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CLOZAPINE IN THE ACUTE MANAGEMENT OF TREATMENT RESISTANT SCHIZOPHRENIA : AN EXPLORATORY CLINICAL STUDY

Amresh Shrivastava1,Megan Johnston2,Avinash De Sousa3,Sushma Sonavane4Nilesh Shah5

1 Department of Psychiatry, Elgin Early Intervention Program for Psychosis, The University of Western Ontario, Ontario, Canada, and Mental Health Resource Foundation, Mumbai, Maharashtra, India.

2 Department of Psychology, University of Toronto, 100 St. George, Toronto, Ontario, Canada.

3 Research Associate4, Professor, Professor and Head

3,4,5 Department of Psychiatry, Lokmanya Tilak Municipal Medical College, Mumba

 

Abstract

Background:TRS’/ treatment resistant schizophrenia or ‘refractory schizophrenia’ define as a result of lack of compliance, and some authors argue that it suggests ‘nothing can be done’, embedding the notion that the patient is resisting the treatment, rather than the illness itself is resistant to treatment, and it has been suggested that the term for ‘incomplete recovery’ be used instead of ‘treatment refractory’

Objective: Clozapine is the drug of choice for treatment resistant schizophrenia. Clozapine is known to be efficacious in both positive and negative symptoms as well is known to improve suicidality and social behaviour in schizophrenia.

Methodology: A total of 100 patients with DSM IV schizophrenia and Kane criteria treatment resistant schizophrenia who were acutely hospitalized were recruited. Psychiatrists administered the Clinical Global Impression – Severity (CGI-S), Positive and Negative Symptom Scale for Schizophrenia (PANSS), Hamilton Depression Rating Scale (HDRS) and Global Assessment of Functioning (GAF) scales while changes from baseline to end point were measured. Statistical analysis using SPSS was performed.

Results: 57% patients completed the study and out of this group 38% showed clinical improvement. The changes for both positive and negative symptom scores were significant (p<0.0001). No differences existed between completed and drop out cases while 61.4% cases had at least one side effect. .

Conclusion:Our results suggest that clozapine is safe and effective in treatment resistant schizophrenia though further studies determining dose related response are needed as well studies that monitor plasma clozapine levels.

Key words: Clozapine, treatment resistant schizophrenia, schizophrenia.

Introduction

About 2/3 of patients of schizophrenia either do not respond to antipsychotics or become resistant to treatment. Much of the burden of schizophrenia is due to chronic state, nonresponse and functional decline.1 Clozapine remains the treatment of choice for such patients and has been consistently shown to be more effective than other atypical as well as typical antipsychotics particularly in negative symptoms and to some extent in cognitive symptoms.2 It has been shown to improve the level of functioning and quality of life and it also reduces the burden of the disease in many patients.3 A recent study suggests that Clozapine delays hospitalization in patients with treatment resistant schizophrenia if they are started on clozapine in the community or successfully discharged from hospital following their index admission.4 Clozapine further has also been shown to reduce suicidality in patients with schizophrenia.5 Despite good efficacy its remains highly under-utilized medication, primarily because of range of life threatening and other side effects and difficulties in frequent blood monitoring.6

In an evidence based review, authors highlighted several limitations in studies conducted in India about clozapine citing that most of the studies were    open-labelled, retrospective chart reviews, or case reports from a total sample of approximately 500 subjects. Despite such limitations the review concluded that    clozapine leads to significant improvement in patients having history of poor response to other antipsychotics.7 The present study was undertaken in a prospective naturalistic design to examine the efficacy and side effects of clozapine in treatment resistant schizophrenia in patients who were hospitalized due to a relapse.

Methods and materials

We carried out   an open level naturalistic study of 3 months follows up in non-governmental psychiatric hospital in Mumbai. We enrolled 100 DSM-IV criteria8 diagnosed schizophrenia patients who also met treatment resistant’s schizophrenia as per Kane’s criteria9 and were hospitalized in an acute state. The inclusion criteria were diagnosis of schizophrenia as per DSM-IV criteria, age between 18-45 years, treatment resistant state and hospitalization in an acute state. Exclusion criteria were pregnancy, presence of current or history of organic mental disorder, neurological conditions, cardiac or metabolic disease or presence of seizures or head injury.   Local ethics committee approved the study. Consenting patients were recruited after discussion about risk, benefits, procedure and cost involved from a sample of an ongoing long term follows up study of first episode schizophrenia. Blood test and ECG was done and all patients were medically cleared. The study design was a treatment as usual (TAU). All patients were paying for their care in this private set-psychiatric centre. Clinical assessment was done using Clinical Global Impression of Severity Scale10, Positive and Negative Symptom Scale for Schizophrenia (PANSS)11, Hamilton Depression Rating Scale (HDRS)12, Global Assessment of Functioning (GAF)8 and a side effect checklist at the base and endpoint of 12 weeks treatment. Clozapine was initiated with a dose of 25 mg per day and increased by 25 mg every 4th or 5th day, with weekly blood count monitoring for the first 4 weeks and thereafter once in 2 weeks and followed up every 2 weeks after discharge.   Outcome criteria was improved and much improved CGIS score of =/< 2. Data was recorded and analyzed using SPSS software.

Results

We recruited 100 patients and 43 dropped out during 12 weeks treatment. Out of the 57 who continued 27 patients recovered as per CGIS criteria. Majority of patients in this study were predominantly male (83%), young, married (50%) and educated. Sample characteristics (Table 1) shows that the duration of illness was 30 months, 59% had either current or past suicide ideation or  history of attempt, 30% subjects had shown violent behavior, 37% had substance abuse, only 18% were never hospitalized, 14% had comorbidity of on both axis I and II. This short term 12 weeks study found  that 38% (27/57) showed  improvement as per CGIS Criteria. There was significant reduction in the total scores of PANSS (p<0.001), positive symptoms (p<0.001) and negative symptoms (p<0.001) from baseline to endpoint (Table 2). The patients who improved did not differ on any base line characteristics from drop out patients (Table 3). 57% patients did not discontinue the treatment. Out of these 35 (61.4%) subjects experienced at least one side effect. In a number of patients additional add-on drug was prescribed, commonest being benzodiazepines in 50%, and trihexyphenidyl in 33% cases (Table 4).

Discussion

A number of studies have confirmed clinical superiority of clozapine in comparison to conventional as well as atypical antipsychotics.13 The sample characteristics appear to what has been generally reported in the literature14 except the duration of illness which was relatively shorter (30 months). Relatively shorter duration of illness observed in our study is not surprising which appears to be related to growing awareness about mental illnesses and increased access to care, patients are reporting relatively earlier for treatment, particularly in urban and metropolis regions.15-16 Clozapine response has generally been from 30-60% the main characteristic has been the quality of response.17 The present study shows improvement in 38% amongst the patients who continued treatment. A number of studies from India and other regions have shown almost similar rate of recovery.18  Authors have found a recovery in 50% subjects in 20 months with no gender differences were seen in the response rate, significant improvement was seen  in an the urban population in India.19 Good response to clozapine has been consistently shown, particularly amongst the resistant patients.

However response around 40% has also been substantially documented.20 Recovery in 38% is relatively low which may partially be due to shorter duration of follow up. Clozapine response is time-specific and incremental response is relatively faster in first 6 months.21 In a one-year follow up comparative study on clozapine versus haloperidol, researchers showed that the  response as defined by more than 20% reduction in PANSS total, score was 27.1% at 6 weeks, 23.4% at 3 months, and 24.7% at 6 months.22 Our study also showed significant reduction (46.52) in psychopathology as per >20% reduction in PANSS total score in 3 months duration which is also similar to what has been reported earlier.23-24 Authors evaluated the short term and long term effectiveness of clozapine in 51 subjects and reported that during the inpatient stay (mean duration 63 days), there was 34.7% reduction in total PANSS rating after starting clozapine at a mean dose of 298.97 mg/day.25

Early introduction of clozapine is now being recommended in guidelines (Texas) though in general there is scepticism. Though clozapine has been used in first episode psychosis, several authors have questioned whether clozapine should be indicated as a first-line treatment for early psychosis.26-27 A recent meta-analysis28 has shown poor response to clozapine but those studies had definite limitations of using low dosage. A moderate level of response in our study may be due to shorter time period and the nature of illness. Though moderate dosage of clozapine was used, dose response relationship in Indian studies remains undetermined.

In this study recovered and unrecovered patients did not significantly differ on any psychopathological parameter like that of age, gender, duration of illness, sub-types of schizophrenia, baseline glucose and triglyceride except baseline weight, A number of other studies have reported a correlation between baseline parameters and clinical recovery.29

One of the landmark studies from Asian countries comparing pattern of clozapine usage showed that patients taking clozapine were significantly younger, had a higher dose of antipsychotic drugs in chlorpromazine equivalents, were more likely to be female, had fewer extrapyramidal symptoms, and had more negative symptoms, admissions and weight gain in the past month than those not receiving clozapine.30 However such differences were not seen in  our study, possibly because of small sample size which could be because  expected predictors were not studied. Most consistent clinical predictor for clozapine response has been extrapyramidal symptoms at baseline31, negative symptoms32, paranoid subtype33 and comorbid substance abuse also indicate faster response.34

A number of patients during the course of treatment do require additional medication either for a side effect, for treatment of different symptoms, delayed response or comorbid conditions. Use of another antipsychotic is common across all antipsychotics leave alone clozapine for treatment of symptoms like anxiety, depression, agitation, sleeplessness, etc. Studies have reported the tendency to combine antipsychotic medications as beneficial for patients, particularly in terms of reducing positive symptoms.35 In a sample of over 70,000 patients regularly receiving antipsychotics, 13.9% were receiving a combination of antipsychotics, and 6.6% of these combinations included clozapine.36 The high rates of combination may be due to late response, distressing symptoms, even from physicians’ preference or undue expectation of symptom remission due to need for early discharge in set-up where patient is paying for the facility.

Daily dose of psychotropic medications are generally lower in India due to ethnic variations, further these patients are also sensitive to a number of side effects in general, leave alone clozapine. In a study although Asian patients received a significantly lower mean clozapine dose (176 mg/day) than the Caucasian group (433 mg/day, P<0.001), plasma clozapine levels were similar between the groups. As a result, Asian patients had more than twice the effective clozapine concentration to dose ratio (P<0.001). The findings remained significant even after controlling for gender, body mass index, cigarette, alcohol and caffeine use.37 In a national survey of prescribing pattern in India average dose among the stabilized schizophrenia patients was reported to be 50 mg by 12%, 75–100 mg by 25%, 150 mg by 23%, 150–300 mg by 24% and more than 300 mg by 14% doctors. About 50% physicians reported effective dose between 150 and 300 mg per day. It is noteworthy that 37% physicians find effective response in symptoms at a dose of 50, 75, and 100 mg per day also. Low-dose maintenance is an interesting finding, which needs confirmation and further study.38

In this study 43% patients dropped out, there was no significant difference between baseline characteristics of those who continues and those who did not. A drop out of 66% at the end of 13 weeks was reported in a study for acute treatment of the first episode of schizophrenia or schizoaffective disorder this was comparable to conventional antipsychotic in one of the previous study.39 Contrarily wheeler reported a Low clozapine discontinuation rates, which was associated with real-world improvements in functional and clinical outcomes.  Further Clozapine was less likely to be withdrawn because of ineffectiveness. Of late all-cause discontinuation has been considered as an outcome criteria.40 Despite the wide range of side effects and complications, clozapine remains the gold standard medication in patients with treatment resistant schizophrenia. Clozapine has affinity for several different receptors, and it may thus elicit a wide range of side-effects, some of which can be as potentially life threatening. Metabolic side effects and weight gain continues to be main challenge in prescribing of clozapine. At number of times a patients who are recovering well have to be withdrawn due to potentially serious side effects like myocarditis, agranulocytosis or seizures.41

We did not find any unreported or unusual side effects. Appearance of high incidence of side effects in short term treatment is particularly significant   particularly when none of these patients were on complex polypharmacy. It is likely that presence of comorbidity, substance abuse and individual sensitivity, particularly in younger population, might be responsible.42

Clozapine is useful in treatment resistant schizophrenia but studies in diverse populations across various groups shall help us understand the parameters that affect efficacy and faster response better. We need further studies that look at older versus younger subjects while also determining a dose related response to Cloazpine. Studies that monitor plasma clozapine levels in Asian patients and their comparison to international data are warranted.

References

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15.     Glick ID, Correll CU, Altamura AC, Marder SR, Csernansky JG, Weiden PJ, Leucht S, Davis JM. Mid-term and long-term efficacy and effectiveness of antipsychotic medications for schizophrenia: a data-driven, personalized clinical approach.J Clin Psychiatry. 2011;72(12):1616-1627.

16.     Shrivastava A, Shah N, Johnston M, Stitt L, Thakar M, Chinnasamy G. Effects of duration of untreated psychosis on long-term outcome of people hospitalized with first episode schizophrenia. Indian J Psychiatry. 2010;52(2):164-167.

17.     Shrivastava A, Shah N. Pattern of clozapine usage in clinical practice: an opinion survey of psychiatrists. Indian J Psychiatry. 2009;51:225-226. 

18.     Thirthalli J, Channaveerachari NK, Subbakrishna DK, Cottler LB, Varghese M, Gangadhar BN Prospective study of duration of untreated psychosis and outcome of never-treated patients with schizophrenia in India. Indian J Psychiatry. 2011;53(4):319-323.

19.     Conley RR, Buchanan RW. Evaluation of treatment-resistant schizophrenia. Schizophr Bull. 1997;23:663–674.

20.     Taylor DM, Duncan-McConnell D. Refractory schizophrenia and atypical antipsychotics. J Psychopharmacol. 2000;14:409–418.

21.     Perkin DO. Clinical trials in schizophrenia with results for the real world. CNS Spectr. 2006;11:9–13.

22.     McEvoy JP, Liberman JA, Stroup TS, Davis SM, Meltzer HY, Rosenheck RA, et al. Effectiveness of clozapine versus olanzapine, quetiapine and risperidone in patient with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry. 2006;163:600–610.

23.     Stroup TS, McEvoy JP, Swartz MS, Byerly MJ, Glick ID, Canive JM. The national institute of mental health clinical antipsychotic trials of intervention effectiveness (CATIE) project: Schizophrenia trial design and protocol development. Schizophr Bull. 2003;29:15–31.

24.     Agid O, Arenovich T, Sajeev G, Zipursky RB, Kapur S, Foussias G, Remington G. An algorithm-based approach to first-episode schizophrenia: response rates over 3 prospective antipsychotic trials with a retrospective data analysis. J Clin Psychiatry. 2011;72(11):1439-1444.

25.     Dutt A, Grover S, Chakrabarti S, Kulhara P, Avasthi A, Basu D, et al. Effectiveness of Clozapine: A study from North India. Asian J Psychiatry. 2010;3:16-19. 

26.     Raja M. Clozapine safety, 35 years later. Curr Drug Saf. 2011;6(3):164-184.

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28.     Szymanski S, Masiar S, Mayerhoff D, Loebel A, Geisler S, Pollack S. Clozapine response in treatment-refractory first-episode schizophrenia. Biol Psychiatry. 1994;35:278–280.

29.     Hector RI. The use of clozapine in the treatment of aggressive schizophrenia. Can J Psychiatry. 1998;43:466–472.

30.     Green AI, Schildkraut JJ. Should clozapine be a first-line treatment for schizophrenia? The rationale for a double-blind clinical trial in first-episode patients. Harv Rev Psychiatry. 1995;3:1–9.

31.     Lerner V, Libov I, Kotler M, Strous RD. Combination of "atypical" antipsychotic medication in the management of treatment-resistant schizophrenia and schizoaffective disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28(1):89-98.

32.     Goyal N, Praharaj SK, Desarkar P, Nizamie H. Electroencephalographic abnormalities in clozapine-treated patients: a cross-sectional study. Psychiatry Investig. 2011;8(4):372-376.

33.     Ng CH, Chong SA, Lambert T, Fan A, Hackett LP, Mahendran R, Subramaniam M, Schweitzer I. An inter-ethnic comparison study of clozapine dosage, clinical response and plasma levels. Int Clin Psychopharmacol. 2005;20(3):163-168.

34.     Tang Y, Mao P, Li FM, Li W, Chen Q, Jiang F, Cai Z, Mitchell PB. Gender, age, smoking behaviour and plasma clozapine concentrations in 193 Chinese inpatients with schizophrenia    Br J Clin Pharmacol. 2007;64(1):49–56.

35.     Couchman L, Maccabe JH, Flanagan RJ  Bowskill S. Plasma clozapine and norclozapine in relation to prescribed dose and other factors in patients aged 65years and over: data from a therapeutic drug monitoring service, 1996-2010., Hum Psychopharmacol. 2012;27(3):277-283.

36.     Solanki RK, Singh P, Swami MK. Clozapine: Current perspective. Indian J Psychiatry. 2007;10:271-276.

37.     Yagcioglu AE, Kivircik BB, Turgut TI, Tümüklü M, Yazici MK, Alptekin K. A double blind controlled study of adjunctive treatment with risperidone in schizophrenic patient partially responsive to clozapine: Efficacy and safety. J Clin Psychiatry. 2005;66:63–72.

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39.     Umbricht DS, Wirshing WC, Wirshing DA, McMeniman M, Schooler NR, Marder SR, Kane JM.Clinical predictors of response to clozapine treatment in ambulatory patients with schizophrenia.              J Clin Psychiatry. 2002;63(5):420-424.

40.     Krivoy A, Malka L, Fischel T, Weizman A, Valevski A. Predictors of clozapine discontinuation in patients with schizophrenia. Int Clin Psychopharmacol. 2011;26(6):311-315.

41.     Pai NB, Vella SC. Reason for clozapine cessation. Acta Psychiatr Scand. 2012;125(1):39-44.

42.     Alvir JM, Lieberman JA, Safferman AZ, Schwimmer JL, Schaaf JA. Clozapine-induced agranulocytosis. Incidence and risk factors in the United States. N Engl J Med. 1993;329(3):162–7.

 

 

Table 1 – Baseline characteristics

 

 Demographics

Values (baseline N = 100)

Age -- Mean (SD)

33.12 (6.71)

Male

83

Female

17

Education

 

       Up to 10th standard

15

       Up to 12th standard

18

       Semiskilled

25

       University

20

       Semi-professional

13

       Professional

09

Marital status

 

       Single

42

       Married

50

       Divorced

08

Sample characterstics

 

       Number enrolled

100

       Completed study

57

       Dropped out

43

Duration of illness (months)

30.42 (8.36)

Type of Schizophrenia

 

       Disorganized Schizophrenia

22

       Paranoid Schizophrenia

22

       Schizoaffective disorder

19

       Undifferentiated Schizophrenia

21

       Residual Schizophrenia

16

Family History of Mental Illness

 

       No history

66

       In first degree relative

18

       In second degree relatives

16

Suicidality

 

       No history of suicide

41

       Past history of suicidal gesture

21

       Past history of  1 or 2 attempts

19

       Past history of > 2 attempts

12

       Currently Suicidal

7

Violence

 

        Past history of violent behaviour

30

        History of violence in this episdoe

20

Substance abuse

 

        No substance abuse

63

        Alcohol

12

         Cannabis

8

         Cannabis and alcohol

5

Previous Hospitalization

 

         Never

18

         Once

35

         Twice

38

         >2

8

Previous antipsychotic

1

2

Olanzapine

29

17

Quetiapine

27

38

Risperidone

16

22

Aripiperazole

16

10

Ziprasidone

11

13

Trifluperazine

1

00

Previous antipsychotics  (n)

 

One

 

Two

 

Three  or more

 

Comorbidity

 

        Axis 1

24

        Axis 2

14

        Axis 3

26

PANSS Total

101.78 (13.19)

PS

25.75 (3.98)

NS

26.88 (5.53)

HDRS

17.05 (3.99)

GAF

35.94 (10.32)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 2 – Change from the baseline in all values

 

 

Baseline

3 months

Reduction

(T1-T2)

p-value

Subjects

100

57

 43

 

Gender – male

83

52

-8.23%

 

CGIS <2

Mean (sd)

5.11 (0.86)

1.51 (0.51)

3.60

 <.001

CGIS   > 2

n (%)

100 (100%)

 35 (62%)

22 (38%)

<.001

PANSS total

101.78 (13.19)

54.43 (10.38)

47.35 (46.52%)

<.001

> 30% PANSS Reduction (n)

-

48 (84.21%)

 

 

PS

25.75 (3.98)

13.00 (4.33)

12.75 (49.51%)

<.001

NS

26.88 (5.53)

11.38 (3.94)

15.50 (57.66%)

<.001

GAF

Mean (sd)

35.94 (10.32)

52.73 (9.94)

-16.79 (-46.72%)

<.001

HDRS

17.05 (3.99)

 

 

 

Mean Dose

 

286.5

 

 

Discontinuation

 

33.09 (5.82)

 

 

Any side effect

 

35 (61.4)

 

 

FBS

(normal = 100)

111.95 (22.50)

139.49 (40.66)

 -27.54 (-24.60%)

<.001

Triglycerides (normal = 120)

114.75 (29.94)

172.50 (43.69)

-57.75 (-50.33%)

<.001

Weight  (Kg) (normal= 50kg)

59.30 (8.66)

63.64 (7.05)

-4.34 (-7.32%)

.002

 

 

 

Table 3 - Comparison of patients who continued treatment and who dropped out from treatment

Parameters

Total

Continued treatment

Dropped out from treatment

F Value /

χ2 value

P-Value

 

N

100

57

43

 

 

Age (years) Mean (sd)

33.12 (6.71)

33.14

 (7.36)

33.09

(5.82)

F = 0.001

p = .972

Gender: Male

83

(83%)

45

(54.2%)

38

(45.8%)

χ2  = 1.54

p = .214

 

Duration of illness (months) Mean (sd)

30.42 (8.36)

30.7

(8.36)

30.5

(8.44)

F = 0.149

p = .700

PANSS Total Mean (sd)

101.78 (13.18)

101.37 (13.58)

102.33

(12.77)

F = 0.128

p = .72

PANSS Positive symptoms Mean (sd)

25.75 (3.97)

25.33

(3.82)

26.3

 (4.14)

F = 1.46

p = .22

PANSS Negative symptoms Mean (sd)

26.88 (5.53)

26.35

(5.46)

27.58

(5.60)

F = 1.21

p = .27

HDRS – Mean (sd)

17.05 (3.99)

17.14

(3.99)

16.93

(4.04)

F = 0.067

p = .79

GAF – Mean (sd0

35.94 (19.31)

35.19 (10.14)

36.93

(10.58)

F = 0.69

p = .40

 

 

 

 

 

 

Table 4 - Major side effects

Variable

Male

(n = 49)

Female

(n = 8)

Total 57

X2(df)

 Sialorrhea

15 (30.6%)

4 (50.0%)

19 (33.3%)

 1.16 (1)

 ANC <1500

3 (6.1%)

1(12.5%)

4(7.0%)

0.43(1)

Abnormal EKG

3 (6.1%)

0 (0.0%)

3 (5.3%)

0.52(1)

Sedation

7 (14.3%)

0 (0.0%)

7 (12.3%)

1.30 (1)

Myoclonic Jerks

2 (4.1%)

1(12.5%)

3 (5.3%)

0.98 (1)

Seizure

0 (0.0%)

1 (12.5%)

1 (1.8%)

6.23 (1)

                                             

  Age                                            

 

 

Age < 35, (n = 32)

Age >35

(n =25)

Total  57

X2(df)

 Sialorrhea

10 (31.3%)

9 (36.0%)

19 (33.3%)

0.14 (1)

 ANC <1500

2 (6.3%)

2 (8.0%)

4 (7.0%)

0.07 (1)

Abnormal EKG

3 (9.4%)

0 (0.0%)

3 (5.3%)

2.47 (1)

Sedation

4 (12.5%)

3 (12.0%)

7 (12.3%)

0.003 (1)

Myoclonic Jerks

2 (6.3%)

1(4.0%)

3 (5.3%)

0.14 (1)

Seizure

0 (0.0%)

1 (4.0%)

1 (1.8%)

1.30 (1)