Addressing Nonresponse in Schizophrenia

John M. Kane, MD

Department of Neurology and the Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine of Yeshiva University, New York; Department of Psychiatry, Zucker Hillside Hospital, Glen Oaks; and Behavioral Health Services, North Shore-Long Island Jewish Health System, Hyde Park, New York

AV 1. Meta-Analysis of First-Line Atypical Antipsychotic Efficacy for Schizophrenia (00:36)

Data from Leucht et al2
Abbreviations are defined before the References

Practice guidelines1 recommend using atypical antipsychotics as first-line treatment for schizophrenia. When choosing medications for individual patients, however, physicians should consider that the first-line atypicals have differing levels of efficacy (AV 1) and varying side effect profiles.2 Clinicians should carefully assess nonresponse to initial antipsychotic treatment to be sure that it is not due to modifiable factors such as an inadequate dosage or poor treatment adherence. Adverse side effects or a comorbid disorder such as substance use may also contribute to nonadherence and, therefore, nonresponse. If nonresponse to the initial antipsychotic continues despite confirming the patient’s diagnosis, optimizing the dose, and/or addressing nonadherence, then other treatment strategies can be tried.

Treatment Strategies for Antipsychotic Nonresponse

Augmenting medications. One strategy for addressing nonresponse is to augment the initial antipsychotic with another antipsychotic or with a mood stabilizer. However, reviews of studies of augmentation with lithium3 (N=611) and valproate4 (N=519) to treat schizophrenia have been inconclusive, and few data support the superior efficacy of adding either agent to an antipsychotic versus using an antipsychotic alone. Adding another antipsychotic is a common strategy, but a review5 (N=1,229) found combination treatment only somewhat superior to monotherapy, and then only in certain clinical situations (eg, concurrent polypharmacy initiation); the authors concluded that the data were insufficient for clinical recommendations.

Switching medications. Another strategy to manage nonresponse to a first antipsychotic trial is to switch the patient to another antipsychotic, perhaps an agent with a different receptor profile. Expert opinion6 varies widely regarding the duration of an adequate initial trial, ranging from 2.5 to 5.5 weeks, but recent data7 indicate that nonresponse in the first 2 weeks is a robust predictor of subsequent nonresponse. When choosing a new medication, clinicians should carefully evaluate the patient and consider factors such as adverse effect profiles and comorbid conditions. The method of switching (eg, abrupt discontinuation of the first drug, a gradual cross-titration of each drug) may be determined by the presence of intolerable side effects or by the pharmacologic profiles of the 2 medications.8

Addressing Treatment-Resistant Schizophrenia

Treatment resistance in schizophrenia is broadly defined as having little or no symptom response to at least 2 antipsychotic trials of an adequate duration and dosage. Clozapine has demonstrated superior efficacy9,10 for patients with treatment-resistant schizophrenia, and national1 and international11,12 treatment guidelines recommend a trial of clozapine for these patients. However, long delays in initiating clozapine for treatment-resistant schizophrenia are common, while different forms of polypharmacy are tried instead, despite little supporting evidence.13 Studies have found that an average of 5 to 10 years elapses from a patient’s first contact with a clinician to first receiving treatment with clozapine. If clozapine is initiated after 2 other treatment trials, per guideline recommendations, then the length of time to its initiation should be several weeks or months rather than several years.14,15

Various reasons exist for physicians’ reluctance to prescribe clozapine, including possible serious adverse effects and the need for frequent blood draws and monitoring. Side effects associated with clozapine include agranulocytosis, weight gain and other metabolic side effects, seizures, hypersalivation, and myocarditis. Because of the risk for agranulocytosis, a baseline WBC count and ANC must be obtained when initiating clozapine and then must be repeated every week for the first 6 months of therapy, every 2 weeks for the next 6 months, and every 4 weeks thereafter.15 Ronaldson et al16 also recommend actively monitoring for myocarditis via C-reactive protein levels, troponin levels, and ECGs during the first 4 weeks of treatment. Physicians may also believe that they do not have sufficient support to administer clozapine treatment—eg, registered pharmacies that can dispense clozapine as required or ready access to a hematologist should a patient develop a blood dyscrasia—or that the blood draws, monitoring, and documentation make a trial of clozapine too difficult.


AV 2. Treatment Adherence With Clozapine Vs Olanzapine, Risperidone, and Quetiapine (00:23)

Data from Ascher-Svanum19

Another obstacle may be physicians’ perception of patients’ attitudes toward clozapine. In a survey17 of psychiatrists, 66% said they believed that, compared with patients treated with other atypical antipsychotics, patients treated with clozapine were less satisfied with their treatment. However, in a survey18 of patients, more than 85% stated that they felt better while taking clozapine and would prefer to remain on the medication rather than switch agents. The need for routine blood monitoring was rated by psychiatrists17 as highly problematic, but 87% of patients18 reported that, despite having to undergo blood testing, the advantages of clozapine outweighed the disadvantages. In fact, the rates of adherence to and persistence with clozapine have been found to be greater than those of other atypical antipsychotics (AV 2).19

Several strategies for optimizing treatment with clozapine while minimizing side effects have been suggested.20 The threshold for therapeutic blood drug levels is between 350–420 ng/mL, and slowly up-titrating the dose is recommended to avoid side effects. If dose-dependent side effects occur, reducing the dose or counteracting the side effect with another medication may help. To facilitate dosage reduction or in the case of partial response, augmentation with another antipsychotic, mood stabilizer, or ECT can be tried. After initiating a trial of clozapine, clinicians should judge whether the benefits for the patient have been sufficient to justify the risks of continuing the treatment.


When patients with schizophrenia inadequately respond to an initial antipsychotic trial, strategies such as addressing nonadherence, raising the dose, and checking for undiagnosed comorbidities can be used. Augmenting with or switching to another first-line antipsychotic are also common strategies. If treatment nonresponse or partial response continues after 2 trials of first-line antipsychotics, a trial of clozapine is indicated. Although physicians may be reluctant to prescribe the medication due to side effect risks and the need for blood monitoring, clozapine remains the most effective drug for patients with treatment-resistant schizophrenia, and many patients report that the benefits of clozapine treatment outweigh the problems. After conducting an adequate trial, clinicians should assess whether the benefits of clozapine treatment outweigh the risks for that patient.

For Clinical Use

Choose an initial atypical antipsychotic for patients with schizophrenia according to the patient’s needs

Try augmenting with or switching to another antipsychotic if patients experience suboptimal response to the first antipsychotic

Initiate a trial of clozapine for patients who have experienced nonresponse to ≥2 antipsychotic trials of adequate dosage and duration

Drug Names

aripiprazole (Abilify), clozapine (Clozaril, FazaClo, and others), lithium (Lithobid an others), olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal and others), ziprasidone (Geodon)


ANC = absolute neutrophil count, ARI = aripiprazole, ECG = electrocardiogram, ECT = electroconvulsive therapy, OLZ = olanzapine, QUE = quetiapine, RIS = risperidone, WBC = white blood cell, ZIP = ziprasidone


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