Dr. Citrome: How to best help patients with residual schizophrenia symptoms
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Patients with treatment-resistant schizophrenia can be broadly defined to include any persons with residual symptoms that cause distress or impairment despite several treatment attempts. Unfortunately, this definition may include most of our patients with schizophrenia.
Clinical trial data on treatment-resistant schizophrenia can be contradictory, leaving “N of 1” empirical treatment trials for individual patients as the current state of the art. This article presents data from clinical trials for pharmacologic and nonpharmacologic options and offers recommendations to try to help our treatment-resistant patients.
Defining treatment resistance
Research reports regarding treatment-resistant or treatment-refractory schizophrenia have relied on operational criteria such as that found in the pivotal study for clozapine1:
- at least 3 periods of treatment in the preceding 5 years with neuroleptic agents from at least 2 different chemical classes at dosages equivalent to ≥1000 mg/d of chlorpromazine for 6 weeks, each without significant symptomatic relief, and
- no period of good functioning within the preceding 5 years.1 In that study, patients also underwent a prospective treatment trial with what we now know are high doses of haloperidol (up to 60 mg/d or higher) and benztropine mesylate (6 mg/d) for a period of 6 weeks to confirm lack of drug responsiveness. Other studies have more relaxed criteria, such as:
- persistent positive symptoms—hallucinations, delusions, or marked thought disorder—after at least 6 contiguous weeks of past or present treatment, with ≥1 typical antipsychotics at doses of ≥600 mg/d in chlorpromazine equivalents
- a poor level of functioning over the past 2 years, as defined by the lack of competitive employment or enrollment in an academic or vocational program and not having age-expected interpersonal relations with someone outside the biologic family with whom ongoing regular contacts were maintained.2
In this study, no prospective period of treatment to confirm lack of drug responsiveness was required.
The most clinically relevant definition of treatment resistance depends on the patient’s individual circumstances. For some patients, targeting positive symptoms is a high priority; for others it may be negative and cognitive symptoms; for others, it may be excitement. Moreover, families may complain of symptoms or behavior that are of little or no concern to your patient.
Although we desire treatment response and remission for our patients, definitions for remission and functional recovery are in flux. Proposed criteria define symptomatic remission as 6-month maintenance of simultaneous ratings of mild or less on delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and negative symptoms.3,4 Emsley et al4 note that reported remission rates vary widely across studies (17% to 88%) and that patients in remission do better than their non-remitted counterparts in several other outcome domains. Also, patients move in and out of remission over time. Predictors of remission include:
- early treatment response
- baseline symptom severity
- subjective well-being.4
Recovery is a more complex construct than remission and includes social outcomes. Although recovery lacks a standard definition, it is the implied goal of treatment. Anything short of recovery can be viewed as inadequate. If we set the bar at this height, many or most of the patients we treat for schizophrenia could be considered treatment-resistant.
Confounding factors
Before concluding that a patient is treatment-resistant, address medication adherence and possible substance use. Partial or nonadherence with antipsychotic treatment is common—approximately one-half of patients are nonadherent5—and associated with relapse and re-hospitalization.6 In addition, an estimated one-half of all individuals with schizophrenia also use substances.7
Be aware of the optimal dose for any particular antipsychotic and factors that can interfere with achieving adequate plasma levels. This means acknowledging that dosing ranges established during registration studies may not reflect the needs of day-to-day clinical practice.8 Pharmacokinetic interactions with other medications, such as carbamazepine or rifampin, can induce liver enzymes and result in subtherapeutic antipsychotic levels. Cigarette smoking also may have this effect. Lowered clozapine or olanzapine plasma levels have been observed in patients who resume smoking after being discharged from a non-smoking inpatient environment. Some antipsychotics, such as ziprasidone and lurasidone, must be taken with food in order to have sufficient bioavailability.9
What does a patient want?
Patients with schizophrenia often have limited insight into their psychotic symptoms.10 Savvy clinicians will attempt to leverage a patient’s insight into ancillary symptoms—such as impaired sleep, anxiety, and dysphoria—to encourage a therapeutic alliance and therefore adherence. If patients feel their concerns are not addressed, they may consider treatment inadequate even though the intensity of their hallucinations and delusions may have decreased.