Familial associations with EEG variants in manic-depressive disease.

Electroencephalographic (EEG) studies of 60 patients with bipolar manic-depressive disease disclosed an incidence of small sharp spikes plus a few other variations in 47% of the sample. In women these EEG features were significantly associated with a history of mental illness in the patient's mother or the maternal side of the family and an absence of mental disorder in the fathers. The reverse was true of women probands without these EEG characteristics. In the men small sharp spikes did not relate to parental psychopathology but half of the sisters of men with these EEG characteristics were found to be mentally ill. On the basis of these observations and previous work, we hypothesize that the small sharp spike EEG pattern might be an inherited characteristic related in some way to the familal transmission of manic-depressive disease.

Quetiapine in patients with schizophrenia. A high- and low-dose double-blind comparison with placebo. Seroquel Study Group.

BACKGROUND: Quetiapine fumarate (Seroquel [ICI 204,636]) is an atypical dibenzothiazepine antipsychotic with a greater affinity for 5-hydroxytryptamine2 (5-HT2) receptors than for D2 dopamine receptors; its efficacy in patients with schizophrenia was shown in early phase 2 trials (maximum dose, 750 mg/d). METHODS: In this multicenter, double-blind, placebo-controlled trial, 286 patients hospitalized with chronic or subchronic schizophrenia (DSM-III-R) were randomized to 6 weeks of treatment with high-dose quetiapine fumarate (< or = 750 mg/d), n = 96; low-dose quetiapine fumarate (< or = 250 mg/d), n = 94; or placebo, n = 96. The Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression Severity of Illness item scores were the primary efficacy variables. Secondary efficacy variables included the BPRS positive-symptom cluster score, the Modified Scale for the Assessment of Negative Symptoms summary score (United States only), and the total score from the negative scale of the Positive and Negative Syndrome Scale (Europe only). Scores were analyzed using an analysis of covariance for change from baseline at end point with last observations carried forward. The model included baseline score (covariate), center, and treatment. Extrapyramidal symptoms were assessed using the Simpson-Angus Scale and the Barnes Akathisia Scale; abnormal involuntary movements were assessed using the Abnormal Involuntary Movement Scale. Frequency distributions of grouped change-from-baseline scores were analyzed using chi 2 tests. RESULTS: Of 280 patients in whom the efficacy of quetiapine was evaluated, 159 (42% of those receiving high-dose treatment; 57%, low-dose treatment; and 59%, placebo) withdrew before trial completion, primarily because of treatment failure. Significant (P < .001, BPRS; P = .003, Clinical Global Impression Severity of Illness item; and P = .003, BPRS positive-symptom cluster) differences were identified between patients receiving high-dose quetiapine and placebo for both primary efficacy variables, with end point differences in the BPRS positive-symptom cluster score showing quetiapine's consistency in reducing positive symptoms. The reduction of negative symptoms was less consistent; high-dose quetiapine was superior on the Modified Scale for the Assessment of Negative Symptoms but not on the negative scale of the Positive and Negative Syndrome Scale. Quetiapine was well tolerated and did not induce extrapyramidal symptoms, sustained elevations of prolactin, or clinically significant changes in hematologic parameters. CONCLUSIONS: Quetiapine is an effective antipsychotic with a favorable safety profile. The optimum dose is probably greater than 250 mg/d.

Electroconvulsive treatment compared with lithium in the management of manic states.

Thirty-four hospitalized manic patients were randomized to treatment with either lithium carbonate or an average series of nine bilateral electroconvulsive treatments (ECTs), followed by maintenance with lithium carbonate. Weekly ratings of manic, depressive, and psychotic symptoms were obtained for eight weeks, and patients were followed up monthly for up to two years. Ratings by nonblind and blind observers indicated that the patients who underwent ECT improved more during the first eight weeks than did patients who were treated with lithium carbonate. This was especially true of patients with mixed symptoms of mania and depression and/or extreme manic behavior. Clinical ratings after eight weeks showed no significant differences between the lithium carbonate- and ECT-treated patients. Likewise, the two groups had comparable rates of relapse, recurrence, and rehospitalization during the follow-up period.

Carbamazepine compared with lithium in the treatment of mania.

Fifty-two hospitalized manic patients were randomized to treatment with either carbamazepine or lithium carbonate after a 2-week drug withdrawal period. All of the probands were tertiary referrals with a high proportion of failures of previous lithium and other treatment. Weekly ratings of manic, depressive, and psychotic symptoms were obtained for 8 weeks, and responders were followed up for up to 2 years. One third of patients responded favorably. Double-blind assessments revealed no statistically reliable differences between the two treatment groups. Patients receiving carbamazepine were somewhat more manageable than patients treated with lithium early in the study, whereas lithium-treated patients remained longer in the follow-up phase. However, numbers of long-term survivors were too small to be conclusive. This study adds to the growing body of evidence that acutely manic patients respond as well to carbamazepine as to lithium. However, monotherapy with either drug is not sufficient for the majority of manic patients who are referred for tertiary care.

Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders. Report of the NIMH Collaborative Study Group comparing lithium carbonate, imipramine, and a lithium carbonate-imipramine combination.

In a double-blind, long-term follow-up study, 117 bipolar patients received lithium carbonate, imipramine hydrochloride, or both and 150 unipolar patients received lithium carbonate, imipramine, both lithium carbonate and imipramine, or placebo. With bipolar patients, lithium carbonate and the combination treatment were superior to imipramine in preventing manic recurrences and were as effective as imipramine in preventing manic recurrences and were as effective as imipramine in preventing depressive episodes. The combination treatment provided no advantage over lithium carbonate alone. With unipolar patients, imipramine and the combination treatment were more effective than lithium carbonate and placebo in preventing depressive recurrences. The combination treatment provided no advantage over imipramine alone. The lithium carbonate-treated group had fewer manic episodes than the other groups. Treatment outcome, which was evaluated primarily in terms of the occurrence of major depression or manic episodes, was significantly related to characteristics of the index episode, ie, the episode that brought the patient into the study.

EEG and neurophysiological studies of early infantile autism.

My aims in this presentation are to review EEG findings that have been published recently in children variously labeled as autistic, schizophrenic, or psychotic. I will also report new results from EEG investigations of an expanded series of Dr. DeMyer's subjects. Sleep research and studies of cerebral evoked responses and the contingent negative variation will be reviewed, and preliminary results of wuantitative analyses of EEG from autistic and normal children will be reported.

Elevation of choline and glycine in red blood cells of psychiatric patients due to lithium treatment.

Levels of choline (Ch) and glycine (Gly) were determined in red blood cells (RBC) from psychiatric patients who were either on lithium therapy or lithium-free and normal subjects. Subjects were divided into four groups: normal subjects who have never received Li+; Li+ free affective patients; Li+ free patients with various psychiatric disorders; and affective patients under Li+ treatment. The patient groups included affective, schizophrenic, schizo-affective disorders, as well as patients with organic brain syndrome and Cornelia de Lange syndrome. In general, all patients on therapeutic dosages of Li+ had significantly higher levels of Ch in RBC when compared to Li+ free normals or patients. Glycine levels in RBC were also significantly higher in patients on Li+ compared to normals or Li+ free affective disorder patients. Plasma Ch was significantly elevated in patients receiving Li+. There was an apparently predictable time course between cessation of Li+ therapy and decreases in levels of Ch and Gly in RBC to normal levels; in Ch of approximately 30-40 days, in Gly of less than 6 days. There were no significant differences in Ch between Li+ free patients, irrespective of their disorder, and normal subjects. RBC Gly levels were equivalent between normal subjects and Li+ free patients. These data imply that elevations in Gly and Ch are more a function of Li+ therapy than of psychiatric diagnosis.

Follow-up of stereotaxic amygdalotomy for seizure and behavior disorders.

Stereotaxic amygdalotomy for the control of unmanageable behavior and/or intractable seizures is a controversial treatment approach with unknown risk-to-benefit ratios. Information about this subject was obtained from a retrospective follow-up study of 58 patients who received this form of treatment 1 to 11 years earlier (average 6 years). Assessments of the patients were made by invesgators external to the surgical treatment system, using structured psychiatric interviews, neuropsychological tests, and EEGs. In addition, global assessments were made, comparing pre- versus postoperative status. The objective data revealed no indication of worsening or damage with similar pre- and postoperative test scores and EEG features. Computer-scored interviews revealed considerable psychopathology in the ambulatory patients. Overall judgments of behavior, seizures, and functional levels indicated that more than a third of the group was probably improved, although the relationship of outcome to the surgery was indeterminate.

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.

Mechanisms of action of ECT: schizophrenia and schizoaffective disorder.

A variety of neurophysiological mechanisms have been suggested to explain the therapeutic action of electroconvulsive therapy (ECT). Processes of kindling, resolution of hemispheric dysfunctions, anticonvulsant effects, and diencephalic stimulation all have been proposed to account for the beneficial effects of ECT. To investigate these, we analyzed clinical, neuropsychological, and electroencephalographic (EEG) data from 110 ECT-treated patients with schizophrenia and schizoaffective disorders, comparing responders with nonresponders. Fifty-four percent of all the patients were rated as very much or much improved. Mechanisms of kindling or anticonvulsant effects were not supported by the data. Dominant hemispheric dysfunctions in schizophrenics were suggested by the neuropsychological test data. There was tenuous support for the sensitization theory and both the neuropsychological and EEG data contradicted the dominant accentuation theory. Taken together with our previous report on ECT-treated patients with affective disorders, we propose that ECT might act by restoration of equilibrium between the hemispheres.

Electroencephalographic findings in relation to diagnostic constructs in psychiatry.

A group of 759 patients with final DSM-I and -II diagnoses of schizophrenia was identified among a cohort of 1494 adults who were hospitalized between 1965 and 1972. Admission EEG recordings were done in each patient during waking, activation procedures, drowsiness, and sleep. All cases were reclassified according to the Feighner et al. criteria, and relationships between the EEG, reassigned diagnosis, and outcome were examined. One-third of the schizophrenics were rediagnosed as having affective, organic, or other disorders. EEG abnormalities predicted diagnostic change and relatively favorable prognosis. Mean alpha frequencies were slower in schizophrenics than in patients with other DSM I-II disorders, and less in patients with Feighner et al. diagnoses of schizophrenia than in some rediagnosed categories. In 1980-82, matched samples from the original cohort with affective, schizophrenic, and mixed Feighner et al. diagnoses were followed and evaluated blindly with the SADS-L. RDC follow-up diagnoses were significantly correlated with the index EEG findings in terms of higher alpha average frequencies proportional to the amount of affective psychopathology. A subgroup of high functioning individuals within the RDC schizophrenic category was identified with affective symptomatology early in the course of illness, normal EEGs, and high alpha average frequencies. Patients with a consistent diagnosis of schizophrenia according to the three nosologic systems were shown to function better in some areas if the index EEG was abnormal. Discriminant function analysis established that DSM-I and -II categories possessed the greatest long-term predictive accuracy which was enhanced by the EEG diagnosis and alpha average to a level of more than 50%. The Feighner et al. and RDC diagnostic systems were not as relevant for prediction of long-term follow-up status.

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.

Plasma GABA predicts acute response to divalproex in mania.

Bipolar I, manic phase inpatients were treated with divalproex sodium, lithium, or placebo in a previously reported parallel group multicenter, double-blind, randomized, controlled acute phase treatment trial. Plasma concentrations of gamma aminobutyric acid (GABA) were measured before and after treatment. Higher pretreatment plasma GABA levels were significantly (p = .04) related to a better clinical response to divalproex (n = 19). Pretreatment plasma GABA levels did not correlate with response to either lithium (n = 13) or placebo (n = 31). Following treatment with divalproex sodium, plasma GABA levels decreased significantly (p < .05), compared to placebo. Pretreatment plasma GABA levels were not related to overall severity of manic symptoms. Plasma GABA may predict response to pharmacologic agents acting on the GABA system.

A placebo-controlled study of lithium combined with neuroleptics in chronic schizophrenic patients.

Lithium combined with major tranquilizers was administered to 22 hospitalized chronic schizophrenic patients with minimal neurotoxicity or other side effects. Moreover, 10 of the patients benefited significantly with lithium as compared to placebo in terms of blind psychiatric and nursing ratings and nonblind clinical judgments of outcome. These results contrast with previous negative reports in the literature and the generally poor prognosis in chronic schizophrenic patients. The authors suggest that a trial combining lithium with psychotropic drugs is warranted in schizophrenic patients who do not respond satisfactorily to conventional treatment

Relation of serum valproate concentration to response in mania.

OBJECTIVE: This study was designed to determine the relation of valproate serum levels to clinical improvement and development of adverse effects in hospitalized patients with acute mania. The initial fixed-dose escalation design, the monotherapy with divalproex, and the control of variables that is possible only with hospitalized patients reduced the confounding factors present in most outpatient studies of serum level-response relationships. METHOD: Sixty-five hospitalized patients who met the Research Diagnostic Criteria for bipolar disorder with mania were treated with divalproex, 750 mg/day for 2 days and then 1,000 mg/day on days 3-5; the dosage was subsequently adjusted as clinically indicated for the remainder of the 21-day study. Manic symptoms were assessed with the Mania Rating Scale, which is derived from the Schedule for Affective Disorders and Schizophrenia. RESULTS: At day 5, patients with serum valproate levels > or = 45 micrograms/ml were two to seven times as likely as patients with levels < 45 micrograms/ml to show 20% or greater improvement in scores on the manic syndrome subscale, the behavior and ideation subscale, elevated mood, increased activity, motor hyperactivity, and psychosis. Endpoint analyses yielded similar results. Adverse experiences characteristic of divalproex treatment were disproportionately associated with serum levels > or = 125 micrograms/ml. CONCLUSIONS: Acutely manic patients treated with divalproex who have valproate serum levels between 45 and 100-125 micrograms/ml are much more likely to have efficacious and well-tolerated responses than patients with lower or higher levels of valproate.

Trazodone, a new antidepressant: efficacy and safety in endogenous depression.

The effectiveness of trazodone was assessed over a 4-week period under double-blind conditions. Twenty-eight inpatients with a diagnosis of endogenous depression received either trazodone, imipramine, or placebo. Trazodone was significantly better than placebo and frequently better than imipramine according to analyses of the results of the Hamilton Psychiatric Scale for Depression, severity of illness and clinical global improvement ratings, and the Global Ward Behavior Scale. Significant improvement was evident in the trazodone group by the end of the first week of therapy, particularly in those symptoms associated with depression and accompanying anxiety. There were fewer side effects with trazodone than with imipramine.

Treatment outcome with clozapine in tardive dyskinesia, neuroleptic sensitivity, and treatment-resistant psychosis.

Thirty-eight chronically ill psychotic patients were treated with clozapine for indications of tardive dyskinesia, severe extrapyramidal side effects caused by other neuroleptics, or treatment-resistant psychosis. Fifty-five percent of all patients and 40% of schizophrenics improved with clozapine. Abnormal involuntary movements were suppressed during treatment and, with 1 exception, returned to baseline levels after clozapine was discontinued. Our results support the conclusion that clozapine's efficacy in refractory cases and its lack of neurological side effects make it a unique neuroleptic with advantages over conventional antipsychotic agents. The drug appears to be safe when treatment is accompanied by frequent clinical and hematologic monitoring.

Comparison of molindone and tranylcypromine in the treatment of refractory depression.

A single-blind parallel study of 20 treatment-resistant hospitalized depressed patients showed that 10-30 mg/day molindone was more effective and less toxic than 20-30 mg tranylcypromine. Molindone-treated patients responded during the first week with particular improvement in anxiety symptoms and agitation. Extrapyramidal symptoms developed in half of the patients on molindone, which were effectively managed with amantadine. Early termination from the study because of clinical worsening or side effects occurred in seven patients on tranylcypromine and in none on molindone. These results suggest that molindone in low dosage may be helpful in the management of refractory depression and may have the further advantage of producing a more rapid response to treatment with fewer disabling side effects.

Electroconvulsive therapy for mania.

Early literature on the use of electroconvulsive therapy (ECT) for mania is reviewed briefly, followed by an account of retrospective and prospective studies that indicate the usefulness of ECT in the treatment of mania. Case vignettes that involve patients with relatively mild manic illnesses are presented, followed by discussion of technical issues, side effects and complications, drug interactions, monitoring, special populations and circumstances, and regulatory aspects. The article concludes with a brief consideration of possible mechanisms of action.

Influence of sex and handedness on hemispheric functioning.

Forty normal adult volunteers comprising an equal number of right- and left-handed males and females solved simple multiplication problems presented visually to one cerebral hemisphere while various competing stimuli were simultaneously presented to the other hemisphere. The contribution of sex of subject, handedness, hemisphere of presentation and the nature of the competing stimulus in relation to task performance was examined. Each of these variables was significantly associated with correct responses and errors, with few statistically significant interactions. Females and dextrals made more correct responses than males or sinistrals. Type of error depended upon which hemisphere received the problem, with the right hemisphere yielding more errors of commission and the left more errors of omission. Simultaneously presented identical or different arithmetic problems resulted in the most errors compared to the other competing stimuli.