Psychiatry Research 226 (2015) 181–185
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Delay in initiation of clozapine: A retrospective study from a tertiary care hospital in North India Sandeep Grover n, Nandita Hazari, Subho Chakrabarti, Ajit Avasthi Department of Psychiatry, Post-Graduate Institute of Medical Education and Research, Chandigarh 160012, India
art ic l e i nf o
a b s t r a c t
Article history: Received 29 August 2014 Received in revised form 30 December 2014 Accepted 31 December 2014 Available online 9 January 2015
This study aimed to assess the delay in initiation of clozapine, number of adequate antipsychotic trials prior to starting clozapine and practice of polypharmacy prior to starting clozapine. A retrospective study design was followed. Treatment records of 200 patients started on clozapine during the period of January 2006–June 2014 were reviewed. The mean delay in clozapine initiation was 1.93 (S.D. 1.82) years and median was 1.5 years. Mean of 3 (S.D. 1.18) adequate antipsychotic trials was given prior to considering clozapine and 27.5% patients had received polypharmacy prior to clozapine. Factors related to delay in starting of clozapine included higher age, longer duration of illness, age more than 20 years of age, polypharmacy, use of an adequate trial of typical antipsychotic medication, patients from urban locality and those with onset of illness prior to introduction of clozapine into Indian market. Findings of the present study suggest that there is a delay of 1.5–2 years in starting of clozapine and about onefourth of patients receive polypharmacy prior to receiving clozapine. These finding suggests that there is a need to change the prescribing habits to reduce the delay in starting of clozapine. & 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Clozapine Treatment resistant schizophrenia Polypharmacy
1. Introduction Treatment resistance in schizophrenia is common and occurs in as many as one-third of patients (Lehman et al., 2004; Mortimer et al., 2010). Treatment resistance in schizophrenia is defined as failure of response to adequate trials of two different antipsychotic agents (Taylor et al., 2010). Clozapine is considered the gold standard in managing patients with treatment resistant schizophrenia (TRS) with 50–80% of patients showing response to clozapine after failure of previous two antipsychotic trials (Kishi et al., 2013). Yet, despite its great clinical utility, clozapine remains underutilised (Goren et al., 2013). Studies from United States of America indicate that only 5–25% of patients who ought to have been initiated on clozapine were actually on the drug (Stroup et al., 2014; Moore et al., 2007a). There are a few studies from various developed countries which suggest that there is a delay before clozapine is initiated in patients with TRS. All these studies have followed retrospective study design. The sample size of these studies has varied from 42 to 664, and the mean delay which has been found in these studies has varied from 2.8 to 6.3 years (Taylor et al., 2003; Harrison et al., 2010; Howes et al., 2012; Najim et al., 2013; Wheeler et al., 2014).
n Corresponding author. Tel.: þ 91 172 2756807; fax: þ 91 172 2744401, 91 172 2745078. E-mail address: [email protected] (S. Grover).
http://dx.doi.org/10.1016/j.psychres.2014.12.046 0165-1781/& 2015 Elsevier Ireland Ltd. All rights reserved.
However, data from one of the studies is reassuring with regard to delay in use of clozapine to have reduced to 1 year in patients presented in last 3 years (Wheeler et al., 2014). The mean number of adequate antipsychotics trials prior to introduction of clozapine in these studies has varied from 2.8 to 4.3 (Taylor et al., 2003; Wheeler et al., 2014). In terms of type of antipsychotic used prior to clozapine, studies suggest that atypical antipsychotic medications were used in 90% of patients (Taylor et al., 2003), polypharmacy was tried in 36.2–65% of cases (Taylor et al., 2003; Howes et al., 2012) and high dose treatment was used in 34.2% of cases (Howes et al., 2012). Various patient and clinical factors which have been reported to be associated with delay in initiation of clozapine include age more than 30 years (Taylor et al., 2003; Najim et al., 2013), longer duration of illness (Howes et al., 2012), completion of 2 adequate antipsychotic trials (Taylor et al., 2003), patients diagnosed with TRS before 1991 (Najim et al., 2013), patients diagnosed with illness before the introduction of clozapine (Taylor et al., 2003) and patients diagnosed with illness before the introduction of risperidone (Najim et al., 2013). One of the studies suggested that Government funding for clozapine influenced the introduction of clozapine and it showed that the mean delay in initiation of clozapine declined from 5.7 (S.D. 3.3) years prior to funding to a 2.8 (S.D. 1.9) years after the introduction of government funding for clozapine (Harrison et al., 2010). However, studies suggest that the delay is shorter if the patient is admitted to the psychiatry hospital more than once (Najim et al., 2013). In terms of consequences
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of reduction in delay in clozapine studies suggest that early initiation of clozapine is possibly associated with reduction in number of hospitalizations (Harrison et al., 2010). In general researchers suggest that a significant proportion of psychiatrists have negative view about clozapine and are reluctant to start clozapine (Nielsen et al., 2010; Cohen, 2014). A study suggest that about two-third of the psychiatrists believed that patients treated with clozapine are less satisfied with their treatment when compared to use of other antipsychotics and similar percentage opined that they would prefer to combine twoantipsychotics rather than using clozapine. Other reasons reported to be were lower use of clozapine are lack of/poor knowledge and experience about use of clozapine (Nielsen et al., 2010). A recent study evaluated clinicians for their attitude towards starting of clozapine and reported that ‘patients concerns about tolerability of clozapine’, ‘patients refusal to follow to the blood monitoring’ and ‘staff concerns about medical complications’ with clozapine were the most important barrier for starting of clozapine (Gee et al., 2014). Studies also suggest that clinicians avoid using clozapine because of frequent monitoring and potential side effects, especially agranulocytosis and neutropenia (Kelly et al., 2007; Warnez and Alessi-Severini, 2014). Due to all these views of psychiatrists, many a times clozapine is underused and starting of clozapine is unduly delayed. India is a developing country where majority of the mental health care is provided at the outpatient level and most of the health care expenditure is done by the patient and the family out of their pocket (Grover et al., 2005; Somaiya et al., 2014). A survey of psychiatrists from India suggests that wider use of clozapine in patients who do not respond to other available antipsychotics (Shrivastava and Shah, 2009) and various studies from India also have shown its proven efficacy (for review see Grover et al., 2010). However, there are no studies from India which have estimated the theoretical delay in starting clozapine. Before considering that the psychiatrists from India have similar negative attitude towards clozapine as reported in studies from Western countries, it is important to understand whether there is underutilization of clozapine or not. One of the parameters which can help in understanding the underutilization of clozapine is delay in initiation. Accordingly, the primary aim of this study was to assess the delay in initiation of clozapine, number of adequate antipsychotic trials prior to starting clozapine and practice of polypharmacy prior to starting clozapine. 2. Methodology This retrospective study was done in a multispeciality tertiary care Hospital in North India after obtaining approval from the Institute Ethics Committee. 2.1. Brief description of the study setting In India, health care is not organized and the patient has the liberty to seek treatment from Government or private set up. There are lots of doctors shopping and patients with psychosis visit various treatment facilities prior to coming to tertiary care centres (Grover et al., 2014). Accordingly, most patients are exposed to psychotropic medications prior to consultation at tertiary care centres. The tertiary care centre, at which this study was done is a Government treatment facility, where no fee is charged for seeking consultation (except for a minimal fee of rupees 10 for the 6 months duration for the paper work). Only few antipsychotics, like chlorpromazine, trifluoperazine and fluphenazine decanoate are available free of cost to the patient for maximum refill duration of 1 month. Additionally trihexyphenidyl is available free of cost. However, most of the patients are prescribed atypical antipsychotics with olanzapine and risperidone being the most commonly used drugs (Grover et al., 2013). Accordingly most of the medication cost is borne by the patient and the family. Hospital provides laboratory services and facilities for other investigations at cost lower than that in the private sector. Patients requiring hospitalization have to pay rupees 185 per day for the bed and food charges. Inpatient consultation and nursing services are also free of cost. Patients have to pay for the cost of investigations and have to purchase their
medications. In case a patient is below poverty line as per the government recommendations, the inpatient facilities including investigations are free of cost. Usually clinicians prefer to use clozapine in patients with TRS. Depending on the preference, some clinicians consider using clozapine after 2 adequate trials of any of the antipsychotics, whereas others prefer to have atleast 1 trial of typical antipsychotic prior to considering use of clozapine. In majority of the cases it is started in the inpatient setting after detailed evaluation involving taking a detailed history with regards to types of symptoms and course of illness both from the patient and reliable informants, medical history and physical examination. With regards to the treatment the evaluation usually involves assessment of dose and duration of previous antipsychotics trials along with response and side effect experienced. Clozapine is considered in those patients who have received 2 antipsychotic trials of at least 6 weeks duration in therapeutic doses of the particular antipsychotic with good treatment compliance. In case clozapine is considered, patient/family is explained about the possible side effects and the requirement for monitoring. Before consideration of clozapine, detailed treatment history is taken and the level of response to each antipsychotic medication received is determined based on the information given by the patient, reliable family caregiver, review of treatment records and the overall global clinician's impression and response is rated in terms of percentage reduction in symptoms. In few cases, data is also available in the form of rating on various scales to reach such a conclusion. For this study, inpatient register for the period of 2006–June 2014 was reviewed to identify the patients who were on clozapine at the time of admission or were started on clozapine. Additionally effort was made to identify the patients who were started on clozapine from the outpatient during the same period. Based on this information treatment records of all the eligible patients were identified. Patients with diagnosis other than schizophrenia, schizoaffective disorder and psychosis NOS, but were started on clozapine were not considered. All the diagnoses are coded as per ICD-10. The available treatment records were reviewed and the sociodemographic and clinical details, including those of previous antipsychotic trials in terms of dose and duration were extracted. For operationalization to define a failed trial, nonresponse/minimal response (defined as less than 20% clinical improvement) to a 6 weeks trial of an antipsychotic (in therapeutic doses) with good compliance (i.e., more than 75% intake of the prescribed doses) was used a cut off to define trial failure. As mentioned above, such information is generated for patients and documented prior to starting of clozapine. After two failed trials, the subsequent duration of medication was cumulatively summed up to calculate the delay in initiation of clozapine. Additionally, the number, types of previous trials (atypical and/or typical) were also recorded. For this study polypharmacy was defined as concurrent use of 2 or more antipsychotic medications for duration of at least 6 weeks and this should not have been the part of any antipsychotic switching strategy. Statistical Package for the Social Science Version 14 (SPSS-14) was used for analysis. Frequencies with percentages were calculated for the categorical variables. Mean and standard deviation were computed for the continuous variables. Comparisons were done using independent samples t test and Mann–Whitney U test. Correlations were studied by using Pearson's correlation coefficient.
3. Results For this study, records of 200 patients who were started on clozapine were considered. The sociodemographic and clinical profile of these patients is as shown in Table 1.The mean age of patients at clozapine initiation was 32.61 (S.D. 11.09) years with a range of 15–67 years. Majority of the patients were males (64%), single (69%), unemployed (37%) or doing household work (24.5%), residing in nuclear families (71.5%) of urban background (74.5%). Paranoid (50%) and undifferentiated schizophrenia (37%) were the two most common subtypes. Mean duration of illness was 10.18 (S.D. 7.47) years at the time of starting clozapine. Only 28 patients had onset of illness prior to 1995, when clozapine was introduced in India. About one third of the patients had a comorbid lifetime diagnosis of a psychiatric disorder and one sixth had comorbid physical disorder. The treatment profile of patient's prior to starting of clozapine is shown in Table 2. Most of the patients (75.5%) included in the study were started on clozapine in the inpatient setting. Majority (93.5%) of the patients fulfilled the criteria for TRS. However, 1% of patients were started on clozapine prior to fulfillment of TRS because of severe extrapyramidal symptoms. Another small proportion of patients was started on clozapine prior to completion of 2 adequate trials. When the data of these patients was reviewed, all of them had received atleast 1 adequate trial and the second
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Table 1 Sociodemographic and clinical profile of patients started on clozapine (N ¼ 200). Variable
Mean (S.D.)/n (%)
Age Sex – Male Education in years Marital status – Currently single Occupation Unemployed Household Currently working Student/retired Family Income per month o Rs. 6000 4Rs. 6000 Religion – Hindu Living arrangement – Nuclear Locality – Urban Psychiatric diagnosis Paranoid schizophrenia Undifferentiated schizophrenia Catatonic schizophrenia Post schizophrenic depression Residual schizophrenia Simple schizophrenia Schizoaffective disorder Psychosis NOS Comorbid psychiatric diagnosisa Lifetime history of severe EPS/Akathisia/Dystonia/NMS History of chronic physical illnessb Age of onset of psychiatric illness (years) Total duration of illness (years)
32.61 128 12.07 138
(11.09) [15–67] (64) (3.49) [0–18] (69)
74 49 54 23
(37%) (24.5%) (27%) (11.5%)
45 155 149 143 149
(22.5%) (77.5%) (74.5%) (71.5) (74.5%)
100 74 3 1 2 1 10 9 64 28 33 22.43 10.18
(50.0%) (37%) (1.5%) (0.63%) (0.63%) (0.63%) (4.45%) (3.82%) (32%) (14%) (16.5%) (8.53) [range 10–67] (7.47) [range 0.5–45]
a In terms of psychiatric comorbidity 12 patients had comorbid OCD, 7 patients had mental retardation of varying severity, 25 patients had comorbid nicotine/alcohol/opioid/cannabis/sedative hypnotic dependence, 8patients had comorbid depressive disorders and 14 patient had other psychiatric diagnosis (total number exceeds 64 because few patients had more than one comorbid disorder). b In terms of physical comorbidity 5 patients had hypothyroidism, 10 had diabetes mellitus, 5 had hypertension, 3 had epilepsy, 3 had Parkinson's disease, 2 each had asthma, Cushing syndrome and 1 each had psoriasis and spastic paraparesis (total number exceeds 33 because few patients had more than one comorbid disorder).
trial was although of therapeutic doses, the duration was between 4 and 6 weeks. In terms of number of adequate trials, in 92% of patients the mean number of adequate trials before starting clozapine exceeded 2 and the mean number of trials received prior to starting of clozapine for the study sample were 3 (1.18). About three-fifth (62%) of patients received at least one adequate trial with typical antipsychotic prior to starting clozapine. About onefourth (27.5%) of the patients received polypharmacy prior to considering clozapine. In terms of type of polypharmacy combination of typical and atypical agents being the most common, seen in 60.8% (31/55) of cases. Mean delay in starting of clozapine was 1.93 (1.82) years and the median was 1.5 years. There was no difference in the mean delay in starting of clozapine in those with or without comorbid diabetes mellitus [mean 2.16 (S.D. 1.40) versus mean 1.91 (S.D. 1.83); t value 0.43; p ¼0.66], epilepsy [mean 1.91 (S.D. 1.82) versus mean 2.51 (S.D. 1.40); t value 0.56; p¼ 0.57] or hypertension [mean 1.94 (S.D. 1.82) versus mean 1.20 (S.D. 1.02); t value 0.90; p ¼0.36]. The mean dose of clozapine used was 278.63 (S.D. 103.02) with a range of 75–700 mg/day. 3.1. Factors associated with delay in starting clozapine There was significant positive correlation of duration of delay of starting clozapine with age (Pearson's correlation coefficient 0.199; p ¼0.005) and duration of illness (Pearson's correlation coefficient 0.318; p o0.001). When those aged up to 20 years, were compared with those aged more than 20 years, mean duration of delay of starting clozapine was more for the later group [mean 0.91 (S.D. 1.05) versus 2.05 (1.86); Mann Whitney U value 1065; po 0.001].
Significant delay in starting clozapine was seen with use of polypharmacy [mean 2.58 (S.D. 2.06) versus 1.68 (1.67); t-test value 3.21; p ¼0.002], use of an adequate trial of typical antipsychotic medication [mean 2.27 (S.D. 2.04) versus 1.37 (1.21); Mann Whitney U value – 3458.5; p¼ 0.002], urban locality [mean 2.11 (S.D. 1.98) versus 1.37 (S.D. 1.11); Mann Whitney U value 3058; p¼ 0.038] and those who had onset of illness prior to introduction of clozapine in India [mean 2.96 (S.D. 2.56) versus 1.76 (1.62); Mann Whitney U value 1601; p ¼0.005]. There was no difference in the duration of delay between patients of either gender, family income, with and without physical or psychiatric comorbidity.
4. Discussion To the best of our knowledge, this is the first study assessing the delay in initiation of clozapine from a developing country and it adds to the available literature. The sample size of the study was 200, which is larger than some of the previous studies on this topic (Taylor et al., 2003; Howes et al., 2012; Najim et al., 2013). Compared to the findings of the previous studies, present study suggests that in a tertiary care centre in Indian setting the mean delay in starting of clozapine is 1.93 years. Studies from the developed countries suggest that the mean delay in starting clozapine varies from 2.8 to 6.3 years (Taylor et al., 2003; Harrison et al., 2010; Howes et al., 2012; Najim et al., 2013; Wheeler et al., 2014). However, the studies which have specifically evaluated the mean delay in starting clozapine during the period of 2011–2013, suggest that the mean duration of delay is only 1 year (Wheeler et al., 2014). When we compare our findings with
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Table 2 Pre-clozapine treatment profile of patients (N ¼ 200). Variable
Mean (S.D.)/N (%)
Setting of starting clozapine Inpatient Outpatient Indication for starting clozapine Treatment resistance Treatment resistanceþ EPS EPS Othersa Mean number of antipsychotic exposures Number of adequate antipsychotic trials 1 2 3 Z4 No. of patients who received at least one adequate typical antipsychotic trial No. of patients who received at least one adequate atypical antipsychotic trial No. of patients who received polypharmacy Polypharmacy combination Atypicals only Typical þ atypical Typicals only Duration of polypharmacy (weeks) Delay in starting clozapine No delay o 3 months 3–12 months 1–3 years 3–5 years 45 years Mean number of adequate trials Delay in starting clozapine Mean dose of clozapine used Clozapine dose categories Upto 100 mg/day 101–200 mg/day 201–300 mg/day 301–400 mg/day 401–500 mg/day 501–600 mg/day 6.1–700 mg/day
151 (75.5%) 49 (24.5%) 171 (85.5%) 16 (8%) 2 (1%) 11 (5.5%) 3.31 (1.39) 16 (8%) 60 (30%) 57 (28.5%) 67 (33.5%) 124 (62%) 195 (97.5%) 55 (27.5%) 21 (10.5%) 31(15.5%) 3 (1.5%) 45.81 (56.48) [range 6–312] 9 17 53 83 24 14 3 (1.18) [range 1–7] 1.93 (1.82) [range 0–10.69] 278.63 (103.02) [range 75–700] 4 (2%) 53 (26.5%) 92 (46%) 32 (16%) 11 (5.5%) 7 (3.5%) 1 (0.5%)
a The others category basically applied to those patients who had received one adequate trial and the second adequate trial was shorter than the 6 weeks duration.
the previous studies it appears that the mean duration is shorter in our setting and is comparable to that reported for recent years from developed countries. Various reasons could be thought for these developed. First, some of the studies from the developed countries have included patients prior to introduction of clozapine (i.e., 1991). In contrast to our study, only very few patients had an onset of illness prior to introduction of clozapine in this country. Second, findings of the present study reflect only the prescription of clozapine confined to one tertiary care academic centre. In contrast, many studies from the west have evaluated the records of the patients attending the primary health care services or community psychiatry hospital (Howes et al., 2012; Najim et al., 2013; Wheeler et al., 2010, 2014), with few patients from tertiary care centres forming the part of the study cohort (Howes et al., 2012; Najim et al., 2013). Third, in some of our patients, clozapine was started before completion of the 2 adequate trials. Accordingly this could have influenced the mean duration of delay. The available treatment guidelines for management of schizophrenia recommend the use of clozapine after two failed trials with antipsychotic agents (either typical or atypical) (Taylor et al., 2010; Moore et al., 2007b; Buchanan et al., 2010; Barnes, 2011). Despite such recommendations and the overwhelming evidence of clozapine effectiveness, prescribing of clozapine appears to be low, delayed and often preceded by attempts at polypharmacy treatment, which lacks clinical evidence of effectiveness. In our study,
the mean number of adequate antipsychotic trials were 3 (1.18), this is in the reported range of 2.8–4.3 from the developed countries (Taylor et al., 2003; Wheeler et al., 2014). When we look at the adherence to the recommendations of the treatment guidelines, in the present study in only 38% of patients the prescribing pattern was in accordance to the recommendations of the guidelines. In three-fifth of the patients clozapine was considered after 3 or more adequate trials. These findings suggest that there is a need to change the prescribing habits to reduce the delay in starting of clozapine. However, it must be remembered that in few cases the delay in starting clozapine could have been possibly due to delay in contacting our treatment services, as all the patients were not on treatment from our centre since the beginning of their illness. However, this data was not coded specifically. Polypharmacy though discouraged by evidence based guidelines is commonly practiced. The rates of polypharmacy of atleast 6 weeks duration in the in the present study was 27.5% which is slightly less than the 36.2–65% reported in patients considered for clozapine in studies from the west (Taylor et al., 2003; Howes et al., 2012). Polypharmacy in psychiatry and in particular with regard to antipsychotics has manifold risks like increased side effects with limited clinical benefit (Ballon and Stroup, 2013). Accordingly there is a need for wider dissemination of knowledge about the risks benefit of polypharmacy over and above a single agent in adequate dose.
S. Grover et al. / Psychiatry Research 226 (2015) 181–185
Present study suggests that there is longer delay in starting of clozapine for those with higher age, longer duration of illness, in those aged more than 20 years of age, those who receive polypharmacy, with use of an adequate trial of typical antipsychotic medication, those from urban locality and in those with onset of illness prior to introduction of clozapine into Indian market. However, it is important to note that certain factors like higher age, longer duration of illness and age more than 20 years may be interrelated factors and should not be considered as independent factors. There was no difference in the duration of delay between patients of either gender, family income, with and without physical or psychiatric comorbidity. Studies from the developed countries also suggest longer duration of illness (Howes et al., 2012) and patients diagnosed with illness before the introduction of clozapine (Taylor et al., 2003) to have longer delay in starting of clozapine. Use of polypharmacy as a factor responsible for delay can be understood from the fact that the mean duration of polypharmacy in the present study was 45.81 weeks, which is responsible for about half of the duration of delay in starting clozapine. Association with receiving at least one adequate typical trial possibly suggests that such a decision must be weighted in terms of benefits and the risks of introduction of clozapine. Relationship with urban locality possibly suggests that patients from urban locality are more apprehensive about the side effects of clozapine and due to this possibly there is a delay in starting clozapine. However, this could also be due to other factors, such as availability of more psychiatrists and doctor shopping that is highly prevalent in Indian setting. The present study has certain limitations. It followed a retrospective study design and the information was obtained as available from case records. Accordingly, it is quite possible that some of the details could have been missed, if not documented properly. We did not evaluate the association of delay of clozapine with various other clinical factors like long term medication compliance, treatment adherence behaviour, duration of seeking treatment from other sources, hospitalization, severity of illness etc. Some of these factors can have significant influence on the clinician's judgement to consider or not to consider clozapine in a particular patient. The present study was limited to a tertiary care centre and does not reflect the clozapine prescription practices in India per se because there is lot of heterogenicity in prescription practices. We also did not specifically assess the delay in starting clozapine while the patient was seeking treatment at our centre and delayed due to adhering to other treatment centres. To conclude, the present study suggests that there is a delay of about 2 years in starting of clozapine and in terms of starting of clozapine, in only 38% of cases, recommendations of treatment guidelines are adhered too. A significant duration is lost because of use of polypharmacy. Accordingly there is a need to increase the awareness among clinicians to reduce the practice of irrational polypharmacy. Clinicians should always consider the pros and cons of using polypharmacy or withholding clozapine in a particular patient.
Funding None. Conflict of interest None. Acknowledgement None.
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Delay in initiation of clozapine: A retrospective study from a tertiary care hospital in North India Sandeep Grover n, Nandita Hazari, Subho Chakrabarti, Ajit Avasthi Department of Psychiatry, Post-Graduate Institute of Medical Education and Research, Chandigarh 160012, India
art ic l e i nf o
a b s t r a c t
Article history: Received 29 August 2014 Received in revised form 30 December 2014 Accepted 31 December 2014 Available online 9 January 2015
This study aimed to assess the delay in initiation of clozapine, number of adequate antipsychotic trials prior to starting clozapine and practice of polypharmacy prior to starting clozapine. A retrospective study design was followed. Treatment records of 200 patients started on clozapine during the period of January 2006–June 2014 were reviewed. The mean delay in clozapine initiation was 1.93 (S.D. 1.82) years and median was 1.5 years. Mean of 3 (S.D. 1.18) adequate antipsychotic trials was given prior to considering clozapine and 27.5% patients had received polypharmacy prior to clozapine. Factors related to delay in starting of clozapine included higher age, longer duration of illness, age more than 20 years of age, polypharmacy, use of an adequate trial of typical antipsychotic medication, patients from urban locality and those with onset of illness prior to introduction of clozapine into Indian market. Findings of the present study suggest that there is a delay of 1.5–2 years in starting of clozapine and about onefourth of patients receive polypharmacy prior to receiving clozapine. These finding suggests that there is a need to change the prescribing habits to reduce the delay in starting of clozapine. & 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Clozapine Treatment resistant schizophrenia Polypharmacy
1. Introduction Treatment resistance in schizophrenia is common and occurs in as many as one-third of patients (Lehman et al., 2004; Mortimer et al., 2010). Treatment resistance in schizophrenia is defined as failure of response to adequate trials of two different antipsychotic agents (Taylor et al., 2010). Clozapine is considered the gold standard in managing patients with treatment resistant schizophrenia (TRS) with 50–80% of patients showing response to clozapine after failure of previous two antipsychotic trials (Kishi et al., 2013). Yet, despite its great clinical utility, clozapine remains underutilised (Goren et al., 2013). Studies from United States of America indicate that only 5–25% of patients who ought to have been initiated on clozapine were actually on the drug (Stroup et al., 2014; Moore et al., 2007a). There are a few studies from various developed countries which suggest that there is a delay before clozapine is initiated in patients with TRS. All these studies have followed retrospective study design. The sample size of these studies has varied from 42 to 664, and the mean delay which has been found in these studies has varied from 2.8 to 6.3 years (Taylor et al., 2003; Harrison et al., 2010; Howes et al., 2012; Najim et al., 2013; Wheeler et al., 2014).
n Corresponding author. Tel.: þ 91 172 2756807; fax: þ 91 172 2744401, 91 172 2745078. E-mail address: [email protected] (S. Grover).
http://dx.doi.org/10.1016/j.psychres.2014.12.046 0165-1781/& 2015 Elsevier Ireland Ltd. All rights reserved.
However, data from one of the studies is reassuring with regard to delay in use of clozapine to have reduced to 1 year in patients presented in last 3 years (Wheeler et al., 2014). The mean number of adequate antipsychotics trials prior to introduction of clozapine in these studies has varied from 2.8 to 4.3 (Taylor et al., 2003; Wheeler et al., 2014). In terms of type of antipsychotic used prior to clozapine, studies suggest that atypical antipsychotic medications were used in 90% of patients (Taylor et al., 2003), polypharmacy was tried in 36.2–65% of cases (Taylor et al., 2003; Howes et al., 2012) and high dose treatment was used in 34.2% of cases (Howes et al., 2012). Various patient and clinical factors which have been reported to be associated with delay in initiation of clozapine include age more than 30 years (Taylor et al., 2003; Najim et al., 2013), longer duration of illness (Howes et al., 2012), completion of 2 adequate antipsychotic trials (Taylor et al., 2003), patients diagnosed with TRS before 1991 (Najim et al., 2013), patients diagnosed with illness before the introduction of clozapine (Taylor et al., 2003) and patients diagnosed with illness before the introduction of risperidone (Najim et al., 2013). One of the studies suggested that Government funding for clozapine influenced the introduction of clozapine and it showed that the mean delay in initiation of clozapine declined from 5.7 (S.D. 3.3) years prior to funding to a 2.8 (S.D. 1.9) years after the introduction of government funding for clozapine (Harrison et al., 2010). However, studies suggest that the delay is shorter if the patient is admitted to the psychiatry hospital more than once (Najim et al., 2013). In terms of consequences
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of reduction in delay in clozapine studies suggest that early initiation of clozapine is possibly associated with reduction in number of hospitalizations (Harrison et al., 2010). In general researchers suggest that a significant proportion of psychiatrists have negative view about clozapine and are reluctant to start clozapine (Nielsen et al., 2010; Cohen, 2014). A study suggest that about two-third of the psychiatrists believed that patients treated with clozapine are less satisfied with their treatment when compared to use of other antipsychotics and similar percentage opined that they would prefer to combine twoantipsychotics rather than using clozapine. Other reasons reported to be were lower use of clozapine are lack of/poor knowledge and experience about use of clozapine (Nielsen et al., 2010). A recent study evaluated clinicians for their attitude towards starting of clozapine and reported that ‘patients concerns about tolerability of clozapine’, ‘patients refusal to follow to the blood monitoring’ and ‘staff concerns about medical complications’ with clozapine were the most important barrier for starting of clozapine (Gee et al., 2014). Studies also suggest that clinicians avoid using clozapine because of frequent monitoring and potential side effects, especially agranulocytosis and neutropenia (Kelly et al., 2007; Warnez and Alessi-Severini, 2014). Due to all these views of psychiatrists, many a times clozapine is underused and starting of clozapine is unduly delayed. India is a developing country where majority of the mental health care is provided at the outpatient level and most of the health care expenditure is done by the patient and the family out of their pocket (Grover et al., 2005; Somaiya et al., 2014). A survey of psychiatrists from India suggests that wider use of clozapine in patients who do not respond to other available antipsychotics (Shrivastava and Shah, 2009) and various studies from India also have shown its proven efficacy (for review see Grover et al., 2010). However, there are no studies from India which have estimated the theoretical delay in starting clozapine. Before considering that the psychiatrists from India have similar negative attitude towards clozapine as reported in studies from Western countries, it is important to understand whether there is underutilization of clozapine or not. One of the parameters which can help in understanding the underutilization of clozapine is delay in initiation. Accordingly, the primary aim of this study was to assess the delay in initiation of clozapine, number of adequate antipsychotic trials prior to starting clozapine and practice of polypharmacy prior to starting clozapine. 2. Methodology This retrospective study was done in a multispeciality tertiary care Hospital in North India after obtaining approval from the Institute Ethics Committee. 2.1. Brief description of the study setting In India, health care is not organized and the patient has the liberty to seek treatment from Government or private set up. There are lots of doctors shopping and patients with psychosis visit various treatment facilities prior to coming to tertiary care centres (Grover et al., 2014). Accordingly, most patients are exposed to psychotropic medications prior to consultation at tertiary care centres. The tertiary care centre, at which this study was done is a Government treatment facility, where no fee is charged for seeking consultation (except for a minimal fee of rupees 10 for the 6 months duration for the paper work). Only few antipsychotics, like chlorpromazine, trifluoperazine and fluphenazine decanoate are available free of cost to the patient for maximum refill duration of 1 month. Additionally trihexyphenidyl is available free of cost. However, most of the patients are prescribed atypical antipsychotics with olanzapine and risperidone being the most commonly used drugs (Grover et al., 2013). Accordingly most of the medication cost is borne by the patient and the family. Hospital provides laboratory services and facilities for other investigations at cost lower than that in the private sector. Patients requiring hospitalization have to pay rupees 185 per day for the bed and food charges. Inpatient consultation and nursing services are also free of cost. Patients have to pay for the cost of investigations and have to purchase their
medications. In case a patient is below poverty line as per the government recommendations, the inpatient facilities including investigations are free of cost. Usually clinicians prefer to use clozapine in patients with TRS. Depending on the preference, some clinicians consider using clozapine after 2 adequate trials of any of the antipsychotics, whereas others prefer to have atleast 1 trial of typical antipsychotic prior to considering use of clozapine. In majority of the cases it is started in the inpatient setting after detailed evaluation involving taking a detailed history with regards to types of symptoms and course of illness both from the patient and reliable informants, medical history and physical examination. With regards to the treatment the evaluation usually involves assessment of dose and duration of previous antipsychotics trials along with response and side effect experienced. Clozapine is considered in those patients who have received 2 antipsychotic trials of at least 6 weeks duration in therapeutic doses of the particular antipsychotic with good treatment compliance. In case clozapine is considered, patient/family is explained about the possible side effects and the requirement for monitoring. Before consideration of clozapine, detailed treatment history is taken and the level of response to each antipsychotic medication received is determined based on the information given by the patient, reliable family caregiver, review of treatment records and the overall global clinician's impression and response is rated in terms of percentage reduction in symptoms. In few cases, data is also available in the form of rating on various scales to reach such a conclusion. For this study, inpatient register for the period of 2006–June 2014 was reviewed to identify the patients who were on clozapine at the time of admission or were started on clozapine. Additionally effort was made to identify the patients who were started on clozapine from the outpatient during the same period. Based on this information treatment records of all the eligible patients were identified. Patients with diagnosis other than schizophrenia, schizoaffective disorder and psychosis NOS, but were started on clozapine were not considered. All the diagnoses are coded as per ICD-10. The available treatment records were reviewed and the sociodemographic and clinical details, including those of previous antipsychotic trials in terms of dose and duration were extracted. For operationalization to define a failed trial, nonresponse/minimal response (defined as less than 20% clinical improvement) to a 6 weeks trial of an antipsychotic (in therapeutic doses) with good compliance (i.e., more than 75% intake of the prescribed doses) was used a cut off to define trial failure. As mentioned above, such information is generated for patients and documented prior to starting of clozapine. After two failed trials, the subsequent duration of medication was cumulatively summed up to calculate the delay in initiation of clozapine. Additionally, the number, types of previous trials (atypical and/or typical) were also recorded. For this study polypharmacy was defined as concurrent use of 2 or more antipsychotic medications for duration of at least 6 weeks and this should not have been the part of any antipsychotic switching strategy. Statistical Package for the Social Science Version 14 (SPSS-14) was used for analysis. Frequencies with percentages were calculated for the categorical variables. Mean and standard deviation were computed for the continuous variables. Comparisons were done using independent samples t test and Mann–Whitney U test. Correlations were studied by using Pearson's correlation coefficient.
3. Results For this study, records of 200 patients who were started on clozapine were considered. The sociodemographic and clinical profile of these patients is as shown in Table 1.The mean age of patients at clozapine initiation was 32.61 (S.D. 11.09) years with a range of 15–67 years. Majority of the patients were males (64%), single (69%), unemployed (37%) or doing household work (24.5%), residing in nuclear families (71.5%) of urban background (74.5%). Paranoid (50%) and undifferentiated schizophrenia (37%) were the two most common subtypes. Mean duration of illness was 10.18 (S.D. 7.47) years at the time of starting clozapine. Only 28 patients had onset of illness prior to 1995, when clozapine was introduced in India. About one third of the patients had a comorbid lifetime diagnosis of a psychiatric disorder and one sixth had comorbid physical disorder. The treatment profile of patient's prior to starting of clozapine is shown in Table 2. Most of the patients (75.5%) included in the study were started on clozapine in the inpatient setting. Majority (93.5%) of the patients fulfilled the criteria for TRS. However, 1% of patients were started on clozapine prior to fulfillment of TRS because of severe extrapyramidal symptoms. Another small proportion of patients was started on clozapine prior to completion of 2 adequate trials. When the data of these patients was reviewed, all of them had received atleast 1 adequate trial and the second
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Table 1 Sociodemographic and clinical profile of patients started on clozapine (N ¼ 200). Variable
Mean (S.D.)/n (%)
Age Sex – Male Education in years Marital status – Currently single Occupation Unemployed Household Currently working Student/retired Family Income per month o Rs. 6000 4Rs. 6000 Religion – Hindu Living arrangement – Nuclear Locality – Urban Psychiatric diagnosis Paranoid schizophrenia Undifferentiated schizophrenia Catatonic schizophrenia Post schizophrenic depression Residual schizophrenia Simple schizophrenia Schizoaffective disorder Psychosis NOS Comorbid psychiatric diagnosisa Lifetime history of severe EPS/Akathisia/Dystonia/NMS History of chronic physical illnessb Age of onset of psychiatric illness (years) Total duration of illness (years)
32.61 128 12.07 138
(11.09) [15–67] (64) (3.49) [0–18] (69)
74 49 54 23
(37%) (24.5%) (27%) (11.5%)
45 155 149 143 149
(22.5%) (77.5%) (74.5%) (71.5) (74.5%)
100 74 3 1 2 1 10 9 64 28 33 22.43 10.18
(50.0%) (37%) (1.5%) (0.63%) (0.63%) (0.63%) (4.45%) (3.82%) (32%) (14%) (16.5%) (8.53) [range 10–67] (7.47) [range 0.5–45]
a In terms of psychiatric comorbidity 12 patients had comorbid OCD, 7 patients had mental retardation of varying severity, 25 patients had comorbid nicotine/alcohol/opioid/cannabis/sedative hypnotic dependence, 8patients had comorbid depressive disorders and 14 patient had other psychiatric diagnosis (total number exceeds 64 because few patients had more than one comorbid disorder). b In terms of physical comorbidity 5 patients had hypothyroidism, 10 had diabetes mellitus, 5 had hypertension, 3 had epilepsy, 3 had Parkinson's disease, 2 each had asthma, Cushing syndrome and 1 each had psoriasis and spastic paraparesis (total number exceeds 33 because few patients had more than one comorbid disorder).
trial was although of therapeutic doses, the duration was between 4 and 6 weeks. In terms of number of adequate trials, in 92% of patients the mean number of adequate trials before starting clozapine exceeded 2 and the mean number of trials received prior to starting of clozapine for the study sample were 3 (1.18). About three-fifth (62%) of patients received at least one adequate trial with typical antipsychotic prior to starting clozapine. About onefourth (27.5%) of the patients received polypharmacy prior to considering clozapine. In terms of type of polypharmacy combination of typical and atypical agents being the most common, seen in 60.8% (31/55) of cases. Mean delay in starting of clozapine was 1.93 (1.82) years and the median was 1.5 years. There was no difference in the mean delay in starting of clozapine in those with or without comorbid diabetes mellitus [mean 2.16 (S.D. 1.40) versus mean 1.91 (S.D. 1.83); t value 0.43; p ¼0.66], epilepsy [mean 1.91 (S.D. 1.82) versus mean 2.51 (S.D. 1.40); t value 0.56; p¼ 0.57] or hypertension [mean 1.94 (S.D. 1.82) versus mean 1.20 (S.D. 1.02); t value 0.90; p ¼0.36]. The mean dose of clozapine used was 278.63 (S.D. 103.02) with a range of 75–700 mg/day. 3.1. Factors associated with delay in starting clozapine There was significant positive correlation of duration of delay of starting clozapine with age (Pearson's correlation coefficient 0.199; p ¼0.005) and duration of illness (Pearson's correlation coefficient 0.318; p o0.001). When those aged up to 20 years, were compared with those aged more than 20 years, mean duration of delay of starting clozapine was more for the later group [mean 0.91 (S.D. 1.05) versus 2.05 (1.86); Mann Whitney U value 1065; po 0.001].
Significant delay in starting clozapine was seen with use of polypharmacy [mean 2.58 (S.D. 2.06) versus 1.68 (1.67); t-test value 3.21; p ¼0.002], use of an adequate trial of typical antipsychotic medication [mean 2.27 (S.D. 2.04) versus 1.37 (1.21); Mann Whitney U value – 3458.5; p¼ 0.002], urban locality [mean 2.11 (S.D. 1.98) versus 1.37 (S.D. 1.11); Mann Whitney U value 3058; p¼ 0.038] and those who had onset of illness prior to introduction of clozapine in India [mean 2.96 (S.D. 2.56) versus 1.76 (1.62); Mann Whitney U value 1601; p ¼0.005]. There was no difference in the duration of delay between patients of either gender, family income, with and without physical or psychiatric comorbidity.
4. Discussion To the best of our knowledge, this is the first study assessing the delay in initiation of clozapine from a developing country and it adds to the available literature. The sample size of the study was 200, which is larger than some of the previous studies on this topic (Taylor et al., 2003; Howes et al., 2012; Najim et al., 2013). Compared to the findings of the previous studies, present study suggests that in a tertiary care centre in Indian setting the mean delay in starting of clozapine is 1.93 years. Studies from the developed countries suggest that the mean delay in starting clozapine varies from 2.8 to 6.3 years (Taylor et al., 2003; Harrison et al., 2010; Howes et al., 2012; Najim et al., 2013; Wheeler et al., 2014). However, the studies which have specifically evaluated the mean delay in starting clozapine during the period of 2011–2013, suggest that the mean duration of delay is only 1 year (Wheeler et al., 2014). When we compare our findings with
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Table 2 Pre-clozapine treatment profile of patients (N ¼ 200). Variable
Mean (S.D.)/N (%)
Setting of starting clozapine Inpatient Outpatient Indication for starting clozapine Treatment resistance Treatment resistanceþ EPS EPS Othersa Mean number of antipsychotic exposures Number of adequate antipsychotic trials 1 2 3 Z4 No. of patients who received at least one adequate typical antipsychotic trial No. of patients who received at least one adequate atypical antipsychotic trial No. of patients who received polypharmacy Polypharmacy combination Atypicals only Typical þ atypical Typicals only Duration of polypharmacy (weeks) Delay in starting clozapine No delay o 3 months 3–12 months 1–3 years 3–5 years 45 years Mean number of adequate trials Delay in starting clozapine Mean dose of clozapine used Clozapine dose categories Upto 100 mg/day 101–200 mg/day 201–300 mg/day 301–400 mg/day 401–500 mg/day 501–600 mg/day 6.1–700 mg/day
151 (75.5%) 49 (24.5%) 171 (85.5%) 16 (8%) 2 (1%) 11 (5.5%) 3.31 (1.39) 16 (8%) 60 (30%) 57 (28.5%) 67 (33.5%) 124 (62%) 195 (97.5%) 55 (27.5%) 21 (10.5%) 31(15.5%) 3 (1.5%) 45.81 (56.48) [range 6–312] 9 17 53 83 24 14 3 (1.18) [range 1–7] 1.93 (1.82) [range 0–10.69] 278.63 (103.02) [range 75–700] 4 (2%) 53 (26.5%) 92 (46%) 32 (16%) 11 (5.5%) 7 (3.5%) 1 (0.5%)
a The others category basically applied to those patients who had received one adequate trial and the second adequate trial was shorter than the 6 weeks duration.
the previous studies it appears that the mean duration is shorter in our setting and is comparable to that reported for recent years from developed countries. Various reasons could be thought for these developed. First, some of the studies from the developed countries have included patients prior to introduction of clozapine (i.e., 1991). In contrast to our study, only very few patients had an onset of illness prior to introduction of clozapine in this country. Second, findings of the present study reflect only the prescription of clozapine confined to one tertiary care academic centre. In contrast, many studies from the west have evaluated the records of the patients attending the primary health care services or community psychiatry hospital (Howes et al., 2012; Najim et al., 2013; Wheeler et al., 2010, 2014), with few patients from tertiary care centres forming the part of the study cohort (Howes et al., 2012; Najim et al., 2013). Third, in some of our patients, clozapine was started before completion of the 2 adequate trials. Accordingly this could have influenced the mean duration of delay. The available treatment guidelines for management of schizophrenia recommend the use of clozapine after two failed trials with antipsychotic agents (either typical or atypical) (Taylor et al., 2010; Moore et al., 2007b; Buchanan et al., 2010; Barnes, 2011). Despite such recommendations and the overwhelming evidence of clozapine effectiveness, prescribing of clozapine appears to be low, delayed and often preceded by attempts at polypharmacy treatment, which lacks clinical evidence of effectiveness. In our study,
the mean number of adequate antipsychotic trials were 3 (1.18), this is in the reported range of 2.8–4.3 from the developed countries (Taylor et al., 2003; Wheeler et al., 2014). When we look at the adherence to the recommendations of the treatment guidelines, in the present study in only 38% of patients the prescribing pattern was in accordance to the recommendations of the guidelines. In three-fifth of the patients clozapine was considered after 3 or more adequate trials. These findings suggest that there is a need to change the prescribing habits to reduce the delay in starting of clozapine. However, it must be remembered that in few cases the delay in starting clozapine could have been possibly due to delay in contacting our treatment services, as all the patients were not on treatment from our centre since the beginning of their illness. However, this data was not coded specifically. Polypharmacy though discouraged by evidence based guidelines is commonly practiced. The rates of polypharmacy of atleast 6 weeks duration in the in the present study was 27.5% which is slightly less than the 36.2–65% reported in patients considered for clozapine in studies from the west (Taylor et al., 2003; Howes et al., 2012). Polypharmacy in psychiatry and in particular with regard to antipsychotics has manifold risks like increased side effects with limited clinical benefit (Ballon and Stroup, 2013). Accordingly there is a need for wider dissemination of knowledge about the risks benefit of polypharmacy over and above a single agent in adequate dose.
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Present study suggests that there is longer delay in starting of clozapine for those with higher age, longer duration of illness, in those aged more than 20 years of age, those who receive polypharmacy, with use of an adequate trial of typical antipsychotic medication, those from urban locality and in those with onset of illness prior to introduction of clozapine into Indian market. However, it is important to note that certain factors like higher age, longer duration of illness and age more than 20 years may be interrelated factors and should not be considered as independent factors. There was no difference in the duration of delay between patients of either gender, family income, with and without physical or psychiatric comorbidity. Studies from the developed countries also suggest longer duration of illness (Howes et al., 2012) and patients diagnosed with illness before the introduction of clozapine (Taylor et al., 2003) to have longer delay in starting of clozapine. Use of polypharmacy as a factor responsible for delay can be understood from the fact that the mean duration of polypharmacy in the present study was 45.81 weeks, which is responsible for about half of the duration of delay in starting clozapine. Association with receiving at least one adequate typical trial possibly suggests that such a decision must be weighted in terms of benefits and the risks of introduction of clozapine. Relationship with urban locality possibly suggests that patients from urban locality are more apprehensive about the side effects of clozapine and due to this possibly there is a delay in starting clozapine. However, this could also be due to other factors, such as availability of more psychiatrists and doctor shopping that is highly prevalent in Indian setting. The present study has certain limitations. It followed a retrospective study design and the information was obtained as available from case records. Accordingly, it is quite possible that some of the details could have been missed, if not documented properly. We did not evaluate the association of delay of clozapine with various other clinical factors like long term medication compliance, treatment adherence behaviour, duration of seeking treatment from other sources, hospitalization, severity of illness etc. Some of these factors can have significant influence on the clinician's judgement to consider or not to consider clozapine in a particular patient. The present study was limited to a tertiary care centre and does not reflect the clozapine prescription practices in India per se because there is lot of heterogenicity in prescription practices. We also did not specifically assess the delay in starting clozapine while the patient was seeking treatment at our centre and delayed due to adhering to other treatment centres. To conclude, the present study suggests that there is a delay of about 2 years in starting of clozapine and in terms of starting of clozapine, in only 38% of cases, recommendations of treatment guidelines are adhered too. A significant duration is lost because of use of polypharmacy. Accordingly there is a need to increase the awareness among clinicians to reduce the practice of irrational polypharmacy. Clinicians should always consider the pros and cons of using polypharmacy or withholding clozapine in a particular patient.
Funding None. Conflict of interest None. Acknowledgement None.
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