Prevalence and impact of patient suicide in psychiatrists: Results from a national French web-based survey.

BACKGROUND: Patient suicide (PS) is known to be a frequent and challenging occupational hazard for mental health professionals. No study previously explored the prevalence and impact of PS in a large sample of French psychiatrists. METHOD: A national web-based survey was performed between September and December 2019 to assess (a) the prevalence of the exposure to PS, (b) the emotional, traumatic and professional impacts of PS, and (c) the perceived support in the aftermath of PS in French psychiatrists. Participants were contacted through email to answer the online 62-item questionnaire, including a measure of traumatic impact through the Impact of Event Scale-Revised. Emotional and professional impacts and perceived support were assessed through dedicated items. RESULTS: A total of 764 psychiatrists fully completed the survey. Of them, 87.3% reported an exposure to PS and 13.7% reported PTSD symptoms afterward. Guilt, sadness and shock were the most frequent emotions. Among the exposed psychiatrists, 15.1% have temporarily considered changing their career path. The most emotionally distressing PS occurred during their ten first years of practice or during residency. A total of 37.1% of respondents felt unsupported and 50.4% reported that no team meeting had been organized in the aftermath. The feeling of responsibility for the death was strongly associated with negative impacts. CONCLUSION: Our results entail considerations to prevent negative mental health outcomes in psychiatrists after PS. Notably, our results advocate for the implementation of educational programs during psychiatric residency and postvention programs in healthcare settings to effectively help psychiatrists in dealing with PS.

Ensuring mental health care during the SARS-CoV-2 epidemic in France: A narrative review.

OBJECTIVE: The lack of resources and coordination to face the coronavirus epidemic raises concerns for the health of patients with mental disorders in a country where we still have memories of the dramatic experience of famine in psychiatric hospitals during the Second World War. This article aims to propose guidance to ensure mental health care during the SARS-CoV epidemic in France. METHODS: The authors performed a narrative review identifying relevant results in the scientific and medical literature and in local initiatives in France. RESULTS: We identified four types of major vulnerabilities among patients with mental disorders during this pandemic: (1) medical comorbidities that are more frequently found among patients with mental disorders (cardiovascular and pulmonary pathologies, diabetes, obesity, etc.) which are risk factors for severe covid-19 infection; (2) age (the elderly form the population most vulnerable to the coronavirus); (3) cognitive and behavioural disorders, which can hamper compliance with confinement and hygiene measures and finally and (4) psychosocial vulnerability as a result of stigmatization and/or socio-economic difficulties. Furthermore, the mental health healthcare system is more vulnerable than other healthcare systems. Current government plans are poorly suited to psychiatric establishments in a context of major shortages of organizational, material and human resources. In addition, a certain number of structural aspects make the psychiatric institution particularly vulnerable: many beds have been closed, wards have high densities of patients, mental health community facilities are closed, and medical teams are understaffed and poorly trained to face infectious diseases. There are also major issues when referring patients with acute mental disorders to intensive care units. To maintain the continuity of psychiatric care in this pandemic situation, several directions can be considered, in particular with the creation of "COVID+ units". These units are under the dual supervision of a psychiatrist and an internist/infectious disease specialist; all new entrants are placed in quarantine for 14 days; the nursing staff receives specific training, daily medical check-ups and close psychological support. Family visits are prohibited and replaced by videoconference. At the end of hospitalization, in particular for the population of patients in compulsory ambulatory care situations, specific case-management are organized with the possibility of home visits, in order to support patients when they get back home and to help them cope with the experience of confinement, which is liable to induce recurrences of mental disorders. The total or partial closure of community mental health facilities is particularly disturbing for patients, but a regular follow-up is possible with telemedicine and should include the monitoring of suicide risk and psycho-education strategies; developing support platforms could also be very helpful in this context. Private practice psychiatrists also have a crucial role of information towards their patients on confinement and barrier measures, and also on measures to prevent the psychological risks inherent in confinement: maintenance of regular sleep r, physical exercise, social interactions, stress management and coping strategies, prevention of addictions, etc. They should also be trained to prevent, detect and treat early warning symptoms of post-traumatic stress disorder, because their prevalence was high in the regions of China most affected by the pandemic. DISCUSSION: French mental healthcare is now facing a great and urgent need for reorganization and must also prepare in the coming days and weeks to face an epidemic of emotional disorders due to the confinement of the general population.

[Ensuring mental health care during the SARS-CoV-2 epidemic in France: A narrative review]. / Assurer les soins aux patients souffrant de troubles psychiques en France pendant l'épidémie à SARS-CoV-2.

OBJECTIVE: The lack of ressources and coordination to face the epidemic of coronavirus raises concerns for the health of patients with mental disorders in a country where we keep in memory the dramatic experience of famine in psychiatric hospitals during the Second World War. This article aims at proposing guidance to ensure mental health care during the SARS-CoV epidemy in France. METHODS: Authors performed a narrative review identifying relevant results in the scientific and medical literature and local initiatives in France. RESULTS: We identified four types of major vulnerabilities in patients suffering from mental disorders during this pandemic: (1) medical comorbidities that are more frequently found in patients suffering from mental disorders (cardiovascular and pulmonary pathologies, diabetes, obesity, etc.) which represent risk factors for severe infections with Covid-19; (2) age (the elderly constituting the population most vulnerable to coronavirus); (3) cognitive and behavioral troubles which can hamper compliance with confinement and hygiene measures and finally and (4) psychosocial vulnerability due to stigmatization and/or socio-economic difficulties. Furthermore, the mental health healthcare system is more vulnerable than other healthcare systems. Current government plans are poorly adapted to psychiatric establishments in a context of major shortage of organizational, material and human resources. In addition, a certain number of structural aspects make the psychiatric institution particularly vulnerable: many beds are closed, wards have a high density of patients, mental health community facilities are closed, medical teams are understaffed and poorly trained to face infectious diseases. We could also face major issues in referring patients with acute mental disorders to intensive care units. To maintain continuity of psychiatric care in this pandemic situation, several directions can be considered, in particular with the creation of Covid+ units. These units are under the dual supervision of a psychiatrist and of an internist/infectious disease specialist; all new entrants should be placed in quarantine for 14 days; the nurse staff should benefit from specific training, from daily medical check-ups and from close psychological support. Family visits would be prohibited and replaced by videoconference. At the end of hospitalization, in particular for the population of patients in compulsory ambulatory care situations, specific case-management should be organized with the possibility of home visits, in order to support them when they get back home and to help them to cope with the experience of confinement, which is at risk to induce recurrences of mental disorders. The total or partial closure of mental health community facilities is particularly disturbing for patients but a regular follow-up is possible with telemedicine and should include the monitoring of the suicide risk and psychoeducation strategies; developing support platforms could also be very helpful in this context. Private psychiatrists have also a crucial role of information with their patients on confinement and barrier measures, but also on measures to prevent the psychological risks inherent to confinement: maintenance of sleep regularity, physical exercise, social interactions, stress management and coping strategies, prevention of addictions, etc. They should also be trained to prevent, detect and treat early warning symptoms of post-traumatic stress disorder, because their prevalence was high in the regions of China most affected by the pandemic. DISCUSSION: French mental healthcare is now in a great and urgent need for reorganization and must also prepare in the coming days and weeks to face an epidemic of emotional disorders due to the containment of the general population.

Anhedonia predicts poor psychosocial functioning: Results from a large cohort of patients treated for major depressive disorder by general practitioners.

BACKGROUND: Anhedonia is a core symptom of major depression and a key prognostic factor that is often poorly explored in clinical trials of major depressive disorder (MDD). Beyond symptomatic remission, psychosocial functioning also reveals difficulty in achieving remission in patients with MDD. The main objective of this study was to explore the interrelationships between social functioning and anhedonia on a longitudinal basis. METHODS: In total, 1570 outpatients treated for MDD with agomelatine were included. Severity of depression and levels of anhedonia and of psychosocial functioning were assessed at inclusion and at 10-14 weeks, with specific standardized scales (MADRS, QFS, SHAPS, CGI). Multivariate regression and mediation analyses were performed. RESULTS: Using multivariate regression, we showed that improvement of anhedonia was the strongest predictor of improvement in psychosocial functioning (odds ratio=7.3 [4.3-12.1] P<0.0001). In addition, mediation tests confirmed that the association between improvement of depressive symptoms and improvement of social functioning was significantly underpinned by the improvement of anhedonia over time. Finally, we explored the determinants of the dissociation of the response, i.e., the persistence of psychosocial dysfunctioning despite a symptomatic response to antidepressant treatment, which remains a widespread situation in clinical practice. We showed that this dissociation was strongly predicted by persistence of anhedonia. CONCLUSION: Our results suggest that anhedonia is one of the strongest predictors of psychosocial functioning, along with symptomatic remission, and should be carefully assessed by health professionals, in order to optimize pharmacological as well as non-pharmacological management of depression.

[Antidepressant and tolerance: Determinants and management of major side effects]. / Antidépresseurs et tolérance : déterminants et prise en charge des principaux effets indésirables.

Antidepressant therapy aims to reach remission of depressive symptoms while reducing the complications and risks of relapse. Even though they have proven their efficacy, it takes several weeks for antidepressants to demonstrate full effectiveness, and adverse effects occur more quickly or (quicker) which can be a source of poor compliance. This latest aspect often leads to dose reduction and/or change of molecule that have the effect of delaying remission. This review attempts to present, from the pharmacological properties of the major classes of antidepressants (monoamine oxidase inhibitor [MAOI], tricyclic antidepressants [TCA], selective serotonin reuptake inhibitor [SSRI] and serotonin and noradrenaline reuptake inhibitor [SNRI]), to the pharmacological mechanisms involved in adverse effects by focusing on sexual dysfunction, nausea/vomiting, and weight changes and sleep disruption. If the activation of dopamine D1/2 or norepinephrine receptors through the autonomic nervous system controls and facilitates sexual desire, increasing serotoninergic transmission through 5-HT1B/2A/2C receptors activation inhibits this process. The pharmacological properties of drugs inducing nausea/vomiting activate opiate receptors µ, increase dopaminergic and serotoninergic transmission activating the dopamine D2 and serotonin 5-HT3 receptors, respectively. Among the causes responsible for weight gain under antidepressant therapy, monoamine neurotransmission still plays an important role. The blockade of serotonin 5-HT2C or histamine H1 receptors is directly responsible for weight gain. Finally, the activation of 5-HT1A/1B/3/7 serotoninergique receptors modulates wakefulness, raid eyes movement or sleep duration. In conclusion, if antidepressant activity of SERT or MAO inhibitors is an indirect consequence of postsynaptic 5-HT, DA, NA receptor activation, it is also responsible for side effects, causes of poor compliance and hence therapeutic failures. Finally, we need to take into account the key role of the nocebo effect in the occurrence of adverse effects. The next generation of antidepressant would aim to have a rapid efficacy in patients unresponsive or resistant to drugs currently available while improving certain effects of tolerance through an optimization of their psychopharmacological properties leading to a reduction of their side effects.

[Placebo effect: clinical, biological and therapeutical involvements in depression]. / L'effet placebo : implications cliniques, biologiques, et thérapeutiques dans la dépression.

The placebo effect is an excellent model for understanding the mechanisms underlying the interaction between a subjective and complex mental activity (beliefs, expectations, hopes, learning, patient-physician relationship, socio-cultural context .) with different neural and biological systems. Initially, research on the placebo effect has focused on the mechanisms of pain and analgesia. The cognitive processes of conditioning and reward anticipation (hope of a relief) were highlighted. The involvement of different neurobiological pathways has been clearly shown: endogenous opioids, CCK, dopaminergic pathways, endocannabinoids, immunological factors... More recently, the field has open towards new perspectives: depression and anxiety, motor disorders, immune system, endocrine system. Intensive research in the field emerges because of its fundamental implications in neuroscience research but also because of the ethical, clinical and therapeutical issues. Moreover, the placebo effect is considered as a main methodological mean issue in clinical trials that allows the demonstration of the efficacy and tolerance of new drugs. In the field of psychiatry, depression is a placebo highly-sensitive disorder: placebo response rates in clinical trials are of the order of 30 % to 40 %. The identification of biological markers of placebo response, such as neuroimaging and quantitative electroencephalography may lead to develop more efficient models in clinical research.

[Anhedonia in depression]. / L'anhédonie dans la dépression.

Anhedonia, or markedly diminished interest or pleasure, is a hallmark symptom of major depression, schizophrenia, and other neuropsychiatric disorders. The term "anhedonia" was introduced by the French psychologist Ribot in 1896 to describe the counterpart to analgesia in his patients, for which "it was impossible to find the least pleasure". Over the last decades, the clinical definition of anhedonia has remained relatively unchanged, but recently, behavioral neurosciences have significantly changed our knowledge of reward-related processes. Now, the construct of anhedonia reflects deficits in hedonic capacity, and is closely linked to the processes of reward valuation, decision-making, anticipation, and motivation. The neural circuits underlying these reward-related mechanisms include essentially the ventral striatum and prefrontal cortical regions. Here, we review the clinical concepts, neural bases and psychopharmacological data related to the deficits of hedonia in depression. Understanding anhedonia will facilitate diagnosis and treatment management.

[Current status and management of patients with bipolar disorder in France: the MONTRA survey]. / Caractéristiques et modalités de prise en charge des patients présentant un trouble bipolaire en France : enquête MONTRA.

OBJECTIVES: The objectives were to assess the characteristics of patients with bipolar disorder (BD) and to evaluate the prescribing practices. METHODS: MONTRA is a quantitative survey conducted between December 2010 and February 2011. Data were extracted by the psychiatrists from the medical files of BD patients seen on four consecutive days of consulting. RESULTS: Four hundred and thirty-nine psychiatrists included 2529 patients (inpatients, n=319; outpatients from mental clinics, n=1090; outpatients consulting in private practice, n=1020). In the total patient population (mean age: 47 years; women, 58%), BD was distributed as follows: BD type I, 56%; BD type II, 40%; other types of BD, 4%; rapid cyclers, 10%. The prevalence of psychiatric comorbidities was high (anxiety disorders, 48%; abuse and dependence on toxic substances, 17 and 10% respectively), 36% of the patients had a history of suicide attempt and the risk of suicide, when assessed, was 6%. In about half the patients (48%), the polarity of the initial bipolar episode was of the depressive type (versus 39% for the manic/hypomanic type). Outpatients were globally independent and did not require assistance in the management of their disease or its treatment whereas the social and professional lives of inpatients were negatively affected by their condition. Based on the psychiatrist's declarations, 39 to 50% of the outpatients were symptom-free, 36 to 40% were in the intercurrent phase with residual symptoms, 11 to 17% presented either a manic or depressive acute BP episode, and 3 to 4% were in a mixed state; among inpatients, 52% presented an acute episode either manic or depressive, 38% were in the intercurrent phase and 9% were in a mixed state. In the symptomatic patients from the total population (61%), the most prevalent symptoms were depressive and corresponded to acute symptoms (patients with a depressive episode, 14%) or residual symptoms (patients in the intercurrent phase, 27%). The predominant depressive polarity was observed in both hospitalized and outpatients. The pharmacological treatment of BD included polytherapy in 73% of the patients. In the manic episodes (n=126), the patients were treated with a Mood Stabilizer (MS, 56%) or an atypical antipsychotic (AAP, 52%) in association. In the depressive episodes (n=342), the patients received an antidepressant drug associated with a MS or an AAP (70%). In symptom-free or symptomatic intercurrent periods (n=1943), the patients were treated with a MS (49-58%) or an AAP (37-49%), in association. CONCLUSION: BD patients evaluated in our survey were in majority diagnosed with BD type I, associated with considerable comorbidity. In the symptomatic patients, the most prevalent symptoms, either acute or residual, were of the depressive type. In the majority of the patients, whatever the clinical status, polytherapy was prescribed for the BD.

[Switch antidepressants: when? How? Why?]. / Changer d'antidépresseur: quand, comment, pourquoi?

BACKGROUND: The switch is generally admitted as one of the available options in the event of non-response to an antidepressant treatment, despite uncertainties about its implementation in current practice: what time window before switching? Is it necessary to proceed with a direct or with a gradual switch? Is it necessary to change for a different pharmacotherapeutic class? How to minimize interaction risks? If a treatment fails because of poor compliance due to intolerance, it is possible to remain within the same therapeutic class and select another treatment with a more favourable safety profile for the patient. In the remaining non-response cases, changing therapeutic class is the more logical course and may be slightly more efficacious than the switch within the same class. LITERATURE FINDINGS: A review of the literature shows that it is recommended to wait 4 to 8 weeks before changing treatment if the response is insufficient. However, an early switch is possible in case of non-response at 2-4 weeks. Direct switch is possible and well tolerated in most instances, except for situations implicating a monoamine oxidase inhibitor (MAOI) or a tricyclic antidepressant. Direct switch is easy and, therefore, compliance issues associated with the complexity of treatment tapering can be avoided. DISCUSSION: From the pharmacologic standpoint, the lack of effect on the cytochrome P450 isoenzymes, the absence of active metabolites, and the poor binding to plasmatic proteins are all important elements to be identified in order to minimize the risk of interaction. Current research on physiopathology of depression and mechanisms of action of drugs both support expectations for new perspectives for patients' care. The switch increases the chances for a treatment to be successful with response rates of 20 to 70% in the open-labelled clinical studies. It also has the advantage of minimizing adverse effects compared to polytherapy. CONCLUSION: A great number of depressed patients require more than one treatment protocol to obtain or maintain a response. Switching is part of the therapeutic pattern of depression and is recommended by the French authorities. The available data allow the specification of switch modalities as function of the evolution of the initial treatment.

[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.

[Events of life and links with severe depression at different ages]. / Evénements de vie et sévérité de la dépression aux différents âges de la vie.

Major depression is a common, severe, chronic, and often life-threatening illness. There is a growing body of evidence that, far from being a disease with purely psychological manifestations, major depression is a systemic disease with deleterious effects on multiple organ systems. Stressful life events have a substantial causal association with depression, and there is now compelling evidence that even early life stress constitutes a major risk factor for the subsequent development of depression. This review will focus on the association between severity of depression and diachronic vulnerability across the life-span, in terms of events of life, stress, and hormonal modulation, with a special focus on depression in young adults, women during postpartum and in depression in ederly people. Given the high prevalence of depressive disorders, the significant burden and the severity of disease in adolescents and young adults experiencing their first episode, they represent a group at high risk of relapse, recurrence, comorbidity and suicide to whom early intervention and prevention efforts should be targeted. Females exhibit different stress sensitivities than males which might contribute to their increased vulnerability for depression and the disease exhibit a prevalence among women which is 2-3x higher than in men. The postpartum period is considered the time of greatest risk for women to develop major depression and postpartum depression affects approximately 15% of women. In old age, depression mainly affects those with chronic medical illness, severe disability or mental decline. Depression in elderly worsens the outcomes of many medical illness and increases mortality. Environmental factors, such as isolation, caregiving and bereavement, contribute to further increase susceptibility to depression or triggering depression in already vulnerable elderly people. Suitable treatment of depression in elderly reduces the symptoms, prevents suicidal ideation, improves cognitive and functional status in order to improve the recovery of a good quality of life, as well as the mortality risk.

[Antidepressants and their onset of action: a major clinical, methodological and pronostical issue]. / Délai d'action des antidépresseurs: une problématique clinique, méthodologique et pronostique fondamentale dans le traitement de la dépression majeure.

Although antidepressant medications are effective in about 50-70% of patients with major depressive disorder (MDD), they have a delayed onset of therapeutic effect. This latency is one of the current major limitations of these medications, in that it prolongs the impairments associated with depression, leaves patients vulnerable to an increased risk of suicide, increases the likelihood that a patient will prematurely discontinue therapy, and increases medical costs associated with severe depression. It is becoming increasingly clear that differences may exist between antidepressants and some evidence suggests that some antidepressant agents may begin to work faster than others. Escitalopram, duloxetine, venlafaxine, and mirtazapine have shown statistically significant differences in some measures of antidepressant action within the first two weeks of treatment, both in placebo-controlled trials and in head-to-head comparisons with other antidepressants. Results of the current review should be regarded with certain important limitations in mind. First, differences in times to onset of antidepressant response have been shown in clinical efficacy studies not specifically designed to detect differences in onset of action (post-hoc analysis). Second, results observed in 'pure' clinical trial samples should not be directly generalized to the real clinical practice since it has been proven in clinical settings that less than one in seven depressed patients would be eligible to participate in antidepressant clinical trials. For instance, depressed patients who are suicidal or who score higher than 30 on the 17-item HAM-D are excluded from antidepressant clinical trials. Third, caution is warranted when applying these findings to clinical populations with more severe depressions with respect to the fact that among clinical populations, severity of depression coincides with comorbidity, including such psychiatric disorders as anxiety disorders, personality disorders and substance abuse. In addition, the magnitudes of the size-effects of antidepressants versus placebo are clearly higher in severely depressed patients. Fourth, specific items on depression rating scales may induce greater antidepressant/placebo differences. For instance, the 17-item HAM-D contains three questions pertaining to sleep. It questions the fact that earlier onset may appear not only via a specific antidepressant effect but also via a non-specific effect on anxiety, sleep, physical pain or other accessory symptoms. Thus, current data do not clearly support claims that one drug reduces the symptoms of depression faster than another, though the existing literature suggests that escitalopram displays some superiority in terms of rapidity of action. Given the potential benefits of early-acting antidepressant treatments, the possibility of superior speed of onset of escitalopram presented here merits further study in adequately designed, prospective clinical trials. A definitive demonstration of early onset of action awaits the results of appropriately designed and powered clinical studies, which may include (1) a prospective definition of early onset of action, (2) more focused assessments of core emotional symptoms and cognitive deficits of depression by using specific and sensitive tools, (3) a data-analytic approach capable of capturing the dynamic nature of symptomatic change (for example, survival analysis), and (4) strategies to minimize biases and heterogeneity of response.

New evidences of gene and environment interactions affecting prenatal neurodevelopment in schizophrenia-spectrum disorders: a family dermatoglyphic study.

BACKGROUND: Several studies have reported an increase of dermatoglyphic anomalies in schizophrenic patients compared to controls. However, the recognition of specific dermatoglyphic variables related to this disorder and their genetic and/or environmental component are still controversial. METHOD: We conducted a dermatoglyphic analysis in a new sample of 617 individuals: 205 patients with schizophrenia-spectrum disorders, 224 healthy first degree relatives and 188 healthy controls. The dermatoglyphic variables studied were: the total a-b ridge count (TABRC) and its fluctuating asymmetry (FAABRC), and the presence of ridge dissociations (RD) and abnormal palmar flexion creases (APFC). RESULTS: Patients, relatives and controls did not differ in TABRC. However, within the patients group those with a low birth weight or absence of psychiatric family history showed lower TABRC than the others. The frequency of ectodermic derivates abnormalities (RD and/or APFC) appeared to be higher in patients and relatives than in controls, while first degree relatives did not differ from patients. Males showed an increased rate of ectodermic derivates abnormalities compared to females in all groups and male patients also presented higher FAABRC than female patients. CONCLUSIONS: Our results suggest a different relative weight of genetic and environmental factors on each dermatoglyphic variable analyzed: i) TABRC may be a sensitive marker to environmental factors in schizophrenia, ii) ectodermal derivates abnormalities appear to be influenced by genetic risk factors, which could be involved both in the disrupted development of ectodermic derivates like dermatoglyphics and central nervous system and in the vulnerability for schizophrenia.

[Fluoxetine: an update of its use in major depressive disorder in adults]. / Episode dépressif majeur: dix ans d'expérience thérapeutique avec la fluoxétine.

The selective serotonin reuptake inhibitors (SSRIs) have emerged as a major therapeutic advance in psychiatry. They have emphasized the pathophysiological role of serotonin (5-HT) in affective disorders. Indeed, SSRIs were developed for inhibition of the neuronal uptake for serotonin (5-HT), a property shared with the TCAs (tricyclic anti-depressants), but without affecting the other various central neuroreceptors (ie, histamine, acetylcholine and adrenergic receptors) that are responsible for many of the safety and tolerability problems with TCAs. In this way, fluoxetine and other SSRIs represent a major advance over tricyclics, because of their lower toxicity. While the position of fluoxetine relative to other selective serotoninergic antidepressants requires further investigation, fluoxetine has a more favorable tolerability profile for a similar efficacy in comparison to tricyclic antidepressants. The pharmacokinetic and pharmacodynamic properties of fluoxetine are well described. After oral administration, fluoxetine is almost completely absorbed. Due to hepatic first-pass metabolism, the oral bioavailability is < 90%. Fluoxetine has a half-life of 2-7 days, whereas the half-life of norfluoxetine ranges between 4 and 15 days. This long half-life of fluoxetine may be advantageous when the patient omits a dose since drug concentrations decrease slightly. On the other hand, in the case of fluoxetine non-response, long washout periods are necessary before switching the patient to a TCA or a MAO inhibitor to avoid drug interactions or the development of a 5-HT syndrome. As a class, SSRIs are considerably more selective in comparison to TCAs in terms of their central nervous system mechanisms, but differ in other clinically relevant aspects. This action affects several specific 5-HT receptors, which, in turn, effects a multitude of neural systems and signalization pathways. However, despite the facilitating serotoninergic neurotransmission, the direct mechanism by which a SSRI exerts its anti-depressant activity remains uncertain. The therapeutic response in major depression for SSRIs (ie 15-20 days) maybe due to a progressive desensitization of somatodendritic 5-HT autoreceptors in the midbrain raphe nucleus. On the other hand, it has also been postulated that 5-HT is a modulator of several neurophysiological pathways, including dopamine, noradrenaline, but also neurotrophic factors, intra-cytoplasmic phosphorylations and nuclear genes expression. Therapeutic activity of SSRIs may finally results in a complex modulation and homeostasis between monoaminergic neurotransmisson and neuronal plasticity. In term of health-care, the introduction of fluoxetine and other SSRIs in the 1980s has radically changed the treatment of depressive disorder worldwide and they have emerged as the first line of treatment for depressive disorders. The efficacy of fluoxetine is now well established in the treatment of major depressive disorder. Indeed, this efficacy has been assessed in numerous clinical controlled trials involving patients with major depressive disorders. Meta-analysis were carried out and confirmed that fluoxetine was as effective as the tricyclic antidepressants, and appeared more effective than placebo in improving the symptoms of depression. However, there is no scientific evidence to suggest that any one SSRI is more effective than another, but not all patients respond to the same agent. Looking to the future, we need further comparative studies of the SSRIs with the next generation of antidepressants such as 5-HT noradrenaline reuptake inhibitors (SNRIs, Venlafaxine). Actually, it is interesting to note that, whereas the emphasis with the SSRIs has been on their selectivity, recent developments have tended to move towards less selective agents, and now to other neurobiological pathways (ie neurotrophic factors). Finally, fluoxetine, in common with other SSRIs, remains today a first-line treatment option for major depressive disorder.

Maternal transmission disequilibrium of the glutamate receptor GRIK2 in schizophrenia.

Schizophrenia is characterized by thought disorders, hallucinations and delusions. Genetic studies have shown a high linkage at chromosome 6q16-21. Among the genes located in this region is the glutamate receptor ionotropic kainate 2 gene (GRIK2 or GLUR6), a functional candidate for susceptibility to schizophrenia. In this study, transmission of GRIK2 was evaluated in 356 schizophrenic patients from three different clinical centers. Whereas paternal transmission shows equilibrium, we observed maternal transmission disequilibrium of GRIK2 in the largest population (p=0.03), which was still significant when all populations were added (p=0.05). These results are similar to the maternal GRIK2 transmission disequilibrium previously reported for autism, and support the presence of a susceptibility gene for schizophrenia at 6q16.

[Neurodevelopmental hypothesis in schizophrenia]. / L'hypothèse neurodéveloppementale dans la schizophrénie.

The hypothesis for a neurodevelopmental basis to the underlying physiopathological disorder leading to schizophrenia has been proposed by many investigators for more than two decades. This hypothesis is supported by -several lines of evidence. Pregnancy and delivery complications, particularly those with known or presumed impact on fetal neurologic development, result in increased risk for psychotic disorders. Other possible etiologic candidates include viral infections. Minor physical anomalies, manifesting as slight anatomical defects of the head, hair, eyes, mouth, hands and feet, as dematoglyphic fluctuating asymmetries, are due to some injury occurring during the first or second trimester of fetal life, and are more common among patients with schizophrenia and in their unaffected siblings than in the general population. But a major Issue in a such neurodevelopmental model theory is the delayed onset of the schizophrenic disorder. Although early signs and prodromal symptoms can be defined retrospectively in patients who have developed schizophrenia, they do have to be confirmed as early predictors in prospective and longitudinal studies. Abnormalities in brain development and maturation seem to begin prenatally, but may continue throughout childhood and the observed changes during these periods must have -consequences for the neuronal circuitry and connectivity. Advances in brain imaging have now led to the identification of a great number of brain abnormalities in schizophrenia. The most consistently replicated structural anomaly present in the brains of patients with chronic schizophrenia is ventricular enlargement. These findings also include medial temporal lobe structures (which include the amygdala, hippocampus, and parahippocampal gyrus), and neocortical temporal lobe regions (superior temporal gyrus). There is also some evidence for frontal lobe abnormalities, particularly prefrontal gray matter and orbitofrontal regions. Similarly, there are findings for parietal lobe abnormalities (particularly of the inferior parietal lobule which includes both supramarginal and angular gyri) and subcortical abnormalities (basal ganglia, corpus callosum, and thalamus) but more equivocal evidence for cerebellar abnormalities. However, it is possible that the brain structural abnormalities observed in schizophrenia are not only due to neurodevelopmental anomalies, but also to an alteration in cortical plasticity and maturation processes that occurs over the long course of the disease. The genetic predisposition for schizophrenia has been confirmed in many studies. It is utterly disappointing that molecular genetic approaches have so far not yielded conclusive evidence for vulnerability or protection genes in schizophrenia. Future studies will likely benefit from: 1) studying more homogeneous patient groups, 2) studying high risk populations such as biological relatives of patients with schizophrenia, 3) using longitudinal and prospective methodological design in order to confirm the predictive validity of neurodevelopmental clues found in patients with schizophrenia, 4) applying newer strategies such as composite phenotypes of developmental origin, in combination with new genetic methods.

Neurological and morphological anomalies and the genetic liability to schizophrenia: a composite phenotype.

BACKGROUND: Neurological soft signs (NSS) and minor physical anomalies (MPA) are frequent in patients with schizophrenia and their biological relatives. We examined whether the NSS and MPA are related to the genetic loading in schizophrenia. METHODS: Patients with schizophrenia (DSM-IV) (n=61), nonpsychotic parents of these patients (n=76) and healthy comparison subjects (n=44) took part in the study. Parents were further classified as "presumed carriers" of the genetic loading (n=26) if they had a second relative with schizophrenia in their ascendants and/or collaterals (first or second degree) or as "presumed noncarriers" (n=50). NSS and MPA were compared in these groups. RESULTS: A multivariate analysis indicated that total NSS and MPA scores, adjusted for age and gender, were significantly related to group status. Univariate tests showed higher scores in motor coordination and integration subscores (p=0.005 and 0.008, respectively) in presumed carriers than in presumed noncarriers. In addition, a discriminant function analysis based on total NSS and MPA scores correctly classified 71% of nonpsychotic parents in presumed carriers or presumed noncarriers. CONCLUSIONS: Neurological impairments and slight morphological anomalies seem to be associated with the genetic risk for schizophrenia, even when the disease itself is absent. Their presence might be a valuable composite intermediate phenotype for genetic studies.