Neuroleptic-induced extrapyramidal symptoms with fever. Heterogeneity of the 'neuroleptic malignant syndrome'.

From 39 reported cases of the "neuroleptic malignant syndrome," three groups were identified: those with concurrent medical problems that could cause fever that accompanied the extrapyramidal symptoms; those with medical problems less clearly related to fever; and those without other medical disorders. Dehydration, infection, pulmonary embolus, and rhabdomyolysis were the common complications of untreated extrapyramidal symptoms. Three patients died, all with medical complications. In 14 cases, no medical cause of fever was identified. Hypotheses about mechanisms for fever include psychiatric illness, disruption of dopaminergic aspects of thermoregulation, and peripheral and central effects on muscle contraction leading to excess heat production. Neuroleptic-induced rigidity should be treated vigorously, with prompt discontinuation of neuroleptic therapy and administration of dopamine agonists in severe cases with or without fever. The cases of extrapyramidal symptoms with fever are too heterogeneous to justify the assumption of a unitary and "malignant" syndrome.

Research as an impetus to improved treatment.

The relation between psychiatric research and treatment remains a controversial subject. A psychopharmacological research program implemented in a state psychiatric hospital resulted in a significantly improved treatment milieu. Diagnosis, length of stay, amounts and types of medications administered, legal commitment status, seclusion and restraint time, etc, were targeted as variables with which to measure change in the milieu. The variables showed significant changes, ie, improvement during the research period, as compared with a control period. The research discipline created a more rigorous approach to diagnosis and treatment. This, in turn, created an improved treatment milieu in which the research protocols could be implemented more meaningfully.

Two dosages of imipramine in hospitalized endogenous and neurotic depressives.

Fifty-one newly hospitalized depressed patients participated in a double-blind comparison of two dosage levels of imipramine hydrochloride (150 mg vs 300 mg daily). Although some patients were suffering from neurotic depressions, they, together with the endogenous depressives, were a severely depressed group who required hospitalization. Improvement occurred with both dosage regimens, although a greater and more consistent improvement was noted in the 300-mg group than in the 150-mg group. There were a few differences between the response of the endogenous and that of the neurotic depressives, as assessed by the physician and self=rating scales. However, endogenous depressives who received 150 mg were overrepresented in the treatment failure group. A comparison of the response of deluded and nondeluded depressives indicated that the deluded patients responded less well than the nondeluded depressives, although half of the delusional group did respond to the treatment.

Effect of antiparkinsonian medication on plasma levels of chlorpromazine.

Twenty-one chronic schizophrenics were stabilized with chlorpromazine therapy at their therapeutic dosage for one month. Trihexyphenidyl hydrochloride or identical placebo was then added according to a double-blind, split crossover design. The duration of each half of the crossover was 15 days. Steady state blood samples were drawn three times weekly during the experimental period and the amount of chlorpromazine was determined. The results indicated there were no differences in the levels obtained between the trihexyphenidyl and the placebo phases. A two-hour postdrug blood sample was also drawn at the end of each phase and again, there were no differences between the two conditions. The importance of these results is discussed.

Butaperazine pharmacokinetics. Effect of dosage regimen on steady state blood levels.

Experimental evidence showed that a higher whole blood steady state drug plasma level was achieved when a patient was given medication three times a day compared to the same total daily dose once a day. In addition, evidence indicated possible enzyme induction by butaperazine in one patient. We have demonstrated that the general stochastic theory developed to investigate the pharmacokinetics of lithium carbonate "in vivo" has more general applicability in that it applies also to butaperazine, and facilitates interpretation of findings (without blood level data) in one other drug study.

Fluphenazine dose, clinical response, and extrapyramidal symptoms during acute treatment.

Fifty-three patients with acute exacerbations of Research Diagnostic Criteria schizophrenic, schizoaffective (mainly schizophrenic), and other nonaffective psychoses completed 24 or 28 days of treatment with randomized, fixed, double-blind doses of 10, 20, or 30 mg of oral fluphenazine hydrochloride daily. In the sample as a whole, improvement was not predicted by dose but was negatively related to duration of illness and of lifetime hospitalization, and to the presence of akathisia during the study (which was unrelated to chronicity). But among patients showing 40% or greater improvement in positive symptoms, percent improvement was predicted by dose and dose per kilogram of body weight; this was not the case for negative symptoms. Severity of acute extrapyramidal symptoms (excluding acute dystonia, dyskinesia, and akathisia) was significantly correlated with dosage per kilogram. Doses greater than 0.2 mg/kg per day were associated with greater clinical improvement but also with a high incidence of extrapyramidal symptoms; doses over 0.3 mg/kg per day were associated with more severe extrapyramidal symptoms. These preliminary results suggest that there is a linear relationship between fluphenazine dosage and acute outcome, and that this relationship is observed in patients whose conditions improve to a criterion level. It is suggested that the nonresponder group may include many patients in whom dose is not relevant because they are unable (for a variety of reasons) to respond to the study treatment conditions; excluding them from analysis may allow a significant dose-response relationship to be observed. Akathisia deserves further study as a possible predictor of nonresponse.

Family management in the prevention of morbidity of schizophrenia. Clinical outcome of a two-year longitudinal study.

Environmental stress may contribute to the clinical morbidity of established cases of schizophrenia treated with optimal neuroleptic drugs. A family-based approach that aimed to enhance the problem-solving capacity of the index patient and his family caregivers was compared with a patient-oriented approach of similar intensity over a two-year period. Thirty-six patients who returned to stressful parental households after florid episodes of schizophrenia (CATEGO and DSM-III) were stabilized with optimal neuroleptics before being randomly assigned to family or individual therapy in a comprehensive community management program. After nine months, family-managed patients had fewer exacerbations of schizophrenia, lower ratings of schizophrenic psychopathology, fewer hospital admissions, and a trend toward lower deficit symptoms and reduced neuroleptic dosage. This reduced clinical morbidity was sustained throughout the second year of less intensive follow-up. The relative efficacy of the family approach in this clinical management study did not appear to be due to prognostic factors, rater bias, stressful life events, or the effectiveness of pharmacotherapy. Definitive tests of these findings with respect to efficacy require further well-designed studies.

Relapse and rehospitalization during maintenance treatment of schizophrenia. The effects of dose reduction and family treatment.

BACKGROUND: Previous studies have examined dose reduction and family treatment in schizophrenia, but none has examined their interaction. This study assessed the impact of dose reduction of antipsychotic medication and family treatment on relapse and rehospitalization during maintenance treatment. METHODS: Subjects were 313 male and female outpatients at 5 centers with a DSM-III-R diagnosis of schizophrenia or schizoaffective disorder. In a 3 x 2 design, subjects were randomized to 1 of 3 medication strategies using fluphenazine decanoate under double-blind conditions: continuous moderate dose (standard) (12.5-50 mg every 2 weeks); continuous low dose (2.5-10 mg every 2 weeks); or targeted, early intervention (fluphenazine only when symptomatic). Subjects also were randomized to 1 of 2 family treatment strategies (supportive or applied). Supportive family management involved monthly group meetings. The more intensive applied family management involved monthly group meetings and home visits where communication and problem-solving skills were taught. Patients and families were treated and assessed for 2 years. RESULTS: Both continuous low-dose and targeted treatment increased use of rescue medication and relapse; only targeted treatment increased rehospitalization. This pattern was consistent across both family treatments; there were no differences between family treatments. CONCLUSIONS: These findings reaffirm the value of antipsychotic medication in preventing relapse and rehospitalization. The absence of family treatment differences may be because both conditions engaged families.

Clozapine withdrawal effects and receptor profiles of typical and atypical neuroleptics.

Withdrawal effects of neuroleptics have not received much attention. Clozapine withdrawal phenomena have been attributed to psychosis arising from D2 supersensitivity, which is unlikely since it has minimal action on D2 receptors. The time course and clinical features of this phenomenon suggest that cholinergic overdrive and gamma-aminobutyric acid (GABA) supersensitivity occurs after withdrawal, since it is strongly anticholinergic and has a GABAergic action. Recently, a number of patients showed marked decompensation when they were switched from clozapine to risperidone, especially when they were rapidly tapered off clozapine. This was probably more due to withdrawal effects than the primary psychosis or a lack of efficacy of risperidone. A slow withdrawal schedule would facilitate homeostatic mechanisms; anticholinergics would be useful in clozapine withdrawal. This area has not received any attention from researchers, nor are there any guidelines for clinicians. This will be particularly important with the widespread use of atypical agents in the future.

Polydipsia and water intoxication in psychiatric patients: a review of the epidemiological literature.

Polydipsia among chronic psychiatric patients is poorly understood and underdiagnosed. It may have three stages: simple polydipsia, polydipsia with water intoxication, and physical complications. Epidemiological surveys have used staff reports and polyuria measures to identify polydipsic patients. Water intoxication has been screened by chart review, weight, or serum sodium data. According to these surveys, polydipsia, not explained by medically induced polyuria, may be present in more than 20% of chronic inpatients. Up to 5% of chronic inpatients had episodes of water intoxication although mild cases may have been missed. Single time point surveys show that 29% of polydipsic patients had presented water intoxication. Methodologically limited clinical studies suggest that polydipsia with water intoxication rather than simple polydipsia may be associated with poor prognosis in schizophrenia. Epidemiological surveys found polydipsia with water intoxication to be associated with chronicity, schizophrenia, smoking, some medications, male gender, and white race. New pathophysiological models need to elucidate these findings.

Continuous infusion of clozapine increases mu and delta opioid receptors and proenkephalin mRNA in mouse brain.

The biochemical mechanisms involved in the actions of the atypical antipsychotic clozapine are still unclear. Because elevated levels of enkephalin in certain areas of the central nervous system may be necessary for antipsychotic activity, we have examined the effect of clozapine on certain receptors and mRNA transcripts involved in the opioid peptidergic system. Clozapine was infused continuously into mice for 21 days and the density of mu and delta opioid receptors was measured in the brains by quantitative receptor autoradiography, and the level of proenkephalin mRNA and dopamine D1 and D2 receptor mRNA were measured by in situ hybridization histochemistry. The results showed that continuous infusion of clozapine increased the density of D1 but not D2 receptors. However, it failed to alter the levels of either D1 or D2 dopamine receptor mRNA. By contrast, clozapine increased the density of mu and delta opioid receptors and increased the levels of proenkephalin mRNA. These results indicate that continuous treatment with clozapine increases opioid peptidergic activity in mouse brain and suggest that alteration of peptidergic activity as well as alteration of dopaminergic activity may be involved in its antipsychotic action.

Polydipsia and water intoxication in a long-term psychiatric hospital.

This cross-sectional survey attempts to establish the prevalence of polydipsia and water intoxication at a state hospital (N = 360) using staff diagnosis, specific gravity of the urine (SPGU), weight changes, and chart review. There were 150 [42%, 95% confidence interval (CI) 37-47%] patients diagnosed as polydipsic by the staff or by SPGU. At least 93 (26%, CI 21-30%) had primary polydipsia not explained by other causes. Chart review identified 17 (5%, CI 3-7%) patients with a history of water intoxication. Using a case-control study design, schizophrenia, extended duration of hospitalization, and heavy smoking were associated with primary polydipsia in a logistic regression analysis (respective odds ratios were 1.6, 1.8, and 3.6). All patients with a history of water intoxication were Caucasian (versus 83% in those without a history) and had significantly more extended hospitalizations (94 vs. 49%). Future case-control studies should combine longitudinal identification of true cases and controls and exhaustive collections of clinical information in a standardized way.

Does akathisia influence psychopathology in psychotic patients treated with clozapine?

BACKGROUND: Akathisia has been reported to predict more severe symptoms and poorer treatment response to typical neuroleptics among patients with schizophrenia. Akathisia has also been associated with symptom exacerbation. This study addressed four questions: 1) Does akathisia predict greater severity in global psychopathology? 2) Is this effect global or specific? 3) Does clozapine treatment alter this relationship? 4) Does severity of psychopathology covary with the level of akathisia? METHODS: Akathisia and clinical symptoms were examined in 33 "treatment refractory" schizophrenic patients treated with clozapine across 16 weeks. Weekly ratings were Barnes Akathisia Rating Scale, Abbreviated Dyskinesia Rating Scale, and Brief Psychiatric Rating Scale (BPRS). Patients were classified as "with" (n = 15) or "without" (n = 18) akathisia. Data analyses involved independent t-test comparisons of selected variables, between-group multivariate analyses of variance across time for BPRS Total scores and Guy's five factors, and partial correlations to assess covariation between BPRS scores and level of akathisia. RESULTS: Akathisia predicted more severe global psychopathology, specific to the Activation (AC) and Thought Disturbance (TH) factors. These relationships did not change with clozapine treatment even when akathisia declined. Interestingly, level of akathisia did not covary with severity of psychopathology. CONCLUSIONS: In this sample, akathisia predicted more severe psychopathology, specific to AC and TH BPRS factor scores. Clozapine treatment did not alter this relationship. Although the presence of akathisia predicted more severe symptoms, the level of akathisia did not covary across time with severity of psychopathology, suggesting an "uncoupling" of these symptom domains.

Comparison of the pressor effect of tyramine after treatment with phenelzine and moclobemide in healthy male volunteers.

This study was conducted to establish the safety, tolerability, side effects, and pressor effects of tyramine on subjects treated with moclobemide, a short-acting reversible and preferential monoamine oxidase inhibitor, and to compare these responses with the responses of subjects treated with phenelzine. Twelve healthy male volunteers participated. An oral tyramine sensitivity test was performed on all subjects 24 hours before the start of a 28-day open-label treatment with phenelzine or moclobemide. A tyramine challenge was performed on day 28 on four subjects treated with phenelzine. The mean dose of oral tyramine required to increase systolic blood pressure by 30 mm Hg was 15 mg. The mean dose of tyramine that produced a clinical response (day 28) in subjects treated with moclobemide was 240 mg. No subject receiving moclobemide responded clinically on day 31 after receiving hourly doses of 20, 40, 80, 160, and 320 mg, respectively. These findings suggest that moclobemide may be used without stringent dietary precautions.

Clozapine plasma levels and convulsions.

Two patients receiving clozapine developed grand mal seizures. The plasma levels in one of the patients at the time of the seizure were approximately 100% higher than on 12 previous occasions. This finding led to the conclusion and the patient's admission that she had taken an overdose. Plasma levels in the other patient exceeded the range the authors had noted in previous studies. The authors emphasize the usefulness of plasma level monitoring in relation to safety, drug defaulting, and side effects.

The 24-hour lithium level as a prognosticator of dosage requirements: a 2-year follow-up study.

The authors have previously described a technique whereby individual lithium dosage requirements can be predicted from 24-hour blood samples. Further experience over a 2-year period has shown the predictions to be reproducible over time. A micromethod for lithium determination is described, as are several cases in which aberrant results were found to indicate inadequate laboratory techniques or patients' failure to take medication. Because the technique reveals immediately those patients at the extremes of dosage ranges, toxicity and the need for frequent sampling can be avoided.

Prediction of individual dosage of nortriptyline.

The authors describe a technique that enables a physician to determine individual patient dosage requirements for nortriptyline from a single 24-hour blood sample. Because the technique reveals immediately those patients at the extremes of dosage ranges, toxicity and the need for time-consuming titration of the dosage regimen can be avoided.

Extrapyramidal side effects in lithium maintenance therapy.

The authors neurologically examined 36 patients who had been maintained on lithium therapy for periods ranging from 6 months to 7 years to determine the presence of parkinson-like side effects. Only a few patients demonstrated rigidity, including cogweel rigidity, and this was at a low level of severity. These results do not support the previously reported frequent occurrence of cogwheel rigidity in patients on lithium maintenance.

Neuroleptic dosage for Asians: a failure to replicate.

Retrospective chart review of 30 Asian patients and 30 matched Caucasian patients failed to replicate a previous report's finding that Asian patients require lower doses of neuroleptic medications than do Caucasian patients.

Chronic phencyclidine abuse and physical assault.

When the authors investigated aggressive behavior on a phencyclidine (PCP) detoxification and rehabilitation unit and compared similar types of behavior on a heroin unit, they found no differences between the two units. The urinary PCP levels of a subgroup of 75 patients admitted to the PCP unit who had PCP-positive urine were significantly higher than those of 75 patients admitted to an acute psychiatric ward because of violent behavior who also had PCP-positive urine. The authors discuss the implications of these findings and the need for more information on the relationship between PCP levels in blood and urine and behavior.