Joyce G. Small

Sertraline Safety and Efficacy in Major Depression: A Double-Blind Fixed-Dose Comparison with Placebo

In a 6-week, randomized, double-blind, multicenter trial, sertraline 50 mg, 100 mg, or 200 mg, or placebo, was administered once daily to 369 patients with DSM-III-defined major depression. Efficacy variables included changes from baseline scores for total Hamilton Rating Scale for Depression (HAMD), HAMD Bech Depression Cluster, Clinical Global Impressions (CGI) Severity, CGI Improvement, and Profile of Mood States Depression/Dejection Factor. For the evaluable-patients analysis, all sertraline groups showed significantly (p < 0.05 or better) greater improvements in all efficacy variables except one when compared with the placebo group. For the all-patients analysis, all efficacy variables in the 50 mg group were statistically significantly (p < 0.05) better than placebo. Side effects increased with increasing dosage but were usually mild and well tolerated. The results of this study show that sertraline 50 mg once daily is as effective as higher dosages for the treatment of major depression with fewer side effects and therapy discontinuations.

Tolerability and efficacy of clozapine combined with lithium in schizophrenia and schizoaffective disorder.

The safety and tolerability of clozapine combined with lithium were investigated because of potential additive risks as well as frequent usage in clinical practice. Ten hospitalized schizophrenic and 10 schizoaffective patients receiving clozapine maintenance therapy with partial therapeutic response were studied in a randomized controlled trial. CGI and PANSS outcome ratings were employed and a cognitive battery was administered at baseline and after 4 weeks of lithium and placebo administration. Barnes and UKU side effect ratings and laboratory safety data were obtained. Combined lithium-clozapine treatment was well tolerated except for reversible neurotoxic reactions in two schizophrenic patients. Safety measures showed no significant variations, even during lithium toxicity. Total WBC and absolute granulocyte counts increased with lithium and declined with placebo. Schizoaffective patients improved with lithium on CGI and PANSS total and negative symptom scales and the cognitive measures, whereas schizophrenic patients did not. Lithium added to clozapine in treatment regimens for hospitalized, treatment-resistant, schizoaffective patients appears to afford potential benefit without harmful effects; for schizophrenic patients, however, it did not afford improvement but posed a risk of lithium toxicity.

Effects of ACTH 4–10 on ECT-induced memory dysfunctions

Double‐blind studies of ACTH 4–10 and placebo were conducted in psychiatric patients receiving bilateral ECT to determine whether the polypeptide exerted anti‐amnesic effects. Observations after a single ECT were suggestive of some positive effects, but studies between seizures after five or six ECTs showed no significant drug‐placebo differences. Although the findings were largely negative, they do not rule out positive effects of ACTH 4–10 on memory. Possibly the designs and timing of the experiments and/or the dosages of ACTH 4–10 employed were unsuitable for demonstrating such influences.

Manic symptoms: An indication for bilateral ECT

As a follow-up to pilot observations that six manic patients who failed to respond to unilateral electroconvulsive therapy (ECT) recovered rapidly when switched to bilateral treatment, a retrospective study was conducted. Twenty-five patients who responded after switchover from unilateral to bilateral ECT, 25 age- and sex-matched controls, and 25 concurrent controls who responded to right unilateral ECT alone were evaluated. Demographic variables and DSM-III diagnosis did not discriminate between the groups, nor were they different in terms of electroencephalographic (EEG) findings, neuropsychological test results, numbers of ECT, and duration of seizure discharges. Standard assessments of psychopathology performed by independent psychiatrists showed no differences in ratings of psychosis or depressive phenomena. However, scales assessing manic symptoms showed highly significant differences with many more features of unrestrained behavior, elevated mood, hurried speech, and other typical features of mania in the patients who were switched from unilateral to bilateral ECT. Although there were no differences in prescribed drugs, the use of prn medications for sleep was greater in the experimental-switched patients than in controls. Patients who responded to unilateral ECT alone exhibited virtually no manic features, whereas those who demonstrated these characteristics failed to respond to unilateral ECT but benefited when switched to bilateral treatment.

The six per second spike and wave--a psychiatric population study.

Abstract Nearly 5% of a population of acutely ill, hospitalized psychiatric patients displayed 6/sec spike-wave complexes. Aside from this high incidence the other associated EEG findings and the age and sex distribution of cases with this pattern were similar to those of other published series. However, the clinical associations with 6/sec spike-wave complexes that are usually cited in the literature, namely head injuries, seizures, syncope and autonomic dysfunctions and emotional disturbances were not evident in this population. Evaluations of subjects with 6/sec spike-waves and two matched control groups, one with normal EEGs and the other with abnormal EEGs, revealed other kinds of significant differences. Fewer psychiatric hospitalizations, less frequent suicide attempts and more surgical procedures with general anesthesia separated the subjects from the patients with normal EEGs. Controls with abnormal EEGs were like the subjects in these respects. Scores on the IPAT Anxiety Scale discriminated the subjects from both control groups with highest values in the patients with 6/sec spike-wave complexes. Direct examination of subjects and controls with attention focused upon epileptiform and vegetative dysfunctions, psychological characteristics and other attributes revealed no additional clinical associations with these EEG signals. The significance of these results was discussed in context with the literature on this subject, relating them to parallel observations in studies of 14 and 6/sec positive spikes. The clinical implications of EEG abnormalities in psychiatric patients and the propensity for studies of such groups to yield contradictory results were considered. The necessity to modify clinical EEG interpretation in the light of population differences was stressed.

Stereotactic Amygdalotomy for Convulsive and Behavioral Disorders

58 patients, whose convulsions and behavioral disorders did not respond to nonsurgical therapy, were treated with stereotactic amygdalotomy between 1963 and 1973. A retrospective study was carried out

Clinical EEG Findings in Mania

Clinical EEG findings from 202 hospitalized manic patients repeated during 131 recurrences of mania were described. Results were considered in the light of current issues in the literature including the incidence of EEG abnormalities and minor variations, relationships between EEG and family history, EEG lateralization and longitudinal course of illness. The majority of patients had normal EEGs or mild nonspecific deviations compatible with effects of psychoactive medications. More definitive EEG abnormalities were observed in 16-percent. Microsleep occurred in 19 percent and small sharp spikes were found in 17 percent of those who drowsed, with lower incidences of 14 and 6 positive bursts and 6 Hz spike-and-slow-waves. Significant relationships between moderate or severe EEG abnormalities and negative familial loading were identified. Lateralized EEG abnormalities appeared in 9 percent of cases, involving the left side significantly more often than the right. With one exception EEG recordings during subsequent episodes did not suggest structural brain changes. Clinical EEG studies are useful in discriminating between primary and secondary affective disorders. They are also sensitive to effects of lithium and other psychoactive medications. The significance of EEG variations including microsleep and other atypical features continues to be elusive. Issues relating to heritability, hemispheric dysfunction and longitudinal course of illness merit further investigation.

Topographic EEG studies of mania

QEEG findings from 39 hospitalized manic patients were accomplished after a drug free period and following pharmacotherapy with lithium or carbamazepine alone or lithium combined with carbamazepine, haloperidol or risperidone. A subsample of 10 drug-free manic patients was compared with normal controls, which revealed lower qEEG amplitudes in the left anterior and midtemporal regions in the patients. Comparisons of drug therapies showed increased delta amplitudes and total power with lithium compared with carbamazepine. Increased fast frequencies were observed in the lithium and carbamazepine plus lithium groups compared with carbamazepine alone. Comparisons of the three drug combination groups revealed increased alpha and beta 1 amplitudes, most with risperidone and least with carbamazepine. Anterior delta and beta 2 amplitudes and interhemispheric coherence were increased directly proportional to plasma lithium levels. Nonresponders to treatment were identified at baseline by increased generalized theta amplitudes. After treatment, the nonresponders had higher amplitudes in the left temporal areas. Numerous qEEG associations with individual ratings of manic symptoms were found, more at baseline than after treatment. In general levels of psychopathology were negatively correlated with qEEG amplitudes. The qEEG findings appear to implicate dominant temporal lobe dysfunctions in mania.

Quetiapine in schizophrenia: onset of action within the first week of treatment

SUMMARY Objective: Three placebo-controlled clinical trials have established the efficacy of the atypical antipsychotic quetiapine (Seroquel*) in schizophrenia. These trials were designed and powered to detect a treatment difference in the primary endpoint at Week 6. The objective of the current analysis was to investigate the effect of quetiapine at earlier timepoints. Research design and methods: A combined analysis of data from three acute, double-blind, placebo-controlled, randomised trials was carried out. The trials comprised hospitalised patients with an acute exacerbation of chronic or subchronic schizophrenia who were randomised to receive quetiapine 150–750 mg/day (n = 422) or placebo (n = 198). Symptoms were assessed using changes from baseline to Week 1 in the Brief Psychiatric Rating Scale (BPRS) total score, BPRS positive symptom cluster score and the individual BPRS items of excitement, tension and depression. Changes from baseline to Weeks 1–6 were calculated for BPRS Factor 1 scores (which measures mood symptoms) and Scale for Assessment of Negative Symptoms (SANS) summary scores. Results: Within 1 week, overall symptom improvement (BPRS total score) was significantly ( p < 0.05) greater with quetiapine than with placebo; improvement also occurred in individual BPRS items of excitement, tension and depression. Improvement in negative symptoms was significantly ( p < 0.05) greater with quetiapine than with placebo from Week 1, as was the BPRS Factor I score from Week 2. More quetiapine- than placebo-treated patients showed a response of positive symptoms to treatment within 1 week ( p < 0.05). Conclusions: The beneficial effects of quetiapine are observed within 1 week across a broad spectrum of symptoms.

Comparative Onset of Improvement in Depressive Symptomatology with Drug Treatment, Electroconvulsive Therapy, and Placebo

Depressive symptomatology responds very similarly to treatment with trazodone, imipramine, placebo, and electroconvulsive therapy. In one study positive therapeutic response was evident within the 1st week of therapy in most patients. If this did not occur, an unfavorable response to treatment was likely to follow. The close resemblance of the electroconvulsive therapy response profiles to those of antidepressant drugs and placebo suggests that it exerts similar effects and that all of the treatments examined probably operate through a final common pathway in those patients who respond. Among the nonresponders, there were few features that distinguished the therapeutic groups.