Short-term Strategies In developing a short-term strategy, the clinician will decide whether the patient will be treated with

an antipsychotic, how treatment will be explained to the patient, which drug will be selected and through which route will it be administered, the dose of that agent, and the setting in which treatment will take place. Nearly every patient with an acute psychotic episode will require drug treatment. Although occasional individuals have demonstrated that their episodes are mild and relatively brief, these individuals are the exception. Moreover, as mentioned previously, there is evidence suggesting that delays in initiating treatment with antipsychotics may have long-lasting effects in worsening psychotic episodes and social adjustment (58). In other words, even if a patient eventually recovers without drugs, it is possible that the amount of time spent in a psychotic state may be related to a worse long-term outcome. Maintaining cooperativeness and trust is an important component of a short-term treatment strategy. The symptoms of acute schizophrenia may include overt suspiciousness or a tendency to misinterpret the intentions of the treatment team. This, plus the cognitive defects, places an additional burden on the clinician that may not be present during the treatment of mood or anxiety disorders. Thus, a successful strategy must include clear explanations of the rationale for treatment and possible drug side effects. Since family members (or significant others/case managers) may be important allies in assuring cooperativeness, family psychoeducation programs are by necessity mandatory in both short- and longterm treatment. The selection of an antipsychotic has become more complex as newer agents have been introduced. Prior to 1990, all antipsychotics were equally effective and differed mostly in their side effect profiles. Newer drugs (including risperidone, olanzapine, and quetiapine) have milder side effects and, in some circumstances, may be more effective (34). However, these drugs are only available as oral agents and they are much more expensive. The choice of a drug can be made most easily when a patient has a history of a positive response and minimal side effects during treatment with a previous, specific, antipsychotic drug regimen. On the other hand, if previous treatment episodes were associated with discomforting side effects, particularly extrapyramidal symptoms (EPS), clinicians should consider either prescribing a conventional antipsychotic at a lower dose or starting with a newer antipsychotic. If the patient has a history of treatment-resistant positive symptoms with one or more conventional antipsychotics, that individual is likely to be resistant to other conventional drugs (27). As a result, patients with a history of treatment refractoriness should probably be treated with a newer antipsychotic. At this point, there is data suggesting that treatment-refractory patients may respond

to clozapine (23) or risperidone (6). The other new antipsychotics have not been studied in this population. Short-term non-compliance and outright drug refusal are common in individuals with schizophrenia. One of the important determinants of non-compliance is a patient's subjective response to an antipsychotic which, in turn, is related to side effects, particularly EPS (55). This suggests that one of the most important strategies for assuring compliance is minimizing EPS. In younger patients who are vulnerable to dystonias, this may mean prescribing antiparkinson medications along with the first doses of a high-potency antipsychotic. In nearly all cases, patients should be treated with a moderate dose of a conventional drug or with a newer antipsychotic. This strategy for minimizing EPS also suggests that agitationa common component of severe psychosisshould be managed with adjunctive benzodiazepines rather than higher doses of antipsychotics. Patients treated with an antipsychotic will usually demonstrate a lessening of acute, positive, psychotic symptoms in a few days to three or four weeks. Some, however, may take up to 12 weeks even when they receive an adequate dose. If a patient fails to respond after four to six weeks of treatment, the clinician should consider ordering a plasma level if the patient is receiving a drug such as haloperidol, fluphenazine, or clozapine where there is sufficient data to interpret the level. If the level is adequate, and the patient has shown no change, the clinician has several options, including raising the dose, augmenting with a benzodiazepine, or changing to another antipsychotic. The relatively high improvement rates on newer antipsychoticsparticularly with clozapine suggest that the most effective option will be to change to a newer drug (38). Long-term Strategies The goals of long-term treatment include preventing relapse, supporting psychosocial and rehabilitation efforts, and avoiding drug toxicities such as tardive dyskinesia. There is also the issue of whether recurrent psychotic episodes somehow kindle or facilitate certain neural substrates, as has been posited for mood disorders (40) and thereby increase symptom severity and decrease psychosocial functioning over the long term. This suggests that the long-term objective is to prevent (multiple) episodes that may kindle or potentiate the neural circuit dysfunction basis of schizophrenia and lead to a poorer future course. Strategies for maintenance treatment should weigh the importance of preventing relapse against the side effects of the antipsychotic medication. This is particularly difficult for the conventional antipsychotics, which often cause EPS at the same doses that are needed for a therapeutic effect. Two major strategies have been studied with conventional drugs. Several groups have utilized an intermittent or targeted drug strategy, which necessitates careful longitudinal monitoring, where medications are withdrawn and then reintroduced at the first symptomatic signs of

the onset of psychosis (11). Unfortunately, this strategy as assessed by the Treatment Strategies in Schizophrenia (TSS) collaborative study, results in a high level of relapse (53). Still, this approach may be useful for a minority of patients with relatively mild episodes, good insight, and easily defined prodromal symptoms. An alternative is to use a fixed, low-dose antipsychotic strategy (24, 30). In the long-run, these latter strategies may provide some very important benefits, but they also require a higher level of psychosocial monitoring and assessment on a continuing basis. Therefore, they are also more expensive. Marder and coworkers (32) have proposed a strategy in which patients are treated with a low dose of a long-acting, depot antipsychotic and are supplemented with an oral antipsychotic for prodromal signs of relapse. This augmentation strategy was effective in reducing the risks associated with low-dose treatment. The dose-reduction strategies previously described may not be relevant for newer antipsychotics, which are associated with a much lower risk of EPS. Unfortunately, there are no controlled, double-blind studies comparing the newer agents with conventional antipsychotic drugs. Nevertheless, experience with the newer antipsychotics, particularly risperidone and olanzapine, indicates that these agents are effective during long-term treatment. If this is proven in long-term studies, it would suggest that these agents can be prescribed at a dose that is most likely to prevent relapse without concern for EPS. Long-acting, depot antipsychotics are indicated for a substantial number of patients with schizophrenia, including individuals with a history of poor compliance, passive individuals who will accept antipsychotic treatment but will not take them otherwise, and individuals with a history of severe psychotic episodes associated with suicidal or aggressive behaviors. Psychosocial treatments are most effective when psychotic symptoms have been adequately controlled. The treatment selected will depend upon the patient's and therapist's goals. Many investigators have presented data suggesting that the psychosocial family environment may either potentiate or decrease the level of symptomatology of patients (20). The family that is highly expressive of emotion does not create schizophrenia but certainly can exacerbate symptoms. Specifically, sending a patient with schizophrenia home to an environment filled with conflict, critical comments, and highly charged emotions may act as a stressor. It is also important to recognize that the family does not cause schizophrenia, but that any family with a schizophrenia member may undergo a profound reorganization, and the other family members may feel confusion, guilt, responsibility, and shame. It is thus critically important that the psychopharmacological approach to schizophrenia be combined with family education. Other evidence suggests that social skills training can be effective in improving the social adjustment of patients with schizophrenia (31). Both family education and social skills training are most

effective when patients are adequately treated with an antipsychotic. Further, the effects of both treatments tend to wane when they are discontinued, suggesting the importance of prolonged treatment with a need for regular "booster sessions" for individuals who have completed treatment. Ultimately, when studying the outcome of schizophrenia, ongoing short- and longterm trials are critically important for designing rational drug therapies in combination with psychosocial therapy for schizophrenia patients. The introduction of newer antipsychotics may result in much greater interest in psychosocial interventions. Patients who receive newer agents may be better candidates for psychosocial treatments when treatment with these agents is associated with improvements in negative and cognitive symptoms, as well as reduced side effects. Also, patients who improve on clozapine or other new, a typical drugs may initially appear ready to return to community life. However, these individuals then experience a series of frustrating failures at work, school, or social relationships, which indicates that pharmacologic treatment alone may not be sufficient to prepare them for their new roles. The reader should also refer to Maintenance Drug Treatment for Schizophrenia on maintenance treatment of schizophrenia in this volume for further details.