon a factorial analysis of PANSS by Lepine and Lançon. Items selected to distinguish the disorganised group were abstraction, disorganization, orientation, and attention. PROCEDURE: Two tasks of embedded figures were administered individually to patients and controls. The Faverge task (Research of Figures-RF) (10) evaluates the ability to recognize the target from spatial complex geometrical figures. The Group Embedded Figure Task (GEFT - Oltman) assesses the detection and maintenance of visual target and its recognition within a complex figure. Performance between patients and controls were compared with the Student T test. The comparison of two clinical subgroups of disorganized and low disorganized patients and control group was performed with an ANOVA. Tuckey test was used for pairwise comparisons. RESULTS: We defined two subgroups of patients, disorganized patients (subscore 12, n=17) and low disorganized patients (subscore<12, n=19). Theses 2 subgroups were similar for age and level of education. Concerning the two tasks, there was no significant difference between schizophrenic patients and normal controls. The comparison between subgroups of disorganized and low disorganized patients, for RF task, showed a decrease of correct answers with disorganized patients (p<0.05). For GEFT task, disorganized patients had a decrease of correct answers p<0.01) and more errors (p<0.01) and omissions (p<0.05). The low disorganized patients exhibited for the two tests comparable performance to controls. The disorganized patients had a decrease of right answers (p<0.05) and more errors (p<0.05) than controls for GEFT task and no significant difference for RF. However, with IQ (evaluated with an abstract reasoning test) introduced as covariate, only correct answers for GEFT task remain significant (p<0.05). DISCUSSION: The weak performance of disorganized schizophrenic patients for two tasks RF and GEFT showed that treatment of visuospatial information was impaired in the first perceptive phase of selection and in the organization of information (RF), especially with the maintenance of visual information in memory (GEFT). By contrast, low disorganized patients demonstrated a correct analytic treatment of elementary processing and visuospatial working memory. CONCLUSION: The severity of disorganization influences the visuospatial context processing and visuospatial working memory. These results show the heterogeneity of cognitive functioning regarding to schizophrenic symptomatologies. This difficulty could be related to a problem of central executive functioning in the visuospatial component of working memory, possibly mediated by the dysfunction of dorsolateral prefrontal cortex.

[Personality tests and gender identification in male transsexuals]. / Tests de personnalité et identification sexuée chez des transsexuels masculins.

The aim of this research project was to study gender identification in male transsexuals compared to male and female controls, using the Rorschach test and the MMPI. In the international literature, many researches have shown that the nature of the human response on Rorschach card III is linked to gender identification, as is the MMPI Mf scale. Ten untreated male homosexual transsexuals and 18 treated and operated male homosexual transsexuals were compared to 10 male and 12 female controls regarding verbal IQ, human content on Rorschach card III and the MMPI Mf scale. Absence of hormonal treatment for the first group of transsexuals was checked by a blood test at the time of the psychological testing. Responses on Rorschach card III were scored according to different kinds of human contents: male (M), female (F), gender-unidentified/neutral (N), bisexual (B), feminine then masculine or the opposite (M/F), and nonhuman (NH). N, B, M/F and NH responses were rare in all Rorschach protocols. As expected, responses given by participants in the control group were significantly more consistent with their anatomical sex than with the opposite sex. Untreated transsexuals do not differ from treated and operated transsexuals on Rorschach data, and both transsexual groups give significantly more female human representations than male controls. Transsexuals' results are similar to female controls. Untreated transsexuals' mean score on the MMPI Mf scale is significantly higher than that of treated and operated transsexuals' score, in the male profile (biological sex). Both groups of transsexuals score higher on the Mf scale in the male profile than in the female profile. The mean Mf score in the male profile is significantly higher than that of male controls, whereas, in the female profile, the mean Mf score is similar to that of female controls. This study shows that for both groups of transsexuals, results are homogenous in respect of Rorschach and MMPI, showing hyper-conformism to self-perceived gender. Results in both groups are similar to results of female controls, but tend to show even more feminine gender identification. The absence of any significant difference between untreated and treated and operated transsexuals seems surprising, suggesting that the hormonal treatment has not had a major impact on gender identification processes. It would doubtless be interesting to study gender identification using even more kinds of data: all human contents in the Rorschach protocol (not just the responses given to card III), MMPI Mf scale, Draw-A-Person Test and Animal-and-Opposite Drawing Test. This would enhance result liability and could provide useful information about how gendter identification processes evolve after surgical sex reassigment.

Translation and validation of the PREE (Patient Rated Elbow Evaluation) to a French version.

BACKGROUND: Only a few outcome measures specific to elbow pathology and the assessment of their impacts on function are valid and reliable when used in French speaking populations. The English version of the Patient Rated Elbow Evaluation (PREE) was determined to be an optimal candidate for translation. HYPOTHESIS: A French version of the PREE (PREE-Fr) will be generated and compared to its original version in terms of reliability and responsiveness. MATERIALS AND METHODS: The PREE was translated following the guidelines of the American Academy of Orthopedic Surgeons. Patients with a variety of elbow pathologies completed the French version of the PREE (PREE-Fr), the Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) and the Mayo Elbow Performance Score (MEPS) on three different occasions. The test-retest reliability of the PREE-Fr was calculated using questionnaires that were filled out with a one-week interval between them. The responsiveness was assessed using questionnaires filled out six months after treatment. RESULTS: A French version of the PREE was generated. Data gathered from 54 patients yielded an intra-class correlation coefficient for reliability of 0.89 (CI95%: 0.79-0.94) for the PREE-Fr. For construct validity, using the Pearson correlation coefficient, we obtained excellent correlation between the PREE-Fr and QuickDASH at day one, one week and six months (0.89-0.96) while that between the PREE and MEPS was good to excellent (0.70-0.95). Responsiveness of the PREE-Fr was assessed and yielded a standardized response mean of 1.03, meaning that a large change was recorded between day one and six months. DISCUSSION: The PREE-Fr should be considered in French speaking populations for patients with elbow pathology, whether it is for research or evaluation purposes as it is valid, reliable and responsive to change.

Changes in [3H]5-HT uptake and [3H]imipramine binding in platelets after chlorimipramine in healthy volunteers. Comparison with maprotiline and amineptine.

In the platelets of normal healthy volunteers (n = 8) taking chlorimipramine (50 mg/day) for 1 week, the saturable uptake of [3H]5-hydroxytryptamine (5-HT) was fully inhibited at the end of the week, but returned to control values after 2 weeks washout. The Bmax of [3H]imipramine binding was decreased by 63% at the end of the treatment and remained significantly decreased below control values after 1 week washout, whereas the Kd values were increased at the end of the treatment, but had returned to baseline values after 1 week washout. The time course of recovery following the administration of chlorimipramine showed some variation between subjects, but it was necessary to wait up to 4 weeks of washout before the Bmax of [3H]imipramine returned to baseline levels. In contrast, neither 1-week treatment with maprotiline (50 mg/day) nor with amineptine (100 mg/day) changed the parameters of [3H]5-HT uptake or [3H]imipramine binding in platelets from healthy volunteers. These results support the following conclusions. (1) [3H]Imipramine binding in platelets can be down-regulated by relatively low, subtherapeutic doses of chlorimipramine. (2) It is possible to dissociate [3H]imipramine binding parameters from [3H]5-HT uptake because the time course of recovery was clearly different, indicating that [3H]imipramine labels a site linked with, but different from, the 5-HT recognition site in the transporter complex. (3) A washout of antidepressants of 4 weeks may be needed when studying the parameters of [3H]imipramine binding in platelets from depressed patients if the previous medication involved chlorimipramine. For antidepressants like maprotiline or amineptine, that act through mechanisms other than inhibition of 5-HT uptake, the time of washout appears to be less critical, although it is not possible to rule out the existence of some secondary modifications influencing the 5-HT transporter complex.

Plasma melatonin and cortisol in patients with obsessive-compulsive disorder: relationship with axillary temperature, physical activity, and clinical symptoms.

BACKGROUND: Many studies have found biological abnormalities in obsessive-compulsive disorder (OCD), although most of them have not been replicated. The investigation of melatonin rhythm may thus provide an indirect clue to neurotransmitter alterations, and allow a biological comparison with depression. METHODS: The circadian variations of plasma melatonin, plasma cortisol, axillary temperature, motor activity, and obsessive-compulsive symptoms have been documented on a circadian basis in 8 patients with OCD compared to 8 paired healthy volunteers. RESULTS: The circadian pattern of axillary temperature was slightly different in OCD patients when compared to control subjects. No significant difference between the two groups could be observed for any other variable studied. CONCLUSIONS: The discrepancies with previous studies are discussed on the basis of the methods used (patients and control subjects samples, biological measurement procedures). An alteration of temperature circadian rhythm hypothesis is suggested.

The cortical serotonin2 receptors studied with positron-emission tomography and [18F]-setoperone during depressive illness and antidepressant treatment with clomipramine.

BACKGROUND: Changes in serotonin (5-HT)2 receptor densities were reported in depression by postmortem studies and following treatment with tricyclic antidepressants in animal studies. Here, 5-HT2 receptors were studied in vivo in depressed patients. METHODS: Cortical 5-HT2 receptors were investigated prospectively using positron-emission tomography and [18F]-setoperone in 7 depressed patients, before and after at least 3 weeks of clomipramine (CMI), 150 mg daily. They were compared to 7 age-matched controls. RESULTS: There was no significant difference between the untreated patients and the controls, except in the frontal region, where the [18F]-setoperone specific binding was slightly lower in patients. After CMI treatment, depression scores significantly improved and [18F]-setoperone specific binding decreased in cortical regions, suggesting receptor occupancy and/or receptor regulation, by CMI; however, no clinical score correlated with the 5-HT2 receptor measurements either in the untreated or in the treated conditions. CONCLUSIONS: These data substantiate the view that tricyclic antidepressants such as clomipramine significantly interact with cortical 5-HT2 serotoninergic receptors in actual therapeutic situations.

Comparison of acetorphan with clonidine for opiate withdrawal symptoms.

OBJECTIVE AND METHOD: The authors compared the effects of acetorphan, an enkephalinase inhibitor, with those of clonidine for the treatment of the opioid withdrawal syndrome. Nineteen patients addicted to heroin or synthetic opiates who were undergoing drug withdrawal and displayed a withdrawal syndrome according to DSM-III criteria were studied for 5 days in a hospital setting. In a double-blind trial, 10 subjects were given acetorphan intravenously and nine were given clonidine; objective signs and subjective symptoms of withdrawal were recorded. RESULTS: On several objective signs, the effect of acetorphan was more marked than that of clonidine, whereas the two drugs exhibited similar efficacy with respect to the subjective components of withdrawal. No side effect was noted in the subjects who received acetorphan. CONCLUSIONS: Enkephalinase inhibition may constitute a novel and safe therapeutic approach to the opioid withdrawal syndrome.

Failure of Farr test in detecting IgM response to dinitrophenyl in mice.

In mouse serum the ammonium sulphate technique does not detect the immune response to the haptenic determinant DNP on polysaccharide, nor the early stage of the primary response to DNP on protein. Specific anti-DNP antibodies are easily detected, in the same sera, by the phage neutralization technique. This failure of the Farr test seems to be related to its inability to measure adequately mouse anti-DNP 19S antibodies.

Schizophrenia and the cannabinoid receptor type 1 (CB1): association study using a single-base polymorphism in coding exon 1.

Abuse of cannabis is frequent among the young and is suspected to precipitate schizophrenia in vulnerable subjects. Cannabinoid receptor (CB1) is particularly concentrated in dopamine-modulated areas of the nervous system. An association between an AAT polymorphism of the CB1 gene and intravenous drug abuse has been previously reported, but not with schizophrenia. In a French Caucasian population, we compared the distribution of a single-base polymorphism revealed by MspI within the first exon of the CB1 gene in patients with schizophrenia (n = 102) and ethnic- and gender-matched controls (n = 63). No significant difference was seen in the allele or genotype distribution between the whole sample of schizophrenic patients and controls. However, we found a borderline lack of allele g and a significant lack of gg genotype in the non-substance-abusing patients compared to substance-abusing patients, the latter being similar to the controls. These results are the first report of an significant association between CB1 receptor and a subtype of schizophrenia. Studies are needed to confirm and further explore the precise role of the cannabinoid system in schizophrenia.

Platelet 3H-imipramine binding and steroid hormones serum concentrations during the menstrual cycle.

The presence of high affinity binding sites for 3H-imipramine (3H-IMI) in human platelets is by now well established. This recognition site is associated with the transporter for 5HT, and may be a biological marker in depression. Fluctuations of other putative biological markers of depression (i.e. platelet MAO activity) have been demonstrated and shown to be correlated with variations in steroid hormones. Therefore, the KD and Bmax of 3H-IMI binding was determined in platelets of young women during the menstrual cycle. Our results indicate that within the limits of intraindividual variations, neither the KD or the Bmax of 3H-IMI binding in platelets is significantly modified during the menstrual cycle.

Lack of circadian rhythm in plasma levels of 3,4-dihydroxyphenylethyleneglycol in healthy human subjects.

In order to investigate the possible existence of a circadian rhythm in plasma free and sulfate-conjugated 3,4-dihydroxyphenylethyleneglycol (DOPEG), the plasma levels of this metabolite (and for comparison, of melatonin and cortisol) were measured in seven healthy volunteers at 4-h intervals over a period of 24 h. Plasma concentrations of melatonin and cortisol showed distinct diurnal variations with acrophases at 2.5 h and 8.5 h, respectively. In contrast, plasma free DOPEG levels were relatively stable over the 24-h period studied. Sulfate-conjugated and free + sulfate-conjugated DOPEG levels showed a slight, non-significant increase in the early afternoon. These results indicate that in contrast to plasma 3-methoxy 4-hydroxyphenylethyleneglycol, plasma free and conjugated DOPEG levels do not exhibit a circadian rhythm.

Changes in human platelet 5 HT level after 1 week of chlorimipramine treatment.

In platelets of six volunteers taking chlorimipramine (50 mg/day) for 1 week, 5-HT levels were markedly decreased at the time of treatment withdrawal, and remained significantly reduced after a 1-week washout. Individual levels in five subjects remained affected during a 3-week washout. The previously reported observations of reduced serotonin concentration in platelets from depressed patients may reflect a residual effect of previous antidepressant treatment.

Reduced Bmax of [3H]-imipramine binding to platelets of depressed patients free of previous medication with 5HT uptake inhibitors.

The high-affinity binding sites for [3H]-imipramine (IMI) present in human platelets are associated with the neuronal uptake system for 5HT. It was recently demonstrated that previous antidepressant therapy with drugs which inhibit 5HT uptake could down-regulate [3H]-IMI binding and that this effect could persist up to 1 month after the end of treatment. We therefore re-examined the reported differences in Bmax of [3H]-IMI binding in platelets between control and depressed untreated patients, to evaluate the residual influence of previous antidepressant medication. The saturation characteristics of [3H]-IMI binding were compared in platelets from 17 depressed patients carefully selected according to previous antidepressant therapy and washout period, who were closely matched, for age and sex, with a group of control healthy volunteers. The results reveal a significant decrease by 47% in the Bmax of [3H]-IMI binding in platelets of untreated depressed patients when compared with controls. There was no significant modification of Kd values for platelet [3H]-IMI binding between the depressed and the control groups. Our results support the view that platelet [3H]-IMI binding is a useful tool as a biological marker in depression.

Short-term lithium administration to healthy volunteers produces long-lasting pronounced changes in platelet serotonin uptake but not imipramine binding.

Platelet [3H]-5HT uptake, [3H]-imipramine binding and endogenous 5HT levels were measured in healthy volunteers during short-term (20 days) administration of lithium, and following its withdrawal. The Vmax of [3H]-5HT uptake was significantly decreased during lithium treatment. Following lithium withdrawal, platelet [3H]-5HT uptake (Vmax) remained decreased and was followed by a pronounced rebound effect in some of the subjects for up to 3 months. The affinity constant (Km) of [3H]-5HT uptake was not modified. Binding of tritiated imipramine during the same period and platelet 5HT levels measured till 14 days after withdrawal was not affected by lithium treatment. As lithium is devoid of in vitro effects on both 5HT uptake and imipramine binding, it is concluded that the effects of lithium on the 5HT transporter do not reflect a direct effect on the transporter complex. Our results indicate that lithium-induced changes at the level of 5HT uptake in platelets are not correlated with concomitant variations in platelet 5HT content and can be dissociated from modifications at the level of imipramine binding sites within the macromolecular complex of the 5HT transporter. Moreover, platelet 5HT uptake is apparently modulated by lithium, with a similar pattern in healthy volunteers and in manic-depressive patients.

In vivo characteristics of dopamine D2 receptor occupancy by amisulpride in schizophrenia.

The relationship between the daily oral dose of the benzamide amisulpride and the striatal D2-dopamine receptors occupancy was investigated in 11 schizophrenic patients using positron emission tomography with 76Br-bromolisuride. The patients were studied before and during chronic treatment with amisulpride over a wide range of doses. The test-retest variability of the method was estimated to be 5.8% in a group of four patients receiving placebo. A curvilinear relationship was demonstrated between the amisulpride doses and the D2-receptor occupancy. A range of 70-80% occupancy of the striatal D2 receptors, suggested as an optimal interval for therapeutic action on positive psychotic symptoms, was obtained with doses of amisulpride ranging between 630 and 910 mg per day, while an occupancy of 85%, suggested to be associated with pronounced extrapyramidal side-effects, was reached with 1,100 mg per day.

Obsessive-compulsive disorder: evaluation of clinical and biological circadian parameters during fluoxetine treatment.

RATIONALE: Many biological abnormalities have been found in obsessive-compulsive disorder (OCD). The circadian rhythm investigations of different clinical and biological parameters may provide a comparison with depression. Fluoxetine is one of the efficient drugs in alleviating symptoms of OCD. The effect of fluoxetine can highlight some clues to the neurotransmitter alterations in the disorder. OBJECTIVE: The present study investigated clinical and biological circadian modifications in OCD patients during a fluoxetine treatment. METHODS: Daily clinical symptoms, and circadian rhythms of axillary temperature, plasma cortisol and plasma melatonin were assessed in eight patients suffering from OCD. These parameters were compared in the same patients, before and after an 8-week fluoxetine treatment period. RESULTS: A therapeutic effect of fluoxetine was obtained. No significant differences were observed either in daily clinical variations or in biological circadian rhythms measured before and after treatment. CONCLUSION: The therapeutic efficacy of fluoxetine was not related to the biological parameters assessed.

Striatal dopamine receptor occupancy during and following withdrawal from neuroleptic treatment: correlative evaluation by positron emission tomography and plasma prolactin levels.

The percentage occupation of striatal dopamine D2 receptors has been evaluated in 25 patients using 76Br-bromospiperone positron emission tomography (PET) and prolactin plasma levels (PRL) during oral neuroleptic treatment (11 studies), 1-90 days following discontinuation of such treatment (16 studies), and 1-120 days after last intramuscular administration of depot neuroleptics (nine studies). The PET-estimated occupation was highly significantly correlated in a sigmoid-like fashion to the logarithm of the chlorpromazine-equivalent dose of oral neuroleptics (suggesting a strict dose-occupation relationship during oral neuroleptic treatment and supporting the D2-mediated hypothesis of neuroleptic action), while PRL was weakly related to daily dosage. Following withdrawal, return to normal receptor availability, as estimated by PET, occurred within 5-15 days (suggesting that protracted effects of neuroleptics after withdrawal are not due to sustained D2 receptor occupation), but PRL values fell even more rapidly. Efficient treatment with depot neuroleptics resulted in marked PET-estimated D2 receptor occupation, stable over the whole 4-week drug-administration interval, suggesting that longer intervals could be appropriate; PRL values bore no relationship to PET-estimated occupation, indicating variable intersubject tolerance to neuro-endocrine dopamine blockade. Overall, PET was much more sensitive than PRL to estimate striatal D2 receptor occupation in vivo.