George Simpson, MD

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, QT

 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.

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.

Strategies to use in the face of failure to respond adequately to clozapine have received little empirical evaluation, although published case studies and expert opinions have suggested some therapeutic possibilities. Treatment options after clozapine trials typically involve an augmentation strategy where a second medication or therapeutic strategy is used concurrently with another antipsychotic medication. Multiple different combinations are possible; most have little empirical support; and none have been shown superior to clozapine as of yet. Therefore, as stated, a clozapine trial is recommended before using augmentation strategies, except when patient objections or medical contraindications rule out the use of clozapine. 

Because there is little research supporting augmentation strategies, such trials should be viewed as mini-experiments in which specific target symptoms are tracked. If there is little or no improvement after a reasonable trial, the augmenting agent should be withdrawn and another strategy pursued. For example, if divalproex sodium (Depakote) is added at therapeutic plasma levels for six to eight weeks and minimal improvement is noted, it should be discontinued before a different strategy is tried. Otherwise, there is the danger of having patients on ever-increasing lists of medications with few benefits and the possibilities of increased side effects and interactions. We have seen many cases of patients with schizophrenia taking three different antipsychotics, several mood stabilizers, benzodiazepines and an antidepressant without any clear documentation of improvement -- a strategy we have termed irrational polypharmacy (Kingsbury et al., 2001).

A number of augmentation strategies have been proposed, which include the addition of lithium, an anticonvulsant, a second antipsychotic, a benzodiazepine or a course of electroconvulsive therapy (ECT). Psychosocial treatment may also be used as an augmentation strategy. No data support a specific ordering of these choices, but each deserves specific comment.

Lithium has not been shown to be an effective augmenting agent for schizophrenia in the few trials conducted, although some case studies have suggested its effectiveness. With clozapine, lithium may raise low leukocyte counts but mask other myeloid processes associated with agranulocytosis. This strategy appears to be used less frequently at present, and we would rate this as a less useful strategy.

Although there are a number of anticonvulsants, there are few published reports of the use of many of the newer ones for augmenting response in schizophrenia. Divalproex is commonly used, although there are inconsistent reports of its effectiveness. Casey et al. (2001) published a preliminary report of a large multicenter study that used this strategy and found it effective early in treatment. It should be noted, however, that the improvement had dissipated by week 4 of the study. Divalproex may affect the levels of other medications and is frequently used as protection for clozapine-induced seizures. Because of its independent risk of agranulocytosis, carbamazepine (Tegretol) use with clozapine is contraindicated. At present, a trial testing the addition of divalproex would seem preferred to the other anticonvulsants until more data accumulate.

Using more than one antipsychotic simultaneously is a common practice, although evidence supporting this practice comes only from case studies and case series. There appears to be no justification for using more than one typical antipsychotic at the same time. Since some of the atypical antipsychotics such as clozapine and quetiapine have relatively weak dopamine (D2) antagonism, there may be some justification for adding a more potent D2 antagonist such as haloperidol, risperidone or olanzapine to augment an inadequate response. Adding even a relatively small dose of a typical antipsychotic, such as 2 mg to 4 mg of haloperidol, to an atypical antipsychotic may augment the therapeutic response at the cost of losing some of the advantages of the atypicals such as low EPS or lack of prolactin elevation.

Although g-aminobutyric acid circuits have been discussed as affecting D2 circuits and some research has been conducted, benzodiazepines have generally not been found to be of value, beyond their nonspecific calming and sedating properties, in treating schizophrenia when used alone or as augmenting agents. Further, there are concerns about their addiction potential and their possible pharmacodynamic interactions with clozapine. Only short-term use of the benzodiazepines in schizophrenia is recommended.

Giving ECT concomitantly with antipsychotic medications has been found to be an effective augmentation strategy (Krueger and Sackeim, 1995). Results appear better when the antipsychotic medication is not discontinued during the course of ECT. This strategy has some research support but appears to be underutilized. We recommend a trial of ECT be considered as a possibly preferred augmentation strategy.

Unlike the other augmentation strategies discussed here, psychosocial treatments are useful and recommended whether or not the patient is resistant to medication treatment. Research clearly supports such interventions as ameliorative for a number of problems, including some aspects of negative symptoms. Like the medications, effective approaches continue to be developed.

Finally, it must be realized that some patients with schizophrenia may remain poorly responsive to treatment despite optimal trials of medications and artful use of augmentation strategies. At such times, it may be necessary to settle for a suboptimal response. Heroic efforts with long lists of medications at higher than useful doses can cause more harm than good. Help in such cases will await further progress in psychopharmacology and in our understanding of the pathophysiology of schizophrenia.

 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.
 

 Kane JM, Aguglia E, Altamura AC et al. (1998), Guidelines for depot antipsychotic treatment in schizophrenia. European Neuropsychopharmacology Consensus Conference in Siena, England. Eur Neuropsychopharmacol 8(1):55-66.
 

 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.
 

 Thompson C (1994), The use of high-dose antipsychotic medication. Br J Psychiatry 164(4):448-458 [see comments].

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