E. Cabrina Campbell

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.

Neuroleptic malignant syndrome.

NMS is an uncommon disorder characterized by hyperthermia, muscle rigidity, autonomic imbalance, altered levels of consciousness and significant mortality. Successful treatment of NMS requires a high degree of suspicion, rapid recognition of clinical signs and symptoms and institution of therapy with dantrolene and possibly dopaminergic agonists. This condition is precipitated by neuroleptic drugs, which are commonly used in many medical specialties. All medical practitioners responsible for primary care, psychiatrists and anesthesiologists should be familiar with the manifestations of the hypermetabolic syndromes of Neuroleptic Malignant Syndrome, Malignant Hyperthermia, and Neuroleptic Malignant-like Syndrome and should be prepared to initiate appropriate therapy.

Treatment outcomes of patients with tardive dyskinesia and chronic schizophrenia

OBJECTIVE We compared the response to antipsychotic treatment between patients with and without tardive dyskinesia (TD) and examined the course of TD. METHOD This analysis compared 200 patients with DSM-IV-defined schizophrenia and TD and 997 patients without TD, all of whom were randomly assigned to receive one of 4 second-generation antipsychotics. The primary clinical outcome measure was time to all-cause treatment discontinuation, and the primary measure for evaluating the course of TD was change from baseline in Abnormal Involuntary Movement Scale (AIMS) score. Kaplan-Meier survival analysis and Cox proportional hazards regression models were used to compare treatment discontinuation between groups. Changes in Positive and Negative Syndrome Scale (PANSS) and neurocognitive scores were compared using mixed models and analysis of variance. Treatment differences between drugs in AIMS scores and all-cause discontinuation were examined for those with TD at baseline. Percentages of patients meeting criteria for TD postbaseline or showing changes in AIMS scores were evaluated with χ(2) tests. Data were collected from January 2001 to December 2004. RESULTS Time to treatment discontinuation for any cause was not significantly different between the TD and non-TD groups (χ(2)(1) = 0.11, P = .743). Changes in PANSS scores were not significantly different (F(1,974) = 0.82, P = .366), but patients with TD showed less improvement in neurocognitive scores (F(1,359) = 6.53, P = .011). Among patients with TD, there were no significant differences between drugs in the decline in AIMS scores (F(3,151) = 0.32, P = .811); 55% met criteria for TD at 2 consecutive visits postbaseline, 76% met criteria for TD at some or all postbaseline visits, 24% did not meet criteria for TD at any subsequent visit, 32% showed a ≥ 50% decrease in AIMS score, and 7% showed a ≥ 50% increase in AIMS score. CONCLUSIONS Schizophrenia patients with and without TD were similar in time to discontinuation of treatment for any cause and improvement in psychopathology, but differed in neurocognitive response. There were no significant differences between treatments in the course of TD, with most patients showing either persistence of or fluctuation in observable symptoms. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00014001.

Neuroleptic malignant syndrome

Since the initial description of neuroleptic malignant syndrome (NMS) 40 years ago, a wealth of clinical data has accumulated on the manifestations, course, treatment, and pathogenesis of this uncommon but serious and potentially lethal drug reaction. Nevertheless, vigilance must be maintained, as this disorder remains obscure to many practising physicians. Here, we review the clinical features of NMS to enhance patient safety and reduce physician liability whenever antipsychotic drugs are administered.

Neuroleptic malignant syndrome in elderly patients

Antipsychotic drugs are widely and increasingly prescribed for neurobehavioral disorders in elderly patients. However, the efficacy of these drugs has not been consistently demonstrated in geriatric populations and there are continuing concerns regarding adverse effects. Among the latter are severe neurological disorders, including neuroleptic malignant syndrome. Although the incidence and mortality of neuroleptic malignant syndrome may have declined with heightened awareness of this disorder and the development of newer drugs, neuroleptic malignant syndrome still occurs in association with the use of antipsychotics. To enhance patient safety and clinical vigilance among practitioners, the authors present a clinical overview of neuroleptic malignant syndrome.

Drug-Induced Extrapyramidal Syndromes: Implications for Contemporary Practice.

The development of drugs to treat psychosis is a fascinating nexus for understanding mechanisms underlying disorders of mind and movement. Although the risk of drug-induced extrapyramidal syndromes has been mitigated by the acceptance of less potent dopamine antagonists, expansive marketing and off-label use has increased the number of susceptible people who may be at risk for these neurologic effects. Clinicians need to be familiar with advances in diagnosis and management, which are reviewed herein. A better understanding of drug-induced effects on the motor circuit may improve patient safety, enhance antipsychotic effectiveness, and provide insights into mechanisms underlying antipsychotic activity in parallel brain circuits.

Recurrent Idiopathic Catatonia: Implications beyond the Diagnostic and Statistical Manual of Mental Disorders 5th Edition.

We describe a case of recurrent, life-threatening, catatonic stupor, without evidence of any associated medical, toxic or mental disorder. This case provides support for the inclusion of a separate category of “unspecified catatonia” in the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) to be used to classify idiopathic cases, which appears to be consistent with Kahlbaum’s concept of catatonia as a distinct disease state. But beyond the limited, cross-sectional, syndromal approach adopted in DSM-5, this case more importantly illustrates the prognostic and therapeutic significance of the longitudinal course of illness in differentiating cases of catatonia, which is better defined in the Wernicke-Kleist-Leonhard classification system. The importance of differentiating cases of catatonia is further supported by the efficacy of antipsychotics in treatment of this case, contrary to conventional guidelines.

Risk of neuroleptic malignant syndrome in patients with NMDAR encephalitis.

In their interesting and informative case report on anti-Nmethyl-D-aspartate receptor (NMDAR) encephalitis, Koksal et al. [1] report a young woman diagnosed with NMDAR encephalitis who responded successfully to surgical removal of an ovarian tumor. They note that she initially presented with post-partum psychosis and was diagnosed with neuroleptic malignant syndrome (NMS) after treatment with risperidone, and they wisely remind clinicians to consider the diagnosis of NMDAR encephalitis in this context. The question of differentiating NMDAR encephalitis from NMS has been raised before; for example, Punia et al. [2] reported two cases referred for the evaluation of NMS who tested positive for NMDAR antibodies. Gulyayeva et al. [3] reported NMDAR encephalitis in a woman who had NMS, and noted the need for increased awareness of NMDAR encephalitis in patients who show worsening of movement disorders after treatment with neuroleptics. All of these authors appropriately note that NMDAR encephalitis may be difficult to distinguish from NMS because of similar overlapping features, e.g., elevated temperatures, obtundation, and catatonic signs. Drawing on similar referrals we received, we wanted to add to the scholarly report by Koksal et al. [4] by emphasizing awareness of the increased risk of NMS in patients with encephalitis as a complication of treatment with neuroleptics, rather than simply as a misdiagnosis or diagnosis to exclude. In 1998, we published a report on five young women who developed NMS after receiving neuroleptics. In all five cases, we observed a common pattern; in each case, a young woman presented with psychotic behavior accompanied by subtle neurologic signs and symptoms. After neuroleptic administration, each woman developed a more acute, fulminant syndrome with fever, rigidity, obtundation, and other features characteristic of NMS which resolved within two to three weeks once neuroleptics were discontinued, similar to the response observed by Koksal et al. It was only after NMS developed in these cases that diagnostic studies were conducted and revealed CSF evidence of encephalitis. No specific pathogens were identified and in retrospect, it is likely that our cases and other cases of encephalitis mimicking psychotic disorders reported historically in the psychiatric literature, represent autoimmune and possibly anti-NMDAR cases [5]. These cumulative reports collectively suggest two key clinical points. First, although treatment with neuroleptics may be necessary and effective in some cases to control agitation and facilitate diagnostic investigation, patients with acute encephalitis of any cause appear to be at high risk for serious neuroleptic-induced neurological reactions, especially NMS [4, 5]. Among published cases of acute encephalitis presenting with psychosis, we found that when neuroleptics were administered, they were reportedly helpful in controlling behavior in 12 patients but not in five others [5]. However, in other case reports of patients with encephalitis presenting as psychosis, four patients had S. N. Caroff (&) E. C. Campbell Philadelphia Veterans Affairs Medical Center, Philadelphia, PA, USA e-mail: stanley.caroff@va.gov

Pharmacological treatment of tardive dyskinesia: recent developments

ABSTRACT Introduction: Tardive dyskinesia (TD) occurs in patients receiving antipsychotic treatment with dopamine receptor antagonists. Despite the prevalence of TD and its negative impact on patients’ lives, there has been a lack of approved treatments and limited evidence from controlled trials of pharmacological treatment. Areas covered: PubMed was searched for English-language papers published during 2007–2016 using terms ‘tardive dyskinesia’ or ‘drug-induced movement disorder’, and ‘treatment’. Studies evaluating pharmacological agents for the treatment of TD were selected. A total of 26 studies (five meta-analyses, twelve randomized controlled trials, and nine open-label observational studies) are reviewed. Expert commentary: Treatment of TD necessitates a stepwise approach. Optimization of antipsychotic therapy should be considered before initiation of antidyskinetic therapies. Data from some recent studies indicate possible improvements in TD after switching antipsychotics or with the use of amantadine, levetiracetam, piracetam, zonisamide, propranolol, vitamin B6, or certain unregulated herbal medicines; although significance of these improvements is unclear and require further investigation in randomized controlled trials. By contrast, recent evidence from Phase III trials of novel vesicular monoamine transporter-2 inhibitors demonstrates they could have a significant effect on TD symptom severity and suggests these agents may have the potential to transform treatment of TD in coming years.

Catatonia, Malignant Catatonia, and Neuroleptic Malignant Syndrome

Malignant catatonia (MC) represents a life-threatening neuropsychiatric disorder that was widely reported long before the introduction of antipsychotic drugs. A review of the world literature on MC indicates that although the prevalence of the condition may have declined since the pre-antipsychotic drug era, it continues to occur and represents a syndrome rather than a specific disease. Although most often the outgrowth of a psychiatric disorder, MC may develop in association with diverse neurologic and medical conditions. From this perspective, neuroleptic malignant syndrome (NMS) may be viewed as a drug-related form of this same MC syndrome. Our review also supports the proposed conceptualization of catatonia as a continuum, with milder forms at one end (termed simple or nonmalignant catatonia) and more severe forms involving hyperthermia and autonomic dysfunction (termed malignant catatonia) at the other end. In addition, findings from our review suggest that simple catatonia, MC and NMS share a common pathophysiology involving reduced dopaminergic functioning in the basal ganglia-thalamocortical circuits, consistent with their identity as variants of the larger unitary catatonic syndrome. Electroconvulsive therapy appears to represent the preferred treatment for MC. Antipsychotic drugs should be withheld whenever MC is suspected.