Emergence of myasthenia gravis during treatment with lithium carbonate.

In a patient with recurrent episodes of severe mania, classical manifestations of myasthenia gravis developed for the first time during treatment with lithium carbonate. Four episodes were recorded in which the appearance of progressive weakness coincided with subacute or long-term lithium carbonate administration during periods of psychiatric remission. In each instance, neurologic symptoms were ameliorated or disappeared shortly after the drug was discontinued or its dosage was reduced. There was no evidence of lithium carbonate toxicity or electrolyte disturbances at any time during treatment. Based on a literature review of animal studies and related clinical reports, a mechanism of peripherally mediated neuromuscular cholinergic insufficiency is proposed. In addition, the differential diagnosis of muscle weakness during lithium carbonate administration is discussed.

Platelet monoamine oxidase in affective disorders.

Platelet monoamine oxidase (MAO) activity was determined with tryptamine as substrate for 61 drug-free patients who had a primary major depressive disorder and for 32 normal controls. Although there were no significant differences between the mean platelet MAO activity of 19 bipolar patients (4.94 nmoles/hr/mg of protein), 42 unipolar patients (4.97 nmoles), and the controls (4.78 nmoles), an analysis of variance indicated that the variance of the bipolar group was significantly greater than that of the other groups. This suggests that there may be subgroups of bipolar patients that differ in their platelet MAO activity but that appear to be distinct from the bipolar I vs bipolar II classification.

Incidence and signficiance of mixed affective states in a bipolar population.

The simultaneous existence of manic and depressive symptoms in a manic-depressive patient was first described by Kraepelin. This so-called mixed state has come to have much theoretical significance in recent hypotheses about the nature of bipolar affective disorders. In this investigation a mixed state is shown to be the initial episode in 31% of 84 manic-depressive outpatients. Moreover, the presence of "mixed" features does not correlate with severity of illness or mood circularity, but does correlate with sedative abuse and poor response to psychopharmacologic treatment. These results suggest that the "continuum hypothesis" and its satellite theories represent viable conceptualizations of the nature of manic-depressive illness.

Neuropsychological assessment and EEG sleep in affective disorders.

The neuropsychological test performance of 76 hospitalized, depressed patients meeting RDC for the presence of affective disorder was assessed as part of a protocol involving amitryptyline (n = 53) or placebo (n = 23). Tests included the Trail-making Test (TMT), the Benton Visual Retention Test, and the Shipley-Hartford Scale. Clinical ratings and data concerning the characteristics of EEG sleep were also obtained. Analysis of data collected after a drug-free period of 2 weeks and again at the end of the protocol yielded the following conclusions. Base-line performance was inferior to norms for these tests, but for the TMT, scores were not as poor as that expected for brain-damaged patients. Poor performance was often associated with older age, the presence of psychotic features, and prolonged sleep latencies. Baseline Hamilton Rating Scale (HRS) was predicted best by TMT part B. However, this association was not as strong as that between HRS and poor sleep efficiency. Treatment with drug or placebo had little differential effect upon test performance over the course of the protocol. It is suggested that further research should utilize tests which have specificity in localizing cerebral lesions, so that any focal deficits in brain function in depression might be identified.

Adjustment of lithium dose during lithium-chlorothiazide therapy.

There has been a long-held belief that lithium salts cannot be used in the presence of thiazide diuretics. Recently, however, thiazides have been demonstrated to be not only safe, but actually indicated in two situations in which lithium salts are used. The first is in the treatment of lithium-induced nephrogenic diabetes insipidus and the second is in severe manic depressive illness in which high doses of lithium do not produce therapeutic serum or intraeythrocytic lithium concentrations. This new information now makes it possible for some manic depressive patients with serious medical illnesses (such as hypertension or congestive heart failure), in whom thiazide diuretics are routinely used, to be treated cautiously with lithium carbonate. This paper analyzes data from 13 patients taking lithium carbonate and varying doses of chlorothiazide in order to indicate the approximate magnitude of downward adjustment of daily lithium dose which the clinician must make to safely give 500, 750, and 1,000 mg/day of chlorothiazide.

Thiazide-lithium synergy in refractory mood swings.

The unfortunate experience with lithium chloride as a salt substitute in the 1940s still directs the clinical usuage of lithium carbonate to a certain extent. We are still warned that lithium salts should never be used in low-sodium situations (e.g., with thiazide diuretics or salt-restricted diets); however, it has recently been shown that thiazide diuretics may be safely used in the treatment of lithium-induced nephrogenic diabetes insipidus (NDI). The authors recapitulate the dangers inherent in the use of this drug combination and present detailed clinical-pharmacologic data on 13 patients which suggest that thiazides are useful in the treatment of lithium-induced NDI and may actually synergize with lithium to produce improved mood control in some lithium-refractory manic-depressive patients.

Urinary MHPG and clinical response to amitriptyline in depressed patients.

The authors treated 18 rigorously diagnosed depressed patients with amitriptyline after baseline urine samples were collected for the measurement of 3-methoxy-4-hydroxphenylglycol (MHPG). Neither age nor severity of depression before treatment correlated with MHPG excretion. There was also no significant correlation between baseline MHPG excretion and clinical response at the end of at least 25 days' treatment with amitriptyline. The authors discuss the relevance of amitriptyline and nortriptyline plasma levels to MHPG and the noradrenergic/serotonergic theories of depression.

Age, dementia, dyskinesias, and lithium response.

Nineteenth-century neuropsychiatrists felt that the aged bipolar patient usually developed chronic mania, which eventually turned into dementia. The authors' elderly patients seemed to experience few such denouements, so they evaluated the course and treatment response of 81 bipolar patients over the age of 55. Fifty-six responded well to lithium. Advanced age had no effect on course or outcome. However, with increased clinical evidence of neurological illness there was an increased incidence of chronic mania, a poorer response to lithium, and more frequent and severe neurotoxicity. Extrapyramidal syndromes were particularly devastating.

Sleep and treatment prediction in endogenous depression.

The prediction of clinical response in depression has been based primarily on clinical symptoms and history. Recently, psychobiologic measures have been used to increase the accuracy of clinical prediction. In 34 drug-free patients with primary endogenous depression treated with amitriptyline, the application of EEG-monitored sleep criteria alone was more significant than clinical status alone in the prediction of clinical response. Prolonged REM latency and reduced difficulty in sleep onset following the administration of amitriptyline were the main sleep variables contributing to this prediction equation. These data suggest a strong relationship between clinical outcome and psychobiologic profile in patients with endogenous depression after a "pharmacologic probe" with a tricyclic antidepressant.

The pharmacological treatment of delusional depression.

The authors investigated the pharmacological treatment of delusional depression by assigning patients on a random double-blind basis to amitriptyline alone, perphenazine alone, or a combination of the two. Fourteen (78%) of the 18 patients assigned to amitriptyline plus perphenazine were responders, compared with seven (41%) of 17 patients treated with amitriptyline alone and three (19%) of the 16 patients treated with perphenazine alone. The combination of amitriptyline and perphenazine was clearly superior (p less than .01).

Familial psychosis and diverse neurologic abnormalities in adult-onset Gaucher's disease.

A family is described in which adult-onset Gaucher's disease developed, followed years later by atypical psychotic disorders with neurologic and electroencephalographic abnormalities. A biochemical investigation of primary and secondary enzyme alterations in the index case was performed in an attempt to identify a pattern that might be specific to this clinical profile. The literature pertaining to CNS involvement in adult patients with Gaucher's disease is also reviewed. An etiologic link may exist between the inherited metabolic disorder and associated neuropsychiatric impairment. The biochemical basis of this hypothesized association remains unclear, however, and further enzymatic and pathologic investigations are warranted.

EEG sleep alterations in olivopontocerebellar degeneration.

All-night polygraphic recordings of the electroencephalogram, horizontal electrooculogram, and submental electromyogram were performed in two patients with familial olivopontocerebellar degeneration. Sleep was characterized by subnormal measurements of both rapid eye movement (REM) and delta (slow-wave) sleep. Phasic eye movements were reduced out of proportion to tonic components of REM sleep. These findings lend further support to theories linking the pontine nuclei to the primary regulation of sleep in both experimental animals and humans.

Anergic depression accompanied by increased intracellular sodium and lithium.

This report describes a patient who experienced chronic retarded depression punctuated by precipitous worsening of mood with hyperphagia or by intermittent euphoric episodes. Ratings of depressive symptom severity changed in close association with intracellular sodium content. Intracellular sodium was highly correlated with intracellular lithium. Difficulties that were encountered in the clinical management of this patient are discussed.

ECT response in psychotic versus nonpsychotic unipolar depressives.

Thirty primary unipolar depressives were studied to determine whether depressed patients with psychotic symptoms respond better to ECT than those without such symptoms. Psychotic (N = 9) and nonpsychotic (N = 21) patients showed equal therapeutic benefit in similar periods of time. Thus, the presence of psychotic symptoms did not enhance the degree of response to ECT in patients with primary unipolar major depression.

Response of energy and suicidal ideation to ECT.

The mean suicidal ideation scores of 37 patients receiving ECT improved significantly earlier than energy items. However, caution is recommended in prematurely dismissing clinical wisdom regarding suicidal risk during treatment for depression.

DSM-III, RDC, and ECT: depressive subtypes and immediate response.

The usefulness of RDC and DSM-III diagnostic subtypes as predictors of response to ECT was examined in a multi-observer, multi-factorial study of 44 depressed patients. Most of the patients met criteria for "endogenous" and/or "melancholic" subtypes of major depressive disorders. None of the RDC or DSM-III subtypes (reactive, secondary, nonpsychotic) identified the least responsive patients. Thus, the presence of "reactive" factors, the absence of psychotic symptoms, or the presence of other illnesses did not reduce the likelihood or degree of immediate response to ECT in patients with major depression.

Transmembrane distribution of lithium and sodium in erythrocytes of depressed patients.

In this investigation the intracellular: extracellular distribution of lithium across the erythrocyte membrane (RBC lithium distribution) was studied in vitro and in vivo. The in vitro studies were conducted by incubating cells from drug-free subjects in lithium-containing physiologic media. The in vivo studies consisted of measurements of plasma and erythrocyte (RBC) lithium and sodium concentrations during lithium carbonate treatment. Previous observations of a correlation between in vitro and in vivo RBC lithium distribution values were verified, and it was found that addition of 0.1 mM ouabain to the in vitro incubation media abolished this correlation. To examine the relationship between RBC lithium distribution and specific clinical features of depression, in vitro studies were conducted with RBCs from 20 depressed patients and 14 nondepressed control subjects. The patients were categorized as having bipolar (manic-depressive), unipolar, or secondary depressive disorders. After in vitro incubation with lithium for 48 h, the RBCs from bipolar patients had lithium distribution values that were similar to those observed in ouabain-treated cells. It appears that the lithium transport characteristics of RBCs of bipolar patients may differ from those of other depressed patients or nondepressed subjects.

EEG sleep in primary depression. A longitudinal placebo study.

Characteristic EEG sleep changes in depression are highlighted by a sleep continuity disturbance, delta sleep reduction, and a shortened REM latency. Since these findings have been derived primarily from only a few baseline recordings, questions regarding their persistence and/or variability have not been previously addressed. As part of an extensive set of investigations of EEG sleep in depression, we examined nightly the sleep of 12 hospitalized, non-delusional, primary depressives who were involved in a program of active psychosocial treatment intervention and received only placebo during a 5-week study period. EEG sleep findings revealed a relative lack of change across time, particularly in those parameters reported to be associated with a primary or 'biologic' depressive episode. While some degree of clinical improvement was noted, the group failed to achieve a state of remission or even partial remission as determined by the Hamilton Rating Scale. It appears that the major sleep alterations associated with such disorders persist for up to at least 5 weeks in the absence of pharmacologic or other somatic intervention.

Evaluation of depression in a general hospital: utility and limitations of the dexamethasone suppression test.

Use of the DST was studied in medically hospitalized, depressed patients. Although complicating medical factors necessarily excluded nearly 60% of referrals, post-dexamethasone plasma cortisol values were significantly higher in 14 major depressives appropriate for the DST as compared to 12 patients with milder, subsyndromal depressive conditions. Using a plasma cortisol criterion of greater than 7 micrograms/dl, the DST identified major depression with 57% sensitivity and 92% specificity in this subsample (p less than 0.005). While limited by a high exclusion rate, the DST may be useful for confirmation of major depression in carefully screened general hospital patients. Implications for research and practice are discussed.

EEG sleep and affective psychoses: I. Schizoaffective disorders.

The sleep electroencephalogram (EEG) was studied in 41 depressed inpatients. EEG sleep records were compared for two diagnostic subgroups; patients with psychotic depression (n = 29) or with schizoaffective disorders (n = 12). As was true in the previous pilot study, no major EEG sleep variables distinguished the patients with psychotic depression from those with schizoaffective disorders. These data are consistent with the theory that all psychotic depressive states may have certain common psychobiologic features such as shortened rapid eye movement (REM) sleep latency.