Gender differences in the response to antipsychotic medication in patients with schizophrenia: An individual patient data meta-analysis of placebo-controlled studies.

OBJECTIVE: To determine whether gender and menopausal status moderate the response to antipsychotic medication in patients with schizophrenia. METHODS: We analyzed data of 22 short-term placebo-controlled registration trials of antipsychotic medications, which included 5,231 patients with schizophrenia. We applied two-step individual patient data meta-regression analyses to establish the influence of gender and menopausal status on treatment response in mean difference in symptom severity and difference in response (>30% symptom reduction). Analyses were performed both with and without correction for baseline (negative) symptom severity. RESULTS: Antipsychotic treatment is associated with larger mean symptom reduction in women than in men with schizophrenia. The number needed to treat (NNT) for a response in women was 6.9, in men 9.4. Although, we found an age by gender effect, the gender by treatment effect was independent of premenopausal status and baseline (negative) symptom severity. CONCLUSION: In the treatment of schizophrenia we found evidence of a higher response to antipsychotic medication in women relative to men. We found no evidence that this effect was driven by menopausal status, or baseline (negative) symptom severity. Despite the impact of gender and age on effect size in acute antipsychotic treatment, efficacy was clinically relevant in all subgroups.

Early Nonresponse in the Antipsychotic Treatment of Acute Mania: A Criterion for Reconsidering Treatment? Results From an Individual Patient Data Meta-Analysis.

OBJECTIVE: To investigate whether early nonresponse to antipsychotic treatment of acute mania predicts treatment failure and, if so, to establish the best definition or criterion of an early nonresponse. DATA SOURCES: Short-term efficacy studies assessing antipsychotics that were submitted to the Dutch Medicines Evaluation Board during an 11-year period as part of the marketing authorization application for the indication of acute manic episode of bipolar disorder. Pharmaceutical companies provided their raw patient data, which enabled us to perform an individual patient data meta-analysis. STUDY SELECTION: All double-blind, randomized, placebo-controlled trials assessing the efficacy of antipsychotics for acute manic episode of bipolar disorder were included (10 trials). DATA EXTRACTION: All patients with data available for completer analysis (N = 1,243), symptom severity scores on the Young Mania Rating Scale (YMRS) at weeks 0, 1, and 2 and at study end point (week 3 or 4). RESULTS: The a priori chances of nonresponse and nonremission at study end point were 40.9% (95% CI, 38.2%-43.6%) and 65.3% (95% CI, 62.0%-68.6%), respectively. Early nonresponse in weeks 1 and 2, defined by cutoff scores ranging from a ≤ 10% to a ≤ 50% reduction in symptoms compared to baseline on the YMRS, significantly predicted nonresponse (≤ 0% symptom reduction) and nonremission (YMRS score higher than 8) in week 3. The predictive value of early nonresponse (PVnr_se) at week 1 for both nonresponse and nonremission at study end point declined linearly with increasing cutoff scores of early nonresponse; nonresponse: 76.0% (95% CI, 69.7%-82.3%) for a ≤ 10% response to 48.7% (95% CI, 45.5%-51.9%) for a ≤ 50% response; nonremission: 92.2% (95% CI, 88.3%-96.1%) for a ≤ 10% response to 76.8% (95% CI, 74.4%-79.5%) for a ≤ 50% response. A similar linear decline was observed for increasing cutoff scores of early nonresponse at week 2 for nonresponse, but not for nonremission at end point: nonresponse 90.3% (95% CI, 84.6%-96.0%) for a ≤ 10% response to 65.0% (95% CI, 61.4%-68.6%) for a ≤ 50% response; nonremission: 94.2% (95% CI, 89.7%-98.7%) for a ≤ 10% response and 93.2% (95% CI, 93.1%-95.1%) for a ≤ 50% response. Specific antipsychotic characteristics did not modify these findings at either time point (week 1: P = .127; week 2: P = .213). CONCLUSIONS: When patients fail to respond early (1-2 weeks) after the initiation of antipsychotic treatment for acute mania, clinicians should reconsider their treatment choice using a 2-stage strategy.

Does Insight Affect the Efficacy of Antipsychotics in Acute Mania?: An Individual Patient Data Regression Meta-Analysis.

Patients having an acute manic episode of bipolar disorder often lack insight into their condition. Because little is known about the possible effect of insight on treatment efficacy, we examined whether insight at the start of treatment affects the efficacy of antipsychotic treatment in patients with acute mania. We used individual patient data from 7 randomized, double-blind, placebo-controlled registration studies of 4 antipsychotics in patients with acute mania (N = 1904). Insight was measured with item 11 of the Young Mania Rating Scale (YMRS) at baseline and study endpoint 3 weeks later. Treatment outcome was defined by (a) mean change score, (b) response defined as 50% or more improvement on YMRS, and (c) remission defined as YMRS score less than 8 at study endpoint. We used multilevel mixed effect linear (or logistic) regression analyses of individual patient data to assess the interaction between baseline insight and treatment outcomes. At treatment initiation, 1207 (63.5%) patients had impaired or no insight into their condition. Level of insight significantly modified the efficacy of treatment by mean change score (P = 0.039), response rate (P = 0.033), and remission rate (P = 0.043), with greater improvement in patients with more impaired insight. We therefore recommend that patients experiencing acute mania should be treated immediately and not be delayed until patients regain insight.

Incidence rates and risk factors of bipolar disorder in the general population: a population-based cohort study.

OBJECTIVE: To estimate the incidence rates (IRs) of bipolar I and bipolar II disorders in the general population according to sociodemographic population characteristics. METHODS: A cohort study (during the years 1996-2007) was conducted in a general practitioners research database with a longitudinal electronic record of 800000 patients throughout the Netherlands [the Integrated Primary Care Information (IPCI) database]. Cases of bipolar disorder were identified and classified by systematic review of medical records. Age- and gender-specific IRs were calculated per calendar year, degree of urbanization, and degree of deprivation. RESULTS: The overall IR of bipolar disorder was 0.70/10000 person-years (PY) [95% confidence interval (CI): 0.57-0.83]; the IR of bipolar I disorder was 0.43/10000 PY (95% CI: 0.34-0.55) and the IR of bipolar II disorder was 0.19/10000 PY (95% CI: 0.13-0.27). Two peaks in the age at onset of the disorder were noticed: one in early adulthood (15-24 years; 0.68/10000 PY) and a larger peak in later life (45-54 years; 1.2/10000 PY). In bipolar II disorder, only one peak, in the 45-54 year age category (IR 0.42/10000 PY), was found. The IRs of bipolar disorder were significantly higher in deprived areas. Similar rates were found for men compared to women and in urban compared to rural areas. No association was found between the onset of first (hypo)manic episode and month or season of birth. CONCLUSIONS: We found two peaks in the age at onset of bipolar disorder, one in early adulthood and one in later life, the former consisting mainly of bipolar I disorder subjects. The incidence of bipolar disorder is higher in deprived areas. The onset of bipolar disorder is not associated with gender, urbanization, or month or season of birth.

Antidepressants use in children and adolescents and the risk of suicide.

OBJECTIVE: Antidepressants use in paediatric patients has been linked with risk of suicidal behaviours. The aim of this paper, therefore, is to examine whether all antidepressants are associated with such risk. METHOD: All 22 paediatric short-term placebo-controlled trials of SSRIs and NSRIs that were submitted to European registration authorities by pharmaceutical companies were identified and examined for events related to suicidality, which were defined as suicide, suicide attempts or suicidal thoughts. Random effect meta-analysis was used to combine the information from all trials. RESULTS: No completed suicides were reported. However, for each compound there was at least one study with an increased risk for events related to suicidality in the active compound group. The overall OR for these events in the depression studies was 1.67 (95% CI: 1.05-2.65) and for anxiety 1.33 (95% CI: 0.33-5.35). CONCLUSIONS: Caution is called for in the use of all SSRIs and NSRIs in the paediatric population. Furthermore, in the absence of contradictory information, caution in the use of other antidepressants in this population should be exercised as well (e.g. tricyclic antidepressants).

Screening for Posttraumatic Stress Disorder: an evaluation of two self-report scales among crime victims.

The validity of the Impact of Events Scale (IES) and the Posttraumatic Stress Disorder (PTSD) Symptom Scale, Self-Report version (PSS-SR) was examined among crime victims. Both instruments performed well as screeners for PTSD. For the IES, sensitivity ranged between .93 and 1.00; for the PSS-SR, sensitivity ranged between .80 and .90. Specificity for the IES ranged between .78 and .84 and for the PSS-SR ranged between .84 and .88. Some individual items from the 2 scales performed just as well as the total scales. The authors conclude that either of these short self-report instruments or their individual items are suitable as screeners for PTSD, specifically in settings where mental health professionals are unavailable. Cross-validation of these results is necessary because of the small sample size in this study.