HomeMedicine By SpecialtyAddictions and DrugsTreating Schizophrenia: What’s the evidence?

Treating Schizophrenia: What’s the evidence?

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Schizophrenia is a chronic mental illness that requires lifelong treatment. Symptoms can be highly disruptive to a patient’s life and include hallucinations, delusions, cognitive impairment, disorganized thoughts, social withdrawal, and lack of motivation. The worldwide prevalence of schizophrenia is 0.5 to 1.5 per cent — with about 1 per cent of the Canadian population affected.

Antipsychotic medications are the cornerstone of treatment for schizophrenia. Most of these fall into one of two classes: first generation or typical antipsychotics, and second generation or atypical antipsychotics (AAPs).

Around one-third of patients with schizophrenia have a poor response to treatment with an antipsychotic. Although not recommended in most clinical practice guidelines, other strategies may be tried in an attempt to improve response to treatment. These may include prescribing an atypical antipsychotic at a dose higher than recommended (high-dose therapy) or prescribing an atypical antipsychotic in combination with another antipsychotic medication (combination therapy). But are these strategies safe and effective?

Olanzapine (Zyprexa), quetiapine (Seroquel), and risperidone (Risperdal) are the most widely used atypical antipsychotics prescribed at doses higher than their product monograph specifies.

“If the patient is still responding to the medication, but hasn’t quite got to where I want him or her to be, then I would still continue to increase the dose….past the maximum recommended dose”  Psychiatrist, Alberta.
“With [olanzapine], I’ve patients above the recommended dose, because there isn’t as much of an issue with akathisia and extrapyramidal symptoms.” Psychiatrist, Quebec.  

When it comes to combining antipsychotic therapies, the most frequently prescribed combinations included risperidone, quetiapine, and/or olanzapine.

“If the medication is not sufficiently effective, and a higher dose won’t be tolerated, I’m hoping that a second medication will be tolerated.” Psychiatrist, Ontario.  

“I might add a second antipsychotic that’s more sedating to help with sleep at night” Psychiatrist, Ontario.

However, clinicians may be very surprised to learn how little evidence exists as to the safety and efficacy of these practices in treating schizophrenia.

The Canadian Agency for Drugs and Technologies in Health (CADTH) – an independent, not-for-profit producer and broker of health technology assessments – recently completed a comprehensive study, with recommendations, examining the high-dose or combination AAP therapy, to treat schizophrenia in patients who had an inadequate response to initial therapy. In none of the 10 randomized controlled trials analyzed did high-dose atypical antipsychotics work better than standard dose atypical antipsychotics. There was a similar lack of evidence on prescribing two antipsychotics simultaneously.  No clinically important benefits were seen with other antipsychotic combinations, and there may be an increase in serious adverse effects.

What are other the best options when schizophrenia symptoms are not being controlled? Exploring adherence to treatment and ruling out substance use are good places to start. Then both CADTH and the Canadian Psychiatric Association Clinical Practice Guidelines recommend either increasing the dose – but within the recommended dose range – or switching to a different antipsychotic drug, rather than combining antipsychotics or going beyond the maximum recommended dose.
Another option when patients are not responding well to therapy is switching to clozapine. Some clinicians may be reluctant to do so because of the risk of serious side effects and the need for blood monitoring.

“The disadvantages are…the weekly blood monitoring, there’s the agranulocytosis, there’s seizures. I mean, it’s hard to get patients on it because you worry they will not be compliant with the weekly blood monitoring.” Psychiatrist, Ontario.

“I wouldn’t [prescribe clozapine]. I would send a patient to someone who is more specialized if I was going to do that.” Psychiatrist, Quebec
But others recognize clozapine as an important and potentially underutilized treatment option.

“I have [prescribe clozapine] from the day it became available in Canada. I would say less than 10 per cent  [of my patients are taking clozapine]. And I should also say that I’m probably underutilizing the drug. It is a very effective drug.”  Psychiatrist, Ontario

To read more on atypical antipsychotic high and combination strategies in schizophrenia, visit www.cadth.ca/aaps

The Canadian Agency for Drugs and Technologies in Health (CADTH) is an independent, not-for-profit producer and broker of health technology assessments. Federal, provincial, and territorial health care decision-makers rely on our evidence-based information to make informed decisions about the effectiveness and efficiency of drugs and other health technologies.


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