Pharmacotherapy of impaired affect in recovering schizophrenic patients. Viloxazine and the depressed schizophrenic--methodological issues. Treatment of secondary depression in schizophrenia. A double-blind, placebo-controlled trial of amitriptyline added to perphenazine. A double-blind, placebo-controlled trial of sertraline for depressive symptoms in patients with stable, chronic schizophrenia. Adjunctive imipramine in the treatment of postpsychotic depression. A controlled trial. Antidepressants in 'depressed' schizophrenic inpatients. A controlled trial.
Prominent and persistent anxiety, depression, and/or negative features characterize a substantial minority of recovered or residually psychotic schizophrenic outpatients and contribute to poor outcome. Because extrapyramidal side effects of typical neuroleptic medications often resemble such features, we first systematically studied the contribution of extrapyramidal side effects to these problems and their treatment. For patients who remained distressed, controlled trials of supplemental thymoleptics were undertaken.
                In trial 1, 92 distressed (depressed and/or anxious) patients and 36 patients in a defect state (patients with negative symptoms) participated in a double-blind, intramuscular challenge that compared centrally acting benztropine mesylate with peripherally acting glycopyrrolate. In trial 2, 57 distressed patients and 22 patients in a defect state were randomly assigned to a double-blind, neuroleptic medication dose-reduction group. In trial 3, 57 chronically distressed patients who were maintained on a low dose of fluphenazine decanoate were randomly assigned to a supplemental desipramine hydrochloride, lithium carbonate, or placebo group under double-blind conditions for 12 weeks.
                For patients who were already maintained on antiparkinsonian medication, impaired affect was not resolved by additional benztropine. Only distressed patients with a family history of severe mental disorder (often affective) showed improvement with neuroleptic medication dose reduction. Patients in the defect-state group reported less dysphoria on a reduced neuroleptic medication dose, but negative symptoms persisted. Desipramine improved diverse aspects of mood and residual psychoticism, possibly as a prophylaxis against minor affective exacerbations. Depression improved in women only. Lithium positively affected multiple indexes of anxiety and anxious depression.
                Most often, persistent affective impairments are neither resistant extrapyramidal side effects nor characterological traits. Thymoleptics improve the nonphasic, chronic types of anxiety and depression in contrast to the acute, episodic forms, for which little support can be found in the literature. A pilot study of a small group of schizophrenic patients manifesting symptoms of a depressive nature was treated in a double-blind study in which viloxazine or a placebo was administered in combination with either chlorpromazine or haloperidol. There appeared to be no difference between the viloxazine-treated group and the placebo-treated group, although the study raised some question as to the adequacies of the dosage utilized since there was an absence of any apparent side effects. In view of these issues concerning the clinical merit of the combination, this obviously requires further investigation. The combination of antidepressants and neuroleptics has been widely recommended and commonly used clinically for the schizophrenic patient who becomes depressed. However, the value of the combination for these patients has not been clearly demonstrated. This report presents results of a double-blind, randomized, placebo-controlled clinical trial designed to evaluate the combination of perphenazine and amitriptyline hydrochloride with that of perphenazine alone in the treatment of 35 ambulatory chronic schizophrenic patients in whom depressive symptoms developed. Results showed that the addition of amitriptyline to perphenazine, when compared with perphenazine alone, was more effective in reducing symptoms of depression after four months of treatment, but less effective in reducing thought disorder. The study concludes that the value of adding an antidepressant to the usual neuroleptic in the treatment of secondary depression in schizophrenia should be reviewed. There have been no studies specifically examining the efficacy of selective serotonin reuptake inhibitor antidepressants for the symptoms of depression in schizophrenia. This study aimed to determine the efficacy and safety of sertraline as a treatment for depressive symptoms in patients with stable, chronic schizophrenia. The Beck Depression Inventory (BDI) was used as the principal outcome measure and other measures of depressive symptoms as secondary outcome measures. Twenty-six patients were entered into a double-blind, placebo-controlled, 8-week trial of sertraline and were included in the intent-to-treat (ITT) analysis (13 in each group). Eight patients in the sertraline group and 12 in the placebo group completed at least four weeks in the study and were considered to have had adequate treatment. On the ITT analysis, the mean score on the BDI fell 14.5% for the sertraline group and 5.6% for the placebo group (p > 0.05); the mean score on the Hamilton Depression Rating Scale (HDRS) fell 16.99% for the sertraline group and 8.3% for the placebo group (p > 0.05). When the analysis was repeated for those who had received adequate treatment, the mean BDI score fell by 28% for the sertraline group and 6% for the placebo group (p = 0.1); the mean HDRS score fell 31% for the sertraline group and 8.6% for the placebo group (p = 0.02). On the Clinical Global Impression-Improvement Scale, 10 of the 13 patients on sertraline improved against four of the 13 in the placebo group (p = 0.05). Sertraline-treated patients showed a significant improvement on the anxiety/ depression subscale of the BPRS on ITT analysis (F = 10.1, p = 0.004). There was no significant effect on negative or positive symptoms. Sertraline was well tolerated. The results suggest that sertraline is useful as a treatment for depressive symptoms in schizophrenia. The efficacy of adjunctive imipramine hydrochloride treatment for syndromally defined postpsychotic depression was assessed in a six-week, double-blind, placebo-controlled study. All patients had been diagnosed as having schizophrenia or schizoaffective disorder, all were receiving stable doses of fluphenazine decanoate, and all had received benztropine mesylate in an attempt to rule out neuroleptic-induced akinesia. Patients randomized to imipramine therapy fared significantly better in terms of their global improvement and in terms of individual symptoms that are components of the depression syndrome. There were no significant differences in outcome psychosis ratings or side effects. This study indicates the existence of an identifiable syndrome of secondary depression in this patient group that is likely to respond favorably to treatment with adjunctive imipramine. Fifty-eight actively psychotic inpatients who initially met criteria for long-standing schizophrenia and subsequently met Research Diagnostic Criteria for a current episode of schizoaffective disorder (mainly schizophrenic) with a depressive syndrome, and who scored at least 30 (mean = 55, SEM = 1.6) on the Brief Psychiatric Rating Scale and 17 (mean = 23, SEM = 0.7) on the Hamilton Rating Scale for Depression, were treated for 5 weeks with haloperidol hydrochloride and benztropine. Haloperidol and benztropine treatment was continued, while those patients who consistently scored greater than 17 on the Hamilton Rating Scale for Depression were randomly assigned to the following double-blind treatment groups for 4 weeks: adjunctive amitriptyline hydrochloride, desipramine hydrochloride, or placebo. Adjunctive desipramine or amitriptyline showed no significant therapeutic advantage, when compared with haloperidol and placebo, on the Brief Psychiatric Rating Scale or the Hamilton Rating Scale for Depression. After 4 weeks of combine therapy, patients receiving adjunctive amitriptyline or desipramine, as compared with those receiving adjunctive placebo, tended to score higher on the Brief Psychiatric Rating Scale hallucinatory behavior item and on the thinking disturbance factor than patients receiving placebo. These results suggest that adjunctive antidepressants are not indicated for the treatment of depressive symptoms in actively psychotic schizophrenic inpatients. Adjunctive antidepressants may retard the rate of resolution of psychosis in this population.
Overall, the literature was of poor quality, and only a small number of trials made useful contributions. Though our results provide some evidence to indicate that antidepressants may be beneficial for people with depression and schizophrenia, the results, at best, are likely to overestimate the treatment effect, and, at worst, could merely reflect selective reporting of statistically significant results and publication bias.
At present, there is no convincing evidence to support or refute the use of antidepressants in treating depression in people with schizophrenia. We need further well-designed, conducted and reported research to determine the best approach towards treating depression in people with schizophrenia.
Note: the 71 citations in the awaiting classification section of the review may alter the conclusions of the review once assessed.