clozapine and Movement-Disorders

Psychosis is a major psychiatric problem that often occurs at the interface of psychiatry and the neurological specialty of movement disorders. Psychotic syndromes are common in treated movement disorder patients, and almost all antipsychotic drugs produce movement disorders. There is little published data on psychosis in movement disorders aside from Parkinson's disease (PD).. In this review, we focus primarily on PD, in which about 30% of treated patients have visual hallucinations and 5-10% have paranoid delusions; dementia with Lewy bodies, a variant of PD in which dementia occurs early and psychotic symptoms are common; Huntington's disease (HD), an inherited disorder that causes behavioral problems, frequently including psychosis; and tardive dyskinesia (TD), a group of movement disorder syndromes caused by antipsychotic drugs. All articles were reviewed in each of the more common movement disorders and indexed in PubMed with keywords including psychosis, psychotic symptoms, antipsychotics, hallucinations and delusions.. Although there are no approved drugs for treating psychotic symptoms in any of the movement disorders, pimavanserin, a 5-HT2A inverse agonist, is thought likely to gain approval in 2015 for treating PD psychosis. We present evidence that clozapine is currently the drug of choice for treating psychosis in patients with parkinsonism; however, blood monitoring requirements make it difficult to use. The choice of treatment of hyperkinetic disorders such as HD and the TD disorders depends on the clinical scenario.

Topics: Animals; Antipsychotic Agents; Clozapine; Humans; Movement Disorders; Piperidines; Psychotic Disorders; Treatment Outcome; Urea

Essential tremor (ET) is one of the most common movement disorders of adults, characterized by postural and kinetic tremor. It often causes embarrassment and more rarely serious disability, requiring treatment. To assess the current state of knowledge on ET therapy and produce recommendations based on the analysis of evidence the authors reviewed the literature regarding pharmacologic and surgical therapies, providing a quality assessment of the studies and the strength of recommendations for each treatment. A committee of experts selected clinical-based questions to guide the search. A systematic literature review was performed to identify all the studies conducted on patients with ET published until September 2010. Articles were classified according to GRADE evidence profile, a system for grading the quality of evidence and the strength of recommendation based on the quality of the studies. The quality of evidence was often rated as "low" or "very low" for the studies analyzed. Propranolol, long-acting propranolol, primidone, and topiramate are recommended as first-line therapy, with restrictions for their side effects. Arotinolol, sotalol, ICI 118.551 and LI 32.468 (experimental drugs), zonisamide, gabapentin, alprazolam, clozapine, and olanzapine are recommended as a second-line treatment. Botulinum toxin type A and thalamic deep-brain stimulation are recommended for refractory ET. The results highlight the need of well-designed direct comparison trials aimed at evaluating relative effectiveness and safety of the drugs currently used in clinical practice. Furthermore, additional controlled clinical trials are required to define other possible treatment strategies for ameliorating the management of ET.

Topics: Animals; Clinical Trials as Topic; Clozapine; Deep Brain Stimulation; Essential Tremor; Humans; Italy; Movement Disorders; Practice Guidelines as Topic; Propranolol; Treatment Outcome

Tardive dyskinesia (TD) is a common and potentially irreversible side effect of dopamine blocking agents, most often antipsychotics. It is often socially and sometimes also physically disabling. The clinical picture can be divided into orofacial, limb-truncal, and respiratory dyskinesia. The clinical options to prevent or mitigate TD include psychoeducation, systematic screening, and evaluation of the need for antipsychotics and/or dosages, managementof known risk factors, and switching to an antipsychotic with a lower risk of TD. There is no evidence-based approach for treating existing TD but several clinical interventions can be effective including discontinuing the antipsychotics or reducing the dosage, switching to clozapine, adding an antidyskinetic agent, or applying deep brain stimulation.

Topics: Animals; Anti-Dyskinesia Agents; Antipsychotic Agents; Botulinum Toxins; Clozapine; Deep Brain Stimulation; Humans; Movement Disorders; Risk Factors

Clozapine is the best treatment option in several clinical circumstances, including treatment-resistant schizophrenia, non treatment-resistant schizophrenia, suicide risk in schizophrenia spectrum disorders, aggressiveness or violence in psychiatric patients, psychosis in Parkinson's disease, prevention and treatment of tardive dyskinesia. However, clozapine is associated with many serious side effects. Furthermore, monitoring requirements, i.e., frequent blood draws and frequent visits, discourage clozapine use. Therefore, the drug is underused. The only way to avoid the underuse of clozapine is full awareness of its side effects and competence to minimize them. The aim of the paper is reviewing the safety profile of clozapine and the suggested strategies in the management of its side effects, including neutropenia, eosinophilia, seizures, myocarditis, weight gain, diabetes, metabolic syndrome, hypersalivation, fever, constipation, ileus, urinary incontinence, sweating. The neuropsychiatric side effects of clozapine are not discussed in this review.

Topics: Animals; Antipsychotic Agents; Clozapine; Drug Monitoring; Humans; Movement Disorders; Psychotic Disorders; Schizophrenia

With dopaminergic systems, non dopaminergic neurotransmission probably plays a major role in parkinsonian syndromes (Multiple System Atrophy, Progressive Supranuclear Palsy, Pure Autonomic Failure, Cortical basal degeneration, Lewy Body Disease). A better understanding of the pathophysiology of these syndromes led to the development of molecules that interact with non dopaminergic systems. Thus, freezing, gait and balance disorders, dysautonomia and neuropsychiatric disorders are likely to benefit from specific treatments. However, due to methodological difficulties related to the evaluation of such molecules, controlled trials are rather rare and the results are often partial and sometimes unclear.

Topics: Anti-Dyskinesia Agents; Botulinum Toxins; Cholinesterase Inhibitors; Clozapine; Dementia; Depressive Disorder; Dopamine; Glutamic Acid; Humans; Movement Disorders; Parkinsonian Disorders; Selective Serotonin Reuptake Inhibitors; Serotonin; Synaptic Transmission; Treatment Outcome

The most frequent problems associated with the older generation of antipsychotic agents are extrapyramidal side effects (EPS) and tardive dyskinesia. Neuroleptic-induced EPS are thought to be caused by blockade of nigrostriatal dopamine tracts resulting in a relative increase in cholinergic activity; tardive dyskinesia is less well understood but is thought to be a supersensitivity response to chronic dopamine blockade. The leading hypothesis for the mechanism of action of the newer generation of atypical antipsychotics is the presence of a high serotonin-to-dopamine receptor blockade ratio in the brain. When serotonergic activity is blocked-as is the case with atypical antipsychotics-dopamine release increases and balances out the dopamine blockade effect at postsynaptic receptor sites, which results in few or no EPS. Prospective data indicate that the risk of tardive dyskinesia in patients taking atypical antipsychotics is less than that for those taking typical antipsychotics. This article reviews the mechanisms of neuroleptic-induced EPS and tardive dyskinesia and discusses the relationship between these movement disorders and atypical antipsychotic agents.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Brain; Clozapine; Dibenzothiazepines; Humans; Movement Disorders; Olanzapine; Pirenzepine; Quetiapine Fumarate; Receptors, Dopamine; Receptors, Serotonin; Risk Factors; Risperidone

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

In schizophrenic patients in maintenance treatment, clozapine, compared to classic neuroleptics, induces relatively few extrapyramidal syndromes (EPS), especially less akathisia and tremor and usually no dystonia or rigidity. In patients with dyskinetic movements (acute or tardive) induced by other neuroleptics, clozapine may reduce or even remove dyskinesia or permit it to disappear. It cannot, however, be excluded that clozapine can induce dyskinesia in extremely rare cases, but it seems more likely that this is due to previous treatment with classic neuroleptics. The earlier clozapine is started, the less chance of development of dyskinesia. The low level of EPS with clozapine may be linked to the special receptor-binding profile of this drug: during treatment with therapeutic doses of clozapine, the level of D2 receptor blockade is too low (40% to 50% occupancy by positron emission tomography) to induce EPS, and the D1 receptor blockade (also 40% to 50% occupancy) has a lower EPS potential than D2 blockade. This binding profile may at the same time contribute to the special antipsychotic properties of clozapine. Other receptor affinities may contribute to the beneficial effect of clozapine in EPS and schizophrenia.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Dopamine Antagonists; Humans; Movement Disorders

Recent research on the role of clozapine in the treatment of Parkinson's disease and other movement disorders is discussed. Most clinical trials have shown resolution of or improvement in psychotic symptoms accompanying Parkinson's disease without worsening of parkinsonian symptoms. Adverse effects appear to be mild at dosages of < 100 mg/day; sedation is the most frequent problem. Most of these studies have serious limitations, however; until better studies have been completed, the decision to use clozapine for Parkinson's disease-related psychosis should be made on a case-by-case basis, with thorough evaluation of risks, benefits, and other therapeutic options. Some patients with Parkinson's disease have shown improvement in tremor and other abnormal movements when given clozapine. Clozapine cannot be recommended for treating tardive dyskinesia on the basis of the research done so far; some trials show dramatic resolution of symptoms, others no benefit. Anticholinergics or dopamine-reuptake inhibitors should be considered before clozapine is given to patients with tardive dyskinesia because of clozapine's potential for serious adverse effects. A few patients with Huntington's disease have responded to clozapine, but again no conclusions can be drawn. Clozapine appears to offer no real advantage over haloperidol for treating choreiform movements in Huntington's disease. The frequency of tics in Tourette's syndrome does not seem to be reduced by clozapine. Clozapine has shown some efficacy as a treatment for psychosis and abnormal movements in Parkinson's disease. Results have been less promising for other movement disorders. Further study in larger populations is needed before any definitive conclusions about clozapine's place in movement disorder therapy can be made.

Topics: Clinical Trials as Topic; Clozapine; Dyskinesia, Drug-Induced; Humans; Huntington Disease; Movement Disorders; Neurocognitive Disorders; Parkinson Disease; Tourette Syndrome

Twelve patients with abnormal involuntary movement disorders were treated with clozapine in a double-blind, placebo-controlled trial. The cohort consisted of individuals with Gilles de la Tourette's syndrome, Huntington's disease, and atypical persistent dyskinesia that was drug induced. Two subjects were dropped from the protocol due to complications. Two patients with Huntington's disease showed a marked decrease in movements; other individuals obtained no significant therapeutic benefits. Seven of the 10 patients completing the trial experienced moderate or marked side effects.

Topics: Adolescent; Adult; Child; Clinical Trials as Topic; Clozapine; Dibenzazepines; Double-Blind Method; Drug Evaluation; Dyskinesia, Drug-Induced; Female; Humans; Huntington Disease; Male; Middle Aged; Movement Disorders; Placebos; Tourette Syndrome

8 male schizophrenic patients participated in a double-blind, cross over study of the extrapyramidal side-effects of haloperidol and clozapine (acute dystonis, Parkinsonism and tardive dyskinesia), together with their effect on homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF). Haloperidol (9 mg/day) caused Parkinsonism, reduced tardive dyskinesias and increased the HVA concentration in the CSF. Clozapine (225 mg/day) had no effect on the neurological phenomena but reduced HVA and 5-HIAA concentrations in the CSF. During the discontinuation phase following the administration of haloperidol, tardive dyskinesia occurred or was aggravated; this did not occur after administration of clozapine. Accordingly, it is suggested that clozapine does not induce dopaminergic hypersensibility and, therefore, will not induce tardive dyskinesias.

Topics: Adult; Aged; Basal Ganglia Diseases; Clinical Trials as Topic; Clozapine; Dibenzazepines; Haloperidol; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Male; Middle Aged; Movement Disorders; Parkinson Disease, Secondary; Phenylacetates; Schizophrenia

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

Aripiprazole can cause irreversible tardive dystonia in some individuals, and additional intervention is sometimes needed. Here, we report the first case of aripiprazole-induced irreversible tardive dystonia in which complete recovery of motor function was achieved using the antipsychotic drug clozapine.. A 24-year-old man with bipolar disorder was treated with aripiprazole and gradually developed tardive dystonia. Thorough medical and neurological examinations were performed to rule out other possible causes of tardive dystonia. Clozapine was administered when the patient did not improve following long-term withdrawal of aripiprazole or adjuvant medications. Before administration of clozapine, the patient was experiencing severe dystonia as assessed by the Extrapyramidal Symptom Rating Scale. Dystonic symptoms began to improve about 1 month after starting administration of clozapine and were completely resolved 3 months after clozapine administration.. Clinicians should note the risk of aripiprazole-induced tardive dystonia and consider clozapine as an alternative and effective treatment modality in cases of irreversible tardive dystonia, particularly when concomitant treatment of psychotic symptoms is required.

Topics: Antipsychotic Agents; Aripiprazole; Bipolar Disorder; Clozapine; Dyskinesia, Drug-Induced; Humans; Male; Movement Disorders; Neurologic Examination; Psychotic Disorders; Treatment Outcome; Young Adult

Tardive dyskinesia (TD) is a delayed and potentially irreversible motor complication arising in patients chronically exposed to centrally active dopamine D2 receptor antagonists, including antipsychotic drugs and metoclopramide. The classical dopamine D2 receptor supersensitivity hypothesis in TD, which stemmed from rodent studies, lacks strong support in humans. To investigate the neurochemical basis of TD, we chronically exposed adult capuchin monkeys to haloperidol (median, 18.5 months; n = 11) or clozapine (median, 6 months; n = 6). Six unmedicated animals were used as controls. Five haloperidol-treated animals developed mild TD movements, and no TD was observed in the clozapine group. Using receptor autoradiography, we measured striatal dopamine D1, D2, and D3 receptor levels. We also examined the D3 receptor/preprotachykinin messenger RNA (mRNA) co-expression, and quantified preproenkephalin mRNA levels, in striatal sections. Unlike clozapine, haloperidol strongly induced dopamine D3 receptor binding sites in the anterior caudate-putamen, particularly in TD animals, and binding levels positively correlated with TD intensity. Interestingly, the D3 receptor upregulation was observed in striatonigral neurons. In contrast, D2 receptor binding was comparable to controls, and dopamine D1 receptor binding was reduced in the anterior putamen. Enkephalin mRNA widely increased in all animals, but to a greater extent in TD-free animals. These results suggest for the first time that upregulated striatal D3 receptors correlate with TD in nonhuman primates, adding new insights to the dopamine receptor supersensitivity hypothesis. The D3 receptor could provide a novel target for drug intervention in human TD.

Topics: Animals; Antipsychotic Agents; Brain; Cebus; Clozapine; Disease Models, Animal; Dopamine Antagonists; Enkephalins; Female; Haloperidol; Iodine Radioisotopes; Movement Disorders; Neurons; Ovariectomy; Protein Binding; Receptors, Dopamine D2; Receptors, Dopamine D3; Sulpiride; Tetrahydronaphthalenes; Up-Regulation

Tardive dyskinesia (TD) is a delayed and potentially irreversible motor complication arising in patients chronically exposed to antipsychotic drugs. As several modern (so-called atypical) antipsychotic drugs are common offenders, combined with the widening clinical indications for prescription as well as exposure of vulnerable individuals, TD will remain a significant drug-induced unwanted side effect. In addition, the pathophysiology of TD remains elusive and therapeutics are difficult. Based on rodent experiments, we have previously shown that the transcriptional factor Nur77 (also known as nerve growth factor inducible gene B or Nr4a1) is induced in the striatum following antipsychotic drug exposure as part of a long-term neuroadaptive process. To confirm this, we exposed adult capuchin (Cebus apella) monkeys to prolonged treatments with haloperidol (median 18.5 months, N = 11) or clozapine (median 6 months, N = 6). Six untreated animals were used as controls. Five haloperidol-treated animals developed mild TD movements similar to those found in humans. No TD was observed in the clozapine group. Postmortem analysis of Nur77 expression measured by in situ hybridization revealed a stark contrast between the two drugs, as Nur77 mRNA levels in the caudate-putamen were strongly upregulated in animals exposed to haloperidol but were spared following clozapine treatment. Interestingly, within the haloperidol-treated group, TD-free animals showed higher Nur77 expression in putamen subterritories compared with dyskinetic animals. This suggests that Nur77 expression might be associated with a reduced risk of TD in this experimental model and could provide a novel target for drug intervention.

Topics: Animals; Antipsychotic Agents; Cebus; Clozapine; Corpus Striatum; Female; Haloperidol; Movement Disorders; Nuclear Receptor Subfamily 4, Group A, Member 1; Putamen; RNA, Messenger; Transcription, Genetic; Up-Regulation

Tardive dyskinesia (TD) is a complex involuntary movement disorder affecting about 23% of neuroleptic-treated patients. Our objective was to retrospectively analyze a combination of tetrabenazine (TBZ), clonazepam (CLONAZ) and clozapine (CLOZ) used simultaneously for TD in psychotic patients. Six patients with severe, unsuccessfully controlled TD were referred for treatment (mean age 51.5 years; three male; four schizophrenics; one bipolar disease; one borderline personality disorder). They were being treated with neuroleptics (classic, three; risperidone, two; olanzapine, one) and developed severe neck and buccolingual dyskinesias. At our clinic, all of them were treated simultaneously with TBZ (mean dose 141.6 mg); CLONAZ (mean dose 4.3 mg); and CLOZ (mean dose 125 mg). In parallel, we stopped the offending medication. With 1 week, we observed a very impressive improvement in symptoms and within 1 month all the patients were free of symptoms. The mean observation period was 4 years. The combination of TBZ, CLONAZ and CLOZ is a rapid and beneficial option for the management of TD. An augmentation effect probably played a role in the rapid alleviation of symptomatology.

Topics: Adrenergic Uptake Inhibitors; Adult; Antipsychotic Agents; Clonazepam; Clozapine; Drug Therapy, Combination; Female; Follow-Up Studies; GABA Modulators; Humans; Male; Middle Aged; Movement Disorders; Psychotic Disorders; Retrospective Studies; Tetrabenazine; Young Adult

Long-term treatment with haloperidol is associated with a number of extrapyramidal side effects. This limitation presents a marked therapeutic challenge. The present method (21 days administration of haloperidol, 5 mg/kg, i.p.) has been established to gain deeper insight into the molecular etiology (inflammation and apoptosis) of haloperidol-induced cellular death. In the present model, besides the corresponding increase in the vacuous chewing movements (VCMs), enhanced oxidative stress, there was a significant increase in cellular markers of inflammation and apoptotic protein (caspase-3), leading to cellular death. We also suggest that this model will be effective in preclinical testing of new chemical entities for the treatment of haloperidol induced tardive dyskinesia and related symptoms.

Topics: Animals; Antipsychotic Agents; Apoptosis; Behavior, Animal; Caspase 3; Clozapine; Disease Models, Animal; Dyskinesia, Drug-Induced; Haloperidol; Humans; Male; Movement Disorders; Pregnatrienes; Rats; Rats, Wistar

Topics: Antipsychotic Agents; Clozapine; Female; Fever; Follow-Up Studies; Humans; Middle Aged; Movement Disorders; Severity of Illness Index

Topics: Analysis of Variance; Animals; Antiparkinson Agents; Antipsychotic Agents; Apomorphine; Aquaporin 4; Clozapine; Corpus Striatum; Disease Models, Animal; Glial Fibrillary Acidic Protein; Haloperidol; Hippocampus; Male; Mastication; Mice; Mice, Knockout; Motor Activity; Movement Disorders

Topics: Adult; Clozapine; Humans; Male; Migraine Disorders; Movement Disorders; Prochlorperazine

Topics: Antiparkinson Agents; Clozapine; Delusions; Drug Therapy, Combination; Humans; Levodopa; Lewy Body Disease; Movement Disorders; Neuroleptic Malignant Syndrome; Severity of Illness Index

The influence of postnatal iron overload upon implications of the functional and interactive role of dopaminergic and noradrenergic pathways that contribute to the expressions of movement disorder and psychotic behaviours in mice was studied in a series of experiments. (1) Postnatal iron overload at doses of 7.5 mg/kg (administered on Days 10-12 post partum) and above, invariably induced a behavioural syndrome consisting of an initial (1st 20-40 min of a 60-min test session) hypoactivity followed by a later (final 20 min of a 60-min test session) hyperactivity, when the mice were tested at adult ages (age 60 days or more). (2) Following postnatal iron overload, subchronic treatment with the neuroleptic compounds, clozapine and haloperidol, dose-dependently reversed the initial hypoactivity and later hyperactivity induced by the metal. Furthermore, DA D(2) receptor supersensitivity (as assessed using the apomorphine-induced behaviour test) was directly and positively correlated with iron concentrations in the basal ganglia. (3) Brain noradrenaline (NA) denervation, using the selective NA neurotoxin, DSP4, prior to administration of the selective DA neurotoxin, MPTP, exacerbated both the functional (hypokinesia) and neurochemical (DA depletion) effects of the latter neurotoxin. Treatment with L-Dopa restored motor activity only in the animals that had not undergone NA denervation. These findings suggest an essential neonatal iron overload, termed "the Youdim factor", directing a DA-NA interactive component in co-morbid disorders of nigrostriatal-limbic brain regions.

Topics: Animals; Animals, Newborn; Antipsychotic Agents; Brain Chemistry; Catecholamines; Clozapine; Denervation; Dopamine; Dopamine Agents; Female; Haloperidol; Iron; Iron Overload; Levodopa; Male; Mice; Mice, Inbred C57BL; Motor Activity; Movement Disorders; MPTP Poisoning; Norepinephrine; Pregnancy; Psychotic Disorders; Signal Transduction; Weight Gain

Motor complications arising after long-term treatment with levodopa remain one of the main challenges in the treatment of patients with Parkinson's disease (PD). Monotherapy with dopamine agonists may delay the onset of motor complications or reduce their severity when added to levodopa treatment. Here, we retrospectively analyzed data from 62 patients with advanced PD who presented with moderate to severe response fluctuations in whom we increased the dose of oral treatment with pergolide beyond 4.5mg daily. Patients had been treated with levodopa for 10.7+/-4.8 years. Pergolide was increased to 8.2+/-4.3 mg per day over a median titration period of 13.5 weeks. Mean daily dose of levodopa prior to pergolide high-dose treatment was 733+/-468 mg and decreased to 348+/-186 mg after pergolide titration. The duration of OFF times decreased from 7.3+/-3.8 to 1.7+/-0.9 h per day (p < 0.001) measured by patients' diaries. Dyskinesias, present for 5.0+/-3.3 h per day at baseline, were reduced to 1.4+/-0.8 h per day (p < 0.001) and the total daily duration of motor fluctuations (off-time duration plus dyskinesia duration) decreased from 10.5+/-7.0 to 2.8+/-2.2 h (p < 0.001). There was a significant improvement in parkinsonian symptoms (baseline to endpoint reduction of UPDRS III from a median of 36 to 8; p < 0.001). To reduce gastrointestinal side effects 23 patients required concomitant treatment with domperidone. Seven patients developed hallucinations during the titration period, six patients required treatment with clozapine. Our data indicate that increasing the dose of pergolide above 5mg per day can dramatically reduce the need for levodopa, motor fluctuations and severity of clinical symptoms. Controlled trials are needed to further substantiate the efficacy and safety of this treatment strategy.

Topics: Adult; Aged; Amantadine; Antiparkinson Agents; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Dyskinesias; Endpoint Determination; Female; Germany; Humans; Male; Middle Aged; Movement Disorders; Parkinson Disease; Pergolide; Psychotic Disorders; Retrospective Studies

A major issue in any systematic review is deciding which trials or studies to include and which to exclude. The Cochrane Collaboration and similar respected organizations have traditionally viewed the randomized trial (RCT) as the only acceptable evidence on treatment outcome. However, many systematic reviews are indeterminate because they include insufficient RCTs whilst they reject large numbers of non-randomized controlled studies. This is particularly true in forensic mental health, a domain where RCT methodology can be problematic. Systematic reviews could become more informative if reviewers knew when, and under what circumstances, non-randomized designs are acceptable for inclusion alongside RCTs.. This pilot study explores whether good-quality, controlled, non-randomized studies can be reliable surrogates for RCTs. We examined two published reviews from the Cochrane Schizophrenia Group. We compared outcomes between (a) randomized trials (that had been included) and non-randomized studies (that had been excluded), and (b) between high- and low-quality studies using an established quality checklist.. In the first review, effect scores were similar for randomized and non-randomized studies and relatively insensitive to study quality. In the second review, the treatment effect was considerably lower for the RCT group - here, however, studies of high-quality showed much smaller effect scores than those of low-quality on two separate outcomes.. Non-randomized controlled studies of high quality can produce outcomes that approximate to those found in RCTs. Trial quality may have a greater impact on treatment effect size than randomization alone, suggesting that randomization should not be seen as a reliable proxy for overall quality. The problems and issues still to be resolved are discussed with recommendations for future research.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Forensic Psychiatry; Humans; Meta-Analysis as Topic; Movement Disorders; Pilot Projects; Reproducibility of Results; Research Design; Schizophrenia; Systematic Reviews as Topic; Therapeutic Community; Treatment Outcome

Studies have shown that neuroleptics regulate expression of the transcription factor FosB/DeltaFosB in the striatum, including the accumbens and caudate-putamen; however, the striatum is also divided into another structural dimension, the striosome and matrix compartments. The precise distribution of FosB/DeltaFosB induced by chronic neuroleptics in these striatal compartments is poorly understood.. Rats received either single acute injections or chronic injections of clozapine (0 or 20 mg/kg, intraperitoneally [IP]), olanzapine (0 or 5 mg/kg, IP), or haloperidol (0 or 1.5 mg/kg, IP) for 25 days. The levels and compartmental distribution of FosB/DeltaFosB were examined.. Chronic clozapine induced clustered FosB/DeltaFosB expression within striosomes of the caudate-putamen. This pattern was due to increased levels of FosB/DeltaFosB in striosomes within the ventrolateral caudate-putamen and reduced levels of basal FosB/DeltaFosB in the matrix in the entire caudate-putamen. In contrast, chronic haloperidol increased FosB/DeltaFosB equally within the matrix and striosomes throughout the entire caudate-putamen. Chronic olanzapine induced an intermediate pattern.. The relative absence of FosB/DeltaFosB expression in the matrix correlates with the lack of parkinsonism of atypical neuroleptics. Expression of FosB/DeltaFosB in the matrix may contribute to parkinsonism of typical neuroleptics.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Caudate Nucleus; Clozapine; Drug Administration Schedule; Haloperidol; Male; Movement Disorders; Neural Pathways; Nucleus Accumbens; Olanzapine; Peptide Fragments; Proto-Oncogene Proteins c-fos; Putamen; Rats; Rats, Wistar; Tissue Distribution; Transcription Factors

Issues to consider when evaluating maintenance drug therapy for patients with schizophrenia are discussed; these include potential adverse effects of antipsychotic therapy, such as weight gain, diabetes mellitus, extrapyramidal symptoms, sexual dysfunction, cognitive dysfunction, and cardiac effects, as well as quality of life. Patients with schizophrenia are more likely to be overweight than the general population. Olanzapine and clozapine have been associated with the greatest weight gain of the newer antipsychotics. While patients with schizophrenia are at increased risk of developing diabetes mellitus independent of antipsychotic therapy, diabetes may be more prevalent in patients taking the newer agents. Acute extrapyramidal symptoms occur in 75-90% of patients receiving first-generation antipsychotics like thioridazine and haloperidol. The probability of tardive dyskinesia (TD) occurring with second- and third-generation agents is less than 1% per year, compared with about 5% per year for the traditional antipsychotics. When patients are switched from a traditional antipsychotic to clozapine or olanzapine, TDs usually abate somewhat. Thioridazine causes a pronounced prolongation of the QTc interval, which can lead to ventricular arrhythmias. The slight increase in QTc interval caused by ziprasidone most likely will not be a problem in healthy individuals. Newer antipsychotics are associated with improved neurocognitive functioning and most cause less prolactin elevation, compared with traditional agents. The newer antipsychotic agents are not devoid of adverse effects, but those that do occur can be managed. Once issues related to adherence are resolved, rehabilitation of patients with schizophrenia will be a high priority.

Topics: Antipsychotic Agents; Benzodiazepines; Clinical Trials as Topic; Clozapine; Continuity of Patient Care; Diabetes Mellitus; Electrocardiography; Humans; Movement Disorders; Olanzapine; Pirenzepine; Quality of Life; Schizophrenia; Weight Gain

Side effects of antipsychotic medications are particularly problematic in elderly patients, who experience many age-related changes that may exacerbate medication side effects. Side effects of particular concern in the elderly include anticholinergic reactions, parkinsonian events, tardive dyskinesia, orthostatic hypotension, cardiac conduction disturbances, reduced bone mineral density, sedation, and cognitive slowing. In addition, elderly patients with schizophrenia often have comorbid medical illnesses-such as cardiovascular disease and dementia of the Alzheimer's type-and are thus likely to be taking multiple medications. The effects of polypharmacy must be carefully considered. Patients, caregivers, and family often have different perspectives on side effects. This article addresses the side effects of the currently available antipsychotic medications in light of these concerns.

Topics: Age Factors; Aged; Antipsychotic Agents; Basal Ganglia Diseases; Clinical Trials as Topic; Clozapine; Comorbidity; Dementia; Dibenzothiazepines; Humans; Movement Disorders; Neuroleptic Malignant Syndrome; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Schizophrenia

Neuroleptic primed Cebus apella monkeys have proven reliable in screening antipsychotics for extrapyramidal side effect (EPS) potential in humans, and the ratio EPS liability/antiamphetamine efficacy ["therapeutic index" (TI)] has fit well with clinical results.. 1) To find the TIs of one new (quetiapine), three potential [NNC 756 (dopamine (DA) D1 antagonist), NNC 22-0031 (alpha-1 adrenergic/5-HT2 serotonergic/DA D1 and D2 antagonist) and DOD 647 (DA D1 and D2 antagonist)] and three old antipsychotics (haloperidol, melperone and clozapine), 2) to test the model further and 3) to gain more insight as to clozapine's neuropharmacology.. Seven monkeys received haloperidol daily for 2 years; all were sensitized to dystonia. All drugs were given SC, in increasing doses until two animals had dystonia/other adverse effects (AE), and in decreasing doses with a fixed dose of dextroamphetamine producing motor unrest and stereotypies, to find the minimum significant antiamphetamine dose (AA). The ratio AE/AA = TI.. Excepting clozapine and DOD 647, all drugs induced dystonia. At 2-4 mg/kg, clozapine caused uncoordinated movements, myoclonic jerks and rough tremor; unlike dystonia, the syndrome was not alleviated but worsened by the anticholinergic, biperiden. DOD 647 up to 2 mg/kg had no adverse effects. The TIs of the new and potential antipsychotics were 3-5 versus 4 for clozapine and 1 for haloperidol and melperone, suggesting that like clozapine, these new drugs will not produce EPS at antipsychotic doses.

Topics: Amphetamine; Animals; Antipsychotic Agents; Cebus; Clozapine; Dextroamphetamine; Disease Models, Animal; Dopamine Agents; Dystonia; Female; Male; Motor Activity; Movement Disorders

Classic neuroleptic drugs produce a syndrome of vacuous jaw movements in rats, and this syndrome has been offered as an animal model of early onset extrapyramidal side effects. The atypical antipsychotics do not produce elevations in vacuous jaw movements, or do so only at very high doses. The purpose of the present study was to determine the impact of the putative antipsychotic, amperozide, on vacuous jaw movements in rats. Groups of rats received daily injections of haloperidol (0.2, 0.4, or 0.8 mg/kg), clozapine (2.0, 4.0, 8.0 mg/kg), amperozide (2.0, 4.0, 8.0 mg/kg) or vehicle for 4 weeks. Once per week, rats were observed for the presence of vacuous jaw movements. Haloperidol increased vacuous jaw movements with increasing doses. Clozapine only produced elevations in vacuous jaw movements at the highest dose. In contrast, increasing doses of amperozide resulted in decreasing vacuous jaw movements for this portion of the dose-response curve. This is the first report of the effect of amperozide on vacuous jaw movements and results are discussed in terms of a potentially unique behavioral profile with respect to this behavior.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Extrapyramidal Tracts; Haloperidol; Jaw; Male; Movement Disorders; Piperazines; Rats; Rats, Sprague-Dawley

The severity of parkinsonian motor disability and dyskinesias was evaluated in seven levodopa-responsive patients with Parkinson's disease after an acute challenge with the mixed dopamine agonist apomorphine, before and after low-dose clozapine (50 mg) for 18 +/- 2 days. There was a significant 59% improvement (p < 0.05) of apomorphine-induced dyskinesias without aggravation of parkinsonian motor disability following clozapine treatment. The results suggest that low-dose clozapine, already shown to improve psychotic symptoms, may help to reduce severe levodopa-induced dyskinesias in parkinsonian patients.

Topics: Aged; Antipsychotic Agents; Clozapine; Humans; Middle Aged; Movement Disorders; Parkinson Disease; Pilot Projects; Treatment Outcome

Hemiballism is a relatively rare hyperkinetic disorder; treatment is based mainly on neuroleptics and drugs that decrease release of dopamine. We report the cases of two patients with hemiballism. After a period of 1 month of nonresponsiveness to haloperidol, amelioration of ballistic movements was observed only a few days after the initiation of clozapine therapy (50 mg/day). Our report suggests that clozapine may be a valuable alternative for patients with hemiballism.

Topics: Aged; Antipsychotic Agents; Clozapine; Functional Laterality; Humans; Male; Movement Disorders

As part of a prospective efficacy and safety monitoring system, patients receiving clozapine are assessed monthly for dyskinetic events (DE), using the Abnormal involuntary Movement Scale (AIMS). Longitudinal analysis of 45 patients revealed 20 with baseline DE, 7 who developed emergent DE after a negative baseline assessment, and 18 patients with no DE symptoms throughout treatment with clozapine. Eight of the 20 patients with baseline DE were assessed to resolution of symptoms, with an average time of 261 +/- 188 days; 5 were evaluated until complete resolution of symptoms (AIMS = 0), with an average time of 691 +/- 462 days. The average time to onset of DE in emergent DE patients was 238 +/- 179 days, and the average time to resolution was 347 +/- 179 days after diagnosis. Four patients attained complete resolution with an average time of 629 +/- 293 days after diagnosis. It appears this emergent type of dyskinesia is different from other currently described dyskinesias. Overall, of the 27 patients having DE at any point in treatment, 15 of 27 (56%) had resolution of symptoms and 10 of 27 (37%) had complete resolution of DE. Clinicians should be aware of the utility of clozapine in dyskinesia and the extended time frame of response.

Topics: Adult; Analysis of Variance; Clozapine; Female; Humans; Longitudinal Studies; Male; Middle Aged; Movement Disorders; Schizophrenia; Time Factors

Topics: Clozapine; Dose-Response Relationship, Drug; Humans; Levodopa; Movement Disorders; Parkinson Disease

Pharmacological agents used for the control of ballistic movements include chloral hydrate, barbiturates, paraldehyde, bromides, phenothiazines, progabide, haloperidol, pimozide, reserpine, tetrabenazine, sodium valproate, and dimethylaminoethanol. These agents are believed to act by different mechanisms, including modification of dopaminergic, GABAergic, or cholinergic mechanisms. We report a case where, after failure of haloperidol, phenobarbital, and pimozide, the hemiballistic movements were controlled with clozapine.

Topics: Adult; Anticonvulsants; Antipsychotic Agents; Clozapine; Haloperidol; Humans; Hypnotics and Sedatives; Male; Movement Disorders; Phenobarbital; Pimozide

(5-Amino-1,3-dimethyl-1H-pyrazol-4-yl)(2-fluorophenyl)methanone (1) was found to have an antipsychotic-like profile in behavioral tests predictive of antipsychotic efficacy but, unlike available antipsychotic agents, did not bind in vitro to dopamine receptors. Upon further evaluation, 1 was found to cause clonic seizures in aged rodents. An examination of related structures revealed that 5-(substituted aminoacetamide) analogues of 1 shared this novel pharmacology and did not cause seizures. The synthesis and pharmacological evaluation of this series of compounds are described. Two compounds, 2-(diethylamino)acetamide (25) and 2-[[3-(2-methyl-1-piperidinyl)propyl]-amino]acetamide (38), were selected for examination in secondary tests. Like known antipsychotics both compounds reduced spontaneous locomotion in mice at doses that did not cause ataxia and inhibited conditioned avoidance selectively in both rats and monkeys. Unlike known antipsychotics neither 25 nor 38 elicited dystonic movements in haloperidol-sensitized cebus monkeys, a primate model of antipsychotic-induced extrapyramidal side effects. Biochemical studies indicated that these compounds act via a nondopaminergic mechanism. Neither 25 nor 38 bound to dopamine receptors in vitro or caused changes in striatal dopamine metabolism in vivo. In addition, they did not raise serum prolactin levels as do known antipsychotics. Although adverse animal toxicological findings have precluded clinical evaluation of these agents, the present results indicate that it is possible to identify at the preclinical level nondopaminergic compounds with antipsychotic-like properties.

Topics: Animals; Antipsychotic Agents; Apomorphine; Ataxia; Avoidance Learning; Brain; Cebus; Chemical Phenomena; Chemistry; Dopamine; Male; Mice; Motor Activity; Movement Disorders; Pyrazoles; Rats; Rats, Inbred Strains; Receptors, Dopamine; Saimiri

Topics: Animals; Antipsychotic Agents; Clozapine; Corpus Striatum; Cyclic AMP; Dopamine; Humans; Limbic System; Movement Disorders; Parasympathetic Nervous System; Receptors, Drug

Tardive dyskinesias, often seen in patients treated with classical neuroleptics, have been attributed to the development of receptor hypersensitivity following prolonged blockade of dopamine (DA)-receptors. In rats with unilateral striatal lesions, development of DA-receptor hypersensitivity following a 6-day treatment with haloperidol can be demonstrated by means of the increased turning response to apomorphine. Addition of atropine to the haloperidol treatment schedule resulted in a further increase in receptor sensitivity, but with a delay of 24 h in its appearance. This finding provides pharmacological support for the observation that tardive dyskinesias are more frequent and more severe in patients treated with a combination of a classical neuroleptic and an anticholinergic agent. Clozapine, despite its anticholinergic property, did not enhance the haloperidol-induced hypersensitivity.

Topics: Animals; Apomorphine; Atropine; Clozapine; Corpus Striatum; Dibenzazepines; Dopamine; Drug Synergism; Haloperidol; Humans; Movement Disorders; Rats; Receptors, Drug; Stereotyped Behavior

Topics: Acetylcholine; Basal Ganglia Diseases; Chorea; Clozapine; Diagnosis, Differential; Dibenzazepines; Drug Synergism; Humans; Hyperkinesis; Long-Term Care; Male; Middle Aged; Movement Disorders; Parasympatholytics; Schizophrenia, Paranoid; Substance Withdrawal Syndrome; Tranquilizing Agents

The present study has compared the abilities of clozapine, haloperidol, chlorpromazine and loxapine to induce dopamine (DA)-receptor hypersensitivity in rats, as measured by the apomorphine response after withdrawal of the antipsychotic drugs. Haloperidose during 1-2 weeks after withdrawal. Clozapine, given prior to apomorphine, reduced the responses of the haloperidol and loxapine groups to the control level. The effects of haloperidol and clozapine were quantified in rats with unilateral striatal lesions. Biochemical investigations showed that tolerance developed to the increase in striatal homovanillic acid (HVA) after chronic treatment with haloperidol, chlorpromazine and loxapine, whereas clozapine (20 mg/kg p.o.) failed to affect the HVA content, and no tolerance developed to the increase seen at 80 mg/kg. Cross-tolerance to the rise in HVA was seen with haloperidol, chlorpromazine and loxapine, but chronicc pretreatment with clozapine failed to affect the rise in HVA induced by a singel dose of the former compounds.

Topics: Animals; Apomorphine; Chlorpromazine; Clozapine; Corpus Striatum; Dibenzazepines; Dibenzoxazepines; Disease Models, Animal; Dopamine; Drug Tolerance; Female; Haloperidol; Homovanillic Acid; Humans; Loxapine; Male; Movement Disorders; Rats; Receptors, Drug; Stereotyped Behavior; Substance Withdrawal Syndrome