TITLE: Atypical Antipsychotics for the Treatment of Schizophrenia: a Review of Combination Therapy and High-Dosing Strategies

Home , Sulpiride

TITLE: Atypical Antipsychotics for the Treatment of Schizophrenia: A Review of Combination Therapy and High-dosing Strategies

DATE: 10 February 2010

CONTEXT AND POLICY ISSUES:

Schizophrenia affects about 0.6% of the population.1 This serious mental illness is a cluster of disorders that alters a person’s perception, thoughts, affects, and behavior.2 Schizophrenia typically presents in young adults; relapses of acute episodes can occur during the lifespan of affected individuals.1 A high proportion (about 80%) of individuals presenting with a “first episode of psychosis” will relapse within 5 years.2 Diagnostic criteria for schizophrenia are currently based on the latest revisions of either the World Health Organization International Statistical Classification of Diseases and Related Health Problems (ICD-10) or the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders (DSM-IV).2

Pharmacotherapy with antipsychotic medications is an essential component of the treatment plan of most individuals with schizophrenia.1 However, despite advances in pharmacotherapy since the 1950’s, up to a third of persons with schizophrenia have a poor response to antipsychotic medications.2 Surveys of prescribing practices in the United Kingdom (UK) showed that the use of doses higher than the ones usually recommended is commonly encountered, either when antipsychotic agents are used alone or in combination with another antipsychotic medication.2 Also, although combination therapy with two antipsychotic agents is not recommended in current clinical management guidelines,1 with the exception of combination therapy with clozapine,2 it appears this practice is not uncommon.2,3 Data from UK, USA, and Canada show that the proportion of patients treated with more than one atypical antipsychotic (AAP) increased over the years.2,4,5 Data from British Columbia indicates that the rate of antipsychotic polypharmacy increased between 1996 when an estimated 28% of patients discharged from hospital were on polypharmacy, compared to 45% in 2000. For patients using clozapine, the rate of polypharmacy increased from 22% in 1996 to 53% in 2000.5 Reasons identified for this increasing prevalence include the use of as required (PRN) medication, the gradual switch from one antipsychotic to another one, as well as the combination of two antipsychotic medications to achieve greater therapeutic response when there has been an unsatisfactory response to a single antipsychotic.2 Overall prevalence rates of antipsychotic

Disclaimer: The Health Technology Inquiry Service (HTIS) is an information service for those involved in planning and providing health care in Canada. HTIS responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources and a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. HTIS responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report.

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polypharmacy range from 4% to 58%,3 and rates up to 69%5 have been reported depending on treatment setting and patient population.

To inform both clinical practice and reimbursement policies, there is a need to evaluate the scientific evidence supporting recent changes in the use of antipsychotic medications for the treatment of schizophrenia. This report will provide a summary of the evidence on the clinical impact of using AAP dual therapy versus monotherapy as well as impact of using AAP high- dosing strategies. Target populations include adolescents (age 13 to 17 years) and adults (age 18 years and older) with schizophrenia (as defined by DSM-IV) or a first psychotic episode. Table 1 lists the AAPs included in this assessment, along with the usual maximum dose as defined in the Canadian Compendium of Pharmaceutical and Specialties (CPS).6

Table 1: Available Atypical Antipsychotic Agents in Canada

Generic Name Trade Name Manufacturer Maximum Dose Aripiprazole Abilify Bristol Myers Squibb 30 mg/day Clozapine* Clozaril Novartis 600-900 mg/day Olanzapine* Zyprexa, Zypexa Zydis Lilly 15 mg/day Paliperidone Invega Janssen-Ortho 12 mg/day Quetiapine* Seroquel, Seroquel XR AstraZeneca 600-800 mg/day Risperidone* Risperdal, Risperdal Janssen-Ortho 8-16 mg/day (oral) oral solution, Risperdal M-tab, Risperdal 50mg every 2 weeks Consta (IM L-A injection) Ziprasidone Zeldox Pfizer 160 mg/day * Generic drug products available for these AAPs; L-A: long-acting

In addition to the AAPs listed in Table 1, we also included asenapine (Saphris, from Schering- Plough) which is an AAP recently approved by the FDA in the USA but which is not yet available in Canada. The usual maximum dose for this drug is 20 mg/day.7

RESEARCH QUESTIONS:

1. How does combination therapy with atypical antipsychotics (including use of another atypical or a traditional antipsychotic as the second agent), compare with atypical antipsychotic monotherapy in terms of clinical benefits and harms?

2. What is the comparative clinical effectiveness of atypical antipsychotic high-dosing strategies (defined as the use of daily doses at the upper end or above the maximum recommended dosing range)?

METHODS:

A limited literature search was conducted on key health technology assessment resources, including OVID’s Medline, the Cochrane Library (Issue 3, 2009), University of York Centre for Reviews and Dissemination (CRD) databases, ECRI, EuroScan, international health technology assessment agencies, and a focused Internet search. The search was limited to English language articles published between 2005 and December 2010. Filters were applied to limit the

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retrieval to health technology assessments, systematic reviews, meta-analyses, and randomized controlled trials.

HTIS reports are organized so that the higher quality evidence is presented first. Therefore, health technology assessments, systematic reviews, and meta-analyses are presented first. These are followed by randomized controlled trials (RCTs) designed to compare an AAP to another antipsychotic drug (whether AAP or a traditional antipsychotic; TAP). Of note, only RCTs described as using a double-blind design were considered for inclusion in this rapid assessment. Also, for either of the two research questions described above, any RCT included in at least one of the included systematic reviews was not appraised and summarized separately.

The Oxman Guyatt tool was used to measure quality of systematic reviews8 whereas the Jadad scale was used to assess the quality of the RCTs.9

SUMMARY OF FINDINGS:

A total of 15 studies addressing the two research questions were included in this synthesis. Among these, a recent guidance document on the treatment of schizophrenia from the National Institute for Health and Clinical Excellence (NICE), four systematic reviews, and two RCTs address the first question about AAP dual therapy versus monotherapy and three systematic reviews and five RCTs address the second question about high-dosing of AAPs.

Research question # 1: How does combination therapy with atypical antipsychotics (including use of another atypical or a traditional antipsychotic as the second agent), compare with atypical antipsychotic monotherapy in terms of clinical benefits and harms?

Health technology assessments

In March 2009, NICE published an updated version of its National Clinical Practice Guideline on Schizophrenia.2 Several aspects of the treatment of this disease were addressed, including non- pharmacological interventions. Several systematic reviews were conducted to inform research questions related to these different therapies. The systematic reviews conducted in the NICE Guideline can generally be considered of high quality. An alternative method was developed by authors of this NICE document to answer research questions for which high-quality evidence was absent. This approach was based on informed consensus among the Guideline Development Group, which could be more prone to bias.2

The NICE Guideline conducted a systematic review to address the augmentation therapy of clozapine with other antipsychotic medication. Six trials were included and five of these studied AAPs available in Canada. All five studies included a mix of inpatient and outpatient settings and subjects met the DSM-IV criteria for schizophrenia. One RCT compared clozapine plus aripiprazole with clozapine plus placebo, and the four others compared clozapine plus risperidone with clozapine plus placebo.

Of note, the sixth RCT compared clozapine plus sulpiride (a TAP available in UK) versus clozapine plus placebo. The authors of the NICE Guideline reported that these six RCTs

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included 252 participants whose condition was not adequately responding to clozapine treatment. They concluded that there is some evidence that clozapine augmentation therapy with a second antipsychotic may improve both total and negative symptoms if administered for an adequate duration.2

Based on these findings, the authors recommended that people with schizophrenia whose illness has not responded adequately to clozapine used at an optimized dose and who are otherwise well managed (i.e. diagnosis is confirmed, there is good adherence to antipsychotic medication treatment as well as co-therapy with psychological treatment), addition of a second antipsychotic medication which does not compound the common adverse effects of clozapine may be considered. An adequate trial of such an augmentation may require 8-10 weeks of treatment.2 The NICE Guideline on the treatment of schizophrenia provided one other recommendation concerning people with a first psychotic episode. It was recommended to avoid initiating regular combined antipsychotic medication, except for short periods (e.g. when changing medication).2 This recommendation is not based on a clearly defined a priori research question and as such could have been based on informal consensus among the NICE Guideline Development Group rather than evidence. Of note, although the conclusion regarding the clinical advantage of clozapine dual therapy when used for at least 8 – 10 weeks is supported by a high-quality systematic review, the authors did not report any summary or pooled estimate, preventing the appreciation of the magnitude of this clinical advantage.

Systematic reviews and meta-analyses

In 2007, Paton et al. published a meta-analysis on the effect of augmentation therapy with a second antipsychotic drug in patients with schizophrenia who partially responded to clozapine monotherapy.10 The quality of this meta-analysis was rated as high, with the possibility of minor flaws. Four RCTs as well as eight open-label studies were included. Based on our a priori selection criteria, we only reported on the meta-analysis of the four RCTs, which were also included in the NICE Guideline. One RCT compared clozapine plus sulpiride with clozapine plus placebo and three RCTs compared clozapine plus risperidone with clozapine plus placebo.

Sulpiride is a TAP which is not available in Canada; however, Paton et al. did not conduct separate analysis based on the drug added to clozapine. When all four RCTs were combined (total of 166 subjects), no advantage of augmentation therapy over monotherapy with clozapine was identified in terms of change in either the Brief Psychiatric Rating Scale (BPRS) or Positive and Negative Syndrome Scale (PANSS) scores. Standardized mean difference (SMD) in the BPRS/PANSS total scores from baseline was - 0.10 [95% confidence interval (CI): - 0.70 to 0.50]. As this analysis was associated with statistically significant heterogeneity (I2=70.9%), which indicates that included studies may not be similar in their design or conduct, authors conducted subanalyses of the data based on duration of treatment as this approach was not associated with heterogeneity (I2=0%). Combining data from the two RCTs which lasted 10 weeks or more produced a response (≥20% reduction in BPRS/PANSS score) in favour of clozapine augmentation compared with clozapine monotherapy (Table 2). When the two RCTs of less than 10 weeks were combined, no difference was observed. The same pattern was reported when absolute change in BPRS/PANSS total scores from baseline was used as the outcome measure (Table 2).

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Table 2: Outcome of the RCTs Lasting 10 Weeks or More and Less Than 10 Weeks Included in Paton et al.10

Dual Therapy vs. Monotherapy Trials ≥ 10 weeks Trials < 10 weeks > 20% reduction in PBRS/PANSS Response rate 42% vs. 9% 26% vs. 27% Relative risk (95% CI) 4.41 (1.38 to 14.07) 0.59 (0.27 to 1.30) Absolute change in BPRS/PANSS Standardized mean - 0.53 (-1.06 to 0.00) 0.33 (-0.60 to 1.27) difference (95% CI) BPRS: Brief Psychiatric Rating Scale; CI: confidence interval; PANSS: Positive and Negative Syndrome Scale

There are a number of limitations for this meta-analysis. First, authors did not report the estimated response rate based on the particular antipsychotic being added to clozapine which prevents determining the effect of specific combinations (e.g. risperidone plus clozapine, versus clozapine monotherapy). The authors however reported that analyzing data by drug did not remove the heterogeneity (I2=57.5%), which suggests that combining all risperidone trials may not lead to fully reliable findings, especially given the small number of trials and subjects. Also, authors stated that the total sample size obtained by combining the four augmentation RCTs is too small to reliably detect any serious and infrequent adverse effects; they stated that adverse effects from using augmentation therapy are predictable from the pharmacology of the augmenting drug, with extrapyramidal symptoms (EPS) and increased prolactin levels being the most common.10 Acknowledging these limitations, findings from Paton et al. are supported by the NICE Guideline recommendations which states that trials of adequate duration (8-10 weeks) should be used when clozapine augmentation therapy is deemed to be necessary.2

In 2009, Taylor and Smith11 published an updated version of the meta-analysis by Paton et al.10 The quality of their meta-analysis was rated as high, with the possibility of including minor flaws. A total of 10 RCTs evaluating the effect of augmentation therapy in persons with schizophrenia having inadequate response to clozapine monotherapy were included. Among these, seven were published in full and the remaining three were available in abstract. Taylor and Smith were able to obtain outcome data from these three unpublished trials by contacting the investigators. A number of different antipsychotics were used as the add-on agent in the included trials. Additions to clozapine included aripiprazole, chlorpromazine, haloperidol, risperidone, and sulpiride.

Overall, findings from Taylor and Smith are consistent with those of Paton et al. Using the change in PANSS/BPRS score, they found that clozapine augmentation therapy was associated with a statistically significant, but small, improvement in symptoms (SMD: -0.180; 95% CI: - 0.356 to -0.004) over clozapine monotherapy. Although the level of heterogeneity observed in the main analysis was not very high (I2=33.5%), authors conducted a subanalysis based on duration of therapy. Pooling of studies lasting 10 weeks or longer showed a small but statistically significant advantage of clozapine combination therapy (SMD: -0.243; 95% CI: - 0.480 to -0.005) whereas pooling of studies of shorter duration did not. When the effect sizes of the two subanalyses were compared, statistical significance was not reached (P=0.31). A meta- regression analysis also showed no association between study duration and outcome. A further sub-analysis failed to show any statistical difference in the risk of treatment withdrawal between the use of augmentation therapy and monotherapy (RR: 1.261; 95% CI: 0.679 to 2.345). These

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additional findings further support the relatively small size of the clinical advantage of clozapine augmentation therapy. Limitations of this meta-analysis include the absence of subanalysis based on the added antipsychotic which prevents determining whether any difference exists based on the antipsychotic added to clozapine. In addition, there was an absence of data on harm risk. Also, outcome data is limited to symptom control measured with PANSS and BPRS as opposed to patient-relevant outcomes.

In 2009, Barbui et al. published a meta-analysis aiming at addressing whether the addition of a second antipsychotic drug improves clozapine response.12 They included both double-blind RCTs as well as open-label RCTs in their analyses and conducted subanalyses of double-blind RCTs to determine the impact of study design on treatment effect estimates. They also conducted subanalyses by trial duration (< 10 weeks versus ≥ 10 weeks). In this rapid assessment, we focused on the results from the double-blind RCTs. The quality of the meta- analysis by Barbui et al. was rated as high. The same four RCTs as in the NICE report adding risperidone to clozapine were included, as well as the RCT adding sulpiride. Amisulpride (not available in Canada) was also added to clozapine in one additional RCT.

Pooling of outcome data from the six double-blind RCTs did not show a statistically significant advantage of combination therapy over monotherapy for change in PANSS or BPRS scores or proportion of patients with no clinically significant response (Table 3). Subanalyses by trial duration reported no advantage for clozapine combination therapy both in short and long follow- up RCTs for symptom control. In terms of proportion of patients with no clinically significant response, there was no statistically significant advantage for clozapine combination therapy in short duration trials, whereas a clinical advantage for clozapine combination therapy was observed in the longer follow-up RCTs (Table 3).12 Of note, pooling of data from open-label RCTs tended to favour clozapine combination therapy for most of the outcome measures and subanalyses, which suggest that less robust study design may amplify the effect of an intervention.

Table 3: Outcomes of Double-Blind RCTs and Subanalyses by Trial Duration in Barbui et al.12 Dual therapy vs. Monotherapy All trials < 10 weeks ≥ 10 weeks Symptom control (PANSS and BPRS - 0.12 0.05 -0.49 score); SMD (95% CI) (- 0.57 to 0.32); (- 0.51 to 0.63) (- 1.09 to 0.10) I2=63.1% Proportion patients with no clinically 0.91 1.02 0.66 significant response; RR (95% CI) (0.75 to 1.11); (0.88 to 1.19) (0.49 to 0.88 I2=51.3% BPRS: Brief Psychiatric Rating Scale; CI: confidence interval; PANSS: Positive and Negative Syndrome Scale; RR: relative risk; SMD: standardized mean difference

As for the other meta-analyses described, the same limitations in terms of the number of subjects studied (total of 230 participants for all double-blind RCTs), the combination of studies using different antipsychotics as the add-on agent, as well as the lack of data on harm risks apply to this meta-analysis. Acknowledging the difference of results based on study design, Barbui et al. concluded that, from a clinical perspective, adding a second antipsychotic agent to patients not adequately responding to clozapine monotherapy has modest to no benefit.

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In 2009, a meta-analysis which included RCTs evaluating any combination of two antipsychotic agents (including non-clozapine agents) was published by Correll et al.13 The quality of the meta-analysis by Correll et al. was rated as high, with the possibility of including minor flaws. Authors stated that because no language restrictions were applied during the literature search, a number of previously unrecognized trials were identified. In total, Correll et al. included 19 RCTs in their meta-analysis. These comprised a total of 1,216 participants. However, because in nine of these RCTs, one antipsychotic combination therapy was compared with two monotherapy arms, separate analyses were done for each of the monotherapy arms, leading to 238 participants in the combination therapy arms being used twice in analyses. Among included RCTs, 15 (1,041 participants, 20 study arms) were categorized by Correll et al. as having a double-blind design. A sensitivity analysis was conducted to compare findings from double-blind RCTs with findings from open-label or single-blind RCTs. Analysis of data from the double-blind RCTs showed that combination therapy with two antipsychotic drugs was associated with a statistically significant reduction in the risk of “lack of efficacy”, as defined in each study (RR: 0.78, 95% CI: 0.65 to 0.93, P=0.005). These double-blind RCTs included clozapine plus TAP, clozapine plus AAP, and TAP plus TAP.

Comparing TAP plus TAP combination therapy versus TAP monotherapy is outside the scope of this rapid assessment. However, as Correll et al. did not report findings from these RCTs separately from the RCTS using an AAP-based combination therapy strategy, it was not possible to exclude this set of comparisons from our assessment. Correll et al. also conducted a sensitivity analysis of RCTs based on their follow up period. They reported that RCTs which lasted 10 weeks or more were associated with a clinical advantage (in terms of risk of lack of efficacy) in favour of antipsychotic combination therapy strategies (RR: 0.65, 95% CI: 0.54 to 0.78, P<0.00001), compared to those which lasted less than 10 weeks. Four other sensitivity analyses done by Correll et al. are relevant to this rapid assessment (Table 4).

Table 4: Risk of “Lack of Efficacy” as Defined in Each of the RCTs Included in Correll et al.13 Subanalysis RR (95% CI) P value Cotreatment including clozapine 0.75 (0.61 to 0.93) 0.008 Cotreatment not including clozapine 0.59 (0.28 to 1.25) 0.17 AAP + AAP versus AAP monotherapy 0.98 (0.87 to 1.10) 0.70 AAP+TAP versus AAP monotherapy 0.59 (0.40 to 0.88) 0.009 AAP – atypical antipsychotic; TAP – traditional antipsychotic

The sensitivity analyses and pooled estimates are derived from a number of study types, and therefore interpretation of these findings should be done with caution. Lastly, in addition to the wide range of combination therapy strategies evaluated by Correll et al., which are potentially associated with significant heterogeneity, an additional limitation from this meta-analysis is the lack of conclusive data on the risk of adverse effects [authors only reported combined data from two RCTS showing that clozapine combination therapy with sulpiride or risperidone was associated with statistically significant higher prolactin levels (weighted mean difference (WMD): 65.1, 95% CI: 51.1 to 79.1, P<0.00001)].13 The latter limitation is likely the result of the design of RCTs which studied antipsychotic combination therapy as these typically enrolled a relatively small number of participants and only lasted a few weeks. Such design does not allow observation of the nature and frequency of serious drug-induced adverse events.

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Randomized controlled trials

In April 2009, Henderson et al. published a 10 week placebo-controlled double-blind crossover RCT to examine the effect of aripiprazole on weight, lipids, glucose metabolism, and psychopathology scores in overweight and obese subjects with schizophrenia treated with a stable dose of olanzapine.14 The rationale for this study was that a limited number of earlier reports indicated that adding aripiprazole to olanzapine may help manage some of the metabolic adverse effects of olanzapine.14 A total of 16 subjects meeting DSM-IV diagnostic criteria for schizophrenia and schizoaffective disorder were initially recruited; 14 completed the 10-week trial. The quality of this exploratory trial was rated as moderate (3 points on a total of 5), with unclear allocation concealment. Authors measured a broad mix of metabolic parameters. Table 5 presents those measures for which the co-administration of aripiprazole to olanzapine was associated with a statistically significant improvement over olanzapine monotherapy.

Table 5: Statistically Significant Improvements with Olanzapine and Aripiprazole from Henderson et al.14

Olanzapine + Olanzapine + P value placebo aripiprazole (between group difference) Changes in weight (lb) 2.1 ± 3.3 - 2.9 ± 4.7 0.003 Change in body mass index (kg/m2) 0.3 ± 0.5 - 0.4 ± 0.7 0.003 Change in triglycerides (mg/dL) 47.6 ± 52.7 - 51.7 ± 78.2 0.001 Change in VLDL-1* and VLDL-2* 2.7 ± 4.6 - 1.9 ± 4.7 0.012 * Main fractions of very low-density lipoprotein cholesterol (VLDL-C) responsible for carrying triglycerides.

Henderson et al. also measured a number of psychopathology scores including PANSS. They reported no significant change in total PANSS score or subscores between subjects treated with olanzapine and aripiprazole combination versus olanzapine monotherapy. A number of study limitations were identified by authors including the sample size of 16 and the duration of 10 weeks.14 Two other potential limitations include the crossover design of this trial which may be a source of bias due to the potential for carry-over effects of the intervention, and that this RCT was supported by an unrestricted grant from Eli Lilly and Co, the manufacturer of olanzapine.

In October 2009, Kane et al. published a 16 week multicentre, double-blind RCT comparing adjunctive therapy with aripiprazole in subjects with schizophrenia inadequately treated with quetiapine or risperidone monotherapy.15 A total of 323 outpatient subjects currently using risperidone or quetiapine and meeting DSM-IV diagnostic criteria for schizophrenia or schizoaffective disorder were randomly assigned to either aripiprazole or placebo. The quality of this RCT was rated as moderate (3 points on a total of 5), with unclear allocation concealment. Authors conducted their main analysis comparing aripiprazole add-on therapy or placebo versus pooled data from patients using quetiapine or risperidone monotherapy. Subgroup analyses were however conducted comparing aripiprazole add-on therapy or placebo versus quetiapine and risperidone monotherapy for some efficacy or harm outcome measures. The main efficacy outcome measure was mean changes from baseline to endpoint in PANSS total score. Several secondary outcome measures were also evaluated, such as the PANSS positive and negative subscales as well as the Clinical Global Impressions – Improvement scale (CGI-I score). Harm

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assessment included adverse events as well as several metabolic parameters. When comparing aripiprazole add-on therapy to either quetiapine or risperidone monotherapy, there was no statistically significant difference in the mean change from baseline to week 16 in PANSS total score between aripiprazole adjunctive therapy and placebo groups (-8.8 versus - 8.9, P=0.942).When data was compared based on antipsychotic subgroup (quetiapine or risperidone) there was also no statistically significant difference between aripiprazole add-on and placebo groups in the change in PANSS total score at 16 week. There were no statistically significant differences in any of the secondary efficacy outcome measures. Comparison of adverse events occurring in 5% or more subjects indicated that fatigue (8.3%), headache (7.1%), and insomnia (6.5%) were the three most common ones encountered with aripiprazole add-on therapy whereas headache (8.5%), insomnia (8.5%), and akathisia (restlessness; 7.2%) were the three most frequent adverse events encountered in subjects using placebo. No statistical analysis was reported for adverse events, but was conducted for metabolic parameters. No statistically significant differences were observed for metabolic parameters with the exception of serum prolactin levels for which aripiprazole adjunctive therapy was associated with a statistically significant decrease from baseline compared to subjects using placebo (-12.6 ng/ml versus -2.2 ng/ml, P<0.001). Subgroup analysis showed that, compared to subjects using placebo, those using adjunctive therapy with aripiprazole experienced a statistically significant decrease in mean serum prolactin levels in the risperidone subgroup (-18.7 ng/ml versus -1.9 ng/ml, P<0.001) but not in the quetiapine subgroup (-3.01 ng/ml versus 0.15 ng/ml, P=0.104). A limitation noted by authors of this RCT is the fact that there was no requirement for a minimum baseline PANSS total score, potentially leading to enrolling mildly symptomatic patients who therefore would not be representative of patients who would typically be considered for antipsychotic adjunctive therapy.15 Financial support for this RCT was provided by Bristol-Myers Squibb (USA) and Otsuka Pharmaceutical Co, Ltd (Japan); both manufacturers have collaborated to the development of aripiprazole.16

Research question # 2: What is the comparative clinical effectiveness of atypical antipsychotic high-dosing strategies (defined as the use of daily doses at the upper end or above the maximum recommended dosing range)?

For this question, the literature search tried to identify RCTs examining high dose versus lower doses of a particular AAP or high dose versus high dose of two distinct AAPs.

Systematic reviews and meta-analyses

Systematic reviews which met our inclusion criteria provided information on the comparative clinical effects of using high-dose of a particular AAP versus using lower doses of the same medication. None provided information on the comparative clinical effects of using high-dose of two different AAPs.

Three Cochrane reviews published in 2009 were identified. Li et al. published a Cochrane review aimed at determining the risperidone dose response relationship in the treatment of schizophrenia and schizophrenia-like psychosis.17 The quality of this systematic review and meta-analysis was rated as high. In order to address the main research question, Li et al. stratified interventions based on pre-defined dosage categories: • Ultra-low dose: < 2 mg/day • Low-dose: 2 - 4 mg/day

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• Standard low-dose: 4 - 6mg/day • Standard high-dose: 6 – 10 mg/day • High-dose: ≥ 10 mg/day

Given the research question relevant to this rapid assessment concerns determining the clinical impact of using antipsychotic high-dosing strategies and that we pre-defined high-dose for risperidone as doses between 8 and 16 mg/day (Table 1), we focused on the findings from Li et al. which related to using risperidone high-dose (≥ 10 mg/day).

Three RCTs using a dose of risperidone of 10mg and greater were included. Data from a total of 1,885 participants were considered in the analysis. Li et al.17 reported findings based on several types of outcomes in over 100 comparisons; only the outcomes and comparisons with statistically significant results are presented in Tables 6 and 7.

Table 6: Statistically Significant Outcomes of High-Dose Risperidone Compared with Lower Doses (Li et al17)

Outcome Relative risk (95% CI) Leaving study early Due to insufficient response HD vs. ULD: 0.66 (0.45 to 0.97) HD vs. LD: 0.48 (0.25 to 0.92) For any reason HD vs. LD: 0.43 (0.26 to 0.71) Due to adverse events HD vs SLD: 1.78 (1.03 to 3.09) Global state (CGI-I): “no clinically important HD vs LD: 0.64 (0.50 to 0.82) response” Global state (global evaluation): “no clinically HD vs SHD: 1.22 (1.00 to 1.51) important response” Mental state (PANSS): “no clinically important HD vs. SHD: 1.24 (1.05 to 1.47) response Risk of movement disorder or EPS HD vs SHD: 1.79 (1.01 to 3.18) HD vs LD: 2.22 (1.19 to 4.14) Risk of any drug adverse event HD vs LD: 1.67 (1.09 to 2.56) HD vs SHD: 1.64 (1.07 to 2.51) CGI-I - clinical global impressions – improvement scale; HD - high dose; LD - low dose; PANSS - positive and negative syndrome scale; SHD – standard high dose; SLD - standard low dose; ULD – ultra low dose

Table 7: Statistically Significant Outcomes of High-Dose Risperidone Compared with Lower Doses (Li et al17)

Outcome Mean difference (95% CI) Mean change in PANSS score HD vs ULD: - 4.30 (-7.95 to -0.65) Mean change in PANSS positive symptom subscale HD vs ULD: - 2.30 (-3.41 to -1.19) Mean change in PANSS negative symptom subscale HD vs ULD: 9.60 (8.42 to 10.78) HD vs SLD: 10.60 (9.37 to 11.83) HD vs SHD: 10.30 (9.13 to 11.47) PANSS - positive and negative syndrome scale; HD - high dose; SHD – standard high dose; SLD - standard low dose; ULD – ultra low dose

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Over 100 different comparisons were analyzed by Li et al and only sixteen of these were associated with a statistically significant difference; these indicated that the use of high-dose risperidone would need to be tailored to certain clinical situations. The statistically significant differences reported above were sometimes in favour of the high-dose regimen:

• The risk of leaving the study early for insufficient response or for any reason was lower with high-dose risperidone versus ultra-low dose and low dose risperidone. • The risk of “no clinically important response” as measured by CGI-I was lower with high- dose versus low-dose risperidone. • The use of high-dose risperidone was associated with a reduction in PANSS total score and positive symptoms subscale (note: a reduction in these scores indicate clinical improvement), compared with the use of ultra-low dose of risperidone.

Other comparisons were not in favour of the high-dose regimen:

• The risk of leaving the study early because of adverse events was higher with high-dose versus standard lower dose risperidone. • The risk of “no clinically important response” in global state or mental state, as measured by “global evaluation” and PANSS score was higher with high-dose versus standard higher dose risperidone. • The use of high-dose risperidone was associated with an increase in PANSS negative symptoms subscale (note: increase in this score indicates worsening of clinical status) versus most of the lower dose regimens. • The use of high-dose risperidone was associated with a higher risk of EPS and overall adverse events versus low dose and standard high-dose regimens.

A number of limitations were identified by authors of the review. All studies but one did not describe blinding in detail and only one study reported that its funding source was a pharmaceutical company.17

The second relevant Cochrane review was published by Nussbaum and Stroup. They aimed at comparing the effects of paliperidone with any other treatment for schizophrenia.18 The quality of this systematic review and meta-analysis was rated as high. This review includes both placebo-controlled and active controlled RCTs. Some of these RCTs used fixed-doses (3mg, 6mg, 9mg, 12mg, and 15mg) whereas others used flexible dose regimens. Subjects enrolled in the included RCTs met DSM-IV criteria for schizophrenia. Although not stated as an objective in their initial protocol, authors undertook a sensitivity analysis on the effect of increasing doses of paliperidone versus placebo.18 The statistically significant findings from this sensitivity analysis are presented in Table 8.

Atypical Antipsychotics for the Treatment of Schizophrenia 11

Table 8: Statistically Significant Findings of Increasing Dose of Paliperidone Compared with Placebo18

Outcome Relative Risk (95% CI) Relapse (recurrence of psychotic symptoms) 12mg/day 0.45 (0.22 to 0.94) >30% reduction in total PANSS score 3 mg/day 0.74 (0.62 to 0.87) 6 mg/day 0.69 (0.58 to 0.82) 9 mg/day 0.68 (0.59 to 0.79) 12 mg/day 0.64 (0.48 to 0.85) 15 mg/day 0.57 (0.46 to 0.71) Leaving study early for any reason 3 mg/day 0.73 (0.57 to 0.92) 6 mg/day 0.74 (0.62 to 0.88) 9 mg/day 0.60 (0.49 to 0.73) 12 mg/day 0.60 (0.49 to 0.73) 15 mg/day 0.46 (0.34 to 0.64)

Among the fixed-doses RCTs, only the 12mg/day paliperidone regimen was found to produce a statistically significant reduction in relapse versus placebo. A clinically important change in global state (> 30% reduction in total PANSS score) was measured in fixed-dose RCTs and reported a favourable effect of paliperidone over placebo with comparatively greater differences in global improvement for higher doses of paliperidone. The same trend was observed for the risk of leaving the study early for any reason (Table 8).

When the same sensitivity analysis was undertaken for RCTs comparing paliperidone to olanzapine 10mg/day, one statistically significant result was obtained: subjects randomized to 3mg/day of paliperidone were more likely to leave the study early (RR: 1.44, 95% CI: 1.04 to 1.98) than those randomized to olanzapine. As included RCTs comparing paliperidone to either risperidone or quetiapine did not use fixed doses, no sensitivity analyses were conducted to determine if there were dose effects. Of note, Nussbaum and Stroup reported two potential limitations of their review: i) they based their analyses on published data and unpublished data supplied by the study authors and the manufacturers, indicating potential for generating skewed estimates due to not being able to access all data, ii) all included studies were funded by the manufacturer of paliperidone.18 Lastly, the above sensitivity analyses were based on a small number of RCTs (varying from one to three, depending the comparison).

The third relevant Cochrane review was published by Duggan et al. and aimed at determining the clinical effects and safety of olanzapine compared with placebo, TAPs, and other AAPs for the treatment of schizophrenia.19 The quality of this systematic review and meta-analysis was rated as high. The authors included a subanalysis of placebo-controlled RCTs which assessed olanzapine dose-response relationship. This subanalysis was done for the outcome measure of “no important clinical response” which was defined as not reaching ≥ 40% reduction in psychotic symptoms measured by any scale (including PANSS and BPRS) by 6 weeks19: • 1 mg/day: RR: 0.98 (95%CI: 0.87 to 1.11) • 5 mg/day: RR: 0.94 (95%CI: 0.74 to 1.18)

Atypical Antipsychotics for the Treatment of Schizophrenia 12

• 10mg/day: RR: 0.82 (95%CI: 0.71 to 0.95) • 15 mg/day: RR: 0.74 (95%CI: 0.56 to 0.97)

Based on the findings of the systematic review, it appears the use of daily doses of 10 mg to 15 mg olanzapine was associated with statistically significant lower risks of “no clinical improvement” (failing to reach a ≥ 40% reduction in psychotic symptoms), over placebo. The intensity of the clinical improvement increased as the dose increased from 10 mg/day to 15 mg/day. Of note, this subanalysis was based on a small number of RCTs (one 15mg/day RCT and two 10mg/day RCTs). Also, it is not clear whether all participants of RCTs included in this review met the DSM-IV diagnostic criteria, which may lead to more heterogeneity. Finally, Duggan et al. stated that 69% of all included RCTs (38/55) reported funding from pharmaceutical companies. There is therefore a risk that the two RCTs on which the above subanalysis was conducted are subject to this potential source of bias.

Randomized controlled trials

The first set of trials which met our inclusion criteria for the second research question provided information on the comparative clinical effects of using high-dose of a particular AAP versus using lower doses of the same medication. The second set provided information on the comparative clinical effects of using high-dose regimens of two different AAPs.

Comparative clinical effects of using high-doses versus lower doses of a particular AAP

In 2008, Kinon et al. published findings from a double-blind RCT aiming at assessing the dose- response relationship of standard and higher doses of olanzapine in patients with schizophrenia.20 This 8-week, fixed-dose RCT compared three daily doses of olanzapine (10mg, 20mg, and 40 mg). A total of 599 subjects (age 18-60 years) meeting DSM-IV criteria for schizophrenia or schizoaffective disorder were enrolled. Study participants had suboptimal response to current treatment and patients meeting criteria for antipsychotic treatment resistance were excluded. The quality of this RCT was rated as moderate (3 points on a total of 5), with unclear allocation concealment. Baseline patient characteristics were similar among the three groups. The primary outcome measure was defined as mean change from baseline in PANSS total score. Secondary outcome measures included PANSS positive and negative subscales as well as other scales (e.g. CGI-I). All three dose groups had statistically significant improvement in PANSS total scores from baseline; no statistically significant dose-response relationship was observed between the three groups (P=0.295). The improvement in PANSS scores from baseline was -23.5 (SD 22.0) for 10 mg/day, -26.7 (SD 19.2) for 20 mg/day, and -25.7 (SD 19.5) for 40 mg/day.20

No statistically significant differences were observed between dosing regimen groups for any of the secondary outcomes.20 As no differences were observed in the planned analyses, authors of the study conducted a number of post-hoc regression analyses. These showed: • A significant statistical interaction was found between baseline PANSS and dose indicating better response at higher dose for patients with higher baseline PANSS values (P=0.023). • A significant statistical interaction between the status of antipsychotic medication use (no medication, TAP, AAP) before entering the study and dose of olanzapine used during the study (P<0.001) was reported. Study participants who were using an AAP at

Atypical Antipsychotics for the Treatment of Schizophrenia 13

randomization showed a statistically significant difference in PANSS score improvement between the three dose groups in favour of the higher dose group (P=0.026), compared to subjects who were either not using any antipsychotic medication (P=0.270) or who were using a TAP (P=0.879) at randomization. • A significant statistical interaction was found between dose and baseline symptom severity (P=0.001) for patients who were using an AAP at randomization indicating a better response at higher dose for patients with higher baseline PANSS values.

Among the various safety parameters and adverse effects measured during the RCT, statistically significant differences between dose groups are reported in Table 9.

Table 9: Statistically Significant Differences in Adverse Events Between Olanzapine Doses20

Adverse Effects Olanzapine dose Dose response P value 10 mg/day 20 mg/day 40 mg/day Fatigue (% of patients) 1.5 2.1 6.6 0.016 Dizziness (% of patients) 2.6 1.6 6.6 0.025 Weight [kg (SD)] (mean 1.9 (3.5) 2.3 (4.2) 3.0 (4.0) 0.003 change from baseline) Prolactin level [ng/ml (SD)] -10.5 (32.3) -1.7 (25.4) 4.9 (27.9) <0.001 (mean change from baseline)

A number of limitations were identified by authors of this RCT. The 8-week study duration may not have allowed enough time to assess the long-term change in metabolic parameters as well as the impact of the between group differences in weight gain. Findings from the post-hoc supplemental analyses were stated by the authors as “suggestive” of differences in the dose- response relationship for patients with more severe symptoms at the onset and who were using an AAP. In addition, the increased incidence of fatigue and dizziness with higher doses of olanzapine may have compromised study blinding.20 Additional limitations include the need to confirm findings from the post-hoc analyses as well as the fact that six of the 14 authors of the RCT (including the primary author) were employees and stockholders of Eli Lilly.

In 2006, Zhong et al. published the findings from an 8-week double-blind multicentre RCT comparing flexible-dose quetiapine (200-800 mg/day) with flexible-dose risperidone (2-8 mg/day) in patients with schizophrenia.21 The quality of this RCT was rated as moderate (4 points on a total of 5), with unclear allocation concealment. A total of 673 adult subjects meeting DSM-IV criteria were randomized. A subanalysis of treatment-emergent adverse events showed that in patients treated with quetiapine, the mean change from baseline in prolactin levels ranged from -25.98 ng/ml at doses less than 200 mg/day to -11.35 ng/ml at doses greater than 600 mg/day. In comparison, mean change from baseline in prolactin levels ranged from 9.33 ng/ml at doses of risperidone less than 2 mg/day to 36.98 ng/ml at doses of greater than 6mg/day21 (note: maximum dose range for risperidone defined in Table 1 is 8-16mg/day). Interpretation of this finding should be done with caution given the dose was not identified as a co-variate for the analysis of prolactin level adverse events in the study methods, no statistical analysis was performed, and there was no information regarding the sample size on which these findings were derived. Also, the two primary authors were or had been employed by

Atypical Antipsychotics for the Treatment of Schizophrenia 14

Astra-Zeneca and the study itself was funded by this pharmaceutical company (which manufactures quetiapine).

In 2006, findings from another study by Kinon et al. were published. This 24-week double RCT aimed to compare olanzapine with ziprazidone in patients with schizophrenia experiencing depressive symptoms. This RCT randomized 394 adult subjects to either olanzapine (10, 15, or 20 mg/day) or ziprazidone (80, 120, or 160 mg/day). All patients met DSM-IV criteria for schizophrenia or schizoaffective disorder and had scores on the Montgomery-Asberg Depression Rating Scale (MADRS) consistent with mild (or more severe) depression. Baseline characteristics were reported to be comparable for both treatment groups with the exception of more patients on ziprasidone (82.3% versus 70.8% for olanzapine) having used an antipsychotic at or within 30 days of study enrollment.22 The quality of this RCT was rated as low (2 points on a total of 5), with unclear allocation concealment. Although most of the analyses compared the entire olanzapine group to the entire ziprasidone group (mean or median daily doses of either olanzapine or ziprasidone not reported), three subanalyses evaluated the dose-response relationship.22 The discontinuation rate by dose (no statistical analysis reported for dose comparisons) of olanzapine was 50.0%, 64.6%, and 52.1% for 10 mg/day, 15 mg/day, and 20 mg/day respectively. The discontinuation rate for 80 mg/day, 120 mg/day, and 160 mg/day of ziprasidone was 72.1%, 67.2%, and 71.6% respectively. Between treatment group comparison showed that more patients on olanzapine completed the RCT [90/202 (44.6%)] than those on ziprasidone [57/192 (29.7%); P=0.003]. There was no statistically significant dose-response observed in olanzapine or ziprasidone treated patients (P>0.5 for all tests; actual proportions not reported) for improvement on the Calgary Depression Scale for Schizophrenia (CDSS) or MADRS scores. Finally, a dose response was not observed for the most common adverse events for patients treated with olanzapine (weight gain, dry mouth, headache) or ziprasidone (insomnia, nausea; actual proportions and P value not reported).

In view of the findings, it does not seem that a dose-response relationship exists when either olanzapine or ziprasidone is used in patients with schizophrenia and depression. Although dose-response analyses were planned a priori for two of the sub-analyses (impact on CDSS and MADRS scores, impact on adverse events), it should be noted that assessment of the dose response relationship was limited to a few outcome measures only. Also, for those performed, not all information was reported, which limits the ability to derive firm conclusions. Lastly, this RCT was funded by Eli Lilly and five of the six authors are employees of this company.

A study published in 2006 (Simpson et al.)23 aimed to compare the clinical effects of two doses of long acting (L-A) risperidone injection in a 52-week double-blind RCT. A total of 324 adult patients meeting DSM-IV criteria for schizophrenia or schizoaffective disorder were randomized to either 25 mg or 50 mg of intramuscular L-A risperidone every two weeks. Baseline characteristics were comparable between the two treatment groups.23 The quality of this RCT was rated as high (5 points on a total of 5), with adequate allocation concealment. Several clinical benefit and harm outcomes were measured through the 52 week trial. The primary endpoint was time to relapse. There was no statistically significant difference between patients receiving the 25mg dose regimen versus those receiving the 50 mg dose regimen in time to relapse (P=0.131). Although the numerical numbers tended to favour the 50 mg dosing group, there was also no statistically significant difference in the 1-year crude incidence of relapse between the two groups (25mg group: 21.6%; 50mg group: 14.9%, P=0.059]. There were no

Atypical Antipsychotics for the Treatment of Schizophrenia 15

statistically significant differences reported in other efficacy endpoint comparisons. In terms of adverse events, the only statistically significant between-group difference (P<0.001) was reported for baseline to endpoint increase in prolactin levels between the 25 mg group [from 24 µg/L (SD:27.5) to 33.7 µg/L (SD:27.4), p<0.05 from baseline] and for the 50 mg group [from 25.6 µg/L (SD:50.9) to 49.6 µg/L (SD:44.2), p<0.01 from baseline].23 Authors reported a limitation that relapse rates were lower than anticipated in the initial study power calculation which may possibly indicate that more subjects would have needed to be enrolled in the study.23 Another limitation is the fact that despite the high quality rating assigned to this RCT, seven of the eight authors were employed by the manufacturer of risperidone (Janssen, and related companies) and the study itself was funded by this company.

Comparative clinical effects of using high-dose regimens of two different AAPs

One RCT met our inclusion criteria for the analysis of high-dose regiments of AAPs. In 2008, Meltzer et al. published the findings of a 6-month double-blind RCT comparing high-dose olanzapine to high-dose clozapine in patients with treatment-resistant schizophrenia.24 The quality of this RCT was rated as moderate (4 points on a total of 5), with unclear allocation concealment. A total of 40 adult patients meeting DSM-IV criteria were randomized to either clozapine (flexible dose range of 300 – 900 mg/day) or olanzapine (flexible dose range of 25 – 45 mg/day). Of note, although the mean dose of clozapine at 6 months [564 mg/day (SD: 243)] did not meet the pre-defined criteria for high-dose clozapine in Table 1 (600-900 mg/day), the median dose did (700 mg/day). In comparison, the 6-months mean and median doses of olanzapine were 33.6 mg/day (SD: 11.2) and 40mg/day, respectively. These meet the pre- defined criteria for high-dose olanzapine from Table 1 (≥ 15 mg/day). In terms of efficacy, no statistically significant differences were reported between the two treatment groups in PANSS total scores measured from baseline to 6 weeks or 6 months [mean differences -1.90 (SE: 3.8), P = 0.61 and 0.41 (SE: 4.3), P = 0.92, respectively) as well as in most of the 29 secondary outcome measures (i.e. PANSS subscales and other psychopathology/cognitive scales or subscales). Statistically significant between group differences reported by Meltzer et al. (generally in favour of clozapine) are described in Table 10.

Table 10: Statistically Significant Differences Between High-Dose Clozapine and High- Dose Olanzapine for Secondary Outcomes and Tolerability Measures Reported by Meltzer et al24

Outcome Mean difference (SE) P value SANS-Attention at 6 weeks - 0.67 (0.3) 0.04 GAF at 6 months 7.61 (2.8) 0.01 WISC-R - Maze at 6 months - 3.14 (0.9) 0.02 VLL-DR at 6 weeks 2.14 (1.0) 0.04 VLL-DR at 6 months -2.47 (1.1) 0.04 Change in weight at 6 months - 12.29 (4.4) 0.01 Change in BMI at 6 months - 2.00 (0.71) 0.06 GAF: Global Assessment of Functioning; SANS: Schedule Assessment of Negative Symptoms; SE: standard error VLL-DR: Verbal List Learning Delayed Recall, WISC-R: Wechsler Intelligence Scale for Children Revised

Based on the findings, it would appear that the use of a median high-dose of clozapine (700mg/day) was generally associated with similar efficacy and cognitive benefit as the use of

Atypical Antipsychotics for the Treatment of Schizophrenia 16

median high-dose of olanzapine (40mg/day), with the exception of four secondary outcome measures. However, tolerability may not be similar, based on differences reported for two metabolic parameters. Key limitations noted by the authors of the study include the small sample size as well as the flexible-dose regimen which may not allow determination of dose- response effects to the same extent as a fixed-dose protocol would.24 Other limitations are the fact that this study was included based on the median dose comparison, as opposed to the mean dose comparison as well as despite lasting six months, this RCT does not provide an appreciation of the long-term metabolic risks (e.g. diabetes) associated with both treatments. In addition, this RCT was partially funded by Eli Lilly.

Limitations

With respect to the first research question about clinical impact of using AAP dual versus monotherapy, limitations specific to each of the included studies were highlighted in the findings summary. Overall, key limitations include:

• Evidence based on a small number of studies with robust design which included a relatively small number of subjects. For example, in the recent (2009) meta-analysis by Barbui et al12 which assessed the effect of clozapine add-on therapy, six double-blind placebo-controlled RCTs were retrieved. A total of 230 subjects had been enrolled. In terms of relevance to Canada, four of these RCTs compared clozapine monotherapy to clozapine + risperidone (Yagcioglu et al 2005, Josiassen et al 2005, Honer et al 2006, and Freudenreich et al 2007); these RCTs enrolled a total of 162 subjects. The two other RCTs used antipsychotic agent which are not available in Canada. • Because of the type of interventions and patients studied, summary and pooled estimates were associated with significant statistical heterogeneity which indicates the need for cautious interpretation of findings from these analyses and subanalyses • Most of the efficacy outcome measures studied in included reviews and RCTs were limited to symptom control, not patient relevant outcomes such as rate of hospitalization and capacity to maintain employment • There was a lack of data on harm risk associated with AAP dual therapy.

Concerning the second research question about clinical impact of using AAP high-dose strategies, limitations specific to each of the included studies were also highlighted in the findings summary. Among these, key limitations are:

• Missing data or data detail was often stated as an issue • The number of RCTs designed to evaluate dose-response of AAPs is small, particularly when interested in the impact of high-dosing strategies. For example, in their recent Cochrane review on risperidone dose in schizophrenia, Li et al17 retrieved three studies which employed a dose of risperidone of 10 mg/day or greater. These enrolled less than 1,000 subjects in total. We retrieved one true dose-response RCT.20 As a consequence, most of the dose-response relationship data came from sub-analyses or post-hoc analyses conducted by systematic reviewers or authors of RCTs. • Duration of several studies may have been too short (i.e. a few weeks) to assess the clinical impact of changes in metabolic parameters which may require several months to a few years to manifest • Funding from the manufacturer of the studied drug was common

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In addition to the above limitations, it is possible that the literature search time period (limited to the last five years) used in this rapid assessment failed to identify other potentially relevant studies given AAPs have been used in clinical practice since the early 1990’s. Finally, concerning the assessment of the clinical impact of high-dosing strategies, the definitions used for high-dose ranges in this rapid assessment were based on dosages from the Canadian product monographs and not from clinical experts.

CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING:

With respect to the first research question about clinical impact of using AAP dual therapy versus monotherapy, evidence indicates that adding an AAP to clozapine may be associated with a small to modest improvement in symptom control in patients not adequately responding to optimized monotherapy with clozapine. Based on the literature, to detect such potential clinical benefit, a trial of 10 weeks of combination therapy seems to be needed. Also, based on the most commonly studied add-on AAP (risperidone), dual therapy with clozapine may be associated with increased risk of elevated prolactin levels as shown in the included studies. The clinical impact of such increased prolactin levels was not measured in the included studies. As for the comparative efficacy of other types of antipsychotic combination therapy involving at least one AAP versus AAP monotherapy, the evidence is limited and overall remains inconclusive.

Concerning the clinical impact of using higher doses of an AAP, evidence is limited. Most of the evidence from well conducted systematic reviews and RCTs is derived from subanalyses and post-hoc analyses. These suggest that escalating doses of certain AAPs to the upper limit of the usual recommended dosing range (or higher, e.g. for olanzapine) may help controlling psychotic symptoms in certain patient subgroups, such as in patients with more severe baseline symptoms or with treatment resistant disease. However, given the nature of these subanalyses and post-hoc analyses, such findings can not be considered definitive at this time.

Combination therapy with two AAPs may occur in the treatment of schizophrenia. Based on the evidence reviewed, clozapine and risperidone may be the most commonly combined AAPs in dual therapy. The use of high doses of AAPs also may occur, and may be limited to patients with treatment-resistant disease. The limited information on both combination AAP therapy and high dose AAP may need to be considered when making decisions about these practices. Patient treatment history may also be a consideration.

PREPARED BY: Michel Boucher, BPharm, MSc, Lead – HTA Development Emmanuel Nkansah, BEng, MIS, MA, Information Specialist Health Technology Inquiry Service Email: [email protected] Tel: 1-866-898-8439

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