At Issue: Translating Research Into Practice:
The Schizophrenia Patient
Outcomes Research Team (PORT) Treatment Recommendations
Anthony F. Lehman, Donald M. Steinwachs, and the Co-Investigators of the PORT Project
The At Issue section of the Schizophrenia Bulletin contains viewpoints and arguments on controversial issues. Articles published in this section may not meet the strict editorial and scientific standards that are applied to major articles in the Bulletin. In addition, the viewpoints expressed in the following articles do not necessarily represent those of the staff or the Editorial Advisory Board of the Bulletin. --The Editors.
Beginning in 1992, the Agency for Health Care Policy and Research and the National Institute of Mental Health funded the Schizophrenia Patient Outcomes Research Team (PORT) to develop and disseminate recommendations for the treatment of schizophrenia based on existing scientific evidence. These Treatment Recommendations, presented here in final form for the first time, are based on exhaustive reviews of the treatment outcomes literature (previously published in Schizophrenia Bulletin, Vol. 21, No. 4, 1995) and focus on those treatments for which there is substantial evidence of efficacy. The recommendations address antipsychotic agents, adjunctive pharmacotherapies, electroconvulsive therapy, psychological interventions, family interventions, vocational rehabilitation, and assertive community treatment/intensive case management. Support for each recommendation is referenced to the previous PORT literature reviews, and the recommendations are rated according to the level of supporting evidence. The PORT Treatment Recommendations provide a basis for moving toward "evidence-based" practice for schizophrenia and identify both the strengths and limitations in our current knowledge base. [Schizophrenia Bulletin 24(1):1-10, 1998. National Institute of Mental Health.]
In 1992 the Agency for Health Care Policy and Research (AHCPR) and the National Institute of Mental Health established a Patient Outcomes Research Team (PORT) for Schizophrenia at the University of Maryland School of Medicine and the Johns Hopkins University School of Public Health. This PORT combines the expertise of three major research centers at two universities: the Center for Research on Services for Severe Mental Illness (Johns Hopkins University and the University of Maryland), the University of Maryland Center for Mental Health Services Research, and the Maryland Psychiatric Research Center (at the University of Maryland). The prime objective of the PORT is to develop recommendations for the treatment of persons with schizophrenia based on a synthesis of the best scientific evidence, with the ultimate goal of improving the quality and cost-effectiveness of care for persons with this diagnosis.
The PORT Treatment Recommendations are statements about the care of persons with schizophrenia based on substantial scientific evidence. They begin with the assumption that an accurate diagnosis of schizophrenia has been made. They also recognize that treatment for an individual will depend on a variety of factors other than a diagnosis of schizophrenia, such as the presence of other psychiatric and medical conditions, personal and social circumstances, and individual variations. By nature of the fact that the Treatment Recommendations are based on scientific studies, they reflect what is known from well-controlled research. However, this requirement that recommendations be based on substantial scientific evidence means they are silent about or may appear to understate the importance of other aspects of treatment that have not been evaluated adequately. Therefore, there are many more recommendations about pharmacotherapies than about psychosocial treatments. This does not mean that psychosocial treatments are less important than medications, but reflects the fact that we know much less about which psychosocial treatments are helpful. Future research may shed light on these other aspects of care that are often viewed by practitioners, consumers, and families as vitally important, but for which we lack adequate scientific evidence for efficacy and effectiveness at the present time. Even with these limitations in mind, it is hoped that the PORT Treatment Recommendations will be used to enhance the treatment currently being offered to persons with schizophrenia.
The PORT Treatment Recommendations are organized according to categories of interventions, consistent with the framework of the recently completed review of the treatment literature by the PORT--see Schizophrenia Bulletin, Vol. 21, No. 4, 1995. The intervention categories are (1) antipsychotic medications; (2) adjunctive pharmacotherapies for anxiety, depression, and aggression/hostility; (3) electroconvulsive therapy; (4) psychological interventions; (5) family interventions; (6) vocational rehabilitation; and (7) assertive community treatment/assertive case management. For each recommendation, a brief rationale and annotations to the above referenced issue of Schizophrenia Bulletin are provided. These earlier literature reviews offer extensive bibliographies for the interested reader.
The level of evidence for each recommendation is also provided. In writing the recommendations, the PORT investigators adopted the criteria on levels of evidence used for development of the AHCPR Depression Guidelines, as follows:
Level A: Good research-based evidence, with some expert opinion, to support the recommendation
Level B: Fair research-based evidence, with substantial expert opinion, to support the recommendation
Level C: Recommendation based primarily on expert opinion, with minimal research-based evidence, but significant clinical experience
We sent initial drafts of these recommendations to experts for review. The experts were asked to rate their level of agreement with each recommendation based on their knowledge of the literature and to provide citations of studies that would argue for revision of the recommendations. Recommendations were modified based on this feedback only if supporting data from published research were provided; that is, opinion alone was not considered adequate to modify a recommendation.
Pharmacotherapies: Treatment of Acute Symptom Episodes.
Recommendation 1. Antipsychotic medications, other than clozapine, should be used as the first-line treatment to reduce psychotic symptoms for persons experiencing an acute symptom episode of schizophrenia.
Rationale. Over 100 randomized double-blind studies consistently support the efficacy of antipsychotic medications relative to placebo in the reduction of the acute positive
symptoms (hallucinations, delusions, thought disorganization, bizarre behavior) of schizophrenia. Approximately 50 to 80 percent of persons will improve significantly with this treatment compared with about 5 to 45 percent on placebo. (Review references: Dixon et al. 1995, p. 568; Umbricht and Kane 1995, p. 603; Level of evidence: A)
Recommendation 2. The dosage of antipsychotic medication for an acute symptom episode should be in the range of 300-1,000 chlorpromazine (CPZ) equivalents per day for a minimum of 6 weeks. Reasons for dosages outside this range should be justified. The minimum effective dose should be used. (Cross-reference tables of CPZ dose equivalents of various antipsychotic agents are included in tables 1-3.)
Rationale. Randomized clinical trials have consistently found that acute positive symptoms in most persons respond to a daily dose of an antipsychotic medication between 300 and 1,000 CPZ equivalents administered for a minimum of 6 weeks. The risk of suboptimal response increases substantially below this range, and there is little evidence of further benefit above this range. Higher doses also carry an increased burden of side effects. (Review reference: Dixon et al. 1995, p. 569; Level of evidence: A)
Recommendation 3. Persons experiencing their first acute symptom episode should be treated with an antipsychotic medication other than clozapine, but dosages should remain in the lower end of the range mentioned in Recommendation 2 (300-500 mg CPZ equivalents per day).
Rationale. Recent studies indicate that persons experiencing their first episode of acute symptoms of schizophrenia respond as well or better to antipsychotic medications in terms of symptom reduction than persons experiencing a recurrent episode. They may also respond to somewhat lower doses. Although "watchful waiting" is an alternative approach raised by concerns about medication side effects, this option is mitigated by concerns that persistent psychosis may complicate the subsequent course of illness. (Review reference: Dixon et al. 1995, p. 574; Level of evidence: B)
Recommendation 4. Massive loading doses of antipsychotic medication, referred to as the practice of "rapid neuroleptization," should not be used.
Rationale. Rapid loading doses of antipsychotic medications have shown no general advantage over more moderate dosing approaches (see Recommendation 2). They also carry a significant side-effect burden. Rapid initiation of antipsychotic treatment is important at the onset of an exacerbation, but not a rapid loading dose. (Review reference: Dixon et al. 1995, p. 569; Level of evidence: A)
Recommendation 5. Since studies have found no superior efficacy of any antipsychotic medication over another in the treatment of positive symptoms, except for clozapine in treatment-refractory patients, choice of antipsychotic medication should be made on the basis of patient acceptability, prior individual drug response, individual side-effect profile, and long-term treatment planning.
Rationale. As above, studies have found no superior efficacy of any of the antipsychotic medications relative to each other in the treatment of positive symptoms. (Review reference: Dixon et al. 1995, p. 573; Level of evidence: A for equivalent efficacy; C for other factors affecting medication choice)
Recommendation 6. Monitoring of plasma levels of antipsychotic medications should be limited to the following circumstances: (1) when patients fail to respond to what is usually an adequate dose; (2) when it is difficult for the clinician to discriminate drug side effects--particularly akathisia or akinesia--from symptoms of schizophrenia such as agitation or negative symptoms (a high blood level might be associated with increased adverse effects); (3) when antipsychotic drugs are combined with other drugs that may affect their pharmacokinetics; (4) in the very young, the elderly, and the medically compromised in whom the pharmacokinetics may be significantly altered; and (5) when noncompliance is suspected. Plasma levels are most useful when using haloperidol, which has only one active metabolite.
Rationale. In general, there is at best a moderate correspondence between plasma drug level and clinical response to antipsychotic medications. Studies suggest an inverted-U or therapeutic window response curve such that persons with moderate plasma levels of haloperidol show a better clinical response than those with low or high levels. The upper end of this therapeutic window is often defined by side effects. Inadequate clinical response to apparently adequate dosages of antipsychotic medications warrants assessment of plasma levels to rule out unusual or altered drug metabolism or noncompliance. (Review references: Baldessarini et al. 1990; Kane and Marder 1993; Level of evidence: B)
Recommendation 7. Prophylactic use of anti-Parkinson agents to reduce the incidence of extrapyramidal side effects (EPS) should be determined on a case-by-case basis, taking into account patient and physician preferences, prior individual history of EPS, and other risk factors for both EPS and anticholinergic side effects. The effectiveness of and continued need for anti-Parkinson agents should be assessed in an ongoing fashion.
Rationale. Although the data are clear that anti-Parkinson agents are effective in reducing or eliminating the EPS of antipsychotic medications, experts disagree about the advisability of using these agents prophylactically. The controversy arises in weighing the risks of EPS against those of the side effects of anti-Parkinson agents. Prophylaxis may be especially important among persons with a prior history of noncompliance or drug discontinuation related to EPS and among persons for whom even mild EPS may lead to drug aversion (e.g., among patients with paranoia or somatic delusions). Avoidance of anticholinergic effects may be especially important in the elderly and in individuals with a history of anticholinergic crises. (Review references: Rifkin and Siris 1987; Davis et al. 1989; Level of evidence: B)
Pharmacotherapies: Maintenance Pharmacotherapy.
Recommendation 8. Persons who experience acute symptom relief with an antipsychotic medication should continue to receive this medication for at least 1 year subsequent to symptom stabilization to reduce the risk of relapse or worsening of positive symptoms.
Rationale. More than 30 clinical trials have confirmed that maintenance therapy with an antipsychotic medication after an initial positive response during an acute symptom episode significantly reduces the risk of symptom relapse during the first year after the acute symptom episode. On average, persons on maintenance therapy experienced symptom relapse over a followup year at a rate of about 20 to 25 percent compared with about 55 percent for those on placebo. The value of maintenance therapy beyond the first year has not been studied extensively. (Review reference: Dixon et al. 1995, pp. 569-570; Level of evidence: A)
Recommendation 9. The maintenance dosage should be in the range of 300 to 600 CPZ equivalents (oral or depot) per day. If the initial dosage to relieve an acute symptom episode exceeds this range, efforts should be made to reduce the dosage gradually to this range, such as a 10 percent reduction in dosage every 6 weeks until either early signs of relapse begin to emerge or until the lower level of this recommended range is achieved (see Recommendation 2). The new maintenance dosage should be at the last level at which symptoms were well controlled. Dosages in excess of 600 CPZ equivalents per day should be avoided unless symptom control and patient comfort are clearly superior at these higher dosages. The lowest effective dose should be used.
Rationale. Maintenance therapy trials have found that maintenance doses below 300 mg CPZ equivalents per day carry an increased risk of relapse, although a substantial proportion of persons (up to 50%) can be maintained successfully at these lower doses, warranting a gradual and carefully monitored effort to reduce dosage over time. There is no evidence that maintenance doses above 600 mg CPZ equivalents per day confer any additional advantage in general. (Review reference: Dixon et al. 1995, pp. 570-572; Level of evidence: A)
Recommendation 10. Reassessment of the dosage level or the need for maintenance antipsychotic therapy should be ongoing. Patients who have had only one episode of positive symptoms before initiation of antipsychotic therapy and who have experienced no positive symptoms during the year of maintenance therapy should be given a trial period off medication, assuming they are aware of the potential risk of relapse and agree to this plan. For patients with more than one prior episode who have experienced good symptom control on the medication during the preceding year, maintenance therapy should be continued unless unacceptable side effects or some other contraindications to antipsychotic treatment have developed. If the maintenance dosage has been high (>600 CPZ equivalents) during the past year, attempts to lower the dosage as described in Recommendation 9 should be considered. Reasons for not attempting to lower dosage should be clearly indicated, such as patient preference in the face of concerns about symptom relapse or life stressors that militate against attempts to lower medications.
Rationale. Clinical trials of maintenance antipsychotic therapy have generally not followed patients in maintenance therapy beyond 1 year, and thus evidence regarding long-term maintenance is lacking (see also rationale for Recommendation 8). (Review references: Kissling 1992; Dixon et al. 1995, pp. 570-571; Level of evidence: C)
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