International Journal of Psychiatry in Clinical Practice, 2007; 11(2): 151 156
ORIGINAL ARTICLE
Antipsychotic use in a first episode psychosis program
RAHUL MANCHANDA1, ROSS M.G. NORMAN1, ASHOK K. MALLA2 & RANITA MANOCHA1 1
Prevention and Early Intervention Program for Psychoses (PEPP), London Health Sciences Centre, London, Ontario, Canada and 2Department of Psychiatry, Douglas Hospital Research Centre, Verdun, Quebec, Canada
Abstract Objective. To conduct a naturalistic, longitudinal study of prescribing patterns of atypical neuroleptics in predominantly drug-naı¨ve first episode non-affective psychosis patients. Methods. Patients with a first episode psychosis were prescribed an antipsychotic as part of a clinical protocol and followed-up for 2 years. Comparisons were made between risperidone and olanzapine, the two most commonly prescribed antipsychotics. Socio-demographic variables and clinical characteristics such as diagnosis, duration of untreated illness and psychosis and level of positive and negative symptoms were assessed using well-established methods. We examined the first antipsychotic given, starting dose, time taken to start and to reach the maximum dose, time on first medication, maximum dose, medication change and concomitant medication use. Results. One hundred and ninety-three consecutive patients consented to start on antipsychotic. The results are provided for risperidone (N / 133) and olanzapine (N /38). The time to initiate antipsychotic medications was significantly longer for outpatients than inpatients. There were no differences between the two groups for time taken to reach the maximum dose, drop out rates or concomitant medication use. The percentage of patients taking an antipsychotic agent at any given time was high (range 79 91%), but half of the patients had changed from their first antipsychotic by 6 months. Conclusions: The reality of clinical practice can be much different than rigid protocols or treatment algorithms of pre-marketing studies or clinical trials. In this sample of first episode psychosis patients, although the majority of patients remained on an antipsychotic, changes in medication over the first 2 years were common. Polypharmacy was not a common practice.
Key Words: First episode psychosis, prescribing patterns, antipsychotics, medication switchover, concomitant medications
Introduction An individual patient’s adherence to prescribed antipsychotic medication is probably the single greatest determinant of the effectiveness of treatment for schizophrenia [1 3]. The introduction of atypical antipsychotics has promised greater effectiveness compared to typicals in the treatment of positive, negative and cognitive symptoms of schizophrenia [4], although recent evidence suggests we should be cautious in assuming this is the case [5]. Large differences may exist between the clinical circumstances of pre-marketing trials and those of actual post-marketing practice [6]. Most evaluations of the effectiveness of psychotropic medications have been sponsored by the pharmaceutical industry and use a highly standardized protocol for dispensing medications. While such research provides valuable evidence regarding the efficacy of compounds, it does not necessarily reflect their utilization in most clinical settings. We need to know more about the
utilization of antipsychotic medications in the ‘‘real world’’ of clinical practice. It is also recognized that there is a need for pharmaco-epidemiological research to be conducted independently of drug companies [7]. Early intervention programs for first episode psychosis (FEP) provide an important opportunity to study the long-term patterns of prescribing antipsychotic medications in relatively treatment naı¨ve individuals from a time closer to the onset of their illness. The objective of the current study was to conduct a naturalistic, longitudinal study of prescribing patterns of atypical antipsychotics in predominantly drug-naı¨ve first episode non-affective psychosis patients. Methods The Prevention and Early Intervention Program for Psychosis (PEPP) in London, Canada provides services to patients (16 50 years old) who meet
Correspondence: Rahul Manchanda, PEPP, London Health Sciences Centre, 392 South Street, London, Ontario, Canada N6A 4G5. Tel: /1 519 667 6866. Fax: /1 519 667 6867. E-mail: [email protected]
(Received 3 April 2006; accepted 3 July 2006) ISSN 1365-1501 print/ISSN 1471-1788 online # 2007 Taylor & Francis DOI: 10.1080/13651500601162385
152
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criteria of a non-affective psychosis, living in a defined urban catchment area of approximately 390,000. Those admitted to the program have not previously received antipsychotic treatment for a cumulative period greater than 1 month. PEPP utilizes an assertive case management model, modified to suit the needs of mostly young people with first episode psychoses and their families. The model involves a comprehensive approach with intensive medical and psychosocial management being provided by a nurse or social worker case manager. Further details of the clinical program are available at www.pepp.ca. The PEPP protocol requires patients to be treated initially with a novel antipsychotic within the generally recommended dose range [8]. The choice of the antipsychotic medication is arrived at as a result of consultation between the psychiatrist, the individual patient and, where applicable, the family. Often the choice of medication is also influenced by the availability of the novel antipsychotic and whether or not it is funded by a government program for patients with low or no income. Risperidone was introduced in Canada in 1993, olanzapine in 1996 and quetiapine in 1998. Patients are offered dosage as low as 0.5 1 mg of risperidone, 5 mg of olanzapine or 50 100 mg of quetiapine which is typically increased over several days to 2, 10 and 300 mg/day, respectively. If needed, the dose of the medication is increased to a maximum tolerated dose of up to 6, 20 and 900 mg, respectively. Symptoms were assessed using the Scale for the Assessment of Positive Symptoms [9] and Scale for the Assessment of Negative Symptoms [10]. Failure to achieve a remission of positive symptoms (remission defined as SAPS global scores of 5/2) despite trials with two novel antipsychotics results in the discussion with the patient and family concerning possible use of clozapine therapy. Older, typical antipsychotic medications were used only as depot preparations when adherence to oral medications becomes problematic, because injectable risperidone consta was not introduced in Canada until 2005. The patients included in this study were admitted to PEPP over a 4-year period and followed-up for at least 2-years after admission. We examined the data to determine the socio-demographic and clinical characteristics of the patients, the first antipsychotic given, the starting dose, time taken to start the medication and to reach maximum dose, maximum dose, time on first medication, change in medication and concomitant medications (anxiolytic, antidepressant, anticholinergic). This information was collected at each visit and more formally assessed and recorded at 3, 6, 12, 18 and 24 months. The information collected included an enquiry as to whether or not the antipsychotic medications were being taken as prescribed.
Results The sample for this study consists of 196 consecutive patients who were accepted to PEPP during a 4-year period. Given the size of the catchment area (390,000) and expected incidence rates, these patients probably approximate an incidence sample of non-affective psychoses for that period of time. Of these, 113 (57.6%) began treatment as inpatients and the remaining 83 (42.4%) were outpatients at the time of their entry into treatment. One hundred and ninety-three patients consented to start an antipsychotic. The majority of the patients were started on either risperidone (N /133) or olanzapine (N /38). The other available atypical neuroleptic, quetiapine, was initiated in only two patients; 13 were prescribed typical neuroleptics and seven received an investigational drug. Further analyses were carried out only with reference to risperidone and olanzapine as these were the two most frequently prescribed antipsychotics. The patients were followed up for 2 years under naturalistic conditions with general clinical guidelines, but no stringent prescription rules that had to be followed. By the end of 1 year there were 152 patients in the program (attrition of 22.5%) and 133 patients at the end of 2 years (further attrition of 12.5%). The overall attrition rate over a 2-year period was 32.2%. There were no significant differences in the baseline socio-demographic and clinical characteristics of those who stayed on in PEPP for 2 years (N /133) versus those who did not complete 2-year follow-up (N /63). There was no difference in the drop out rate from the patients in risperidone or olanzapine group. Over the 2-year period, 41 of the patients initially prescribed risperidone (30.8%) and 14 of these initially prescribed olanzapine (36.8%) had dropped out of treatment (x2 /0.49, ns). Also, a comparison was made on the sociodemographic and clinical characteristics at entry into PEPP for those initially prescribed risperidone (N /133) or olanzapine (N /38). There were no significant differences between the groups on these socio-demographic variables or symptom ratings based on SAPS and SANS at baseline (Table I). Information being presented here is based on all the patients who were in the program at any given assessment point. The dose and duration on the first antipsychotic is shown in Table II. The time to initiate antipsychotic medications following acceptance to PEPP was significantly longer for outpatients (mean /2.65 weeks, SD /7.9) compared to (mean / /0.42 weeks, SD /1.5) (t /3.41, P B/0.001). The minus figure indicates that patients admitted to the program through the inpatient unit were actually started on their regular antipsychotic medications before formal entry in the Program. The mean starting doses for risperidone and olanzapine were 1 and 5.5 mg, respectively, and the maximum doses given
Antipsychotic use in a first episode psychosis program 153 Table I. Baseline socio-demographic variables, diagnosis, duration of untreated psychosis/illness and the mean total scores on positive and negative symptoms in the risperidone and olanzapine groups. There was no difference between the two groups on these variables.
Mean Age H.S. ]/ Single Male Scz Spec Dis Median DUP (weeks) Median DUI (weeks) SAPS Total SANS Total
Risperidone (N /133)
Olanzapine (N /38)
24.9 (9/7.4) 45 (33.8%) 108 (81.2%) 100 (75.2%) 82 (61.6%) 21.4 (9/111.5)
26.9 (9/8.5) 13 (34.2%) 27 (71.1%) 33 (86.9%) 22 (57.8%) 20.1 (9/105)
n.s. n.s. n.s. n.s. n.s. n.s.
188.3 (9/264.3)
208.5 (9/212.9)
n.s.
32.2 30.0
33.7 29.7
n.s. n.s.
were 8 and 25 mg, respectively. The mean time taken to reach the maximum dose did not differ significantly between the two groups (11.7 (SD 6.2) weeks for risperidone and 11.8 (SD 18.3) weeks for olanzapine); the median times were 5 and 4 weeks, respectively. The total number of patients in the program taking on antipsychotic agent was high. Of the 152 patients in the program at 1 year 138 (90.8%) reported taking on antipsychotic and 105/133 (78.9%) at 2 years. None of our patients were given more than one antipsychotic agent on a regular basis during the 2-year follow-up. The number of times that the patients switched an antipsychotic were as follows: to a second antipsychotic 80 (40.4%), to a third antipsychotic 47 (23.7%), to a fourth antipsychotic 15 (7.6%) and, four (2%) were switched to a fifth antipsychotic during the 2-year period. At the 2-year mark the medication distribution for patients taking an antipsychotic (N /105) was as follows: risperidone 41 (39.1%), olanzapine 29 (27.6%) and others 35 (33.3%). We looked specifically at those patients who were started on risperidone (N /133) or olanzapine (N / 38) as the first line antipsychotic. Of those patients remaining in the program at 6 months, only 61 of 119 (51.3%) of those initially prescribed risperidone Table II. The mean time taken to initiate risperidone or olanzapine for inpatients and outpatients, mean dose of the antipsychotic and the mean time taken to reach the maximum dose of the first antipsychotic given to them (/x¯ /mean). Risperidone (N /133) Time to initiate (weeks) Inpatient Outpatient Start dose (mg) Max. dose (mg) Time to max. dose (weeks)
1 6 (/x¯ 2) 1 24 (/x¯ 6) 0.5 5 (/x¯ 1.0) 0.5 8 (/x¯ 3.3) 2 99 (/x¯ 11.7)
Olanzapine (N /38) 1 10 (/x¯ 1.5) 1 54 (/x¯ 5.5) 2.5 10 (/x¯ 0.5) 2.5 25 (/x¯ 13.3) 2 88 (/x¯ 11.8)
and 16 of 32 (50%) of those initially prescribed olanzapine were still taking their original medications (x2 /0.02, ns). By 24 months, 26 of 92 (28.3%) patients still in the program who were initially prescribed risperidone were still taking it and for olanzapine the relevant figures were 4 out of 24 (16.6%) with the difference not reaching statistical significance (x2 /1.33, ns). We examined if there are any baseline sociodemographic or clinical variables associated with those who do or do not switch medications by 6 months. There were no significant findings on gender, age of onset of psychosis, age at entry to PEPP, duration of untreated illness (DUI) or duration of untreated psychosis (DUP). Further, there were no difference in initial level of symptoms as measured by global and total scores on SAPS and SANS. Table III presents information on the use of risperidone or olanzapine as reflected at each of the assessments points of 3, 6, 12, 18 and 24 months. Table III presents the number of patients still on the originally prescribed medication (at baseline) as well as the number who began the risperidone or olanzapine at varying times since the beginning of treatment. Table III. Total patients on risperidone and olanzapine during 2 years of treatment. Antipsychotics (APS) Risperidal (N ) Baseline
Olanzapine (N )
133
38
3 months since baseline new
98 84 14
43 20 23
6 months since baseline since 3 months new
75 61 10 4
45 16 19 10
12 months since baseline since 3 months since 6 months new
53 41 2 4 6
48 14 16 6 12
18 months since baseline since 3 months since 6 months since 12 months new
43 31 2 3 3 4
41 9 11 4 9 8
24 months since baseline since 3 months since 6 months since 12 months since 18 months new
41 26 2 2 2 4 5
29 4 8 2 5 6 4
The above table shows the total number of patients who took risperidone or olanzapine at different time points during the two years of follow-up. The table also shows the number of patients who were started on risperidone or olanzapine at each time point and those who remained on it throughout the two year period.
2 (6.9%) 0 7 (24.1%)
2 (6.9%) 3 (10.3%)
29
5 (12.2%) 2 (4.8%) 12 (29.3%) 1 (2.4%) 0 9 (21.9%) 6 (13.9%) 1 (2.3%) 13 (30.2%) 1 (2.1%) 0 14 (29.2%) 11 (20.7%) 1 (1.9%) 19 (35.8%)
4 (7.5%) 5 (9.6%) 4 (8.9%) 5 (11.1%)
53 45
Risp Olanz
1 (2.2%) 1 (2.2%) 13 (28.9%)
1 (2.4%) 2 (4.8%) 3 (7.3%) 1 (2.4%) 4 (9.3%) 2 (4.6%)
43 48
Risp Olanz
2 (4.2%) 7 (14.6%)
41 41
Olanz
Risp
24 18 12
10 (13.3%) 5 (6.6%) 24 (32%) 1 (2.3%) 1 (2.3%) 10 (10.2%)
14 (18.7%) 5 (6.7%) 6 (13.9%) 6 (13.9%)
75 43
Olanz
Risp
6
13 (13.3%) 7 (7.1%) 23 (23.5%) 3 (7.9%) 2 (5.3%) 6 (15.8%) 20 (15%) 11 (8.3%) 22 (16.5%)
15 (15.3%) 11 (11.2%) 8 (21%) 16 (42.1%) 38 (28.6%) 38 (28.6%)
98 38
Olanz
Risp
3
Anxiolytic reg prn Anticholinergic reg prn Antidepressants
133 Concomitant Medications
Risp
This is the first naturalistic study of atypical antipsychotic use in predominantly drug-naı¨ve patients in a first episode psychosis program who were followed for 2 years. Data from such a study are more likely to represent ongoing clinical practice than pre-marketing drug trials conducted in standardized conditions with specific inclusion/exclusion criteria. This study primarily focused on the pattern of utilization of risperidone and olanzapine, the first two atypical antipsychotics introduced in Canada. A comparison of the clinical efficacy and side effect profile of these two medications has been addressed separately [11]. Patients in both groups showed substantial improvement with no significant differences between the two groups on efficacy or side effects. We have observed that achieving a remission of positive symptoms is also positively influenced by better premorbid adjustment, higher level of adherence to medication and shorter DUI and higher levels of social support [12,13]. The improved neurological side effect profile of atypical antipsychotics has led to the speculation that patients receiving atypical compared to typical antipsychotics will show greater adherence. Although there is some evidence to support greater adherence for patients receiving atypicals for periods of less than a year [14], there is no research to support this in the longer term. It is frequently suggested that non-adherence is a direct result of disease processes in schizophrenia [1]. The early intervention program
0
Discussion
Time (months)
The use of concomitant anxiolytic, antidepressant and anticholinergic medications was also recorded and the results are summarized in Table IV. Anxiolytics were the most frequent concomitant medications in both risperidone and olanzapine groups at baseline (28.6 and 21%, respectively), 3 months (15.3 and 13.3%) and at 6 months (18.6 and 17.4%). At no time point was there a significant difference between patients on risperidone and olanzapine in the use of anxiolytics. For both groups of patients the use of anxiolytics was substantially decreased over time. At the end of 2 years only 4.8% in the risperidone group and 6.9% in the olanzapine group were being prescribed anxiolytics. Although, at initiation of treatment the prn use of anxiolytics appears somewhat higher in the olanzapine (42.1%) compared to risperidone group (28.6%), this is not statistically significant (chi-square /2.51, ns). Antidepressant use increased from baseline (16.5% and 15.8 for risperidone and olanzapine, respectively) to 2 years (29.3 and 24.1%). Anticholinergics were used more frequently in the risperidone compared to olanzapine group at all time points: baseline (15 vs. 7.8%) and 2 years (12.2 vs. 6.9%). None of these differences are statistically significant using chisquare.
Olanz
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Table IV. The frequency of concomitant psychotropic medications taken by patients on risperidone or olanzapine at different time points during their 2-year follow-up.
154
Antipsychotic use in a first episode psychosis program 155 in PEPP is guided by a medication algorithm and specific group interventions previously described [8]. Interestingly, even within this algorithm there was noticeable variation in clinical practice. We found that a large proportion of patients go off their first antipsychotic medication within the first 6 months (48.7 and 50% for risperidone and olanzapine, respectively) or 12 months (61.3 and 51.7%) with a further reduction in usage thereafter. Of these continuing in the program, only 28.3% of patients on risperidone and 16.6% on olanzapine remained on the first prescribed antipsychotic at the end of 2 years. In the recent CATIE trial [5] the rates of discontinuation for the first antipsychotic in the study ranged from 64 to 82%. However, patients continuing to take any neuroleptic at 12 (90.1%) or 24 (78.9%) months at our centre was much higher than the rate typically reported [15]. We speculate that this may be related to the specialized features of our early intervention program [8]. PEPP utilizes an assertive case management model, modified to suit the needs of mostly young people and their families, as its central framework. The model involves a comprehensive approach with intensive psychiatric care and psychosocial management, the latter provided by a nurse or social worker case manager. The case manager’s role is achieved through close partnership with families and a strong therapeutic relationship with the patient. Furthermore, whenever possible, case managers also liaise with community services, educational institutions and employers to reintegrate the patient to his or her full potential. Engagement in the program and emphasis on adherence to treatment is an integral part of the service provided. The low mean dose of risperidone and olanzapine in this study is in keeping with the clinical practice among patients with FEP [16]. However, despite having a protocol for prescribing atypical antipsychotics to their maximum dose in 6 weeks, the clinical reality is that initiating and adjusting the dose progressed over a longer period. Further, approximately 15% of FEP in our centre have persistent psychosis despite treatment [17] which would explain the dose adjustment being continued over an extended period in some patients. Interestingly, polypharmacy was not a common practice in this study. Most likely, this is because the first episode patients were previously untreated. The treatment protocol at PEPP recommends using a single atypical neuroleptic only unless all treatments (including typical neuroleptics or clozapine) have failed to provide an improvement. This is also emphasized in the psycho-education groups for families as well as in the ongoing education to patients. Also, patients who are not responding to treatment are discussed at case rounds and polypharmacy is generally discouraged. All patients are assessed on a regular basis using standardized rating
scales for depression and anxiety which would guide towards the most rational use of concomitant medications. Anxiolytics were the commonest coprescriptions at baseline with progressive decline in use over time. This is consistent with the common clinical presentation of agitation and anxiety during the initial stages of the first episode. Antidepressants were co-prescribed in both groups. Perhaps this represents the co-morbid mood disorder or mood related symptomatology in patients with schizophrenia [18]. Anticholinergics were prescribed more often in the risperidone group consistent with the increased frequency of extrapyramidal symptoms in patients on risperidone [19]. The observation that patients were not prescribed more than one neuroleptic at a time, polypharmacy was not common and that a significant proportion of patients remained on the neuroleptic during the 2year follow-up may be unique to a first episode psychosis program. There are no data to meaningfully compare to the current findings. Nevertheless, we observed that half the patients changed their antipsychotic during the first 6 months. This may suggest an ambivalence with regards to medication, experiencing a side effect or perceived lack of satisfactory response. Unless patients with FEP are observed closely and regularly with intensive case management, there is a risk of patients not following up/adhering with the recommended treatment. The validity of the results presented obviously depends upon how representative is the sample. All patients within a defined geographical area who sought help for a first episode of a non-affective psychosis were probably included. Further, the 2year follow-up was under naturalistic setting with clinical guidelines, but no rules that had to be enforced for clinical care. The attrition rate of 32.2% from the program is in keeping with the literature [20]. The findings report a clinical reality in terms of time taken to adjust and maximize the dose, non-adherence and change in prescribed antipsychotics and the use of concomitant medications in relatively drug-naı¨ve first episode psychoses patients. Key points . Large differences exist between prescription patterns of pre-marketing trials and those of actual clinical practice . First episode psychosis outpatients take much longer than inpatients to commence antipsychotic medications . Half of the patients change the first antipsychotic agent within 6 months irrespective of the initial medication prescribed . Concomitant psychotropic medication use did not differ between those prescribed risperidone versus olanzapine
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References [1] Fenton WS, Blyler CR, Heinssen RK. Determinants of medication compliance in schizophrenia: empirical and clinical findings. Schizophr Bull 1997;23(4):637 51. [2] Malla A, Norman RMG, Manchanda R, Townsend L. Symptoms, cognition, treatment adherence and functional outcome in first episode psychosis. Psychol Med 2002; 132(6):1 11. [3] Robinson D, Woemer MG, Alvir JM, et al. Predictors of relapse following response from a first episode of schizophrenia or schizo-affective disorder. Arch Gen Psychiatry 1999;56(3):241 7. [4] Jibson MD, Tandon R. New atypical antipsychotic medications. J Psychiatr Res 1998;32:215 28. [5] Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. New Engl J Med 2005;353(12):1209 23. [6] Martin K, Begaud B, Latry P, Miremont-Salame G, Fourrier A, Moore N. Differences between clinical trials and post-marketing use. Br J Clin Pharmacol 2003;57(1): 86 92. [7] Verdoux H, Begaud B. Pharmaco-epidemiology: what do (and don’t) we know about utilization and impact of psychotropic medications in real-life conditions? Br J Psychiat 2004;185:93 4. [8] Malla A, Norman RMG, McLean TS, Scholten D, Townsend L. A Canadian programme for early intervention in non-affective psychotic disorders. Aust NZ J Psychiatry 2003;37:407 13. [9] Andreason NC. Scale for the Assessment of Positive Symptoms (SAPS). Department of Psychiatry, College of Medicine, The University of Iowa, Iowa City, IA; 1984. /
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
[10] Andreason NC. Scale for the Assessment of Negative Symptoms (SANS). Department of Psychiatry, College of Medicine, The University of Iowa, Iowa City, IA; 1983. [11] Malla A, Norman RMG, Scholten D, et al. A comparison of two novel antipsychotics in first episode non-affective psychosis: one year outcome on symptoms, motor side effects and cognition. Psychiatr Res 2004;129:159 69. [12] Malla A, Norman R, Schmitz N, et al. Predictors of rate and time to remission in first episode psychosis: a two year outcome study. Psychol Med 2006;36:649 58. [13] Norman RMG, Malla AK, Manchanda R, Harricharan R, Takhar J, Northcott S. Social support and three year symptoms and admission outcomes for first episode psychosis. Schizophr Res 2005;80:227 34. [14] Dolder CR, Lacro JP, Dunn LB, Jeste DV. Antipsychotic medication adherence: is there a difference between typical and atypical agents? Am J Psychiatry 2002;159:103 8. [15] Marder SR. Overview of partial compliance. J Clin Psychiatry 2003;64(Suppl 16):3 9. [16] Remington G. Rational pharmacotherapy in early psychosis. Br J Psychiatry 2005;187(Suppl 48):577 84. [17] Manchanda R, Norman RMG, Malla AK, Harricharan R, Northcott S. Persistent psychoses in first episode patients. Schizophr Res 2005;80:113 6. [18] Addington DD, Azorin JM, Falloon IR, Gerlach J, Hirsch SR, Siris SG. Clinical issues related to depression in schizophrenia: an international survey of psychiatrists. Acta Psychiatr Scand 2002;105:189 95. [19] Task Force of the World Psychiatric Association. The usefulness of the second-generation antipsychotic medications. Curr Opin Psychiatry 2002;15:S7 16. [20] Nose M, Barbui C, Tausella M. How often do patients with psychosis fail to adhere to treatment programs? A Systematic review. Psychol Med 2003;33:1149 60. /
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ORIGINAL ARTICLE
Antipsychotic use in a first episode psychosis program
RAHUL MANCHANDA1, ROSS M.G. NORMAN1, ASHOK K. MALLA2 & RANITA MANOCHA1 1
Prevention and Early Intervention Program for Psychoses (PEPP), London Health Sciences Centre, London, Ontario, Canada and 2Department of Psychiatry, Douglas Hospital Research Centre, Verdun, Quebec, Canada
Abstract Objective. To conduct a naturalistic, longitudinal study of prescribing patterns of atypical neuroleptics in predominantly drug-naı¨ve first episode non-affective psychosis patients. Methods. Patients with a first episode psychosis were prescribed an antipsychotic as part of a clinical protocol and followed-up for 2 years. Comparisons were made between risperidone and olanzapine, the two most commonly prescribed antipsychotics. Socio-demographic variables and clinical characteristics such as diagnosis, duration of untreated illness and psychosis and level of positive and negative symptoms were assessed using well-established methods. We examined the first antipsychotic given, starting dose, time taken to start and to reach the maximum dose, time on first medication, maximum dose, medication change and concomitant medication use. Results. One hundred and ninety-three consecutive patients consented to start on antipsychotic. The results are provided for risperidone (N / 133) and olanzapine (N /38). The time to initiate antipsychotic medications was significantly longer for outpatients than inpatients. There were no differences between the two groups for time taken to reach the maximum dose, drop out rates or concomitant medication use. The percentage of patients taking an antipsychotic agent at any given time was high (range 79 91%), but half of the patients had changed from their first antipsychotic by 6 months. Conclusions: The reality of clinical practice can be much different than rigid protocols or treatment algorithms of pre-marketing studies or clinical trials. In this sample of first episode psychosis patients, although the majority of patients remained on an antipsychotic, changes in medication over the first 2 years were common. Polypharmacy was not a common practice.
Key Words: First episode psychosis, prescribing patterns, antipsychotics, medication switchover, concomitant medications
Introduction An individual patient’s adherence to prescribed antipsychotic medication is probably the single greatest determinant of the effectiveness of treatment for schizophrenia [1 3]. The introduction of atypical antipsychotics has promised greater effectiveness compared to typicals in the treatment of positive, negative and cognitive symptoms of schizophrenia [4], although recent evidence suggests we should be cautious in assuming this is the case [5]. Large differences may exist between the clinical circumstances of pre-marketing trials and those of actual post-marketing practice [6]. Most evaluations of the effectiveness of psychotropic medications have been sponsored by the pharmaceutical industry and use a highly standardized protocol for dispensing medications. While such research provides valuable evidence regarding the efficacy of compounds, it does not necessarily reflect their utilization in most clinical settings. We need to know more about the
utilization of antipsychotic medications in the ‘‘real world’’ of clinical practice. It is also recognized that there is a need for pharmaco-epidemiological research to be conducted independently of drug companies [7]. Early intervention programs for first episode psychosis (FEP) provide an important opportunity to study the long-term patterns of prescribing antipsychotic medications in relatively treatment naı¨ve individuals from a time closer to the onset of their illness. The objective of the current study was to conduct a naturalistic, longitudinal study of prescribing patterns of atypical antipsychotics in predominantly drug-naı¨ve first episode non-affective psychosis patients. Methods The Prevention and Early Intervention Program for Psychosis (PEPP) in London, Canada provides services to patients (16 50 years old) who meet
Correspondence: Rahul Manchanda, PEPP, London Health Sciences Centre, 392 South Street, London, Ontario, Canada N6A 4G5. Tel: /1 519 667 6866. Fax: /1 519 667 6867. E-mail: [email protected]
(Received 3 April 2006; accepted 3 July 2006) ISSN 1365-1501 print/ISSN 1471-1788 online # 2007 Taylor & Francis DOI: 10.1080/13651500601162385
152
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criteria of a non-affective psychosis, living in a defined urban catchment area of approximately 390,000. Those admitted to the program have not previously received antipsychotic treatment for a cumulative period greater than 1 month. PEPP utilizes an assertive case management model, modified to suit the needs of mostly young people with first episode psychoses and their families. The model involves a comprehensive approach with intensive medical and psychosocial management being provided by a nurse or social worker case manager. Further details of the clinical program are available at www.pepp.ca. The PEPP protocol requires patients to be treated initially with a novel antipsychotic within the generally recommended dose range [8]. The choice of the antipsychotic medication is arrived at as a result of consultation between the psychiatrist, the individual patient and, where applicable, the family. Often the choice of medication is also influenced by the availability of the novel antipsychotic and whether or not it is funded by a government program for patients with low or no income. Risperidone was introduced in Canada in 1993, olanzapine in 1996 and quetiapine in 1998. Patients are offered dosage as low as 0.5 1 mg of risperidone, 5 mg of olanzapine or 50 100 mg of quetiapine which is typically increased over several days to 2, 10 and 300 mg/day, respectively. If needed, the dose of the medication is increased to a maximum tolerated dose of up to 6, 20 and 900 mg, respectively. Symptoms were assessed using the Scale for the Assessment of Positive Symptoms [9] and Scale for the Assessment of Negative Symptoms [10]. Failure to achieve a remission of positive symptoms (remission defined as SAPS global scores of 5/2) despite trials with two novel antipsychotics results in the discussion with the patient and family concerning possible use of clozapine therapy. Older, typical antipsychotic medications were used only as depot preparations when adherence to oral medications becomes problematic, because injectable risperidone consta was not introduced in Canada until 2005. The patients included in this study were admitted to PEPP over a 4-year period and followed-up for at least 2-years after admission. We examined the data to determine the socio-demographic and clinical characteristics of the patients, the first antipsychotic given, the starting dose, time taken to start the medication and to reach maximum dose, maximum dose, time on first medication, change in medication and concomitant medications (anxiolytic, antidepressant, anticholinergic). This information was collected at each visit and more formally assessed and recorded at 3, 6, 12, 18 and 24 months. The information collected included an enquiry as to whether or not the antipsychotic medications were being taken as prescribed.
Results The sample for this study consists of 196 consecutive patients who were accepted to PEPP during a 4-year period. Given the size of the catchment area (390,000) and expected incidence rates, these patients probably approximate an incidence sample of non-affective psychoses for that period of time. Of these, 113 (57.6%) began treatment as inpatients and the remaining 83 (42.4%) were outpatients at the time of their entry into treatment. One hundred and ninety-three patients consented to start an antipsychotic. The majority of the patients were started on either risperidone (N /133) or olanzapine (N /38). The other available atypical neuroleptic, quetiapine, was initiated in only two patients; 13 were prescribed typical neuroleptics and seven received an investigational drug. Further analyses were carried out only with reference to risperidone and olanzapine as these were the two most frequently prescribed antipsychotics. The patients were followed up for 2 years under naturalistic conditions with general clinical guidelines, but no stringent prescription rules that had to be followed. By the end of 1 year there were 152 patients in the program (attrition of 22.5%) and 133 patients at the end of 2 years (further attrition of 12.5%). The overall attrition rate over a 2-year period was 32.2%. There were no significant differences in the baseline socio-demographic and clinical characteristics of those who stayed on in PEPP for 2 years (N /133) versus those who did not complete 2-year follow-up (N /63). There was no difference in the drop out rate from the patients in risperidone or olanzapine group. Over the 2-year period, 41 of the patients initially prescribed risperidone (30.8%) and 14 of these initially prescribed olanzapine (36.8%) had dropped out of treatment (x2 /0.49, ns). Also, a comparison was made on the sociodemographic and clinical characteristics at entry into PEPP for those initially prescribed risperidone (N /133) or olanzapine (N /38). There were no significant differences between the groups on these socio-demographic variables or symptom ratings based on SAPS and SANS at baseline (Table I). Information being presented here is based on all the patients who were in the program at any given assessment point. The dose and duration on the first antipsychotic is shown in Table II. The time to initiate antipsychotic medications following acceptance to PEPP was significantly longer for outpatients (mean /2.65 weeks, SD /7.9) compared to (mean / /0.42 weeks, SD /1.5) (t /3.41, P B/0.001). The minus figure indicates that patients admitted to the program through the inpatient unit were actually started on their regular antipsychotic medications before formal entry in the Program. The mean starting doses for risperidone and olanzapine were 1 and 5.5 mg, respectively, and the maximum doses given
Antipsychotic use in a first episode psychosis program 153 Table I. Baseline socio-demographic variables, diagnosis, duration of untreated psychosis/illness and the mean total scores on positive and negative symptoms in the risperidone and olanzapine groups. There was no difference between the two groups on these variables.
Mean Age H.S. ]/ Single Male Scz Spec Dis Median DUP (weeks) Median DUI (weeks) SAPS Total SANS Total
Risperidone (N /133)
Olanzapine (N /38)
24.9 (9/7.4) 45 (33.8%) 108 (81.2%) 100 (75.2%) 82 (61.6%) 21.4 (9/111.5)
26.9 (9/8.5) 13 (34.2%) 27 (71.1%) 33 (86.9%) 22 (57.8%) 20.1 (9/105)
n.s. n.s. n.s. n.s. n.s. n.s.
188.3 (9/264.3)
208.5 (9/212.9)
n.s.
32.2 30.0
33.7 29.7
n.s. n.s.
were 8 and 25 mg, respectively. The mean time taken to reach the maximum dose did not differ significantly between the two groups (11.7 (SD 6.2) weeks for risperidone and 11.8 (SD 18.3) weeks for olanzapine); the median times were 5 and 4 weeks, respectively. The total number of patients in the program taking on antipsychotic agent was high. Of the 152 patients in the program at 1 year 138 (90.8%) reported taking on antipsychotic and 105/133 (78.9%) at 2 years. None of our patients were given more than one antipsychotic agent on a regular basis during the 2-year follow-up. The number of times that the patients switched an antipsychotic were as follows: to a second antipsychotic 80 (40.4%), to a third antipsychotic 47 (23.7%), to a fourth antipsychotic 15 (7.6%) and, four (2%) were switched to a fifth antipsychotic during the 2-year period. At the 2-year mark the medication distribution for patients taking an antipsychotic (N /105) was as follows: risperidone 41 (39.1%), olanzapine 29 (27.6%) and others 35 (33.3%). We looked specifically at those patients who were started on risperidone (N /133) or olanzapine (N / 38) as the first line antipsychotic. Of those patients remaining in the program at 6 months, only 61 of 119 (51.3%) of those initially prescribed risperidone Table II. The mean time taken to initiate risperidone or olanzapine for inpatients and outpatients, mean dose of the antipsychotic and the mean time taken to reach the maximum dose of the first antipsychotic given to them (/x¯ /mean). Risperidone (N /133) Time to initiate (weeks) Inpatient Outpatient Start dose (mg) Max. dose (mg) Time to max. dose (weeks)
1 6 (/x¯ 2) 1 24 (/x¯ 6) 0.5 5 (/x¯ 1.0) 0.5 8 (/x¯ 3.3) 2 99 (/x¯ 11.7)
Olanzapine (N /38) 1 10 (/x¯ 1.5) 1 54 (/x¯ 5.5) 2.5 10 (/x¯ 0.5) 2.5 25 (/x¯ 13.3) 2 88 (/x¯ 11.8)
and 16 of 32 (50%) of those initially prescribed olanzapine were still taking their original medications (x2 /0.02, ns). By 24 months, 26 of 92 (28.3%) patients still in the program who were initially prescribed risperidone were still taking it and for olanzapine the relevant figures were 4 out of 24 (16.6%) with the difference not reaching statistical significance (x2 /1.33, ns). We examined if there are any baseline sociodemographic or clinical variables associated with those who do or do not switch medications by 6 months. There were no significant findings on gender, age of onset of psychosis, age at entry to PEPP, duration of untreated illness (DUI) or duration of untreated psychosis (DUP). Further, there were no difference in initial level of symptoms as measured by global and total scores on SAPS and SANS. Table III presents information on the use of risperidone or olanzapine as reflected at each of the assessments points of 3, 6, 12, 18 and 24 months. Table III presents the number of patients still on the originally prescribed medication (at baseline) as well as the number who began the risperidone or olanzapine at varying times since the beginning of treatment. Table III. Total patients on risperidone and olanzapine during 2 years of treatment. Antipsychotics (APS) Risperidal (N ) Baseline
Olanzapine (N )
133
38
3 months since baseline new
98 84 14
43 20 23
6 months since baseline since 3 months new
75 61 10 4
45 16 19 10
12 months since baseline since 3 months since 6 months new
53 41 2 4 6
48 14 16 6 12
18 months since baseline since 3 months since 6 months since 12 months new
43 31 2 3 3 4
41 9 11 4 9 8
24 months since baseline since 3 months since 6 months since 12 months since 18 months new
41 26 2 2 2 4 5
29 4 8 2 5 6 4
The above table shows the total number of patients who took risperidone or olanzapine at different time points during the two years of follow-up. The table also shows the number of patients who were started on risperidone or olanzapine at each time point and those who remained on it throughout the two year period.
2 (6.9%) 0 7 (24.1%)
2 (6.9%) 3 (10.3%)
29
5 (12.2%) 2 (4.8%) 12 (29.3%) 1 (2.4%) 0 9 (21.9%) 6 (13.9%) 1 (2.3%) 13 (30.2%) 1 (2.1%) 0 14 (29.2%) 11 (20.7%) 1 (1.9%) 19 (35.8%)
4 (7.5%) 5 (9.6%) 4 (8.9%) 5 (11.1%)
53 45
Risp Olanz
1 (2.2%) 1 (2.2%) 13 (28.9%)
1 (2.4%) 2 (4.8%) 3 (7.3%) 1 (2.4%) 4 (9.3%) 2 (4.6%)
43 48
Risp Olanz
2 (4.2%) 7 (14.6%)
41 41
Olanz
Risp
24 18 12
10 (13.3%) 5 (6.6%) 24 (32%) 1 (2.3%) 1 (2.3%) 10 (10.2%)
14 (18.7%) 5 (6.7%) 6 (13.9%) 6 (13.9%)
75 43
Olanz
Risp
6
13 (13.3%) 7 (7.1%) 23 (23.5%) 3 (7.9%) 2 (5.3%) 6 (15.8%) 20 (15%) 11 (8.3%) 22 (16.5%)
15 (15.3%) 11 (11.2%) 8 (21%) 16 (42.1%) 38 (28.6%) 38 (28.6%)
98 38
Olanz
Risp
3
Anxiolytic reg prn Anticholinergic reg prn Antidepressants
133 Concomitant Medications
Risp
This is the first naturalistic study of atypical antipsychotic use in predominantly drug-naı¨ve patients in a first episode psychosis program who were followed for 2 years. Data from such a study are more likely to represent ongoing clinical practice than pre-marketing drug trials conducted in standardized conditions with specific inclusion/exclusion criteria. This study primarily focused on the pattern of utilization of risperidone and olanzapine, the first two atypical antipsychotics introduced in Canada. A comparison of the clinical efficacy and side effect profile of these two medications has been addressed separately [11]. Patients in both groups showed substantial improvement with no significant differences between the two groups on efficacy or side effects. We have observed that achieving a remission of positive symptoms is also positively influenced by better premorbid adjustment, higher level of adherence to medication and shorter DUI and higher levels of social support [12,13]. The improved neurological side effect profile of atypical antipsychotics has led to the speculation that patients receiving atypical compared to typical antipsychotics will show greater adherence. Although there is some evidence to support greater adherence for patients receiving atypicals for periods of less than a year [14], there is no research to support this in the longer term. It is frequently suggested that non-adherence is a direct result of disease processes in schizophrenia [1]. The early intervention program
0
Discussion
Time (months)
The use of concomitant anxiolytic, antidepressant and anticholinergic medications was also recorded and the results are summarized in Table IV. Anxiolytics were the most frequent concomitant medications in both risperidone and olanzapine groups at baseline (28.6 and 21%, respectively), 3 months (15.3 and 13.3%) and at 6 months (18.6 and 17.4%). At no time point was there a significant difference between patients on risperidone and olanzapine in the use of anxiolytics. For both groups of patients the use of anxiolytics was substantially decreased over time. At the end of 2 years only 4.8% in the risperidone group and 6.9% in the olanzapine group were being prescribed anxiolytics. Although, at initiation of treatment the prn use of anxiolytics appears somewhat higher in the olanzapine (42.1%) compared to risperidone group (28.6%), this is not statistically significant (chi-square /2.51, ns). Antidepressant use increased from baseline (16.5% and 15.8 for risperidone and olanzapine, respectively) to 2 years (29.3 and 24.1%). Anticholinergics were used more frequently in the risperidone compared to olanzapine group at all time points: baseline (15 vs. 7.8%) and 2 years (12.2 vs. 6.9%). None of these differences are statistically significant using chisquare.
Olanz
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Table IV. The frequency of concomitant psychotropic medications taken by patients on risperidone or olanzapine at different time points during their 2-year follow-up.
154
Antipsychotic use in a first episode psychosis program 155 in PEPP is guided by a medication algorithm and specific group interventions previously described [8]. Interestingly, even within this algorithm there was noticeable variation in clinical practice. We found that a large proportion of patients go off their first antipsychotic medication within the first 6 months (48.7 and 50% for risperidone and olanzapine, respectively) or 12 months (61.3 and 51.7%) with a further reduction in usage thereafter. Of these continuing in the program, only 28.3% of patients on risperidone and 16.6% on olanzapine remained on the first prescribed antipsychotic at the end of 2 years. In the recent CATIE trial [5] the rates of discontinuation for the first antipsychotic in the study ranged from 64 to 82%. However, patients continuing to take any neuroleptic at 12 (90.1%) or 24 (78.9%) months at our centre was much higher than the rate typically reported [15]. We speculate that this may be related to the specialized features of our early intervention program [8]. PEPP utilizes an assertive case management model, modified to suit the needs of mostly young people and their families, as its central framework. The model involves a comprehensive approach with intensive psychiatric care and psychosocial management, the latter provided by a nurse or social worker case manager. The case manager’s role is achieved through close partnership with families and a strong therapeutic relationship with the patient. Furthermore, whenever possible, case managers also liaise with community services, educational institutions and employers to reintegrate the patient to his or her full potential. Engagement in the program and emphasis on adherence to treatment is an integral part of the service provided. The low mean dose of risperidone and olanzapine in this study is in keeping with the clinical practice among patients with FEP [16]. However, despite having a protocol for prescribing atypical antipsychotics to their maximum dose in 6 weeks, the clinical reality is that initiating and adjusting the dose progressed over a longer period. Further, approximately 15% of FEP in our centre have persistent psychosis despite treatment [17] which would explain the dose adjustment being continued over an extended period in some patients. Interestingly, polypharmacy was not a common practice in this study. Most likely, this is because the first episode patients were previously untreated. The treatment protocol at PEPP recommends using a single atypical neuroleptic only unless all treatments (including typical neuroleptics or clozapine) have failed to provide an improvement. This is also emphasized in the psycho-education groups for families as well as in the ongoing education to patients. Also, patients who are not responding to treatment are discussed at case rounds and polypharmacy is generally discouraged. All patients are assessed on a regular basis using standardized rating
scales for depression and anxiety which would guide towards the most rational use of concomitant medications. Anxiolytics were the commonest coprescriptions at baseline with progressive decline in use over time. This is consistent with the common clinical presentation of agitation and anxiety during the initial stages of the first episode. Antidepressants were co-prescribed in both groups. Perhaps this represents the co-morbid mood disorder or mood related symptomatology in patients with schizophrenia [18]. Anticholinergics were prescribed more often in the risperidone group consistent with the increased frequency of extrapyramidal symptoms in patients on risperidone [19]. The observation that patients were not prescribed more than one neuroleptic at a time, polypharmacy was not common and that a significant proportion of patients remained on the neuroleptic during the 2year follow-up may be unique to a first episode psychosis program. There are no data to meaningfully compare to the current findings. Nevertheless, we observed that half the patients changed their antipsychotic during the first 6 months. This may suggest an ambivalence with regards to medication, experiencing a side effect or perceived lack of satisfactory response. Unless patients with FEP are observed closely and regularly with intensive case management, there is a risk of patients not following up/adhering with the recommended treatment. The validity of the results presented obviously depends upon how representative is the sample. All patients within a defined geographical area who sought help for a first episode of a non-affective psychosis were probably included. Further, the 2year follow-up was under naturalistic setting with clinical guidelines, but no rules that had to be enforced for clinical care. The attrition rate of 32.2% from the program is in keeping with the literature [20]. The findings report a clinical reality in terms of time taken to adjust and maximize the dose, non-adherence and change in prescribed antipsychotics and the use of concomitant medications in relatively drug-naı¨ve first episode psychoses patients. Key points . Large differences exist between prescription patterns of pre-marketing trials and those of actual clinical practice . First episode psychosis outpatients take much longer than inpatients to commence antipsychotic medications . Half of the patients change the first antipsychotic agent within 6 months irrespective of the initial medication prescribed . Concomitant psychotropic medication use did not differ between those prescribed risperidone versus olanzapine
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References [1] Fenton WS, Blyler CR, Heinssen RK. Determinants of medication compliance in schizophrenia: empirical and clinical findings. Schizophr Bull 1997;23(4):637 51. [2] Malla A, Norman RMG, Manchanda R, Townsend L. Symptoms, cognition, treatment adherence and functional outcome in first episode psychosis. Psychol Med 2002; 132(6):1 11. [3] Robinson D, Woemer MG, Alvir JM, et al. Predictors of relapse following response from a first episode of schizophrenia or schizo-affective disorder. Arch Gen Psychiatry 1999;56(3):241 7. [4] Jibson MD, Tandon R. New atypical antipsychotic medications. J Psychiatr Res 1998;32:215 28. [5] Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. New Engl J Med 2005;353(12):1209 23. [6] Martin K, Begaud B, Latry P, Miremont-Salame G, Fourrier A, Moore N. Differences between clinical trials and post-marketing use. Br J Clin Pharmacol 2003;57(1): 86 92. [7] Verdoux H, Begaud B. Pharmaco-epidemiology: what do (and don’t) we know about utilization and impact of psychotropic medications in real-life conditions? Br J Psychiat 2004;185:93 4. [8] Malla A, Norman RMG, McLean TS, Scholten D, Townsend L. A Canadian programme for early intervention in non-affective psychotic disorders. Aust NZ J Psychiatry 2003;37:407 13. [9] Andreason NC. Scale for the Assessment of Positive Symptoms (SAPS). Department of Psychiatry, College of Medicine, The University of Iowa, Iowa City, IA; 1984. /
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
[10] Andreason NC. Scale for the Assessment of Negative Symptoms (SANS). Department of Psychiatry, College of Medicine, The University of Iowa, Iowa City, IA; 1983. [11] Malla A, Norman RMG, Scholten D, et al. A comparison of two novel antipsychotics in first episode non-affective psychosis: one year outcome on symptoms, motor side effects and cognition. Psychiatr Res 2004;129:159 69. [12] Malla A, Norman R, Schmitz N, et al. Predictors of rate and time to remission in first episode psychosis: a two year outcome study. Psychol Med 2006;36:649 58. [13] Norman RMG, Malla AK, Manchanda R, Harricharan R, Takhar J, Northcott S. Social support and three year symptoms and admission outcomes for first episode psychosis. Schizophr Res 2005;80:227 34. [14] Dolder CR, Lacro JP, Dunn LB, Jeste DV. Antipsychotic medication adherence: is there a difference between typical and atypical agents? Am J Psychiatry 2002;159:103 8. [15] Marder SR. Overview of partial compliance. J Clin Psychiatry 2003;64(Suppl 16):3 9. [16] Remington G. Rational pharmacotherapy in early psychosis. Br J Psychiatry 2005;187(Suppl 48):577 84. [17] Manchanda R, Norman RMG, Malla AK, Harricharan R, Northcott S. Persistent psychoses in first episode patients. Schizophr Res 2005;80:113 6. [18] Addington DD, Azorin JM, Falloon IR, Gerlach J, Hirsch SR, Siris SG. Clinical issues related to depression in schizophrenia: an international survey of psychiatrists. Acta Psychiatr Scand 2002;105:189 95. [19] Task Force of the World Psychiatric Association. The usefulness of the second-generation antipsychotic medications. Curr Opin Psychiatry 2002;15:S7 16. [20] Nose M, Barbui C, Tausella M. How often do patients with psychosis fail to adhere to treatment programs? A Systematic review. Psychol Med 2003;33:1149 60. /
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