Prescription practices and attitude of psychiatrists towards clozapine: A survey of psychiatrists from India

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AJP-793; No. of Pages 9 Asian Journal of Psychiatry xxx (2015) xxx–xxx

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Prescription practices and attitude of psychiatrists towards clozapine: A survey of psychiatrists from India Sandeep Grover *, Srinivas Balachander, Subho Chakarabarti, Ajit Avasthi Department of Psychiatry, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India

A R T I C L E I N F O

A B S T R A C T

Article history: Received 25 May 2015 Received in revised form 20 September 2015 Accepted 28 September 2015 Available online xxx

Aim: To assess the attitude of psychiatrists towards clozapine and also to evaluate the prescription practices of psychiatrists for clozapine. Methodology: An email survey was sent to 3381 psychiatrists from India, of whom 548 (16.2%) responded. Results: Mean number of years in clinical practice was 12.59 (SD—10.1) for participating psychiatrists. Majority of the participants rated their knowledge about clozapine to be good (61.5%)/very good (34.5%). The primary indication for use of clozapine for almost all the participants was treatment resistance and most of the psychiatrists initiated clozapine either in the dose of 25 mg OD (44.3%) or 12.5 mg OD (37%). Half (51.8%) of the psychiatrists preferred to use clozapine as BD dosing schedule, and median doses required to stabilize the patients ranged from 137.5 to 400 mg/day. Once the clozapine dose had been stabilized, about half (51%) of the psychiatrists advised blood monitoring at monthly intervals. Almost all psychiatrists rated effectiveness of clozapine to be better than other antipsychotics. In terms of tolerability, 45.3% of the psychiatrists rated it as ‘same as other antipsychotics’ and 15.9% rated it as better than other antipsychotics. Most common patient and therapist related factors associated with reluctance to start clozapine were history of poor medication compliance and need for monitoring, respectively. Upon reviewing the prescription of other psychiatrists, participating psychiatrists reported that in about 28.46% of patients clozapine was not prescribed though indicated. Conclusions: This survey suggests that clozapine is underused in India, although psychiatrists have adequate knowledge about the drug but many psychiatrists have negative attitude towards clozapine. ß 2015 Elsevier B.V. All rights reserved.

Keywords: Clozapine Survey India Attitude Prescription

1. Introduction Clozapine is an atypical antipsychotic medication which has been found to be more efficacious than other antipsychotics. However, due to its side effect profile, its use is usually limited to patients with treatment resistant schizophrenia (TRS). It is possibly the only antipsychotic medication which has been shown to be superior to other medications in patients of schizophrenia who are partially or non-responsive to treatment, and is the only evidencebased medication for TRS (Kane and Correll, 2010). The CATIE trial suggested that time to discontinuation for clozapine is longer than other atypical antipsychotics, and it is more effective than quetiapine in management of depressive symptoms in patients with chronic schizophrenia (McEvoy et al., 2006; Meltzer et al., 2003; Nakajima et al., 2015). Clozapine has also been shown to

* Corresponding author. Tel.: +0091 172 2756807; fax: +0091 172 2744401. E-mail address: [email protected] (S. Grover).

reduce the incidence of suicide (Krakowski et al., 2006), aggression (Krakowski et al., 2006), risk of relapse of substance abuse (Brunette et al., 2006), rate of rehospitalization (Tiihonen et al., 2006) and is associated with lowest risk of premature mortality even after controlling for clinical monitoring and other potential confounders (Tiihonen et al., 2009; Hayes et al., 2015). Clozapine is often under-used (Nielsen et al., 2010) and its initiation is often delayed (Howes et al., 2012; Grover et al., 2015a). Data from Australia demonstrate that only 8.4% of individuals with refractory schizophrenia are prescribed clozapine (Vella and Pai, 2012). Similarly, data from the United Kingdom shows that only 30% of the patients who actually require clozapine are prescribed the same (Downs and Zinkler, 2007). According to a study, significant proportions of psychiatrists (64%) prefer to combine two antipsychotics rather than use clozapine (Nielsen et al., 2010). In contrast, the evidence suggests that patients receiving clozapine are happier and more satisfied with the medication but are less happy with regard to the blood test than estimated by the

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Please cite this article in press as: Grover, S., et al., Prescription practices and attitude of psychiatrists towards clozapine: A survey of psychiatrists from India. Asian J. Psychiatry (2015), http://dx.doi.org/10.1016/j.ajp.2015.09.013

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clinicians (Hodge and Jespersen, 2008). The Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS) trial also demonstrated that treatment with clozapine is associated with better subjective rating of mental health compared to other atypical antipsychotics, i.e., risperidone, olanzapine, quetiapine and amisulpiride (Lewis et al., 2006). Other researchers who have evaluated patients’ perceptions about clozapine also affirm that for majority of patients advantages of clozapine outweigh its disadvantages (Taylor et al., 2000). Despite all this evidence, because of the possible side effects like agranulocytosis, seizures, myocarditis etc., its use is dreaded by the psychiatrists. Psychiatrists often have negative attitude towards using clozapine (Nielsen et al., 2010). A recent survey of clinical staff reported that patients concerns about tolerability and patients’ refusal to adhere to blood test monitoring are the common barriers to clozapine prescription (Gee et al., 2014). In India, where almost all antipsychotic medications are available, olanzapine and risperidone have been reported to be the most commonly prescribed antipsychotic medications (Grover et al., 2014), and clozapine forms only a small proportion of the total prescriptions of antipsychotic (Grover and Avasthi, 2010). A recent study from our tertiary care centre, found an average of 1.5 years of delay in initiation of clozapine (Grover et al., 2015a). There is no data from India with respect to the attitude of psychiatrists towards clozapine. In this background, this survey aimed to assess the attitude of the psychiatrists towards clozapine and also to evaluate the prescription practices of the psychiatrists for clozapine. 2. Methodology This survey was carried out in the month of December 2014 by using Survey Monkey electronic platform. The survey comprised 40 questions covering various aspects of clozapine use by the clinicians. The invitation and the link for the survey was sent by email to 3930 psychiatrists in India. This was sent to all the psychiatrists twice during the weekends for 4 consecutive weekends. The e-mail explained the purpose of survey, clearly mentioned that the survey has not received ethical clearance from Institutional Ethics Committee and that the participation is voluntary. Besides the survey link, the mail also contained a link, by using which the recipient of the mail could opt out of the survey. Those who responded to the survey or opted out were sent subsequent reminders. The data obtained was analysed by using SPSS-14. Frequency and percentages were calculated for the categorical variables and mean and standard deviations were calculated for continuous variables. Additionally medians were also calculated for the continuous variables. Comparisons were done by using Chi-square test, t-test, Mann–Whitney U test, Fischer exact test, ANOVA as per the requirements. Associations between different variables were studied by using Pearson’s correlation coefficient or Spearman’s rank correlation. 3. Results 3.1. Profile of the participating psychiatrists The survey was sent to 3930 psychiatrists. Of these, emails of 491 bounced back and 58 opted out of the survey. Of the remaining 3381 psychiatrists, 548 (16.2%) responded to the survey. At the time of responding to the survey, majority (N = 534; 97.4%) were practicing in India and very few (N = 14; 2.6%) were practicing abroad. The mean age of the participants was 38.9 (SD—10.74) with a median of 36 years and a range of 24–75 years. Majority of the participants were in the age range of 30–39 years (N = 240;

43.8%), followed by those aged less than 30 years (N = 106; 19.3%), and those aged between 40 and 49 years (N = 103; 18.8%). Majority of the participants were male (N = 453; 82.7%). The mean number of years in clinical practice (including the number of years of training) was 12.59 (SD—10.1) with a median of 9 years and range of 6 months to 49 years. A quarter (N = 143; 26.1%) of those who responded were holding a faculty position in government run institutes or medical colleges and another onefourth (N = 123; 22.4%) of the respondents were into full time private practice. One-fifth (N = 114; 20.8%) of the participants while on the faculty of a teaching institute were at the same time were also into private practice. Another one-fifth (N = 103; 18.8%) were working as Senior Resident (equivalent to a registrar). A very small number of participants (N = 37; 6.8%) were working as a teaching faculty in a privately-run institute and a small proportion (N = 28; 5.1%) of them were trainee residents. The mean number of patients with schizophrenia seen in a month by these clinicians was 96.78 (SD 140.31) with a median of 50 and range of 0–1500. 3.2. Practice pattern for use of clozapine The details of clozapine use pattern are given in Table 1. Only few (N = 37; 6.8%) participants had a dedicated clozapine clinic at their work place. Majority of the participants rated their knowledge about clozapine to be good (61.5%) or very good (34.5%). The mean number of patients started on clozapine by the participants was 432.92 (SD 4415.52) with a median of 65 patients. The primary indication for use of clozapine for almost all participants was patients with treatment resistance and most psychiatrists initiated clozapine either in the dose of 25 mg once daily (44.3%) or 12.5 mg once daily (37%). More than half (51.8%) of the psychiatrists preferred to use it in twice daily dosing schedule, and rest (46.9%) preferred to use it in once daily dosing schedule. Only occasional psychiatrists preferred to use it in three or four divided doses per day. In terms of blood monitoring, once the clozapine dose had been stabilized, about half (51%) of the psychiatrists advised it at monthly intervals. About one-fifth of the psychiatrists monitored the heamogram at 3 monthly intervals and 8.2% did so at 2 monthly intervals. The participating psychiatrists reported that they used clozapine in 11.26% of their patients with psychosis and 3.49% of their affective disorder patients. The median dose range which was required by the patients to stabilize was 137.5 to 400 mg/day. Nearly half of the participants (49.6%) reported lower limit of the dose of Clozapine to be 100 mg or less and only 15.7% reported it to be 200 mg/day or higher. Similarly, 73% reported the higher limit of the dose range to be up to 400 mg/day and only 2.6% reported it more than 600 mg/day. 3.3. Side effects encountered As shown in Table 2, sedation and hypersalivation were the two most common side effects encountered by most of the psychiatrists. Other commonly encountered side effects were weight gain, constipation, raised blood sugar levels, hypotension, enuresis and obsessive compulsive symptoms. Among the intolerable side effects reported by patients, again the most common were sedation and hypersalivation. Other common intolerable side effects included weight gain and constipation. 3.4. Management of side effects The preferred strategies for management of hypersalivation included use of glycopyrrolate (53.8%), waiting for some time for tolerance to develop (45.6%), use of amitriptyline (37%) or trihexiphenidyl (36.8%) and reduction in dose of clozapine

Please cite this article in press as: Grover, S., et al., Prescription practices and attitude of psychiatrists towards clozapine: A survey of psychiatrists from India. Asian J. Psychiatry (2015), http://dx.doi.org/10.1016/j.ajp.2015.09.013

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Table 1 (Continued )

Table 1 Clozapine use profile. Variable

Frequency (%)/mean (SD)

Dedicated clozapine clinic Knowledge about clozapine Very good Good No so good Poor Over the years, in about how many patients you would have initiated clozapine? (N = 524) What is the primary indication for which you start clozapine? Treatment resistance Augmentation of other antipsychotics Sedation None of the above Preclozapine investigations DLC & TLC Platelet count LFT RFT ECG EEG Serum electrolytes Fasting blood sugar Lipid profile Investigations done while monitoring the use of clozapine DLC & TLC Platelet count LFT RFT ECG EEG Serum electrolytes Fasting blood sugar Lipid profile What is the most commonly used starting dose of clozapine by you? 12.5 mg OD 25 mg OD 12.5 mg BD 25 mg BD 50 mg OD 50 mg BD 100 mg OD 100 mg BD What is your most preferred dosing for clozapine? Twice daily Once daily Thrice daily Four times a day How frequently do you monitor haemogram of a patient on stable dose of clozapine (i.e., say after 3 months of starting clozapine)? Weekly Monthly 2 monthly 3 monthly Never Others If a patient refuses to take clozapine, how frequently do you recommend family members to give it surreptitiously? Always Never Often Rarely In about what percentage of your patients with psychotic disorders, do you use clozapine? In about what percentage of your patients with affective disorders, do you use clozapine?

37 (6.8%) 189 (34.5%) 337 (61.5%) 17 (3.1%) 5 (0.9%) 432.92 (4415.52) [median 65; range 1–100,000]

Variable

Frequency (%)/mean (SD)

What is the usual dose range of clozapine which is required by your patients to stabilize?

143.50 (85.40)–371.79 (146.61) [median 137.5– 400; range 12.5–900]

DLC—differential Leucocyte count; TLC—total leucocyte count; RFT-renal function test; LFT—liver function test; ECG—electrocardiogram; EEG—Electroencephalogram.

(28%). Constipation is usually managed with dietary management (82.8%), use of Isabgoul husk (68.8%), or other laxatives (45.2%), waiting for some time for tolerance to develop (25%) and dose reduction of clozapine (16.3%). Sedation is most commonly managed by change in the timing of medication (68.1%) or waiting for some time for tolerance to develop (51.3%). Other commonly used measures were either dose reduction (42%) or using the dosing in divided doses (29.2%). Use of modafinil or armodafinil was considered as a strategy to manage sedation by one fifth (19%) of respondents (Table 3).

522 (95.3%) 17 (3.1%) 2 (0.4%) 7 (1.3%) 544 (99.3%) 268 (48.9%) 316 (57.7) 223 (40.7) 410 (74.8%) 94 (17.2%) 151 (27.6%) 455 (83%) 391 (71.4%)

3.5. Clozapine and polypharmacy Three-fourth (76.3%) of the psychiatrists agreed that they combine clozapine with other antipsychotics and this was done in 27.19 (SD—27.05) % of cases. In terms of the most preferred antipsychotic for combination, the first choice was risperidone, closely followed by amisulpiride. However, when the cumulative frequency of all the three indicated choices was taken into account, amisulpiride (60.8%) was one of the 3 most preferred agents, followed by risperidone (55.3%), aripiprazole (41.8%) and haloperidol (27.4%) (Table 4).

545 (99.5%) 160 (29.2%) 122 (22.3%) 55 (10%) 187 (34.1%) 25 (4.6%) 00 357 (65.1%) 293 (53.5%)

3.6. Attitude of psychiatrists Almost all psychiatrists rated effectiveness of clozapine to be better than other antipsychotics (see Table 5) and on a scale of 0–10 the mean score for effectiveness for psychotic disorders was 7.53 and for negative symptoms of schizophrenia was 5.47. In

203 (37%) 243 (44.3%) 44 (8%) 20 (3.7%) 26 (4.7%) 5 (0.9%) 4 (0.7%) 3 (0.5%)

Table 2 Side effects of clozapine.

48 (8.8%) 279 (51%) 45 (8.2%) 103 (18.8%) 7 (1.3%) 65 (11.9%)

8 (1.5%) 361 (65.9%) 61 (11.1%) 118 (21.5%) 11.26 (10.91) [median 10; range 0–98] 3.49(6.29) [median range 0–70]

1;

Common intolerable side effects of clozapine, reported by patients seen in your clinical practice frequency (%)

Variable

Common side effects of clozapine which you encounter in your clinical practice frequency (%)

Agitation Obsessive compulsive symptoms Enuresis Hypertension Hypotension Tachycardia Raised fasting blood glucose Myocarditis Deranged lipid profile Fever Extrapyramidal symptoms Hyperprolactinemia Constipation Weight gain Hypersalivation Sedation Blood dyscrasias Nausea Seizures None

10 (1.8%) 112 (20.4%)

6 (1.1%) 44 (8%)

136 (24.8%) 15 (2.7%) 155(28.3%) 159 (29%) 189 (34.5%)

75 5 55 24 34

(13.7%) (0.9%) (10%) (4.5%) (6.2%)

19 48 7 9 13 172 238 368 392 49 18 77 19

(3.5%) (8.8%) (1.3%) (1.6%) (2.4%) (31.4%) (43.5%) (67.2%) (71.5%) (8.9%) (3.3%) (14.1%) (3.5%)

284 (51.8%) 257 (46.9%) 6 (1.1%) 1 (0.2%)

14 192 22 24 25 327 435 522 524 51 71 87 –

(2.6%) (35%) (4%) (4.4%) (4.6%) (59.7%) (79.4%) (95.3%) (95.6%) (9.3%) (13%) (15.9%)

Please cite this article in press as: Grover, S., et al., Prescription practices and attitude of psychiatrists towards clozapine: A survey of psychiatrists from India. Asian J. Psychiatry (2015), http://dx.doi.org/10.1016/j.ajp.2015.09.013

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Table 3 Management strategies for common side effects of clozapine. Variable

Frequency (%)

How do you manage increased salivation associated with clozapine? (multiple responses permitted) Clonidine Amitriptyline Glycopyrrolate Trihexiphenidyl Amisulpiride Reduce dose of clozapine Wait for some time for tolerance to develop Don’t do anything Stop clozapine

31 198 288 197 57 150 244 42 4

(5.8%) (37%) (53.8%) (36.8%) (10.7%) (28%) (45.6%) (7.9%) (0.8%)

How do you manage constipation associated with clozapine (multiple responses permitted) Dietary management Isabgoul husk Other laxatives Reduce the dose of clozapine Wait for some time for tolerance to develop Stop clozapine Do not do any thing

443 368 242 87 134 5 10

(82.8%) (68.8%) (45.2%) (16.3%) (25%) (0.9%) (1.8%)

How do you manage sedation associated with clozapine (multiple responses permitted) Reduce the dose of clozapine Do not change the dose, but the timing of medication Divide the doses to the morning time Wait for some time for tolerance to develop Stop clozapine Add modafinil or Armodafinil Add SSRIs Do not do any thing Any other

230 (42%) 373 (68.1%) 160 281 8 104 9 14 33

(29.2%) (51.3%) (1.5%) (19%) (1.6%) (2.6%) (6%)

terms of tolerability, 45.3% of the psychiatrists rated it as ‘same as other antipsychotics’ and 15.9% rated it as better than other antipsychotics. However, about two-fifth (38.9%) of the psychiatrists rated it as ‘poorer than other antipsychotics’ on tolerability. More than three-fifth (61.3%) of the psychiatrists reported that they prefer to use clozapine in patients who have failed 2 adequate Table 4 Clozapine and polypharmacy. Variable

Frequency (%)/ mean (SD)

Do you combine clozapine with other antipsychotic—Yes In what percentage of your patients receiving clozapine, do you combine it with some other antipsychotics? When you combine clozapine with other antipsychotics, what are the 3 most commonly prescribed other antipsychotics (please list them in the sequence of preference) First preference—Risperidone First preference—Amisulpiride First preference—Aripiprazole

418 (76.3%)

When you combine clozapine with other antipsychotics, what are the 3 most commonly prescribed other antipsychotics (please list them in the sequence of preference) Olanzapine Risperidone Amisulpiride Aripiprazole Haloperidol Quetiapine Trifluoperazine

27.19 (27.05) [median 20; range 0–100]

184 (33.6%) 177 (32.3%) 66 (12%)

trials of antipsychotic monotherapy. About one-sixth (17.3%) preferred to use polypharmacy in such a scenario and another 10% reported use of polypharmacy with clozapine as one of the agent. A small proportion of psychiatrists opted electro-convulsive therapy (ECT) along with an antipsychotic if they encountered a patient who has failed 2 adequate trials of antipsychotic monotherapy. When asked for the patient related reasons for reluctance on part of the psychiatrist to start clozapine, the most common reason was history of poor medication compliance. Other common reasons for reluctance on part of psychiatrists for using clozapine were presence of medical comorbidity (51.3%), older age (32.5%), refusal by the patient (31.6%) and in children or adolescents (24.3%). Other reasons are shown in Table 5. In terms of psychiatrist related factors, the most common reason for not starting clozapine was need for monitoring (50.5%). Other common reasons were apprehension of possible metabolic side effects (38.5%), possibility of blood dyscrasias (38%), possible seizures (23.5%) and other common side effects (23.5%). Although, about two-fifth of the psychiatrists referred the patients on clozapine to other the psychiatrists, yet a significant proportion of the psychiatrist preferred not to refer the patient to some other psychiatrist for starting of clozapine. In the opinion of the psychiatrists upon reviewing the prescription of other psychiatrists, 28.46% of patients had not been prescribed clozapine though indicated. One-third (35.4%) of the psychiatrists ‘never’ used clozapine along with ECT. About two-third (65.9%) of the psychiatrists never recommended the surreptitious use of clozapine for their patients. Only one-fifth (21.5%) of them rarely recommended and one tenth (11.1%) often recommended surreptitious use of clozapine. 3.7. Patients’ perceptive as perceived by the psychiatrists When psychiatrists were asked about factors which make patients reluctant for clozapine, the common reasons reported were blood monitoring (74.8%), side effects (62.8%), patient scared of the anticipated side effects when explained about the same (45.6%) and clozapine considered to be dangerous (19.3%). Other reasons are given in Table 6. In terms of treatment satisfaction about two-third (67.3%) of the psychiatrists reported that patients were more satisfied with clozapine as compared to other antipsychotics and another one-fourth (26.3%) reported that their patients were as satisfied with clozapine as with other antipsychotics (see Table 6). 3.8. Years of practice in psychiatry and attitude towards clozapine and its use It was seen that those who were into psychiatric practice for longer duration more often preferred to combine clozapine with other antipsychotics (Spearman Rank Correlation = 0.133, p value = 0.002**), gave lower rating to clozapine in the management of psychotic disorders (Spearman Rank Correlation = 0.136, p value = 0.001***), rated clozapine higher in the management of negative symptoms (Spearman Rank Correlation = 0.110, p value = 0.01**) and had started greater number of patients on clozapine (Spearman Rank Correlation = 0.519, p value <0.001***). 4. Discussion

88 (16.1%) 303 (55.3%) 333 (60.8%) 229 (41.8%) 150 (27.4%) 42 (7.7%) 67 (12.2%)

Despite its proven efficacy in patients with TRS, clozapine is usually considered as a last resort. Hence it is often underused. Very few studies across the globe have evaluated the psychiatrist’s attitude towards clozapine (Nielsen et al., 2010; Gee et al., 2014). Only one survey from India has looked at the prescribing practices of the psychiatrists and this in general did not evaluate the attitude

Please cite this article in press as: Grover, S., et al., Prescription practices and attitude of psychiatrists towards clozapine: A survey of psychiatrists from India. Asian J. Psychiatry (2015), http://dx.doi.org/10.1016/j.ajp.2015.09.013

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AJP-793; No. of Pages 9 S. Grover et al. / Asian Journal of Psychiatry xxx (2015) xxx–xxx Table 5 Attitude of psychiatrists towards clozapine. Variable How would you rate effectiveness of clozapine, when compared to other antipsychotics? Better Poor Same How would you rate the effectiveness of clozapine in a patient with psychotic disorder on a 0–10 point scale? (N = 545) How would you rate the effectiveness of clozapine for negative symptoms on a 0–10 point scale? (N = 544) How would you rate tolerability to clozapine, when compared to other antipsychotic? Better than other antipsychotics Poorer than other antipsychotics Same as other antipsychotics If a patient has failed 2 adequate trials of antipsychotic monotherapy, what would be your next strategy Clozapine Combine antipsychotic with ECT Combine clozapine with other antipsychotic Combine two antipsychotics other than clozapine Others According to you, what are the patient related factors which are commonly associated with reluctance on your part to start clozapine? History of poor medication compliance Poor social support Cost of clozapine Refusal by patient to get admitted Patient refusing to take clozapine Medical comorbidity Elderly Children and Adolescent Reluctance on part of caregiver None According to you, which of the following factors make you reluctant to start clozapine? Need for monitoring Possible blood dyscrasias Possible seizures Possible metabolic side effects Other side effects like fever, constipation, hypersalivation, sedation You are not convinced that clozapine may be better than other antipsychotic None How frequently do you refer the patient to some other psychiatrist, if patient is already on clozapine? Always Never Occasionally Often If you are reluctant to start clozapine, how frequently do you refer a patient to some other psychiatrist for starting of clozapine? Always Never Occasionally Often Doesn’t apply to me When you see patients with psychotic disorders who are already on treatment from elsewhere, according to your experience, in what approximate percentage of patients, do you think, clozapine is indicated, but was not started? (N = 543) Do you combine clozapine with Electroconvulsive therapy? Frequently Never Occasionally

5

Table 6 Patients’ perceptive as perceived by the psychiatrists. Frequency (%)/ mean (SD)

524 (95.6%) 3 (0.5%) 21 (3.8%) 7.53(1.00) [median 8; range 3–10] 5.47(1.70) [median 5; range 0–9]

87 (15.9%) 213 (38.9%) 248 (45.3%)

336 (61.3%) 45 (8.2%) 55 (10%) 95 (17.3%) 17 (3.1%)

369 (67.3%) 253 (46.2%) 121 (22.1%) 82 (15%) 173 (31.6%) 281 (51.3%) 178 (32.5%) 133 (24.3%) 192 (35%) 22 (4%)

277 208 129 211 129

(50.5%) (38%) (23.5%) (38.5%) (23.5%)

13 (2.4%) 117 (21.9%)

3 (0.5) 328 (59.9%) 202 (36.9%) 15 (2.7%)

1 (0.2%) 252 (46%) 62 (11.3%) 11 (2%) 222 (40.5%) 28.46(22.30) [median 25; range 0–100]

32 (5.8%) 194 (35.4%) 322 (58.8%)

Variable According to you, which of the following factors make patients reluctant to the option of clozapine? Cost of clozapine Need to get admitted Side effects Blood monitoring Patient scared of the anticipated side effect, when explained about the same Patient not convinced that clozapine may be better than other antipsychotic Patient consider clozapine is a dangerous drug to use Patient considers that, benefits of clozapine donot outweighs the side-effects None How would you rate the satisfaction of your patients with treatment, who are on clozapine compared to other antipsychotic? As satisfied with clozapine as with other antipsychotics Less satisfied with clozapine compared other antipsychotics More satisfied with clozapine compared other antipsychotics

Frequency (%)

98 79 344 410 250

(17.9) (14.4%) (62.8%) (74.8%) (45.6%)

35 (6.4%) 106 (19.3%) 48 (8.8%) 21 (3.8%)

144 (26.3%) 35 (6.4%) 369 (67.3%)

of the psychiatrists towards clozapine (Shrivastava and Shah, 2009). Considering the lack of data from developing countries like India, this survey was an attempt to fill this void. The survey included 548 Indian psychiatrists and most of them were still practicing in India. Previous surveys which have evaluated the prescribing practices and attitude of psychiatrists towards clozapine have included 100–144 psychiatrists or other mental health professionals (Nielsen et al., 2010; Gee et al., 2014; Shrivastava and Shah, 2009). The sample size of the present survey was at least 3.8 times greater than the largest earlier survey. In one of the previous surveys, trainee psychiatrists formed the major proportion of the participants (Gee et al., 2014) and in another survey, psychiatrists from university hospitals formed the largest group (Nielsen et al., 2010). These sampling characteristics could influence the findings of these studies with regard to the attitude of psychiatrists towards clozapine. It is quite possible that the attitudes of trainees may not necessarily represent the prescription pattern, because they may not have a say in the decision to prescribe medications. Similarly, those in university hospitals may be more inclined to keep themselves updated with recent developments and treatment guidelines and may have a more positive attitude towards clozapine. In the present survey there was nearly equal distribution of the psychiatrists having clinical practice only in the teaching hospital, those doing both private practice and also in a teaching job, those in full time private practice, and trainees. Therefore, findings of the present survey can be generalized to the clinical practice of clozapine in India. The mean age of participants in this survey was 38.9 (SD— 10.74) with a median of 36 years and a range of 24–75 years. Majority of the participants were in the age range of 30–39 years. This age profile is similar to that of participants in the study by Gee et al. (2014). The mean number of years in clinical practice of the participating psychiatrists in the present study was comparable to that of participants in a previous survey from India on clozapine prescribing practices (Shrivastava and Shah, 2009). Majority of the participants rated their knowledge about clozapine to be good or very good. Previous surveys which have assessed the self-rated familiarity with treatment guidelines, also show that psychiatrists rate themselves as having high familiarity with the prescribing guidelines for clozapine (Gee et al., 2014). Although we did not specifically enquire about familiarity with the

Please cite this article in press as: Grover, S., et al., Prescription practices and attitude of psychiatrists towards clozapine: A survey of psychiatrists from India. Asian J. Psychiatry (2015), http://dx.doi.org/10.1016/j.ajp.2015.09.013

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treatment guidelines, yet knowledge about clozapine could be considered nearer to the same. The mean number of patients started on clozapine by the participants was 432.92 (SD 4415.52) with a median of 65 patients. This indicates that the participants were using clozapine and the results of practice pattern in this survey may reliably reflect what is actually happening in the clinical practice. 4.1. Practice pattern for use of clozapine There is only one earlier survey from India, which has evaluated the clozapine prescribing practices (Shrivastava and Shah, 2009) of 117 psychiatrists. Compared to the earlier surveys (Nielsen et al., 2010; Gee et al., 2014; Shrivastava and Shah, 2009) the present survey evaluated the prescription patterns in more detail. Almost all participants used it for patients with treatment resistance and majority of the psychiatrists started clozapine either in the dose of 25 mg once daily (44.3%) or 12.5 mg once daily (37%). When we compare these findings with the recommendations of various treatment guidelines (Lehman et al., 2004; Taylor et al., 2012a,b; NICE, 2014), it is apparent that majority of the psychiatrists were following the standard recommendations. This finding is also similar to that of the previous survey from India wherein 12% of psychiatrists preferred to start it in the dose of 12.5 mg/day and another 58% reported to start with 25 mg/day (Shrivastava and Shah, 2009). Overall more than half (51.8%) of the psychiatrists preferred to use it in twice daily dosing schedule and a slightly lower proportion (46.9%) preferred to use it in once daily dosing schedule. There are no specific guidelines for the same, but textbooks do recommend that once patient is stabilized on clozapine, it should preferably be given as once daily dose at night-time (Sadock et al., 2009). Thus, there is a need to increase the awareness of the psychiatrists about the recommended dosing schedule of clozapine, particularly once the patient has been stabilised on clozapine. In terms of monitoring of haemogram once the clozapine dose has been stabilized, about half (51%) of the psychiatrists did so at monthly intervals and about a third of them monitored the same less frequently. American Psychiatric Association guidelines recommend monitoring haemogram every week for first 6 months and then at least 2 weekly for another 6 months and monthly after a year. The present survey indicated that in routine clinical practice, monitoring of haemogram is not found feasible at short intervals after an initial stabilization phase of about 3 months. In the previous survey from India, 80% of the participants preferred to carry out blood monitoring every week during the first month of therapy and then at monthly interval in the next 6 months. Moreover, only 38% preferred to practice regular haematological monitoring with only 5% of psychiatrists continued to monitor the haemogram every 2 weekly after a year of starting clozapine. Further, this survey showed that 80% of the psychiatrists were comfortable carrying out hematological investigations as and when needed after one year of starting clozapine (Shrivastava and Shah, 2009). The authors have concluded that there could be cultural reasons behind this lower frequency of monitoring haemogram by the psychiatrists. Some other psychiatrists from India have also argued for less frequent hematological monitoring (Tharyan, 1998). There is a need for further research on this issue as haematological monitoring is a major cause of concern for psychiatrists who are reluctant to start clozapine and it is also an issue with patients. Existing literature suggests that about one-third of the patients with schizophrenia fail to respond to two adequate trials of antipsychotic medications and can be considered as having TRS. When we look at the findings of the present survey only 11.26% of patients with schizophrenia were receiving clozapine. Additionally, participants also reported that 28.5% of the patients who were

earlier under the care of some other psychiatrists, should have been started on clozapine. These findings clearly indicate that clozapine as a molecule is rather underused in the clinical practice. A previous survey too suggests that clozapine is often underused (Nielsen et al., 2010). The underuse may also explain the delay in initiation of clozapine as reported in some of the earlier studies (Howes et al., 2012; Grover et al., 2015a). In terms of affective disorders, psychiatrists reported use of clozapine in only 3.5% patients. Data from randomized control trials suggest that use of clozapine either alone or in combination with other treatment in patients with bipolar disorder is useful in management of symptoms of mania, depression, rapid cycling and psychotic symptoms. Evidence also suggests that use of clozapine is associated with reduction in number and duration of hospitalizations, number of concomitant psychotropic medications, number of hospital visits for somatic reasons and self-harm, suicidal ideations and aggressive behaviour and improvement in social functioning (Li et al., 2015). Data from China suggest frequent use of clozapine among patients with bipolar disorders and it is considered as drug of choice in patients with treatment resistant bipolar disorders (Li et al., 2015). The median dose range of clozapine as required by the patients to stabilize was 137.5 to 400 mg/day, with a broad range of 12.5– 900 mg/day. The finding of the present study is in accordance with recommendations of treatment guidelines, which suggest a dose range of 150–900 mg/day (Lehman et al., 2004; Taylor et al., 2012a,b; NICE, 2014). In the earlier survey from India, about half of the psychiatrists opined that 150–300 mg/day was the effective dose of clozapine and another one-third reported effective dose to be less than 150 mg/day (Shrivastava and Shah, 2009). It can be said that findings of index survey are somewhat in agreement with those of the earlier survey, as the lower limit for the effective dose in the index survey was up to 100 mg/day for about half of the participants and the higher limit was up to 300 mg/day for about three-fourth of the psychiatrists. Studies from UK suggest that average dose of clozapine required by patients is about 450 mg/day (NICE, 2014). Possibly in Indian setting, patients require lower doses. Similar findings have been reported in relation to the dose of other psychotropics and this could be due to ethnic and genetic variations between people from India and the West (Chaudhry et al., 2008). The side effect profile as reported by the psychiatrists is very typical for clozapine (Sagy et al., 2014). Sedation, hypersalivation, weight gain and constipation emerged as the most common intolerable side effects. Proper and effective strategies recommended for managing these side effects can help the patients receiving clozapine and also possibly increase the use of clozapine. For management of hypersalivation, among the non-pharmacological measures, waiting for some time for tolerance to develop was a preferred method by slightly less than half of the psychiatrists. Among the pharmacological measures, glycopyrrolate emerged as the most preferred agent followed by amitriptyline and trihexiphenidyl. Only about one-fourth of the psychiatrists used reduction of dose of clozapine as a strategy for management of hypersalivation. Sedation as a side effect was most commonly managed by change in timing of medication or waiting for some time for tolerance to develop. Other commonly used measures were dose reduction and shifting the doses to the morning time. These findings suggest that sedation is more often managed without addition of any specific medication. Constipation was commonly managed by dietary measures and use of laxatives. Recently a review evaluated the four milder but bothersome side effects with clozapine and concluded that there are no guidelines for management of these side effects (Sagy et al., 2014). However the strategies reported in the present survey are in accordance with the existing literature (Sagy et al., 2014).

Please cite this article in press as: Grover, S., et al., Prescription practices and attitude of psychiatrists towards clozapine: A survey of psychiatrists from India. Asian J. Psychiatry (2015), http://dx.doi.org/10.1016/j.ajp.2015.09.013

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The rate of polypharmacy with clozapine being one of the antipsychotics was reported by three-fourth (76.3%) of the psychiatrists. The proportion of patients in whom clozapine was being used along with other antipsychotics was 27.2%. Clozapine is often used in combination with other antipsychotics either to augment the effect of other antipsychotics or is used in patients who respond partially or do not respond to clozapine (Taylor et al., 2012a,b; Paton et al., 2007). In some cases combination is also tried because of intolerable side effects of clozapine or for countering the side effects of clozapine (Kreinin et al., 2006). As this survey did not specifically enquire about the indications for combinations, the rate of polypharmacy can be considered in the acceptable range. The most commonly used agents are amisulpiride, risperidone, aripiprazole and haloperidol. It is important to note that there is some evidence to support the beneficial effect of amisulpiride in the management of clozapine associated hypersalivation (Kreinin et al., 2006, 2011). Data from the controlled trials for the effectiveness of combination of clozapine and various other antipsychotics is not convincing (Muscatello et al., 2014). There is a need for the clinicians to be aware of this in order to avoid the use of unnecessary combinations. The most convincing evidence is available for combined used of clozapine and ECT (Grover et al., 2015b) among patients who do not respond to clozapine. The present survey shows that one third of psychiatrists never preferred to use this combination and about three-fifth of them used it only occasionally. The earlier survey of psychiatrists from India too had shown that 17% of psychiatrists never chose to use combination of clozapine and ECT, whereas one-fourth used it routinely and 30% of the psychiatrists used it in special circumstances (Shrivastava and Shah, 2009). Thus, there is a need to increase the awareness of the psychiatrists about the effectiveness of combination of clozapine and ECT as it may not only help in improving the treatment outcomes but also may help in reduction of medication load. 4.2. Attitude of psychiatrists towards clozapine Majority of the psychiatrists rated the effectiveness of clozapine to be better than other antipsychotics and the mean score for effectiveness for psychotic disorders was 7.53 which is very similar to that noted in the survey of mental health professionals from United Kingdom and Denmark (Nielsen et al., 2010; Gee et al., 2014). The effectiveness of Clozapine for management of negative symptoms was rated as 5.47 on a scale of 0–10, which can be considered as reasonable effectiveness. For tolerability of clozapine, about three-fifth of the psychiatrists rated it to be ‘same as other antipsychotics’ or ‘better than other antipsychotics’. It is surprising that despite the knowledge and possibly clinical experience of beneficial effects of clozapine and its acceptable tolerability, clozapine was underused by the participating psychiatrists. Thus, there is an urgent need to understand the barriers for prescription of clozapine. When asked about the next therapeutic option for those patients ‘who had failed 2 antipsychotic trials’, about one-fourth of the psychiatrists reported either combining antipsychotic medications or combining an antipsychotic with ECT. Another 10% reported using clozapine in combination with another antipsychotic medication. If one compares these findings with the recommendations of various treatment guidelines (Lehman et al., 2004; Taylor et al., 2012a,b; NICE, 2014) it is quite obvious that many psychiatrists had reluctance to start clozapine and certainly deviated from the recommendations of these treatment guidelines. About two third of the psychiatrists reported that they were reluctant to use clozapine in patients with history of poor medication compliance and about an half reported that presence

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of medical comorbidity was one of the factors that made them reluctant to use clozapine. There are no studies which have evaluated the pros and cons of use of clozapine in this subgroup of patients. However, previous surveys also suggest that medical comorbidity does contribute to lower prescription rates of clozapine (Gee et al., 2014). Other reasons, which were reported to be associated with reluctance to use clozapine, included poor social support, resistance on the part of caregivers and refusal by patients to take clozapine. Some of these reasons can be managed by providing adequate and factual information to the patients and their caregivers. About one-third and one-fourth of psychiatrists were reluctant to start clozapine for elderly and children/ adolescents, respectively. There is reasonable level of evidence available for the efficacy and effectiveness of clozapine in children and adolescents with TRS (Schneider et al., 2014; Sarkar and Grover, 2013). Evidence for efficacy/effectiveness of clozapine is well known among elderly especially those with TRS (Pridan et al., 2015). There is also evidence to suggest that use of clozapine actually leads to reduction in direct cost of treatment (Thara, 2005). Nevertheless, about one-fifth of the psychiatrists considered cost of clozapine to be an important reason for their reluctance to use clozapine. Therefore, much of the reluctance on part of psychiatrists to adequately use clozapine could be arising due to the lack of knowledge, experience and possibly unfounded apprehensions. Among clinician related factors for their reluctance to start clozapine, need for monitoring was responsible for the same in about half of psychiatrists. Other common reason was anticipation of side effects. Further, about one-third of psychiatrists reported referring the patient on clozapine to a fellow colleague. Authors from other parts of the globe also report prescriber fear to be an important contributory reason for underuse of clozapine (Cohen, 2014; Cirulli, 2005). There are reports that clinicians have a tendency to overestimate the prevalence and severity of side effects (Nielsen et al., 2010; Hodge and Jespersen, 2008). Therefore improving the knowledge of psychiatrists about the incidence of serious or fatal side effects and ease of managing various other side effects can reduce their reluctance to use clozapine. Anticipated metabolic side effects made 38.5% of psychiatrists reluctant to use clozapine. Clozapine is often considered to be associated with highest rate of metabolic syndrome. However, most studies that have reported the prevalence rates have been cross-sectional in nature (Malhotra et al., 2013) and only few studies have prospectively evaluated the development of metabolic syndrome (Grover et al., 2011; Josiassen et al., 2009). These prospective studies point out that the metabolic syndrome seen in patients receiving clozapine should not be attributed to clozapine alone as nearly one-third of the patients already have metabolic syndrome at the time of starting clozapine. A recent study shows that use of clozapine is actually associated with lower mortality rates even after controlling for potential confounders (Hayes et al., 2015). When asked about referring the patient to some other psychiatrist in case they themselves were reluctant to start clozapine, most psychiatrists did not actually do so. This can be considered as an ethical problem as these practitioners not only are reluctant to use clozapine but also possibly deprive such patients from this effective treatment by not referring them. When asked about factors which make the patients reluctant to accept the option of treatment with clozapine, blood monitoring was reported to be the most common reason by about three-fourth of psychiatrists. Other common factors reported were side effects of clozapine and scare of anticipated side effects. These findings are similar to that noted by Gee et al. (2014). However, a study from United Kingdom which involved 570 patients reported that

Please cite this article in press as: Grover, S., et al., Prescription practices and attitude of psychiatrists towards clozapine: A survey of psychiatrists from India. Asian J. Psychiatry (2015), http://dx.doi.org/10.1016/j.ajp.2015.09.013

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majority of patients did not find blood monitoring to be difficult (Taylor et al., 2012a,b). About two-third of the participating psychiatrists reported that those on clozapine were more satisfied with treatment as when compared to those on other antipsychotics and one-fourth reported that patients were as satisfied with clozapine as with other antipsychotics. These findings are similar to the one reported from United Kingdom wherein 71% of psychiatrists felt that patients were more satisfied with clozapine than with other antipsychotic and only 19% reported less satisfaction of patients with clozapine as compared to other antipsychotic (Gee et al., 2014). However, a survey of psychiatrists from Denmark, reported that 66% of psychiatrists found their patients to be less satisfied with clozapine when compared with other antipsychotic (Nielsen et al., 2010). Evaluation of patients receiving clozapine demonstrated that use of clozapine was associated with greater satisfaction than with other antipsychotics (Lewis et al., 2006; Waserman and Criollo, 2000). The present study has some limitations. The survey was based on the opinions expressed by the psychiatrists and did not evaluate the exact prescriptions. The response rate to the survey was only 16%. Participation in the survey was voluntary and it is quite possible that many psychiatrists who did not complete the questionnaire may actually not be using clozapine. The survey did not evaluate some other reasons like frequent change of psychiatrists could have obviated use of clozapine. The choices given for different situations as part of this survey could have been limited. Hence certain other factors which could influence the attitude and practice pattern may not have been covered. Further the study did not evaluate the monitoring of heamogram during the initial phase of treatment, management strategies used for metabolic disturbances including weight gain, mortality as a side effect or outcome and other serious adverse effects. Future studies must attempt to overcome these limitations. To conclude, the present survey demonstrates that clozapine is underused by psychiatrists in India. Major barrier to use of clozapine is reluctance on the part of the clinicians to subject their patients to frequent blood monitoring. Many presumed patient related factors, which made the psychiatrists reluctant to use clozapine, are actually due to their own lack of knowledge. Prescription of clozapine for the needy patients can be increased by improving the knowledge of psychiatrists about its effectiveness including in special populations. Further there is a need to inform the psychiatrists that clozapine is a cost effective treatment. Reducing their apprehension about the side effects by providing information about actual incidence rates and by improving their knowledge about patient reported experiences and outcome with clozapine, possibly the prescription rates could be improved. In terms of prescription patterns most of the psychiatrists were seen to follow the treatment guidelines in terms of their recommendation for the dose initiation. However, the recommendations for haematological monitoring were not followed by a substantial number of psychiatrists. Accordingly, there is a need for long term studies to evaluate the benefits and risks associated with reduction in frequency of haematological monitoring. Conflict of interest statement None. Source of funding None.

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Please cite this article in press as: Grover, S., et al., Prescription practices and attitude of psychiatrists towards clozapine: A survey of psychiatrists from India. Asian J. Psychiatry (2015), http://dx.doi.org/10.1016/j.ajp.2015.09.013