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Evidence-Based Reviews

Treatment-resistant psychosis: Are 2 antipsychotics more effective than 1?

Combining antipsychotics is ‘safe’ for schizophrenia patients when the benefits outweigh the risks of ineffective single-drug therapy.

Vol. 4, No. 7 / July 2005

Off-label prescribing of two or more antipsychotics for treatment-resistant psychosis carries inherent risks for both schizophrenia patients and their psychiatrists. You can reduce these risks by demonstrating that your patient will benefit more from combining antipsychotics than from monotherapy alternatives.

Until more empiric data become available, clinicians carry the burden of documenting individual patient response to justify combining antipsychotics. This article can help you identify and counsel possible candidates for this therapy, assess the risks and benefits, and defend your treatment choicesif necessary.

What Does ‘Combining’ Mean?

For this discussion, “combining antipsychotics” does not mean simultaneously using two or more antipsychotics to treat psychosis. Rather, it refers to using two or more antipsychotics for long-term control of psychotic symptoms. It does not apply to short-term tactics, such as overlapping antipsychotics when switching between them or combining a parenteral and an oral antipsychotic when treating an acute episode.

How long must a combination be used to qualify as long-term treatment? No standard exists, but a period >6 weeks exceeds normal short-term treatment.

How Safe Are Combinations?

Patient risk. Combination antipsychotics are used to treat 10% to 20% of schizophrenia patients in this country and >90% of those in some Asian countries, such as Japan.1 Statistics on the prevalence of combining antipsychotics seldom:

  • distinguish between short- and long-term use
  • identify when practitioners use combinations to treat co-existing symptoms such as insomnia, rather than for psychosis.

Even so, these numbers seem to indicate that combination therapy is not unsafe for patients with treatment-resistant schizophrenia (Box).2,3 Qualitatively greater safety problems with antipsychotic combinations—compared with monotherapy—would show up, even in our relatively crude post-marketing surveillance system.

Clinicians, however, must define safety in terms of risks and benefits. Given that every medication has risks—some (such as allergic reactions) unique to the individual patient—adding another drug to a treatment regimen will always add risk. When considering more than one antipsychotic, ask yourself:

  • Do benefits outweigh risks?
  • Is a combination the least risky way to achieve these benefits?

Practitioner risk can also influence treatment selection. Medical risks of combining antipsychotics may be small, but a poor outcome from this off-label use might be more likely to lead to a lawsuit than the same poor outcome with another medication choice.

How much does a practitioner’s perception of medicolegal risk influence treatment selection? No doubt, comfort level varies greatly. I have frequently met prescribers who use antipsychotic combinations instead of clozapine for fear of being sued should agranulocytosis occur.


Defining treatment-resistant schizophrenia

Most trials have used criteriafrom the seminal clozapine study to define “treatment resistant” schizophrenia:

  • History of poor response to one or more antipsychotics.
  • Demonstrated nonresponse to adequate dosage and duration of a nonclozapine antipsychotic before starting clozapine.2

This work defines treatment resistance as persistent positive symptoms despite treatment with ≥2 different antipsychotics other than clozapine.

Newer antipsychotics are different. The original clozapine studies found little likelihood that patients who had not responded to haloperidol would respond to chlorpromazine. Newer-generation antipsychotics are pharmacologically more heterogeneous than the first-generation agents, however, and failure to respond to one might not mean that none of the others will help.

When to start clozapine? Solid evidence is limited, but a consensus panel has recommended starting clozapine after two unsuccessful trials of newer-generation antipsychotics, with the option to try a third antipsychotic (first- or newer-generation) if clinically warranted.3

Symptoms vs function. In clinical practice, defining treatment resistance as persistent positive symptoms may exclude patients impaired by severe negative symptoms and/or disorganized thought processes. The treatment goal is to restore function, not just to reduce psychosis. As treatments evolve, we can expect more emphasis on a recovery model that addresses total patient well-being and combines psychosocial and pharmacologic interventions.

A Practical View

Medical risks. Treating patients with antipsychotic combinations may be associated with medical risks (Table 1). Patients are less likely to adhere to complex medication regimens than to simple ones. Thus, adding a second antipsychotic may decrease adherence to the first antipsychotic and to other medications, such as for hypertension, diabetes, etc.

Increased side-effect risk has been reported with antipsychotic combinations.4 Side effects include those expected from one or both drugs in the combination, especially extrapyramidal effects when conventional antipsychotics are included.4,5 Because the total antipsychotic dosage can be considerably higher than usual in patients receiving combinations,5 some of the increased side effect burden is probably related to high dosing, rather than to the combinations.

Pharmacodynamic or pharmacokinetic interactions or the loss of an agent’s advantages are infrequently reported, perhaps because prescribers are not looking for these effects or do not consider them worth reporting. Of particular concern is tardive dyskinesia (TD), which may develop when conventional antipsychotics are added to agents with very low propensity to cause TD—such as clozapine.

Table 1

Potential risks and benefits of combining antipsychotics

Medical risks

Decreased adherence to multiple medications

Increased and/or unexpected side effects

Increased potential for undesirable pharmacokinetic or pharmacodynamic interactions

Difficulties in making rational dose adjustments

Loss of advantages of one of the medications

Nonmedical risks

Lack of evidence to defend practice in medicolegal cases

Increased costs if combining second-generation antipsychotics

Increased quality assurance scrutiny and paperwork

Medical benefits

Reduced symptoms

Reduced metabolic side effects (such as partially substituting another atypical antipsychotic for a high clozapine dosage)

Nonmedical risks. Table 1 also lists potential nonmedical risks associated with combining antipsychotics. No literature exists to help you assess how these considerations might affect your practice.

litigation. As noted, some clinicians prefer combining antipsychotics instead of using clozapine because they fear legal action should a patient develop agranulocytosis. In the author’s view, this fear is not well-grounded. Successful lawsuits typically find evidence that the clinician committed errors of omission or commission. In the case of blood monitoring for clozapine-induced neutropenia, the parameters are clear and enforced. You must follow community standards of practice, which provide a strong legal defense.

Administrative scrutiny. Quality assurance programs are increasingly identifying and monitoring antipsychotic combinations—an obvious target by being frequent, lacking a strong evidence base, increasing costs, and raising liability concerns. Typically, such programs discourage antipsychotic combinations and impose administrative hurdles to starting or continuing them.

Gathering data and documenting it in the patient’s medical record—to be discussed later—is key to demonstrating that a combination’s superior efficacy for the individual patient justifies its use.

Medical benefits. Guidelines and algorithms for drug treatment of schizophrenia either omit combination antipsychotics or suggest this strategy when all else has failed.6,7 Lack of evidence for a practice is not the same as evidence against it, however. A combination may be better for some patients than any available antipsychotic monotherapy.

Antipsychotic combinations have been examined in more literature reviews than randomized controlled trials—all of which have addressed augmenting clozapine with another antipsychotic (Table 2).8-12 Augmentation with psychotropics other than a second antipsychotic has most often been tested for negative and cognitive symptoms,4 but some evidence has shown adjunctive anticonvulsants and cognition-enhancing agents to improve positive symptoms.6

Reducing side effects is not directly related to treatment-resistant psychosis, but some articles describe managing clozapine’s metabolic side effects by partially substituting another atypical antipsychotic.11,13

Because clozapine is the treatment of choice for treatment-resistant psychosis, consider tactics that maintain its benefits while reducing its metabolic liabilities. Reducing the clozapine dosage (if feasible) is the first-line approach, but partially substituting another antipsychotic might help if psychotic symptoms return.

Table 2

Results of studies using combination antipsychotic therapy


Type of trial

First author

Outcome measures





Positive, negative, and depressive symptoms





Positive and negative symptoms





Positive and negative symptoms





Body weight, serum glucose





Positive and negative symptoms


RCT: randomized controlled trial; LCS: large case series

*Sulpiride and amisulpride are not available in the United States.

Clinical Management Hints

Document, document, document. Crucial to “non-standard” treatments such as combining antipsychotics is using and documenting good medical practices. These include:

  • accurately assessing patients
  • carefully weighing illness risks vs treatment risks
  • talking regularly to patients about their treatment and therapeutic options (Table 3).

Documenting these practices is enormously helpful to other clinicians who see your patient and to validate the quality of your treatment to external reviewers, such as quality assurance, the Joint Commission on Accreditation of Healthcare Organizations, or juries. Clearly document failure or refusal of more-standard therapies, as well as your efforts to establish that neither antipsychotic alone has produced as beneficial a response as the two agents combined.

Use objective measures. Brief scales to measure psychotic symptoms are being increasingly used in public mental health settings.6 For example, four psychosis items from the Brief Psychiatric Rating Scale (hallucinations, unusual thought content, paranoia, and disorganized thought) can quickly assess and capture much of the variance of the full scale in patients with schizophrenia.14

When properly used, these objective and reliable scales can document clinical change and track illness course across time and providers. Other objective outcome measures can contribute to quality of care and its documentation. For more information, visit the Substance Abuse and Mental Health Services Administration Web site (see Related Resources).

Although it seems obvious that persistent illness is not a good thing, the risks of persistent psychosis vary from patient to patient. Some function relatively well despite ongoing psychotic thoughts, whereas others are terribly impaired, demoralized, and/or suicidal. The rationale for nonstandard treatment such as an antipsychotic combination is to reduce patient suffering and risk and/or to increase function.

Discuss options with patients. Finally, schizophrenia patients (and involved significant others) need to understand and participate in treatment. Ongoing discussion of treatment options is an important part of this process. For example, initially reluctant patients often come to accept clozapine treatment after discussing its risks and benefits with clinicians and other patients who are taking clozapine. Documenting these discussions is as beneficial to the patient and clinician as is documenting symptoms and treatment effects.

Table 3

3 tips for managing risk and medications

Use objective, quantifiable symptom measures at regular intervals

Document patient’s risk of persistent psychosis, based on history

Discuss risks and benefits of other treatment options with the patient and/or family at regular intervals

Related resources

  • How to use medication in a systematic and effective way, as part of the overall treatment for severe mental illness. In: Evidence-based practices: Shaping mental health services toward recovery. Medication management approaches in psychiatry. Substance Abuse and Mental Health Services Administration. U.S. Department of Health and Human Services.
  • Texas Medication Algorithm Project (TMAP).
  • Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with schizophrenia, 2nd ed. Am J Psychiatry 2004;161(suppl):1–56.

Drug brand names

  • Clozapine • Clozaril
  • Haloperidol • Haldol
  • Quetiapine • Seroquel
  • Risperidone • Risperdal
  • Ziprasidone • Geodon


Dr. Miller receives research support from or is a consultant or speaker for Abbott Laboratories, Almirall, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., Eli Lilly and Co., Janssen Pharmaceutica, Pfizer Inc., and InforMedix.


1. Miller A, Craig CS. Combination antipsychotics: pros, cons, and questions. Schizophr Bull 2002;28(1):105-9.

2. Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988;45(9):789-96.

3. Miller AL, Hall CS, Buchanan RW, et al. The Texas Medication Algorithm Project antipsychotic algorithm for schizophrenia: 2003 update. J Clin Psychiatry 2004;65(4):500-8.

4. Stahl SM, Grady MM. A critical review of atypical antipsychotic utilization: Comparing monotherapy with polypharmacy and augmentation. Curr Med Chem 2004;11(3):313-27.

5. Centorrino F, Goren JL, Hennen J, et al. Multiple versus single antipsychotic agents for hospitalized psychiatric patients: Case-control study of risks versus benefits. Am J Psychiatry 2004;161(4):700-6.

6. Miller AL. Polypharmacy in schizophrenia: science, art, and fiction. Curr Psychosis Ther Rep (in press).

7. Miller AL, Chiles JA, Chiles JK, et al. The Texas Medication Algorithm Project (TMAP) schizophrenia algorithms. J Clin Psychiatry 1999;60(10):649-57.

8. Shiloh R, Zemishlany Z, Aizenberg D, et al. Sulpiride augmentation in people with schizophrenia partially responsive to clozapine. A double-blind, placebo-controlled study. Br J Psychiatry 1997;171:569-73.

9. Josiassen RC, Joseph A, Kohegyi E, et al. Clozapine augmented with risperidone in the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry 2005;162(1):130-6.

10. Anil Yagcioglu AE, Kivircik Akdede BB, Turgut TI, et al. A double-blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safety. J Clin Psychiatry 2005;66(1):63-72.

11. Reinstein MJ, Sirotovskaya LA, Jones LE, et al. Effect of clozapine-quetiapine combination therapy on weight and glycaemic control. Clin Drug Invest 1999;18(2):99-104.

12. Agelink MW, Kavuk I, Ak I. Clozapine with amisulpride for refractory schizophrenia. Am J Psychiatry 2004;161:924-5.

13. Kaye NS. Ziprasidone augmentation of clozapine in 11 patients. J Clin Psychiatry 2003;64(2):215-16.

14. Shores-Wilson K, Biggs MM, Miller AL, et al. Itemized clinician ratings versus global ratings of symptom severity in patients with schizophrenia. Int J Methods Psychiatr Res 2002;11(1):45-53.

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