Stanley N. Caroff

Neuroleptic malignant syndrome.

Neuroleptic malignant syndrome is a rare but potentially fatal reaction associated with neuroleptic drugs. It occurs in about 0.2% of patients treated with neuroleptics. Risk factors include previous episodes, dehydration, agitation, and the rate and route of neuroleptic administration. Although NMS has been reported in patients with diverse psychiatric diagnoses, as well as in normal subjects, patients with organic brain disorders or mood disorders, particularly when receiving lithium, may be at increased risk. Standardized criteria for the diagnosis of NMS have been developed and emphasize the classic findings of hyperthermia, muscle rigidity, mental status changes, and autonomic dysfunction. The syndrome lasts 7 to 10 days in uncomplicated cases receiving oral neuroleptics. Treatment consists primarily of early recognition, discontinuation of triggering drugs, management of fluid balance, temperature reduction, and monitoring for complications. Use of dopamine agonists or dantrolene or both should be considered and may be indicated in more severe, prolonged, or refractory cases. Electroconvulsive therapy has been used successfully in some cases and is particularly useful in the post-NMS patient. As a result of these measures, mortality from NMS has declined in recent years although fatalities still occur. Neuroleptics may be safely reintroduced in the management of the majority of patients recovered from an NMS episode, although a significant risk of recurrence does exist, dependent in part on time elapsed since recovery and dose or potency of neuroleptics used. Data drawn from clinical observations and basic studies support the primary role of an acute reduction in brain dopamine activity in the development of NMS. Additional studies of facilitating cofactors may lead to innovative risk-reduction strategies and the development of safer neuroleptic drugs.

Extrapyramidal side-effects of antipsychotics in a randomised trial

BACKGROUND There are claims that second-generation antipsychotics produce fewer extrapyramidal side-effects (EPS) compared with first-generation drugs. AIMS To compare the incidence of treatment-emergent EPS between second-generation antipsychotics and perphenazine in people with schizophrenia. METHOD Incidence analyses integrated data from standardised rating scales and documented use of concomitant medication or treatment discontinuation for EPS events. Mixed model analyses of change in rating scales from baseline were also conducted. RESULTS There were no significant differences in incidence or change in rating scales for parkinsonism, dystonia, akathisia or tardive dyskinesia when comparing second-generation antipsychotics with perphenazine or comparing between second-generation antipsychotics. Secondary analyses revealed greater rates of concomitant antiparkinsonism medication among individuals on risperidone and lower rates among individuals on quetiapine, and lower rates of discontinuation because of parkinsonism among people on quetiapine and ziprasidone. There was a trend for a greater likelihood of concomitant medication for akathisia among individuals on risperidone and perphenazine. CONCLUSIONS The incidence of treatment-emergent EPS and change in EPS ratings indicated that there are no significant differences between second-generation antipsychotics and perphenazine or between second-generation antipsychotics in people with schizophrenia.

Regional brain function in schizophrenia: II. Repeated evaluation with positron emission tomography.

Cerebral glucose metabolism was measured twice in a sample of 15 schizophrenics and eight controls, using positron emission tomography (PET) with 18-F-fluorodeoxyglucose. Studies were separated by three to 33 weeks. Patients were unmedicated during the first study, and the majority were receiving neuroleptics during the second study. There were no changes from study 1 to study 2 in average whole-brain metabolic rates, regional cortical activity, or the gradient of subcortical to cortical activity. The steeper subcortical to cortical gradient in schizophrenics, present in the first study, persisted in the second. Changes in this gradient were uncorrelated with changes in clinical status. Laterality (right-left) was stable across studies, and changes toward higher right relative to left hemispheric metabolism were correlated with clinical improvement. The results support the hypothesis of abnormal hemispheric activity in schizophrenia and implicate the subcortical-cortical gradient as another dimension that merits further exploration.

Clinical correlates of tardive dyskinesia in schizophrenia: Baseline data from the CATIE schizophrenia trial

OBJECTIVE To examine the clinical characteristics of individuals with schizophrenia that develop tardive dyskinesia (TD) associated with antipsychotic treatment. METHODS Baseline data on 1460 patients with schizophrenia were collected as part of the Clinical Antipsychotic Trials of Intervention Effectiveness schizophrenia study. Subjects who met Schooler-Kane criteria for probable TD were compared to those without TD. Multiple regression analyses were used to examine the relationship between TD and clinical variables. RESULTS 212 subjects met the Schooler-Kane criteria for probable TD and 1098 had no history or current evidence of TD. Subjects with TD were older, had a longer duration of receiving antipsychotic medication, and were more likely to have been receiving a conventional antipsychotic and an anticholinergic agent. After controlling for important baseline covariates, diabetes mellitus (DM) and hypertension did not predict TD, whereas substance abuse significantly predicted TD. Differences in cognitive functioning were not significantly different after controlling for baseline covariates. The TD subjects also had higher ratings of psychopathology, EPSE, and akathisia. CONCLUSION Our results confirm the established relationships between the presence of TD and age, duration of treatment with antipsychotics, treatment with a conventional antipsychotic, treatment with anticholinergics, the presence of EPS and akathisia, and substance abuse. Subjects with TD had higher ratings of psychopathology as measured by the PANSS. We found no support for DM or hypertension increasing the risk of TD, or for TD being associated with cognitive impairment.

Effectiveness of Switching From Antipsychotic Polypharmacy to Monotherapy

OBJECTIVE This randomized trial addressed the risks and benefits of staying on antipsychotic polypharmacy or switching to monotherapy. METHOD Adult outpatients with schizophrenia taking two antipsychotics (127 participants across 19 sites) were randomly assigned to stay on polypharmacy or switch to monotherapy by discontinuing one antipsychotic. The trial lasted 6 months, with a 6-month naturalistic follow-up. Kaplan-Meier and Cox regression analyses examined time to discontinuation of assigned antipsychotic treatment, and random regression models examined additional outcomes over time. RESULTS Patients assigned to switch to monotherapy had shorter times to all-cause treatment discontinuation than those assigned to stay on polypharmacy. By month 6, 86% (N=48) of those assigned to stay on polypharmacy were still taking both medications, whereas 69% (N=40) of those assigned to switch to monotherapy were still taking the same medication. Most monotherapy discontinuations entailed returning to the original polypharmacy. The two groups did not differ with respect to psychiatric symptoms or hospitalizations. On average, the monotherapy group lost weight, whereas the polypharmacy group gained weight. CONCLUSIONS Discontinuing one of two antipsychotics was followed by treatment discontinuation more often and more quickly than when both antipsychotics were continued. However, two-thirds of participants successfully switched, the groups did not differ with respect to symptom control, and switching to monotherapy resulted in weight loss. These results support the reasonableness of prescribing guidelines encouraging trials of antipsychotic monotherapy for individuals receiving antipsychotic polypharmacy, with the caveat that patients should be free to return to polypharmacy if an adequate trial on antipsychotic monotherapy proves unsatisfactory.

Genomewide Association Study of Movement-Related Adverse Antipsychotic Effects

BACKGROUND Understanding individual differences in the development of extrapyramidal side effects (EPS) as a response to antipsychotic therapy is essential to individualize treatment. METHODS We performed genomewide association studies to search for genetic susceptibility to EPS. Our sample consisted of 738 schizophrenia patients, genotyped for 492K single nucleotide polymorphisms (SNPs). We studied three quantitative measures of antipsychotic adverse drug reactions-the Simpson-Angus Scale (SAS) for Parkinsonism, the Barnes Akathisia Rating Scale, and the Abnormal Involuntary Movement Scale (AIMS)-as well as a clinical diagnosis of probable tardive dyskinesia. RESULTS Two SNPs for SAS, rs17022444 and rs2126709 with p = 1.2 x 10(-10) and p = 3.8 x 10(-7), respectively, and one for AIMS, rs7669317 with p = 7.7 x 10(-8), reached genomewide significance (Q value < .1). rs17022444 and rs7669317 were located in intergenic regions and rs2126709 was located in ZNF202 on 11q24. Fourteen additional signals were potentially interesting (Q value < .5). The ZNF202 is a transcriptional repressor controlling, among other genes, PLP1, which is the major protein in myelin. Mutations in PLP1 cause Pelizaeus-Merzbacher disease, which has Parkinsonism as an occurring symptom. Altered mRNA expression of PLP1 is associated with schizophrenia. CONCLUSIONS Although our findings require replication and validation, this study demonstrates the potential of genomewide association studies to discover genes and pathways that mediate adverse effects of antipsychotics.

An international consensus study of neuroleptic malignant syndrome diagnostic criteria using the Delphi method.

OBJECTIVE The lack of generally accepted diagnostic criteria for neuroleptic malignant syndrome (NMS) impedes research and clinical management of patients receiving antipsychotic medications. The purpose of this study was to develop NMS diagnostic criteria reflecting a broad consensus among clinical knowledge experts, represented by an international multispecialty physician panel. PARTICIPANTS Eleven psychiatrists, 2 neurologists, 2 anesthesiologists, and 2 emergency medicine specialists participated in a formal Delphi consensus procedure. EVIDENCE A core bibliography consisting of 12 prominent, current reviews of the NMS literature was identified by an objective, comprehensive electronic search strategy. Each panel member was given a copy of these references and asked to examine them before commencing the survey process. CONSENSUS PROCESS After reviewing the core bibliography, panel members were asked to list any clinical signs or symptoms or diagnostic studies that they believed, on the basis of their knowledge and clinical experience, were useful in making a diagnosis of NMS. In subsequent survey rounds, panel members assigned priority points to these items, and items that failed to receive a minimum priority score were eliminated from the next round. Information about individual panel member responses was fed back to the group anonymously in the form of the group median or mean and the number of members who had ranked or scored each survey item. The a priori consensus endpoint was defined operationally as a change of 10% or less in the mean priority score for any individual item, and an average absolute value change of 5% or less across all items, between consecutive rounds. The survey was conducted from January 2009 through September 2009. RESULTS Consensus was reached on the fifth round regarding the following criteria: recent dopamine antagonist exposure, or dopamine agonist withdrawal; hyperthermia; rigidity; mental status alteration; creatine kinase elevation; sympathetic nervous system lability; tachycardia plus tachypnea; and a negative work-up for other causes. The panel also reached a consensus on the relative importance of these criteria and on the following critical values for quantitative criteria: hyperthermia, > 100.4°F or > 38.0°C on at least 2 occasions; creatine kinase elevation, at least 4 times the upper limit of normal; blood pressure elevation, ≥ 25% above baseline; blood pressure fluctuation, ≥ 20 mm Hg (diastolic) or ≥ 25 mm Hg (systolic) change within 24 hours; tachycardia, ≥ 25% above baseline; and tachypnea, ≥ 50% above baseline. CONCLUSIONS These diagnostic criteria significantly advance the field because they represent the consensus of an international multispecialty expert panel, include critical values, provide guidance regarding the relative importance of individual elements, and are less influenced by particular theoretical biases than most previously published criteria. They require validation before being applied in clinical settings.

Malignant Hyperthermia Susceptibility in Neuroleptic Malignant Syndrome

The relationship between neuroleptic malignant syndrome (NMS) and malignant hyperthermia (MH) was investigated using the in vitro skeletal muscle contracture test to screen for MH-susceptibility in NMS patients. The maximum contracture tension which developed following exposure to halothane (1–3%), and incremental doses of fluphenazine (0.2–25.6 mM) was measured in muscle obtained from seven NMS, six MH, and six control patients. Comparison of the cumulative responses to fluphenazine revealed no significant differences among the groups. However, the response (mean ± SEM) to halothane in the NMS group (1.7 ± 0.7 g), which was similar to the response in the MH group (1.5 ± 0.2 g), was significantly greater than the response found in controls (0.2 ± 0.1 g). In addition, live of seven NMS patients could be diagnosed as MH-susceptible, based on the development of muscle contractures greater than 0.7 g in response to 1–3% halothane. In contrast, none of the controls were MH-susceptible. These findings appear to correlate with clinical evidence suggesting an association between NMS and MH.

Residual catatonic state following neuroleptic malignant syndrome.

Neuroleptic malignant syndrome (NMS) is usually a self-limited disorder, with most cases resolving within 2 weeks after antipsychotic drug discontinuation. However, the course of NMS may not always be short-lived. In this report, the authors describe five patients who developed a residual catatonic state that persisted after acute hyperthermic symptoms of NMS had subsided and compare them with 27 similar cases in the literature. Two of our patients recovered gradually with supportive treatment. Three patients were treated with electroconvulsive therapy (ECT). Of these, two showed a positive response, although one died later of intercurrent pneumonia. A third patient did not respond to ECT, but recovered gradually thereafter. Although dopamine agonists or benzodiazepines have been advocated for the treatment of residual symptoms in previous case reports, ECT was the treatment most often associated with a rapid response and no mortality, even in patients refractory to pharmacotherapy. In conclusion, catatonic and parkinsonian symptoms of NMS may persist as a residual state lasting for weeks to months after more fulminant acute symptoms abate. These residual symptoms may be more likely to develop in patients with pre-existing structural brain disorders. Although patients may improve gradually with supportive care or pharmacotherapy, ECT can often be highly effective in treating the residual catatonic state that follows NMS.

Movement Disorders Induced by Antipsychotic Drugs: Implications of the CATIE Schizophrenia Trial

Drug-induced movement disorders have dramatically declined with the widespread use of second-generation antipsychotics, but remain important in clinical practice and for understanding antipsychotic pharmacology. The diagnosis and management of dystonia, parkinsonism, akathisia, catatonia, neuroleptic malignant syndrome, and tardive dyskinesia are reviewed in relation to the decreased liability of the second-generation antipsychotics contrasted with evidence from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial. Data from the CATIE trial imply that advantages of second-generation antipsychotics in significantly reducing extrapyramidal side effects compared with haloperidol may be diminished when compared with modest doses of lower-potency first-generation drugs.