clozapine and Tardive-Dyskinesia

Though clozapine is recommended for treatment of tardive dyskinesia (TD) relating to the use of antipsychotic medications, studies comprehensively investigating the treatment effect of clozapine on TD are still limited.. This review examines the effectiveness of clozapine as an intervention for tardive dyskinesia and dystonia in patients with all psychiatric conditions. Effectiveness of clozapine, duration to exert the effect and dosage used were also analysed.. A search in the PubMed, PsycINFO and clinicaltrials databases was performed, using the search terms "Clozapine" AND "dyskinesia" OR "dystonia". Full-text articles that reported the use of clozapine to treat abnormal involuntary movements and were written in English were included.. A total of 48 studies were identified, of which 13 were clinical trials and 35 were case reports. Significant improvement was seen in 86.7% of patients with schizophrenia spectrum disorders (average dose of clozapine = 355 mg/day) and 93% of patients with other psychiatric disorders (average dose of clozapine = 152.5 mg/day). Patients with other psychiatric diagnoses had faster improvement than the patients with schizophrenia spectrum disorders. Variation in improvements and dosage were also seen in the clinical trials.. Results suggested an overall effectiveness of clozapine in the treatment of TD for patients with a range of psychiatric conditions. Different response time and clozapine dosage were seen in patients with different psychiatric conditions, suggesting different treatment protocols are required for different conditions. Most of the studies identified are of inadequate qualities, highlighting the need for high quality studies to provide clearer evidence.

Topics: Antipsychotic Agents; Clozapine; Humans; Mental Disorders; Schizophrenia; Tardive Dyskinesia

Tardive dyskinesia (TD) is an antipsychotic-induced movement disorder that typically occurs after long-term exposure to antipsychotic drugs. There is evidence that switching to clozapine reduces TD. This meta-analysis reviews the effect of switching to clozapine on the severity of TD.. The PubMed, PsycINFO, and Embase databases were searched for clozapine, tardive dyskinesia, and related keywords. The search was restricted to articles written in English and Dutch, and it was last updated on October 13, 2015.. Sixteen studies were included in the meta-analysis. Inclusion criteria were a diagnosis of schizophrenia or a related disorder, a switch to clozapine monotherapy, and reports of scores on a TD rating scale before and after the switch to clozapine.. Two independent investigators extracted the data. Data were converted to standardized mean change scores and analyzed in a random-effects model.. A random-effects model showed that the overall effect of switching to clozapine was a significant reduction in TD (npatients = 1,060, d = -0.40, P < .01), especially in the 4 studies that investigated the severity of TD as a primary outcome (npatients = 48, d = -2.56, P = .02).. The overall results show that clozapine treatment can yield a slight reduction in TD. The severity of TD was reduced greatly in patients with moderate to severe TD. In patients with minimal to mild TD, switching to clozapine seldom worsens TD and a trend toward reduction is seen. These results support that a switch to clozapine should be considered for patients with moderate to severe TD and/or patients who experience substantial discomfort due to TD.

Topics: Antipsychotic Agents; Clozapine; Drug Substitution; Humans; Schizophrenia; Severity of Illness Index; Tardive Dyskinesia

Tardive dyskinesia is defined as involuntary athetoid or choreiform movements that develop due to the use of neuroleptic drugs for at least a few months. Tongue, lower face, jaw, upper and lower extremities are the most affected parts of the body in tardive dyskinesia. Quality of life is negatively affected because of the low remission rates. Besides tardive dyskinesia, involuntary movements may appear after discontinuation, change or a reduction in the dose of antipsychotic medications, which is called withdrawal-emergent dyskinesia (WED). Unlike tardive dyskinesia, the involuntary movements involve mainly the neck, trunk, and limbs and regress in shorter period of time in WED. A consensus has not yet been reached for the treatment of WED. Restarting the previous antipsychotic agent with slow titration or switching to an atypical antipsychotic with low affinity for dopamine D2 receptors are among the primary options for treatment. As WED is one of the predictors of tardive dyskinesia development, early detection and treatment is believed to have positive effect on the quality of life. In this report, the case of a patient followed up for bipolar disorder type I (BD-I) and started on clozapine for WED after discontinuation of haloperidol on account of adverse effects is discussed. It is necessary for clinicians to consider these types of complications when discontinuing or changing treatment. Further research is needed in order to reach a common approach for the treatment of WED.

Topics: Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Humans; Quality of Life; Tardive Dyskinesia

​​ Tardive dyskinesia (TD) is a condition of potentially irreversible abnormal involuntary movements associated with dopamine receptor blocking agents, such as antipsychotics. While prevention is the best strategy, it is not always possible. This report outlines strategies to reduce TD symptoms, including the use of the FDA-approved treatment options (valbenazine and deutetrabenazine).

Topics: Adrenergic Uptake Inhibitors; Adult; Clozapine; Humans; Psychiatry; Serotonin Antagonists; Tardive Dyskinesia; Tetrabenazine; Valine

Tardive dyskinesia is a delayed and potentially irreversible motor complication arising from chronic exposure to antipsychotic drugs. Interaction of antipsychotic drugs with G protein-coupled receptors triggers multiple intracellular events. Nevertheless, signaling pathways that might be associated with chronic unwanted effects of antipsychotic drugs remain elusive. In this study, we aimed to better understand kinase signaling associated with the expression of tardive dyskinesia in nonhuman primates.. We exposed capuchin monkeys to prolonged haloperidol (n = 10) or clozapine (n = 6) treatments. Untreated animals were used as controls (n = 6). Half of haloperidol-treated animals (5) developed mild tardive dyskinesia similar to that found in humans. Using Western blots and immunochemistry, we measured putamen total and phosphorylated protein kinase levels associated with canonical and noncanonical signaling cascades of G protein-coupled receptors.. Antipsychotic drugs enhanced pDARPP-32 and pERK1/2, but no difference ws observed in phosphoprotein kinase levels between dyskinetic and nondyskinetic monkeys. On the other hand, comparison of kinase levels between haloperidol-treated dyskinetic and nondyskinetic monkeys indicated that dyskinetic animals had lower GRK6 and β-arrestin2 levels. Levels of pAkt and pGSK-3β were also reduced, but only haloperidol-treated monkeys that developed tardive dyskinesia had reduced pGSK-3β levels, whereas pAkt levels in dyskinetic animals positively correlated with dyskinetic scores. Interestingly, double immunofluorescence labeling showed that putamen dopamine D3 receptor levels were upregulated and that D3/pAkt colocalization was enriched in haloperidol-treated animals displaying tardive dyskinesia.. Our results suggest that upregulation of putamen dopamine D3 receptor and alterations along the noncanonical GRK6/β-arrestin2/Akt/GSK-3β molecular cascade are associated with the development of tardive dyskinesia in nonhuman primates. © 2019 International Parkinson and Movement Disorder Society.

Topics: Animals; beta-Arrestin 2; Cebus; Clozapine; Dopamine and cAMP-Regulated Phosphoprotein 32; G-Protein-Coupled Receptor Kinases; Glycogen Synthase Kinase 3 beta; Haloperidol; MAP Kinase Signaling System; Phosphorylation; Proto-Oncogene Proteins c-akt; Putamen; Receptors, Dopamine D3; Signal Transduction; Tardive Dyskinesia

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Obsessive-Compulsive Disorder; Psychiatric Status Rating Scales; Risperidone; Tardive Dyskinesia; Time Factors; Treatment Outcome

Tardive dyskinesia (TD) is a potentially disabling condition encompassing all delayed, persistent, and often irreversible abnormal involuntary movements arising in a fraction of subjects during long-term exposure to centrally acting dopamine receptor-blocking agents such as antipsychotic drugs and metoclopramide. However, the pathogenesis of TD has proved complex and remains elusive. To investigate the mechanism underlying the development of TD, we have chronically exposed 17 Cebus apella monkeys to typical (11) or atypical (6) antipsychotic drugs. Six additional monkeys were used as controls. Using autoradiography, Western blot and in situ hybridization techniques, we compared neurochemical components of the dopamine, serotonin, and glutamate neurotransmitter systems modulating striatal activity in monkeys chronically exposed to haloperidol and clozapine. Five (5) out of 11 monkeys treated with haloperidol develop TD, whereas none of the monkeys treated with clozapine develop TD. Haloperidol treatment significantly upregulated the levels of serotonin 5-HT

Topics: Animals; Antipsychotic Agents; Clozapine; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dyskinesia, Drug-Induced; Female; Haloperidol; Haplorhini; Putamen; Tardive Dyskinesia

Tardive dystonia (TDt) is a debilitating side effect of long-term antipsychotic treatment. Even though TDt is associated with increased psychiatric morbidity, mortality, and severely decreased quality of life, there are no treatment modalities for TDt. Clozapine has been used as a treatment option for TDt in patients with schizophrenia. Interestingly, several recent case reports have indicated that it can enhance or induce TDt. We report a case of clozapine-associated TDt that was treated with low-dose aripiprazole (0.5 mg/day). The patient was a 51-year-old Korean woman with schizophrenia that had been admitted to the psychiatric ward for her florid psychotic symptoms. The patient's TDt symptoms began to develop after 1 year of clozapine (200 mg/day) treatment. Her motor symptoms improved markedly after adding low-dose aripiprazole (0.5 mg/day) to clozapine (175 mg/day). Aripiprazole is a dopamine D2 receptor partial agonist that exhibits partial agonistic activity against serotonin-1A (5-HT1A) receptors and full antagonistic activity against 5-HT2A receptors. The dopaminergic tone in the surrounding milieu is important for aripiprazole activity. In addition, antioxidative effects of aripiprazole may manage the neurotoxic effects of clozapine. To our knowledge, only one report has described a patient with clozapine-associated TDt that was treated with moderate doses of aripiprazole (10-15 mg). This case report may be the first report of low-dose aripiprazole treatment of clozapine-associated TDt.

Topics: Antipsychotic Agents; Aripiprazole; Clozapine; Diagnosis, Differential; Female; Humans; Middle Aged; Schizophrenia; Tardive Dyskinesia

Tardive dyskinesias (TD) are serious, often irreversible side effects of dopamine blocking agents, most commonly first-generation antipsychotics. No definitive treatment exists, with different interventions showing inconsistent results. We report a case of TD presenting after 12 years of olanzapine therapy in a 66-year-old Hispanic male with paranoid schizophrenia. The TD symptoms were successfully treated within a few weeks by switching to clozapine. Two cases of olanzapine-induced TD treated with clozapine have previously been reported, but in those cases, the symptom onset was quicker, ranging from a few months to a few years after initiation of olanzapine therapy, and the treatment response was relatively slower. Clinicians should carefully monitor for symptoms of TD after prolonged treatment with olanzapine and other antipsychotics. If otherwise indicated for psychiatric treatment, clozapine can be considered a good choice for patients with TD in preventing or reversing the debilitating consequences of this condition.

Topics: Aged; Antipsychotic Agents; Benzodiazepines; Clozapine; Humans; Male; Olanzapine; Schizophrenia, Paranoid; Tardive Dyskinesia