In light of the number of studies conducted to examine the treatment of cognitive impairment associated with schizophrenia (CIAS), we critically reviewed recent CIAS trials. Trials were identified through searches of the website “www.clinicaltrials.gov” using the terms “schizophrenia AND cognition,” “schizophrenia AND neurocognition,” “schizophrenia AND neurocognitive tests,” “schizophrenia AND MATRICS,” “schizophrenia AND MCCB,” “schizophrenia AND BACS,” “schizophrenia AND COGSTATE,” and “schizophrenia AND CANTAB” and “first-episode schizophrenia AND cognition.” The cutoff date was 20 April 2011. Included trials were conducted in people with schizophrenia, the effects on cognition were either a primary or secondary outcome, and the effect of a pharmacologically active substance was examined. Drug challenge, pharmacokinetic, pharmacodynamic, or prodrome of psychosis studies were excluded. We identified 118 trials, with 62% using an add-on parallel group design. The large majority of completed trials were underpowered to detect moderate effect sizes, had ≤8 weeks duration, and were performed in samples of participants with chronic stable schizophrenia. The ongoing add-on trials are longer, have larger sample sizes (with a number of them being adequately powered to detect moderate effect sizes), and are more likely to use a widely accepted standardized cognitive battery (eg, the MATRICS Consensus Cognitive Battery) and MATRICS guidelines. Ongoing studies performed in subjects with recent onset schizophrenia may help elucidate which subjects are most likely to show an effect in cognition. New insights into the demands of CIAS trial design and methodology may help increase the probability of identifying treatments with beneficial effect on cognitive impairment in schizophrenia.

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Following a placebo washout period of 3-7 days, 251 hospitalized patients with a major depressive episode (DSM I11 and RDC criteria) were treated with either Org 3770 (20-60 mg/day) or amitnptyline (75-225 mg/day) for six consecutive weeks in this randomized, double-blind, multicentre study. Forty-one patients (19 Org 3770,22 amitriptyline) withdrew before completion of the 6-week active treatment period. In both groups, the main reason for withdrawal was lack of efficacy. However, fewer patients in the Org 3770 group than in the amitriptyline group withdrew as a result of adverse events (one and three patients, respectively). The severity of depressive symptoms and general psychopathology, as assessed by HPRSD (total and factors) and BPRS scales, improved to the same extent after 6 weeks' treatment with Org 3770 and amitriptyline. Similar improvement in global functioning, as assessed by GAS scale, was observed in both treatment groups. There were no statistically significant differences between the two treatments on all scales used. Dry mouth and sweating were reported significantly more often in the amitriptyline group. Other adverse events, such as constipation, dizziness, tremor and muscle weakness, occurred more frequently in the amitriptyline-treated patients as well. The results of this study indicate that Org 3770 has similar antidepressant efficacy to amitriptyline and a more favourable tolerability profile in patients with major depression.

The efficacy and tolerability of the new antidepressant Org 3770 were evaluated in a multicentre, double-blind, clomipramine-controlled trial. In total, 174 patients (126 women and 48 men), aged 18-75 years, who were suffering from a moderate or severe major depressive episode, were randomly assigned to 6 weeks of treatment with either Org 3770, 20-80 mg/day, or clomipramine, 50-200 mg/day. All patients were hospitalized at the time of the trial. Depressive symptoms, assessed by 21-item HPRSD, MADRS, BPRS and GAS, improved significantly in both groups of patients after 6 weeks of treatment. Org 3770 was comparable to clomipramine with respect to improvements assessed by all the primary efficacy variables, both in moderately and severely depressed patients. Adverse clinical experiences, such as dry mouth, constipation, tremor, vertigo/dizziness, faintness on rising, and nausea, were reported by fewer patients in the Org 3770-treated group than in the clomipramine-treated group. These differences were particularly pronounced during the first 3 weeks df treatment. With respect to tremor, the difference between the two groups was statistically significant @,-s,ded = 0.03) after both 3 and 6 weeks of treatment. This study shows that Org 3770 is as effective as clomipramine in treating moderate or severe depression, while being better tolerated.

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A meta‐analysis was performed on efficacy and safety data from 4 randomized, double‐blind, 6‐week, single‐center studies comparing mirtazapine (n= 194; 5–35 mg/day) with amitriptyline, (n= 193, 40–280 mg/day) and placebo (n= 193) in outpatients with a DSM‐III diagnosis of major depressive episode. On all the main cllicacy variables both active drugs consistently produced significantly greater improvements and significantly greater percentages of responders or remitters than placebo. The meta‐analysis of adverse events shows that mirtazapine was better tolerated than amitriptyline, particularly with respect to anticholinergic and cardiac adverse events. There were no differences between mirtazapine and placebo regarding the incidence of serotonergic adverse events. In conclusion, the results of this meta‐analysis demonstrate that mirtazapine is as effective as amitriptyline but has a better tolerability profile.

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