clozapine and Tremor

Parkinson's disease is a neurodegenerative disorder that manifests clinically with variable degrees of tremor, muscle rigidity, bradykinesia and postural instability. Tremor-predominant Parkinson's disease is characterised by prominent tremor of one or more limbs with a relative lack of significant rigidity and bradykinesia. Despite the lack of other disabling motor symptoms, the tremor of tremor-predominant Parkinson's disease can be very disabling, especially if a postural and kinetic component exists. A wide variety of treatments for Parkinson's disease tremor are currently available and include use of oral medications, injections with botulinum toxin and neurosurgical procedures. Some of the first line medications (levodopa, dopamine agonists, anticholinergics) are very effective in controlling tremor. However, some patients with Parkinson's disease tremors are unresponsive to first line drugs and treatment with second line medications (clozapine, amantadine, clonazepam, propranolol, neurontin) should be attempted. In the small number of patients with disabling tremor that is refractory to all medications, neurosurgical intervention should be considered. Both thermocoagulation and deep brain stimulation at several different neuroanatomical sites (thalamus, globus pallidus, subthalamic nucleus) offer good to excellent tremor control with relatively low risk to the patient.

Topics: Acetates; Amantadine; Amines; Antiparkinson Agents; Botulinum Toxins; Cholinergic Antagonists; Clonazepam; Clozapine; Cyclohexanecarboxylic Acids; Dopamine Agonists; Electric Stimulation Therapy; Gabapentin; Gamma Rays; gamma-Aminobutyric Acid; Globus Pallidus; Humans; Neurosurgical Procedures; Parkinson Disease; Propranolol; Radiosurgery; Thalamus; Tremor

Clozapine, the only commercially available atypical neuroleptic, is approved for the treatment of schizophrenic patients who are unresponsive to or intolerant of typical neuroleptics. It has an unusual pharmacologic profile compared with standard neuroleptics, and it follows that clinical response to this drug is also different. It has shattered the notion that a drug must be capable of inducing or worsening parkinsonism to be a potent antipsychotic. Based on these findings, it is being used increasingly by neurologists for psychiatric and nonpsychiatric problems in patients with movement disorders. The most common use for clozapine among neurologists is in the management of drug-induced psychosis in Parkinson's disease (PD). This problem has been a source of increased morbidity and mortality in PD because of a lack of adequate therapeutic intervention. At this time, because of success in numerous open trials, with improvement of > 80% of patients, clozapine therapy for psychosis in PD is becoming the standard of care. It also appears to be of value in the management of some motor features of PD, including tremors and dyskinesia and possibly even sensory symptoms such as akathisia and pain. The literature also suggests that clozapine may be of potential benefit in hyperkinetic movement disorders including essential tremor, Huntington's disease, and tardive dyskinesia. We review the current data concerning the use of clozapine in patients with these movement disorders and others.

Topics: Antiparkinson Agents; Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Dyskinesia, Drug-Induced; Humans; Huntington Disease; Movement Disorders; Parkinson Disease; Psychotic Disorders; Tremor

The advent of clozapine has marked a major advance in the treatment of schizophrenia because of its low incidence of extrapyramidal side effects and superior efficacy. Because of a relatively high incidence of agranulocytosis, approved indications for use are limited to treatment-refractory or neuroleptic-intolerant patients with schizophrenia. However, an emerging body of literature suggests that clozapine may be preferable to typical neuroleptics for treating psychosis in certain neurologic disorders. In addition, clozapine may have a place in the treatment of movement disorders that are caused by or are a result of the pharmacologic treatment of some neurologic illnesses. In general, clozapine doses used in these settings are lower than that for treating psychosis in schizophrenia. This article reviews the experience with clozapine in selected neurologic disorders.

Topics: Clinical Trials as Topic; Clozapine; Drug Administration Schedule; Humans; Levodopa; Nervous System Diseases; Neurocognitive Disorders; Parkinson Disease; Tremor

Topics: Clozapine; Humans; Parkinson Disease; Psychotic Disorders; Tremor

Patients with essential tremor (ET) may not respond to commonly used drugs. Clozapine, an atypical neuroleptic drug, has been reported to improve postural Parkinson's disease tremor clinically resembling ET. The effects of a single dose of 12.5 mg clozapine and placebo were evaluated in a randomized, double-blind, crossover study in 15 drug-resistant patients with ET. Patient responders with more than 50% improvement after a single dose of clozapine subsequently received the drug (39+/-9 mg up to 50 mg) unblinded for a period of 15.8+/-7.7 months. Tremor was effectively reduced by a single dose of clozapine in 13 of 15 patients (p <0.01). Sedation was the only side effect reported during the clozapine test; however, the time course of sedation and of the antitremor effect were not coincident. A significant reduction of tremor was reported with chronic clozapine treatment (p <0.01) with no tolerance to drug antitremor effect, whereas sedation markedly decreased after 6-7 weeks of therapy. No clozapine-induced hematologic side effects were observed in our cohort of patients during long-term treatment. Our results suggest that in selected drug-resistant ET cases, clozapine should be considered before resorting to neurosurgical options.

Topics: Antipsychotic Agents; Clozapine; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Treatment Outcome; Tremor

Four open-label studies have reported beneficial effects of clozapine on the tremor of idiopathic Parkinson's disease (PD). We performed a double-blind crossover trial with a 2-week washout, comparing low-dose clozapine to benztropine for the treatment of tremor in PD. Twenty-two subjects enrolled and 19 completed the study. Benztropine and clozapine were equally effective in improving tremor and the motor score of the United Parkinson's Disease Rating Scale at mean doses of 3.0 and 39 mg/day, respectively. Significant adverse events were experienced with each drug, but leukopenia was not encountered. We conclude that the atypical antipsychotic drug clozapine is helpful in the treatment of tremor in PD and should be considered when all other drug therapies fail.

Topics: Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Antipsychotic Agents; Benztropine; Clozapine; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Parkinson Disease; Treatment Outcome; Tremor

The effects of the acute administration of clozapine on parkinsonian mixed tremor (i.e., resting and postural tremors) were evaluated to establish clozapine's predictive value for long-term response and to determine if there is a difference in the pharmacologic responses of the two tremors. We also investigated the correlation between reduction of tremor and induction of sedation after acute and chronic administration of clozapine. Clozapine (12.5 mg) or placebo were administered po in a double-blind manner to 17 PD patients with mixed L-dopa-resistant tremors. Two patients did not reach 50% improvement and were considered nonresponders. The remaining 15 patients reported moderate to marked reduction of tremor. Responsive patients in the acute test moved on to a long-term, open clozapine add-on study receiving an average daily dose +/- SD of 45 +/- 9.6 mg for a period of 15.5 +/- 8.3 months. A significant reduction of both resting (p < 0.05) and postural (p < 0.05) tremors was observed under clozapine from the first week of treatment through the entire period of the study. There was no statistically significantly difference between the degree of improvement for resting and postural tremors after either single or chronic clozapine administration. Sedation was the only side effect reported after clozapine; however, the time courses of sedation and tremor reduction did not coincide in the acute or in the chronic experimental paradigm, where it decreased considerably in a few weeks in all patients. During long-term clozapine treatment, neither systemic side effects nor worsening of motor disability scores were noted. Thus we wish to propose an acute test or a therapeutic attempt, or both, with clozapine before defining a case of mixed parkinsonian tremor as resistant tremor and therefore resorting to a neurosurgical approach.

Topics: Aged; Antipsychotic Agents; Clozapine; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Parkinson Disease; Posture; Rest; Severity of Illness Index; Treatment Outcome; Tremor

Neuroleptic-induced extrapyramidal side effects (EPS) were evaluated in 92 patients treated with clozapine for the first time and 59 patients treated with haloperidol followed in a drug monitoring program. Side effects were measured by the Columbia University Rating Scale, the Simpson Dyskinesia Scale and the Hillside Akathisia Scale. The cumulative incidence rate for tremor was found to be 24.4% in the clozapine group and 39.3% in the haloperidol group. This did not amount to a statistically significant group difference. Bradykinesia was observed in 21.8% of the patients treated with clozapine and in 47.7% of the patients of haloperidol (P = 0.011). In the clozapine group the akathisia incidence rate was 5.6%, whereas haloperidol patients showed a higher rate of 31.7% (P = 0.005). Our results show higher incidence rates of tremor and bradykinesia during clozapine treatment than previous studies. We conclude that clozapine is not entirely free of EPS, but they are usually less severe and of a different quality than side effects induced by typical antipsychotics.

Topics: Adult; Akathisia, Drug-Induced; Basal Ganglia Diseases; Clozapine; Dyskinesia, Drug-Induced; Female; Haloperidol; Humans; Male; Tremor

After preliminary observations on 5 psychotic and 7 nonpsychotic parkinsonian patients had shown unexpected impressive beneficial effects of the atypical neuroleptic clozapine on tremor, an open clinical study including 12 patients was started. Under a dosage-range approximately 25-50 mg/day significant reduction of tremor intensity and tremor related functional disability (CURS, Sweet's scale) was achieved. Akinesia was not deteriorated, initial fatigue disappeared spontaneously. Pharmacological mode of action of clozapine's antitremor effect remains unclear. Its broad receptor binding spectrum with strong antiserotonergic properties might here play a major role.

Topics: Aged; Aged, 80 and over; Clozapine; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Parkinson Disease; Tremor

In an open trial 25 tremor patients were treated with clozapine in small doses (18-75 mg per day). The effect was measured with a new movement analyzer. Nine of 12 essential tremor patients were greatly improved. In six of nine patients with Parkinson tremor and in two combined essential tremor/Parkinson tremor patients tremor almost disappeared. Sedation is a major side effect, but decreases in most patients with time. The risk of agranulocytosis makes blood control necessary.

Topics: Alcoholism; Clinical Trials as Topic; Clozapine; Dibenzazepines; Double-Blind Method; Humans; Parkinson Disease; Tremor

Movement abnormalities are frequently reported in children with 22q11.2 deletion syndrome (22q11.2DS), but knowledge in this area is scarce in the increasing adult population. We report on five individuals illustrative of movement disorders and other motor abnormalities in adults with 22q11.2DS. In addition to an increased susceptibility to neuropsychiatric disorders, seizures, and early-onset Parkinson disease, the underlying brain dysfunction associated with 22q11.2DS may give rise to an increased vulnerability to multiple movement abnormalities, including those influenced by medications. Movement abnormalities may also be secondary to treatable endocrine diseases and congenital musculoskeletal abnormalities. We propose that movement abnormalities may be common in adults with 22q11.2DS and discuss the implications and challenges important to clinical practice.

Topics: Adult; Clozapine; Diagnosis, Differential; DiGeorge Syndrome; Female; Humans; Male; Middle Aged; Movement Disorders; Myoclonus; Parkinsonian Disorders; Patellar Dislocation; Phenotype; Spinal Cord Compression; Tremor; Young Adult

In several previous studies, tremulous jaw movements in rats have been used to assess the effects of antiparkinsonian drugs and atypical antipsychotics. Because antihistamines such as diphenhydramine are used as antiparkinsonian agents, and atypical antipsychotic drugs such as clozapine and olanzapine have high affinity for histamine H1 receptors, the present study investigated the effects of H1 antagonists on cholinomimetic-induced jaw movements. Diphenhydramine, doxepin, and mepyramine (all injected IP 2.5-20.0 mg/kg) were assessed for their ability to block the jaw movements induced by 5.0 mg/kg of the anticholinesterase tacrine. Within this dose range, only diphenhydramine produced a robust and significant reduction in jaw movement activity. Thus, diphenhydramine was subjected to further testing, which employed procedures previously used to assess the effects of other antitremorogenic drugs, such as clozapine. Diphenhydramine did not induce jaw movement activity. In addition to suppressing jaw movement activity after acute injections, diphenhydramine also suppressed tacrine-induced jaw movements after repeated (14-day) administration. In summary, the present results show that diphenhydramine suppresses cholinomimetic-induced jaw movements, an effect that is similar to other antiparkinsonian or antitremor drugs such as anticholinergics, L-DOPA, DA antagonists, and clozapine. Nevertheless, doxepin produced only mild effects, and mepyramine, which has a higher affinity and selectivity than diphenhydramine for H1 receptors, failed to suppress cholinomimetic-induced jaw movements. These results suggest that diphenhydramine suppresses tremulous movements through a mechanism that does not depend upon antagonism of histamine H1 receptors.

Topics: Animals; Antidepressive Agents, Tricyclic; Antipsychotic Agents; Benzodiazepines; Cholinergic Agents; Clozapine; Diphenhydramine; Dose-Response Relationship, Drug; Doxepin; Histamine H1 Antagonists; Jaw; Male; Movement; Olanzapine; Pirenzepine; Pyrilamine; Rats; Rats, Sprague-Dawley; Receptors, Histamine H1; Receptors, Muscarinic; Tacrine; Tremor

Topics: Clozapine; GABA Agonists; GABA Antagonists; Humans; Muscimol; Tremor

Topics: Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Humans; Male; Middle Aged; Schizophrenia; Tremor

The purpose of this study was to compare the subchronic, low-dose effects of clozapine with those of olanzapine in a learned behavioral task previously shown to distinguish between clozapine and haloperidol with acute and subchronic treatment regimes. Rats were trained to use a single forelimb to press a force-recording operandum and simultaneously to lick water from a dipper that remained available while forelimb force exceeded a modest lower limit. Analysis of the resulting forcetime recordings provided measures of task engagement (time on task-analogous to response rate), lick rhythm, tremor, ballistic (maximum force) and tonic (hold force) forelimb force measures, as well as the durations of the individual responses. In a between-groups dosing design, five separate groups of rats received vehicle, clozapine 1.0 or 5.0 mg/kg, olanzapine 0.5 or 1.0 mg/kg daily for 27 days. A 7-day withdrawal period followed. On days 22 and 26 of antipsychotic drug treatment, all rats additionally received 0.3 mg/kg trihexyphenidyl or 1.0 mg/kg quipazine, respectively. The effects of olanzapine and clozapine were similar in that both drugs reduced time on task, increased response duration, and slowed lick rhythm. The two drugs differed in that clozapine reduced the force and tremor measures but olanzapine did not. Both tolerance and withdrawal effects, as reflected by the tremor measure, were observed for clozapine but not for olanzapine. Trihexyphenidyl further increased the duration of responses already lengthened by clozapine; in contrast, trihexyphenidyl decreased the duration lengthening effect of olanzapine. Taken together, the results indicated that olanzapine did not have the antitremor and hypotonic effects displayed by clozapine, and olanzapine did not induce tolerance and withdrawal phenomena as clozapine did.

Topics: Animals; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Benzodiazepines; Clozapine; Drug Tolerance; Forelimb; Male; Muscarinic Antagonists; Olanzapine; Pirenzepine; Quipazine; Rats; Rats, Sprague-Dawley; Serotonin Receptor Agonists; Substance Withdrawal Syndrome; Tremor; Trihexyphenidyl

A 58-year-old man with chronic paranoid-hallucinatoric psychosis had transient episodes with marked paranoid delusions, auditory hallucinations without confusion, shakiness of both upper extremities, tachycardia and sweating. EMG performed with surface electrodes revealed many silent periods in postural active muscles with maximum duration of 120 ms; blood glucose was 65-75 mg/dl. At other times, blood glucose was 135-140 mg/dl, EMG revealed few silent periods in postural active muscles with maximal duration of 50 ms and the patient noted some vibration in his outstretched hands only. Drug-induced asterixis (clozapine, benperidol) amplified by relative hypoglycemia was therefore assumed, and symptoms disappeared after oral antidiabetics were reduced.

Topics: Antipsychotic Agents; Clozapine; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Electromyography; Fasciculation; Glyburide; Hallucinations; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Middle Aged; Motor Neurons; Muscle, Skeletal; Myoclonus; Neurologic Examination; Paranoid Disorders; Tremor

Asterixis (flapping tremor) can be induced by treatment with psychopharmacologic agents. We observed 10 cases of asterixis in psychiatric inpatients, most with affective spectrum disorders being treated with combination therapy. The drugs most often used were clozapine (eight cases), lithium (seven cases), and carbamazepine (seven cases). There were neither metabolic disorders nor structural brain lesions that might explain the occurrence of asterixis. Because dosage in general was moderate and serum levels were within therapeutic boundaries in most cases, the symptom seemed to have been caused by an interaction of drugs rather than by a single agent. Therefore clozapine, carbamazepine, and lithium should be combined with each other only with great care.

Topics: Adult; Aged; Carbamazepine; Clozapine; Female; Humans; Male; Middle Aged; Mood Disorders; Psychotropic Drugs; Tremor

Topics: Agranulocytosis; Clozapine; Ethnicity; Humans; Neutropenia; Parkinson Disease; Tremor

Topics: Clozapine; Female; Humans; Middle Aged; Schizophrenia; Tremor

Tremor at rest is a classic symptom of Parkinson's disease that causes significant disability and distress for the patient and is generally only weakly responsive to conventional treatment, like anticholinergic and dopaminergic medication. This study describes the treatment with Clozapine in patients with Parkinson's disease, who despite optimal antiparkinson medical therapy still have a major disabling tremor at rest. Clozapine is an "atypical" neuroleptic agent, producing fewer extra pyramidal side effects common to conventional antipsychotic drugs. Clozapine, however, has as its most serious complication agranulocytosis, and hence all patients taking Clozapine must undergo blood tests at least several times a month. Under these frequent blood monitoring conditions, in this study Clozapine produced a substantial alleviation of parkinsonian tremor in 17 of 23 patients (73%). The beneficial response was reached with a relative low dose of Clozapine (18 mg./day), while previous antiparkinson medication was kept unchanged. The improvement of tremor at rest was noticeable generally within 2 weeks of beginning Clozapine therapy. No tolerance to the antitremor efficacy of Clozapine was seen during study-period of at least 6 months. Leucopenia developed in one patient, other major adverse events were hypersalivation and day-time drowsiness. These findings confirm the substantial antitremor efficacy of Clozapine in Parkinson's disease.

Topics: Aged; Aged, 80 and over; Clozapine; Disability Evaluation; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Neurologic Examination; Parkinson Disease; Tremor

A 54-year-old woman with acute schizoaffective psychosis was treated with lithium carbonate (1,350 mg daily) and zuclopenthixol. On admission, clozapine was added (250 mg daily). Because extrapyramidal symptoms (rigor, akinesia) developed, she was additionally given biperiden retard (4 mg daily) from the fourth hospital day onwards. Eleven days after admission she began to complain of "unsteadiness" and "tremors" in her arms and she had asterixis (flapping tremor) on holding up her arms. The electromyogram showed electrical pauses of 60-120 ms, typical for asterixis. There were no significant metabolic or organic cerebral changes that could have accounted for the symptoms which presumably had been induced by the drugs even though their dosage was not unusual. The symptoms in fact regressed completely after the clozapine dose had been reduced, at first to 125 mg then to 50 mg. Previous experience has suggested that the risk of asterixis is particularly high when lithium and clozapine are taken together.

Topics: Biperiden; Clopenthixol; Clozapine; Drug Therapy, Combination; Electromyography; Female; Humans; Lithium Carbonate; Middle Aged; Psychotic Disorders; Tremor