Medical treatment of mental illness.

Psychotherapeutic drugs have dramatically improved the prognosis for patients with severe mental illness. The drug treatments are not a panacea. The medications sometimes cause irreversible side effects, and they are not helpful for all patients. They allow large numbers of individuals to leave the hospital, but to return to communities that are often poorly prepared to provide continuing care. Despite their limitations, psychotherapeutic drugs relieve a great deal of human suffering. They also involve psychiatry in modern biological science. This has led to the continuing search for more effective medications based on the study of possible biochemical substrates of psychiatric disorders.

Plasma beta-endorphin immunoreactivity in schizophrenia.

Plasma beta-endorphin-like immunoreactivity was measured by a method that was equally sensitive to beta-endorphin and [Leu5]-beta-endorphin. Immunoreactivity in 98 schizophrenic patients did not differ greatly from that in 42 normal subjects. No immunoreactivity was detectable in dialyzates from first-time hemodialysis of eight nonpsychotic renal patients and nine schizophrenic patients. These results are not compatible with recent reports of extremely high concentrations of [Leu5]-beta-endorphin in hemodialyzates from schizophrenic patients.

Effects of naloxone on schizophrenia: reduction in hallucinations in a subpopulation of subjects.

Endogenous opiate-like peptides (endorphins) are putative neuroregulators located throughout the mammalian brainstem. There is some evidence for their role in pain, stress, and affect. We report that the opiate antagonist, naloxone, alters some schizophrenic symptoms. In a double-blind, cross-over study, naloxone produced decreases in auditory hallucinations in some schizophrenic patients. This finding supports the hypothesis that the endorphins may play a roll in modulating hallucinations in a highly selected subgroup of chronically hallucinating schizophrenic patients.

Abnormal rapid eye movement latencies in schizophrenia.

Several previous studies have observed short rapid eye movement (REM) latencies in schizophrenic patients without major affective disorder. This study was designed to meet several of the criticisms of those previous studies. Using Research Diagnostic Criteria, we compared the sleep patterns of schizophrenic patients with those of normal controls and patients with major depressive disorder and schizoaffective disorder. All patients were medication free, and REM latency was explicitly defined using both strict and lenient criteria. Chronically ill paranoid or undifferentiated schizophrenics could not be distinguished from patients with major depressive disorder or schizoaffective disorder using any definition of REM latency. These results were not due to longer REM latency in the particular sample of patients with major depressive disorder. They had abnormally low REM latencies; however, the schizophrenic patients showed similar decrements. These data cast serious doubt on the specificity of short REM latency as a biological marker for major depressive disorder.

Some observations on the opiate peptides and schizophrenia.

With the discovery of the opiate peptides, several major avenues of research became apparent. These peptides produced a great deal of focused attention on their anatomy, biochemistry, and physiology. In this article, we present an overview of some of the main research issues and recent findings in the field of opiate peptides. The possible relationship of the opiate peptide neuronal systems to schizophrenia is discussed in light of attempts to alter schizophrenic symptoms with opiate antagonists, beta-endorphin, and dialysis. It is hypothesized that if the opiate peptides are involved in schizophrenia, then their involvement with dopamine systems and/or with stress responses may be critical.

Subtypes of depression based on excretion of MHPG and response to nortriptyline.

We investigated the relationship between urinary excretion of MHPG and the clinical response of 17 depressed patients to nortriptyline hydrochloride. Plasma concentrations of nortriptyline were monitored to assure optimal doses. Patients were classified as having "low" or "normal-high" excretion of MHPG based on one to five 24-hour urine specimens. Hamilton Depression Rating Scale scores were not reduced significantly more among the nine low excreters as compared with the eight normal-high excreters. However, when a true bimodal distribution of MHPG excretion was created by comparing only the six lowest excreters with the six highest excreters, the low group improved significantly more than the high group. This differential response to nortriptyline somewhat supports the notion that MHPG excretion may predict response to specific tricyclics. Collecting urine for MHPG determination in depressed patients is not easy; the variability of excretion within patients is considerable, and the range of MHPG excretion closely parallels that in normal persons. The clinical utility of this procedure is still to be determined.

Physostigmine in mania.

Seven men and one woman with primary affective disorder, mania, were given a slow intravenous infusion of physostigmine salicylate. In six patients, mood and thought content changed from mania toward depression as evaluated by either a visual analog mood scale or the Pettersen scale. Two other patients, who were the only predominantly irritable manics in the study, demonstrated little change in their hostility, although one became somewhat depressed. These findings are consistent with earlier reports of suppression of manic symptoms after physostigmine infusion in some but not all patients with mania. The pharmacologic mechanism of physostigmine reversal of manic symptoms may be the direct result of increased cholinergic activity or a result of the effect of increased cholinergic activity on other brain neurotransmitters.

Impaired central error-correcting behavior in schizophrenia.

Previous work has suggested that normal subjects are able to recognize and correct their own errors of movement without using exteroceptive signals. This ability may be impaired in schizophrenia. Twelve normal subjects, 12 alcoholics, and 14 schizophrenics performed a step-function tracking task designed to prevent the use of exteroceptive signals in correcting errors of movement. The mean probability of correcting an error without external cues was approximately .38 in schizophrenics, .70 in normal subjects, and .75 in hospitalized alcoholic patients. There was no difference between groups in the ability to initiate correct responses. The results suggest that schizophrenics are deficient in the ability to monitor ongoing motor behavior on the basis of internal, self-generated cues.

Pituitary response to thyrotropin-releasing hormone in depression.

Plasma thyrotropin (TSH) levels varied relatively little over minutes to days in the same individual not subjected to challenge with thyrotropin-releasing hormone (TRH). Thus, the TSH response to stimulation with TRH is not likely to be confounded by spontaneous changes of comparable degree. Variable numbers of depressed patients showed a blunted response to TRH stimulation of the pituitary, but the exact prevalence of this phenomenon remains to be clearly defined. In any case, the pituitary response to TRH stimulation was not correlated with the prevailing level of depression, nor did this response to an initial TRH challenge predict the degree of clinical change during a 15-day treatment during which three intravenous doses of 600 mug of TRH were given. Depressed patients, as do schizophrenics and normal patients, show diminished TSH responses to repeated challenges with TRH. Whether or not these three groups differ in regard to the rate at which the pituitary response can be abolished remains to be determined.

Neurochemistry of dopamine in Huntington's dementia and normal aging.

We measured the dopamine metabolite homovanillic acid (HVA) in cerebrospinal fluid (CSF) before and after probenecid administration in normal controls and in patients with Huntington's disease. Baseline CSF HVA concentrations correlated positively with age in normal control subjects. Baseline CSF HVA concentrations were reduced in patients with Huntington's disease, and the degree of this reduction correlated with the severity of dementia and with the duration of disease. These results suggest that changes in the metabolism of dopamine by dopaminergic neurons may be associated with the dementia of Huntington's disease as well as with normal aging. These changes in dopaminergic functioning are apparently different in Huntington's disease than in normal aging and can be detected by measuring CSF HVA concentration.

Platelet methylene reductase activity in schizophrenia.

A case of a folate-responsive psychosis that was associated with a defect in N5-10-methylenetetrahydrofolate reductase (methylene reductase) suggested the need to examine whether abnormally low activity of this enzyme might be of etiological importance in schizophrenia. We now report that there were no statistically significant differences in the platelet methylene reductase activity of chronic schizophrenics, compared with either hospitalized or nonhospitalized age-matched control subjects. Although it is possible that a larger survey might reveal a subpopulation of schizophrenics who are characterized by abnormal methylene reductase activity, this study suggests that chronic schizophrenia is not generally associated with such changes.

Vasodilators in senile dementias: a review of the literature.

The rationale for the use of vasodilators in the aged has changed from the attempt to increase cerebral blood flow to the attempt to improve cerebral metabolism. Review of 102 studies of eight vasodilators showed that significantly more controlled studies claimed practical clinical benefit from drugs supposed to improve neuronal intermediary metabolism with secondary vasodilatation than from drugs supposed to have only vasodilator action (P less than .005). Studies of both classes of drugs often suffered from poor study design, inappropriate and inconsistent application of outcome measurements, as well as negative bias due to selection of severely demented subjects. Future studies should be placebo-controlled investigations of drugs with primarily metabolic action, address questions of dose and time response, consistently use appropriate outcome measurement, and concentrate on the elderly in whom cognitive improvement is possible.

Computed tomography in schizophrenics and normal volunteers. I. Fluid volume.

Recent findings of enlarged ventricles and sulcal widening in the computed tomographic (CT) scans of schizophrenic subjects have raised questions about the etiology and treatment of this disorder. Measures obtained from computerized analyses of CT scans of 30 schizophrenic and 33 normal subjects showed no significant difference between the groups in ventricular or sulcal fluid volumes. The discrepancy between our findings and those of other investigators may have been due to different measurement techniques or to differences in the samples. A second study was undertaken to examine the first possibility. Its results suggest that our findings and those based on measurements of planimetric ventricle-brain ratios (VBRs) are highly correlated, but that VBRs from one study may not be compared with those in another to establish population differences. Differences in patient samples appear to constitute an important source of discrepancy in CT findings.

Cerebral ventricular size and neuropsychological impairment in young chronic schizophrenics. Measurement by the standardized Luria-Nebraska Neuropsychological Battery.

The relationship between size of cerebral ventricles in chronic schizophrenics and performance on a comprehensive neuropsychological battery, the Standardized Luria-Nebraska Neuropsychological Battery, was investigated. Ventricular size was determined by using a planimeter to measure the size of the lateral ventricles and the ventricular body, if present, on the computerized tomographic (CT) scan image that showed the largest lateral ventricles. This number was divided by the size of the brain as a whole on the same image of the CT scan to yield a ventricular brain ratio. This ratio was then correlated with the scores on the Luria-Nebraska Neuropsychological Battery. Eight of the 14 scales of the Luria-Nebraska Neuropsychological Battery correlated significantly at the .05 level with the ventricular brain ratio in a sample of 42 chronic schizophrenics with an average age of 32.3 years. Overall, there was a multiple correlation of .72 between the ventricular brain ratio and Luria scores. The overall ventricular brain ratio for the schizophrenics was significantly above that found in normal populations. Changes in the size of the ventricles in schizophrenics appear to have significant correlates with measures of neuropsychological performance.

beta-Endorphin and schizophrenia.

To study the effects of beta-endorphin in chronic schizophrenia, nine male patients participated in a double-blind crossover comparison of a single intravenous 20-mg injection of beta-endorphin and saline. Bolus injection of beta-endorphin from an albumin-coated syringe produced markedly higher plasma concentrations than did slow intravenous infusion from a non-albumin-coated syringe. Beta-endorphin intravenously injected in nine patients produced a statistically significant increase in serum prolactin levels. In one patient, both 10 mg of morphine sulfate and 20 mg of beta-endorphin produced similar increases in the alpha power of the EEG. In eight patients, beta-endorphin administration was associated with a statistically significant but not clinically obvious improvement in schizophrenic symptoms.

Pharmacological investigations of the cholinergic imbalance hypotheses of movement disorders and psychosis.

The hypotheses of relative cholinergic underactivity in Huntington's disease, tardive dyskinesia, mania, and schizophrenia were pharmacologically investigated, using physostigmine and choline chloride. Intravenous physostigmine improved the involuntary movements of all of four patients with tardive dyskinesia and three of six patients with Huntington's disease. Physostigmine infusion also decreased manic symptoms in six of nine patients with mania, but had no beneficial effects in three patients with schizophrenia. Precursorloading with choline chloride may increase brain acetylcholine levels and central cholinergic activity. In patients with movement disorders a transient improvement during physostigmine infusion predicted a positive response to a trial of oral choline chloride. One manic patient may have been improved by choline chloride, however choline chloride did not improve symptoms in four of six schizophrenix patients. Chronic treatment with oral choline chloride increases plasma levels of choline during administration and for approximately 48 hr after discontinuation of treatment. A single 5-g dose of choline chloride also transiently raises plasma choline levels. These results with physostigmine support the hypotheses of cholinergic underactivity in Huntington's disease, tardive dyskinesia, and mania. Agents which might chronically increase cholinergic activity such as choline chloride should be further tested in these disorders.

Neuroleptic effects in Tourette syndrome predict dopamine excess and acetylcholine deficiency.

Tourette syndrome (TS) may be characterized by relatively excessive CNS dopamine activity and by relatively deficient CNS acetylcholine activity. New evidence for this hypothesis derives from comparisons of neuroleptic effects in TS with neuroleptic ability to block in vitro and in vivo assays of dopamine and cholinergic muscarinic receptors. These data support the concept of dopamine hyperactivity in TS, possibly mediated by supersensitive dopamine type 2 receptors (which are not linked to adenylate cyclase). These data also suggest that cholinergic activity may be relatively deficient in TS, which is consistent with the dopamine-acetylcholine imbalance hypothesis of hyperkinetic movement disorders.

Coexisting tardive dyskinesia and parkinsonism: a case report.

A case report is presented of a patient with remitting tardive dyskinesia coexistent with neuroleptic-induced parkinsonism. The patient received benztropine and physostigmine challenges on successive days and the effects on both syndromes are described. The clinical course of both diseases is discussed in terms of a balance hypothesis between dopaminergic and cholinergic neurotransmission.

Pilot study on the effects of fenfluramine on negative symptoms in twelve schizophrenic inpatients.

We treated 12 chronic schizophrenic inpatients with fenfluramine, an anorexigenic drug that depletes serotonin, to test the hypothesis that the "negative" symptoms of schizophrenia might be related to brain serotonin activity. We measured change in both positive and negative symptoms in a double-blind, parallel-design trial of fenfluramine or placebo. Negative symptoms improved over time in some individuals within the active treatment group, but not in individuals within the placebo group. However, group comparisons of active treatment versus placebo were not significant.

Possible associations among plasma prolactin levels, tardive dyskinesia, and paranoia in treated male schizophrenics.

To determine whether there is an association between prolactin (PRL) levels and psychopathology or tardive dyskinesia during neuroleptic treatment, we measured plasma prolactin levels and neuroleptic activity (NA) in 33 chronically treated male schizophrenics. Neuroleptic dose, plasma NA, and PRL were significantly intercorrelated. Plasma PRL levels were also measured in 8 male schizophrenics recently withdrawn from neuroleptics and in 18 normal male controls. In treated patients, but not in controls, PRL levels decreased with age and duration of illness, two variables that we interpreted as indirect measures of neuroleptic exposure. PRL levels in patients recently withdrawn from neuroleptics were lower than in treated patients or controls, which was suggestive of rebound hypoprolactinemia. A prolactin index, calculated as the ratio of PRL levels to NA, was inversely correlated with paranoid symptoms and tardive dyskinesia in younger treated patients. These results lead to speculation that tuberoinfundibular dopaminergic supersensitivity develops in chronically treated schizophrenics and that it is associated with nigrostriatal supersensitivity, manifested by tardive dyskinesia, and paranoid symptoms, which may reflect mesolimbic supersensitivity.