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The interaction of subjective experience and attitudes towards specific antipsychotic-related adverse effects in schizophrenia patients
European Psychiatry 28 (2013) 340–343
Available online at
www.sciencedirect.com
Original article
The interaction of subjective experience and attitudes towards specific antipsychotic-related adverse effects in schizophrenia patients T. Fischel a,b,1, A. Krivoy a,*,b,1, M. Kotlarov b, Z. Zemishlany a,b, O. Loebstein a,b, H. Jacoby a, A. Weizman a,b,c a
Geha Mental Health Center, 1, Helsinki Street, P.O. Box 103, 49100 Petach-Tikva, Israel Sackler’s Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel c Felsenstein Medical Research Center, Petach-Tikva, Israel b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 9 April 2012 Received in revised form 14 June 2012 Accepted 16 June 2012 Available online 19 September 2012
Background: Discontinuation of antipsychotic drugs in schizophrenia patients is a major concern, since it results in relapse and re-hospitalizations. Non-adherence is strongly associated with negative-subjective response to antipsychotics, which is composed of the subjective experience of negative drug effects and attitude towards the treatment. Objective: To investigate the elements of subjective experience and subjective attitude towards specific drug-related adverse effects, leading to a generally negative-subjective attitude towards antipsychotics. Methods: Schizophrenia inpatients (n = 84) were administered a questionnaire measuring attitude and experience on eight subscales: weight gain, sedation, sexual anhedonia, extra-pyramidal syndrome, affective flattening, excessive sleep, diminished sociability and metabolic syndrome. DAI-30 was used to measure attitude towards drugs, and PANSS to assess psychopathology. Results: Weak correlation was found between subjective experience and attitude on most of the subscales. The only strong, albeit inverse, correlation between experience and attitude that was found was with regard to affective flattening, experienced by 37% of the sample, and it also predicted negative drug attitude as measured by the DAI-30, RR: 1.87 (95% CI: 1.06–3.3, df = 1, x2 = 4.525, P < 0.05). Conclusion: Negative attitude towards most adverse drug effects did not correlate with personal experience. Drug-related affective flattening should be evaluated routinely, since experiencing it may predict negative attitude towards drugs, potentially leading to poor compliance and relapse. ß 2012 Elsevier Masson SAS. All rights reserved.
Keywords: Schizophrenia Antipsychotic drugs Subjective attitude Subjective experience Affective flattening
1. Introduction Discontinuation of antipsychotic drugs (APD) is associated with poor treatment outcomes and higher risk for relapse and rehospitalization of schizophrenia patients [16,12,17]. Three large non-industry sponsored studies have compared the effectiveness of first generation APD and second generation APD. In addition to not finding a significant difference between old and new APD on measures of efficacy, quality of life or compliance, all three studies have shown high discontinuation rates of APD; in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), 74% of study patients discontinued medication after less than 18 months; median time to discontinuation was 4.6 months [13]. In the European First Episode Schizophrenia Trial (EUFEST), it was found that following first episode psychosis and treatment, overall discontinuation rate at 12 months follow-up was 43.5%
* Corresponding author. Tel.: +972 3 925 8230; fax: +972 3 925 8235. E-mail address: [email protected] (A. Krivoy). 1 Both authors contributed equally to this manuscript. 0924-9338/$ – see front matter ß 2012 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.eurpsy.2012.06.005
[11]. The Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLESS) showed 40% discontinuation rate at 52 week follow-up [10]. These data have led the Schizophrenia Outcome Research Team (PORT) to conclude that the choice of APD should be made on the basis of individual preference, prior treatment response and side effect experience, adherence history and individual side effect profile [3], thus underlining the importance of the patients’ subjective responses to medication in general and APD specifically [4,15]. Subjective response to drug effects is composed of parameters such as the subjective feelings regarding quality of life measures, sense of well-being, satisfaction with the drug and the subjective experience of APD adverse effects. All these parameters were shown to be important determinants in the clinical outcome of APD treatment [4]. According to Awad and Hogan [1], this response is the subjective interpretation of physiological changes following the administration of a medication. Patients’ attitudes towards positive and negative effects of a drug was shown to predict APD compliance and treatment prognosis [4,5]. Subjective attitude towards APD was assessed with the Drug Attitude Inventory (DAI) developed by Hogan et al. [8].
T. Fischel et al. / European Psychiatry 28 (2013) 340–343
Subjective responses are clinically important and probably understudied. Previous studies showed correlation between experience of undesired effects of APD and negative attitude towards APD. However, most studies assessed the subjective experience of undesired APD effects as a summation variable and not by specific adverse effects. In the current study, we aimed to explore the elements of APD-related adverse effects subjective experience and previous attitude leading to generally negative attitude towards APD in schizophrenia inpatients. 2. Patients and methods 2.1. Participants Participants in the study consisted of 84 schizophrenia inpatients, recruited from a cohort of consecutive admissions to the Geha Mental Health Center (GHMC) – a large regional mental health center in Petah Tikva, Israel – inpatient wards. The patients were approached near their discharge from hospitalization, after the acute phase of their admission. Diagnosis of schizophrenia was established according to DSM-IV criteria and confirmed by two senior psychiatrists. Inclusion criteria included: at least four weeks on antipsychotic drugs and the patient being able to provide informed consent. The study was approved by the Institutional Review Board and written informed consent was obtained from all participants. Each participant completed the above-mentioned questionnaires in the presence of one of the investigators, who provided assistance when needed. Demographic data were extracted from computerized chart records for each patient, and the Positive and Negative Syndrome Scale (PANSS) was completed by fullstandardized interview by trained psychiatrists for measuring the severity of psychopathology.
341
subscale). For each item, the patient was asked to rate his perceived level of interference caused by the symptoms on a likertlike scale of 1 (not at all) to 5 (extreme to the point of considering discontinuation of the drug treatment). In addition, the patient was asked to indicate for each item whether he actually had experienced the symptom while being on the treatment administered during the study (yes = 1/no = 0). Two summation scores were extracted from the m-SRA results: an attitudes’ score (52 to 260) and a subjective experience score (SES) (1 to 52). Both scores were calculated for the total questionnaire as well as for the specific symptomatic domains according to the original SRA subscales. The Cronbach a value for internal consistency of the mSRA scale was 0.88. 2.3. Statistical analysis SPSS version 17 software (SPSS inc., Chicago, IL) was used for data analysis. Comparison was done by three scales: DAI-30 that measures general attitude towards APD (the score can be generated as a continuous variable or a dichotomous one, e.g. negative or positive,), the mean score of the m-SRA symptoms subscales that measures attitude towards specific APD adverse effects and the SES which was computed as a mean of all positive items on the m-SRA. Score means were used rather than sums because each subscale was composed of a different number of items. Correlation was performed with the Spearman’s correlation coefficient. Stepwise logistic binary regression consisted of DAI-30 positive or negative as a dependant variable, and subscales of attitude and experience (the m-SRA subscales) as well as age, sex and length of illness were used as covariates. Significance was set at P < 0.05. 3. Results
2.2. Measures Attitude towards current antipsychotic drugs was assessed using the DAI [8], which was developed as a predictor of compliance of schizophrenia patients. The instrument is a selfcompleted questionnaire composed of 30 dichotomous items (agree/not agree). Total score is the sum of positive items and reversed negative items. The DAI-30 was constructed by collecting statements from schizophrenia patients about their attitudes towards antipsychotic medication. These statements were found to discriminate significantly between compliant and non-compliant patients. The DAI-30 score ranges between 30 to +30 and can therefore also be calculated as a dichotomous variable. A positive result reflects a positive attitude towards APD while a negative result reflects the opposite attitude [9]. In order to assess APD-related adverse effects, we used a modified version of the Subjective Response to Antipsychotics (SRA) questionnaire [18]. The original SRA measures ‘‘all responses to changes in mental, physical and social domains attributed by the patient to his/her current antipsychotic medication’’. Items were collected by interviewing patients about changes they attributed to the medications. The original SRA questionnaire is a 74-item instrument with the following eight subscales: recovery, weight gain, sexual anhedonia, sedation, affective flattening, extrapyramidal side effects, diminished sociability, and increased sleep. Higher scores indicated more effects attributed to the antipsychotic medication by the patient. For our modified SRA (mSRA), we used the items and the symptomatic subscales of the original SRA to measure both attitude and subjective experience of side effects. We added two additional items regarding metabolic side effects (blood tests with high levels of lipids and glucose) to the original 50 items of negative response (omitting the 24 items of the ‘‘recovery’’
A total of 84 inpatients with schizophrenia were recruited for the study. Clinical and demographic characteristics of the study population are shown in Table 1. Ranking of m-SRA subscales by Table 1 Demographic and clinical characteristics of the study population (n = 84). Age (years) Mean Median Range
39.8 12.6 37 19–47
Sex (M/F) Education (years) Smokers (%) Cigarette pack years Married (%) Employed (%) Substance abuse (%) Familial psychopathology (%) Total PANSS score Age at first admission Length of illness (years) Length of current treatment (weeks)
56/28 11.7 1.9 55 (66.3) 22 27 16 (19.3) 19 (21.6) 22 (26.2) 22 (26.2) 77.6 18 24.8 6.8 15 11.6 24.2 51.2
Current treatment (%) FGA Monotherapy Combineda
36 (43.9) 55 (65.5)
a
SGA Monotherapy Combineda
15 (18.3) 32 (38.1)
Clozapine Monotherapy Combineda
9 (11.3) 17 (20.2)
Combination
24 (16.5)
Combined with another class of antipsychotic drugs.
T. Fischel et al. / European Psychiatry 28 (2013) 340–343
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8
8
7
Expreience Attitude
7
Table 3 Sociodemographic and clinical profile of those who experienced affective flattening from antipsychotic treatment and those who did not.
6
6
5
5 4
4 3
3 2 2 1
1
Metabolic Sedation Sleepiness Affective Weight Flatenning Gain
EPS
Sociability
Sex anhedonia
Fig. 1. Comparison of the rankings of adverse effects in negative attitude and in subjective experience. Numbers represent relative position on a scale of 1 to 8: with 8 representing most negative attitude and stronger subjective experience.
attitude and experience score is shown in Fig. 1. Metabolic signs and EPS were ranked at the top of the scale, as being most disruptive for schizophrenia patients, while affective flattening was ranked at the bottom of the scale. The symptoms that were experienced most often were sedation, excessive sleepiness, weight gain and EPS. For most of the m-SRA subscales, patients reported experiencing at least one of the items in the subscale. However, 63% (n = 53) did not experience any affective flattening and 49% (n = 41) did not experience any metabolic signs. Analysis of the negative attitudes in those two subscales revealed a significant difference between those who experienced affective flattening and those who did not (2.94 1.01 vs. 2.19 0.93, P < 0.001, respectively). No significant difference was found between those who experienced metabolic symptoms and those who did not (3.96 1.39 vs. 3.81 1.42, NS, respectively). Correlation between m-SRA subscale scores of attitude, the level of the symptoms and DAI30 score is shown in Table 2. Attitudes and experience correlated inversely with weight gain (P = 0.045) and antipsychotic-induced EPS (P = 0.021). Experiencing sedation correlated negatively with DAI-30 (P = 0.042). However, affective flattening was the only adverse effect that showed a significant inverse correlation between subjective experience and attitude and between subjective experience and DAI-30, and these results remained significant following Bonferroni correction for multiple comparisons. Attitudes towards the eight specific antipsychotic adverse effects did not correlate with DAI-30 (Table 2). In a binary logistic regression analysis in which all subscales scores of attitude and experience were entered as covariates of negative DAI-30, only the level of subjective experience of affective flattening was shown to be significantly related to DAI-30 negative score (B = 2.16, Exp. b=8.7, 95% CI: 1.65–45.4, P = 0.011). The same analysis, adjusted for age, sex and duration of illness yielded: B = 2.317, Exp. b=10.1, 95% CI: 1.8–5.5, P = 0.008, for experience of
Education (years) Employed Married PANSS FGA treatment Duration of current treatment (weeks)
Affective flattening
No affective flattening
P
11.8 2 8/31 (25%) 6/31 (20%) 84 17 23/31 (74%) 26 61
11.6 1.8 11/53 (20%) 10/53 (20%) 73 17 32/53 (60%) 22 44
NS NS NS NS NS NS
FGA: first generation antipsychotic; PANSS: Positive And Negative Syndrome Scale.
affective flattening and B = 0.043, Exp. B = 1.04, 95% CI: 1.01–1.08, P = 0.045 for age, as predictors of negative DAI-30 score. On a dichotomous analysis of experiencing at least one of the items of affective flattening (n = 31, 37%) vs. none (n = 53, 63%), relative risk for negative DAI-30 score was 1.87 (95% CI: 1.06–3.3, df = 1, x2 = 4.525, P < 0.05). The DAI-30 score did not differ significantly between patients with atypical and those with typical APD or clozapine. No difference was detected in PANSS scores between positive and negative DAI-30 scores nor was there a significant correlation between those two scales. No significant differences were detected in the sociodemographic and clinical profile of those who experienced affective flattening from antipsychotic treatment as compared to those who did not (Table 3). Dosages for antipsychotic agents were converted into Defined Daily Dose (DDD), which is the average maintenance dosage as defined by the WHO Collaborating Center for Drug Statistics Methodology. The DDDs of antipsychotics (data are not shown) in the two groups and the proportional use of typical and atypical antipsychotics were similar (Table 3). 4. Discussion In this study, we investigated the association between specific negative effects of APD as perceived by schizophrenia inpatients (subjective response) and their general attitude towards APD, as a predictor for APD-discontinuation. We found weak correlation between actually experiencing a specific adverse effect and having a negative attitude towards it, using the m-SRA symptoms subscales (weight gain, sedation, EPS, excessive sleep, diminished sociability, sexual anhedonia and metabolic syndrome). However, as a composite score, subjective experience was found to be strongly correlated with general negative attitude as measured by the DAI-30. The exception was the experience of APD-related affective flattening, which correlated significantly with having a negative attitude towards it and in addition predicted general negative attitude towards APD as assessed by the DAI-30.
Table 2 The correlations (Spearman’s rho values) between attitude towards specific antipsychotic-related symptoms and between subjective experiences.
*
Symptom
Attitude vs. experience
P
Attitude vs. DAI-30
P
Weight gain Sexual anhedonia Sedation Affective flattening EPS Diminished sociability Excessive sleep Metabolic symptoms Total
0.219 0.207 0.066 0.351 0.252 0.157 0.089 0.003 0.129
0.045* 0.059 0.551 0.001**,a 0.021* 0.153 0.422 0.975 0.242
0.015 0.01 0.079 0.157 0.06 0.079 0.005 0.075 0.114
0.898 40.902 0.498 0.174 0.609 0.498 0.966 0.517
P < 0.05, **P < 0.01; EPS: extrapyramidal syndrome. a Remains significant following Bonferroni correction.
Experience vs. DAI-30 0.028 0.137 0.234 0.251 0.137 0.075 0.165 0.1 2.48
P 0.810 0.239 0.042* 0.029* 0.239 0.519 0.155 0.390 0.032*
T. Fischel et al. / European Psychiatry 28 (2013) 340–343
Similar results were found in a cross-sectional survey [6] of stable outpatients with schizophrenia receiving various APD in a naturalistic treatment setting. Psychopathology, antipsychoticinduced side effects and sociodemographic factors had no statistically significant effect on positive feelings and attitudes regarding APD. However, positive symptoms and sedation were found to be associated with negative attitude. A prospective 3months follow-up study [7] of 42 patients starting atypical APD found a weak correlation between APD-induced side effects and attitude towards drugs, as measured by DAI-30. A recent study [19] comparing the scores of the SRA, the DAI-10, the Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS) and the Subjective Well-being to Neuroleptics (SWN) in 320 schizophrenia outpatients found a weak correlation between the various scales. However, all were found to correlate with quality of life. In our sample only subjective experience of affective flattening was found to be a predictor of negative attitude on the DAI-30 scale which, as was mentioned above, was shown to predict compliance to APD in schizophrenia patients [2,4,9]. Our study focused on the subjective experience of affective flattening in an acute treatment setting of schizophrenia inpatients. Although negative attitude towards symptoms was ranked last, the attitude towards APD of those who had experienced these symptoms was significantly more negative than of those who had not experienced them. The flattening of affect could not be related to sociodemographic variables or pharmacological treatment (Table 3). Only few studies on subjective response of schizophrenia patients investigated the impact of specific symptoms on the attitude towards APD. Hofer et al. [7] explored the correlation between specific adverse events and attitude, using the Udvalg for Kliniske Undersogelser (UKU) side effect rating scale, and found it to be significant between negative DAI scores and increased duration of sleep. In this study however, the subjective experience of affective flattening was not evaluated. Another study [14] based on an internet database of comments about prescribed medications found that the predominant reported effects of all APD’s, consisted of sedation, cognitive impairment and emotional flattening or indifference. It seems that the subjective experience of APD-related affective flattening is under-acknowledged and under-studied. It is of note that it is difficult to explore subjective experiences for side effect that does not have an experiential dimension (i.e., lipid levels and high blood pressure). However, patients are aware of pathological laboratory/ physiological parameters and can relate to it. Our study is limited by its relatively small sample size and by its cross-sectional nature causing it to ignore the potential improvement in psychopathology over the treatment period. The total PANSS scores, however, were similar for the negative and positive DAI-30 scores, indicating that the global severity of psychopathology does not affect the subjective attitude towards antipsychotic treatment. Another limitation of our study is the lack of direct measurement of compliance at follow-up. Further longitudinal, large-scale studies in schizophrenia patients treated with firstgeneration and second-generation APD are needed to substantiate our findings. Moreover, trans-cultural and translational dimensions cannot be ignored and we cannot address whether our findings can be generalized to other cultures. 5. Conclusions Our preliminary results emphasize the importance of actively exploring APD-related affective flattening in schizophrenia patients maintained on APD. Targeting this symptom could serve
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as a possible intervention for minimizing APD non-compliance. Further prospective studies should establish the prognostic value of the subjective experience of APD-related affective flattening on the course of the illness, the adherence to treatment and the rate of relapse and readmission. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Funding: This study did not receive support from any funding agency in the public, commercial, or not-for-profit sectors. References [1] Awad AG, Hogan TP. Subjective response to neuroleptics and the quality of life: implications for treatment outcome. Acta Psychiatr Scand Suppl 1994;380: 27–32. [2] Awad AG, Voruganti LN, Heslegrave RJ, Hogan TP. Assessment of the patient’s subjective experience in acute neuroleptic treatment: implications for compliance and outcome. Int Clin Psychopharmacol 1996;11(Suppl. 2):55–9. [3] Buchanan RW, Kreyenbuhl J, Kelly DL, Noel JM, Boggs DL, Fischer BA, et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull 2010;36(1):71–93. [4] Gaebel W, Riesbeck M, von WM, Burns T, Derks EM, Kahn RS, et al. Drug attitude as predictor for effectiveness in first-episode schizophrenia: results of an open randomized trial (EUFEST). Eur Neuropsychopharmacol 2010;20(5): 310–6. [5] Hellewell JS. Patients’ subjective experiences of antipsychotics: clinical relevance. CNS Drugs 2002;16(7):457–71. [6] Hofer A, Kemmler G, Eder U, Honeder M, Hummer M, Fleischhacker WW. Attitudes toward antipsychotics among outpatient clinic attendees with schizophrenia. J Clin Psychiatry 2002;63(1):49–53. [7] Hofer A, Rettenbacher MA, Edlinger M, Kemmler G, Widschwendter CG, Fleischhacker WW. Subjective response and attitudes toward antipsychotic drug therapy during the initial treatment period: a prospective follow-up study in patients with schizophrenia. Acta Psychiatr Scand 2007;116(5): 354–61. [8] Hogan TP, Awad AG, Eastwood R. A self-report scale predictive of drug compliance in schizophrenics: reliability and discriminative validity. Psychol Med 1983;13(1):177–83. [9] Hogan TP, Awad AG, Eastwood MR. Early subjective response and prediction of outcome to neuroleptic drug therapy in schizophrenia. Can J Psychiatry 1985;30(4):246–8. [10] Jones PB, Barnes TR, Davies L, Dunn G, Lloyd H, Hayhurst KP, et al. Randomized controlled trial of the effect on quality of life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006;63(10): 1079–87. [11] Kahn RS, Fleischhacker WW, Boter H, Davidson M, Vergouwe Y, Keet IP, et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet 2008; 371(9618):1085–97. [12] Lacro JP, Dunn LB, Dolder CR, Leckband SG, Jeste DV. Prevalence of and risk factors for medication non-adherence in patients with schizophrenia: a comprehensive review of recent literature. J Clin Psychiatry 2002;63(10):892–909. [13] Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353(12):1209–23. [14] Moncrieff J, Cohen D, Mason JP. The subjective experience of taking antipsychotic medication: a content analysis of Internet data. Acta Psychiatr Scand 2009;120(2):102–11. [15] Naber D. Subjective effects of antipsychotic drugs and their relevance for compliance and remission. Epidemiol Psichiatr Soc 2008;17(3):174–6. [16] Novick D, Haro JM, Suarez D, Perez V, Dittmann RW, Haddad PM. Predictors and clinical consequences of non-adherence with antipsychotic medication in the outpatient treatment of schizophrenia. Psychiatry Res 2010;176(2–3): 109–13. [17] Velligan DI, Weiden PJ, Sajatovic M, Scott J, Carpenter D, Ross R, et al. Strategies for addressing adherence problems in patients with serious and persistent mental illness: recommendations from the expert consensus guidelines. J Psychiatr Pract 2010;16(5):306–24. [18] Wolters HA, Knegtering R, Wiersma D, van den Bosch RJ. Evaluation of the subjects’ response to antipsychotics questionnaire. Int Clin Psychopharmacol 2006;21(1):63–9. [19] Wolters HA, Knegtering H, van den Bosch RJ, Wiersma D. Effects and side effects of antipsychotic treatment in schizophrenia: pros and cons of available self-rating scales. Schizophr Res 2009;112(1-3):114–8.
Available online at
www.sciencedirect.com
Original article
The interaction of subjective experience and attitudes towards specific antipsychotic-related adverse effects in schizophrenia patients T. Fischel a,b,1, A. Krivoy a,*,b,1, M. Kotlarov b, Z. Zemishlany a,b, O. Loebstein a,b, H. Jacoby a, A. Weizman a,b,c a
Geha Mental Health Center, 1, Helsinki Street, P.O. Box 103, 49100 Petach-Tikva, Israel Sackler’s Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel c Felsenstein Medical Research Center, Petach-Tikva, Israel b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 9 April 2012 Received in revised form 14 June 2012 Accepted 16 June 2012 Available online 19 September 2012
Background: Discontinuation of antipsychotic drugs in schizophrenia patients is a major concern, since it results in relapse and re-hospitalizations. Non-adherence is strongly associated with negative-subjective response to antipsychotics, which is composed of the subjective experience of negative drug effects and attitude towards the treatment. Objective: To investigate the elements of subjective experience and subjective attitude towards specific drug-related adverse effects, leading to a generally negative-subjective attitude towards antipsychotics. Methods: Schizophrenia inpatients (n = 84) were administered a questionnaire measuring attitude and experience on eight subscales: weight gain, sedation, sexual anhedonia, extra-pyramidal syndrome, affective flattening, excessive sleep, diminished sociability and metabolic syndrome. DAI-30 was used to measure attitude towards drugs, and PANSS to assess psychopathology. Results: Weak correlation was found between subjective experience and attitude on most of the subscales. The only strong, albeit inverse, correlation between experience and attitude that was found was with regard to affective flattening, experienced by 37% of the sample, and it also predicted negative drug attitude as measured by the DAI-30, RR: 1.87 (95% CI: 1.06–3.3, df = 1, x2 = 4.525, P < 0.05). Conclusion: Negative attitude towards most adverse drug effects did not correlate with personal experience. Drug-related affective flattening should be evaluated routinely, since experiencing it may predict negative attitude towards drugs, potentially leading to poor compliance and relapse. ß 2012 Elsevier Masson SAS. All rights reserved.
Keywords: Schizophrenia Antipsychotic drugs Subjective attitude Subjective experience Affective flattening
1. Introduction Discontinuation of antipsychotic drugs (APD) is associated with poor treatment outcomes and higher risk for relapse and rehospitalization of schizophrenia patients [16,12,17]. Three large non-industry sponsored studies have compared the effectiveness of first generation APD and second generation APD. In addition to not finding a significant difference between old and new APD on measures of efficacy, quality of life or compliance, all three studies have shown high discontinuation rates of APD; in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), 74% of study patients discontinued medication after less than 18 months; median time to discontinuation was 4.6 months [13]. In the European First Episode Schizophrenia Trial (EUFEST), it was found that following first episode psychosis and treatment, overall discontinuation rate at 12 months follow-up was 43.5%
* Corresponding author. Tel.: +972 3 925 8230; fax: +972 3 925 8235. E-mail address: [email protected] (A. Krivoy). 1 Both authors contributed equally to this manuscript. 0924-9338/$ – see front matter ß 2012 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.eurpsy.2012.06.005
[11]. The Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLESS) showed 40% discontinuation rate at 52 week follow-up [10]. These data have led the Schizophrenia Outcome Research Team (PORT) to conclude that the choice of APD should be made on the basis of individual preference, prior treatment response and side effect experience, adherence history and individual side effect profile [3], thus underlining the importance of the patients’ subjective responses to medication in general and APD specifically [4,15]. Subjective response to drug effects is composed of parameters such as the subjective feelings regarding quality of life measures, sense of well-being, satisfaction with the drug and the subjective experience of APD adverse effects. All these parameters were shown to be important determinants in the clinical outcome of APD treatment [4]. According to Awad and Hogan [1], this response is the subjective interpretation of physiological changes following the administration of a medication. Patients’ attitudes towards positive and negative effects of a drug was shown to predict APD compliance and treatment prognosis [4,5]. Subjective attitude towards APD was assessed with the Drug Attitude Inventory (DAI) developed by Hogan et al. [8].
T. Fischel et al. / European Psychiatry 28 (2013) 340–343
Subjective responses are clinically important and probably understudied. Previous studies showed correlation between experience of undesired effects of APD and negative attitude towards APD. However, most studies assessed the subjective experience of undesired APD effects as a summation variable and not by specific adverse effects. In the current study, we aimed to explore the elements of APD-related adverse effects subjective experience and previous attitude leading to generally negative attitude towards APD in schizophrenia inpatients. 2. Patients and methods 2.1. Participants Participants in the study consisted of 84 schizophrenia inpatients, recruited from a cohort of consecutive admissions to the Geha Mental Health Center (GHMC) – a large regional mental health center in Petah Tikva, Israel – inpatient wards. The patients were approached near their discharge from hospitalization, after the acute phase of their admission. Diagnosis of schizophrenia was established according to DSM-IV criteria and confirmed by two senior psychiatrists. Inclusion criteria included: at least four weeks on antipsychotic drugs and the patient being able to provide informed consent. The study was approved by the Institutional Review Board and written informed consent was obtained from all participants. Each participant completed the above-mentioned questionnaires in the presence of one of the investigators, who provided assistance when needed. Demographic data were extracted from computerized chart records for each patient, and the Positive and Negative Syndrome Scale (PANSS) was completed by fullstandardized interview by trained psychiatrists for measuring the severity of psychopathology.
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subscale). For each item, the patient was asked to rate his perceived level of interference caused by the symptoms on a likertlike scale of 1 (not at all) to 5 (extreme to the point of considering discontinuation of the drug treatment). In addition, the patient was asked to indicate for each item whether he actually had experienced the symptom while being on the treatment administered during the study (yes = 1/no = 0). Two summation scores were extracted from the m-SRA results: an attitudes’ score (52 to 260) and a subjective experience score (SES) (1 to 52). Both scores were calculated for the total questionnaire as well as for the specific symptomatic domains according to the original SRA subscales. The Cronbach a value for internal consistency of the mSRA scale was 0.88. 2.3. Statistical analysis SPSS version 17 software (SPSS inc., Chicago, IL) was used for data analysis. Comparison was done by three scales: DAI-30 that measures general attitude towards APD (the score can be generated as a continuous variable or a dichotomous one, e.g. negative or positive,), the mean score of the m-SRA symptoms subscales that measures attitude towards specific APD adverse effects and the SES which was computed as a mean of all positive items on the m-SRA. Score means were used rather than sums because each subscale was composed of a different number of items. Correlation was performed with the Spearman’s correlation coefficient. Stepwise logistic binary regression consisted of DAI-30 positive or negative as a dependant variable, and subscales of attitude and experience (the m-SRA subscales) as well as age, sex and length of illness were used as covariates. Significance was set at P < 0.05. 3. Results
2.2. Measures Attitude towards current antipsychotic drugs was assessed using the DAI [8], which was developed as a predictor of compliance of schizophrenia patients. The instrument is a selfcompleted questionnaire composed of 30 dichotomous items (agree/not agree). Total score is the sum of positive items and reversed negative items. The DAI-30 was constructed by collecting statements from schizophrenia patients about their attitudes towards antipsychotic medication. These statements were found to discriminate significantly between compliant and non-compliant patients. The DAI-30 score ranges between 30 to +30 and can therefore also be calculated as a dichotomous variable. A positive result reflects a positive attitude towards APD while a negative result reflects the opposite attitude [9]. In order to assess APD-related adverse effects, we used a modified version of the Subjective Response to Antipsychotics (SRA) questionnaire [18]. The original SRA measures ‘‘all responses to changes in mental, physical and social domains attributed by the patient to his/her current antipsychotic medication’’. Items were collected by interviewing patients about changes they attributed to the medications. The original SRA questionnaire is a 74-item instrument with the following eight subscales: recovery, weight gain, sexual anhedonia, sedation, affective flattening, extrapyramidal side effects, diminished sociability, and increased sleep. Higher scores indicated more effects attributed to the antipsychotic medication by the patient. For our modified SRA (mSRA), we used the items and the symptomatic subscales of the original SRA to measure both attitude and subjective experience of side effects. We added two additional items regarding metabolic side effects (blood tests with high levels of lipids and glucose) to the original 50 items of negative response (omitting the 24 items of the ‘‘recovery’’
A total of 84 inpatients with schizophrenia were recruited for the study. Clinical and demographic characteristics of the study population are shown in Table 1. Ranking of m-SRA subscales by Table 1 Demographic and clinical characteristics of the study population (n = 84). Age (years) Mean Median Range
39.8 12.6 37 19–47
Sex (M/F) Education (years) Smokers (%) Cigarette pack years Married (%) Employed (%) Substance abuse (%) Familial psychopathology (%) Total PANSS score Age at first admission Length of illness (years) Length of current treatment (weeks)
56/28 11.7 1.9 55 (66.3) 22 27 16 (19.3) 19 (21.6) 22 (26.2) 22 (26.2) 77.6 18 24.8 6.8 15 11.6 24.2 51.2
Current treatment (%) FGA Monotherapy Combineda
36 (43.9) 55 (65.5)
a
SGA Monotherapy Combineda
15 (18.3) 32 (38.1)
Clozapine Monotherapy Combineda
9 (11.3) 17 (20.2)
Combination
24 (16.5)
Combined with another class of antipsychotic drugs.
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8
8
7
Expreience Attitude
7
Table 3 Sociodemographic and clinical profile of those who experienced affective flattening from antipsychotic treatment and those who did not.
6
6
5
5 4
4 3
3 2 2 1
1
Metabolic Sedation Sleepiness Affective Weight Flatenning Gain
EPS
Sociability
Sex anhedonia
Fig. 1. Comparison of the rankings of adverse effects in negative attitude and in subjective experience. Numbers represent relative position on a scale of 1 to 8: with 8 representing most negative attitude and stronger subjective experience.
attitude and experience score is shown in Fig. 1. Metabolic signs and EPS were ranked at the top of the scale, as being most disruptive for schizophrenia patients, while affective flattening was ranked at the bottom of the scale. The symptoms that were experienced most often were sedation, excessive sleepiness, weight gain and EPS. For most of the m-SRA subscales, patients reported experiencing at least one of the items in the subscale. However, 63% (n = 53) did not experience any affective flattening and 49% (n = 41) did not experience any metabolic signs. Analysis of the negative attitudes in those two subscales revealed a significant difference between those who experienced affective flattening and those who did not (2.94 1.01 vs. 2.19 0.93, P < 0.001, respectively). No significant difference was found between those who experienced metabolic symptoms and those who did not (3.96 1.39 vs. 3.81 1.42, NS, respectively). Correlation between m-SRA subscale scores of attitude, the level of the symptoms and DAI30 score is shown in Table 2. Attitudes and experience correlated inversely with weight gain (P = 0.045) and antipsychotic-induced EPS (P = 0.021). Experiencing sedation correlated negatively with DAI-30 (P = 0.042). However, affective flattening was the only adverse effect that showed a significant inverse correlation between subjective experience and attitude and between subjective experience and DAI-30, and these results remained significant following Bonferroni correction for multiple comparisons. Attitudes towards the eight specific antipsychotic adverse effects did not correlate with DAI-30 (Table 2). In a binary logistic regression analysis in which all subscales scores of attitude and experience were entered as covariates of negative DAI-30, only the level of subjective experience of affective flattening was shown to be significantly related to DAI-30 negative score (B = 2.16, Exp. b=8.7, 95% CI: 1.65–45.4, P = 0.011). The same analysis, adjusted for age, sex and duration of illness yielded: B = 2.317, Exp. b=10.1, 95% CI: 1.8–5.5, P = 0.008, for experience of
Education (years) Employed Married PANSS FGA treatment Duration of current treatment (weeks)
Affective flattening
No affective flattening
P
11.8 2 8/31 (25%) 6/31 (20%) 84 17 23/31 (74%) 26 61
11.6 1.8 11/53 (20%) 10/53 (20%) 73 17 32/53 (60%) 22 44
NS NS NS NS NS NS
FGA: first generation antipsychotic; PANSS: Positive And Negative Syndrome Scale.
affective flattening and B = 0.043, Exp. B = 1.04, 95% CI: 1.01–1.08, P = 0.045 for age, as predictors of negative DAI-30 score. On a dichotomous analysis of experiencing at least one of the items of affective flattening (n = 31, 37%) vs. none (n = 53, 63%), relative risk for negative DAI-30 score was 1.87 (95% CI: 1.06–3.3, df = 1, x2 = 4.525, P < 0.05). The DAI-30 score did not differ significantly between patients with atypical and those with typical APD or clozapine. No difference was detected in PANSS scores between positive and negative DAI-30 scores nor was there a significant correlation between those two scales. No significant differences were detected in the sociodemographic and clinical profile of those who experienced affective flattening from antipsychotic treatment as compared to those who did not (Table 3). Dosages for antipsychotic agents were converted into Defined Daily Dose (DDD), which is the average maintenance dosage as defined by the WHO Collaborating Center for Drug Statistics Methodology. The DDDs of antipsychotics (data are not shown) in the two groups and the proportional use of typical and atypical antipsychotics were similar (Table 3). 4. Discussion In this study, we investigated the association between specific negative effects of APD as perceived by schizophrenia inpatients (subjective response) and their general attitude towards APD, as a predictor for APD-discontinuation. We found weak correlation between actually experiencing a specific adverse effect and having a negative attitude towards it, using the m-SRA symptoms subscales (weight gain, sedation, EPS, excessive sleep, diminished sociability, sexual anhedonia and metabolic syndrome). However, as a composite score, subjective experience was found to be strongly correlated with general negative attitude as measured by the DAI-30. The exception was the experience of APD-related affective flattening, which correlated significantly with having a negative attitude towards it and in addition predicted general negative attitude towards APD as assessed by the DAI-30.
Table 2 The correlations (Spearman’s rho values) between attitude towards specific antipsychotic-related symptoms and between subjective experiences.
*
Symptom
Attitude vs. experience
P
Attitude vs. DAI-30
P
Weight gain Sexual anhedonia Sedation Affective flattening EPS Diminished sociability Excessive sleep Metabolic symptoms Total
0.219 0.207 0.066 0.351 0.252 0.157 0.089 0.003 0.129
0.045* 0.059 0.551 0.001**,a 0.021* 0.153 0.422 0.975 0.242
0.015 0.01 0.079 0.157 0.06 0.079 0.005 0.075 0.114
0.898 40.902 0.498 0.174 0.609 0.498 0.966 0.517
P < 0.05, **P < 0.01; EPS: extrapyramidal syndrome. a Remains significant following Bonferroni correction.
Experience vs. DAI-30 0.028 0.137 0.234 0.251 0.137 0.075 0.165 0.1 2.48
P 0.810 0.239 0.042* 0.029* 0.239 0.519 0.155 0.390 0.032*
T. Fischel et al. / European Psychiatry 28 (2013) 340–343
Similar results were found in a cross-sectional survey [6] of stable outpatients with schizophrenia receiving various APD in a naturalistic treatment setting. Psychopathology, antipsychoticinduced side effects and sociodemographic factors had no statistically significant effect on positive feelings and attitudes regarding APD. However, positive symptoms and sedation were found to be associated with negative attitude. A prospective 3months follow-up study [7] of 42 patients starting atypical APD found a weak correlation between APD-induced side effects and attitude towards drugs, as measured by DAI-30. A recent study [19] comparing the scores of the SRA, the DAI-10, the Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS) and the Subjective Well-being to Neuroleptics (SWN) in 320 schizophrenia outpatients found a weak correlation between the various scales. However, all were found to correlate with quality of life. In our sample only subjective experience of affective flattening was found to be a predictor of negative attitude on the DAI-30 scale which, as was mentioned above, was shown to predict compliance to APD in schizophrenia patients [2,4,9]. Our study focused on the subjective experience of affective flattening in an acute treatment setting of schizophrenia inpatients. Although negative attitude towards symptoms was ranked last, the attitude towards APD of those who had experienced these symptoms was significantly more negative than of those who had not experienced them. The flattening of affect could not be related to sociodemographic variables or pharmacological treatment (Table 3). Only few studies on subjective response of schizophrenia patients investigated the impact of specific symptoms on the attitude towards APD. Hofer et al. [7] explored the correlation between specific adverse events and attitude, using the Udvalg for Kliniske Undersogelser (UKU) side effect rating scale, and found it to be significant between negative DAI scores and increased duration of sleep. In this study however, the subjective experience of affective flattening was not evaluated. Another study [14] based on an internet database of comments about prescribed medications found that the predominant reported effects of all APD’s, consisted of sedation, cognitive impairment and emotional flattening or indifference. It seems that the subjective experience of APD-related affective flattening is under-acknowledged and under-studied. It is of note that it is difficult to explore subjective experiences for side effect that does not have an experiential dimension (i.e., lipid levels and high blood pressure). However, patients are aware of pathological laboratory/ physiological parameters and can relate to it. Our study is limited by its relatively small sample size and by its cross-sectional nature causing it to ignore the potential improvement in psychopathology over the treatment period. The total PANSS scores, however, were similar for the negative and positive DAI-30 scores, indicating that the global severity of psychopathology does not affect the subjective attitude towards antipsychotic treatment. Another limitation of our study is the lack of direct measurement of compliance at follow-up. Further longitudinal, large-scale studies in schizophrenia patients treated with firstgeneration and second-generation APD are needed to substantiate our findings. Moreover, trans-cultural and translational dimensions cannot be ignored and we cannot address whether our findings can be generalized to other cultures. 5. Conclusions Our preliminary results emphasize the importance of actively exploring APD-related affective flattening in schizophrenia patients maintained on APD. Targeting this symptom could serve
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as a possible intervention for minimizing APD non-compliance. Further prospective studies should establish the prognostic value of the subjective experience of APD-related affective flattening on the course of the illness, the adherence to treatment and the rate of relapse and readmission. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Funding: This study did not receive support from any funding agency in the public, commercial, or not-for-profit sectors. References [1] Awad AG, Hogan TP. Subjective response to neuroleptics and the quality of life: implications for treatment outcome. Acta Psychiatr Scand Suppl 1994;380: 27–32. [2] Awad AG, Voruganti LN, Heslegrave RJ, Hogan TP. Assessment of the patient’s subjective experience in acute neuroleptic treatment: implications for compliance and outcome. Int Clin Psychopharmacol 1996;11(Suppl. 2):55–9. [3] Buchanan RW, Kreyenbuhl J, Kelly DL, Noel JM, Boggs DL, Fischer BA, et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull 2010;36(1):71–93. [4] Gaebel W, Riesbeck M, von WM, Burns T, Derks EM, Kahn RS, et al. Drug attitude as predictor for effectiveness in first-episode schizophrenia: results of an open randomized trial (EUFEST). Eur Neuropsychopharmacol 2010;20(5): 310–6. [5] Hellewell JS. Patients’ subjective experiences of antipsychotics: clinical relevance. CNS Drugs 2002;16(7):457–71. [6] Hofer A, Kemmler G, Eder U, Honeder M, Hummer M, Fleischhacker WW. Attitudes toward antipsychotics among outpatient clinic attendees with schizophrenia. J Clin Psychiatry 2002;63(1):49–53. [7] Hofer A, Rettenbacher MA, Edlinger M, Kemmler G, Widschwendter CG, Fleischhacker WW. Subjective response and attitudes toward antipsychotic drug therapy during the initial treatment period: a prospective follow-up study in patients with schizophrenia. Acta Psychiatr Scand 2007;116(5): 354–61. [8] Hogan TP, Awad AG, Eastwood R. A self-report scale predictive of drug compliance in schizophrenics: reliability and discriminative validity. Psychol Med 1983;13(1):177–83. [9] Hogan TP, Awad AG, Eastwood MR. Early subjective response and prediction of outcome to neuroleptic drug therapy in schizophrenia. Can J Psychiatry 1985;30(4):246–8. [10] Jones PB, Barnes TR, Davies L, Dunn G, Lloyd H, Hayhurst KP, et al. Randomized controlled trial of the effect on quality of life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006;63(10): 1079–87. [11] Kahn RS, Fleischhacker WW, Boter H, Davidson M, Vergouwe Y, Keet IP, et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet 2008; 371(9618):1085–97. [12] Lacro JP, Dunn LB, Dolder CR, Leckband SG, Jeste DV. Prevalence of and risk factors for medication non-adherence in patients with schizophrenia: a comprehensive review of recent literature. J Clin Psychiatry 2002;63(10):892–909. [13] Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353(12):1209–23. [14] Moncrieff J, Cohen D, Mason JP. The subjective experience of taking antipsychotic medication: a content analysis of Internet data. Acta Psychiatr Scand 2009;120(2):102–11. [15] Naber D. Subjective effects of antipsychotic drugs and their relevance for compliance and remission. Epidemiol Psichiatr Soc 2008;17(3):174–6. [16] Novick D, Haro JM, Suarez D, Perez V, Dittmann RW, Haddad PM. Predictors and clinical consequences of non-adherence with antipsychotic medication in the outpatient treatment of schizophrenia. Psychiatry Res 2010;176(2–3): 109–13. [17] Velligan DI, Weiden PJ, Sajatovic M, Scott J, Carpenter D, Ross R, et al. Strategies for addressing adherence problems in patients with serious and persistent mental illness: recommendations from the expert consensus guidelines. J Psychiatr Pract 2010;16(5):306–24. [18] Wolters HA, Knegtering R, Wiersma D, van den Bosch RJ. Evaluation of the subjects’ response to antipsychotics questionnaire. Int Clin Psychopharmacol 2006;21(1):63–9. [19] Wolters HA, Knegtering H, van den Bosch RJ, Wiersma D. Effects and side effects of antipsychotic treatment in schizophrenia: pros and cons of available self-rating scales. Schizophr Res 2009;112(1-3):114–8.