18 The Open Conference Proceedings Journal, 2012, 3, 18-23 Open Access Systematic Review and Meta-analysis of Anticholinergic Side Effects of Long-acting Antipsychotics Mehmet Ozbilen*,1 and Ranga Rattehalli2 1North Essex Partnership NHS Foundation Trust, Colchester, UK 2Newsam Centre, Leeds, UK Abstract: Background: There are few studies on the anticholinergic side effects of long-acting antipsychotics. They tend to be used with stigmatized, severely ill and non-concordant patients rather than first episode psychosis. Aim: To investigate prevalence/incidence rate of anticholinergic side effects of long-acting antipsychotics. Methods: We included all participants with schizophrenia, schizoaffective disorder or schizotypal disorder on depot antip- sychotics in the trials within all Cochrane reviews published by the Cochrane schizophrenia group. A search was under- taken in the Cochrane Database and data extracted into Microsoft Excel to analyze frequencies, prevalence and confidence intervals of the anticholinergic side effects of all identified long-acting antipsychotic medications. Result: We found seven reviews for seven depot antipsychotics. For example for fluphenazine decanoate at least a quarter of the participants experienced blurred vision 24.5% (CI 11 to 47) in the short-term, 16 % (CI 10-27) in the medium-term, and 21.4 % (CI 16-28) in the long-term. Conclusion: The anticholinergic side effects of long-acting depot antipsychotics are not any more frequent than the anti- cholinergic side effects of oral antipsychotics. There is no evidence to suggest that oral medications are better tolerated than long-acting depot preparations. Keywords: Long-acting antipsychotics, depot, schizophrenia, anticholinergic side effects, blurred vision, dry mouth, constipa- tion. INTRODUCTION extrapyramidal side effects of antipsychotics, the anticho- linergic side effects can also be problematic. We will exam- Patients with first episode schizophrenia usually respond ine these in more detail and compare the anticholinergic side well to treatment [1]. However, relapses even during the first effect profiles of the identified antipsychotics. year of the course of the illness are frequent and many times associated with their clinical deterioration [2]. A previous search by M.O. [4] in Embase, PsychInfo, Medline identified three quantitative studies on anticholiner- Long-acting injections are generally used with people gic side effects [5-7]. Following this a systematic overview who experience significant complications of non- of anticholinergic side effects over the short-term was pub- concordance, e.g. relapse and often re-hospitalization. There lished [8]. However, there is no study which has systemati- is no published head-to-head comparison of outcomes among cally investigated anticholinergic side effects of Cochrane first-episode patients receiving drugs with long-acting injec- reviews for depot antipsychotics over the short-, medium- tions and those receiving oral medication. However, non- and long-term. adherence is a considerable problem with first-onset psycho- sis [3]. AIM In spite of all the support and monitoring, non- concordance to medication leading to relapse is very com- We aim to systematically investigate incidence/pre- mon and this issue could be addressed by using long-acting valance rates of anticholinergic side effects for long-acting depot antipsychotics to aid compliance in this group of gen- depot antipsychotics over short-, medium- and long-term. erally young patients in their 20s. However, the conventional antipsychotic depot injections are not free of side effects METHODS which happen to be a common reason for discontinuation of Criteria for Considering Reviews for This Study the medication. Although clinicians often focus on the The included studies were any systematic review under- taken by the Cochrane Schizophrenia Group with at least one *Address correspondence to this author at the North Essex Partnership NHS of the arms having long-acting antipsychotic depot. The type Foundation Trust, Crisis Resolution and Home Treatment (CRHT) Colches- ter, CO4 5JL, United Kingdom; Tel: +44 (0)120 62 28758; of participants were anyone with a diagnosis of schizophre- Fax: +44 (0)120 62 287309; E-mail: [email protected] nia, schizophreniform disorder, schizotypal disorder diag- 2210-2892/12 2012 Bentham Open Systematic Review and Meta-analysis of Anticholinergic Side Effects The Open Conference Proceedings Journal, 2012, Volume 3 19 nosed using any diagnostic criteria irrespective of gender, acting injections, whereas bromperidol, metylperidol, risper- age or ethnicity that were treated with depot antipsychotic idone and flupenthixol depot were less constipating. Nearly a medications. The outcome measures were the preva- quarter of the patients experienced dry mouth with fluphe- lence/incidence of the anticholinergic side effects: - Blurred nazine and long-acting risperidone and one sixth of the pa- vision, constipation, dry mouth, urinary retention, nasal stuf- tients on fluspirilane decanoate. However, bromperidol and finess, hyperthermia, increased salivation, tachycardia and pipotiazine depot and methylperidol were less of a cause for confusion. dry mouth and not much different to placebo. There were data on increased salivation, tachycardia and urinary reten- Search Method for Identifying of The Studies tion in the short-term with risperidone, fluphenazine, brom- peridol and methylperidol but these figures were comparable Cochrane library was searched by M.O. using the search to that of placebo. Surprisingly, nasal stuffiness, hyperther- term hm-schiz in ‘search all text’ in 2007. The titles of all mia and confusion were only reported in the placebo arms in reviews identified by this way were retrieved and those rele- the short-term (Table 1). vant for pharmacological care were selected. The reviews which met the inclusion criteria were included. Rejected In the medium-term blurred vision was significantly reviews were recorded with reason for rejection. higher with fluphenazine. Blurred vision was comparable to placebo with fluspirilene decanoate and flupenthixol de- M.O. extracted all the data from the full text articles us- canoate. Similarly, dry mouth was comparable to placebo ing data extraction forms and entered the data into an excel with bromperidol, fluspirilene decanoate and fluphenazine. spreadsheet. Dummy tables were constructed to guide analy- For other depot medications for this side effects there were sis. The data was grouped into short-term (up to 3 months), no data reported and recorded over medium-term except for medium-term (3 to 6 months), and long-term (over 6 placebo. As in the short-term results, nasal stuffiness, hyper- months). Unclear issues were resolved by discussion with the thermia and confusion were also only reported in the placebo supervisor (C.E.A). If any issues remained which could not arms and surprisingly as well for constipation (Table 2). have been resolved with the above steps, the original studies have been re-inspected. The problem with data extractions of In the long-term over half of the patients experienced such studies has been detailed in the previous study [8]. blurred vision with flupenthixol and over one fifth with flu- Simple frequencies, proportions and confidence intervals phenazine. Over a third of the patients experienced constipa- were calculated using the method recommended by Wilson tion with fluphenazine. Dry mouth was seen in over half of [9]. the patients with flupenthixol and fluphenazine while it was seen with a third of the patients for pipotiazine depot. The RESULTS rates of increased salivation and urinary retention for flupen- thixol were similar to that of placebo. Again nasal stuffiness, In total 7 reviews of depot antipsychotics were included. hyperthermia, tachycardia and confusion were reported only In addition there were some data on depot antipsychotics in the placebo arm (Table 3). from 46 reviews which compared oral drugs with other typi- cals or atypicals but did not specifically mention that they DISCUSSION used depot. We included only the trials arms which reported data on depot medications. This is a comprehensive review looking into the anticho- linergic side effects of long-acting antipsychotics. The pau- There were data on anticholinergic side effects for brom- city of comparisons between long-acting injectable first- and peridol depot, flupenthixol depot, depot fluphenazine, flus- second-generation antipsychotic agents makes this review pirilene decanoate, depot methylperidol, depot pipotiazine useful as this topic has received limited attention in the lit- palmitate and long-acting risperidone. erature but certainly relevant for the outcome of patients. Although many of these reviews did include studies re- The study has included all the depot antipsychotic found in porting anticholinergic effects, they also included studies in Cochrane trials at the time our study was completed. which anticholinergic effects were not reported. For exam- The data was checked twice to ensure accuracy. All data ple, in the review ‘Depot flupenthixol decanoate for schizo- were collected from the Cochrane reviews which select stud- phrenia and other psychotic disorder’ only two out of the 15 ies using rigorous criteria to ensure quality. Our study was included studies reported anticholinergic effects. 13 out 15 also inexpensive as all the data was free for us to access on- included studies had no data reported or recorded. line in the