Before deciding that a patient has treatment-resistant schizophrenia, one must first determine that the patient is compliant with medication. Covert noncompliance or partial noncompliance can be missed. A trial with a depot antipsychotic can be helpful in ruling out noncompliance. Similarly, there can be large variations in plasma levels of antipsychotics, even with the same dose. Therapeutic levels of most typical and atypical antipsychotics have not been determined, but blood levels of medications may help determine whether a patient is a rapid metabolizer (or noncompliant).
Effective treatment also presupposes an accurate diagnosis. Conditions such as temporal-lobe epilepsy may mimic symptoms of schizophrenia, while comorbid conditions such as endocrinopathies can impact response. Before determining that a patient has treatment-resistant schizophrenia, it is always useful to carefully review the diagnosis.
Beyond these considerations, discussion of treatment-resistant schizophrenia must start with definitions of what constitutes an adequate trial of an antipsychotic medication, how many trials are necessary and whether certain medications or classes of medications are needed before a patient is determined to be resistant to treatment. Defining what constitutes an inadequate response is also necessary. Unfortunately, there is no unanimity concerning any of these issues.
Research protocols typically define an inadequate response as scores above a certain level on commonly used validated inventories such as the Brief Psychiatric Rating Scale (BPRS) or the Positive and Negative Syndrome Scale (PANSS) and/or an inadequate decrease in score after a defined course of treatment. Although more formal, these research definitions overlap the informal, clinical criteria of persistent target problems such as positive, negative or disorganized symptoms; persistent poor functioning; or frequent relapses despite adequate doses of medication (determined, for example, by using depot antipsychotics). For purposes of this discussion, treatment resistance is defined as an inadequate response from one adequate trial of a typical antipsychotic medication and two of the atypical antipsychotics, excluding clozapine (Clozaril). Since an adequate trial of a typical antipsychotic is defined differently than for the atypicals, each will be discussed separately.
Accumulated evidence suggests that response to each of the typical or first-generation antipsychotics will be similar if they are given at equivalent doses. For example, Kane et al. (1998) showed that fewer than 5% of patients with a documented history of treatment resistance showed any response when treated with haloperidol (Haldol). Further, other research has consistently shown that high-dose strategies lead to greater side effects without measurably improving the response (Thompson, 1994).
An adequate trial of a typical antipsychotic is often defined as six weeks at a dosage level of 1000 mg/day in chlorpromazine (Thorazine) equivalents. Based on the previously cited research, we recommend only one adequate trial of a typical antipsychotic, and we do not recommend heroic doses. As an example, little or no response to 20 mg/day of haloperidol after six to eight weeks should be considered a failure. An inadequate response should lead to trials of the atypical antipsychotics.
The second-generation or atypical antipsychotics currently available include risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel) and ziprasidone (Geodon). Clozapine will be discussed separately. These agents all appear to have superior efficacy in several symptom and side-effect dimensions than do the typical antipsychotics. Although these four atypicals differ on important side effects such as extrapyramidal symptoms (EPS), weight gain, QTC widening, and glucose and lipid control, there is no convincing evidence that any of these medications have superiority to the others. Also, unlike the typical agents, it is unclear whether these atypicals are basically interchangeable in their therapeutic response, so failure of one does not preclude a trial with another one. At this point, more research exists for the increased efficacy of clozapine, risperidone and olanzapine, although evidence of the increased efficacy of ziprasidone is beginning to appear.
An adequate trial of an atypical antipsychotic should be at least eight to 12 weeks on a higher dose of the medication -- for example 12 mg/day of risperidone, 40 mg/day of olanzapine, 800 mg/day of quetiapine or 200 mg/day of ziprasidone. We recommend two full trials with atypicals before abandoning this group of medications as the single therapeutic agent. However, we do not have a hierarchical ordering of preferences, believing that side effects should influence selections. We would stress two trials since there seems little to be gained in trying a third before moving on to clozapine. Some would suggest that a trial with quetiapine should not be counted as one of the two trials due to the lack of supportive clinical data for quetiapine.
The Clozapine Equation
Failure from these trials should lead to a trial with clozapine, which has generally been found superior to other available agents. Because of its many side effects -- including agranulocytosis and lowered seizure threshold -- and the requirement for weekly blood monitoring (which may enhance compliance) for at least the first six months (with biweekly monitoring thereafter), clozapine is only approved for treatment-resistant schizophrenia despite its greater efficacy.
The superiority of clozapine may take time to emerge. Therefore, a minimum trial of three or four months should be undertaken, although some would recommend longer trials of six months or a year before concluding that a person is unresponsive to clozapine. Typical clozapine doses range from 300 mg/day to 500 mg/day, and doses of up to 900 mg/day can be used. Some data suggest that minimum plasma levels between 350 ng/ml and 500 ng/ml are associated with increased therapeutic response (Kronig et al., 1995). A lack of noticeable response at two months may be better assessed with a clozapine blood level.
Casey DE, Daniel D, Tracy K et al. (2001), Improved antipsychotic effect of divalproex combined with risperidone or olanzapine for schizophrenia. Poster No. 437. Presented at the 26th Biennial Congress of the World Federation for Mental Health. Vancouver, British Columbia; July 24.
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Kingsbury SJ, Yi D, Simpson GM (2001), Psychopharmacology: rational and irrational polypharmacy. Psychiatr Serv 52(8):1033-1036.
Kronig MH, Munne RA, Szymanski S et al. (1995), Plasma clozapine levels and clinical response for treatment-refractory schizophrenic patients. Am J Psychiatry 152(2):179-182.
Krueger RB, Sackeim HA (1995), Electroconvulsive therapy and schizophrenia. In: Schizophrenia, Hirsch SR, Weinberger DR, eds. Oxford, England: Blackwell Science, pp503-545.
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