Evidence-Based Reviews

Antipsychotic combinations: Blind step or logical?

Current Psychiatry. 2008 July;7(7):41-53

References

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Treatment guidelines—such as the Texas Medication Algorithm Project’s updated treatment algorithm for schizophrenia²³—reflect the paucity of controlled studies of antipsychotic combinations. The expert consensus panel that developed the TMAP algorithm recommends clozapine augmentation with an FGA or SGA, or electroconvulsive therapy after adequate trials of antipsychotic monotherapy, including clozapine. The panel recommends reserving other antipsychotic combinations as a last-line strategy (see Related Resources).

Table 1

Take-home points about antipsychotic polypharmacy

Long-term antipsychotic polypharmacy is common, even in schizophrenia patients without treatment-refractory psychosis
Controlled clinical trials do not support antipsychotic polypharmacy; many clinicians use this strategy, however, so it may have perceived value
Which antipsychotic combinations are best—in terms of efficacy and safety—is unclear
Controlled trials of combination antipsychotic therapy are difficult to conduct, which limits the availability of evidence to inform clinical practice
Whenever you initiate antipsychotic polypharmacy, document your rationale and the alternatives you considered

‘Sensible’ pharmacology

Despite the lack of supporting evidence, many clinicians apparently are using antipsychotic polypharmacy for schizophrenia patients with treatment-resistant psychosis. Moreover, reports that up to one-fourth of outpatients and one-half of inpatients may receive antipsychotic polypharmacy^2-7 suggest that this approach is not being reserved for treatment-resistant psychosis. Rather, it is being used in non-treatment-refractory schizophrenia patients as well—a practice Stahl labeled a “dirty little secret.”²⁴

Before you consider using antipsychotic polypharmacy for a schizophrenia patient, we suggest that you answer a series of questions to rationalize your decision (Table 2). These questions seem intuitive, but they represent appropriate clinical practice and may support the use of multiple antipsychotics in selected patients.

Which combination? If you determine that a patient is an appropriate candidate for antipsychotic polypharmacy, think about the pharmacologic profiles of available agents. Administering 2 antipsychotics may augment pharmacologic activity, provide an additive effect, or worsen your patient’s symptoms.

Although data from well-controlled studies of clozapine + risperidone do not support its efficacy,^9-12 this combination is rational from a pharmacologic perspective. Clozapine shows a lower D2 receptor occupancy (16% to 68%) than that of risperidone (63% to 89%),²⁵ so risperidone’s additional D2 receptor occupancy may enhance a patient’s response to clozapine. Table 3 lists other potentially “sensible” antipsychoticantipsychotic combinations.

Table 2

Questions to consider before initiating antipsychotic polypharmacy

Ask yourself, ‘Have I…
Determined if my patient is taking the prescribed medication correctly or even at all?
Allowed for an adequate trial—dosage and duration—of antipsychotic monotherapy?
Maximized the dosage of the current antipsychotic?
Tried at least 2 to 3 trials of a first-generation and/or second-generation antipsychotic?
Tried an adequate trial of clozapine?
Re-evaluated my patient’s diagnosis?
Considered tolerability and safety issues associated with adding another antipsychotic?
Considered drug-drug interactions that may occur as a result of adding another antipsychotic?
Considered nonpharmacologic alternatives, including psychosocial interventions?
Augmented with a nonantipsychotic medication, such as valproic acid?
Considered my patient’s ability to pay for an additional antipsychotic?
Considered whether I can monitor my patient more closely while he/she is on multiple antipsychotics?

Table 3

Theoretically beneficial antipsychotic combinations

Antipsychotic #1	Antipsychotic #2	Theoretical pharmacologic benefit	Theoretical safety/tolerability concerns
Clozapine	Olanzapine	Additional D2 receptor occupancy	Anticholinergic effects, metabolic adverse events, orthostasis, sedation
Aripiprazole	Quetiapine	D2 agonist/antagonist in addition to ‘fast on/fast off’ D2 blockade; unique 5HT activity	Sedation
Quetiapine	Olanzapine	Differing D2 blockade properties with minimal increase in EPS risk; 2 agents with structural similarity to clozapine	Anticholinergic effects, metabolic adverse events, orthostasis, sedation
Aripiprazole	Loxapine	D2 agonist/antagonist plus a typical antipsychotic that has atypical properties at low doses; 2 agents thought to not potentiate weight gain	Orthostasis, sedation
D2: dopamine; 5HT: serotonergic; EPS: extrapyramidal symptoms

Safety/tolerability

Reduced dosages. Combining antipsychotics may allow you to increase treatment efficacy and improve patient tolerability. Lower dosages of 2 antipsychotics may cause fewer side effects than a high dosage of 1 antipsychotic.

For example, case reports and retrospective studies^26,27 suggest that adding aripiprazole to clozapine may improve antipsychotic efficacy and reduce metabolic adverse events in treatment-resistant patients. In these cases, clozapine dosages were lower than those usually used in patients with schizophrenia.

Metabolic effects. Carefully weigh the propensity of some antipsychotics to induce weight gain, hyperlipidemia, or glucose dysregulation if you plan to use these agents as part of a polypharmacy regimen. Among SGAs, clozapine and olanzapine are associated with the highest risks of metabolic adverse effects, followed by quetiapine and risperidone. Aripiprazole and ziprasidone are less likely than other SGAs to cause these effects.²⁸

A recent study found a higher incidence of metabolic syndrome in patients receiving antipsychotic polypharmacy. The increased incidence was linked to demographics and clinical risk factors, however, and was not independently associated with the use of multiple antipsychotics.²⁹

Because evidence is scarce and inconclusive, the risk of metabolic adverse events is unknown when antipsychotics are combined. Exercise caution when combining antipsychotics—particularly those known to cause adverse metabolic effects—in case the risk is additive.