Psychiatry Research EG

Despite the development of effective medications for the treatment of schizophrenia, many people do not respond adequately. To address this problem, the use of two or more antipsychotics simultaneously is a commonly used treatment strategy. Although the use of antipsychotics in combination is common in clinical practice, the risks and benefits have not been evaluated systematically to date. The evidence base behind antipsychotic polypharmacy is limited and its use has been considered both ‘a therapeutic option’ and ‘a dirty little secret’ [1,2]. According to the procedural manual for the schizophrenia module of the Texas Algorithm, antipsychotic polypharmacy is considered only after trials with four atypical antipsychotics, including clozapine, have failed [3]. However, because new-generation antipsychotic medications appear to have a different efficacy profile compared with both conventional agents and each other, there may be a rationale behind the use of antipsychotic polypharmacy. Adding conventional agents to typical ones may be to attain a more rapid onset or to ‘top up’ the effect, as well as in cross tapering situations in which the patient becomes stuck on the combination therapy [1,4]. Data from a Graylands Hospital drug utilization review in November 2007 showed that 55% of all inpatients were prescribed two or more antipsychotics. There has been an increasing trend toward antipsychotic polypharmacy since 2002, during which 37% of patients were receiving polypharmacy [5]. This is consistent with data collected overseas, where prevalence rates for the treatment of patients with two or more antipsychotics simultaneously range from 10 to 64%. It was also reported that 25% of patients with schizophrenia may be receiving antipsychotic polypharmacy mainly as a combination of an atypical and a conventional agent [1,4]. In a study in Australia, 47% of patients received prescriptions for two antipsychotic medications and 8% received prescriptions for three medications [6]. A study in Australia examining people receiving outpatient treatment for schizophrenia showed a 13% rate of multiple antipsychotic prescription use [7]. One Japanese study indicated that the rate of antipsychotic polypharmacy exceed 90% [8]. A recent study in the UK showed an intermediate rate of 30% [9]. There is controversy about positive and negative effects of antipsychotic combination. When studying the combination of clozapine and risperidone [10], the authors concluded that it is safe, well tolerated, and also improves overall symptoms. The same conclusion was drawn for the combination of clozapine and sulpiride [11]. Conversely, the use of polypharmaceutical combinations in treatment- resistant schizophrenics is not always effective. One study published in 2004 compared olanzapine monotherapy with combination therapy with olanzapine and sulpiride and found no significant difference in positive or negative symptoms [12]. Similar conclusions were reported in studies in the combination of risperidone and clozapine [13,14]. As polypharmacy is becoming more widespread, concerns regarding its safety have been raised. Other concerns, including increased rate of side effects, pharmacokinetic interactions, reduced adherence to complex medication regimens, and increased costs, have also been raised. Difficulties with respect to dose adjustments and longterm effects have also been taken into consideration [15]. Individuals with a diagnosis of schizophrenia are at higher risk of cardiovascular morbidity and mortality than those belonging to the general population [16]. Higher rates of newonset diabetes compared with those in the general population and increased risk of physical disease leading to natural death were also reported in schizophrenic individuals [17]. Sudden death due to prolongation of the QT interval was also reported in both the typical and atypical antipsychotic groups [18]. Other concerns include tardive dyskinesia, excessive sedation, increased prolactin levels, postural hypertension, and anticholinergic and metabolic adverse effects [19]. Other studies [20] considering the complex relationship between antipsychotic use and mortality have suggested that cardiovascular risk is inversely associated with the intensity of use of antipsychotic drugs, whereas Bralet et al. [21] reported higher mortality rates among schizophrenic patients administering higher doses of antipsychotics