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A Systematic Review of Combination and High-Dose Atypical Antipsychotic Therapy in Patients with Schizophrenia [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2011 Dec. (CADTH Optimal Use Report, No. 1.1B.)

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A Systematic Review of Combination and High-Dose Atypical Antipsychotic Therapy in Patients with Schizophrenia [Internet].

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CAC and ACP have identified atypical antipsychotics (AAPs) for schizophrenia — specifically, high-dose and combination therapy — as being a priority topic for optimal practice initiatives, based on the following criteria:

  • Large deviations from optimal utilization (overuse or underuse)
  • Size of patient populations
  • Impact on health outcomes and cost-effectiveness
  • Benefit to multiple jurisdictions
  • Measurable outcomes
  • Potential to effect change in prescribing and use.


Schizophrenia is a chronic, recurrent mental illness that requires lifelong treatment1 and is associated with symptoms that include hallucinations, delusions, cognitive impairment, disorganized thoughts, social withdrawal, and amotivation.2

Patients with schizophrenia are at an increased risk for numerous other medical illnesses, suicide, substance abuse, homelessness, unemployment, and premature death.3 Worldwide prevalence has been estimated at 0.5% to 1.5%4 of the general population, and in Canada in 2004, prevalence was estimated at about 1% of the population or 234,305 people.5,6

Diagnostic criteria for schizophrenia are currently based on the latest revisions of the World Health Organization International Statistical Classification of Diseases and Related Health Problems (ICD-10) and the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV).7 For a diagnosis of schizophrenia, the DSM-IV requires that two or more of the following symptoms be present for a significant portion of one month or more: delusions, hallucinations, disorganized speech, catatonic behaviour, or negative symptoms.7

Symptoms of schizophrenia can be classified by different symptom domains, including positive or negative.4 Positive symptoms include hallucinations and delusions, while negative symptoms include affective flattening, loss of interest, and alogia.8

The total financial burden of schizophrenia in Canada was estimated to be C$6.85 billion in 2004.9 The annual direct health care and non-health costs were estimated at C$2.02 billion (2004 data) with acute (23%) and non-acute (38%) hospital care accounting for the majority of these costs.9

Management of Schizophrenia

Antipsychotic medications form the cornerstone of treatment for schizophrenia, as they target the characteristic symptoms of the disease.4 The underlying principles for the administration of pharmacotherapy include the individualization of medication (including patient preferences), simple medication regimens, appropriate dosing, regular evaluation of response and adverse events,3 and short- and long-term clinical efficacy, safety, and tolerability.1

Although there have been important developments in this area over the last 40 years, about one-third of people with schizophrenia still have a poor response to antipsychotic medications.7 Surveys of prescribing practices in the United Kingdom (UK) showed that the use of doses higher than those usually recommended is commonly encountered, when antipsychotic agents are used either alone or in combination with another antipsychotic medication.7 Although combination therapy with two antipsychotic agents is not recommended in current clinical management guidelines,3 with the debatable exception of clozapine-based combination therapy,7 it appears this practice is not uncommon.7,10 Two longitudinal studies from the United States (US) reported that 9.5% to 22.0% of patients with schizophrenia received two antipsychotic agents concurrently,11,12 and the proportion of patients treated with more than one AAP increased from 3.3% in 1999 to 13.7% in 2004.11 Data from British Columbia indicate that the rate of antipsychotic polypharmacy increased between 1996, when an estimated 28% of patients discharged from hospital were on polypharmacy, and 2000, when the number was 45%. For patients using clozapine, the rate of polypharmacy increased from 22% in 1996 to 53% in 2000.13 Reasons identified for this increasing prevalence include the use of as-required (PRN) medication and the gradual switch (bridging) from one antipsychotic to another, 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.7 Overall, prevalence rates of antipsychotic polypharmacy range from 4% to 58%,10 and rates up to 69%13 have been reported, depending on treatment setting and patient population.

Technology Description — Atypical Antipsychotics

Most existing antipsychotic therapies fall into one of two classes. The typical antipsychotics (TAP; also known as conventional antipsychotics or neuroleptics) are of the first-generation antipsychotic class. The atypical antipsychotics (AAP) are of the second-generation antipsychotic class.

Seven AAPs are currently available in Canada: aripiprazole, clozapine, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone. Two other AAPs, asenapine and iloperidone, were recently approved in the US, while sulpiride and amisulpride are available in the European Union (Table 1).

Table 1. List of Atypical Antipsychotics available in Canada and US.

Table 1

List of Atypical Antipsychotics available in Canada and US.

Copyright © 2011 Canadian Agency for Drugs and Technologies in Health.

Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial- NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at

Bookshelf ID: NBK169721


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