Recommendation 11. Targeted, intermittent dosage maintenance strategies should not be used routinely in lieu of continuous dosage regimens because of the increased risk of symptom worsening or relapse. These strategies may be considered for patients who refuse maintenance or for whom some other contraindication to maintenance therapy exists, such as side-effect sensitivity.
Rationale. The relatively few studies of targeted, intermittent dose strategies suggest that the relapse rate is higher than for continuous maintenance therapy. Therefore, this approach is recommended only for the circumstances identified above. (Review reference: Dixon et al. 1995, pp. 570-571; Level of evidence: B)
Recommendation 12. Depot antipsychotic maintenance therapy should be strongly considered for persons who have difficulty complying with oral medication or who prefer the depot regimen. Depot therapy may be used as a first-option maintenance strategy.
Rationale. Controlled trials have produced inconsistent results with regard to whether depot medication reduces the risk of relapse in comparison with oral medication. However, the design of these studies, which by definition include personswilling to accept medication in a clinical trial, may bias against any advantage of depot medication. Further, the duration of these studies has been inadequate to demonstrate a strong advantage for depot medication. In persons for whom compliance is a problem, depot medication offers clear advantages if it is accepted by the patient. If acceptable to the patient, depot medication is just as appropriate as oral medication as the first-line maintenance therapy strategy. (Review reference: Dixon et al. 1995, p. 573; Level of evidence: B)
Pharmacotherapies: New Antipsychotic Medications.1
Recommendation 13. A trial of clozapine should be offered to patients with schizophrenia or schizoaffective disorder whose positive symptoms do not robustly respond to adequate trials of two different classes of antipsychotic medications. Exceptions include patients who cannot receive clozapine due to a history of blood dyscrasia or cardiac arrhythmia. Lack of response to previous antipsychotic trials is defined by persistent symptoms after two 6-week trials of up to 1,000 CPZ equivalents of antipsychotic agents from two different chemical classes (e.g., phenothiazines and butyrophenones). An adequate clozapine trial should last at least 3 months at a dosage from 300 to 800 mg per day. Dosages should reflect the lowest possible effective dose. If patients do not respond, a blood level should be obtained and dosages slowly increased to 800 mg to the extent that side effects are tolerated. If effective, clozapine should be continued as maintenance therapy.
Rationale. Controlled clinical trials have found that clozapine produces significant clinical improvement in at least 30 percent of patients who fail to achieve an adequate response to or cannot tolerate conventional antipsychotic medications. It should be considered only after other antipsychotic medications prove inadequate because of its low but significant risk of agranulocytosis, complexity of management (weekly white cell count reports), and cost. The level of evidence for the differential effectiveness of clozapine among outpatients is limited by the low number of studies of outpatients. (Review reference: Buchanan 1995, pp. 580-584; Level of evidence: A for inpatients; B for outpatients)
Recommendation 14. A trial of clozapine should be offered to patients with schizophrenia or schizoaffective disorder who have repeatedly displayed violent behavior and persistent psychotic symptoms that have not been responsive to trials of at least two different types of antipsychotic medications (as defined in Recommendation 13).
Rationale. Randomized clinical trials, as well as nonrandomized studies, suggest that clozapine significantly reduces hostility among treatment-refractory patients. It should only be considered after other antipsychotic medications prove inadequate. (Review reference: Buchanan 1995, p. 582; Level of evidence: B)
Recommendation 15. A trial of clozapine should be offered to patients who require antipsychotic therapy, but who experience intolerable side effects to other antipsychotic agents, including severe or very distressing tardive dyskinesia, persistent dystonia, and neuroleptic malignant syndrome.
Rationale. A limited body of evidence suggests that clozapine causes substantially less tardive dyskinesia than antipsychotic medications, although there are reports of cases in which tardive dyskinesia has worsened on clozapine. For the patient with severe tardive dyskinesia for whom ongoing treatment with another antipsychotic agent poses a substantial risk of continuation or further progression of the movement disorder, but for whom antipsychotic therapy is essential to prevent serious relapse, a trial with clozapine is indicated. (Review reference: Buchanan 1995, p. 587; Level of evidence: B)
Recommendation 16. Persons who achieve an adequate reduction in positive symptoms on conventional antipsychotic medications, but who have significant EPS that do not respond adequately to anti-Parkinson agents, should be offered a trial of risperidone. An adequate risperidone trial for this purpose should last from 6 to 12 weeks at a dosage from 4 to 10 mg per day. Dosages should reflect the lowest possible effective dose. Per Recommendation 1, risperidone also can be used as a first-line medication.
Rationale. In clinical t rials, risperidone has been found to be at least as effective as other antipsychotic medications in reducing the positive symptoms of schizophrenia. Its major potential advantage over other antipsychotic medications is that it produces fewer EPS at the lower end of its effective dose range (4-10 mg per day). Therefore, for patients on the older antipsychotic agents and in whom EPS is a significant problem, risperidone offers an alternative. (Review reference: Umbricht and Kane 1995, pp. 602-604; Level of evidence: B)
1As of the writing of these recommendations (September 1996), additional antipsychotic agents were expected to reach the market within the next 1 to 2 years. These agents include olanzapine, quetiapine, sertindole, and ziprasidone. No recommendations specific to these newer compounds are included because the level of data on them is more limited than for clozapine and risperidone. Until proven otherwise, the use of these newer compounds, when marketed, should follow the recommendations for antipsychotic agents other than clozapine.
Pharmacotherapies: Adjunctive Pharmacotherapies.
Recommendation 17. Persons who experience persistent and clinically significant, associated symptoms of anxiety, depression, or hostility, despite an adequate reduction in positive symptoms with antipsychotic therapy, should receive a trial of adjunctive pharmacotherapy. A trial of a benzodiazepine or propranolol is merited for persistent anxiety. An antidepressant trial should be considered for persistent depression. Adjunctive therapy with lithium, a benzodiazepine, or carbamazepine should be considered for persistent hostility or maniclike symptoms. The reasons for the absence of such trials for appropriate patients should be documented. Certain adjunctive medications should be avoided in patients currently receiving clozapine to avoid synergistic side effects; for example, respiratory depression with benzodiazepines and bone marrow suppression with carbamazepine.
Rationale. Anxiety and tension may respond to treatment with adjunctive benzodiazepines, although a few studies reported a waning effect of these agents, perhaps due to tolerance, after a few weeks of treatment. Disruptive, dangerous, or assaultive behavior may be modified by the addition of benzodiazepines or carbamazepine to an antipsychotic regimen. Evidence of the usefulness of benzodiazepines for this indication comes from open or retrospective studies, and no double-blind studies have thus far addressed its efficacy. Similarly, these behaviors are cited as potentially responsive to adjunctive carbamazepine, although most evidence is from open studies, with only one positive double-blind study. Excitement and irritability (often classified as "affective symptoms") seem to benefit from adjunctive lithium treatment, with a small amount of evidence that benzodiazepines and carbamazepine also might be useful. Antidepressants seem to benefit patients who have episodic signs and symptoms of depressive illness in addition to schizophrenia, if they are administered in phases of illness other than the active, psychotic exacerbation phase. Antidepressants can be efficacious without exacerbating psychotic symptoms when used adjunctively with antipsychotics. Most studies of adjunctive treatments for schizophrenia were done with patients who had chronic schizophrenia and who were often designated as treatment refractory. Little is known about the efficacy of adjunctive agents for first-episode schizophrenia, for patients experiencing acute episodes of psychosis, or for stable patients receiving maintenance antipsychotic therapy. Little is known about the long-term effectiveness of adjunctive agents. (Review reference: Johns and Thompson 1995, pp. 612-613; Level of evidence: B)
Recommendation 18. Persons who experience persistent and clinically significant positive symptoms despite adequate antipsychotic therapy, including trials with the newer antipsychotics (clozapine or risperidone), should receive a trial of adjunctive pharmacotherapy as described in Recommendation 17.
Rationale. No adjunctive agent has demonstrated clear and consistent benefit in a majority of persons with schizophrenia. However, the most promising agents are the benzodiazepines (which may be useful in as many as 50% of patients with schizophrenia), lithium, and carbamazepine (which may be of mild or modest value to treatment-nonresponsive patients). Very little evidence supports a role for adjunctive propranolol. Valproate, calcium channel blockers, antidepressants, clonidine, and dopaminergic agents have no demonstrated use in terms of global improvement, although they may be useful for individual symptom complexes. Positive symptoms may improve when benzodiazepines, carbamazepine, lithium, or propranolol are added to antipsychotics. Adjunctive benzodiazepines produced significant improvement of positive symptoms in about half the double-blind studies that addressed this question. Adjunctive carbamazepine produced significant improvement in only a fraction of double-blind studies. Adjunctive lithium seems to alleviate, to some degree, positive symptoms in a subgroup of patients. Finally, adjunctive propranolol produces only slim evidence of a therapeutic effect on positive symptoms in a minority of double-blind studies. (Review reference: Johns and Thompson 1995, pp. 611-612; Level of evidence: C)
Electroconvulsive Therapy (ETC).
Recommendation 19. Patients who have not responded to recommended antipsychotic therapy should be considered for a trial of ECT alone or in combination with an antipsychotic if (a) the person has been ill for less than 1 year or, if ill for more than 1 year, is in the early phase of an acute exacerbation or (b) affective or catatonic symptoms are predominant.
Rationale. There are scientifically sound studies that show that ECT reduces acute symptoms in schizophrenia. Some authors dispute this finding, however, with several pointing to the problem of affective symptoms in schizophrenia and the diagnostic confounding of schizophrenia with affective disorders. The majority of authors indicate that a secondary role is most appropriate, and there is a general consensus that the effects of ECT on schizophrenia are short lived. A few studies with minimal data show continued improvement at followup of several years when ECT is followed by maintenance antipsychotic therapy. Catatonic schizophrenia and schizoaffective disorder seem to be most responsive to ECT, and in general the affective symptoms respond selectively to it. (Review reference: Johns and Thompson 1995, pp. 610-611; Level of evidence: B)
Recommendation 20. The dosage of ECT (i.e., number of treatments) used to treat patients with schizophrenia should be comparable to that used for patients with affective disorders (about 12 treatments).
Rationale. Three controlled studies found definite improvement after 12 or fewer treatments, and another study indicates that the average number of treatments needed for improvement is 13.6. (Review reference: Johns and Thompson 1995, pp. 6 10-611; Level of evidence: B)
Recommendation 21. Regressive forms of ECT are not recommended for persons with schizophrenia.
Rationale. Most reviewers indicate that selected patients with severe and chronic schizophrenia may benefit from modified ECT, but others indicate that the procedure is "drastic," "experimental," and "controversial." (Review reference: Johns and Thompson 1995, pp. 610-611; Level of evidence: C)
Recommendation 22. Individual and group psychotherapies adhering to a psychodynamic model (defined as therapies that use interpretation of unconscious material and focus on transference and regression) should not be used in the treatment of persons with schizophrenia.
Rationale. The scientific data on this issue are quite limited. However, there is no evidence in support of the superiority of psychoanalytic therapy to other forms of therapy, and there is a consensus that psychotherapy that promotes regression and psychotic transference can be harmful to persons with schizophrenia. This risk, combined with the high cost and lack of evidence of any benefit, argues strongly against the use of psychoanalytic therapy, even in combination with effective pharmacotherapy. (Review reference: Scott and Dixon 1995b, p. 623; Level of evidence: C)
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