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SCHIZOPHRENIA: A REVIEW OF TREATMENTSHEALTH SYSTEMS EDITIONStage 1Stage 2Stage 3Stage 4Stage 5Stage 6• Atypical antipsychotic• Atypical or conventional antipsychotic• Not the same atypical from stage 1• Clozapine• May try earlier if history of recurrent suicidality, violence,or substance abuse• Clozapine plus• Conventional or atypical antipsychotic or ECT• Trial of single atypical or conventional agent not tried instages 1 and 2• Combination therapy, such as atypical plus conventional antipsychotic;combination of atypical and/or conventional antipsychotics plus ECT;or conventional or atypical antipsychotic plus mood stabilizerSource: Reference 29. Adapted with permission of the Texas Department of StateHealth Services.ECT: electroconvulsive therapy.Figure 1. Algorithm for the treatment of schizophrenia. A patient should progressto the next stage if he or she experiences a partial response or nonresponse tothe current stage.Improvements in sleep disturbance and agitationmay be seen in the first 2 days of antipsychotic therapy;however, the full effect may not be seen for 6 to8 weeks. If the patient reports no symptom relief in 2to 4 weeks, either the antipsychotic dose should beincreased or a new agent should be selected. 1,21Recommended doses of FGAs and SGAs are givenin TABLE 2. 22 These doses have been suggested by themanufacturers of the respective agents; however,practitioners often prescribe outside of the recommendedrange. While this often is unavoidable in treatment-resistantpatients, the practice may result in adverseevents and limited additional efficacy. Also, manypatients probably will not require the higher end ofthe dosing range for FGAs. Specifically, patientsexperiencing their first psychotic break will likely respondto much lower doses of antipsychotics and be moresensitive to adverse events than a patient in a moreadvanced stage of schizophrenia. 21 Additionally, it shouldbe noted that the total daily dose of most antipsychoticscan be administered once daily if tolerated, and thiswill improve adherence. Exceptions tothis are clozapine, quetiapine, andziprasidone, which probably will requiremultiple daily doses to control symptoms.Finally, treatment with multipleantipsychotics should be considered alast resort and avoided if at all possible,as it often provides no additionalefficacy and increases the risk of intolerableside effects.In general, FGAs are more affordablethan SGAs, with perphenazine andfluphenazine costing more than otherFGAs. Currently, the only generic SGAsare clozapine and risperidone. Costshould be a major consideration whenchoosing an antipsychotic, with a preferencefor FGAs if a patient can toleratethem.Other Medications: Whereas antipsychoticsremain the primary pharmacologictreatment for schizophrenia, anumber of other medications may beused to augment them. One such classis the mood stabilizers, which oftenare used in patients experiencing increasedagitation or aggression. Overall, patientswith schizophrenia are not violent;however, episodes in which positivesymptoms are exacerbated may lead toincreased agitation. 3 During suchinstances, mood stabilizers may be beneficial.In a meta-analysis of 11 studiescomparing antipsychotic monotherapywith lithium augmentation, more patients receivinglithium had a clinically significant response, with anumber needed to treat of 8. 23 Two small studies havecompared antipsychotic monotherapy with carbamazepineaugmentation; in these studies, patients oncarbamazepine showed clinically significant overallglobal improvement. 24 Similarly, there is only limitedevidence to support the use of augmentation therapywith valproate, including a single small study showingless agitation in the valproate augmentation groupversus the antipsychotic monotherapy group. 25 A metaanalysisof five studies evaluating the efficacy of antipsychoticaugmentation with lamotrigine showed that20% to 30% of clozapine-resistant patients withschizophrenia had a clinically significant improvementwhen lamotrigine was added. 26 In a randomized, double-blind,placebo-controlled study of patients withschizophrenia, the addition of topiramate resulted ina reduction of both positive and negative symptomscompared with patients on antipsychotic monotherapy.27 Mood stabilizers have great potential for theHS-8U.S. Pharmacist • November 2009 • www.uspharmacist.com
SCHIZOPHRENIA: A REVIEW OF TREATMENTStreatment of schizophrenia, but more research is needed.Benzodiazepines have been studied for their benefitsin augmenting antipsychotics. Although the studieshave been small, they have shown some advantageover antipsychotic monotherapy in treating agitationin schizophrenia. This effect is short-lived, however,with a return of symptoms within 1 hour of a benzodiazepinedose. 28One of the most straightforward algorithms forthe treatment of schizophrenia was published by theTexas Department of State Health Services (FIGURE 1).This algorithm is based on evidence when available,and expert consensus where no evidence exists. If apatient fails trials of two stages of this algorithm withno appreciable improvement in symptoms, the diagnosisof schizophrenia should be re-evaluated, andthe possibility of co-occurring substance abuse shouldbe considered. 29ADHERENCEA number of studies have been designed to measurepatient adherence to antipsychotics compared withother medications, but the results are difficult to interpret.This is primarily because each study defines andmeasures nonadherence differently. A meta-analysisof adherence studies reported that patients take an averageof 58% of their prescribed antipsychotic doses(range 24%-90%). The meta-analysis found that patientstake medications for physical ailments an average of76% of the time (range 60%-92%), implying thatadherence to antipsychotics may be lower than adherenceto other medications. 30 Some barriers to care inpatients with schizophrenia include stigma about mentalillness, lack of access to care, and fragmentation ofservices. 5 A pharmacist can help a patient overcomethese barriers through education and identification ofpatient-assistance programs when financial issues arise.Additionally, the pharmacist may recommend the useof long-acting depot antipsychotic injections to improveadherence to medication therapy. Recommended dosesof depot antipsychotics are given in TABLE 2.CONCLUSIONDespite the fact that there is no cure for schizophrenia,providing patients with guideline-based treatmentssupported by primary literature will afford the bestopportunity for controlling the symptoms of their illness.The process of choosing appropriate medicationsand monitoring for appropriate adverse reactions shouldbe facilitated by a pharmacist whenever possible.HEALTH SYSTEMS EDITIONREFERENCES1. Freedman R. Schizophrenia. N Engl J Med. 2003;349:1738-1749.2. Siris SG. Suicide and schizophrenia. J Psychopharmacol. 2001;15:127-135.3. Tandon R, Nasrallah HA, Keshavan MS. Schizophrenia, “just thefacts” 4. Clinical features and conceptualization. Schizophr Res.2009;110:1-23.4. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,Text Revision (DSM-IV-TR). Washington, DC: American PsychiatricAssociation; 2000.5. Keshavan MS, Roberts M, Wittmann D. Guidelines for clinical treatmentof early course schizophrenia. Curr Psych Rep. 2006;8:329-334.6. Petersen L, Jeppesen P, Thorup A, et al. A randomized multicentretrial of integrated versus standard treatment for patients with a firstepisode of psychotic illness. BMJ. 2005;331:602-608.7. Pae CU. A review of the safety and tolerability of aripiprazole. ExpertOpin Drug Saf. 2009;8:373-386.8. Newcomer JW. Second-generation (atypical) antipsychotics andmetabolic effects: a comprehensive literature review. CNS Drugs.2005;19(suppl 1):1-93.9. Leucht S, Corves C, Arbter D, et al. Second-generation versus firstgenerationantipsychotic drugs for schizophrenia: a meta-analysis. Lancet.2009;373:31-41.10. Honigfeld G, Arellano F, Sethi J, et al. Reducing clozapine-relatedmorbidity and mortality: 5 years of experience with the Clozaril NationalRegistry. J Clin Psychiatry. 1998;59(suppl 3):3-7.11. Haddad PM, Wieck A. Antipsychotic-induced hyperprolactinemia:mechanisms, clinical features and management. Drugs. 2004;64:2291-2314.12. Cutler AJ, Kalali AH, Weiden PJ, et al. Four-week, double-blind,placebo- and ziprasidone-controlled trial of iloperidone in patients withacute exacerbations of schizophrenia. J Clin Psychopharmacol. 2008;28(2suppl 1):S20-S28.13. FDA Psychopharmacological Drugs Advisory Committee. Briefingdocument for Zeldox ® capsules (ziprasidone HCl). July 19, 2000.14. Glassman AH, Bigger JT Jr. Antipsychotic drugs: prolonged QTcinterval, torsade de pointes, and sudden death. Am J Psychiatry.2001;158:1774-1782.15. Leucht S, Komossa K, Rummel-Kluge C, et al. A meta-analysis ofhead-to-head comparisons of second-generation antipsychotics in thetreatment of schizophrenia. Am J Psychiatry. 2009;166:152-163.16. Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generationantipsychotics. Arch Gen Psychiatry. 2003;60:553-564.17. Jones PB, Barnes TRE, Davies L, et al. Randomized controlled trialof the effect on quality of life of second- and first-generation antipsychoticdrugs on schizophrenia: Cost Utility of the Latest AntipsychoticDrugs in Schizophrenia Study (CUtLASS I). Arch Gen Psychiatry.2006;63:1079-1087.18. Lieberman JA, Stroup TS, McEvoy JP, et al, for the ClinicalAntipsychotic Trials of Intervention Effectiveness (CATIE) Investigators.Effectiveness of antipsychotic drugs in patients with chronic schizophrenia.N Engl J Med. 2005;353:1209-1223.19. McEvoy JP, Lieberman JA, Stroup TS, et al, for the CATIE Investigators.Effectiveness of clozapine versus olanzapine, quetiapine, andrisperidone in patients with chronic schizophrenia who did not respondto prior atypical antipsychotic treatment. Am J Psychiatry. 2006;163:600-610.20. Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for suicidalityin schizophrenia: International Suicide Prevention Trial (Inter-SePT). Arch Gen Psychiatry. 2003;60:82-91.21. APA Practice Guidelines. Lehman AF, Lieberman JA, Dixon LB, etal. Practice guideline for the treatment of patients with schizophrenia.2nd ed. www.psychiatryonline.com/pracGuide/loadGuidelinePdf.aspx?file=Schizophrenia2e_Inactivated_04-16-09. Accessed October 13,2009.22. Micromedex Healthcare Series [Intranet database]. Greenwood Village,CO: Thomson Healthcare. Accessed October 13, 2009.23. Leucht S, Kissling W, McGrath J. Lithium for schizophrenia.Cochrane Database Syst Rev. 2007;(3):CD003834.24. Leucht S, Kissling W, McGrath J. Carbamazepine for schizophrenia.Cochrane Database Syst Rev. 2007;(3):CD001258.25. Schwarz C, Volz A, Li C, Leucht S. Valproate for schizophrenia.Cochrane Database Syst Rev. 2008;(3):CD004028.26. Tiihonen J, Wahlbeck K, Kiviniemi V. The efficacy of lamotrigine inclozapine-resistant schizophrenia: a systematic review and meta-analysis.Schizophr Res. 2009;109:10-14.27. Afshar H, Roohafza H, Mousavi G, et al. Topiramate add-on treatmentin schizophrenia: a randomised, double-blind, placebo-controlledclinical trial. J Psychopharmacol. 2009;23:157-162.28. Volz A, Khorsand V, Gillies D, Leucht S. Benzodiazepines forschizophrenia. Cochrane Database Syst Rev. 2007;(1):CD006391.29. Moore TA, Buchanan RW, Buckley PF, et al. The Texas MedicationAlgorithm Project antipsychotic algorithm for schizophrenia: 2006update. J Clin Psychiatry. 2007;68:1751-1762.30. Cramer JA, Rosenheck R. Compliance with medication regimens formental and physical disorders. Psychiatr Serv. 1998;49:196-201.HS-9U.S. Pharmacist • November 2009 • www.uspharmacist.com
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