The Choice of Drugs for Schizophrenia
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《新英格兰医药杂志》
Schizophrenia is a serious chronic illness that requires lifelong medication. In some patients, the illness is refractory to even highly effective medications such as clozapine, and these patients desperately need more effective treatment regimens. Less dopamine is blocked with clozapine than with other antipsychotic medications, and adding more potent dopamine-blocking drugs, such as risperidone, to clozapine may achieve better efficacy. Three randomized, controlled trials examined the strategy of adding risperidone to clozapine for patients whose illness is refractory to treatment with clozapine alone. In this issue of the Journal, Honer et al.1 report the results of a trial supported by the Stanley Medical Research Institute that addresses this question. This study's investigators did not find any beneficial effects of risperidone augmentation and found a slight worsening in working memory among patients treated with risperidone. In contrast, two previous trials,2,3 which were industry-funded, showed a clear benefit for risperidone augmentation. What are the explanations for these contradictory results?
Although all three trials appeared to be well designed, they had important differences. Honer and colleagues used an average of 2.8 mg per day of risperidone, and the investigators involved in the other two trials with positive findings used substantially higher doses (4.3 to 5.1 mg per day). The dose used in the Honer study may have been too low to achieve efficacy. Previous studies showed that 2 mg per day of risperidone yielded 50 percent of the benefit found with 4 mg or more per day.4 In addition, the two trials that showed positive results included patients with less severe schizophrenia (i.e., with lower scores on the Positive and Negative Syndrome Rating Scale) than in the Honer study. The Honer trial may have focused on patients who were too sick for augmentation to make a difference. Nonetheless, the Honer trial was carefully conducted, and its negative findings introduce palpable doubt about the efficacy of augmentation therapy in refractory schizophrenia. Given the contradictory results among these studies, more industry-funded and independently funded trials are needed.
Like these trials of augmentation therapy, previous trials assessing the primary antipsychotic agents for patients with schizophrenia also had inconsistent results. A meta-analysis, which included mostly industry-funded randomized, controlled trials, showed that the second-generation (i.e., atypical) antipsychotic drugs clozapine, olanzapine, risperidone, and amisulpride were more effective than first-generation (typical) antipsychotic agents.4,5,6,7 Clozapine was the most effective of the second-generation antipsychotic medications, and some second-generation agents (quetiapine, sertindole, and aripiprazole) were not more effective than placebo.4,5,6,7 The large Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), sponsored by the National Institute of Mental Health,8 showed olanzapine to be superior to the other second-generation agents (quetiapine, ziprasidone, and risperidone) and the first-generation agent (perphenazine) studied, in terms of the primary end point, which was time to discontinuation. Many patients in the CATIE trial received 3 mg per day of risperidone or 80 mg per day of ziprasidone, doses that might have been too low in this population,4 and patients with tardive dyskinesia, whose disease was more resistant to treatment, were not randomly assigned to receive perphenazine.
In selecting therapy for patients with schizophrenia, consideration of medication side effects and costs is important (Table 1). The highly effective second-generation agent clozapine causes potentially lethal agranulocytosis in about 1 percent of patients, but the risk of death can be virtually eliminated by requiring weekly evaluation of platelet counts and discontinuation of the drug if these counts are abnormal. Many first-generation agents produce severe extrapyramidal side effects as well as tardive dyskinesia. Haloperidol, a first-generation agent, causes a 10 percent increase in weight at the time of initial treatment for schizophrenia,9 and patients who are later treated with a second-generation atypical antipsychotic agent have an additional 5 to 10 percent weight gain. Typically, the weight gain is rapid in the first month and plateaus after several months. Early weight gain at three to six weeks10,11 is highly predictive of total gain; continued weight gain may be avoided by intervening with a weight-control program or by switching medications. First-generation agents are much less expensive than second-generation agents. However, a generic form of the second-generation agent amisulpride is widely available outside the United States, and generic risperidone will be available shortly.
Table 1. Efficacy, Side Effects, and Costs of Antipsychotic Medications.
The early diagnosis and treatment of the first episode of schizophrenia are important and may prevent or delay more severe disease and the need to consider augmentation therapy. We have known for 30 years that a delay in initiating treatment with antipsychotic medication may increase the need for hospitalization over the subsequent five years.12,13 Unfortunately, the pathologic changes associated with schizophrenia (loss of brain tissue and enlarged ventricles) progress despite treatment with antipsychotic agents. There is limited evidence from randomized, controlled trials that olanzapine (and perhaps other second-generation agents) may slow this progression.14 Prompt diagnosis and treatment of the first episode of schizophrenia are important in preventing progression, preserving family ties, and preventing weight gain.
One important difference between augmentation with a second medication and treatment with the primary antipsychotic agent is that a second medication may be tried and stopped, but a primary medication is typically needed for the rest of the patient's life. Patients who stop taking antipsychotic medications have a relapse rate of about 10 percent per month, until eventually almost all patients have a relapse. In the trials of augmentation therapy with the use of a variety of drugs (e.g., other antipsychotic agents, mood stabilizers, or antidepressants), there have been hints of efficacy but no definitive proof.15 The most important aspects of the decision to initiate a second drug or to change the primary drug are careful assessment of efficacy and the recognition that a drug is not helping and should be discontinued.
I recommend striving for as complete a remission as possible, remembering that the achievable end point needs to be individualized and may vary from minimal improvement to complete remission. In some cases, several second-generation atypical agents must be tried before it is clear that no further improvement is possible. Although the side effects of medication are a major concern, patients do not always have the side effects that worry clinicians, and patients' quality of life is improved tremendously when symptoms of schizophrenia are controlled. In caring for patients with refractory schizophrenia, clinicians must balance efficacy, the prevention of disease progression, and the side effects of medication as they tailor treatment to the individual patient.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Psychiatric Institute, University of Illinois at Chicago, Chicago, and the University of Maryland Psychiatric Research Center, Baltimore.
References
Honer WG, Thornton AE, Chen EYH, et al. Clozapine alone versus clozapine and risperidone with refractory schizophrenia. N Engl J Med 2006;354:472-482.
Anil Yagcioglu AE, Kivircik Akdede BB, Turgut TI, et al. A double-blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safety. J Clin Psychiatry 2005;66:63-72.
Josiassen RC, Joseph A, Kohegyi E, et al. Clozapine augmented with risperidone in the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry 2005;162:130-136.
Davis JM, Chen N. Dose response and dose equivalence of antipsychotics. J Clin Psychopharmacol 2004;24:192-208.
Heres S, Davis JM, Maino K, Jetzinger E, Kissling W, Leucht S. Why olanzapine beats risperidone, risperidone beats quetiapine and quetiapine beats olanzapine again: an analysis of head-to-head studies on second-generation antipsychotics. Am J Psychiatry (in press).
Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry 2003;60:553-564.
Leucht S, Pitschel-Walz G, Engel RR, Kissling W. Amisulpride, an unusual "atypical" antipsychotic: a meta-analysis of randomized controlled trials. Am J Psychiatry 2002;159:180-190.
Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1209-1223.
Zipursky RB, Gu H, Green AI, et al. Clinical correlates of weight gain in first episode patients treated with olanzapine and haloperidol. Presented at the annual meeting of the American Psychiatric Association, San Francisco, May 17–22, 2003 (poster).
Davis JM. A meta-analytic overview of second-generation antipsychotic-induced long-term weight gain. Am J Psychiatry (in press).
Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 2005;19:Suppl 1:1-93.
Davis JM, Chang SS. Does psychotherapy alter the course of schizophrenia? In: Brady JP, Brodie HKH, eds. Controversy in psychiatry. Philadelphia: W.B. Saunders, 1978:595-620.
May PR, Tuma AH, Yale C, Potepan P, Dixon WJ. Schizophrenia -- a follow-up study of results of treatment. Arch Gen Psychiatry 1976;33:481-486.
Lieberman JA, Tollefson GD, Charles C, et al. Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch Gen Psychiatry 2005;62:361-370.
Remington G, Saha A, Chong SA, Shammi C. Augmentation strategies in clozapine-resistant schizophrenia. CNS Drugs 2005;19:843-872.(John M. Davis, M.D.)
Although all three trials appeared to be well designed, they had important differences. Honer and colleagues used an average of 2.8 mg per day of risperidone, and the investigators involved in the other two trials with positive findings used substantially higher doses (4.3 to 5.1 mg per day). The dose used in the Honer study may have been too low to achieve efficacy. Previous studies showed that 2 mg per day of risperidone yielded 50 percent of the benefit found with 4 mg or more per day.4 In addition, the two trials that showed positive results included patients with less severe schizophrenia (i.e., with lower scores on the Positive and Negative Syndrome Rating Scale) than in the Honer study. The Honer trial may have focused on patients who were too sick for augmentation to make a difference. Nonetheless, the Honer trial was carefully conducted, and its negative findings introduce palpable doubt about the efficacy of augmentation therapy in refractory schizophrenia. Given the contradictory results among these studies, more industry-funded and independently funded trials are needed.
Like these trials of augmentation therapy, previous trials assessing the primary antipsychotic agents for patients with schizophrenia also had inconsistent results. A meta-analysis, which included mostly industry-funded randomized, controlled trials, showed that the second-generation (i.e., atypical) antipsychotic drugs clozapine, olanzapine, risperidone, and amisulpride were more effective than first-generation (typical) antipsychotic agents.4,5,6,7 Clozapine was the most effective of the second-generation antipsychotic medications, and some second-generation agents (quetiapine, sertindole, and aripiprazole) were not more effective than placebo.4,5,6,7 The large Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), sponsored by the National Institute of Mental Health,8 showed olanzapine to be superior to the other second-generation agents (quetiapine, ziprasidone, and risperidone) and the first-generation agent (perphenazine) studied, in terms of the primary end point, which was time to discontinuation. Many patients in the CATIE trial received 3 mg per day of risperidone or 80 mg per day of ziprasidone, doses that might have been too low in this population,4 and patients with tardive dyskinesia, whose disease was more resistant to treatment, were not randomly assigned to receive perphenazine.
In selecting therapy for patients with schizophrenia, consideration of medication side effects and costs is important (Table 1). The highly effective second-generation agent clozapine causes potentially lethal agranulocytosis in about 1 percent of patients, but the risk of death can be virtually eliminated by requiring weekly evaluation of platelet counts and discontinuation of the drug if these counts are abnormal. Many first-generation agents produce severe extrapyramidal side effects as well as tardive dyskinesia. Haloperidol, a first-generation agent, causes a 10 percent increase in weight at the time of initial treatment for schizophrenia,9 and patients who are later treated with a second-generation atypical antipsychotic agent have an additional 5 to 10 percent weight gain. Typically, the weight gain is rapid in the first month and plateaus after several months. Early weight gain at three to six weeks10,11 is highly predictive of total gain; continued weight gain may be avoided by intervening with a weight-control program or by switching medications. First-generation agents are much less expensive than second-generation agents. However, a generic form of the second-generation agent amisulpride is widely available outside the United States, and generic risperidone will be available shortly.
Table 1. Efficacy, Side Effects, and Costs of Antipsychotic Medications.
The early diagnosis and treatment of the first episode of schizophrenia are important and may prevent or delay more severe disease and the need to consider augmentation therapy. We have known for 30 years that a delay in initiating treatment with antipsychotic medication may increase the need for hospitalization over the subsequent five years.12,13 Unfortunately, the pathologic changes associated with schizophrenia (loss of brain tissue and enlarged ventricles) progress despite treatment with antipsychotic agents. There is limited evidence from randomized, controlled trials that olanzapine (and perhaps other second-generation agents) may slow this progression.14 Prompt diagnosis and treatment of the first episode of schizophrenia are important in preventing progression, preserving family ties, and preventing weight gain.
One important difference between augmentation with a second medication and treatment with the primary antipsychotic agent is that a second medication may be tried and stopped, but a primary medication is typically needed for the rest of the patient's life. Patients who stop taking antipsychotic medications have a relapse rate of about 10 percent per month, until eventually almost all patients have a relapse. In the trials of augmentation therapy with the use of a variety of drugs (e.g., other antipsychotic agents, mood stabilizers, or antidepressants), there have been hints of efficacy but no definitive proof.15 The most important aspects of the decision to initiate a second drug or to change the primary drug are careful assessment of efficacy and the recognition that a drug is not helping and should be discontinued.
I recommend striving for as complete a remission as possible, remembering that the achievable end point needs to be individualized and may vary from minimal improvement to complete remission. In some cases, several second-generation atypical agents must be tried before it is clear that no further improvement is possible. Although the side effects of medication are a major concern, patients do not always have the side effects that worry clinicians, and patients' quality of life is improved tremendously when symptoms of schizophrenia are controlled. In caring for patients with refractory schizophrenia, clinicians must balance efficacy, the prevention of disease progression, and the side effects of medication as they tailor treatment to the individual patient.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Psychiatric Institute, University of Illinois at Chicago, Chicago, and the University of Maryland Psychiatric Research Center, Baltimore.
References
Honer WG, Thornton AE, Chen EYH, et al. Clozapine alone versus clozapine and risperidone with refractory schizophrenia. N Engl J Med 2006;354:472-482.
Anil Yagcioglu AE, Kivircik Akdede BB, Turgut TI, et al. A double-blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safety. J Clin Psychiatry 2005;66:63-72.
Josiassen RC, Joseph A, Kohegyi E, et al. Clozapine augmented with risperidone in the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry 2005;162:130-136.
Davis JM, Chen N. Dose response and dose equivalence of antipsychotics. J Clin Psychopharmacol 2004;24:192-208.
Heres S, Davis JM, Maino K, Jetzinger E, Kissling W, Leucht S. Why olanzapine beats risperidone, risperidone beats quetiapine and quetiapine beats olanzapine again: an analysis of head-to-head studies on second-generation antipsychotics. Am J Psychiatry (in press).
Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry 2003;60:553-564.
Leucht S, Pitschel-Walz G, Engel RR, Kissling W. Amisulpride, an unusual "atypical" antipsychotic: a meta-analysis of randomized controlled trials. Am J Psychiatry 2002;159:180-190.
Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1209-1223.
Zipursky RB, Gu H, Green AI, et al. Clinical correlates of weight gain in first episode patients treated with olanzapine and haloperidol. Presented at the annual meeting of the American Psychiatric Association, San Francisco, May 17–22, 2003 (poster).
Davis JM. A meta-analytic overview of second-generation antipsychotic-induced long-term weight gain. Am J Psychiatry (in press).
Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 2005;19:Suppl 1:1-93.
Davis JM, Chang SS. Does psychotherapy alter the course of schizophrenia? In: Brady JP, Brodie HKH, eds. Controversy in psychiatry. Philadelphia: W.B. Saunders, 1978:595-620.
May PR, Tuma AH, Yale C, Potepan P, Dixon WJ. Schizophrenia -- a follow-up study of results of treatment. Arch Gen Psychiatry 1976;33:481-486.
Lieberman JA, Tollefson GD, Charles C, et al. Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch Gen Psychiatry 2005;62:361-370.
Remington G, Saha A, Chong SA, Shammi C. Augmentation strategies in clozapine-resistant schizophrenia. CNS Drugs 2005;19:843-872.(John M. Davis, M.D.)