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

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

Combination	Type of trial	First author	Outcome measures	Results
Clozapine/sulpiride*	RCT	Shiloh8	Positive, negative, and depressive symptoms	Positive
Clozapine/risperidone	RCT	Josiassen9	Positive and negative symptoms	Positive
Clozapine/risperidone	RCT	Yagcioglu10	Positive and negative symptoms	Negative
Clozapine/quetiapine	LCS	Reinstein11	Body weight, serum glucose	Positive
Clozapine/amisulpride*	LCS	Agelink12	Positive and negative symptoms	Positive
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.