Clinical and quantitative EEG studies of mania.

BACKGROUND: Earlier EEG studies reported essentially normal findings during acute manic episodes but some atypical EEG characteristics and distinctions between familial and sporadic cases were described. Recently quantitative EEG (qEEG) studies differentiating mania from schizophrenia and depression have been published. METHODS: Clinical EEGs were obtained in 202 patients hospitalized for acute mania. EEGs were repeated in 75 patients rehospitalized for subsequent manic attacks. Quantitative EEGs were recorded in 37 patients who were able to cooperate after drug washout and again on completion of randomly assigned pharmacotherapy. RESULTS: Normal EEGs were obtained in most patients. Moderately abnormal EEGs in 16% were significantly associated with absent family histories of affective disorder. Left sided abnormalities were more common than right. "Small sharp spikes" and "microsleep" were encountered in 17% and 10% respectively of patients who drowsed. EEG findings during subsequent episodes did not suggest increasing CNS vulnerability. qEEGs showed significant differences between each of the therapeutic agents compared-lithium, carbamazepine, and lithium combined with carbamazepine, haloperidol or risperidone. Nonresponders at baseline had significantly more diffuse theta activity than responders. During pharmacotherapy nonresponders had higher amplitudes in the left temporoparietal areas. LIMITATION: Clinical EEG findings confirmed previous reports but did not contain original observations. Applications of qEEG were limited by requirements for patient cooperation.

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.

Melatonin for sleep EEG.

Melatonin 3 mg and secobarbital 100 mg assigned randomly were given to 40 psychiatric patients for sleep induction during EEG recording. Nine patients who did sleep naturally comprised a comparison group. EEGs were read blind; most were interpreted as mildly abnormal or within normal limits. No statistically significant differences between the three groups were observed in response to photic stimulation, hyperventilation or in frequency of paroxysmal variants. The electroencephalographer was able to identify the melatonin patients significantly more accurately than those who received secobarbital on the basis of lack of EEG manifestations of fast frequencies typical of barbiturate effects. Self-assessments of drowsiness, anxiety and performance on a perceptual-motor task were similar in the melatonin and secobarbital patients. However, the secobarbital group showed more impairment on a locomotion test than those who received melatonin or slept spontaneously. The results suggest that melatonin is a plausible alternative for EEG sleep sedation, especially for ambulatory patients.

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.

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.

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.

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.

Comparison of therapeutic modalities for mania.

The results of sequential therapeutic trials in hospitalized manic patients conducted over a 16-year period are summarized, followed by an analysis of pooled data to assess relative efficacy. No clinically important baseline differences were found in the patients admitted to these studies despite the long time span. They were not overly "difficult to treat" or treatment resistant, and most were discharged to the community. Nearly all outcome measures showed statistically significant differences between groups after 8 weeks of treatment. The best responses occurred in the patients who received a mean series of nine electroconvulsive therapy (ECT) treatments with sparing use of neuroleptics followed by lithium maintenance. The next best outcome was observed with lithium combined with low doses of standard neuroleptics or risperidone. The combination of carbamazepine and lithium had significantly fewer neurological side effects than moderate doses of haloperidol with lithium, with equivalent therapeutic results. Monotherapy with either lithium or carbamazepine was less effective than the combination treatments. Minor differences in study design may contribute to the variance in outcome.

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.

Lithium combined with carbamazepine or haloperidol in the treatment of mania.

Hospitalized manic patients were withdrawn from psychoactive medications for 2 weeks after which they were randomized to double-blind treatment with carbamazepine plus lithium [CBZ-Li] or haloperidol plus lithium [HAL-Li] with benztropine. Unit dosages of Li 300 mg, CBZ 200 mg and HAL 2 mg were titrated to therapeutic plasma levels and maintained for 8 weeks. No rescue medications were permitted after 3 weeks. Standard ratings of psychopathology and side effects were accomplished weekly. Sixty patients entered the study but only 33 remained for randomization after drug washout. By 8 weeks both groups were improved from baseline without statistically reliable differences between them. However HAL-Li patients had more extrapyramidal side effects that were major reasons for dropout, whereas CBZ-Li patients were more often noncompliant and initially required more rescue medications. We conclude that either combination treatment can be beneficial but CBZ-Li has the advantage because of fewer neurologic side effects.

EEG monitoring during ECT research.

The current practice of monitoring brain electrical activity with single channel recordings during ECT induced seizures does not meet contemporary EEG standards. Multichannel recordings are essential for artifact identification, determination of seizure endpoint, and assessment of electrophysiological features in different brain regions. Careful attention to technical aspects and detailed descriptions are important for interpretation and for scientific communication. Standardized procedures for EEG monitoring during ECT should be developed for general clinical use and for research and training applications.

Sleep induction for EEG revisited: technical note.

Forty-two patients each were randomly assigned in equal numbers to receive either zolpidem or secobarbital for sleep EEG recording. Three groups were compared; zolpidem, secobarbital and a control group of patients who drowsed spontaneously. All patients were evaluated before and immediately after the EEG and several hours later with measures of anxiety, perceptual-motor performance, locomotion, and subjective judgments of sleepiness. EEG response to standard activation procedures, signs of drowsiness and sleep and overall diagnoses were compared among the three groups. No differences emerged in demographic measures, psychiatric diagnoses, current drug treatment and experience with hypnotics. There were no statistically significant differences among the three groups or between the patients receiving the hypnotics on the anxiety performance and locomotion measures or degree of alertness. As a result of the experimental design, the unmedicated control patients showed EEG signs of drowsiness and sleep significantly sooner than patients receiving hypnotics. They also showed more slow or paroxysmal activity in response to hyperventilation, which may have been due to their greater effort. These results led us to retain secobarbital as the hypnotic for EEG sleep, mainly for economic reasons.

Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group.

OBJECTIVE: To compare the effectiveness of divalproex sodium with that of lithium and placebo in patients with acute mania. DESIGN: Randomized, double-blind, parallel-group study of treatment outcomes in patients with manic-depressive illness. PATIENTS: A total of 179 hospitalized, acutely manic patients meeting the Research Diagnostic Criteria for manic disorder, approximately half of whom had been nonresponsive to lithium previously, were studied at nine university-affiliated hospitals. INTERVENTIONS: After a minimum 3-day washout period, random assignment for 21 days to divalproex, lithium, or placebo in a 2:1:2 ratio. Dosage of divalproex and lithium was increased if tolerated to a target concentration of 1041 mumol/L (150 micrograms/mL) or 1.5 mmol/L (conventionally expressed as milliequivalents per liter), respectively. MAIN OUTCOME MEASURES: Primary outcome measures were changes in the Mania Rating scale derived from the Schedule for Affective Disorders and Schizophrenia. RESULTS: Intent-to-treat analysis for efficacy was based on data from 68, 35, and 73 patients in the divalproex, lithium, and placebo groups, respectively. Groups were initially comparable except that all eight patients with four or more manic episodes in the previous year were in the divalproex group. In 30%, 33%, and 51% of the above groups, treatment was prematurely terminated due to lack of efficacy, with fewer premature terminations from divalproex than placebo (P = .017). The proportions of patients improving at least 50% were higher for divalproex and lithium groups than for the placebo group: 48% for divalproex (P = .004) and 49% for lithium (P = .025) vs 25% for placebo. Divalproex was as effective in rapid-cycling manic patients as in other patients. CONCLUSIONS: Both divalproex and lithium were significantly more effective than placebo in reducing the symptoms of acute mania. The efficacy of divalproex appears to be independent of prior responsiveness to lithium.

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.

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.

Inhibition of lettuce seed germination by cycloheximide and chloramphenicol is alleviated by kinetin and oxygen.

Kinetin alleviates cycloheximide inhibition and oxygen alleviates chloramphenicol inibition of germination of lettuce seeds (Lactuca sativa L. cv Grand Rapids). The effect is not due to increased but rather a substitution for protein synthesis. A cytokinin and energy supply appear prime requirements for germination.

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.

Anticonvulsants in affective disorders.

The current status of anticonvulsant drugs compared to other treatments for the management of affective disorders is evaluated. Data from controlled studies suggest that carbamazepine is superior to placebo, equivalent to neuroleptics, and comparable to lithium for mania, at least in relatively treatment-refractory patients. Carbamazepine may also be useful as an antidepressant and for prophylaxis. Valproate and clonazepam show promise in the treatment of mania and for prophylaxis, but the number of patients studied in controlled trials is small. Lorazepam and other benzodiazepines may be useful antimanic agents, and alprazolam exerts antidepressant effects, although its efficacy relative to the tricyclics is unclear. Electroconvulsive therapy (ECT) is effective for both mania and depression. Established treatments are carbamazepine and ECT for mania and ECT for depression. Still experimental are valproate and clonazepam for mania; carbamazepine and alprazolam for depression; and carbamazepine, ECT, valproate, and clonazepam for maintenance. Combinations with lithium appear promising but await double-blind trials. The place of other anticonvulsants in the treatment of affective disorders is unknown.