When and Why to Initiate Antipsychotic Polypharmacy, and with Which Agents

By Jackson, Elizabeth A.; Spiegel, Aila J. et al. | Current Psychiatry, April 2016 | Go to article overview

When and Why to Initiate Antipsychotic Polypharmacy, and with Which Agents


Jackson, Elizabeth A., Spiegel, Aila J., Graham, Rebecca L., Current Psychiatry


Mr. C, age 31, who has a 7-year history of schizophrenia and is currently on perphenazine, 24 mg twice a day, presents for psychiatric admission after experiencing paranoid delusions. Notable symptoms include delusions of reference and persecution, along with affective flattening and intermittent suicidal ideation. Perphenazine is tapered, and he is started on quetiapine, titrated to 600 mg/d.

Past antipsychotic trials include aripiprazole, olanzapine, paliperidone, haloperidol, and ziprasidone. Because of his refractory symptoms and tolerability issues with other antipsychotics, Mr. C is switched to clozapine, 400 mg/d. His symptoms improve, but he experiences dose-limiting sialorrhea. Risperidone, 1 mg/d, is added to clozapine, which helps his psychosis and improves his functional status. Additionally, Mr. C develops enough insight to recognize his delusions and use skills learned in psychotherapy to cope with them.

Antipsychotic polypharmacy (APP), the concurrent use of [greater than or equal to] 2 antipsychotics, is a topic of debate among mental health care providers. Studies indicate the prevalence of APP can reach upwards of 40%, with 1 systematic review citing more recent median APP prevalence in North America as 17%, an increase from a median of 12.7% in the 1980s. (1) Other studies cite more recent figures as around 20%. (2-3)

The literature lists several reasons for use of long-term APP, including:

* incomplete cross-titration

* accidental continuation of APP that was intended to be temporary

* monotherapy failure

* mitigation or enhancement of effects of other antipsychotics (Table 1). (1,4)

Other factors include direct-to-consumer advertising, external pressures to decrease hospital stays, and low doctor-to-patient ratios. (5) Although it can take as long as 16 weeks to see clinically significant improvement with an antipsychotic, prescribers might expect results after 4 weeks of treatment. (6) Therefore, treatments could be labeled ineffective because trials did not last long enough, leading to premature use of polypharmacy. Combinations of a first- and second-generation antipsychotic (SGA) or 2 SGAs are most common. (2,7,8)

Treatment guidelines (Table 2, page 52) (9-17) suggest APP could be considered after several failures of monotherapy, including clozapine monotherapy, although some guidelines do not address the issue or recommend against APP because of lack of efficacy and safety data. Additionally, APP poses safety concerns (Table 3, page 52). (18,22) Recommendations for APP with combinations that do not include clozapine generally are not provided, because high-level evidence to support this strategy is lacking. Data on safety and efficacy of APP are mixed, with much of the literature dominated by case reports and uncontrolled studies. (19)

What to initiate

Clozapine.'Higher-level evidence is available for clozapine APP. The combination of clozapine and risperidone is one of the most thoroughly studied and, therefore, is a reasonable first choice. Randomized controlled trials (RCTs) examining clozapine plus risperidone (23-29) have yielded mixed results and have not provided conclusive information regarding benefit for positive vs negative symptoms. (24-28)

One RCT reported a significant change in Brief Psychiatric Rating Scale (BPRS) total and positive symptom scores. (27) Other RCTs have shown a non-significant trend toward greater change in total, positive, and negative symptom scores with the clozapine-risperidone combination compared with clozapine monotherapy. (25,28) In terms of cognition, this combination provided no additional benefit. (23) Response, defined as [greater than or equal to] 20% reduction in total BPRS or Positive and Negative Syndrome Scale (PANSS) scores, for clozapine plus risperidone range from 13% to 83%, compared with 8% to 29% for clozapine plus placebo. (24,25,27,29)

Data from 1 study (27) suggest a number needed to treat of 4 to achieve at least a 20% improvement in BPRS scores with clozapine plus risperidone vs clozapine monotherapy. …

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