Hyper/neuroinflammation in COVID-19 and suicide etiopathogenesis: Hypothesis for a nefarious collision?

Accumulating scientific and clinical evidence highlighted pathological hyperinflammation as a cardinal feature of SARS-CoV-2 infection and acute COVID-19 disease. With the emergence of long COVID-19 syndrome, several chronic health consequences, including neuropsychiatric sequelae, have gained attention from the public and medical communities. Since inflammatory mediators have also been accredited as putative biomarkers of suicidal ideations and behaviors, hyper- and neuroinflammation might share some colliding points, overlapping and being interconnected in the context of COVID-19. This review aims to provide a summary of current knowledge on the molecular and cellular mechanisms of COVID-19-associated hyper/neuroinflammation with focus on their relevance to the inflammatory hypothesis of suicide development. Subsequently, strategies to alleviate COVID-19 hyper/neuroinflammation by immunomodulatory agents (many of which at experimental stages) as well as psychopharmacologic/psychotherapeutic approaches are also mentioned. While suicide risk in COVID-19 survivors - until now little known - needs further analysis through longitudinal studies, current observations and mechanistic postulates warrant additional attention to this possibly emerging mental health concern.

Type A competitiveness traits correlate with downregulation of c-Fos expression in patients with type 1 diabetes.

AIM: Type A personality has been associated with increased survival in people with type 1 diabetes (T1D). Systemic low-grade inflammation may play a critical role, as suggested in recent reports, although the links between the inflammatory circulating transcriptome and Type A remain unknown. This prompted our exploration of the potential associations between Type A personality and c-Fos gene expression, a candidate gene closely linked to inflammatory processes, in T1D. METHODS: Type A personality was assessed by Bortner questionnaire in patients with T1D, and two subscales - 'speed' and 'competitiveness' - were used to measure these specific dimensions of Type A. Expression of the c-Fos gene was assessed by a quantitative real-time polymerase chain reaction technique. RESULTS: This pilot study included 20 men with T1D. Multivariable analyses showed an independent inverse association between Type A competitiveness score and c-Fos expression, while a regression model adjusted for age, body mass index and HbA1c levels revealed a significant inverse relationship between c-Fos transcripts and Type A competitiveness (P = 0.003). CONCLUSION: This strong association between Type A competitiveness and reduced c-Fos expression is in line with recent data suggesting a psychobiological influence of the Type A profile in T1D via inflammatory pathways.

New insights into the pharmacogenomics of antidepressant response from the GENDEP and STAR*D studies: rare variant analysis and high-density imputation.

Genome-wide association studies have generally failed to identify polymorphisms associated with antidepressant response. Possible reasons include limited coverage of genetic variants that this study tried to address by exome genotyping and dense imputation. A meta-analysis of Genome-Based Therapeutic Drugs for Depression (GENDEP) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D) studies was performed at the single-nucleotide polymorphism (SNP), gene and pathway levels. Coverage of genetic variants was increased compared with previous studies by adding exome genotypes to previously available genome-wide data and using the Haplotype Reference Consortium panel for imputation. Standard quality control was applied. Phenotypes were symptom improvement and remission after 12 weeks of antidepressant treatment. Significant findings were investigated in NEWMEDS consortium samples and Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) for replication. A total of 7062 950 SNPs were analyzed in GENDEP (n=738) and STAR*D (n=1409). rs116692768 (P=1.80e-08, ITGA9 (integrin α9)) and rs76191705 (P=2.59e-08, NRXN3 (neurexin 3)) were significantly associated with symptom improvement during citalopram/escitalopram treatment. At the gene level, no consistent effect was found. At the pathway level, the Gene Ontology (GO) terms GO: 0005694 (chromosome) and GO: 0044427 (chromosomal part) were associated with improvement (corrected P=0.007 and 0.045, respectively). The association between rs116692768 and symptom improvement was replicated in PGRN-AMPS (P=0.047), whereas rs76191705 was not. The two SNPs did not replicate in NEWMEDS. ITGA9 codes for a membrane receptor for neurotrophins and NRXN3 is a transmembrane neuronal adhesion receptor involved in synaptic differentiation. Despite their meaningful biological rationale for being involved in antidepressant effect, replication was partial. Further studies may help in clarifying their role.

[Mindfulness-based interventions in obsessive-compulsive disorder: Mechanisms of action and presentation of a pilot study]. / Les interventions basées sur la pleine conscience dans le trouble obsessionnel compulsif : mécanismes d'action et présentation d'une étude pilote.

Obsessive-compulsive disorder (OCD) is a frequent and severe disease, potentially inducing a major impairment for the patient and burden for their family. Recent research in psychiatry and neuroscience have led to better comprehension of the disease's mechanisms and helped to improve its treatment. However, a large proportion of patients have refractory symptoms, including for traditional cognitive and behavioral therapy by exposure and response prevention (ERP), leading clinicians to look for new treatments. Mindfulness-based interventions (MBI) are a new type of approach, initially based on Buddhist meditation, which aims to provide better consciousness of the present moment. It has been successfully developed in some psychiatric diseases and other general medical conditions such as chronic pain. The two main programs using mindfulness meditation, Mindfulness-based stress reduction (MBSR) and Mindfulness-based cognitive therapy (MBCT), have shown effectiveness for the reduction of depressive and anxiety symptoms and relapses of depressive episodes in unipolar depression. It has no side effects and is well tolerated by patients. Its action relies on the specific correction of cognitive deficits in attention, emotion regulation and executive functions which are shared by OCD, GAD and depression. For OCD, we make the hypothesis that Mindfulness-Based Interventions could reduce the cognitive bias specifically existing in this pathology, such as dysfunctional beliefs, and therefore improve the symptoms. This article first reviews the existing literature on clinical trials involving Mindfulness-Based Interventions in OCD which comprises a small number of clinical studies based on very different types of protocols. At this time, and due to the lack of gold-standard studies with a large number of patients, no proof of the efficiency of mindfulness-based interventions in OCD has been shown. In a second section, following our hypothesis on the mechanisms of specific and non-specific action of this therapy in OCD, we propose a cognitive model of mindfulness-based therapy action in OCD involving the correction of OCD's cognitive bias. In this model, mindfulness-based therapy is supposed to treat specifically the cognitive aspects of the disease, while ERP is focused on its behavioral part. Then we present a clinical study aiming to prove the feasibility and the interest of the use of mindfulness in OCD, carried out in two different clinical centers. One of them used MBCT while the second used MBSR. Its results show the feasibility of mindfulness-based therapy in OCD patients and tend to prove that it could be more effective in young patients suffering from less severe forms of OCD. In parallel, attention tests and fMRI scans were done at the beginning and at the end of the therapy. Their results will be published separately. We also discuss the putative role of a specific form of MBCT adapted for OCD, specifically for its benefits in psychoeducation, which could reduce the dysfunctional beliefs present in OCD patients. Finally, we propose a therapeutic strategy in which the MBCT could complement the classical ERP therapy, as a "maintenance" treatment, aiming to extend the relapse of OCD symptoms. This article is a step further in the use of mindfulness-based therapy for OCD which could be added to the existing treatments reducing the patient's symptoms and improving their quality of life.

Copy number variants and therapeutic response to antidepressant medication in major depressive disorder.

It would be beneficial to find genetic predictors of antidepressant response to help personalise treatment of major depressive disorder (MDD). Rare copy number variants (CNVs) have been implicated in several psychiatric disorders, including MDD, but their role in antidepressant response has yet to be investigated. CNV data were available for 1565 individuals with MDD from the NEWMEDS (Novel Methods leading to New Medications in Depression and Schizophrenia) consortium with prospective data on treatment outcome with either a serotonergic or noradrenergic antidepressant. No association was seen between the presence of CNV (rare or common), the overall number of CNVs or genomic CNV 'burden' and antidepressant response. Specific CNVs were nominally associated with antidepressant response, including 15q13.3 duplications and exonic NRXN1 deletions. These were associated with poor response to antidepressants. Overall burden of CNVs is unlikely to contribute to personalising antidepressant treatment. Specific CNVs associated with antidepressant treatment require replication and further study to confirm their role in the therapeutic action of antidepressant.

Mindfulness-based cognitive therapy for bipolar disorder: a feasibility trial.

BACKGROUND: The present open study investigates the feasibility of Mindfulness-based cognitive therapy (MBCT) in groups solely composed of bipolar patients of various subtypes. MBCT has been mostly evaluated with remitted unipolar depressed patients and little is known about this treatment in bipolar disorder. METHODS: Bipolar outpatients (type I, II and NOS) were included and evaluated for depressive and hypomanic symptoms, as well as mindfulness skills before and after MBCT. Patients' expectations before the program, perceived benefit after completion and frequency of mindfulness practice were also recorded. RESULTS: Of 23 included patients, 15 attended at least four MBCT sessions. Most participants reported having durably, moderately to very much benefited from the program, although mindfulness practice decreased over time. Whereas no significant increase of mindfulness skills was detected during the trial, change of mindfulness skills was significantly associated with change of depressive symptoms between pre- and post-MBCT assessments. CONCLUSIONS: MBCT is feasible and well perceived among bipolar patients. Larger and randomized controlled studies are required to further evaluate its efficacy, in particular regarding depressive and (hypo)manic relapse prevention. The mediating role of mindfulness on clinical outcome needs further examination and efforts should be provided to enhance the persistence of meditation practice with time.

[Psychiatry]. / Psychiatrie.

Methods of brain stimulation such as transcranial magnetic stimulation, deep brain stimulation and vagus nerve stimulation may have a place in the treatment of depression or severe anxiety disorders resistant to conventional treatments. Several advances in chronotherapy as well as developments in treatment protocols have helped to prolong the antidepressant effect of sleep deprivation. The clinical applications of these methods in depressive episodes and especially in bipolar depression are discussed. The complete remission of a depressive episode and the maintenance of therapeutic benefit beyond the mere reduction of symptoms, have become important issues. The persistence of residual depressive symptoms is associated with increased risk of relapse: their recognition and treatment are illustrated in this article.

Self- and clinician-rated Montgomery-Asberg Depression Rating Scale: evaluation in clinical practice.

BACKGROUND: Time- and cost-effective self-rating scales of depressive symptoms are particularly valuable for frequent use in large-scale effectiveness trials. The aim of the present study was to examine the psychometric properties of the French version of the self-rated Montgomery-Asberg Depression Rating Scale (MADRS-S) and determine whether it might complement the MADRS in monitoring depression severity and change over time in routine clinical practice. METHODS: Sixty-three adult outpatients with a current depressive episode completed the MADRS-S and were interviewed with the MADRS on two occasions, within a 1-month interval. RESULTS: All patients readily accepted the MADRS-S. It showed good to excellent internal consistency (Cronbach's alpha 0.85 at Time 1; 0.94 at Time 2). Its factor structure revealed that a single component explained a large proportion of variability (47.0% at Time 1; 68.8% at Time 2). Concurrent validity of the self- and clinician-rated versions was good (Pearson's correlation coefficients for total scores 0.81 at Time 1; 0.91 at Time 2). The MADRS-S was sensitive to change over the 4-week observation period (correlation of 0.71 between change scores on self- and clinician-rated instruments). LIMITATIONS: Generalizability is restricted to outpatients with moderate to severe depression, and the MADRS-S ability to measure treatment effects needs to be examined. CONCLUSIONS: The present study indicates that the MADRS-S displays favourable psychometric properties and suggests that it might be a valid complement to the MADRS, both in research settings and clinical practice.

Self-rated residual symptoms do not predict 1-year recurrence of depression.

BACKGROUND: Residual depressive symptoms are generally documented as a risk factor for recurrence. In the absence of a specific instrument for the assessment of residual symptoms, a new 25-item Depression Residual Symptom Scale (DRSS) was elaborated and tested for recurrence prediction over a 1-year follow-up. SAMPLING AND METHODS: Fifty-nine patients in remission after a major depressive episode (MDE) were recruited in two centres. They were assessed with the DRSS and the Montgomery-Asberg Depression Rating Scale (MADRS) at inclusion and followed for 1 year according to a seminaturalistic design. The DRSS included specific depressive symptoms and subjective symptoms of vulnerability, lack of return to usual self and premorbid level of functioning. RESULTS: Severity of residual symptoms was not significantly associated with increased risk of recurrence. However, DRSS score was significantly higher among patients with three or more episodes than one to two episodes. Number of previous episodes and treatment interruption were not identified as significant predictors of recurrence. CONCLUSION: The proposed instrument is not predictive of depressive recurrence, but is sensitive to increased perception of vulnerability associated with consecutive episodes. Limitations include small sample size, seminaturalistic design (no standardisation of treatment) and content of the instrument.

Prevalence of pathological gambling in Switzerland after the opening of casinos and the introduction of new preventive legislation.

OBJECTIVE: This survey aimed to evaluate the prevalence of pathological gambling (PG) in the Swiss population in 2005 and the link between PG and alcohol abuse. This replication study made it possible to compare the prevalence rates of PG measured before and after the introduction of casinos and new preventive legislation. METHOD: A total of 2803 telephone interviews were completed using standardized assessment instruments for identifying gamblers (South Oaks Gambling Screen) and alcohol abuse (CAGE). RESULTS: The past-year prevalence rates were 0.8% for problem and 0.5% for PG. No relationship was found between alcohol abuse and gambling behaviour. The past-year prevalence of disordered gambling did not change between 1998 and 2005. CONCLUSION: Despite widespread openings of casinos in Switzerland since 2002, the prevalence estimates of past-year disordered gambling have remained stable. The discussion focuses on different factors (social measures, legal obligations and social adaptational capacities) that may account for the stabilization of prevalence estimates.

A stepwise drug treatment algorithm to obtain complete remission in depression: a Geneva study.

QUESTIONS UNDER STUDY/PRINCIPLES: We describe the proportion of severely depressed outpatients reaching complete remission at the different stages of a drug treatment algorithm. We compare several treatment options for SSRI (selective serotonin reuptake inhibitor) non-responders and test the feasibility of the algorithm in clinical conditions. METHODS: Patients with severe depressive disorders (ICD-10; MADRS > or = 25) admitted to an academic outpatient clinic were enrolled in this algorithm-guided sequential treatment protocol (starting with an SSRI and ending with a tricyclic, lithium, triodothyronine combination). The general principle of the algorithm was to boost the drug therapy in the event of non-response. RESULTS: 135 patients entered the study and 131 were eligible for analysis. From this group, 86 patients dropped out (65.6%), 40 reached complete remission (30.5%) and 5 patients did not reach remission at all (3.8%). In the 117 patients to whom a last observation carried forward approach was applied, the median improvement of the MADRS score was 48.0% (range -20.7%-100%), with 48.7% of patients considered responders, 23.1% partial responders and 28.2% non-responders. Median retention time was 8 weeks (range 2-34). CONCLUSIONS: This algorithm-guided antidepressant treatment was acceptable for clinicians and resulted in an elevated final response rate among study completers. However, the dropout rate was high, mainly due to treatment interruption or non-observance.

Lithium dose prediction based on 24 hours single dose levels: a prospective evaluation.

The authors present the results of the utilization of a pharmacokinetic prediction test for lithium posology. Based on a single point (plasma lithium determination 24 h after a single dose) such a test aims to adapt the posology as soon as the second day of treatment rather than after one week as clinicians must wait for a steady state to be achieved. Built on the previous work of Perry, the test targeted the plasma lithium level at 0.8 +/- 0.1 mmol l(-1). Thirty-one patients took part in the study. There were two drop-out cases and the results were available for 29 patients: among them, 51% had their plasma level in the targeted zone. Although there was no control group, the prediction test often allowed us to use a higher dose than the usual fixed dose whose amount is limited by the risk of overdosing for the slower metabolizers.

The effect of fluoxetine on the pharmacokinetics and safety of risperidone in psychotic patients.

In this open, 30-day trial, the pharmacokinetics, safety and tolerability of a combination therapy of risperidone (4 or 6 mg/day)and fluoxetine (20mg/day from day 6) were evaluated in 11 psychotic inpatients. CYP2D6 genotyping revealed that 3 and 8 patients were poor metabolizers (PMs) and extensive metabolizers (EMs) of debrisoquine, respectively. The mean (+/- SD) AUC of risperidone increased from 83.1 +/- 46.8 ng.h/ml and 398.3 +/- 33.2 ng.h/ml (monotherapy) to 345.1 +/- 158.0 ng.h/ml (p < 0.05) and 514.0 +/- 144.2 ng.h/ml (p < 0.001) when coadministered with fluoxetine in EMs and PMs, respectively. The AUC of the active moiety (risperidone plus 9-hydroxy-risperidone) increased from 470.0 +/- 170.0 ng.h/ml to 663.0 +/- 243.3 ng.h/ml (p < 0.05)and from 576.3 +/- 19.6 ng.h/ml to 788.0 +/- 89.1 ng.h/ml (ns) in EMs and PMs, respectively. In EMs, the AUC of 9-hydroxy-risperidone remained similar (monotherapy vs. combination therapy: 386.8 +/- 153.0 ng.h/ml vs. 317.7 +/- 125.2 ng.h/ml, ns),whereas it increased in PMs (178.3 +/- 23.5 ng.h/ml vs. 274.0 +/- 55.1 ng.h/ml (p < 0.05)). Ten of the 11 patients showed a clinical improvement (reduction of 20% or more in total PANSS score and 70% on the mean MADRS score compared to baseline). The severity and incidence of extrapyramidal symptoms and adverse events did not significantly increase when fluoxetine was added.

Concentrations of the enantiomers of fluoxetine and norfluoxetine after multiple doses of fluoxetine in cytochrome P4502D6 poor and extensive metabolizers.

Plasma concentrations of the enantiomers of fluoxetine (FLX) and norfluoxetine (NFLX) were measured at days 7, 14, and 23 of oral administration of 20 mg of racemic fluoxetine in 11 patients who were comedicated with risperidone. Eight patients were genotyped as being cytochrome P4502D6 extensive metabolizers (EMs) and three as cytochrome P4502D6 poor metabolizers (PMs). No statistically significant differences were calculated between EMs and PMs in the concentrations of (R)-FLX and (R)-NFLX for all days examined (day 23, mean +/- SD for (R)-FLX and (R)-NFLX in EMs, 16 +/- 5 and 29 +/- 20 ng/mL, respectively; in PMs, 16 +/- 1 and 20 +/- 2 ng/mL, respectively). However, concentrations of (S)-FLX and (S)-NFLX were higher and lower, respectively, in PMs as compared with EMs (day 7, p = 0.037 and p = 0.036; day 14, p = 0.014 and p = 0.014; day 23, p = 0.068 and p = 0.038). On day 23, mean (S)-FLX and (S)-NFLX in EMs were (mean +/- SD) 39 +/- 26 and 63 +/- 26 ng/mL, and in PMs they were 88 +/- 7 and 19 +/- 2 ng/mL. This study confirms the results of the single-dose studies showing that CYP2D6 is involved in the demethylation of FLX to NFLX, with a stereoselectivity toward the (S)-enantiomer. The data also clearly show that the CYP2D6 genotype has an important influence on the concentrations of the (S)- but not of the (R)-enantiomer of FLX and NFLX after multiple doses.

Pharmacokinetic drug interaction potential of risperidone with cytochrome p450 isozymes as assessed by the dextromethorphan, the caffeine, and the mephenytoin test.

Two published case reports showed that addition of risperidone (1 and 2 mg/d) to a clozapine treatment resulted in a strong increase of clozapine plasma levels. As clozapine is metabolized by cytochrome P450 isozymes, a study was initiated to assess the in vivo interaction potential of risperidone on various cytochrome P450 isozymes. Eight patients were phenotyped with dextromethorphan (CYP2D6), mephenytoin (CYP2C19), and caffeine (CYP1A2) before and after the introduction of risperidone. Before risperidone, all eight patients were phenotyped as being extensive metabolizers of CYP2D6 and CYP2C19. Risperidone at dosages between 2 and 6 mg/d does not appear to significantly inhibit CYP1A2 and CYP2C19 in vivo (median plasma paraxanthine/caffeine ratios before and after risperidone: 0.65, 0.69; p = 0.89; median urinary (S)/(R) mephenytoin ratios before and after risperidone:0.11, 0.12; p = 0.75). Although dextromethorphan metabolic ratio is significantly increased by risperidone (median urinary dextromethorphan/dextrorphan ratios before and after risperidone: 0.010, 0.018; p = 0.042), risperidone can be considered a weak in vivo CYP2D6 inhibitor, as this increase is modest and none of the eight patients was changed from an extensive to a poor metabolizer. The reported increase of clozapine concentrations by risperidone can therefore not be explained by an inhibition of CYP1A2, CYP2D6, CYP2C19 or by any combination of the three.

Prevalence estimates of pathological gambling in Switzerland.

OBJECTIVE: The purpose of this study was to evaluate the prevalence of pathological gambling in the Swiss adult population before the introduction of new forms of gambling, and the link between pathological gambling and alcohol abuse. METHOD: 2526 telephone interviews were completed using standardized assessment instruments for identifying potential and probable pathological gamblers (SOGS) and alcohol abuse (CAGE). RESULTS: The current prevalence of probable and potential pathological gamblers were estimated to be 0.8% and 2.2%, respectively. The results also show a clear correlation between alcohol abuse and gambling behaviours. CONCLUSION: For the first time estimations are available of the Swiss prevalence rates of pathological gambling. Considering the link between gambling availability and increases in the prevalence of pathological gambling and the correlation between alcohol abuse and pathological gambling, the implications of these results for the prevention and treatment of this debilitating disorder are discussed.

Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a randomized double-blind study. The Risperidone Study Group.

OBJECTIVE: The purpose of this study was to compare the short-term efficacy and safety of risperidone and clozapine in treatment-resistant chronic schizophrenic patients. METHOD: In a controlled double-blind, multicenter study, 86 inpatients with chronic schizophrenia (DSM-III-R), who were resistant to or intolerant of conventional neuroleptics, were randomly assigned to receive risperidone or clozapine for 8 weeks after a 7-day washout period. After a 1-week dose-titration phase, doses were fixed at 6 mg/day of risperidone and 300 mg/day of clozapine for 1 week and then adjusted according to each patient's response. The final mean doses were 6.4 mg/day of risperidone and 291.2 mg/day of clozapine. Treatment efficacy and safety were evaluated with several well-known rating scales. RESULTS: Both risperidone and clozapine significantly reduced the severity of psychotic symptoms (scores on the Positive and Negative Syndrome Scale and the Clinical Global Impression scale) from baseline, with no significant between-group differences. At endpoint, 67% of the risperidone group and 65% of the clozapine group were clinically improved (reduction of 20% or more in total Positive and Negative Syndrome Scale score). Risperidone appeared to have a faster onset of action. In both groups extrapyramidal symptoms and other adverse events were few, and their severity was generally mild. Neither group showed evidence of a relation between drug plasma concentrations and clinical effectiveness. CONCLUSIONS: Risperidone was well tolerated and as effective as medium doses of clozapine in patients with chronic schizophrenia who had been resistant to or intolerant of conventional neuroleptics.

The serotonin paradox: Negative symptoms and SSRI augmentation.

Negative symptoms of schizophrenia are often difficult to treat and may be associated with poorer long-term outcome. As depressive and negative symptoms show some overlap, augmentation of neuroleptics by antidepressants has repeatedly been investigated for efficacy against negative symptoms in schizophrenic patients. Studies on SSRI augmentation of neuroleptic medication reveal some evidence for increased efficacy of conventional antipsychotics in negative symptoms after addition of SSRIs. Since no correlation could be found between improvement of negative symptoms on the one hand and positive, depressive or extrapyramidal motor symptoms on the other, a direct effect seems likely. SSRIs may therefore be an alternative to clozapine, especially in patients for whom there are contraindications against clozapine treatment. As yet, there is no convincing rationalization for the paradox that both serotonergic and antiserotonergic substances, e.g. atypical antipsychotics, may improve negative symptoms.

The association carbamazepine-mianserin in opiate withdrawal: a double blind pilot study versus clonidine.

Our clinic has fortuitously developed the therapeutic use of the association of mianserin (maximum daily dose 90 mg) and carbamazepine (maximum daily dose 400 mg) in opiate withdrawal management. If animal studies have suggested efficacy of mianserin in such indication, no human studies have been performed. To test the efficacy of such an association, a comparison was made to clonidine (maximum daily dose 0.600 mg) in a one week treatment period according to a double blind pilot study design. Thirty-two patients were included (16 in each treatment group). The two treatments did not differ in the intensity of the withdrawal, according to the rate of retention in treatment and symptoms, and the psychic distress which were auto-evaluated every other day with the Opiate Withdrawal Questionnaire and several Visual Analog Scales (VAS). The clonidine group, however, scored significantly higher (P < 0.05) on the VAS rating of the global feeling of satisfaction on the last day. The patients in the mianserin group fortuitously had a moderately lower number of daily heroin intakes but there was no significant correlation between this variable and the global OWQ scores on Days 1, 3, 5 and 7. Given the size of the groups, we cannot conclude that the association carbamazepine-mianserin is as effective as clonidine, but a real effectiveness is probable. A study versus placebo would be necessary to draw more definitive conclusions.