A PET study evaluating dopamine D2 receptor occupancy for long-acting injectable risperidone.

OBJECTIVE: Long-acting injectable risperidone represents the first clinically available depot atypical antipsychotic. The present study used positron emission tomography (PET) to evaluate its dopamine D(2) binding profile at doses of 25, 50, or 75 mg administered every 2 weeks. METHOD: After achieving stabilization with one of the doses, nine patients with a diagnosis of schizophrenia or schizoaffective disorder underwent [(11)C]raclopride PET to measure D(2) occupancy. Participants were scanned twice during the 2-week injection interval: within 3 days after injection (postinjection) and within 5 days before the next injection (preinjection). At the same time, plasma was collected for measurements of risperidone plus 9-hydroxyrisperidone. RESULTS: Mean post- and preinjection D(2) occupancy levels for the 25-, 50-, and 75-mg doses were 71.0% and 54.0%, 74.4% and 65.4%, and 81.5% and 75.0%, respectively. There was a significant correlation between dose and plasma concentrations of risperidone plus 9-hydroxyrisperidone, and the estimated plasma concentration associated with 50% D(2) occupancy (ED(50)) was 11.06 ng/ml. Prolactin levels were not correlated with drug levels or D(2) occupancy. CONCLUSIONS: All three doses of injectable risperidone showed peak D(2) occupancy levels above the 65% threshold associated with optimal clinical response; the 75-mg dose approximated the 80% threshold linked to increased risk of extrapyramidal symptoms. Doses of 25 or 50 mg should provide therapeutic efficacy while minimizing the risk of extrapyramidal symptoms.

Augmentation strategies in clozapine-resistant schizophrenia.

The introduction of antipsychotics in the 1950s revolutionised the treatment of schizophrenia, but it soon became apparent that a substantial number of patients demonstrated a suboptimal response to these antipsychotics. Clozapine proved to be beneficial in patients whose symptoms were treatment resistant, but it too had limitations, with as many as 40-70% of those treated with clozapine demonstrating inadequate response to this drug as well. The availability of other 'atypical' antipsychotics offers options, but clozapine appears to remain the most effective option in treatment-resistant schizophrenia. This, of course, raises the question of what to do when clozapine is only partially effective. To address the issue of treatment in patients who have demonstrated a suboptimal response to clozapine, efforts have focused on a variety of augmentation strategies, including numerous medications and electroconvulsive therapy. The current body of evidence consists largely of data from smaller open trials and case series/reports, although data from a limited number of controlled studies are now available. Not surprisingly, the evidence drawn from the former is more supportive of augmentation strategies, although the controlled trials are not without positive findings. The available information is certainly not so overwhelming as to endorse any single augmentation approach. Indeed, it argues for more controlled data and cautions us regarding the cost-benefit ratio in adopting this strategy. Over and above the added adverse effects of another treatment, there is evidence to indicate that actual clinical worsening can occur. Without compelling evidence, clinicians must resort to guiding principles. The potential benefits of augmentation cannot be ruled out, but it should be approached with caution and in a systematic fashion. Factors compromising clozapine response should first be ruled out, and any augmentation trials should be guided by existing evidence and a treatment plan that incorporates a clear understanding of target symptoms. A means of evaluating outcome effectively needs to be in place, and the trial should be circumscribed to prevent needless polypharmacy. A priori, an endpoint needs to be established and the trial discontinued unless results firmly support added benefits.

The use of pharmacotherapy in the prodrome of schizophrenia.

In treating schizophrenia there has been a shift in focus, with more attention being paid to early intervention based on the notion that effective treatment at this point can improve outcome. Most of this work has centred on pharmacotherapeutic interventions during the first psychotic break. More recently, attention has turned to the potential value of intervening even earlier, that is during the so-called "prodrome" that has been identified as predating the first psychotic break by as much as 4-5 years. We now have a limited number of published reports addressing this topic and these are reviewed here.

"Extended" antipsychotic dosing in the maintenance treatment of schizophrenia: a double-blind, placebo-controlled trial.

OBJECTIVE: In the treatment of schizophrenia, all currently available oral antipsychotics are administered at least once daily, with strict adherence strongly encouraged to minimize risk of relapse. Based on a better understanding of the brain kinetics of antipsychotics, we have proposed a variation of this approach, "extended" dosing, which allows for intermittent but regular dosing. METHOD: We carried out a randomized, double-blind, placebo-controlled trial evaluating 35 individuals with DSM-IV-defined schizophrenia who had been stabilized on antipsychotic therapy. Over a 6-month interval, 18 subjects received their medication as usual (daily), while 17 received their antipsychotic therapy every second day (extended). Outcome measures included clinical scales to assess symptoms (Brief Psychiatric Rating Scale [the primary outcome measure], Calgary Depression Scale), illness severity (Clinical Global Impressions-Severity of Illness scale), and relapse (ie, rehospitalization) rates. Side effects were also assessed, including movement disorders (Barnes Akathisia Scale, Simpson-Angus Scale, Abnormal Involuntary Movement Scale) and weight. The study was conducted from February 2003 to July 2007. RESULTS: Individuals in the extended dosing group were not at greater risk of symptom exacerbation, relapse, or rehospitalization; indeed, more rehospitalizations occurred in those receiving regular dosing. At the same time, though, there was no indication that side effects were significantly reduced in the extended dosing group. CONCLUSIONS: These results challenge the long-standing dogma that oral antipsychotics must be administered daily in stabilized patients with schizophrenia. Further studies with larger samples are needed to replicate these findings, as well as to elucidate whether postulated clinical advantages can be established and determined to outweigh potential risks. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00431574.

Determining rates of hepatitis C in a clozapine treated cohort.

OBJECTIVE: To determine the prevalence rates of hepatitis C in patients with schizophrenia and schizoaffective disorder being treated with clozapine. METHODS: Clozapine-treated outpatients and inpatients were recruited from the Centre for Addiction and Mental Health Schizophrenia Program in Toronto, Canada. All subjects had liver function tests, and positive HCV status was defined as a positive qualitative HCV RNA assay. Subjects completed a self-report questionnaire assessing HCV risk factors, past history of liver disease, previous diagnosis of human immunodeficiency virus (HIV), past hepatitis B virus (HBV) infection and current alcohol use. RESULTS: 110 subjects participated in the study and the HCV prevalence rate (antibody and viremia-positive) was 2.7%, compared to a 0.8% prevalence rate in Canada. All study subjects had established housing, none reported a history of HIV, and only one patient had a history of HBV infection. A total of 9% drank two or more drinks on a typical day drinking and 7% endorsed having six or more drinks on one occasion at least monthly. Two of 3HCV-viremia positive subjects had HCV risk factors, specifically intravenous drug use and intranasal cocaine use. There was no difference between HCV infected and HCV negative subjects on liver function tests. CONCLUSIONS: Our study demonstrates elevated rates of HCV in clozapine-treated patients compared to the general population in Canada and are congruent with reports from United States centres. Our study highlights the importance of homelessness and patterns of high-risk behaviour when interpreting HCV prevalence rates in this sub-population of patients and should be explored in future studies.

Treatment of clozapine-induced hypersalivation with ipratropium bromide: a randomized, double-blind, placebo-controlled crossover study.

OBJECTIVE: Clozapine-induced hypersalivation (CIH) occurs in up to 57% of treated patients and can be the source of considerable subjective distress. Previous open-label studies suggest that sublingual ipratropium bromide may be effective in treating CIH. METHOD: We conducted a randomized, double-blind, placebo-controlled crossover trial to evaluate the efficacy of ipratropium in 20 individuals with CIH between September 2006 and August 2007. This study was 5 to 6 weeks in duration, based on the participants' clozapine blood-monitoring schedule, and it consisted of two 2-week crossover phases separated by a 1- or 2-week washout period. Primary outcome measures included the reduction in the Toronto Nocturnal Hypersalivation Scale (TNHS) and the Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I) scales. Secondary outcomes included visual analog scales assessing hypersalivation severity (VAS-S) and distress (VAS-D). RESULTS: No significant reduction in CIH was found on the TNHS (P = .379), CGI-S (P = .266), or CGI-I (P = .599). Moreover, no difference was noted between study groups on the VAS-S (P = .969) and VAS-D (P = .527). There was no difference in the number of CIH responders at the conclusion of the 2-week placebo (40%, n = 8) and ipratropium (45%, n = 9) study phases (45%, n = 9) according to the TNHS. Randomization order did not have a significant effect on TNHS, CGI-S, or CGI-I scores. Tolerability was comparable between groups, with dry mouth occurring in 1 placebo group subject and 2 ipratropium group subjects. CONCLUSIONS: Despite the reports of some preliminary studies that ipratropium is an efficacious treatment for CIH, ipratropium failed to demonstrate significant clinical effect in comparison to placebo. Further research should explore the efficacy of other locally acting anticholinergic agents or other classes of medications. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00381589.

Monthly administration of long-acting injectable risperidone and striatal dopamine D2 receptor occupancy for the management of schizophrenia.

OBJECTIVE: Long-acting risperidone administered intramuscularly biweekly is approved for the management of schizophrenia. However, dosing of long-acting antipsychotics is frequently extended in clinical practice, and a recent clinical trial has lent support to monthly dosing of long-acting risperidone. The objective of this positron emission tomography (PET) study was to examine the striatal dopamine D(2) binding of long-acting risperidone administered intramuscularly once a month. METHOD: Following at least 3 maintenance monthly injections of 50 mg long-acting risper-idone, 7 patients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder under-went PET using [(11)C]raclopride to measure D(2) binding potential within 4 days of the next scheduled injection. Data were collected from May to October 2003. This PET study was part of a larger 52-week clinical study wherein individuals received long-acting risperidone once monthly over a 1-year interval. One-year follow-up data were obtained from the 52-week parent investigation. RESULTS: The mean +/- SD D(2) receptor occupancy was 56% +/- 24% (range, 29%-82%). Of note, there were 4 subjects with less than 60% D(2) occupancy, none of whom relapsed over the course of the 1-year follow-up. The mean +/- SD total plasma level of risperidone plus 9-hydroxyrisperidone was 16.6 +/- 12.3 ng/mL (range, 5.7-40.8). CONCLUSION: As with plasma levels, there was considerable variability in D(2) occupancy levels for individuals receiving long-acting risperidone. This work suggests a possibility that sustained D(2) occupancy at or above the accepted threshold with acute clinical response may not be necessary to maintain response, a hypothesis with important clinical implications as we consider antipsychotic dosing and future antipsychotic development. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00236353.

Managing the neuropsychiatric complications of hepatitis C treatment.

Interferon-alpha is the mainstay of hepatitis C treatment and has been linked to several neuropsychiatric complications, including depression, anxiety, mania, psychosis and cognitive changes. This article reviews the management of neuropsychiatric adverse effects and the risks of interferon-alpha treatment to psychiatric patients.

Clozapine-induced hypersalivation: a review of treatment strategies.

OBJECTIVE: Clozapine-induced hypersalivation (CIH) is a significant side effect affecting about one-third of patients treated with clozapine. CIH can be stigmatizing, can affect quality of life, and can result in discontinuation of clozapine treatment. The purpose of this review is to provide an understanding of CIH, specifically, its pathophysiology, measurement, and the evidence for CIH treatment alternatives. METHODS: We searched MEDLINE from 1980 to June 2006 for all reported pharmacologic treatment studies related to CIH. We identified additional references by a manual search of the bibliographies of retrieved articles. RESULTS: Several studies reported improvement of CIH with both selective and nonselective anticholinergic medications. However, with the exception of local anticholinergic agents such as ipratropium bromide and atropine eye drops, potential systemic adverse effects limit the effectiveness of this class of medications. Open-label studies of clonidine, an alpha2 antagonist, suggest that it may be beneficial in managing CIH. Other pharmacologic treatments, such as amisulpride and botulinum toxin, may be useful in refractory CIH cases. CONCLUSION: Although few randomized controlled trials were found in the literature, this review highlights potential treatment alternatives for this common and disabling cause of hypersalivation. Prompt and effective treatment of CIH may assist with treatment tolerability, adherence, and outcomes in patients with treatment-refractory schizophrenia. Information on funding and support and author affiliations appears at the end of the article.