Emmanuelle Weiller

Form, frequency and burden of sleep problems in general health care: a report from the WHO Collaborative Study on Psychological Problems in General Health Care

Summary The WHO Collaborative Study on Psychological Problems in General Health Care examined the frequency, form, course and outcome of psychological problems in general health care settings. A total of 25,916 general health care attenders at 15 sites in 14 countries were screened using the 12-item General Health Questionnaire (GHQ-12). Of those screened, 5,438 were assessed in detail using a Primary Health Care version of the Composite International Diagnostic Interview (CID1-PHC) in conjunction with the Brief Disability Questionnaire, the Social Disability Schedules, a self rated overall health status form and the 28-item General Health Questionnaire. The analysis has shown that sleep problems were common at all sites with: 26.8% of all patients having some form of sleep problem and 15% of the patients examined had trouble falling or staying asleep. Of those with sleep problems, 51.5% had a well-defined International Classification of Diseases 10th Revision (ICD-10) mental disorder (such as depression, anxiety, somatoform disorders or alcohol problems) and 48.5% of those with sleep problems for at least two weeks or more did not fulfil the criteria for any well defined ICD-10 diagnosis. Persons with sleep problems reported a degree of disability in the performance of their daily activities and social roles even when they had no symptoms of psychological disorders. When such symptoms were present the disability was significantly increased.

Comorbidities in social phobia

In a sample of 2096 consecutive primary care patients recruited in the Paris region, social phobia was a highly prevalent disorder (5.1% ). The most frequent comorbid condition was depressive episode, which affected 70% of patients with social phobia of early onset (at less than 15 years of age), while the highest association was with agoraphobia (odds ratio 10.4). No association was observed with generalized anxiety disorder. Alcohol abuse and suicidal ideation and attempts are also commonly associated with social phobia. However, when patients presented to a general practitioner with comorbid depression present, 76% were recognized as cases (though only 11% were identified as having an anxiety disorder), but in the absence of depression, only 46% were identified as cases. Given the degree of disability caused by social phobia, there is an obvious need for improved education of both doctors and patients regarding its status as a disorder, and its treatability.

Escitalopram Therapy for Major Depression and Anxiety Disorders

Background: Randomized controlled clinical trials have demonstrated that escitalopram is efficacious in a range of mood and anxiety disorders, but the individual trials are insufficiently large to allow a full exploration of its tolerability. Objective: To assess (he tolerability and safety of escitalopram through analysis of all randomized controlled clinical trials in major depressive disorder and anxiety disorders. Methods: Analyses of tolerability were based on data from all available randomized, double-blind, controlled studies completed by December 2006 in which escitalopram was compared with placebo or active compounds (citalopram, fluoxetine, paroxetine, sertraline, venlafaxine). Adverse events (AEs) that occurred more frequently with escitalopram than with placebo were listed, and tolerability and safety were evaluated. Results: Nausea was the only AE with an incidence greater than or equal to 10% and 5 percentage points greater than with placebo during short-term treatment. In general, AEs were mild to moderate in severity. AEs related to sexual dysfunction were similarly frequent with escitalopram and Citalopram, but were higher with paroxetine. No suicide occurred among escitalopram-treated patients, and there were no significant differences between escitalopram and placebo in incidence of suicidal behavior, measured by self-harm and suicidal thoughts. The 8 week withdrawal rate due to AEs was higher with escitalopram than with placebo (7.3% vs 2.8%; p < 0,001) but lower than with paroxetine (6.6% vs 9.0%; p < 0.01) or venlafaxine (6.1% vs 13.2%; p < 0.01) (Fishers Exact test, 2 tailed). Compared with paroxetine, escitalopram resulted in significantly fewer discontinuation symptoms (average increase in Discontinuation Emergent Signs and Symptoms Scale of 1.6 vs 3.9; p < 0.01). There were no clinically relevant changes in clinical laboratory values in patients treated with escitalopram. Mean weight change after 6 months of treatment with escitalopram (0.58 ± 2.63 kg) was similar to that with placebo (0.15 ± 2.33 kg). The incidence of cardiovascular events was similar to that with placebo. The risk of AEs was no higher in special patient populations, such as the elderly (≥65 y of age) or those with hepatic dysfunction. Conclusions: Based on data from randomized controlled trials involving more than 4000 escitalopram-treated patients, escitalopram (10–20 mg/day) is safe and well tolerated in short- and long-term treatment.

Effect of asenapine on manic and depressive symptoms in bipolar I patients with mixed episodes: Results from post hoc analyses

BACKGROUND The efficacy of agents useful for mania is largely unproven in patients with mixed episodes. METHODS The efficacy of asenapine in the treatment of mixed episodes was assessed using post hoc analyses on pooled data from two identically designed 3-week, randomized, double-blind, flexible dose, placebo- and olanzapine-controlled trials and their 9-week, double-blind olanzapine-controlled extension study. Efficacy was measured by changes on Young Mania Rating Scale (YMRS) and Montgomery-Åsberg Depression Rating Scale (MADRS) total scores, and was analysed through analysis of covariance on observed cases of the intent-to-treat dataset. RESULTS In the intent-to-treat population, 295 patients had a DSM-IV-TR mixed episode (placebo: 66; olanzapine: 122; asenapine: 107) in the 3-week trials. Of these, 102 patients (olanzapine: 56; asenapine: 46) entered the 9-week extension study. At week 3, decreases in YMRS and MADRS total scores, were significantly (p<0.01) greater with asenapine (YMRS: -15.0; MADRS: -8.2) versus placebo (YMRS: -11.5; MADRS: -4.5); olanzapine did not separate from placebo (YMRS: -13.3; MADRS: -6.5). At week 12, further decreases in YMRS and MADRS total scores were observed with asenapine (YMRS: -22.4; MADRS: -11.9); non-statistically different from olanzapine (YMRS: -20.2; MADRS: -7.9). LIMITATIONS Results are from post hoc analyses of trials that were not designed to specifically evaluate mixed episodes. CONCLUSIONS These exploratory analyses provide supportive evidence for the efficacy of asenapine in treating the associated symptoms of mania and depression in bipolar I patients with mixed episodes.

DSM-5 mixed specifier for manic episodes: Evaluating the effect of depressive features on severity and treatment outcome using asenapine clinical trial data

BACKGROUND To describe the frequency of mixed specifier as proposed in DSM-5 in bipolar I patients with manic episodes, and to evaluate the effect of mixed specifier on symptom severity and treatment outcome. METHODS This post-hoc analysis used proxies for DSM-5 mixed features specifier by using MADRS or PANSS items. RESULTS Of the 960 patients analysed, 34%, 18% and 4.3% of patients, respectively, had ≥3 depressive features with mild (score ≥1 for MADRS items and ≥2 for PANSS item), moderate (score ≥2 MADRS, ≥3 PANSS) and severe (score ≥3 MADRS, ≥4 PANSS) symptoms. In patients with ≥3 depressive features and independent of treatment: MADRS remission (score ≤12) rate decreased with increasing severity (61-43%) and YMRS remission (score ≤12) was similar for mild and moderate patients (36-37%), but higher for severe (54%). In asenapine-treated patients, the MADRS remission rate was stable regardless of baseline depressive symptom severity (range 64-67%), whereas remission decreased with increasing severity with olanzapine (63-38%) and placebo (49-25%). Reduction in YMRS was significantly greater for asenapine compared with placebo at day 2 across the 3 severity cut-offs and continued to decrease throughout the treatment period. The difference between olanzapine and placebo was statistically significant in mild and moderate patients. LIMITATIONS Results are from post-hoc analyses. CONCLUSIONS These analyses support the validity of proposed DSM-5 criteria. They confirm that depressive features are frequent in bipolar patients with manic episodes. With increasing baseline severity of depressive features, treatment outcome was poorer with olanzapine and placebo, but remained stable with asenapine.

Social phobia in primary care: level of recognition and drug use.

A study was conducted in Paris among primary care physicians as part of a World Health Organization study entitled Psychological Problems in General Health Care. Though social phobia is associated with significant impairment and drug use, the level of problem recognition by general practitioners was low. Social phobia (n=38) was identified as a psychological case in 53% of the patients in whom social phobia was not comorbid with depression, and in 66% when comorbid with depression. This low level of recognition was comparable to that observed for depression where only 66% of the depressed patients (n=121) were recognized as psychological cases. Psychotropic drug use was high: 61% of patients with social phobia had taken at least one psychotropic drug in the last month, compared to only 32% of those without social phobia. This difference was explained by a significant difference in the use of anxiolytics (45.4 versus 12.1%). The use of psychotropic drugs was twice as frequent in patients with social phobia who were depressed than in those not depressed. The results of this study emphasize the crucial need for primary care physician training in the recognition and treatment of mental disorders.

Baseline anxiety effect on outcome of SSRI treatment in patients with severe depression: escitalopram vs paroxetine

Abstract Objective: To investigate if treatment outcome for severely depressed patients depends on their baseline level of anxiety. Research design and methods: Patients with a primary diagnosis of severe major depressive disorder (n = 459) were randomised to 24 weeks of double-blind treatment with escitalopram (20 mg) or paroxetine (40 mg). Post hoc analyses of efficacy in patients with a baseline HAM-A total score ≤20 (n = 171) or >20 (n = 280) were based on analysis of covariance (ANCOVA) (ITT, LOCF). Results: At week 24, the mean change from baseline in MADRS total scores was −24.2 for escitalopram-treated patients (n = 141) and −21.5 for paroxetine-treated patients (n = 139) (p < 0.05) in high baseline anxiety patients and the mean change from baseline in HAM-A total score was −17.4 (escitalopram) and −15.1 (paroxetine) (p < 0.05). When examining the proportion of complete remitters (CGI-S = 1) after 24 weeks of treatment, there was an increasing treatment difference as a function of baseline HAM-A total score in favour of escitalopram (ITT, LOCF). There was no treatment difference in the low baseline anxiety group. Significantly more patients (p < 0.01) withdrew from the paroxetine group (31%) than from the escitalopram group (17%), partly as the result of significantly more withdrawals due to AEs (p < 0.05). Incidence of AEs and withdrawals were not related to baseline anxiety and there were no significant differences in the incidence of individual AEs with escitalopram compared to paroxetine. Limitations: The post hoc nature of these analyses, the absence of placebo control group, and the requirement that patients should be suffering from severe depression, limit the generalisability of the results. Conclusion: Patients with severe depression together with comorbid anxiety symptoms responded significantly better to treatment with escitalopram 20 mg compared with paroxetine 40 mg. Contrary to paroxetine, escitalopram maintained its efficacy with increasing baseline anxiety levels.

Recurrent Brief Depression: Clinical and Epidemiological Issues

Initially based on empirical observations, the concept of RBD has led to operational diagnostic criteria allowing further studies in various and large populations. In line with the hypothesis of a continuum from normal sad mood to major depression, the spectrum of affective disorders is thus probably more in agreement with everyday clinical practice. Moreover, recurrent and so-called subthreshold conditions have been concurrently investigated in other fields of psychopathology. Nevertheless, many methodological problems and clinical implications of RBD still require further research. The question of a precise definition of the disorder, even if a consensus seems to be obtained about some key points, remains partially to be addressed, for example, concerning the problem of the reliability of assessment. The possibility of a seasonality of the episodes needs further investigations, as do the relationships between RBD and personality disorders such as borderline personality disorder. Finally, the important question of prophylactic treatment of RBD remains unsolved, as antidepressants have failed to demonstrate any efficacy and some neuroleptics have been proposed in particular conditions. Angsts prediction that clinical relevance, impairment, distress and public health impact of affective disorders could be related not only to the duration of an episode but also to the recurrence of episodes, possibly referring to a kindling model, has therefore been confirmed. His major contribution has been to underline, in various forms of affective disorders, the importance of conducting longitudinal clinical as well as epidemiologic studies to refine our psychopathological knowledge.

Efficacy and Safety of Brexpiprazole (OPC-34712) as Maintenance Treatment in Adults with Schizophrenia: a Randomized, Double-Blind, Placebo-Controlled Study

Abstract Background: Brexpiprazole has previously demonstrated efficacy in acute schizophrenia trials. The objective of this trial was to assess the efficacy, safety, and tolerability of maintenance treatment with brexpiprazole in adults with schizophrenia. Methods: Patients with an acute exacerbation of psychotic symptoms were converted to brexpiprazole (1–4mg/d) over 1 to 4 weeks and entered a single-blind stabilization phase. Those patients who met stability criteria for 12 weeks were randomized 1:1 to double-blind maintenance treatment with either brexpiprazole (at their stabilization dose) or placebo for up to 52 weeks. The primary efficacy endpoint was the time from randomization to impending relapse. Safety and tolerability were also assessed. Results: A total of 524 patients were enrolled, 202 of whom were stabilized on brexpiprazole and randomized to brexpiprazole (n=97) or placebo (n=105). Efficacy was demonstrated at a prespecified interim analysis (conducted after 45 events), and so the trial was terminated early. The final analysis showed that time to impending relapse was statistically significantly delayed with brexpiprazole treatment compared with placebo (P<.0001, log-rank test). The hazard ratio for the final analysis was 0.292 (95% confidence interval: 0.156, 0.548); mean dose at last visit, 3.6mg. The proportion of patients meeting the criteria for impending relapse was 13.5% with brexpiprazole and 38.5% with placebo (P<.0001). During the maintenance phase, the incidence of adverse events was comparable to placebo. Conclusions: or patients with schizophrenia already stabilized on brexpiprazole, maintenance treatment with brexpiprazole was efficacious, with a favorable safety profile.

Are old-old patients with major depression more likely to relapse than young-old patients during continuation treatment with escitalopram?

BackgroundEscitalopram has shown efficacy and tolerability in the prevention of relapse in elderly patients with major depressive disorder (MDD). This post-hoc analysis compared time to relapse for young-old patients (n = 197) to that for old-old patients (n = 108).MethodRelapse prevention: after 12-weeks open-label treatment, remitters (MADRS ≤12) were randomised to double-blind treatment with escitalopram or placebo and followed over 24-weeks. Patients were outpatients with MDD from 46 European centers aged ≥75 years (old-old) or 65-74 years of age (young-old), treated with escitalopram 10-20mg/day. Efficacy was assessed using the Montgomery Åsberg Depression Rating Scale (MADRS).ResultsAfter open-label escitalopram treatment, a similar proportion of young-old patients (78%) and old-old patients (72%) achieved remission. In the analysis of time to relapse based on the Cox model (proportional hazards regression), with treatment and age group as covariates, the hazard ratio was 4.4 for placebo versus escitalopram (χ2-test, df = 1, χ2= 22.5, p < 0.001), whereas the effect of age was not significant, with a hazard ratio of 1.2 for old-old versus young-old (χ2-test, df = 1, χ2 = 0.41, p = 0.520). Escitalopram was well tolerated in both age groups with adverse events reported by 53.1% of young-old patients and 58.3% of old-old patients. There was no significant difference in withdrawal rates due to AEs between age groups (χ2-test, χ2 = 1.669, df = 1, p = 0.196).ConclusionsYoung-old and old-old patients with MDD had comparable rates of remission after open-label escitalopram, and both age groups had much lower rates of relapse on escitalopram than on placebo.