ABSTRACT
Objectives:
To assess disability and quality of life (QOL) in treatment resistant schizophrenia (TRS) on long term clozapine therapy and assess their correlation with positive, negative and cognitive symptoms.
Methodology:
Disability and QOL in forty patients with TRS (as per modified Kane’s criteria) were assessed using World Health Organization Disability Assessment Schedule 2.0 and World Health Organization Quality of Life–BREF. Scale for assessment of positive symptoms, scale for assessment of negative symptoms and Addenbrooke’s cognitive examination-III were used to assess positive, negative and cognitive symptoms. Medication adherence rating scale assessed medication adherence.
Results:
Disability and QOL correlated significantly with medication adherence, negative and cognitive symptoms but not with positive symptoms. Subgroup analysis revealed significant difference between medication adherence (good vs poor) and cognitive (impairment vs non-impairment) groups.
Conclusion:
Negative and cognitive symptoms, and medication adherence correlated with disability and QOL.
Keywords: Clozapine, disability, quality of life, treatment-resistant schizophrenia
INTRODUCTION
About one-third of patients with schizophrenia are treatment-resistant, and clozapine is the recommended treatment.[1] Partial remission in psychopathology and poor functioning in treatment-resistant schizophrenia (TRS) causes significant disability and poor quality of life (QOL). Even though studies have reported improvement in psychopathology in TRS (positive, negative, and cognitive symptoms) with clozapine, very few studies have looked into other outcome variables like disability and QOL.[2,3] Treatment with clozapine in chronic schizophrenia results in significant improvement in quality of life (QOL), work functioning, and capacity for independent living.[4] In patients with schizophrenia who were initiated on clozapine therapy, two separate studies have reported improvement in disability[5] and QOL.[3] However, these studies assessed the effect of short-term use of clozapine and did not evaluate cognitive symptoms which contribute significantly to disability and QOL.
Therefore, we aimed to assess disability and quality of life in patients with TRS on long-term treatment with clozapine therapy and assess their correlation with positive, negative, and cognitive symptoms and other clinical variables.
MATERIALS AND METHODS
The study was conducted at outpatient services of a tertiary care general hospital of a medical school in North India. The participants were recruited if they were aged 18–60 years, of either gender, diagnosed as schizophrenia as per DSM-5, verified by MINI 7.0.2, and met the criteria of TRS as per the modified Kane’s criteria (i.e., two different classes of antipsychotics for adequate dose and duration, <20% reduction in symptoms on brief psychiatric rating scale (BPRS) with haloperidol and BPRS score >45), on treatment with clozapine for at least 6 months and on stable dose of clozapine for 4 weeks. Patients with severe neurological illnesses, other psychiatric disorders except for nicotine dependence, and those not willing to give informed consent were excluded.
This being a descriptive study, only correlation analysis was planned. An ideal sample size estimation was done following the estimation technique as described by Hulley et al., 2013[6] by using the formula N = [(Z α + Z β)/C] 2 + 3, where N = sample size required; α = type one error (0.05); β = type two error (0.20); r = correlation coefficient of clinical significance, the standard normal deviate for α = Zα, the standard normal deviate for β = Zβ - C = 0.5 × ln[(1 + r)/(1 - r)]. Using this formula, with a power of 0.8, we estimated the need of sample size of 40, for correlation coefficients of 0.43 and above.
Socio-demographic and clinical details were collected on a semi-structured questionnaire. Brief psychiatric rating scale (BPRS) was used for defining TRS as per modified Kane’s criteria. Positive, negative, and cognitive symptoms were assessed using scale for assessment of positive symptoms (SAPS), scale for assessment of negative symptoms (SANS), and Addenbrooke’s cognitive examination-III (ACE III). Medication adherence rating scale (MARS) was used for medication adherence. Disability and QOL were assessed using World Health Organization Disability Assessment Schedule 2.0. and World Health Organization Quality of Life–BREF (WHOQOL-BREF), respectively.
Statistical analysis was performed using Statistical Package for Social Science Version 22 (SPSS-22). Data were assessed for normal distribution using the Shapiro–Wilk test. The correlation was done for continuous variables. Correlation between various scales, disability and QOL scores, socio-demographic, and clinical variables were calculated using Pearson’s and Spearman’s correlation as appropriate. Mann–Whitney U-test was performed for subgroup analysis between patients and significantly different variables. P < 0.05 was considered statistically significant. Permission was obtained from Institute Ethics Committee (IECPG 661/23.01.2019).
RESULTS
A total of sixty-one participants met the inclusion criteria, but 21 of them refused to participate due to logistic and personal reasons. Forty participants were recruited after obtaining written informed consent.
Socio-demographic and clinical details of the sample are summarized in Table 1. The disability scores (mean ± SD) on the domains of understanding and communicating, getting around, self-care, getting along with people, life activities, and participation in society were 13.88 ± 3.71, 10.38 ± 3.12, 7.55 ± 2.46; 12.33 ± 3.34; 20.65 ± 5.94, and 20.13 ± 4.29, respectively. The QOL scores (mean ± SD) on the domains of physical health, psychological health, social relation, and environmental were 11.96 ± 2.05, 11.87 ± 2.67, 12.78 ± 1.70, and 13.56 ± 2.40, respectively.
Table 1.
Socio-demographic and clinical profile of patients with treatment-resistant schizophrenia (n=40)
| Characteristics | Variable | Values |
|---|---|---|
| Age in years (mean±SD) | 34.48±10.74 | |
| Sex [n (%)] | Male | 24 (60.0%) |
| Female | 16 (40.0%) | |
| Marital status [n (%)] | Never married | 32 (80.0%) |
| Married | 7 (17.5%) | |
| Widowed | 1 (2.5%) | |
| Education [n (%)] | Middle | 1 (2.5%) |
| Intermediate | 22 (55%) | |
| Graduate | 16 (40%) | |
| Postgraduate | 1 (2.5%) | |
| Occupation [n (%)] | Unemployed | 21 (52.5%) |
| Unskilled worker | 6 (15%) | |
| Professional | 2 (5%) | |
| Student | 3 (7.5%) | |
| Housewife | 5 (12.5%) | |
| Business | 3 (7.5%) | |
| Religion [n (%)] | Hindu | 36 (90%) |
| Muslim | 3 (7.5%) | |
| Sikhism | 1 (2.5%) | |
| Monthly income [n (%)] | <5000 | 30 (75%) |
| 5,000–20,000 | 6 (15%) | |
| >20,000 | 4 (10%) | |
| Score on SAPS (mean±SD) | 62.48±16.93 | 59 (48.5–73.25) |
| Score on SANS (mean±SD) | 67.8±15.67 | 64.5 (54.25–77.75) |
| Score on ACE-III (mean±SD) | 75±15.25 | 76.5 (61–89) |
SAPS=scale for assessment of positive symptoms, SANS=scale for assessment of negative symptoms, ACE III=Addenbrooke’s cognitive examination-III, MARS=medication adherence rating scale
The total and domain scores of WHODAS 2.0 had a significant positive correlation with SANS (ρ = 0.660, P = 0.001) and a significant negative correlation with the score of ACE-III (ρ = -0.738, P = 0.001) and MARS (ρ = -0.398, P = 0.01) [Table 2]. Domain scores of WHOQOL–BREF had a significant positive correlation with the total scores of SANS and a significant negative correlation with total scores of ACE-III and MARS. We did not find a significant correlation with SAPS [Table 3]. Gender-based sub-analysis did not show a significant association.
Table 2.
Correlation of various domains of disability (WHODAS 2.0) with psychopathology (n=40)
| Variable | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| SANS | 1 | ||||||||||
| SAPS | 0.099 | 1 | |||||||||
| ACE-III | -0.704** | -0.151 | 1 | ||||||||
| MARS | -0.711** | -0.228 | 0.533** | 1 | |||||||
| Understanding and communicating | 0.647** | 0.244 | -0.690** | -0.365* | 1 | ||||||
| Getting around | 0.465** | 0.135 | -0.503** | -0.246 | 0.750** | 1 | |||||
| Self-care | 0.375* | 0.389* | -0.508** | -0.260 | 0.701** | 0.524** | 1 | ||||
| Getting along with people | 0.481** | 0.173 | -0.626** | -0.264 | 0.706** | 0.608** | 0.590** | 1 | |||
| Life activities | 0.606** | 0.285 | -0.676** | -0.366* | 0.704** | 0.554** | 0.592** | 0.642** | 1 | ||
| Participation in society | 0.655** | 0.254 | -0.657** | -0.441** | 0.722** | 0.581** | 0.521** | 0.726** | 0.750** | 1 | |
| WHODAS Total Score | 0.660** | 0.291 | -0.738** | -0.398* | 0.899** | 0.775** | 0.744** | 0.838** | 0.882** | 0.875** | 1 |
SAPS=scale for assessment of positive symptoms, SANS=scale for assessment of negative symptoms, ACE III=Addenbrooke’s cognitive examination-III, MARS=medication adherence rating scale. *P<0.05; **P<0.0045 (Bonferroni correction)
Table 3.
Correlation of quality of life (WHOQOL-BREF) with psychopathology (n=40)
| Variable | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
|---|---|---|---|---|---|---|---|---|
| SANS | 1 | |||||||
| SAPS | 0.099 | 1 | ||||||
| ACE-III | -0.704** | -0.151 | 1 | |||||
| MARS | -0.711** | -0.228 | 0.533** | 1 | ||||
| Physical health | -0.647** | -0.172 | 0.615** | 0.491** | 1 | |||
| Psychological health | -0.776** | -0.174 | 0.698** | 0.580** | 0.875** | 1 | ||
| Social relation | -0.392* | -0.192 | 0.441** | 0.330* | 0.644** | 0.697** | 1 | |
| Environmental | -0.456** | -0.269 | 0.599** | 0.417** | 0.775** | 0.750** | 0.680** | 1 |
SAPS=scale for assessment of positive symptoms, SANS=scale for assessment of negative symptoms, ACE III=Addenbrooke’s cognitive examination-III, MARS=medication adherence rating scale. *P<0.05; **P<0.005 (Bonferroni correction-P<0.006)
Based on the study by Wang et al., 2019,[7] the subjects were divided into cognitive non-decline group (ACE-III score ≥85) and the cognitive decline group (ACE-III score <85). Disability total score showed a significant difference between the two groups, and this was reflected across all domains.
We took a cutoff of 7 for MARS score based on the study by Verdoux et al., 2020[8] to group study subjects in to high medication adherence group (MARS score ≥7) and the low adherence group (MARS score <7). Disability total score showed a significant difference between the high medication adherence group and the low adherence group.
Further analysis revealed that domains of understanding and communicating, getting around, life activities, and participation in society showed significant difference between the high medication adherence group and low adherence group. All domains of QOL showed significant difference between the cognitive non-decline group and the cognitive decline group. Similarly, all domains of QOL showed a significant difference between high medication adherence group (score ≥7 of MARS) and the low adherence group (score <7 of MARS) except social relation [Supplementary Table 1].
Supplementary Table 1.
Predictors of disability and quality of life with cognitive functions and medication adherence
| Variable | Total scores on ACE-III | U (P)# | Total scores on MARS | U (P)# | ||
|---|---|---|---|---|---|---|
|
|
|
|||||
| Cognitive decline group (score <85) (n=26) | Cognitive non-decline group (score v85) (n=14) | Poor adherence group (score <7) (n=11) | Good adherence group (score ≥7) (n=29) | |||
| Domains of WHODAS 2.0 | ||||||
| Understanding and communicating | 24.83 | 12.46 | 69.500 (0.001) | 28.18 | 17.59 | 75.000 (0.010) |
| Getting around | 24.08 | 13.86 | 89.000 (0.008) | 27.41 | 17.88 | 83.500 (0.021) |
| Self-care | 23.94 | 14.11 | 92.500 (0.010) | 24.55 | 18.97 | 115.000 (0.170) |
| Getting along with people | 24.98 | 12.18 | 65.500 (0.001) | 25.14 | 18.74 | 108.500 (0.119) |
| Life activities | 25.85 | 10.57 | 43.000 (0.001) | 26.36 | 18.28 | 95.000 (0.050) |
| Participation in society | 25.17 | 11.82 | 60.500 (0.001) | 26.91 | 18.07 | 89.000 (0.032) |
| Domains of WHOQOL-BREF | ||||||
| Physical health | 16.42 | 28.07 | 76.000 (0.003) | 13.45 | 23.17 | 82.000 (0.018) |
| Psychological health | 15.63 | 29.54 | 55.500 (0.001) | 11.00 | 24.10 | 55.000 (0.001) |
| Social relation | 16.44 | 28.04 | 76.500 (0.002) | 15.82 | 22.28 | 108.000 (0.108) |
| Environmental | 15.87 | 29.11 | 61.500 (0.001) | 13.95 | 22.98 | 87.500 (0.028) |
WHOQOL-BREF=World Health Organization; quality of life–BREF, WHODAS2.0=World Health Organization Disability Assessment Schedule 2.0, ACE III=Addenbrooke’s cognitive examination-III, MARS=medication adherence rating scale. #Mann–Whitney U-test
DISCUSSION
We studied disability and quality of life in forty patients with TRS on long-term clozapine therapy. The mean age of our subjects was relatively young compared to most of the studies.[9,10] Although the study population showed a comparatively higher proportion of subjects completing graduation, half of them were unemployed. Treatment resistance, lack of complete remission of symptoms, and the side effect of drugs could have resulted in only 12.5% of the study participants being involved in an earnable job. The mean dose of clozapine was 315 mg/day. Although a similar daily mean dose (340 mg/day) was reported by Krivoy et al., 2018,[11] Indian studies have reported dose of 250 mg–278 mg/day.[12,13] Higher mean dose of clozapine in our study could be because of treatment resistance and long duration (~4 years) of treatment.
Negative symptoms correlated positively with disability, whereas medication adherence and cognitive functions correlated negatively with disability. This is in line with findings in literature where disability is associated with negative symptoms and cognitive symptoms[14,15] and medication adherence improved disability.[16] Similarly, negative symptoms had negative correlation with QOL, whereas medication adherence and cognitive functions had significant positive correlation with QOL. This is in line with Indian study (Grover et al, 2021) in which significant improvement in QOL at 3-months follow-up was reported after starting clozapine in patients with TRS. A meta-analysis reported that negative, positive, and general psychopathology correlated to poor QOL.[17] Medication adherence and cognitive symptoms improved QOL in patients with schizophrenia. Cognitive functions and medication adherence revealed more disability and poor QOL in patients with TRS in cognitively impaired and poor medication adherence group.[18,19] However, in our study, positive symptoms did not correlate significantly with disability as well as QOL. This could be due to less prominence of positive symptoms in our study population that had long duration of illness (~15 years).
The present study is limited by small sample size, cross-sectional study design, and lack of controls that may have helped in teasing out effect of illness on disability from the effect of clozapine. However, scale-based assessments of symptoms and predefined long duration of clozapine are the strengths of the study.
CONCLUSION
Disability and QOL correlated with negative symptoms, cognitive symptoms, and medication adherence in patients with TRS on long-term clozapine therapy. Our study highlights the importance of implementing strategies for reducing negative symptoms, planning cognitive remediation therapy, and ensuring medication adherence in patients with TRS on long-term clozapine therapy.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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