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.

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.

Radiographic screening for ECT: use and usefulness.

Members of the Association for Convulsive Therapy were surveyed by mail about use of muscle relaxants and radiologic studies for ECT. One hundred eleven completed responses were received (69%), indicating that 40% routinely acquire pre-ECT spine and skull radiographs taking from 1 to 10 films. From patients receiving more than one course of ECT, 57 pre- and post-ECT pairs of films taken within 1 month of the start and end of a course, respectively, were selected. The films were identified only by age and sex of the patient and were evaluated by a radiologist. A senior psychiatrist reviewed the pre-ECT radiographic reports to determine whether a change in routine ECT procedure was required. Few clinically significant radiologic findings in the pre- or post-ECT films were noted.

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.

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.

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.

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.

Multiple personality disorder. A clinical investigation of 50 cases.

To study the clinical phenomenology of multiple personality, 50 consecutive patients with DSM-III multiple personality disorder were assessed using clinical history, psychiatric interview, neurological examination, electroencephalogram, MMPI, intelligence testing, and a variety of psychiatric rating scales. Results revealed that patients with multiple personality are usually women who present with depression, suicide attempts, repeated amnesic episodes, and a history of childhood trauma, particularly sexual abuse. Also common were headaches, hysterical conversion, and sexual dysfunction. Intellectual level varied from borderline to superior. The MMPI reflected underlying character pathology in addition to depression and dissociation. Significant neurological or electroencephalographical abnormalities were infrequent. These data suggest that the etiology of multiple personality is strongly related to childhood trauma rather than to an underlying electrophysiological dysfunction.

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.

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.

Computerized EEG profiles of haloperidol, chlorpromazine, clozapine and placebo in treatment resistant schizophrenia.

In this paper we have described early applications of computerized EEG techniques in psychopharmacology. Perhaps our most remarkable finding was there were practically no differences between very chronic drug free schizophrenic patients and normals, which contradicts much of the EEG imaging literature. To us, the most likely explanation is that most of the anterior slowing observed in other studies was due to contamination from orbital artifacts, which we took exceptional pains to remove. Lingering effects of neuroleptic medications may also have contributed. Alternatively, EEG deviations in schizophrenia may recede when the illness reaches a very chronic stage, although this hypothesis is less tenable. There were significant differences between placebo and the three neuroleptics in terms of increased amplitudes in the delta and theta frequency bands in the anterior head regions, which is compatible with data from other studies. These changes were most pronounced with clozapine and least prominent with haloperidol, with chlorpromazine occupying an intermediate position. This order happens to parallel their relative antiserotonergic, antihistaminic and anticholinergic properties. The latter may have been partially obscured by the addition of benztropine. In a subgroup of patients who were recorded under each of the treatment conditions, there were more fast frequencies with clozapine than with the other neuroleptics agreeing with Roubicek and Major. This could be a function of clozapine's increased adrenergic activity as reported by Ackenheil. An unexpected finding was that patients who responded to clozapine had higher amplitudes in the alpha spectrum, most pronounced in the left anterior quadrant, than did the nonresponders. These differences between responders and nonresponders obtained whether patients were on placebo, haloperidol or clozapine. Curiously, Buchsbaum et al. found that anxious patients who responded to benzodiazepines also had higher alpha amplitudes in the same brain regions, which differentiated them from nonresponders. These findings clearly warrant future scientific investigation. In this regard, the generalizability of our data is limited by the extremely chronic, treatment-resistant population studied. However, promising directions for further research in EEG and psychopharmacology have been identified.