Strategies to use in the face of failure to respond adequately to clozapine(Drug information on 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 If there is little or no improvement after a reasonable trial, the augmenting agent should be withdrawn and another strategy pursued.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(Drug information on 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(Drug information on 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.Augmentation Possibilities
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(Drug information on 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(Drug information on quetiapine) have relatively weak dopamine (D2) antagonism, there may be some justification for adding a more potent D2 antagonist such as haloperidol(Drug information on haloperidol), risperidone(Drug information on risperidone) or olanzapine(Drug information on 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.Nonpharmacologic Strategies
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.