Impact of clozapine on disability and course of illness in patients with schizophrenia: A study from North India.

AIM: The aim of this study was to evaluate the impact of long-term use of clozapine on disability and course of illness among patients with treatment-resistant schizophrenia.
MATERIALS AND METHODS: 102 participants who have been receiving clozapine for a mean duration of 5 years were evaluated on Positive and Negative Syndrome Scale (PANSS) rating, Clinical Global Impression (CGI) severity rating, and Indian Disability Evaluation and Assessment Scale (IDEAS) and the scores were compared with the scores on the same scales at the time of starting clozapine.
RESULTS: There was a significant reduction in both CGI-severity scores and scores in all the four domains of IDEAS, alongside a significant reduction on all three subscales of PANSS with clozapine treatment. The CGI global improvement subscale was rated as very much improved for 80 patients. In terms of course of symptoms, at 6 months of clozapine use, three-fourth of the patients were rated as having partial recovery with no relapse of symptoms, but with passage of time, the proportion of patients in the category of "complete recovery" was found to be increasing. Higher CGI severity at the follow-up, lower CGI global improvement, and poorer efficacy index were associated with higher disability at the follow-up.
CONCLUSIONS: The present study suggests that clozapine has a significant beneficial impact on disability and course of illness among patients with treatment-resistant schizophrenia. Copyright:

INTRODUCTION

Clozapine was introduced in 1958, but within a few years, it was taken off the market because of the dreaded complication of agranulocytosis.[1] However, after being proved more efficacious than chlorpromazine in 1988, and more effective than all other marketed antipsychotics in subsequent studies, clozapine was approved for the management of treatment-resistant schizophrenia (TRS).[2] It was approved with recommendations for strict monitoring for agranulocytosis. Over the years, clozapine has been shown to not only have efficacy/effectiveness for the management of positive symptoms but also has been shown to have some beneficial effects for negative symptoms, cognitive symptoms, depressive symptoms, suicidality, and aggression among patients with schizophrenia. In addition, besides psychopathology, studies have evaluated the efficacy/effectiveness of clozapine in terms of quality of life.[3] However, there is a lack of data with respect to the effectiveness of clozapine on disability and psychosocial functioning.[4] A systematic review and meta-analysis included data from nine randomized controlled trials (RCTs), which compared clozapine with a typical or another atypical antipsychotic medication among adult patients with TRS concluded that clozapine does have beneficial effects on psychosocial functioning, both in short term and long term, but it is not superior to other antipsychotic medications.[4] A closure look at this review further suggests that in terms of psychosocial outcome, only one study included a measure for disability in the form of EuroQol-Five Dimension scale. In majority of the studies, the psychosocial outcome was measured in the form of functioning or quality of life. Frequently, the occurrence of psychiatric symptoms and disability is out of synchrony, thus making measurement of disability or functional impairment necessary, alongside psychiatric symptoms, while assessing treatment outcome.[5] Disability is one of the most important outcome measures of severe mental disorders as it not only determines functionality but also determines the social benefits which a person gets due to his illness.[67] There are limited data on effect of clozapine on disability from developing countries, and available long-term data are maximum for a period of 2 years.[4] In this background, the present study aimed to evaluate the impact of long-term use of clozapine on disability among patients with schizophrenia. An additional aim of the study was to evaluate the course of the symptoms while receiving clozapine.

MATERIALS AND METHODS

This study followed a retrospective-prospective study design. To be included in the study, the participants were required to be receiving clozapine for at least 1 year. Furthermore, patients were required to have baseline Positive and Negative Syndrome Scale (PANSS) rating,[8] Clinical Global Impression (CGI) severity rating,[9] and the rating on Indian Disability Evaluation and Assessment Scale (IDEAS)[10] and must not have received electroconvulsive therapy (ECT) after starting clozapine. These patients were rated again on these scales during the prospective follow-up to evaluate the impact of clozapine use on these outcome variables by the same clinician. Patients who concurrently received ECT or a second antipsychotic medication along with clozapine were excluded. Similarly, patients for whom the baseline rating was not available were excluded.

The course of the illness was assessed using a semi-structured interview with the patient and the caregiver. In addition, the clinical notes during the follow-up duration were also taken into account, while rating the clinical course. The clinical course was rated as complete recovery, partial recovery with no relapse, partial recovery with relapse, one or more relapse with full remission, one or more relapse with incomplete remission, and continuous illness. These ratings were done at the time of follow-up assessment for the durations of 6 months, 12 months, 2 years, and 5 years of clozapine use as applicable.

Written informed consent was obtained from all the participants, and the study was approved by the ethics committee of the institute.

Data were analyzed using the Statistical Package for the Social Sciences version 16 (SPSS for Windows, Version 16.0. Chicago, SPSS Inc, 2007). Categorical variables were analyzed in terms of frequency and percentages. Continuous variables were analyzed as mean and standard deviation (SD). Paired t-test was used for comparison of PANSS, CGI, and IDEAS scores before and after clozapine use.

RESULTS

One hundred and thirty-seven patients for whom baseline ratings available, were approached for the study, of whom, 35 were excluded from the study, because of concomitant use of ECT or another antipsychotic medication. Resultantly, the study sample comprised 102 participants. The mean age of the study sample was 31.6 (SD: 9.3; range: 16–67 years) years; majority of them were male (n = 62; 60.8%) and currently single (n = 74; 72.5%). Nearly half of the study participants were unemployed (n = 48; 47.1%) at the time of starting clozapine. One-fourth of the participants were employed (n = 34; 33.3%), while another one-fifth (n = 20; 19.6%) were housewives/household workers. On an average, the study participants had received 12.7 years of schooling (range: 0–20). About three-fourth of them were Hindus (n = 73; 71.6%) and around two-third resided in urban localities (n = 75; 73.5%).

The mean age of onset of the illness was 21.5 (SD – 7.2; range: 12–51) years with a median of 20 years. The mean duration of illness at the time of follow-up assessment was 14.21 (SD: 9.39; range: 2–63; median = 14) years and mean duration of untreated psychosis was 1.5 (SD: 1.82; range: 0.1–10; median = 1) years. The average duration of illness before starting clozapine was 5.04 (SD: 4.8; range: 1–24; median = 3) years. Before starting clozapine, all participants had received at least two adequate trials with antipsychotics, with a mean number of trials before clozapine being 2.8 (SD = 1.0; range = 2–7). Out of those who had received two or more antipsychotic trials, more than one-third (n = 41; 40.2%) of the patients had received a trial of at least one typical and one atypical antipsychotic before starting clozapine. Among the various previous antipsychotics used, olanzapine was the most commonly (n = 66; 64.7%) used atypical antipsychotic and haloperidol (n = 25; 24.5%) was the most commonly used typical antipsychotic. The mean delay in starting clozapine was estimated to be 1.84 (SD – 2.52; range: 0–10; median – 0.75) years.

JJust before starting clozapine about three fourth (n = 51; 73.9%) of the participants were on only 1 antipsychotic (73.9%), with olanzapine (n = 26; 25.5%) being the most common antipsychotic, and this was followed by risperidone (n = 21; 20.6%). About one-fourth (n = 25; 24.5%) of the participants were on 2 antipsychotics, while 5 (4.9%) participants were on three antipsychotics simultaneously just before starting clozapine. Around one-third of the participants (n = 35, 34.3%) had received polypharmacy (i.e., concurrent use of 2 or more antipsychotic medications in adequate therapeutic doses for at least 6 weeks) before starting clozapine.

The mean duration of clozapine use at the follow-up assessment was 5.04 (SD – 4.8; range: 1–24) year with a median of 3 years. The mean dose of clozapine used in the study sample was 270.9 (SD = 99.75; range = 87.5–600) mg/day with a median of 250 mg/day. Besides clozapine, these patients received psychosocial intervention as usual, i.e., psychoeducation (in all the patients). Depending on the need, some of the patients also received social skill training, rehabilitation, and family intervention.

On comparing PANSS score at the time of starting clozapine and at follow-up, there was a significant reduction in the scores in all the three subscales of PANSS [Table 1]. There was also a significant reduction in both CGI-severity scores and scores in all four domains of IDEAS [Table 1]. The CGI global improvement subscale was rated as very much improved for 80 patients, much improved for 20 patients, minimally improved for 1 patient, and no change for 1 patient. In terms of CGI-efficacy index, 77 patients were rated to have marked improvement in symptoms, with 13 reporting no side effects and 59 having side effects, but these did not interfere with their functioning. Five patients were rated to have marked improvement, but the side effects with clozapine were associated with significant interference in functioning. About one-sixth of the patients (n = 23; 22.6%) were rated to have a moderate level of improvement with no side effects or side effects not interfering with functioning. One patient each was rated as having moderate improvement with side effects of clozapine interfering with functioning, and one patient had minimal improvement with no side effects.

Table 1

Impact of clozapine on psychopathology and disability

Variables	Mean (SD) [range]		Paired t-test value	P (two-tailed)
	Baseline	Follow-up
PANSS
Positive score	23.7 (7.3) [7-40]	8.9 (2.9) [7-23]	16.4	<0.001***
Negative score	23.4 (10.2) [7-49]	13.5 (4.4) [7-25]	8.4	<0.001***
General psychopathology	52.6 (10.1) [34-80]	27.7 (7.8) [16-49]	19.2	<0.001***
PANSS total score	99.8 (21.5) [53-162]	50.27 (12.89) [30-90]	17.2	<0.001***
CGI
CGI-severity	6.5 (0.54) [5-7]	3.1 (0.89) [1-7]	36.4	<0.001***
IDEAS
Self-care	3.3 (0.6) [1-4]	0.8 (0.7) [0-2]	27.8	<0.001***
Interpersonal relationships	3.4 (0.7) [1-4]	1.2 (0.8) [0-3]	30.9	<0.001***
Communication	3.4 (0.6) [1-4]	1.0 (0.7) [0-3]	21.4	<0.001***
Work	3.8 (0.5) [1-4]	1.8 (1.22) [0-4]	12.0	<0.001***
IDEA total score of four domains	13.9 (1.85) [7-16]	4.9 (2.9) [0-12]	27.7	<0.001***
IDEAS score for duration of illness	3.07 (0.97) [1-4]	3.30 (0.93) [1-4]	-2.42	0.02*
IDEAS total score with duration of illness	17.03 (2.14) [10-20]	8.25(3.09) [1-16]	17.3	<0.001***

*P≤0.05, ***P<0.001. SD – Standard deviation; PANSS – Positive and Negative Syndrome Scale; CGI – Clinical Global Impression; IDEA – Indian Disability Evaluation and Assessment; IDEAS – IDEA Scale

In terms of course of symptoms, at 6 months of clozapine use, three-fourth of the patients were rated as having partial recovery with no relapse of symptoms with only 10.8% of patients rated as having complete recovery. At 1 year, more than half (54.9%) were rated as having partial recovery with no relapse of symptoms and one-fifth (21.5%) were rated as having complete recovery. However, with passage of time, the proportion of patients in the category of “complete recovery” kept on increasing and those with partial recovery kept on decreasing. Few patients also experienced one or more relapses with passage of time [Table 2].

Table 2

Clinical course of illness while on clozapine

	Frequency
	6 months (n=102), n (%)	12 months (n=102), n (%)	24 months (n=93)#, n (%)	5 years (n=61)#, n (%)	10 years (n=24)#, n (%)
Complete recovery	11 (10.8)	22 (21.5)	28 (30.1)	21 (34.4)	8 (33.3)
Partial recovery, no relapse	73 (71.5)	56 (54.9)	36 (38.7)	19 (31.1)	4 (16.6)
Partial recovery, with relapse	2 (2.0)	2 (2.0)	3 (3.2)	-	-
One or more relapse, full remission	4 (3.9)	9 (8.8)	14 (15.0)	11 (18.0)	6 (25)
One or more relapse, with incomplete remission	4 (3.9)	5 (49)	6 (6.4)	5 (8.2)	1 (4.2)
Continuous illness	8 (7.9)	8 (7.9)	6 (6.4)	5 (8.2)	5 (20.8)

#Numbers reflect the number of patients who had completed the said duration of clozapine use

Relationship of disability with other outcome measures

As is evident from Table 3, CGI severity at the baseline and at last assessment had a significant association with disability at the follow-up. Lower CGI global improvement and poorer efficacy index were associated with higher disability at the follow-up. Higher level of residual psychopathology as assessed using PANSS at the follow-up was associated with higher disability at the follow-up.

Table 3

Relationship of disability at follow-up with Indian Disability Evaluation and Assessment Scale scores

	Self-care	Interpersonal relationships	Communication	Work	IDEAS total score including score for duration of illness
CGI severity at the time of starting clozapine	0.28 (0.004)**	0.33 (0.001)***	0.25 (0.01)**	0.22 (0.03)*	0.31 (0.002)**
CGI severity at the follow-up	0.45 (0.01)**	0.61 (<0.001)***	0.51 (<0.001)***	0.51 (<0.001)***	0.48 (<0.001)***
CGI global improvement at the follow-up	0.18 (0.07)	0.25 (0.01)**	0.21 (0.032)*	0.21 (0.03)*	0.31 (0.002)**
CGI efficacy index at follow-up	0.32 (0.001)***	0.42 (<0.001)***	0.42 (<0.001)***	0.42 (<0.001)***	0.51 (<0.001)***
PANSS positive at follow-up	0.25 (0.01)**	0.31 (0.002)**	0.39 (<0.001)***	0.39 (<0.001)***	0.23 (0.02)*
PANSS negative at follow-up	0.45 (<0.001)***	0.57 (<0.001)***	0.63 (<0.001)***	0.63 (<0.001)***	0.48 (<0.001)***
PANSS general psychopathology at follow-up	0.51 (<0.001)***	0.52 (<0.001)***	0.57 (<0.001)***	0.57 (0.001)***	0.51 (0.001)***
PANSS total score at follow-up	0.53 (<0.001)***	0.59 (<0.001)***	0.66 (<0.001)***	0.55 (<0.001)***	0.68 (<0.001)***

*P≤0.05; **P≤0.01; ***P≤0.001. IDEAS – Indian Disability Evaluation and Assessment Scale; CGI – Clinical Global Impression; PANSS – Positive and Negative Syndrome Scale

DISCUSSION

It is often suggested that outcome assessment in patients with mental illnesses should not be limited to the assessment of psychopathology as this does not reflect a holistic approach to clinical management. It is suggested that assessment of outcome of any intervention should include other outcome measures such as psychosocial functioning, personal recovery, social reintegration, quality of life, satisfaction with treatment, cognitive impairment, treatment-related side effects, disability, and perceived stigma. Meltzer,[11] while discussing the definition of TRS, suggested that outcome must be considered in multiple domains and listed psychopathology, cognitive function, side effects, social functioning, independent living, work function, quality of life, readmission rates, family burden, compliance, cost of illness and treatment, and societal impact of illness as some of the outcome variables. He considered these factors to be somewhat independent of each other and suggested scales to objectively measure each of them separately.[11]

In terms of beneficial effect of clozapine, besides psychopathology, among the various psychosocial variables, limited information is available for quality of life and other outcomes have rarely been evaluated. In view of the same, the present study aimed to evaluate the effectiveness of clozapine in reduction of disability in a group of patients, receiving clozapine for a mean duration of about 5 years. Disability was assessed using IDEAS, which is a valid and standard scale recommended for assessment of disability in the Indian context.

The present study showed a significant reduction in the level of psychopathology and disability among patients receiving clozapine Overall, majority of the patients were rated as “very much improved” or “much improved.” Accordingly, it can be said that clozapine not only leads to reduction in psychopathology but also leads to reduction in disability in long run. Available data from RCTs for a maximum duration of 2 years suggest that clozapine leads to improvement in the psychosocial functioning in patients with TRS.[4] The findings of the present study provide further evidence to these findings. However, in the present study, the assessment involved evaluation of disability using a scale, designed specifically to assess, disability associated with mental illness. The present study also suggests that reduction in disability parallels reduction in psychopathology and clinical global improvement.

In terms of course of symptoms, the present study suggests that with passage of time, there is a further improvement with clozapine. Some of the authors suggest that compared to the conventional antipsychotics, an adequate trial with clozapine should be of 6-month duration.[12] The present study extends this notion further, i.e., continuation of clozapine leads to further improvement at 1 and 2 years subsequently. Accordingly, it can be said that, in patients showing partial improvement with clozapine by 6 months of trial, clinicians should wait for longer duration of time to see further benefits with clozapine.

The present study has certain limitations. The limitations of the present study include small sample size, extraction of baseline data from the case records, retrospective rating of course of symptoms after starting clozapine, limiting the study to those who were continued only on clozapine monotherapy, with respect to use of antipsychotics. We did not evaluate the relation of disability with other psychosocial measures, work functioning, job attainment, marital rates, etc.

CONCLUSIONS

The present study suggests that clozapine has a significant beneficial impact on disability among patients with schizophrenia. Improvement in disability is associated with reduction in psychopathology. In terms of course of symptoms, by 6 months of treatment, more than three-fourth of the patients are rated as having partial improvement with clozapine, and by 1–2 years, the proportion of patients rated as having complete recovery from symptoms reaches about half of the study participants. Accordingly, it can be said that clozapine not only improves psychopathology but also improves the disability and clinical course of symptoms.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.