Recommendations for the treatment of schizophrenia based on existing scientific evidence were developed by the Schizophrenia Patient Outcomes Research Team (PORT). Based on exhaustive reviews of the treatment outcomes literature, the treatment recommendations focus on treatments for which there is substantial evidence of efficacy.
By surveying a random sample of persons with schizophrenia, the PORT also examined patterns of usual care for conformance to its treatment recommendations (select to access).
Adapted from Schizophrenia Bulletin 1998:24(1);1-10. Editor's Note: 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 do not necessarily represent those of the staff or the Editorial Advisory Board of the Bulletin.
By Anthony F. Lehman, Donald M. Steinwachs, and the Co-Investigators of the PORT Project
Abstract / Background / Treatment Recommendations
Discussion / References / Author Information
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, based on exhaustive reviews of the treatment outcomes literature (published in Schizophrenia Bulletin, Vol. 21, No. 4, 1995), focus on those treatments for which there is substantial evidence of efficacy.
The recommendations address:
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's 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.
Key words: Mental health services, quality of care.
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 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's 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 it 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's treatment recommendations will be used to enhance the treatment currently being offered to persons with schizophrenia.
The PORT's 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:
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:
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.
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 chlorpromazifle (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, 2, 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)
Port recommended total
daily dose range(mg/day)
CPZ-equivalence Acute Maintenance
Medication CPZ equivalence¹ multiplier² therapy therapy
_______________________________________________________________________________________________________
Chlorpromazine 100 1 300-1000 300-600
Triflupromazine 25 4 75-250 75-250
Mesoridazine 50 2 150-400³ 150-300
Thioridazine 100 1 300-800³ 300-600
Acetophenazine 20 5 60-200 60-120
Fluphenazine HCl 2 50 6-20 6-12
Perphenazine 10 10 30-100 30-60
Prochlorperazine 15 6 50-150 50-100
Trifluoperazine 5 20 15-50 15-30
Chlorprothixene 100 1 300-1000 300-600
Thiothixene 5 20 15-50 15-30
Haloperidol 2 50 6-20 6-12
Loxapine 10 10 30-100 30-60
Molindone 10 10 30-100 30-60
Clozapine 50 2 200-600 200-800
Risperidone 1 100 4-10 4-10
Note: PORT = Patient Outcomes Research Team. HCl - hydrochloride. Adapted from Zito (1994) and Kane (1996).
¹Approximate dose equivalent to 100 mg of chlorpromazine (relative potency); may not be the same at lower versus higher doses.
²This number multiplied by the dose of antipsychotic medication results in the chlorpromazine-equivalent dose.
³To avoid the risk of retinopathy, doses of 400 mg (mesoridazine) and 800 mg (thioridazine)should not be exceeded.
Decanoate dosing schedule _______________________________________________________________________________________________________
Q Every Week Q Every 2 Week Q Every 3 Weeks Q Every 4 Weeks
_______________________________________________________________________________________________________
FPZ- Oral CPZ- FPZ- Oral CPZ- FPZ- Oral CPZ- FPZ- Oral CPZ-
DEC FPZ HCl EQ DEC FPZ HCl EQ DEC FPZ HCl EQ DEC FPZ HCl EQ
(mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg)
_______________________________________________________________________________________________________
6.25 10 500 6.25 5 250 6.25 3.3 165 6.25 2.5 125
(.25cc) (.25cc) (.25cc) (.25cc)
12.5 20 1000 12.5 10 500 12.5 6.6 333 12.5 5.0 250
(.50cc) (.50cc) (.50cc) (.50cc)
18.75 30 1500 18.75 15 750 18.75 10.0 500 18.75 7.5 375
(.75cc) (.75cc) (.75cc) (.75cc)
25 40 2000 25 20 1000 25 13.3 665 25 10.0 500
(1.0cc) (1.0cc) (1.0cc) (1.0cc)
37.5 60 3000 37.5 30 1500 37.5 20.0 1000 37.5 15.0 750
(1.50cc) (1.50cc) (1.50cc) (1.50cc)
50 80 4000 50 40 2000 50 26.3 1315 50 20.0 1000
(2.0cc) (2.0cc) (2.0cc) (2.0cc)
Note: Q = quantity. Fluphenazine decanoate (FPZ-DEC) doses are converted to daily oral fluphenazine hydrochloride (oral FPZ HCl) doses and to estimated daily chlorpromazine-equivalent (CPZ-EQ) doses. Decanoate conversions are based on empirical rule suggested by Kane (25 mg every 3 weeks of decanoate is equivalent to 665 CPZ-EQ per day). These are theoretically determined values and should be interpreted as approximations only. Therefore, comparisons of daily CPZ-EQ doses derived from these values with Patient Outcomes Research Team (PORT)-recommended oral dosings should not be made. However, decanoate doses below the lines are not recommended. Adapted from Zito (1994) and Kane (1996).
HPL-DEC Q every month HPL Q every day CPZ-EQ _______________________________________________________________________________________________________ 50 mg (1.0 cc) 5 mg 250 mg 100 mg (2.0 cc) 10 mg 500 mg 150 mg (2.5 cc) 15 mg 750 mg 200 mg (3.0 cc) 20 mg 1000 mg
Note: Q = quantity. Haloperidol decanoate (HPL-DEC) doses are converted to daily oral haloperidol (HPL) doses and to estimated daily chlorpromazine-equivalent (CPZ-EQ) doses. Decanoate conversions are based on the following rule: 5 mg oral HPL per day is equivalent to 50 mg HPL-DEC every month. These are theoretically determined values and should be interpreted as approximations only. Therefore, comparisons of daily CPZ-EQ doses derived from these values with Patient Outcomes Research Team (PORT)-recommended oral dosings ranges should not be made. Adapted from Zito (1994) and Kane (1996).
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:
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 Sins, 1987; Davis et al., 1989; Level of evidence: B)
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. 569-70; 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 percent) 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. 570-2; 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 (more than 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. 570-1; Level of evidence: C)
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. 570-1; 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 persons willing 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)
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. 580-4; Level of evidence: A for inpatients; B for outpatients)
1 As 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.
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)