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Antipsychotics-To Respond or Not to Respond?
Brian Miller, MD, PhD, MPH
A new study brings us closer to answering why antipsychotics are successful in treating schizophrenia in some patients and not in others.
Non-response to Short-term Antipsychotic Drugs in Schizophrenia
• Many patients with schizophrenia do not respond to antipsychotics, but the epidemiology of this phenomenon is unclear
• Variable definitions of “response” contribute to wide estimates of antipsychotic nonresponse rates
• Therefore, more precise estimates of antipsychotic nonresponse are needed
• Samara and colleagues[1] computed nonresponse and nonremission rates in a large dataset of randomized multicenter trials
• Study authors used individual patient data from pharmaceutical industry-sponsored RCTs of olanzapine or amisulpride versus one of five other antipsychotics or placebo in patients with acute exacerbation of schizophrenia
• Treatment efficacy was measured using the PANSS in 8 studies and the BPRS in the other 8 studies
• Response was assessed over a period of 4 to 6 weeks of follow-up
• Patients who received placebo or an inadequate antipsychotic dose (based on expert consensus guidelines[2]) were excluded
• 6221 patients, mean age 37, 66% male, and mean illness duration 14 years were included
• The primary criterion for antipsychotic nonresponse was a ≤ 0% reduction in the psychopathology total score. Secondary criteria included the percentage of nonresponders in 25% steps, as well as <20% reduction
• Remission was defined based on consensus criteria defined by Andreasen and colleagues[3], with 8 key PANSS items rated as “mildly present” or better for at least six months
• The authors also investigated nonresponse and nonremission rates for positive symptoms
• Analyses were based on the last observation carried forward method
• Nonresponse and nonremission frequencies were synthesized for each study using a weighted average of their logit transformations, with 95% confidence intervals
• When necessary, BPRS scores were converted to PANSS scores using an established algorithm[4]
• The overall nonresponse for the ≤ 0% cutoff was 20%; and for the < 20% cutoff was 38%
• The pooled percentage of no symptomatic remission was 67%
• These percentages did not change substantially in sensitivity analyses excluding one study of first-episode psychosis and another study of patients with prominent negative symptoms
• Earlier onset of illness and lower baseline severity were significantly associated with higher nonresponse rates
• Treatment with either olanzapine, risperidone, or amisulpiride was significantly associated with lower nonresponse rates
• The authors concluded that about 2 in 10 patients did not show any symptom improvement; about 4 in 10 show a < 25% reduction in symptoms; and about 2 in 3 patients did not meet criteria for remission after 4 to 6 weeks of antipsychotic therapy
• They note that no firm conclusions can be made for specific antipsychotic agents based on the available data
• Study strengths include the large patient sample and the use of individual participant-level data
• Limitations of the study include highly selected patients for RCTs, that results are based only on short-term data, and that data were derived from a “convenience sample” of RCTs from two pharmaceutical companies
• The authors concluded that short-term antipsychotic non-response rates in acute psychosis are notably high, and that uniformity in the reporting of response and remission data in future trials would be important to the field
REFERENCES:
1. Samara MT, Nikolakopoulou A, Salant G, Leucht S. How many patients with schizophrenia do not respond to antipsychotic drugs in the short term? An analysis based on individual patient data from randomized controlled trials. Schizophr Bull. 2018 Jul 2. [epub ahead of print]
2. Gardner DM, Murphy AL, O’Donnell H, et al. International consensus study of antipsychotic dosing. Am J Psychiatry. 2010;167:686–693.
3. Andreasen NC, Carpenter WT Jr, Kane JM, et al. Remission in schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry. 2005;162:441–449.
4. Leucht S, Rothe P, Davis JM, Engel RR. Equipercentile linking of the BPRS and the PANSS. Eur Neuropsychopharmacol. 2013;23:956–959.
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