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To test the functional implications of impaired white matter (WM) connectivity among patients with schizophrenia and their relatives, we examined the heritability of fractional anisotropy (FA) measured on diffusion tensor imaging data acquired in Pittsburgh and Philadelphia, and its association with cognitive performance in a unique sample of 175 multigenerational non-psychotic relatives of 23 multiplex schizophrenia families and 240 unrelated controls (total = 438).
We examined polygenic inheritance (h2r) of FA in 24 WM tracts bilaterally, and also pleiotropy to test whether heritability of FA in multiple WM tracts is secondary to genetic correlation among tracts using the Sequential Oligogenic Linkage Analysis Routines. Partial correlation tests examined the correlation of FA with performance on eight cognitive domains on the Penn Computerized Neurocognitive Battery, controlling for age, sex, site and mother's education, followed by multiple comparison corrections.
Significant total additive genetic heritability of FA was observed in all three-categories of WM tracts (association, commissural and projection fibers), in total 33/48 tracts. There were significant genetic correlations in 40% of tracts. Diagnostic group main effects were observed only in tracts with significantly heritable FA. Correlation of FA with neurocognitive impairments was observed mainly in heritable tracts.
Our data show significant heritability of all three-types of tracts among relatives of schizophrenia. Significant heritability of FA of multiple tracts was not entirely due to genetic correlations among the tracts. Diagnostic group main effect and correlation with neurocognitive performance were mainly restricted to tracts with heritable FA suggesting shared genetic effects on these traits.
Substantial weight gain is common with many atypical antipsychotics.
To evaluate the extent, time course and predictors of weight gain and its effect on study retention among people with first-episode psychosis treated with olanzapine or haloperidol.
Survival analysis assessed time to potentially clinically significant weight gain (⩾7%) and the effect of weight gain on study retention. Weight gain during the 2-year study was summarised using last-observation-carried-forward (LOCF), observed cases and study completion approaches.
After 2 years of treatment, LOCF mean weight gain was 10.2 kg (s.d.=10.1) for olanzapine (n=131) and 4.0 kg (s.d.=7.3) for haloperidol (n=132); observed cases mean weight gain was 15.4 kg (s.d.=10.0) for olanzapine and 7.5 kg (s.d.=9.2) for haloperidol. Change in body mass index was significantly predicted only by treatment group (P < 0.0001).
Olanzapine was associated with significantly greater weight gain than haloperidol, with both leading to greater weight gain than previously described.
Duration of untreated psychosis (DUP) may contribute to the observed heterogeneity of the treatment response in first-episode schizophrenia.
To examine the relationship of DUP and premorbid function with clinical outcomes following up to 2 years of antipsychotic treatment.
For a subsample (n = 191) of subjects participating in a clinical trial, DUP and premorbid function were prospectively compared with clinical response to olanzapine or haloperidol.
Shorter DUP and good premorbid function each independently are associated with better clinical response, including improvement in overall psychopathology and negative symptoms. Premorbid function also is associated with positive symptom, social and vocational outcomes.
Earlier antipsychotic treatment is associated with better outcomes in first-episode schizophrenia. Poor premorbid function could indicate an illness subtype less likely to respond to antipsychotic treatment regardless of when it is instituted.
Previous meta-analyses of fluoxetine as an antidepressant have many methodological problems, including diagnosis of major depression, validity of outcome measures and lack of intention-to-treat analyses.
To provide an estimate of the effect of fluoxetine compared with placebo and tricyclic antidepressants (TCAs), and to investigate reasons for early discontinuation from acute treatment.
Randomised trials were analysed using both intention-to-treat, efficacy and end-point.
Fluoxetine was superior to placebo but effect size was low. In trials comparing fluoxetine v. TCA, the results for all trials and for the USA trials showed a trend in favour of fluoxetine. Those for the non-USA trials showed a trend in favour of TCA. When combined, the results showed that significantly fewer patients on fluoxetine discontinued treatment because of adverse events.
Fluoxetine is superior to placebo, irrespective of the analytical approach use, whereas the results obtained v. TCAs depend on the approach used. Hence, the results should be interpreted in this light.
Data concerning appropriate treatment in panic disorder following an initial response to acute therapy are limited.
To assess the safety and efficacy of continued fluoxetine treatment following successful acute therapy of panic disorder.
Patients who responded to acute fluoxetine treatment were randomised to 24 weeks of continued fluoxetine or placebo.
Fluoxetine responders randomised to continue on their acute-phase fluoxetine dose experienced statistically significant improvement in panic attack frequency and phobia rating scale score over 24 weeks of therapy, while those switched to placebo experienced statistically significant worsening in Hamilton Anxiety (HAM–A), Hamilton Depression (HAM–D) and SCL–90–R rating scores.
Fluoxetine was associated with improved clinical outcomes compared with placebo during continuation therapy.
Olanzapine is a novel antipsychotic agent displaying a unique and pleotrophic pharmacology, which distinguishes it from other existing treatments. Clinical investigations employing olanzapine have demonstrated a number of potential therapeutic advantages in reference not only to placebo but also to contemporary drug standards in the management of psychosis. This paper reviews data on the pharmacokinetics, efficacy and safety of olanzapine, its benefits for quality of life, and economic aspects to assist clinicians in determining where they can usefully employ it.
The effectiveness of antipsychotic monotherapy in schizoaffective disorder is limited, and further constrained by safety concerns.
We aimed to compare the efficacy, tolerability and safety profile of the new pharmaceutical, olanzapine, with haloperidol.
Data were assessed from 300 DSM – III – R schizoaffective subjects from a larger double-blind prospective international study. Subjects were randomly allocated to six weeks of olanzapine (5–20 mg) or haloperidol (5–20 mg) treatment; responders were followed for up to one year of double-blind, long-term maintenance therapy.
Olanzapine-treated patients achieved a statistically significant greater improvement than haloperidol-treated patients on overall measures of efficacy, including clinical response. Significantly fewer olanzapine patients left the study early, and fewer adverse events were observed among those receiving olanzapine. During maintenance, olanzapine-treated patients continued to experience additional improvement, with fewer EPS but more weight gain than those on haloperidol.
Olanzapine demonstrated substantial advantages over the conventional antipsychotic haloperidol in the management of schizoaffective disorder.
Tardive dyskinesia is important in the side-effect profile of antipsychotic medication.
The development of tardive dyskinesia was evaluated in patients treated with double-blind, randomly assigned olanzapine or haloperidol for up to 2.6 years.
Tardive dyskinesia was assessed by the Abnormal Involuntary Movement Scale (AIMS) and Research Diagnostic Criteria for Tardive Dyskinesia (RD-TD); it was defined as meeting RD-TD criteria at two consecutive assessments. The risk of tardive dyskinesia, the relative risk, incidence rate, and incidence rate ratio were estimated.
The relative risk of tardive dyskinesia for the overall follow-up period for haloperidol (n=522) v. olanzapine (n=1192) was 2.66 (95% CI=1.50–4.70). Based on data following the initial six weeks of observation (during which patients underwent medication change and AIMS assessments as frequently as every three days), the one-year risk was 0.52% with olanzapine (n=513) and 7.45% with haloperidol (n=114). The relative risk throughout this follow-up period was 11.37 (95% Cl=2.21–58.60).
Our results indicated a significantly lower risk of tardive dyskinesia with olanzapine than with haloperidol.
Three studies compared olanzapine and haloperidol given orally in maintenance therapy for schizophrenia and related psychoses.
Data were from double-blind extensions of acute studies. The subjects met criteria for schizophrenia, schizophreniform disorder or schizoaffective disorder. Subjects had responded to acute therapy (Brief Psychiatric Rating Scale total score decreased $ 40% from baseline (Studies 1, 2, and 3) or was $ 18 (Studies I and 2)) and were out-patients at their last acute phase visit. Relapse was defined as hospitalisation for psychopathology. Subjects treated with olanzapine in the three studies were pooled to form the olanzapine group and subjects treated with haloperidol were pooled to form the haloperidol group.
Olanzapine-treated subjects experienced less relapse (P=0.034). The Kaplan-Meier estimated one-year risk of relapse was 19.7% with olanzapine and 28% with haloperidol.
Olanzapine was superior to haloperidol in the maintenance therapy of schizophrenia and related psychoses.