clozapine and Parkinson-Disease--Secondary

This review addresses two questions. First, why does clozapine apparently occupy low levels of dopamine D2 receptors in patients, in contrast to all other antipsychotic drugs which occupy 70-80% of brain dopamine D2 receptors? Second, what is the receptor basis of action of antipsychotic drugs which elicit low levels of Parkinsonism? Antipsychotic doses of clozapine occupy between 0% and 50% of D2 receptors, as measured in patients by a variety of radioligands. It has recently been found, however, that the percent occupancy of a receptor by a drug depends on the radioligand used to measure that receptor. Based on this new finding, this review concludes that clozapine clinically occupies high levels of D2 receptors in the absence of any radioligand. This occupancy is estimated to be of the order of 70-80% in the dopamine-rich region of the human striatum, and even higher in the limbic D2-containing regions which are low in endogenous synaptic dopamine. This conclusion arises from two different approaches. One approach is to relate the reported clozapine occupancies in the human striatum with the dissociation constants of the various radioligands at the D2 receptor. This relation extrapolates to approximately 70-80% occupancy by clozapine when clozapine competes with endogenous dopamine at the D2 receptor. The second approach is to calculate the D2 occupancy of each antipsychotic drug, using the average spinal fluid concentration and the correct dissociation constant of the antipsychotic, thereby revealing that all antipsychotic drugs, including clozapine, occupy approximately 70-80% of dopamine D2 receptors in the human striatum, and possibly higher in the limbic regions. As determined by the new dissociation constants, antipsychotic drugs which elicit Parkinsonism (trifluperazine, chlorpromazine, raclopride, haloperidol, fluphenazine, risperidone) bind more tightly than dopamine to D2, while those antipsychotic drugs which elicit little or no Parkinsonism (melperone, seroquel, perlapine, clozapine, remoxipride, molindone, sulpiride, olanzapine, sertindole) bind more loosely than dopamine to D2 receptors. Compared to the tightly bound antipsychotic drugs, the more loosely bound antipsychotics generally require higher clinical doses, require fewer days for clinical adjustment, but may dissociate from the D2 receptor more rapidly and could lead to clinical relapse somewhat earlier than that found with the traditional tightly bound antipsychotic drugs.

Topics: Antipsychotic Agents; Binding, Competitive; Cholinergic Antagonists; Clozapine; Corpus Striatum; Dopamine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Resistance; Dyskinesia, Drug-Induced; Humans; Levodopa; Ligands; Limbic System; Nerve Tissue Proteins; Parkinson Disease, Secondary; Protein Binding; Psychoses, Substance-Induced; Psychotic Disorders; Radioligand Assay; Receptors, Dopamine D2; Receptors, Muscarinic; Receptors, Serotonin; Recurrence; Serotonin Antagonists; Tomography, Emission-Computed

The incidence of acute extrapyramidal symptoms (EPS)--akathisia, dystonia, and parkinsonism--associated with traditional antipsychotics varies, but most researchers agree that neuroleptic-induced EPS occur in 50% to 75% of patients who take conventional antipsychotics. Atypical antipsychotics were developed to widen the therapeutic index and to reduce EPS. Although the mechanisms are unclear, the risk of EPS is less with the novel antipsychotics than with conventional drugs, and agents that produce low levels of acute EPS are likely to produce less tardive dyskinesia. Nevertheless, clinicians should exercise caution when comparing data from investigations of the novel antipsychotics and, until long-term data become available, should administer the new drugs at doses below the EPS-producing level.

Topics: Akathisia, Drug-Induced; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clinical Trials as Topic; Clozapine; Dibenzothiazepines; Drug Administration Schedule; Dyskinesia, Drug-Induced; Dystonia; Humans; Olanzapine; Parkinson Disease, Secondary; Pirenzepine; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Schizophrenia; Substance Withdrawal Syndrome

Most traditional neuroleptics have a narrow therapeutic-to-toxic index, and thus, the novel antipsychotics are the result of a search to substantially widen the distance between the dose that treats psychosis and the one that produces adverse effects. In vitro binding profiles have been created for the atypical antipsychotics that have been approved by the U.S. Food and Drug Administration (FDA)-clozapine, olanzapine, and risperidone and those that are under FDA review-quetiapine and sertindole. These profiles, which were compared with that of the typical neuroleptic haloperidol, provide guidance for predicting the adverse effects produced by these drugs. Most conventional antipsychotics have central nervous system effects, particularly extrapyramidal symptoms (EPS) and tardive dyskinesia, sedation, and dulling of cognition. Other adverse effects of the typical antipsychotics include the neuroleptic malignant syndrome, orthostatic hypotension, changes in liver function, anticholinergic and antiadrenergic side effects, sexual dysfunction, and weight gain. The newer agents have a lower incidence of EPS and tardive dyskinesia, while weight gain and changes in blood pressure and liver function tests are adverse effects that have been associated with the use of the newer agents. The favorable side effect profile of these new antipsychotics is likely to make patients more willing to continue treatment, and thus these agents represent a step forward in the treatment of patients with severe, chronic mental illness.

Topics: Akathisia, Drug-Induced; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Haloperidol; Humans; Olanzapine; Parkinson Disease, Secondary; Pirenzepine; Receptors, Neurotransmitter; Seizures; Sleep; Weight Gain

This review summarizes the amino acid sequences of the human dopamine and serotonin receptors and their human variants. The review also examines the receptor basis of the atypical antipsychotic drugs that elicit less parkinsonism than the typical antipsychotics. Because the dissociation constant of a drug varies with the radioligand, the dissociation constants of many neuroleptics are here summarized for the dopamine D2-, D4- and serotonin S2A-receptors using different radioligands. Radioligands of low solubility in the membrane (having low tissue/buffer partition) result in lower values for the neuroleptic dissociation constants, compared to radioligands of high membrane solubility. Such studies yield the intrinsic K value for a neuroleptic in the absence of a competing ligand. Clozapine, for example, has an intrinsic K value of 1.6 nM at the D4-receptor, in agreement with the value of 1.6 nM when directly measured with [3H]clozapine at D4. However, because clozapine competes with endogenous dopamine, the in vivo clozapine concentration to occupy 75% of the dopamine D4-receptors is derived to be approximately 13 nM. This agrees with the value of 12 to 20 nM in the plasma water (or spinal fluid) observed in treated patients. Moreover, in L-DOPA psychosis (in Parkinson's disease), the clozapine concentration for 75% blockade of D4 is predicted to be approximately 3 nM. This agrees with the value of approximately 1.2 nM observed by Meltzer et al. in plasma water (Neuropsychopharmacology, 12, 39-45 (1995)). This analysis supports the concept and practical value of the intrinsic K values. Some atypical neuroleptics (remoxipride, clozapine, perlapine, seroquel and melperone) have high intrinsic K values (ranging from 30 to 88 nM) at the D2-receptor, making them displaceable by high levels of endogenous dopamine in the caudate/putamen. In contrast, however, typical neuroleptics (i.e., those that typically cause parkinsonism) have intrinsic K values of 0.3 to 6 nM, making them less displaceable by endogenous dopamine. A relationship exists between the neuroleptic doses for rat catalepsy and the D2/D4 ratio of the intrinsic K values. Thus, the atypical neuroleptics appear to fall into two groups, those that bind loosely to D2 and those that are selective at D4.

Topics: Amino Acid Sequence; Animals; Antipsychotic Agents; Clozapine; Humans; Molecular Sequence Data; Parkinson Disease, Secondary; Rats; Receptors, Dopamine; Receptors, Serotonin

Although antipsychotic drugs are the mainstay of treatment in older patients with schizophrenia, much of the theoretical work underpinning their use is based on evidence gained from younger patients. With respect to dosages, there has been little work comparing plasma concentrations of antipsychotics in older patients with those of younger patients. However, there are well documented changes in the pharmacokinetics of these drugs in the elderly, particularly in their hepatic metabolism and renal excretion. There is also evidence that older patients experience more adverse effects from antipsychotics than younger patients. Such effects include extrapyramidal symptoms, postural hypotension and falls. For these reasons it is recommended that starting doses of antipsychotic drugs in older patients should be in the region of 25 to 50% of that recommended for younger patients, and should be slowly increased. Selection of a particular antipsychotic agent is best made on the basis of individual patient characteristics and the adverse effect profiles of particular drugs.

Topics: Aged; Aging; Akathisia, Drug-Induced; Antipsychotic Agents; Clozapine; Drug Prescriptions; Dyskinesia, Drug-Induced; Dystonia; Humans; Parkinson Disease, Secondary; Schizophrenia

Since the introduction of chlorpromazine in the 1950s, neuroleptic medications have been the mainstay of treatment of schizophrenia and other psychotic disorders. These medications do not always lead to complete remission of symptoms but they have allowed many patients to lead more productive and satisfying lives away from the restrictions of chronic hospitalisation. However, neuroleptics are associated with a number of adverse effects that can compromise their effectiveness. Extrapyramidal adverse effects include acute dystonic reactions, neuroleptic-induced Parkinsonism and akathisia. They can often be treated with neuroleptic dose reduction, addition of anticholinergic or beta-blocking agents, or medication change. Later-onset movement disorders such as tardive dyskinesia or dystonia require careful evaluation and may be treated with dose reduction or change of neuroleptic to an atypical agent. Potentially fatal reactions such as agranulocytosis and neuroleptic malignant syndrome can rarely occur and often require significant medical intervention. Clozapine offers some advantages over 'typical' neuroleptics but has a unique adverse effect profile which includes agranulocytosis.

Topics: Akathisia, Drug-Induced; Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Dyskinesia, Drug-Induced; Dystonia; Humans; Neuroleptic Malignant Syndrome; Parasympathetic Nervous System; Parkinson Disease, Secondary

Clozapine and risperidone were the first two "second-generation" antipsychotic drugs approved for schizophrenia. There is currently little information about their comparative efficacy from head-to-head clinical trials. The purpose of this study was to examine the comparative efficacy of clozapine and risperidone for positive and negative symptoms, depression, parkinsonian side effects, and indexes of neuroendocrine function in schizophrenic patients who met a priori criteria for partial response to traditional neuroleptic agents.. After a baseline fluphenazine treatment period, 29 patients participated in a 6-week, double-blind, parallel-group comparison of the effects of these agents.. Clozapine was superior to risperidone for positive symptoms and parkinsonian side effects, but there were no significant differences between the drugs on two measures of negative symptoms, Brief Psychiatric Rating Scale total scores, and depression scores. The clozapine patients, but not the risperidone patients, demonstrated significant reductions from the fluphenazine baseline in positive symptoms, total symptoms, and depression. In addition, clozapine produced fewer effects on plasma prolactin than risperidone or fluphenazine. The mean daily doses during week 6 of the trial were 403.6 mg of clozapine and 5.9 mg of risperidone.. The findings from this study indicate that these drugs have both important differences and similarities in their comparative efficacy in chronically ill, partially responsive patients with schizophrenia. Further research on second-generation antipsychotic drugs in this patient population that addresses key methodological issues, such as optimal dose and treatment duration, are needed.

Topics: Adult; Antipsychotic Agents; Basal Ganglia Diseases; Chronic Disease; Clozapine; Double-Blind Method; Drug Administration Schedule; Female; Human Growth Hormone; Humans; Hydrocortisone; Male; Parkinson Disease, Secondary; Prolactin; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Previous studies on the use of clozapine in neuroleptic-resistant chronic schizophrenic patients have demonstrated positive effects on tardive dyskinesia but were less conclusive about chronic akathisia and parkinsonism. The aim of the present study was to investigate the short-term (18 weeks) efficacy of clozapine in neuroleptic-resistant chronic schizophrenic patients with coexisting tardive dyskinesia, chronic akathisia, and parkinsonism.. Twenty chronic, neuroleptic-resistant schizophrenic patients with coexisting tardive dyskinesia, parkinsonism, and chronic akathisia were treated with clozapine. Assessment of tardive dyskinesia, parkinsonism, and chronic akathisia was made once weekly for 18 weeks with the Abnormal Involuntary Movement Scale (AIMS), Simpson-Angus Rating Scale for Extrapyramidal Side Effects, and Barnes Rating Scale for Drug-Induced Akathisia (BAS).. At the end of 18 weeks of clozapine treatment, improvement rates were 74% for tardive dyskinesia, 69% for parkinsonism, and 78% for chronic akathisia. A statistically significant reduction in the scores on the AIMS and Simpson-Angus Scale was achieved at Week 5 and on the BAS at Week 6 (p < .0001).. Relatively low doses of clozapine are effective for the treatment of neuroleptic-induced extrapyramidal syndromes in neuroleptic-resistant chronic schizophrenic patients. The relief of tardive dyskinesia, parkinsonism, and chronic akathisia in this group of patients occurs more rapidly than the reduction in psychotic symptoms. Disturbing, long-term extrapyramidal syndromes in chronic schizophrenic patients should be considered an indication for clozapine treatment.

Topics: Adult; Akathisia, Drug-Induced; Antipsychotic Agents; Basal Ganglia Diseases; Chronic Disease; Clozapine; Comorbidity; Drug Administration Schedule; Dyskinesia, Drug-Induced; Female; Humans; Male; Parkinson Disease, Secondary; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Topics: Aged; Biperiden; Clinical Trials as Topic; Clozapine; Dibenzazepines; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Haloperidol; Humans; Male; Parkinson Disease, Secondary; Piperidines; Psychotic Disorders; Thioridazine

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

Coexistence of idiopathic Parkinson's disease (iPD) and schizophrenia can pose great diagnostic and therapeutic challenges because of their pathophysiology. Our case highlights such challenges in management. We present a case of 73-year-old man who had parkinsonism for last several years and was also diagnosed with schizophrenia. Due to lack of collateral information about the onset of symptoms and clinical course, it was difficult to distinguish iPD from neuroleptic-induced parkinsonism. Even though, certain clinical findings may help to differentiate between the two conditions, single positron emission computerized tomography/DatScan was used to confirm the diagnosis of iPD. Treatment of coexisting iPD and schizophrenia can be challenging, and a delicate pharmacologic balance must be maintained to ensure adequate symptomatic control. Current evidence suggests that clozapine is a better choice for managing psychosis in these patients due to its unique receptor profile and better safety data.

Topics: Aged; Clozapine; Humans; Male; Parkinson Disease; Parkinson Disease, Secondary; Positron-Emission Tomography; Schizophrenia

Topics: Akathisia, Drug-Induced; Antipsychotic Agents; Brain; Chlorpromazine; Clozapine; Dopamine; Dyskinesia, Drug-Induced; Humans; Parkinson Disease, Secondary; Risk Factors; Schizophrenia

"Atypical anti-psychotics" are substances of choice in treating drug-induced psychosis (DP) in Parkinson's disease (PD). We report on four patients with DP who received treatment with ziprasidone after previously applied clozapine and quetiapine had failed. Three patients showed a significant improvement of DP, without deterioration of motor function. In one case, ziprasidone considerably increased decline in off-periods. Two patients developed pathological laughing as a possible side-effect of ziprasidone. Ziprasidone may serve as an additional "atypical anti-psychotic" for the treatment of DP in PD but can also induce deterioration of motor function.

Topics: Aged; Antiparkinson Agents; Antipsychotic Agents; Clozapine; Dibenzothiazepines; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Laughter; Levodopa; Male; Middle Aged; Neurologic Examination; Parkinson Disease; Parkinson Disease, Secondary; Piperazines; Psychoses, Substance-Induced; Quetiapine Fumarate; Thiazoles

Clozapine is the least likely anti-psychotic to induce extrapyramidal symptoms (EPS). We present a surprising case of a woman schizophrenic patient treated with clozapine suffering from EPS. Single photon emission computed tomography (SPECT) revealed a low density of presynaptic dopamine transporters in our patient's brain. A comorbid diagnosis of Parkinson's disease in schizophrenia was confirmed in this way. This helped us to find a proper therapeutic strategy for our patient.

Topics: Antipsychotic Agents; Brain; Clozapine; Diagnosis, Differential; Female; Humans; Middle Aged; Parkinson Disease, Secondary; Parkinsonian Disorders; Recurrence; Schizophrenia; Schizophrenic Psychology; Tomography, Emission-Computed, Single-Photon

Abrupt clozapine withdrawal can cause rebound psychosis and severe somatic symptoms in psychiatric patients. We report on the case of an advanced Parkinson's disease patient who developed myoclonus, tremor, rigidity, hyperreflexia, and stupor after abrupt clozapine withdrawal. The patient's symptoms resolved with treatment with cyproheptadine. This clinical picture suggests serotonergic rebound as an explanation for the patient's symptoms, although other pharmacological mechanisms are possible. Clozapine should be gradually withdrawn over a period of 1 to 2 weeks when possible, and abruptly discontinued only when necessary.

Topics: Aged; Antipsychotic Agents; Carbidopa; Clozapine; Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Drug Therapy, Combination; Hallucinations; Humans; Levodopa; Male; Neurologic Examination; Parkinson Disease; Parkinson Disease, Secondary; Substance Withdrawal Syndrome

Clozapine (CZP) is an atypical antipsychotic drug that does not appear to block striatal dopamine receptors. In six patients who met the criteria of HIV-associated psychosis and who had previously developed moderate parkinsonism as a result of the use of typical neuroleptic agents, CZP was added in an open, rising dose study. Subjects were evaluated at baseline after at least 7 days without neuroleptic drugs and then monthly for 3 months of the experimental treatment using three rating scales: Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI), and motor examination of the Unified Parkinson's Disease Rating Scale (UPDRS). A significant reduction in psychopathology as represented in the BPRS total score (54.2 at baseline versus 23.9 at month 3) and CGI (2 and 8, respectively) was obtained with a mean CZP dose of 27.08 mg/day. Parkinsonism also improved by an average of 76.5% at the end of the study. One patient did not complete the study as a result of a progressive decrease in leukocyte count while on CZP. These preliminary results suggest that the pharmacologic properties of CZP may be of value in the management of HIV-psychotic patients.

Topics: Adult; AIDS Dementia Complex; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Neurocognitive Disorders; Neurologic Examination; Parkinson Disease, Secondary; Psychiatric Status Rating Scales

Topics: Antipsychotic Agents; Clozapine; Dopamine; Dopamine D2 Receptor Antagonists; Humans; Muscarinic Antagonists; Parkinson Disease, Secondary; Radioligand Assay; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Receptors, Dopamine D4; Receptors, Muscarinic; Receptors, Serotonin; Serotonin Antagonists

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Carbon Radioisotopes; Clozapine; Corpus Striatum; Dopamine Antagonists; Female; Humans; Male; Olanzapine; Parkinson Disease, Secondary; Pirenzepine; Psychiatric Status Rating Scales; Raclopride; Radioligand Assay; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Tomography, Emission-Computed

We tested the effects of clozapine, and "atypical" neuroleptic with high affinity for the D4 (dopaminergic), and the 5-HT1c and 5-HT2 (serotonergic) receptor subtypes on locomotor activity in an animal model of Parkinson's disease showing a bimodal response curve to increasing doses of a D2 agonist. Sulpiride (D2 antagonist) and ritanserin (5-HT1c and 5-HT2 antagonist) were used for comparison. The D1 agonist SKF 38393 at a dose of 8 mg/kg significantly reversed the akinesia induced by chronic reserpine treatment (1 mg/kg for 5 days) and alpha-methyl-p-tyrosine pretreatment (300 mg/kg). In this model, the addition of a low dose of a D2 agonist, LY 171555 (quinpirole, 1 microgram/kg), inhibited the effects of SKF 38393, whereas the same drug at higher doses (5-50 microgram/kg) restored and potentiated the stimulatory response to D1 stimulation. Clozapine inhibited the inhibitory phase and potentiated the stimulatory phase of the curve. Sulpiride inhibited both phases of the dose-response curve (inhibitory/stimulatory), whereas ritanserin had no effect. We believe these results may reflect a disinhibition phenomenon possible mediated by the blockade by clozapine of a subpopulation of inhibitory, dopamine (DA) receptors belonging to the D2 "family."

Topics: Animals; Antipsychotic Agents; Brain; Clozapine; Dose-Response Relationship, Drug; Male; Mice; Motor Activity; Neural Inhibition; Parkinson Disease, Secondary; Psychomotor Performance; Receptors, Dopamine D2; Receptors, Dopamine D4; Receptors, Serotonin; Synaptic Transmission

We report six cases of psychosis in patients with akinetic-rigid syndromes who were treated with risperidone.. Five of the six patients experienced intolerable exacerbation of parkinsonism. Four subsequently did well on clozapine therapy. One patient required nursing home placement and a feeding gastrostomy as a result of the worsening parkinsonism during risperidone treatment, but was able to return home and have the gastrostomy removed after switching from risperidone to clozapine. Two of the five patients who worsened motorically also developed encephalopathy during risperidone treatment; the encephalopathy resolved when the patients were switched to clozapine treatment. Only one patient, the youngest, did well on risperidone therapy.. We believe that risperidone is not a substitute for clozapine in treating psychosis in parkinsonian patients and should be used with caution.

Topics: Aged; Antiparkinson Agents; Clozapine; Dyskinesia, Drug-Induced; Humans; Male; Parkinson Disease; Parkinson Disease, Secondary; Psychoses, Substance-Induced; Risperidone

Long-term experience with clozapine has shown that the agent has a motor and mental side effect profile that is distinct in many ways from classical neuroleptics. It can produce a parkinsonian-like bradykinesia and mild akathisia, but no rigidity and rarely tremor. In patients with tardive dyskinesia induced by other neuroleptics, clozapine permits the dyskinesia to disappear in about half the cases. That clozapine may induce tardive dyskinesia in extremely rare cases cannot be excluded, but it seems more likely that this tardive dyskinesia in clozapine-treated patients is due to previous treatment with classical neuroleptics. The earlier clozapine is started, the less chance for development of tardive dyskinesia. As do other neuroleptics, clozapine can elicit sedation and asthenia, but corresponding to the motoric extrapyramidal syndrome, clozapine causes emotional indifference ("mental parkinsonism"), depression, and restlessness to a significantly lesser degree, which may be of importance in the higher compliance seen with this drug.

Topics: Affective Symptoms; Akathisia, Drug-Induced; Antipsychotic Agents; Asthenia; Basal Ganglia Diseases; Clozapine; Dyskinesia, Drug-Induced; Dystonia; Humans; Parkinson Disease, Secondary; Schizophrenia; Schizophrenic Psychology

The importance of persistent negative symptoms in schizophrenia as a limiting factor in psychosocial and vocational rehabilitation has been increasingly emphasized. As a result, treatment trials and new drug development programs are focusing more attention on negative symptoms. Unfortunately, there is enormous phenomenological overlap between negative symptoms and neuroleptic-induced parkinsonism. We report data from a cohort of 56 clozapine-treated patients demonstrating significant correlations between measures of akinesia and anergia. Despite an average drug washout of over 2 weeks, the persistence of drug-induced parkinsonism can confound the assessment of therapeutic drug effects on negative symptoms.

Topics: Adolescent; Adult; Basal Ganglia Diseases; Clozapine; Female; Humans; Male; Parkinson Disease, Secondary; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology

Topics: Aged; Antipsychotic Agents; Clozapine; Diagnosis, Differential; Humans; Male; Neurologic Examination; Parkinson Disease, Secondary; Psychiatric Status Rating Scales; Psychoses, Substance-Induced; Psychotic Disorders

Topics: Clozapine; Dibenzazepines; Dyskinesia, Drug-Induced; Humans; Metoclopramide; Nausea; Parkinson Disease, Secondary

Topics: Antiparkinson Agents; Antipsychotic Agents; Clozapine; Haloperidol; Humans; Parkinson Disease; Parkinson Disease, Secondary; Receptors, Cholinergic; Sleep

Through the study of the pharmacological and clinical actions of chlozapine, a new drug used in psychiatry, we are questioning one of the traditional statements on the therapeutic action of antipsychotics: the affirmation that those must have, concomitantly, antipsychotic action and intense extrapyramidal effects (drug-induced parkinsonism). Combining our own investigations and those of other authors, the generally accepted concepts on the possible biochemical mechanisms involved in the etiology of endogenous psychosis are criticized. Although there is evidence of alterations of the dopaminergic system in schizophrenia and also changes due to the action of neuroleptics, we cannot reject, given the dissociation of effects obtained with chlozapine, the possibility that the repercussion on the nigrostriatal dopaminergic system be only one of the many probably mechanisms of action of psychotropic drugs. Thus, such anatomical and neurochemical systems could be involved only in a secondary manner in the biochemical alterations typical of schizophrenia.

Topics: Brain; Clozapine; Dibenzazepines; Extrapyramidal Tracts; Humans; Iatrogenic Disease; Norepinephrine; Parkinson Disease, Secondary; Receptors, Dopamine

1. The anti-dopaminergic effects of several dibenzodiazepines were examined on the dopamine-stimulated adenylate cyclase in rat striatal homogenates. The "cis" isomer of clozapine, HF-2046, was the most potent in this respect and perlapine, which is devoid of neuroleptic activity, was the weakest. 2. The anti-muscarinic effects of the same compounds were measured by using the muscarinic affinity label 3H-propylbenzilylcholine mustard. HF-2046 was the most potent and loxapine the least potent of the drugs used. 3. The anti-dopaminergic effects of the drugs correlate well with neuroleptic but not with extrapyramidal effects. The anti-dopaminergic/anti-muscarinic ratio, however, correlates well with extrapyramidal rather than neuroleptic effects.

Topics: Adenylyl Cyclases; Animals; Cerebral Cortex; Choline; Clozapine; Corpus Striatum; Dibenzazepines; Dibenzothiazepines; Dopamine Antagonists; Homovanillic Acid; Loxapine; Male; Parasympatholytics; Parkinson Disease, Secondary; Piperazines; Rats; Receptors, Cholinergic

Three main biogenic amine hypotheses for the origin of schizophrenia are discussed. The dopamine theory of schizophrenia postulates a pathogenetic connection between the disease and changes in the activity of dopaminergic cells in the brain. The theory is mainly based on findings on the mechanism of action of neuroleptics, on the clinical features and pharmacology of the amphetamine psychosis, and on some amphetamine effects in animals. Several results are in good agreement with the assumption of a state of hyperactivity of central dopamine neurons, whereas others, e.g. the lack of an increased dopamine turnover, are not. According to another theory, schizophrenia is caused by reversible damage to central norepinephrine cells. So far the only empirical basis for this theory is the finding that the activity of dopamine-beta-hydroxylase, a marker enzyme for noradrenaline cells, is lowered in the brains of schizophrenic patients. Thus further confirmation is required. The transmethylation hypotheses assume that hallucinogenic amine metabolites are produced in the body and lead to the appearance of schizophrenic symptoms. Whether or not the occurrence of DMPEA, presumably an oxymethylation product of the dopamine metabolism, is specific for schizophrenics is still open to question; if it is, the meaning of this finding is obscure. Current results leave open the possibility that N-dimethyltryptamine or other N-methylated hallucinogenic biogenic amine metabolites cause the disease; however, this hypothesis is hardly confirmed by positive empirical results.

Topics: Amphetamines; Basal Ganglia Diseases; Clozapine; Dopamine; Dopamine beta-Hydroxylase; Humans; N,N-Dimethyltryptamine; Parkinson Disease, Secondary; Receptors, Adrenergic; Schizophrenia; Tranquilizing Agents