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A Critical Review of Atypical Antipsychotic Utilization: Comparing Monotherapy with Polypharmacy and Augmentation
S.M. Stahl1,2* and M.M. Grady1
1Neuroscience 2University

Education Institute, 5857 Owens Avenue Suite 102, Carlsbad, CA 92008, USA

of California, San Diego, USA

Abstract: The atypical antipsychotics risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole have become first-line treatment for schizophrenia because they reduce the positive symptoms of psychosis but do not have a high incidence of extrapyramidal symptoms. However, these agents, like other antipsychotics, may take as long as 16 or more weeks to produce a response, and even with prolonged treatment are unlikely to evoke responses greater than 50% improvement in symptoms. This has led to the experimental use of high atypical antipsychotic doses, antipsychotic polypharmacy, and augmentation with other psychotropic drugs, all of which occur commonly in clinical practice. This article reviews the current evidence for these increasingly common means of treating schizophrenia and psychosis, with particular emphasis on polypharmacy and augmentation. To date, there are only two controlled studies of antipsychotic polypharmacy involving an atypical antipsychotic; the rest of the data are uncontrolled trials and case reports that describe a mixture of positive and negative findings. One multicenter, double-blind trial shows a faster onset of action when divalproex is added to risperidone or olanzapine than with antipsychotic monotherapy. A small double-blind study demonstrates efficacy when lamotrigine is added to clozapine. The rest of the data on augmentation with anticonvulsants are uncontrolled, and most report adverse effects. With the exception of divalproex, there are currently no compelling data to justify the use of antipsychotic polypharmacy or augmentation. Existing evidence suggests that the best treatments for schizophrenia and psychosis may be long-term trials of a sequence of atypical antipsychotic monotherapies at therapeutic doses.

Keywords: atypical, antipsychotic, polypharmacy, augmentation INTRODUCTION The "atypical" antipsychotics represent a major breakthrough in the treatment of schizophrenia, as they not only can prevent the significant side effects associated with the older agents at therapeutic doses, but may also have greater efficacy in the treatment of negative and cognitive symptoms. In fact, except for clozapine, which has a unique but serious side effect profile, these agents, which include risperidone, olanzapine, quetiapine, and ziprasidone*, have become the first-line treatment for schizophrenia in the United States. As monotherapies, the atypical antipsychotics have efficacy at least comparable to the older conventional antipsychotics in that they reduce the positive symptoms of psychosis, such as delusions and hallucinations [1-2]. They may even be efficacious for negative and cognitive symptoms, which do not seem to improve with conventional antipsychotics [1]. However, the "atypicality"
*Address correspondence to this author at the Neuroscience Education Institute, 5857 Owens Avenue Suite 102, Carlsbad, CA 92008, USA; Email: smstahl@neiglobal.com *Aripiprazole, an antipsychotic with a mechanism of action different than both the conventional and atypical antipsychotics, was approved in November 2002. Aripiprazole is not included in this analysis because at the time of writing there were no data documenting its use in conjunction with other agents. 0929-8673/03 $45.00+.00

of these agents stems not from their potential superiority with regard to efficacy but rather from their definitive superiority with regard to two specific adverse effects: Extrapyramidal symptoms (EPS) in all cases and prolactin elevation in most cases [2]. With the exception of risperidone [3], none of the atypical antipsychotics consistently raise prolactin, and in fact some may actually lower prolactin levels slightly [4]. More notably, at therapeutic doses, none of the atypical antipsychotics has a high incidence of extrapyramidal symptoms, although this can occur in some patients, especially at high doses [1-2, 5]. Avoiding EPS enhances tolerability, which may also improve compliance. Furthermore, EPS are associated with worsened negative and cognitive symptoms, and thus preventing EPS may itself be associated with better efficacy [2]. However, the atypical antipsychotics are not miracle drugs. Although for the most part they do not cause prolactin elevation or EPS, these agents do have potentially significant side effects, including weight gain and increased risk of diabetes mellitus (the side effect profile differs for each agent; for a review of atypical antipsychotic side effect profiles please see reference 5). In addition, even if atypical antipsychotics do ultimately provide better relief of a greater number of symptoms than the conventional antipsychotics, the time to response for most patients can still be as long as 16-20 weeks [6-7]. Most randomized studies in the literature have a duration of only four to eight weeks; however, rare studies assessing response rates across longer time periods
2004 Bentham Science Publishers Ltd.

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have shown that it may take longer than eight weeks for some patients to achieve a clinical response. Mahmoud et al. [6] found that risperidone response rates, defined as a 30% improvement in total score on the Positive and Negative Syndrome Scale (PANSS), increased from 35% at month 4 to nearly 50% at month 8, and again to nearly 60% at month 12. Notable increase in response rates beyond eight weeks has also been demonstrated in another as yet unpublished study for both olanzapine and risperidone [Data on file, Eli Lilly]. In particular, time to response may be longer for patients with past episodes, as each successive episode may increase the time to remission [7]. Response to an atypical antipsychotic is generally defined in clinical trials as a 20-30% improvement in symptoms. In a fairly typical 28-week double-blind study comparing olanzapine and risperidone, over 60% of the total study population achieved a response when the criterion was a 20% improvement in Positive and Negative Syndrome Scale total score (PANSS) [8]. However, when the criterion was a 50% improvement in total PANSS, the overall response rate dropped to 17%. Other studies show similar drops in response rates when the criteria are more stringent [6]. Thus, while superior to the conventional antipsychotics, these agents may not provide the early and robust responses that clinicians seek when faced with patients having severe and disabling symptoms. This has led to the experimental use of high atypical antipsychotic doses, antipsychotic polypharmacy, and augmentation in clinical practice. Such practices frequently occur after a trial of one or possibly two atypical antipsychotic monotherapies, as determined in an analysis of outpatient prescribing practices with the California Medicaid program (Medi-Cal) (figure 1) [9]. In the United States, the annual rates in one outpatient study of atypical-atypical antipsychotic polypharmacy for schizophrenic patients were 4.8% in 1999 and 5.1% in 2000, while the rates of combining an atypical antipsychotic with any antipsychotic were 17.9% in 1999 and 16.5% in 2000 [IMS Health, National Disease and Therapeutic Index]. In a recent analysis of Medi-Cal data from May 1999 through August 2000, 4.1% of patients prescribed an atypical antipsychotic received two or more atypical antipsychotics (risperidone, olanzapine, or quetiapine) simultaneously for 60 days or more, while 9.8% of patients prescribed any antipsychotic received two or more simultaneously for 60 days or more [9]. Augmentation of antipsychotics with psychotropic drugs of other classes is also a frequent practice in the treatment of schizophrenia, particularly with anticonvulsants, antidepressants, and benzodiazepines [9-10]. The growing rates of high atypical antipsychotic doses, antipsychotic polypharmacy, and augmentation warrant an evaluation of the existing data surrounding the efficacy and safety of these practices. While recent reviews have assessed the evidence for certain types of antipsychotic polypharmacy [11-12], to date there are no comprehensive reviews of all forms of antipsychotic polypharmacy as well as common forms of augmentation with other psychotropic drugs. This article will review the current evidence for these increasingly common means of treating schizophrenia and psychosis, with particular emphasis on polypharmacy and augmentation, and assess the value of such practices as

compared to atypical antipsychotic monotherapies (see figures 2 and 3). High Doses of Atypical Antipsychotics The therapeutic dosing range for each of the atypical antipsychotics is based on manufacturers recommendations, randomized clinical trials, and actual clinical practice. The currently accepted therapeutic range for risperidone is 4-8 mg/day, for olanzapine is 10-20 mg/day, for quetiapine is 200-800 mg/day, and for ziprasidone is 40-160 mg/day [13]. However, prescribed doses commonly exceed these recommendations [9]. Atypical antipsychotics, which are already the most expensive psychotropic drug class [9], can be twice as expensive at high doses. However, the monetary costs may be justified if treatment with high doses is supported by empirical evidence. Therefore, to determine the value of using high doses of the first-line atypical antipsychotics, a Medline search was undertaken and the following terms were cross-referenced with each other: atypical, risperidone, olanzapine, quetiapine, ziprasidone, high dosing, dose. More evidence exists for high doses of olanzapine than for the other atypical antipsychotics. These data, which consist mostly of case reports and uncontrolled trials, generally demonstrate that doses of olanzapine greater than 20 mg/day may enhance efficacy without adverse effects [1429]. Three double-blind studies assessing high doses of olanzapine have been published, all with treatment-resistant populations [18, 23, 30]. In one, 25 mg/day olanzapine was compared to 1200 mg/day chlorpromazine plus 4 mg/day benztropine [18]. Only 7% of olanzapine patients responded; there were no significant differences between groups in terms of efficacy. In another, olanzapine was compared to clozapine and found to be "noninferior" in terms of efficacy, with better tolerability [23]. 70% of the 88 olanzapine patients received doses above 20 mg/day. The third study compared clozapine, olanzapine, risperidone, and haloperidol over 14 weeks [30]. The first 8 weeks was a fixed dose trial, with olanzapine administered at 20 mg/day. Dosing was flexible over the subsequent 6 weeks; the mean olanzapine dose was 30.4 mg/day at endpoint. Patients in the olanzapine group showed improvement from week 8 to week 14 that was not observed in the other treatment groups. There is currently little support for high doses of the other atypical antipsychotics. Evidence exists that quetiapine is more effective at the higher end of its therapeutic range [31], but there are no controlled data for the use of doses above 800 mg/day. Data regarding use of risperidone above 8 mg/day illustrate the increased risk of EPS [32-33], while data for high doses of ziprasidone are not available. Increasing the dose in patients with partial responses or breakthrough symptoms is faster and easier than switching to another agent, and it is possible that it would result in improved efficacy. There are also some patients who may be rapid metabolizers, and thus require higher doses than the average patient. However, although some patients may benefit from higher doses, this method of treatment can increase the risk of side effects, especially motor side effects. Positron emission tomography (PET) data demonstrate that dopamine 2 (D2) receptor occupancy of 70% is necessary for

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therapeutic benefits, while occupancy greater than 80% is associated with extrapyramidal symptoms [34]. Doses at the upper end of the recommended range for the first-line antipsychotics may already result in 80% occupancy of D2 receptors in the nigrostriatal pathway [35], so that doses above those ranges are more likely to induce EPS. In particular, the risk of EPS with risperidone is dosedependent and may even increase above 4 mg/day [36]. The increased risk of side effects at higher doses may be different for each of the four atypical antipsychotics. The lack of available data makes it difficult to determine whether or not using doses above the recommended ranges is a safe and effective treatment alternative for partial responders. Currently, the known risk of EPS with risperidone and the lack of controlled data with quetiapine and ziprasidone should restrict the use of high doses of these agents. High dose use of olanzapine should be cautious, and should be
Table 1.

reserved for those patients who do not exhibit side effects at therapeutic doses. Polypharmacy Antipsychotic polypharmacy refers to the use of two or more antipsychotics concurrently in a single patient. Antipsychotic polypharmacy occurs frequently within clinical practice, with rates ranging from 5-18% in outpatient studies [IMS Health, National Disease and Therapeutic Index] and up to 50% in inpatient studies [37]. To determine if the use of antipsychotic polypharmacy is evidence-based, we performed a comprehensive review of the published literature on the efficacy and safety of antipsychotic polypharmacy. All studies are shown in tables 1 through 4. The following terms were cross-referenced with each other: risperidone, olanzapine, quetiapine, ziprasidone, clozapine,

Positive Studies of Atypical Antipsychotic polypharmacy: Improvement with No Side Effects

Study Combo n* Scale Results Adverse Effects

Open-Label 1. Raskin et al. 2000 [47] 2. Reinstein et al. 1999 [83] 3. Friedman et al. 1997 [87] Case Report 1. Lerner et al. 2000 [38] 2. Mantonakis et al. 1998 [39] 3. Takhar 1999 [50] 4. Goss 1995 [51] 5. Waring et al. 1999 [52] 6. Witz et al. 2000 [53] 7. Bacher & Kaup 1996 [56] 8. Tyson et al. 1995 [63] 9. Risch et al. 1994 [64] 10. Morera et al. 1999 [65] 11. Zervas et al. 1998 [66] 12. Adesanya & Pantelis 2000 [68] 13. Raju et al. 2001 [69] 14. Raskin et al. 2000 [70] 15. Rhoads 2000 [80] 16. Kaye 2003 [82] 17. Stubbs et al. 2000 [88] 18. Mowerman & Siris [89] 19. Cooke & de Leon 1999 [93] R, O R, O O, pimozide R, thioridazine Atypical, Conv O, sulpiride R, Conv R, C R, C R, C R, C R, C R, C R, C O, C Z, C C, sulpiride C, loxapine C, haloperidol 5 3 1 1 31 1 18 1 3 2 12 2 2 3 1 11 1 7 1 BPRS None BPRS None None PANSS, CGI None None None BPRS None None PANSS PANSS None None None BPRS None 30% improvement in BPRS 1 responder Clinical improvement Clinical improvement 2/3 of patients discharged PANSS reduced by 50, CGI reduced from 7 to 1 Effective in 10/18 patients Clinical improvement Clinical improvement Clinical improvement Clinical improvement in 8 patients Clinical improvement Clinical improvement 25% improvement in PANSS Clinical improvement Reduction in clozapine-associated side effects Clinical improvement Clinical improvement Effective None Not reported Not reported None None None None None Not reported None None Not reported None Not reported None None None None None O, sulpiride Q, C C, pimozide 6 65 7 BPRS PANSS None BPRS 37% improvement in BPRS, 32% improvement in PANSS Reduction in weight and diabetes mellitus Clinical improvement None None None

*n equals the number of patients receiving combination treatment Abbreviations: C clozapine; R risperidone; Q quetiapine; O olanzapine; Z ziprasidone; Conv conventional; BPRS Brief Psychiatric Rating Scale; PANSS Positive and Negative Symptom Scale; CGI Clinical Global Improvement

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Table 2.

Studies of Atypical Antipsychotic polypharmacy: Improvement with Side Effects

Study Combo n* Scale Results Adverse Effects

Double-Blind 1. Shiloh et al. 1997 [85] Open-Label 1. Henderson et al. 1996 [58] 2. Taylor et al. 2001 [60] Case Report 1. Seger et al. 2001 [40] 2. Chue et al. 2001 [42] 3. McCarthy & Terkelsen 1995 [61] 4. Patel et al. 1997 [62] 5. Mantonakis et al. 1998 [67] 6. Gupta et al. 1998 [81] R, O R, Q R, C R, C R, C O, C 1 1 2 1 3 2 None None None None None BPRS Clinical improvement Clinical improvement Clinical improvement Improvement in psychosis Clinical improvement in 2 patients Clinical Improvement Priapism Sexual side effects at 8 mg R "Minimal" side effects Worsened checking/touching Head tremor (1 patient) Drooling (1 patient) R, C R, C 12 13 BPRS PANSS, CGI 83% achieved >20% improvement in BPRS 54% achieved >20% improvement in PANSS Mild akathisia, hypersalivation Increased compulsive behavior (1 patient) C, sulpiride 16 BPRS, SAPS, SANS, HAM-D Significant improvement in BPRS, SAPS, SANS Increase in prolactin

*n equals the number of patients receiving combination treatment Abbreviations: C clozapine; R risperidone; Q quetiapine; O olanzapine; Conv conventional; BPRS Brief Psychiatric Rating Scale; PANSS Positive and Negative Symptom Scale; CGI Clinical Global Improvement; SAPS- Scale for the Assessment of Positive Symptoms; SANS Scale for the Assessment of Negative Symptoms; HAM-D Hamilton Depression Rating Scale

atypical, neuroleptic, conventional, polypharmacy, combination, adjunctive. The data are presented here according to the particular agents combined and fall into the following antipsychotic polypharmacy categories: atypicalatypical (risperidone, olanzapine, quetiapine, ziprasidone), atypical-conventional, atypical-clozapine, and clozapineconventional. Conventional-conventional polypharmacy is not addressed, as this review is intended to assess various uses of atypical antipsychotics. Atypical-Atypical Antipsychotic Polypharmacy (Risperidone, Olanzapine, Quetiapine, Ziprasidone) As discussed earlier, the class of atypical antipsychotics is defined as the four first-line atypical antipsychotics in this analysis (risperidone, olanzapine, quetiapine, ziprasidone). Six letters and one open-label trial have been published on the concurrent use of two or more of these agents [38-44]. The open-label trial assessed the pharmacokinetic effects of adding 3 mg bid risperidone to 300 mg bid quetiapine [44]. Risperidone had no significant effect on the pharmacokinetics of quetiapine. Cumulatively, the six published letters discuss the case reports of 12 patients. Nine of the patients received risperidone-olanzapine therapy [3840], two received risperidone-quetiapine therapy [41-42], and one received quetiapine-olanzapine therapy [43]. Some of the case reports described efficacy with no adverse effects, some described efficacy with adverse effects, and others described only adverse effects. There are no published reports of atypical antipsychotic polypharmacy involving ziprasidone. There are no controlled data on any atypical-atypical antipsychotic polypharmacy combinations in the literature.

Atypical-Conventional Antipsychotic Polypharmacy In this analysis, a conventional antipsychotic is defined as any antipsychotic other than risperidone, olanzapine, quetiapine, ziprasidone, clozapine, or aripiprazole. Although some may consider sulpiride an atypical antipsychotic, it elevates prolactin and is not a serotonin-dopamine antagonist and is therefore included here as a conventional agent [4546]. Literature regarding the simultaneous use of one of the four first-line atypical antipsychotics and a conventional antipsychotic is sparse. There are no double-blind studies and only one open-label study. In a ten-week open-label trial of olanzapine and sulpiride combination treatment [47], the six patients had a mean reduction in the Brief Psychiatric Rating Scale (BPRS) score of 37%. Fifty cases of atypicalconventional antipsychotic polypharmacy have been described in nine separate articles [48-56]. These cases involved risperidone, olanzapine, or quetiapine. Both efficacy [50, 52-53, 56] and adverse effects [48-49, 54-55] were reported. There are no published reports of ziprasidoneconventional antipsychotic polypharmacy. Atypical-Clozapine Antipsychotic Polypharmacy There are more publications documenting the use of clozapine in conjunction with risperidone than for any other form of antipsychotic polypharmacy. Nonetheless, there are no double-blind studies. Four open-label trials have been performed to assess the efficacy and/or safety of clozapinerisperidone polypharmacy in treatment-resistant schizophrenia [57-60]. In a 4-week trial, Henderson and Goff [58] found that 10 of 12 patients experienced at least a 20% improvement in BPRS total score, with 7 of the patients

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Table 3.

Negative Studies of Atypical Antipsychotic polypharmacy: Notable Side Effects and/or No Improvement
Study Combo n* Scale Results** Adverse Effects

Double-Blind 1. Potter et al. 1989 [86] Open-Label 1. Henderson et al. 2001 [57] 2. De Groot et al. 2001 [59] Case Report 1. Beelen et al. 2001 [41] 2. Hedges & Jeppson 2002 [43] 3. Gomberg 1999 [48] 4. Jarventausta & Leinonen 2000 [49] 5. Mujica & Weiden 2001 [54] 6. Terao & Kojima 2001 [55] 7. Chong et al. 1997 [71] 8. Chong et al. 1996 [72] 9. Koreen et al. 1995 [73] 10. Godleski & Semyak 1996 [74] 11. Beauchemin 2002 [75] 12. Senechal et al. 2002 [77] 13. Kontaxakis et al. 2002 [78] 14. Diaz & Hogan 2001 [84] 15. Grohmann et al. 1989 [91] 16. Peacock & Gerlach 1994 [92] R, Q O, Q O, Conv O, levomepromazine O, haloperidol R, haloperidol R, C R, C R, C R, C R, C R, C R, C Q, C C, haloperidol C, conventional 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 4 None None None None None None None None None None None None None None None None Not reported Not reported Not reported Not reported Not reported Not effective Not reported No improvement Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported QTc prolongation (overdose) Seizure (recently discontinued clonazepam) Parkinsonian symptoms worsened during combo NMS developed after 2 years NMS Increased psychosis Arrhythmia Worsened hoarding Mild oculogyric crisis Agranylocytosis NMS Neutropenia Neurotoxic syndrome Neutrophil count dropped Death Agranulocytosis (n=1), cardiovascular effects (n=3), death (n=1) Increased psychosis R, C R, C 20 12 None BPRS Not reported No responders Elevated prolactin Orthostatic hypotension (1 patient) C, chlorpromazine 20 BPRS Combo superior to chlorpromazine but not to clozapine Not reported

17. Cooke & de Leon 1999 [93]

C, perphenazine

None

Not effective

*n equals the number of patients receiving combination treatment **For double-blind studies, study is considered negative if combination therapy is not superior to atypical monotherapy Abbreviations: C clozapine; R risperidone; Q quetiapine; O olanzapine; Conv conventional; NMS neuroleptic malignant syndrome; BPRS Brief Psychiatric Rating Scale

showing a 20% improvement in negative symptoms as well. The most common side effects were akathisia (4 patients) and hypersalivation (5 patients). In a later study that did not assess efficacy, Henderson et al. [57] found that the combination of clozapine and risperidone resulted in elevated prolactin levels. In a study by Taylor et al. [60], 7 of 13 treatment-resistant patients (mean rating of 5.1 on the May scale) who had shown partial response to clozapine achieved a 20% reduction in the PANSS during clozapine-risperidone treatment. De Groot et al. [59] assessed the efficacy of clozapine-risperidone therapy in 12 treatment-resistant inpatients. After at least six months of clozapine monotherapy, risperidone was added. None of the 12

patients responded with a 20% or greater reduction in BPRS in this 4-week study. The rest of the literature on clozapine-risperidone polypharmacy consists of case reports [61-79]. Just over half of these articles report efficacy [61-70], while the rest report adverse effects that include neutropenia [77], agranulocytosis [74], arrhythmia [71], oculogyric crisis [73], and neuroleptic malignant syndrome [75]. There are no controlled or open-label trials in the literature on clozapine-olanzapine polypharmacy. Furthermore, only three cases have been described in the literature for this form of treatment [80-81]. All three

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Table 4.

Pharmacokinetic and Other Studies of Atypical Antipsychotic Polypharmacy

Study Combo n* Scale Results Adverse Effects

Open-Label 1. Potkin et al. 2002 [44] Case Report 1. Raaska et al. 2002 [76] 2. Procyshyn et al. 2002 [79] 3. Allen 2000 [90] R, C R, C C, haloperidol 2 8 1 None None None No significant change in serum clozapine Combination patients smoked less Clozapine increased haloperidol plasma levels Not reported Not reported None R, Q 12 None No significant PK effects

*n equals the number of patients receiving combination treatment Abbreviations: C clozapine; R risperidone; Q quetiapine; PK- pharmacokinetic

patients showed improvement, although one experienced significant drooling. A single case report of 11 patients treated with clozapine-ziprasidone polypharmacy has been published [82]. Ziprasidone was added in an effort to lower the dose of clozapine, and thus relieve side effects; positive results were reported for all 11 patients. One open-label study [83] and one case report [84] have been published on clozapine-quetiapine combination therapy. Reinstein et al. [83] performed an open-label study of 65 patients who had responded to clozapine after 6 months but had developed diabetes. The dose of clozapine was lowered by 25% when quetiapine was added. Final doses ranged from 150-600 mg/day for clozapine and 200-800 mg/day for quetiapine; each patient received these medications in a ratio of 1 mg clozapine to 2 mg quetiapine. Combination therapy resulted in significant weight loss and lowered rates of diabetes mellitus. The only other published report of clozapine-quetiapine polypharmacy is a case in which a patients neutrophil count dropped from 1,800/mm3 to 1,400/mm 3 when quetiapine was cross-titrated with clozapine [84]. Clozapine-Conventional Antipsychotic Polypharmacy There are only two double-blind studies of antipsychotic polypharmacy, both of which involve clozapine [85-86]. Shiloh et al. [85] compared the efficacy of clozapinesulpiride combination treatment in 16 patients to clozapine monotherapy over 10 weeks in a population partially responsive to clozapine. The mean clozapine dose was between 400 and 450 mg/day for both groups, while sulpiride was dosed at 600 mg/day. There was a significantly greater reduction in positive and negative symptoms in the combination group, as measured by the Scale for the Assessment of Positive Symptoms (SAPS), the Scale for the Assessment of Negative Symptoms (SANS), and the total BPRS. The response was more pronounced in younger experimental patients with lower baseline SAPS. Although the groups were randomized, the control group had a longer total duration of hospitalization than the experimental group, which may obscure the results. Still, there were no differences between groups in terms of baseline clinical status. One patient in the experimental group experienced a worsening of pre-existing tardive dyskinesia. There was also a significant increase in serum prolactin levels in the experimental group, but not the control group.

P o t t e r et al. [86] compared the efficacies of chlorpromazine monotherapy, clozapine monotherapy, and clozapine-chlorpromazine combination therapy in a doubleblind, flexible-dose study. Patients receiving monotherapy could receive doses up to 600 mg/day for either agent, while those in the combination group (n=20) could receive doses up to 400 mg/day for either agent. There were no differences between the three groups for total BPRS. In this study, the combination group showed significant improvement compared to the chlorpromazine group, but not to the clozapine group, on the withdrawal, conceptual disorganization, unusual thoughts, and hostility items on the BPRS. There were no notable side effects. The remaining literature for clozapine-conventional antipsychotic polypharmacy consists of one open-label trial [87] and six case reports [88-93]. In the open-label trial [87], clozapine was combined with pimozide in seven patients, and the mean BPRS total score was reduced from 51 to 27, with no significant adverse effects reported. Two case reports described positive results, one with the combination of clozapine and sulpiride [88] and the other with the combination of clozapine and loxapine [89], while a third describes a pharmacokinetic effect between clozapine and haloperidol [90]. Three other case reports of clozapineconventional antipsychotic polypharmacy describe adverse effects [91-93], including death [91-92]. The Value of Polypharmacy Our review of the literature shows that there is a dearth of evidence regarding the use of antipsychotics in combination. Of the 54 publications found, only two are controlled. Despite the lack of evidence, antipsychotic polypharmacy is common within clinical practice. There are certain instances in which antipsychotic polypharmacy is necessary, for instance, during cross-titration of two antipsychotic agents or as needed for breakthrough symptoms [94-95]. Such practice is clearly justified. However, antipsychotics are frequently co-prescribed as long-term therapy, a use with little rationale or evidence. This may occur because crosstitration is halted at the first sign of improved efficacy, rather than continued until only the second drug remains, out of fear that altering the treatment regimen will jeopardize the response. It may also occur because clinicians are seeking greater or more rapid responses than they generally achieve with atypical antipsychotic monotherapy. It is important to note that optimal responses to atypical antipsychotic

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monotherapy are often not seen until after 16 weeks of treatment [6-7]. It can be difficult to explain to patients and their families that time is an important factor in treatment outcome; often it is tempting to add a second drug just for the sake of "doing something". However, the fact that often a response is not seen until after 16 or more weeks of treatment suggests that any improvement seen with the
Table 5.

addition of a second drug could have been achieved with continued monotherapy of the first drug. Thus, the second drug may be superfluous and only add to the cost of treatment, not the quality of treatment. Regrettably, rarely do any published studies of polypharmacy discontinue one of the two agents to assess the impact of the combination.

Positive Studies of Augmentation of Atypical Antipsychotics: Improvement with no Side Effects

Study Combo n* Scale Results Adverse Effects

Double-Blind 1. Casey et al. 2003 [95] 2. Tiihonen et al. 2003 [139] Open-Label 1. Littrell et al. 2001 [97] 2. Norrie 2000 [112] 3. Dursun et al. 1999 [144] Case Report 1. Grove et al. 2000 [98] 2. Chong et al. 1998 [102] 3. Meltzer et al. 1994 [111] 4. Megna et al. 2002 [116] 5. Usiskin et al. 2000 [118] 6. Landry 2001 [119] 7. Martin et al. 2000 [124] 8. Thomas & Labbate 1998[ 125] 9. Gajwani & Tesar 2000 [126] 10. Blier et al. 1998 [135] 11. Boshes et al. 2001 [136] 12. Dursun & Deakin 2001 [141] 13. Saba et al. 2002 [143] 14. Dursun & Devarajan 2000 [145] 15. Navarro et al. 2001 [146] 16. Levy et al. 2002 [147] 17. Junghan et al. 1993 [158] O, valproate R, valproate C, valproate antipsychotic, gabapentin C, gabapentin C, gabapentin O, lithium O, lithium O, lithium C, lithium C, lithium antipsychotic, lamotrigine C, lamotrigine C, topiramate C, topiramate O, topiramate C, carbamazepine 147 2 1 1 11 1 1 5 1 1 1 1 17 3 1 1 None BPRS None BPRS, CABS None None None None None None None BPRS BPRS None None None None Clinical improvement BPRS reduced from 43 to 21 Valproate treated clozapine-induced myoclonus Significant reduction in CABS Prevention of clozapine-induced seizure Prevention of clozapine-induced seizure Clinical improvement Clinical improvement Lithium reversed olanzapine-associated neutropenia Combination stabilized neutrophil count Reversed clozapine-induced granulocytopenia Clinical improvement when combined with clozapine Clinical improvement Topiramate reversed clozapine-induced weight gain Prevention of clozapine-induced seizure Topiramate reversed induced weight olanzapine-gain No difference in agranulocytosis between clozapine monotherapy and combination treatment Not reported Not reported None None Not reported Not reported None Not reported Not reported Not reported Not reported None None None None None None O, valproate C, valproate C, lamotrigine 10 10 6 PANSS Hostility PANSS BPRS Clinical improvement Greater improvement in combination group Significant improvement Not reported Not reported None O or R, divalproex C, lamotrigine 122 34 PANSS, dBPRS BRPS, PANSS Significant differences favoring combo treatment Significant differences favoring combo treatment None None

*n equals the number of patients receiving combination treatment Abbreviations: C clozapine; R risperidone; O olanzapine; PANSS Positive and Negative Symptom Scale; dBPRS derived Brief Psychiatric Rating Scale; BPRS- Brief Psychiatric Rating Scale; CABS Corrigan Agitated Behavior Scale

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Table 6.

Studies of Augmentation of Atypical Antipsychotics: Improvement with Side Effects

Study Combo n* Scale Results Adverse Effects

Case Report 1. Sanders & Lehrer 1998 [99] 2. Bertoldo 2002 [103] 3. Kando et al. 1994 [107] R, valproate R, valproate C, valproate 1 1 55 None None None Clinical improvement at 10 mg risperidone Clinical improvement Clinical improvement in 74% of patients Edema Hand tremor Sedation

*n equals the number of patients receiving combination treatment Abbreviations: C clozapine; R risperidone

Table 7.

Negative Studies of Augmentation of Atypical Antipsychotics: Notable Side Effects and/or No Improvement
Study Combo n* Scale Results Adverse Effects

Case Report 1. Baldassano & Ghaemi 1996 [100] 2. Lauterbach 1998 [101] 3. Wirshing et al. 1997 [106] 4. Costello & Suppes 1995 [108] 5. Madeb et al. 2002 [109] 6. Pantelis & Adesanya 2001 [110] 7. Jablonowski et al. 2002 [117] 8. Matthews & Dimsdale 2001 [120] 9. Spiller et al. 2002 [121] R, valproate R, valproate C, divalproex C, valproate C, valproate C, valproate C, gabapentin O, gabapentin Q, gabapentin 1 1 1 1 1 1 1 1 1 None None None None None None None None None Not reported Not reported Not reported Not reported Not reported Not reported Improved sleep Not reported Not reported Edema Catatonia Hepatic encephalopathy Neurotoxicity Agranulocytosis Neutropenia, agranulocytosis Worsened psychosis Overdose: priapism Overdose: coma, hypotension, respiratory depression NMS Dystonia Fever, confusion, creatine phosphokinase Delirium Priapism Diabetic ketoacidosis Diabetic ketoacidosis Seizure Reversible neurotoxicity Agranulocytosis None Neutropenia None Myoclonus NMS Fatal agranulocytosis

10. Berry et al. 2003 [127] 11. Durrenberger & de Leon 1999 [128] 12. Swanson et al. 1995 [129] 13. Chen & Cardasis 1996 [130] 14. Owley et al. 2001 [131] 15. Koval et al. 1994 [132] 16. Peterson & Byrd 1996 [133] 17. Garcia et al. 1994 [134] 18. Lee & Yang 1999 [137] 19. Valevski et al. 1993 [138] 20. Dursun & Deakin 2001 [141] 21. Damiani & Christensen [142] 22. Dursun & Deakin 2001 [141] 23. Rittmannsberger & Leblhuber 1992 [155] 24. Muller et al. 1988 [156] 25. Gerson et al. 1991 [157]

O, lithium R, lithium R, lithium R, lithium R, lithium C, lithium C, lithium C, lithium C, lithium C, lithium antipsychotic, lamotrigine R, lamotrigine antipsychotic, topiramate C, carbamazepine C, carbamazepine C, carbamazepine

1 1 1 1 1 1 1 2 1 1 17 1 9 2 1 1

None None None None None None None None None None BPRS None BPRS None None None

Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported No improvement when combined with olanzapine or risperidone Not reported No improvement Not reported Not reported Not reported

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Study 26. Sassim & Grohmann 1988 [161] 27. Grohmann et al. 1989 [162] 28. Cobb et al. 1991 [163] 29. Klimke & Klieser 1994 [164] 30.Jackson et al. 1995 [165] 31. Bredbacka et al. 1993 [166]

Combo C, diazepam C, benzodiazepine C, benzodiazepine C, lorazepam C, benzodiazepine C, benzodiazepine

n* 39 189 2 1 3 2

Scale None None None None None None

Results Not reported Not reported Not reported Not reported Not reported Not reported

Adverse Effects Cardiorespiratory collapse (8%), dizziness (28%), sedation (44%) Increased risk of severe drug Sedation, hypersalivation, ataxia Patient died in sleep following 1st administration of combination Delirium Cardiorespiratory dysregulation (1 patient); death (1 patient)

*n equals the number of patients receiving combination treatment Abbreviations: C clozapine; R risperidone; O olanzapine; Q quetiapine; NMS neuroleptic malignant syndrome; BPRS Brief Psychiatric Rating Scale

Table 8. Pharmacokinetic Studies of Augmentation of Atypical Antipsychotics

Study Placebo-Controlled 1. Apseloff et al. 2000 [123] Open-Label 1. Spina 2000 [105] 2. Centorrino et al. [113] 3. Facciola et al. [114] 4. Potkin et al. 2002 [122] 5. Lucas et al. 1998 [149] 6. Olesen & Linnet 1999 [150] 7. Ono et al. 2002 [152] 8. Spina 2000 [105] Case Report 1. Van Wattum 2001 [104] 2. Kossen et al. 2001 [140] 3. Licht et al. 2000 [151] 4. de Leon & Bork 1997 [153] 5. Spina et al. 2001 [154] R, valproate C, lamotrigine O, carbamazepine R, carbamazepine R, carbamazepine 1 1 1 1 1 None None None None None Increase in valproate plasma level Plasma clozapine level tripled Olanzapine levels increased with carbamazepine discontinuation Carbamazepine lowered plasma levels of risperidone Carbamazepine lowered plasma levels of risperidone Not reported Not reported Not reported Not reported Not reported R, valproate C, valproate C, valproate Q, lithium O, carbamazepine O, carbamazepine R, carbamazepine R, carbamazepine 10 11 21 10 11 5 11 11 None None None None None None None None Valproate had no effect on risperidone plasma levels Minor increase in total clozapine metabolites Nonsignificant trend for higher clozapine levels and lower norclozapine levels Combination tolerated with no significant PK effects Increased olanzapine clearance 36% lower concentration-to-dose ratio than with olanzapine monotherapy Carbamazepine lowered plasma levels of risperidone Carbamazepine lowered plasma levels of risperidone None Not reported Not reported Not reported Not reported None Z, lithium 12 None Ziprasidone had no effect on steady-state lithium concentrations or renal clearance of lithium None Combo n* Scale Results Adverse Effects

*n equals the number of patients receiving combination treatment Abbreviations: C clozapine; R risperidone; Q quetiapine; O olanzapine; Z ziprasidone; PK pharmacokinetic

There are many potential costs of long-term antipsychotic polypharmacy. First, using two atypical antipsychotics together may eliminate those very features that make the treatment "atypical" i.e. the reduced motor side effects. Combining antipsychotics may increase D2 receptor blockade in the pathway controlling psychosis, but may also increase blockade in the pathway responsible for motor symptoms, so that the combination treatment would have

little benefit over conventional antipsychotic monotherapy yet be several times more expensive. Antipsychotic polypharmacy can increase the risk of other adverse effects as well, including the potential for negative drug interactions. Side effects associated with combination therapy may themselves require treatment with additional drugs, further complicating the patients regimen and potentially reducing compliance.

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In summary, there is currently no compelling evidence to support long-term antipsychotic polypharmacy. There are few theoretical benefits and many theoretical detriments. Although individual patients may respond to antipsychotic polypharmacy without side effects, adequate trials have not yet determined the costs versus the benefits of this option. Augmentation Numerous psychotropic agents are used as augmenting agents in schizophrenia. This review is restricted to those agents used most frequently to enhance the antipsychotic response in schizophrenia, and excludes agents used primarily to treat depressive symptoms or side effects. A review of Medi-Cal data determined that the most frequent augmenting agents in schizophrenia are anticonvulsants, and in particular divalproex and gabapentin [9]. Thus, the following terms were cross-referenced with each other in a Medline search: antipsychotic, schizophrenia, augmentation, quetiapine, ziprasidone, risperidone, olanzapine, clozapine, anticonvulsant, antiepileptic, divalproex (and other derivations), gabapentin, carbamazepine, lithium, topiramate, lamotrigine, benzodiazepine. Studies included are restricted to those reporting augmentation of atypical antipsychotics, including clozapine. All studies are summarized in tables 5 through 8. Divalproex Augmentation Valproic acid (also, valproate sodium, or valproate; often formulated as divalproex sodium) is one of the most commonly used agents for adjunct treatment in schizophrenia [9-10]. A 4-week, double-blind, randomized, multicenter study [96] assessed the use of divalproex combined with olanzapine or risperidone in patients with acute schizophrenia. 249 patients were randomly assigned to olanzapine monotherapy, risperidone monotherapy, divalproex plus olanzapine, or divalproex plus risperidone. Atypical antipsychotics were titrated over 6 days to a fixed dose of 15 mg/day (olanzapine) or 6 mg/day (risperidone). The mean modal dose of divalproex was 2364 mg/day for the olanzapine combination group and 2259 mg/day for the risperidone combination group. Improvements in symptoms were noted in all treatment groups, as measured by the PANSS total and positive scores. However, the improvement on the total PANSS was significantly greater for the combination groups than for the monotherapy groups beginning at day 3 and lasting through day 21 of treatment, and was numerically greater at all time points. The improvement on the PANSS positive subscale was significantly greater with combination treatment from day 3 through day 14, and numerically greater throughout the study. There were no efficacy differences between olanzapine combination and risperidone combination treatment, nor were there efficacy differences between olanzapine and risperidone monotherapy. Interestingly, divalproex augmentation lowered total cholesterol when combined with olanzapine or risperidone, and enhanced weight gain induced by risperidone but not by olanzapine. Other published reports for divalproex augmentation of olanzapine or risperidone are either open-label [97] or case reports [98]. In a one-year open-label trial [97], valproate (mean dose 1425 mg/day) was added to stable olanzapine

treatment (mean dose 19 mg/day) in 10 schizophrenic patients with at least mild hostility, as measured by a score of at least 3 on the PANSS hostility item. Hostility scores were significantly reduced from baseline to endpoint. Additional data for olanzapine-valproate combination treatment in schizophrenia include a single case report of 2 patients [98]. Several case reports of risperidone-valproate combination treatment in schizophrenia have been published [99-104]. Some of these report increases in risperidone plasma levels with the addition of valproate [103-104]; however, a matched-groups study [105] found no significant effect of valproate on risperidone plasma levels. There are no published data documenting the use of valproate as adjunct treatment to either quetiapine or ziprasidone. There are several case reports [106-111] and one open-label trial [112] of clozapine-valproate combination treatment. In the open-label trial, greater improvement was seen in the combination group (n=10) than in the clozapine monotherapy group (n=8), as measured by the PANSS. Some of the case reports also describe the combination as efficacious [107], but many also describe serious adverse effects associated with combination treatment [106, 108110]. Published studies of the effects of valproate on clozapine levels are somewhat conflicting, as both increased [113] and decreased [114] clozapine metabolite levels have been reported. However, the changes were small and most likely not clinically significant. Gabapentin, Lithium, and Other Anticonvulsants Although gabapentin is one of the most frequently used anticonvulsants for augmentation of atypical antipsychotics in schizophrenia [115], there are no published reports demonstrating efficacy of this method. Reduction of agitation has been reported in a retrospective study of 11 treatment-resistant patients who received adjunct gabapentin treatment [116]. There is also a published report of a single schizophrenic patient who experienced exacerbation of psychosis with the addition of gabapentin to clozapine [117]. The only other published data are case reports that describe the addition of gabapentin as prophylaxis for clozapine-induced seizures [118-119] and two cases of adverse effects associated with overdose of gabapentin and olanzapine [120] or gabapentin and quetiapine [121]. One open-label study demonstrated tolerability of quetiapine-lithium combination in 10 patients, most of whom were bipolar [122]. A placebo-controlled study found no effect of ziprasidone on renal clearance or steady-state concentrations of lithium [123]. There are published cases of olanzapine-lithium combination [124-127], risperidonelithium combination (128-131), and clozapine-lithium combination [132-138]. Most report adverse effects [127134, 137], including neuroleptic malignant syndrome [127], neurotoxicity [137], diabetic ketoacidosis [132-133], delirium [130], and dystonia [128]. A small double-blind study of lamotrigine augmentation of clozapine has been conducted [139]. 34 clozapine patients received either lamotrigine or placebo during a 12-week trial. Significantly greater improvement occurred with lamotrigine treatment for positive symptoms and general psychopathology as measured by the PANSS. There was no significant improvement in negative symptoms. In addition

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to the double-blind trial, four case reports [140-143] and one open-label trial [144] of atypical-lamotrigine combination in schizophrenia are published. Significant improvement was seen for clozapine-lamotrigine combination treatment in the open-label trial (n=6), as measured by the BPRS [144]. Only four case reports exist for topiramate augmentation of atypical antipsychotics [141, 145-147]. Three of the publications reported positive results [145-147], while the other reported negative results [141]. Controlled data reporting the use of carbamazepine as an adjunct in schizophrenia are for augmenting conventional antipsychotics only [148]. The only published reports found for carbamazepine augmentation of olanzapine [149-151] or risperidone [105, 152-154] assessed the effects on plasma levels and did not address efficacy or adverse effects. These open-label trials [105, 149-150, 152] and case reports [151, 153-154] demonstrate that carbamazepine may lower plasma levels of both olanzapine and risperidone. Three case reports of clozapine-carbamazepine have been published, all of which report serious side effects including myoclonus [155], neuroleptic malignant syndrome [156], and agranulocytosis [157]. However, a retrospective chart history of 147 patients found no difference in agranulocytosis between patients treated with clozapine-carbamazepine combination and those treated with clozapine monotherapy [158]. There are no published reports of carbamazepine augmentation of either quetiapine or ziprasidone. Benzodiazepines Studies of benzodiazepine augmentation of conventional antipsychotics suggest that this treatment is effective in onethird to one-half of patients, and is most effective for patients with agitation and anxiety [reviewed in 159-160]. However, there are no controlled data for benzodiazepine augmentation of atypical antipsychotics. Case reports of clozapine-benzodiazepine treatment describe only adverse effects [161-166]. The Value of Augmentation There are potential theoretical benefits of augmenting atypical antipsychotics with drugs from another pharmacologic class since combining different mechanisms of action could be synergistic and improve efficacy without increasing side effects associated with D2 antagonism. However, combining agents from different classes still carries the risk of drug interactions and development of other side effects. The evidence for augmentation of atypical antipsychotics varies depending on the particular agent. Controlled studies with conventional antipsychotics suggest that augmentation with benzodiazepines is most likely useful as an acute treatment for patients with agitation and hostility, but controlled studies do not exist for atypical antipsychotics. As mentioned earlier, a multicenter double-blind study demonstrates the safety and efficacy of only one augmenting agent in schizophrenia, namely divalproex [96]. Controlled studies combining divalproex and an atypical antipsychotic also show additive benefits in bipolar disorder, strengthening the appeal of this particular augmenting strategy [167-168]. Unfortunately, there are no controlled data for augmentation of atypical antipsychotics with other

anticonvulsants even though this is a frequent and expensive practice, especially with gabapentin. Thus, the evidence currently suggests that divalproex is perhaps the best evidence-based augmentation option when multiple monotherapies fail (Figure 3). Optimizing Monotherapy Although high dosing, polypharmacy, and augmentation of atypical antipsychotics are common in clinical practice (Figure 1), this review has demonstrated that there are few published studies on either the safety or the efficacy of these approaches. Furthermore, the majority of the data that do exist are case reports and uncontrolled trials. With the exception of divalproex augmentation, polypharmacy and other augmentation strategies are not currently supported as evidence-based treatment options unless the best-evidenced treatments, namely atypical antipsychotic monotherapies at therapeutic doses, have truly failed (Figures 2 and 3).

Fig. (1). Common utilization patterns antipsychotics in California Medi-Cal [9].

for

atypical

In order to determine if an atypical antipsychotic monotherapy has been ineffective, it is essential to maintain treatment for an adequate duration at a therapeutic dose. Although most randomized controlled trials have lasted eight weeks or less, there are rare studies that assess the change in response rates across time beyond eight weeks that suggest that it may take 16 weeks or longer for some patients to exhibit a response to an atypical antipsychotic [67]. Furthermore, negative and cognitive symptoms, which are the most debilitating symptoms of schizophrenia, may also take the longest to respond to treatment [2]. It is important, therefore, to give patients trials of atypical antipsychotic monotherapy that last longer than 8 weeks whenever possible before switching or adding other drugs, in order to give the monotherapy a chance to work. Switching too early may prevent a response, while adding an agent may obscure the true cause of the response.

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adjusting the pharmacological treatment. This may be particularly true for patients sensitive to EPS, as negative and cognitive symptoms can not only occur secondary to EPS [2], but can also be exacerbated by anticholinergic agents that are used to treat EPS [5]. If one atypical antipsychotic monotherapy fails, it thus seems reasonable to try monotherapy with another atypical antipsychotic before resorting to other methods of pharmacologic treatment that have little evidence but high costs. Most clinicians have observed patients who respond better to one monotherapy than to another, but few studies have evaluated the efficacy of one first-line atypical antipsychotic after switching from another, and those that exist do not have clear guidelines regarding the reason for the switch. Monotherapy switches to monotherapy may be most helpful in patients with inadequate early response or early side effects. For example, randomized open-label studies have demonstrated that switching to either ziprasidone [169] or aripiprazole [170] from a conventional antipsychotic, risperidone, or olanzapine can lead to increased efficacy. However, the patients in these studies were not necessarily treatment-resistant, and details regarding the reasons for switching were not reported. Nevertheless, such switches often emulate common clinical management scenarios. On the other hand, the efficacy of monotherapy switches to another monotherapy is not as encouraging for patients with well documented treatment resistance (rather than treatment intolerance or failure to respond to short treatment intervals). For example, in an open-label study of patients resistant to at least one conventional antipsychotic (treatment duration at least 6 weeks) and at least one atypical antipsychotic (either clozapine or risperidone for 6 weeks), only 16.7% reached response criteria when treated with olanzapine and the mean PANSS score was not significantly

Fig. (2). Proposal: Monotherapy, monotherapy, monotherapy, plus tincture of time [173].

It is also important to have realistic expectations of what the drug can achieve. Although possible, most patients do not achieve more than a 30% improvement in symptoms [6, 8], even after a year of pharmacological treatment [6]. This, in part, may be due to lingering negative and cognitive symptoms, which are often the most difficult to treat of the symptom dimensions in schizophrenia. Incorporating psychosocial therapy may be important to the resolution of these symptoms and may be a more effective option than

Fig. (3). Proposal: what if monotherapies really fail? [173].

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improved [29]. Likewise, in a double-blind study of patients resistant to at least three conventional antipsychotics, half of whom also failed treatment with risperidone, neither chlorpromazine nor olanzapine effected a significant improvement in symptoms [18]. Thus, on the basis of the evidence and costs of the available options, a sequence of monotherapies (Figure 2) might be better recommended for patients with inadequate trials of a prior monotherapy or intolerability of a prior monotherapy. This can serve as an alternative to polypharmacy or poorly documented augmentation strategies, especially attempting to extend trial periods to 16-20 weeks whenever possible. In addition, monotherapies that were not effective in previous short-term trials may be effective if retested in longer trials. The Drug Utilization Review Board of the California Department of Health Services Medi-Cal division proposes a sequence of several if not all five monotherapies (figure 2) prior to other treatment options. This approach has been adopted in order to place the best evidence, lowest cost therapeutic options early in the treatment sequence and to keep an open formulary so that all monotherapies remain available to prescribers. The recently revised Texas Implementation of Medication Algorithm (TIMA) also recommends at least three monotherapies, including clozapine, before resorting to combination treatment [171]. If an adequate response is not seen with therapeutic doses of any of the atypical antipsychotic monotherapies, several options can be tried before antipsychotic polypharmacy [172]. The approach taken by the Drug Utilization Review Board of the California Department of Health Services MediCal division is shown in figure 3 [173]. Adding divalproex to an atypical antipsychotic may have the best chance to provide enhanced antipsychotic efficacy. Alternatively, patients who have a partial response and no side effects at therapeutic doses may benefit from high doses of olanzapine or possibly quetiapine. Patients who do not benefit from atypical antipsychotic monotherapies may also do better if switched to conventional antipsychotic monotherapy or to clozapine. Polypharmacy should be reserved for patients who have not responded to any of the above options. Patients who do receive polypharmacy should be monitored closely for both efficacy and pharmacokinetic effects. If polypharmacy does not demonstrate enhanced efficacy, patients should be returned to monotherapy. CONCLUSION The best treatment for schizophrenia, according to existing evidence, is long-term atypical antipsychotic monotherapy at therapeutic doses. Nonetheless, not all patients will respond to atypical antipsychotic monotherapy. Controlled trials of antipsychotic polypharmacy and augmentation are needed so that the risks versus the benefits can be determined and treatment can be optimized for patients who do not benefit from atypical antipsychotic monotherapy. REFERENCES
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