The adrenergic α2 antagonist atipamezole alters the behavioural effects of pramipexole and increases pramipexole concentration in blood plasma.

Pramipexole is a dopaminergic agonist used in Parkinson's disease treatment. It is thought to exert its therapeutic and side effects through actions on dopamine D3 receptors. In a recent study, we found that at doses occupying D3 but not D2 receptors pramipexole reduced locomotion and operant responding for primary and conditioned reinforcement. These effects, however, were not blocked by a D3 receptor antagonist and were present in D3 knockout mice, suggesting non-D3 receptor mechanisms. Among the next highest affinity binding sites of pramipexole are adrenergic α2 receptors. Here we explored α2 receptor involvement in the behavioural effects of pramipexole. We found that the α2 antagonist atipamezole, which was itself behaviourally silent, counteracted pramipexole's reduction of locomotion, but not operant responding for water or a conditioned reinforcer. The resulting behavioural profile was similar to that of a higher dose of pramipexole, leading to the hypothesize that atipamezole mediates its behavioural effects by increasing pramipexole effective dose. In support of this hypothesis, we found that atipamezole increased pramipexole concentration in blood plasma. This is not likely due to an effect on drug metabolism since pramipexole is not known to undergo metabolic transformation. Future work should examine two alternative hypotheses; that pramipexole plasma concentration is elevated as the result of 1) competition with atipamezole for renal excretion, or 2) atipamezole blockade of peripheral α2 binding sites, thereby preventing pramipexole distribution to α2-rich tissues. The suggestion of adrenergic effects of pramipexole is important in light of recent interest in adrenergic pathophysiology in Parkinson's disease.

Low dose pramipexole causes D3 receptor-independent reduction of locomotion and responding for a conditioned reinforcer.

Pramipexole is a clinically important dopamine receptor agonist with reported selectivity for dopamine D3 receptors over other dopaminergic and non-dopaminergic sites. Many of its behavioural effects are therefore attributed to D3 receptor activity. Here we relate pramipexole's ex vivo D2 and D3 receptor binding (measured using [(3)H]-(+)-PHNO binding experiments) to its effects on locomotion and operant responding for primary and conditioned reinforcers. We show that pramipexole has inhibitory behavioural effects on all three behaviours at doses that occupy D3 but not D2 receptor. However, these effects are 1) not inhibited by a D3 selective dose of the antagonist SB-277011-A, and 2) present in D3 receptor knockout mice. These results suggest that a pharmacological mechanism other than D3 receptor activity must be responsible for these behavioural effects. Finally, our receptor binding results also suggest that these behavioural effects are independent of D2 receptor activity. However, firmer conclusions regarding D2 involvement would be aided by further pharmacological or receptor knock-out experiments. The implications of our findings for the understanding of pramipexole's behavioural and clinical effects are discussed.

Increased dopamine D2 receptor binding after long-term treatment with antipsychotics in humans: a clinical PET study.

RATIONALE: Dopamine D2 receptor upregulation in the striatum is regularly seen in response to the administration of traditional antipsychotics in animal experiments. This is associated with hyperactivity and, for this reason, D2 receptor upregulation has long been postulated as central to tardive dyskinesia (TD). OBJECTIVE: Using positron emission tomography (PET), the present study attempted to determine whether antipsychotic-induced D2 receptor up-regulation also occurs in humans. METHODS: The long-term effects of traditional and novel antipsychotics on dopamine D2 receptors were investigated in nine subjects meeting DSM-IV criteria for schizophrenia who were deemed eligible for temporary treatment washout. Subjects had been treated with traditional antipsychotics (haloperidol n=3, perphenazine n=1) and novel antipsychotics (risperidone n=3, olanzapine n=2) in the moderate to high dosage range. Fourteen days after treatment withdrawal, the binding potentials (BPs) of dopamine D2 receptors were measured using 11[C] raclopride. The obtained BPs were compared to the BPs from antipsychotic-naive control subjects with schizophrenia. RESULTS: There was a significant increase in the D2 BP in both groups combined that reached 34%. The increases in the D2 BPs in the groups treated with conventional and novel antipsychotics were 37% and 31%, respectively. Significantly, the patients showing the highest degree of D2 receptor upregulation (98%) developed severe and persistent TD shortly after being started on a new antipsychotic with low affinity for D2 receptors. CONCLUSION: This study demonstrates for the first time, using in vivo neuroreceptor imaging, that dopamine D2 receptor binding is increased after long-term treatment with antipsychotics in humans. The data suggest that both traditional and novel antipsychotics with high affinity for dopamine D2 receptors are associated with a substantial increase in D2 receptor binding. The present data in humans agree well with animal data that implicate D2 receptor-mediated mechanisms in motor hyperactivity.

Contrasting clozapine prescribing patterns in the east and west?

INTRODUCTION: Polypharmacy is common in the treatment of schizophrenia and it may be especially common in the East. In this survey, we compared the effect of clozapine, an atypical neuroleptic, on polypharmacy in two groups of patients with schizophrenia in two different settings. MATERIALS AND METHODS: The medical charts of patients on stable doses of clozapine from a Canadian psychiatric centre and that of a Southeast Asian centre were analysed to evaluate the daily dose requirement and the concomitant medications prescribed. The beliefs of the Asian psychiatrists on the concomitant use of another neuroleptic were also examined. RESULTS: The mean daily dose of clozapine was 408 mg/day for the Canadian subjects and 169 mg/day for the Asian sample. Of the Canadian sample, none were prescribed another neuroleptic, 45% were on a benzodiazepine, and 10% were receiving an anticholinergic agent. The Singapore sample indicated 28% of the subjects on another neuroleptic, with 36% taking an anticholinergic agent and 28% on a benzodiazepine. The Asian psychiatrists prescribed a second neuroleptic in the belief that it would reduce cost and enhance the antipsychotic effect. CONCLUSIONS: This study suggests that there are regional differences in the prescription patterns and daily dose requirements of clozapine.

Effect of clozapine on polypharmacy.

Prescribing patterns for a group of outpatients with schizophrenia were surveyed for changes after the initiation of clozapine. Data were drawn from computerized pharmacy records, direct case record reviews, and interviews with the attending psychiatrists. The number of patients with two or more psychotropic drugs decreased by 31 percent after the initiation of clozapine, and a trend toward the use of clozapine without additional neuroleptics was detected. Decreases occurred in the use of anticholinergic agents, carbamazepine, and benzodiazepines, but selective serotonin reuptake inhibitors and sodium valproate were more likely to be prescribed concomitantly with clozapine.

The Canadian experience with risperidone for the treatment of schizophrenia: an overview.

OBJECTIVE: To summarize published data to date by Canadian authors and from Canadian sources on risperidone, a novel neuroleptic indicated in the management of schizophrenia and related psychotic disorders. It was introduced in Canada in 1993. DATA SOURCES: A MEDLINE search was performed using "risperidone" as a keyword. Three Canadian journals were also searched manually. STUDY SELECTION: Articles published between January 1991 and June 1996 by Canadian authors or involving Canadian patients. DATA EXTRACTION: Retrieved articles were categorized according to data on efficacy, safety, resource use/economics and other miscellaneous aspects. Articles were abstracted and summarized. Some non-Canadian sources were used for comparison. DATA SYNTHESIS: The initial Canadian multicentre trial found resperidone (6 mg daily) to be superior to haloperidol (20 mg daily) in reducing positive and negative symptoms, with fewer extrapyramidal side effects (EPS). Various case reports have extended both the clinical use and safety profile of risperidone, while neuro-imaging studies have tried to clarify its mechanism of action. Economic studies suggest substantial cost benefits due to prevention of hospitalization as well as improvement in quality of life. CONCLUSIONS: Canadian research has contributed considerably to the current knowledge regarding risperidone. Future studies, both controlled and naturalistic, will need to focus on comparisons with the various new compounds now available.

Insight, neurocognitive function and symptom clusters in chronic schizophrenia.

Only recently has there been interest in the systematic study of insight in schizophrenia. The present investigation was designed to evaluate the specific relationship between psychopathological symptoms, neurocognitive deficits and awareness of illness in chronic schizophrenia. Fifty-eight outpatients with the DSM-III-R diagnosis of schizophrenia were rated on David's Schedule for Assessing Insight, the Positive and Negative Syndrome Scale (PANSS), the Calgary Depression Scale and the Wisconsin Card Sorting Test (WCST). Results indicate that there is a significant association among these variables and that approximately 44% of the variance in the dependent variable could be explained by this combination of independent variables. Notably, however, negative symptoms were only moderately inversely correlated with awareness of illness, and they were not associated with scores on the WCST. Moreover, neither negative symptoms nor per cent perseverative errors contributed significantly to the prediction of insight in schizophrenia. These findings argue against the notion that unawareness of illness is the product of neuropsychological dysfunction in the frontal lobes. Instead, the most significant associations and predictors of insight were related to the positive symptoms of schizophrenia.

Neuroleptic dosing in chronic schizophrenia: a 10-year follow-up.

OBJECTIVE: To evaluate neuroleptic dosing patterns in individuals with schizophrenia over a 10-year interval. METHOD: Changes in neuroleptic dosing between 1980 and 1990 were followed in 65 patients with a diagnosis of chronic schizophrenia. RESULTS: According to more recent dosing guidelines, doses were already high at the time of initial evaluation, yet overall they continued to increase during the next decade of treatment for both males and females. Patients were almost equally divided, however, by those who underwent an increase (n = 33) and those whose dose remained stable (n = 4) or was decreased (n = 28). CONCLUSION: A considerable number of patients with schizophrenia appear to receive progressively higher neuroleptic doses over the course of their illness, despite a lack of empirical data to support such an approach. Results are discussed in terms of current dosing recommendations and factors influencing dose changes.

The D2 receptor occupancy profile of loxapine determined using PET.

Positron emission tomography (PET) studies of typical neuroleptics suggest that 60% to 80% of striatal D2 occupancy may be sufficient for optimal clinical treatment of psychosis. Therefore, striatal D2 occupancy may be used as an index to determine the optimal dose range. Toward this end, we determined the in vivo D2 profile of loxapine, using [11C]-raclopride and PET. Seven patients selected from a clinical population were scanned while taking steady-state oral loxapine from 10 to 100 mg/day. Their D2 receptor occupancy was estimated by comparing them to age-matched data from neuroleptic-naive patients. The D2 receptor occupancy ranged from 52% to 90%, and there was a very strong relationship between dose and D2 occupancy, suggesting that 15 to 30 mg/day of loxapine would produce, the putatively optimal, 60% to 80% striatal D2 blockade. This dose range is much lower than that used in most clinical settings and points to the potential efficacy of loxapine at lower doses.

Clozapine: current status and role in the pharmacotherapy of schizophrenia.

OBJECTIVE: This study evaluates clozapine and its present role in the pharmacotherapy of schizophrenia. METHOD: Clozapine's current clinical status is reviewed, as is its position with respect to other treatment options. RESULTS: Clozapine represents the prototype of "atypical" neuroleptics, with evidence of clinical efficacy in both positive and negative symptoms, as well as a diminished risk of extrapyramidal side effects. It is the only neuroleptic to date that has established itself as having little, if any, risk of tardive dyskinesia. More recent research has focused on its potential for overall savings in health care costs, as well as possible benefits in the area of neuropsychological functioning. CONCLUSION: Evidence suggesting that the course of schizophrenia can be altered by effective treatment favours a systematic approach that optimizes treatment options. While clozapine does not represent a 1st-line agent because of its risk of agranulocytosis, it has an integral role to play in treatment-resistant schizophrenia or in individuals experiencing intolerable side effects with conventional neuroleptics.

Depot neuroleptic therapy: clinical considerations.

The management of schizophrenia is generally a long-term process with neuroleptics representing the cornerstone of treatment. Although not without their own limitations, depot neuroleptics offer an important alternative to oral agents, and they should be routinely considered as an option in any long-term treatment planning. The present article reviews depot neuroleptics, and focuses particularly on clinical considerations pertaining to their use.

Erotomanic delusions and electroconvulsive therapy: a case series.

BACKGROUND: Erotomania, as a primary disorder, is categorized in DSM-III-R under delusional (paranoid) disorder. However, erotomanic delusions also are seen frequently in the context of other psychiatric disorders. There is increasing evidence that patients with such delusions often have an underlying affective disorder and effective treatment of the underlying disorder can lead to resolution of the erotomanic delusions. METHOD: The case histories of three patients with prominent affective features and erotomanic delusions are presented. RESULTS: Each patient was treated with bilateral electroconvulsive therapy (ECT) after experiencing treatment failure with numerous other somatic therapies. One showed only a slight and transient improvement, while two demonstrated resolution of the erotomanic delusions. CONCLUSION: Bipolar and schizoaffective disorder should be considered in patients with erotomanic delusions, and ECT may offer an effective alternative when other somatic treatments have failed.

Antiparkinsonian drugs in the treatment of neuroleptic-induced extrapyramidal symptoms.

Most patients on neuroleptic therapy experience extrapyramidal symptoms in one form or another during treatment. While the risk of extrapyramidal symptoms appears diminished with the newer and "atypical" neuroleptics (for example, risperidone, remoxipride, clozapine), it is not eliminated. It is essential that the treating clinician monitor for such side effects since if they are left untreated they can be an ongoing source of discomfort to the patient and may affect compliance with therapy. Antiparkinsonian medication represents the mainstay of treatment for neuroleptic-induced extrapyramidal symptoms. Their clinical use is reviewed here with reference to mode of action, indications, choice, side-effects and precautions.

Clinical considerations in the use of risperidone.

Clinical studies to date have shown that risperidone is an effective antipsychotic agent in the treatment of both positive and negative symptomatologies, with a side-effect profile that is superior to standard neuroleptics. It may represent a potentially useful first-line agent in the treatment of schizophrenia, and clinicians may consider switching to risperidone if current neuroleptic therapy yields poor control of symptoms or problematic side-effects, such as extrapyramidal symptoms or tardive dyskinesia. This article discusses the relevant clinical considerations in switching neuroleptics and proposes practical guidelines on issues such as dosing and course of therapy with risperidone.

Dosaging patterns in schizophrenia with depot, oral and combined neuroleptic therapy.

A group of patients with chronic schizophrenia were evaluated according to the form of neuroleptic treatment they were receiving: depot, oral or combined (depot/oral or oral/oral). The patients treated with the combined therapy received significantly higher dosages of neuroleptic than those treated with either depot or oral therapy, which did not differ from each other. Daily maintenance dosages were generally well above recent guidelines.