Khan, Faheem

Naqvi, Haider A

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eCommons@AKUDepartment of Psychiatry Medical College, PakistanMay 2011Evidence based treatment of schizophrenia: do weknow enoughFaheem KhanAga Khan UniversityHaider A NaqviAga Khan UniversityFollow this and additional works at: http://ecommons.aku.edu/pakistan_fhs_mc_psychiatryPart of the Mental Disorders Commons, Psychiatric and Mental Health Commons, and thePsychiatry CommonsRecommended CitationKhan, F., Naqvi, H. (2011). Evidence based treatment of schizophrenia: do we know enough. Journal of the Pakistan MedicalAssociation, 61(5), 507-9.Available at: http://ecommons.aku.edu/pakistan_fhs_mc_psychiatry/7507 J Pak Med AssocEvidence Based MedicineEvidence based treatment of schizophrenia: Do we know enough?Faheem Khan, Haider A. NaqviDepartment of Psychiatry, Aga Khan University, Karachi, Pakistan.BackgroundSchizophrenia is a disorder which lasts for a person'slifetime. Treating it is a formidable challenge for clinician'sconsidering the chronic nature of its course, rate of relapse,side effects of medicines and limited choice of medications.Since 1950s, with the advent of Chlorpromazine  efforts havebeen made to alleviate the symptoms of schizophrenia andmake them useful in terms of social and occupationalfunctioning. Expected success of Antipsychotic (AP)medications depends on the results of the efficacy andeffectiveness trials.1Numerous studies have been done to evaluate theefficacy of conventional and atypical antipsychotic.2-5 Thereare many issues with these studies: some had limited samplesize, mostly comparing antipsychotics with placebo andothers were sponsored by pharmaceutical industry. In a studyanalyzing the role of pharmaceutical industry in influencingresults, Heres et al concluded that in around 92% of studiesresults were skewed towards funding industry.6 This could bedue to the fact that the Industry spends huge sum of money indeveloping a compound through tedious process of researchand only clinically viable compounds see the light of Phase IIand III research. Another issue is the usefulness of theefficacy trial in real world clinical situation where situation ismuch different; patients often have co-morbid condition,chronic nature of the condition and explicit preferences fortherapy dictates decision making. Catie - Study Design and Results:Clinical Antipsychotics Trial of InterventionEffectiveness (CATIE) is the double-blind randomized-control trial, conducted in naturalistic settings across fiftyseven geographical and variable clinical setting sites ofUnited States of America (USA).7 The study wasconducted on 1493 patients, from October 2001 toDecember 2004. The idea behind such a trial was to havehigh internal and external validity. The trial was funded byNational Institute of Mental Health. The aim was to assesand compare effectiveness of first generation and secondgeneration (atypical) antipsychotics. The study also lookedinto side effects of medications. It also intends to measurethe efficacy of Clozapine over other atypical APs. Studywas conducted in three phases. Primary out-come measurewas "time to discontinue", for any cause; lack oftolerability; lack of efficacy; clinical decision and patientdecision. Secondary outcome measure was assessed byscores on Positive and Negative syndrome scale (PANS)and scores on Clinical global impression scale (CGI).Higher scores point towards more severe psychopathologyand severity of illness respectively. Safety was alsomeasured at intervals to see any neurological, metabolicand laboratory derangement. For estimation of primary out-come measure, authors used Kaplan-Meier curve. Coxproportional-hazards regression model was used tocompare treatment groups.PHASE 01:A total of 1493 patients were assigned todouble blind treatment with olanzapine (7.5 mg to 30 mg perday), perphenazine (8 to 32 mg per day), quetiapine (200 to800 mg per day), ziprasidone (40 to 160 mg per day) orrisperidone (1.5 to 6 mg per day) for up to 18 months. Peoplewith Tardive dyskinesia were excluded to receiveperphenazine. These patients were not with the first episodeof psychosis. Data from one center (n=33) was excluded dueto data integrity issues. Out of 1460 individuals who wererandomized initially, 371 completed the phase 1 trial (1089discontinued). PHASE 02: In the stage 543 patients entered in to twopathways; "efficacy" pathway with clozapine (n=99) or"tolerability" (n=444) pathway with ziprasidone. A total of509 patients left the study before the start of this phase. PHASE 03: This was an open-label phase of thestudy. Patients were free to select one among 09 AP regimens;270 patients entered in this phase of the trial. Results of this study were published in differentjournals as they came up.7-9 The most prominent finding wasall-cause discontinuation rate of 74% at 18 months. In termsof discontinuation of medication due to any cause before thecompletion of the study, Olanzapine fared better thenQuetiapine (hazard ratio, 0.63; P<0.001) Risperidone (hazardratio, 0.75: P=0.0002) and also with other medications. Thediscontinuation due to intolerable side effects was similaramong all the groups, with more individuals discontinuingOlanzapine due to weight gain (07 percent or more of thebaseline body weight) and increase in glycosylatedhaemoglobin, cholesterol and triglyceride leading tometabolic syndrome. In case of perphenazine Extrapyramidalsymptoms were the most common reason for discontinuation(08 percent vs. 02 percent to 04 percent, P=0.002).Research team was unable to find any superiorefficacy of Atypical over conventional AP, i.e. Perphenazine.Perphenazine was however most cost-effective whencompared with newer atypical APs. Clozapine was the mosteffective compound compared with all the otherantipsychotics used in this study. Irrespective of the class ofantipsychotics, there was improvement in neuro-cognitivefunctioning. However this effect remained significant onlyfor two months. Among all, Ziprasiodne was most weightneutral and did not come up with any metabolic side-effects.In the last phase which was open label, very few patientsselected conventional antipsychotics (Fluphenazinedecanoate, n=09 or Perphenazine, n=04)Critique: One of the main critiques of this study is thatresearchers have used drug doses which are on the higher sidecompared to actual clinical practice.  This could have causeda difference in the results. Another objection was thatalthough the total period of study was 18 months, much morethan previous studies, it was still short considering the longcourse of schizophrenia, delays in response and side-effectsof medications. . Open label component of the trial couldhave also caused a possible bias.10CATIE results are important in view of theprevailing health care situation in Pakistan; health is an outof pocket expenditure for most Pakistanis. Government'scontribution is dismally low, i.e. US $ 04 out of US $ 18 percapita. Considering the Global economic recession,affordable health care is becoming a challenge for mostpatients and their family members. Given the lack ofdifference between the efficacy of conventional and atypicalAPs, an affordable care becomes a reality to the vastmajority of patients with schizophrenia in a developingcountry like Pakistan. Given the extra pyramidal side effects(EPSE) with conventional APs and Metabolic syndromewith atypical APs clinicians are advised caution in terms ofdrug prescription. Every patient who is on AP should bereviewed periodically for dose-adjustment in order toachieve symptoms remission, review drug side effects andenhance compliance. In conclusion the best practice evidence on treatmentof schizophrenia remain open to interpretation given thetrade-offs between efficacy, side effects, affordability andimplicit personal preferences. The perennial question, that doVol. 61, No. 5, May 2011 508we know enough, still remains unanswered. References1. Nasrallah HA. The roles of efficacy, safety, and tolerability in antipsychoticeffectiveness: practical implications of the CATIE schizophrenia trial. J ClinPsychiat 2007; 68 (Suppl 1): 5-11.2. Leucht S, Wahlbeck K, Hamann J, Kissling W. New generation antipsychoticsversus low-potency conventional antipsychotics: a systematic review and meta-analysis. Lancet 2003; 361: 1581.3. Geddes J, Freemantle N, Harrison P, Bebbington P. Atypical antipsychotics inthe treatment of schizophrenia: systematic overview and meta-regressionanalysis. BMJ 2000; 321: 1371.4. Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiat 2003; 60: 553-64.5. Leucht S, Barnes TRE, Kissling W, Engel RR, Correll C, Kane JM. Relapseprevention in schizophrenia with new-generation antipsychotics: a systematicreview and exploratory meta-analysis of randomized, controlled trials. Am JPsychiat 2003; 160: 1209-22.6. Heres S, Davis J, Maino K, Jetzinger E, Kissling W, Leucht S. Why olanzapinebeats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine:an exploratory analysis of head-to-head comparison studies of second-generation antipsychotics. Am J Psychiat 2006; 163: 185-94.7. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, PerkinsDO, et al. Effectiveness of antipsychotic drugs in patients with chronicschizophrenia. NEJM 2005; 353: 1209-23.8. Stroup TS, Lieberman JA, McEvoy JP, Davis SM, Swartz MS, Keefe RSE, etal. Results of phase 3 of the CATIE schizophrenia trial. Schizophr Res 2009;107: 1-12.9. Swartz MS, Stroup TS, McEvoy JP, Davis SM, Rosenheck RA, Keefe RSE, etal. What CATIE found: results from the schizophrenia trial. Psychiat Serv 2008;59: 500-6.10. Ericksen J, Stuart ME, Stern C. CATIE Trial Review of Phases 1 and 2.CALIFORNIA PHARMACIST 2008; LV: 52-6.509 J Pak Med Assoc

Evidence based treatment of schizophrenia: do we know enough

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Evidence based treatment of schizophrenia: do we know enough

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