A meta-analysis of profile and time-course of symptom change in acute schizophrenia treated with atypical antipsychotics.
ABSTRACT The profile and time-course of symptom response in acute schizophrenia is unclear. For the present study, we hypothesized that the time-course would be nonlinear. A meta-analysis was performed using randomized, controlled clinical trials of five atypical antipsychotics reported in nine electronic databases. Studies were of subjects experiencing an acute exacerbation of illness, with multiple BPRS or PANSS data-points as outcome measures. A mixed factorial repeated-measures ANOVA was used. Twenty-one published clinical trials were identified. Reduction in total symptoms from baseline to 4 wk was associated with a linear decline in symptomatology (F=23.4, d.f.=1, 7, p=0.002) without attenuation of effect. In contrast, from baseline to 6 wk the linear symptom reduction (F=76.5, d.f.=1, 12, p<0.001) eventually flattened at the end of the trial (F=87.2, d.f.=1, 12, p<0.001). Secondary analyses showed a similar pattern for typical antipsychotics, and the same profile for risperidone and olanzapine as for atypical agents as a whole. Inclusion of LOCF data altered the results at 4 wk, but not 6 wk; completion rates had no effect on results. In conclusion, this meta-analysis confirms our hypothesis for 6-wk data. The profile of symptom change is one of linear symptom reduction until 4 wk, with a flattening of treatment effects by 6 wk. A curvilinear profile of schizophrenia symptom reduction has possible implications with respect to trial design and clinical decision-making.
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ABSTRACT: A quantitative systems pharmacology model that combines in vitro/preclinical neurophysiology data, human imaging data, and patient disease information was used to blindly predict steady-state clinical efficacy of vabicaserin, a 5-HT2C full agonist, in monotherapy and, subsequently, to assess adjunctive therapy in schizophrenia. The model predicted a concentration-dependent improvement of positive and negative syndrome scales (PANSS) in schizophrenia monotherapy with vabicaserin. At the exposures of 100 and 200 mg b.i.d., the predicted improvements on PANSS in virtual patient trials were 5.12 (2.20, 8.56) and 6.37 (2.27, 10.40) (mean (95% confidence interval)), respectively, which are comparable to the observed phase IIa results. At the current clinical exposure limit of vabicaserin, the model predicted an ~9-point PANSS improvement in monotherapy, and <4-point PANSS improvement adjunctive with various antipsychotics, suggesting limited clinical benefit of vabicaserin in schizophrenia treatment. In conclusion, the updated quantitative systems pharmacology model of PANSS informed the clinical development decision of vabicaserin in schizophrenia.CPT: pharmacometrics & systems pharmacology. 04/2014; 3:e111.
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ABSTRACT: CONTEXT: Antipsychotic treatment is the first-line treatment option for schizophrenia. Individual studies suggested they can significantly affect brain structure and account for progressive brain changes observed during the illness. OBJECTIVES: To quantitatively examine the effect of antipsychotics as compared to illness related factors on progressive brain changes in schizophrenia. DATA SOURCES: Electronic databases were searched until April 2012. All magnetic resonance imaging studies reporting progressive brain changes in schizophrenia subjects and antipsychotic exposure were retrieved. STUDY SELECTION: 30 longitudinal MRI studies with antipsychotic administration in schizophrenia patients met the inclusion criteria. DATA EXTRACTION: Brain volumes before and after antipsychotic exposure, duration of illness, severity of psychotic symptoms as well as demographic, clinical, and methodological variables were extracted from each publication, or obtained directly from its authors. DATA SYNTHESIS: The overall sample was of 1046 schizophrenia patients and 780 controls for a median duration of follow-up of 72.4 weeks. At baseline, patients showed significant whole brain volume (WBV) reductions and enlarged lateral ventricle (LV) volumes compared to controls. No baseline volumetric abnormalities were detected in the gray matter volumes (GMV), white matter volumes (WMV), cerebrospinal fluid (CSF) and caudate nucleus (Cd). Longitudinally, there were progressive GMV decreases and LV enlargements in patients but not in controls. The GMV decreases were inversely correlated with cumulative exposure to antipsychotic treatments, while no effects were observed for duration of illness or illness severity. CONCLUSIONS: Schizophrenia is characterized by progressive gray matter volume decreases and lateral ventricular volume increases. Some of these neuroanatomical alterations may be associated with antipsychotic treatment.Neuroscience & Biobehavioral Reviews 06/2013; · 10.28 Impact Factor
- European Neuropsychopharmacology 08/2008; 18. · 5.40 Impact Factor