Atypical Antipsychotics for Schizophrenia: Combination Therapy and High Doses


Project Line:
Health Technology Review
Project Number:

The Canadian Agency for Drugs and Technologies in Health (CADTH) has undertaken an optimal use project to assess the clinical and economic impact of using atypical antipsychotic combination therapy, as well as high-dosing treatment strategies, in adolescents and adults with schizophrenia.

The current project has several key components:

  • Appraise the clinical and cost-effectiveness of combination and high-dose therapy with atypical antipsychotic agents for the treatment of schizophrenia
    • Develop optimal use recommendations or advice
  • Identify gaps in current clinical practice and use, and then propose evidence-based interventions to address these gaps
    • Support the implementation of these interventions.

CADTH seeks feedback from interested stakeholders at key stages during optimal use projects.

By reviewing the evidence and developing optimal use reports, recommendations, and tools, CADTH provides health professionals, policy-makers, and patients with the evidence-based resources they need to make informed decisions.

An expert advisory committee CERC (COMPUS Expert Review Committee), comprising experts from across Canada, has been established to help CADTH provide guidance on optimizing practice related to high dose or combination use atypical antipsychotic agents within Canadian populations with schizophrenia.

Key Messages

CADTH’s work on this project resulted in the following key messages:

  • When a patient with schizophrenia is not adequately responsive to an antipsychotic agent, increasing the dose (within the recommended range), or switching to a different antipsychotic agent is recommended – switching to clozapine should be considered as an option.
  • High-dose strategies or combining atypical antipsychotic drugs with other antipsychotic agents are not known to be more effective and may be more harmful than treatment with a recommended dose of one antipsychotic agent.


Schizophrenia affects up to 1% of the Canadian population; it is often diagnosed in persons in the 16 to 30 years age group. The total financial burden of schizophrenia in Canada was estimated to be C$6.85 billion in 2004.

Newer antipsychotic drugs (also known as atypical antipsychotics) are commonly used to treat this condition. In Canada, the following atypical antipsychotic drugs are available: aripiprazole, clozapine, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone. Two other atypical antipsychotic agents were recently approved in the United States: asenapine and iloperidone. The use of these medications at doses higher than usually recommended is increasing. In addition, the proportion of patients treated with more than one atypical antipsychotic agent has increased in recent years.

By reviewing the evidence, developing optimal use recommendations, and providing supporting intervention tools, CADTH will give health professionals, policy-makers, and patients the evidence-based resources they need to make sound decisions in this therapeutic area.


Summary Reports

Final Reports