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 trials, 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. 602-4; Level of evidence: B)
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 manic-like 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. 612-3; 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 percent 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. 611-2; 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. 610-1; 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. 610-1; 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. 610-1; 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 phannacotherapy. (Review reference: Scott and Dixon, 1995b, p. 623; Level of evidence: C)
Recommendation 23. Individual and group therapies employing well-specified combinations of support, education, and behavioral and cognitive skills training approaches designed to address the specific deficits of persons with schizophrenia should be offered over time to improve functioning and enhance other targeted problems, such as medication noncompliance.
Rationale. Although the scientific data for this recommendation are limited and flawed, controlled studies have found some additional benefit when a supportive form of psychotherapy is added to pharmacotherapy for persons with schizophrenia. The most effective forms and doses of these therapies and their modes of action remain unknown. (Review reference: Scott and Dixon, 1995b, pp. 623-7; Level of evidence: B)
Recommendation 24. Patients who have ongoing contact with their families should be offered a family psychosocial intervention that spans at least 9 months and provides a combination of education about the illness, family support, crisis intervention, and problem-solving skills training. Such interventions should also be offered to non-family caregivers.
Rationale. Randomized clinical trials have repeatedly demonstrated that family interventions that provide some combination of illness education, support, problem-solving training, and crisis intervention, in combination with appropriate pharmacotherapy, reduce 1-year relapse rates from a 40 to 53 percent range to a 2 to 23 percent range. (Review reference: Dixon and Lehman, 1995, p. 639; Level of evidence: A)
Recommendation 25. Family interventions should not be restricted to patients whose families are identified as having high levels of "expressed emotion" (criticism, hostility, overinvolvement).
Rationale. Although the earlier controlled trials of family psychoeducation programs focused on the variable of family expressed emotion as a mediator of the impact of this intervention on outcomes, more recent studies have found that these interventions offer substantial benefit to patients and families regardless of the level of expressed emotion. (Review reference: Dixon and Lehman, 1995, p. 639; Level of evidence: B)
Recommendation 26. Family therapies based on the premise that family dysfunction is the etiology of the patient's schizophrenic disorder should not be used.
Rationale. Research has failed to substantiate hypothesized causal links between family dysfunction and the etiology of schizophrenia. Therefore, therapies specifically designed from this premise are not empirically founded. Although there has been little or no randomized, controlled research on the impact of family therapies arising from this orientation, experts in the field have expressed strong caution against the use of these techniques. The presumption that family interaction causes schizophrenia, especially as an alternative to biological risk factors, has led to serious disruption in clinician/family trust without any evidence of therapeutic effectiveness. The repudiation of the theoretical premise of these therapies, the lack of empirical studies, and the strong clinical opinion raising concerns about the potential harm caused by these approaches lead to this recommendation. (Review reference: Dixon and Lehman, 1995, p. 631; Level of evidence: C)
Recommendation 27. Persons with schizophrenia who have any of the following characteristics should be offered vocational services. The person:
- Identifies competitive employment as a personal goal.
- Has a history of prior competitive employment.
- Has a minimal history of psychiatric hospitalization.
- Is judged on the basis of a formal vocational assessment to have good work skills.
Rationale. Controlled studies of vocational rehabilitation interventions for persons with schizophrenia have not shown consistent or significant impacts on outcomes other than those directly related to involvement in the rehabilitation program (e.g., increased involvement in sheltered work). However, these studies have been flawed by the failure to control for individual characteristics that may alter a person's vocational potential. They have identified subgroups of recipients post hoc who benefited from the interventions. The above characteristics have been found to be predictive of better vocational outcomes in persons with schizophrenia, and therefore persons with these characteristics should be offered such services. (Review reference: Lehman, 1995, pp. 647-53; Level of evidence: C)
Recommendation 28. The range of vocational services available in a service system for persons with schizophrenia living in the community who meet the criteria defined in Recommendation 27 should include:
- Prevocational training.
- Transitional employment.
- Supported employment.
- Vocational counseling and education services (job clubs, rehabilitation counseling, postemployment services).
Rationale. Recent controlled studies have reported significantly improved vocational outcomes for the supported employment model, which emphasizes rapid placement in a real job setting and strong support from a job coach or other employment specialist to adapt to and sustain the job. Therefore, unless ongoing research fails to substantiate these early findings, supported employment should definitely be available to persons meeting the aforementioned criteria. Scientific data supporting the effectiveness of the other forms of vocational services mentioned above are lacking, but some persons who are good candidates for supported employment may benefit from the addition of these services as well, so they are mentioned in the recommendation. (Review reference: Lehman, 1995, pp. 647-53; Level of evidence: B)
Recommendation 29. Systems of care serving persons with schizophrenia who are high service users should include assertive case management (ACM) and assertive community treatment (ACT) programs.
Rationale. Persons with disabling schizophrenia who are at high risk for discontinuation of treatment or for repeated crises require an array of clinical, rehabilitation, and social services to address their needs. Coordination, integration, and continuity of services among providers over time can be substantially enhanced through ACM and ACT. Randomized trials have demonstrated consistently the effectiveness of these programs in reducing inpatient use among such high-risk patients. Several studies also support improvements in clinical and social outcomes. These studies suggest that both ACT and ACM are superior to conventional case management for high-risk cases. (Review reference: Scott and Dixon, 1995a, pp. 659-64; Level of evidence: A)
Recommendation 30. Assertive community treatment programs should be targeted to individuals at high risk for repeated rehospitalizations or who have been difficult to retain in active treatment with more traditional types of services.
Rationale. The original ACT studies reporting efficacy for these approaches targeted these high-risk persons. The efficacy of either model with lower risk patient groups has not been established. The high cost of ACT therefore warrants careful targeting for cost-effectiveness. (Review reference: Scott and Dixon, 1995a. pp. 659-64; Level of evidence: B)
The PORT's treatment recommendations represent a concerted and systematic effort to develop guidelines about the treatment of persons with schizophrenia distilled narrowly from available scientific evidence. As such, they reflect both the strengths and limitations of this knowledge base. Such recommendations are useful from at least two major perspectives.
First, they form a basis for disseminating current knowledge into practice. The treatment recommendations provide focal points or benchmarks for asking whether current practices measure up to what is known to be helpful based on the best scientific evidence available. Such questions about the quality of care should be asked by treatment practitioners, patients, families, service system planners, and health care payers. Are we providing care based on the best knowledge available?
These recommendations can challenge practitioners and service systems to do better and can challenge patients and families to expect better services. The recommendations are recommendations, not mandates, because individual patient needs vary considerably from the average. However, the treatment recommendations should stimulate close examination of practices at both the aggregate and the individual patient levels to ensure that treatments are offered in the most effective manner.
Second, they serve to highlight what we do not know. Not all of the gaps in our knowledge about treatment can be filled by evidence developed in clinical trials. Clinical wisdom can and should be accumulated and shared directly from practical experience. But there are many aspects of treatment for schizophrenia that need careful, ongoing scientific scrutiny to ensure that, whenever possible, objective evidence of effectiveness is the basis for practice. It should be good news that treatment recommendations such as those presented here will be outdated in the not too distant future and that new knowledge will require their modification, as well as the addition of new recommendations. In short, we should practice what we know today while we are continually learning to change practices for tomorrow.
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Anthony F. Lehman, M.D., Principal Investigator of the Schizophrenia Patient Outcomes Research Team, is Professor of Psychiatry, University of Maryland School of Medicine and Co-Director of the Center for Mental Health Services Research, University of Maryland, Baltimore, MD.
Donald M. Steinwachs, Ph.D., Co-Principal Investigator, is Professor of Health Policy and Management and Chair of the Department of Health Policy and Management, The Johns Hopkins University School of Hygiene and Public Health, Baltimore, MD.
Co-investigators at the Center for Mental Health Services Research, University of Maryland School of Medicine include Lisa B. Dixon, M.D., M.P.H.; Howard H. Goldman, M.D., Ph.D.; Fred Osher, M.D.; Leticia Postrado, Ph.D.; Jack E. Scott, Sc.D.; and James W. Thompson, M.D.
Co-Investigators from the Department of Health Policy and Management, Johns Hopkins University School of Hygiene and Public Health include Maureen Fahey, M.A.; Pamela Fischer, Ph.D.; Judith Ann Kasper, Ph.D.; Alan Lyles, Sc.D.; and Elizabeth Ann Skinner, M.S.W.
Co-Investigators from the Maryland Psychiatric Research Center include Robert Buchanan, M.D.; William T. Carpenter, Jr., M.D.; and Jerome Levine, M.D. The Co-Investigator from the RAND Corporation is Elizabeth Ann McGlynn, Ph.D.
The Co-Investigator from the Department of Veterans Affairs Northeast Program Evaluation Center and Yale University is Robert Rosenheck, M.D.
The Co-Investigator from the University of Maryland School of Pharmacy is Julie Zito, Ph.D.
Adapted from the article published in Schizophrenia Bulletin 1998:24(1);1-10.
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The Schizophrenia Patient Outcomes Research Team (PORT) Treatment Recommendations. 1998. Agency for Healthcare Quality and Research, Rockville, MD. http://www.ahrq.gov/clinic/schzrec.htm