INTRODUCTION:

Antipsychotic polypharmacy has risk of adverse events¹, high cost², metabolic syndromes³, and decreased patient’s adherence.⁴ Most treatment guidelines follow antipsychotic monotherapy as first line treatment.^5-7 In real clinical practice antipsychotic polypharmacy is very common, polypharmacy rates (4.1-48.0%) has been found in previous studies.^2,8-12.

The available pharmacological treatments and treatment guidelines are still far from meeting all the needs in the management of schizophrenia indicated by high rates of polypharmacy.¹² In spite of high efficacy of Second Generation Antipsychotics clinicians often attempt experimental use of high dose First Generation Antipsychotics, antipsychotic polypharmacy in clinical practice hoping for early and robust responses in patients with severe symptoms.¹³ There was also a significant increase in patients receiving antipsychotic polypharmacy across a decade.¹⁴ Thus, the study aimed with a particular focus on antipsychotic polypharmacy and the combination of atypical antipsychotics with other psychotropic drugs in India.

METHODOLOGY:

The study was a prospective medical record review conducted at the Department of Psychiatry at Kasturba Hospital, Manipal, a 1472 bed hospital. Following a standard protocol all the 139 schizophrenic Patients admitted in Psychiatry ward. A written informed consent in local language (Kannada and Malayalam) and English was obtained from the patient or care providers. The Cases of schizophrenia were identified and data on treatment pattern were collected from medical records.

RESULTS:

Antipsychotic monotherapy and Combination Therapy

Table 1: The rates of antipsychotic monotherapy and combination therapy

Antipsychotic monotherapy and Combination Therapy	Patients (n=139)
Antipsychotic monotherapy	96 (69.06)
Antipsychotic combination therapy (2 Antipsychotics)	40 (28.77)
Antipsychotic combination therapy (3 Antipsychotics)	3 (0.007)
Total	139

A total of 139 schizophrenic patients were enrolled in the study. Antipsychotic monotherapy was observed in 96(69.06) patients, while 40(28.77) were prescribed two antipsychotics and 3(0.007) were prescribed three antipsychotic drugs. In total 43 (30.93) patients received combination therapy.

Demographic Profile:

As shown in Table 2 most of the patients who received monotherapy were males 59(42.45%) patients and 37 (26.62%) patients were females. 26(18.71) males and 17(12.23) females received combination therapy. The male to female ratio was found to be 1.46: 1. The average age among the patients was 34.44±11.94 years. Age distribution showed that higher numbers of patients belonged to the age group 21-30 years. In the present study it was observed that majority of the males belonged to the lower age group of less than 40 years while females dominated in higher age group of more than 40 years. In the monotherapy group 39(28.06) patients were married and 57(41.01) patients were single. In combination therapy group 18(12.95) were married and 25(17.99) were single.

The average length of hospital stay for all the 139 patients was 12.37±8.4 days with a minimum period of one day to a maximum of 46 days. Distribution of patients according to the Outcome at discharge shown that majority of the patients were ‘Improved’, 128(92.09 %) patients. 10(7.19%) patients were unchanged during the time of discharge and one patient recovered at the time of discharge.

Table: 2 Sociodemographic profile of study sample (n = 139)

	Monotherapy (n = 96)	Combination Therapy (n=43)
Age Group (in years)
< 20	12 (8.63)	6 (4.32)
21 - 30	41 (29.50)	18 (12.95)
31 - 40	21 (15.11)	9 (6.42 )
41 - 50	11 (7.91)	4 (2.88 )
51 - 60	9 (6.47)	4 (2.88 )
61 - 70	1 (0.72)	1 (0.72 )
> 70	1 (0.72)	1(0.72 )
Gender wise distribution
Males	59 (42.45 )	26 (18.71 )
Females	37 (26.62 )	17 (12.23 )
Marital Status
Married	39 ( 28.06)	18 (12.95 )
Single	57 ( 41.01)	25 ( 17.99)

ICD 10 Sub Class wise Distribution Pattern:

As shown in Table 3 F20.0 Paranoid Schizophrenia received maximum prescriptions for monotherapy 60(43.17) and combination therapy 26(18.71) where as for F20.6 Simple Schizophrenia there were no patients in both groups.

Table 3: ICD 10 Sub Class wise Distribution Pattern n = 139

ICD Code	ICD – 10 Sub Class	Monotherapy (n = 96)	Combination Therapy (n=43)
F20.0	Paranoid Schizophrenia	60 (43.17)	26 (18.71)
F20.1	Hebephrenic Schizophrenia	1 (0.72 )	1 (0.72)
F20.2	Catatonic Schizophrenia	6 (4.32)	3 (2.16)
F20.3	Undifferentiated Schizophrenia	21(15.11)	8 (5.76 )
F20.5	Residual Schizophrenia	3 (2.16 )	2 (1.44 )
F20.8	Other Schizophrenia	1 ( 0.72)	0 (0.00 )
F20.9	Unspecified Schizophrenia	3 (2.16 )	2 (1.44 )
F20.4	Post Schizophrenic Depression	1 (0.72 )	1 (0.72 )
F20.6	Simple Schizophrenia	0 ( 0.00)	0 (0.00 )

Comparison of adjunct medication used for schizophrenia between antipsychotic monotherapy and combination therapy:

As shown in Table 4 Anxiolytics 55(37.99) and Anticholinergics 54(37.29) in monotherapy group and combination therapy group 24(17.26) received maximum prescriptions where as Mood Stabilizers received minimum prescriptions 12(8.29) for monotherapy and 6 (4.32) for combination therapy

Table 4: Comparison of adjunct medication used for schizophrenia between antipsychotic monotherapy and combination therapy

Adjunct Drugs	Monotherapy (n= 96)	Combination Therapy (n = 43)
Mood Stabilizers	12 (8.29)	6 (4.32)
Antidepressants	19 (13.12)	8 (5.76)
Anticholinergics	54 (37.29)	24 (17.26)
Anxiolytics	55 (37.99)	24 (17.26)

Prescription pattern of Antipsychotics with Anxiolytics Antidepressants Mood Stabilizers and Anticholinergics:

As shown in Table 5 among anxiolytics tab lorazepam was prescribed maximum 68(48.92%) patients. tab flurazepam and tab alprazolam was prescribed minimum only one patient. Among antidepressants tab fluoxetine and tab setraline was prescribed maximum both 7 (5.04%) patients. tab velnlafaxine, tab dosulepin, tab mirtazapine, tab bupropion and tab seligilin was prescribed minimum1 (0.72%). Among mood stabilizers lithium was prescribed maximum, for 6(4.32%) patients and topiramate was prescribed minimum (1.44%). Among anticholinergics tab benzhexol was prescribed maximum in 78(56.12%) patients after that inj promethazine was prescribed mostly for 12(8.63%) patients. tab metaclopromide and tab procyclidine was prescribed minimum one patient.

Combination of antipsychotics

A total of 96 (68.09%) patiens were on monotherapy. In combination therapy most patients were in the combination SGA + FGA and a total of 29 patients (20.86%) received this combination. A total of 15 (10.79%) patients SGA + SGA. The combination of FGA + FGA was the least combination used only one patient received this combination. Details are described in table 6.

Table 6: Combination of antipsychotics (n = 139)

SGA + SGA	15 (10.79)
FGA + FGA	1 (0.71)
SGA + FGA	29 (20.86)

*SGA – Second Generation Antipsychotic

*FGA – First Generation Antipsychotic

Combination of SGA + SGA.

A total of 15 patients received combination of SGA + SGA. Maximum (3) patients received the combination clozapine + aripiprazole. The combination of olanzapine + ziprasidone, resperidone + clozapine were observed in 2 patients. The combination of olanzapine + resperidone, resperidone + quetiapine, olanzapine + aripiprazole, clozapine + quetiapine, clozapine + ziprazidone were seen in one patient.

Combination of SGA + FGA.

A total of 32 patients received a combination of SGA + FGA. Maximum patienta (8) was in the combination haloperidol + resperidone followed by olanzapine + zuclopentixol among 7 patients. A total of 6 patients received resperidone + zuclopentixol and haloperidol + olanzapine. The combination of haloperidol + aripiprazole, chlorpromazine + olanzapine, clozapine + zuclopentixol, resperidone + chlorpromazine, resperidone + fluphenazine was observed in one patient each.

Combination of FGA + FGA.

Only one patient received combination of FGA + FGA and the combination was chlorpromazine + haloperidol.

DISCUSSIONS:

A total 43 (30.93) patients received combination therapy similar to study by Fourrier et al.¹⁵(1996) in France which showed 34.4 % received combination therapy and Centorrino et al.¹⁶ (1998) in USA showed that 43 % got combination therapy. A Study by Andor et al.¹⁷ has shown monotherapy for FGAs (68.4%) and combination (31.6%) while monotherapy for SGAs was (84.6%) and combination therapy (15.4%). Study by Burns et al.¹⁸ had shown 47.4% monotherapy 18.3% combination for FGAs and SGAs. Most of the patients who received monotherapy 59(42.45%) patients and combination therapy 26(18.71) were males. This observation is similar to a study by Dutta et al.¹⁹ carried out in the year 2003 in Uttaranchal, India and Andor et al.¹⁷ study in the year 2003 in Switzerland. The average age among the patients was 34.44±11.94 years, which is similar to other Indian studies by Chaudhary et al.²⁰(2004) in Assam and Padmavathi et al.²¹ study in Chennai. The present study is also supported by a study conducted by Meltzer et al.²²Age distribution showed that higher numbers of patients belonged to the age group 21-30 years as supported by Welham et al.²³ (1991) in Australia. In the present study it was observed that majority of the males belonged to the lower age group of less than 40 years while females dominated in higher age group of more than 40 years, similar to a study by Welham et al.⁶² which revealed a female predominance in the 40 – 50 age group.

Majority of the patients were unmarried in both the groups 57(41.01) in monotherapy group 25(17.99) in combination therapy group which is similar to studies by Mallinger et al.²⁴ New York and Rosenheck et al.²⁵(2006), whereas study in USA by Ren et al.²⁶ (1999) showed a higher percentage of unmarried patients (76.3%). Previous reports suggest that the percentage of schizophrenic patients, who get married, is usually lower than normal individuals or those with other psychiatric disorders. The low marital rates may be attributed to the poor pre-morbid adjustment impairing the development of relationships, social and occupational disability arising due to the illness, besides the clinical symptoms and early age of onset.^27-29,30 An association between mental illness and marital problems has been documented by Indian studies too. However a study from India reported that 70% of their first episode patients were married and 80% of the marriages were intact on follow up for up to 10 years.^31-33 Paranoid schizophrenia was the most prominent diagnosis among all sub classes. This is similar to studies by Dutta et al.¹⁹ (2003) in Uttaranchal India and Burns et al.¹⁸ (2000) in United Kingdom.

Augmentation therapy involves the addition of a nonantipsychotic drug to an antipsychotic drug. Several guidelines may be followed regarding augmentation. Augmentation should be used only in adequately responding patients and they are rarely effective for schizophrenic symptoms when used alone. Augmentation responders usually improve symptomatically. In the present study anticholinergics and anxiolytics were the major drug class which was prescribed most in combination with antipsychotics in 56.83% patients and 57.55% patients respectively. Acquaviva et al.³⁴study (2002) in France showed 32.9% prescriptions for anticholinergics which were less than our study but a study by Fourrier et al.¹⁵(1996) in France shows 86.1% prescription for anticholinergics and Ungavari et al.³⁵ (1996) study in Hong Kong shows 61.8 % which were higher than our study. Study by Fourrier et al¹⁵ showed 52.3% prescriptions for anxiolytics which was comparable to our study. Anticholinergics are routinely used to treat extrapyramidal symptoms that may occur in most patients’ receiving neuroleptic treatment.³⁴ Benzodiazepines are used for a variety of purposes in schizophrenia including anxiety, agitation, disruptive behaviour, motor disturbances and sometimes also for the augmentation of antipsychotic therapy to alleviate positive symptoms. Addition of a benzodiazepine to an antipsychotic may be as acceptable as antipsychotic monotherapy for people with schizophrenia. The effectiveness of benzodiazepines to calm acutely ill patients early in treatment has been documented.³⁶ Among anxiolytics tab lorazepam was prescribed maximum (48.92%) similar to study by Magliano et al.³⁷ in Italy (1998).

Use of combination of drugs can be due to a number of reasons. First, when a patient is improving poorly, a physician may add medications to what is currently prescribed; when the patient shows some improvement, the physician may be reluctant to change this regimen. Second, when changing medications, a physician noting an improvement while a new medication is being increased and an old medication decreased may stop the cross-titration and continue co prescribing both antipsychotic medications. Third, shorter hospital stays may increase pressure to hasten therapeutic response and create pressure for polypharmacy. Fourth, industry sponsored seminars may promote the use of one company's medication in combination with other medications. Fifth, clinicians may feel that different medications are better for different symptoms, even though the drugs are similar. Finally, busy doctors may be more inclined to prescribe multiple drug prescriptions than doctors who have more time and are under less pressure. Whatever the reason, the fact that combination has been shown across several studies to be a relatively common practice suggesting a need for research to determine whether the approach to treatment with two antipsychotic medications is warranted and, if so, under which circumstances.^38-39

In combination therapy most patients were in the combination second generation antipsychotics + first generation antipsychotics (SGA + FGA) in 20.86% of patients similar to study by Andor E etal.⁵⁰ which shows SGA + FGA was the most common combination but 59.1% got this combination which is more than our study. A total 10.79% patients received combination of SGAs which is similar to a study by Clark et al.⁴⁰ which received 12.4 % prescriptions for SGA. A total of 0.71% of patients received combination FGAs. Maximum patients had received a combination of haloperidol + resperidone (H + R) unlike a study by Mccque RE et al.⁴¹ which showed that haloperidol and olanzepine was the most frequently used combination

REFERENCE:

1. Centorrino F, Goren JL, Hennen J, Salvatore P, Kelleher JP, RJ. Multiple versus single antipsychotic agents for hospitalized psychiatric patients: case-control study of risks versus benefits. Am J Psychiatry. 2004; 161: 700-706.

2. Stahl SM, Grady MM. High-cost use of second-generation antipsychotics under California's Medicaid program. Psychiatr Serv. 2006; 57: 127-129.

3. Correll CU, Frederickson AM, Kane JM, Manu P. Does antipsychotic polypharmacy increase the risk for metabolic syndrome? Schizophr Res. 2007; 89: 91-100.

4. Fleischhacker WW, Uchida H. Critical review of antipsychotic polypharmacy in the treatment of schizophrenia. Int J Neuropsychopharmacol. 2012:1-11. [Epub ahead of print]

5. Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, et al; World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Treatment Guidelines for Schizophrenia. World Federation of Societies of Biological Psychiatry. (WFSBP) guidelines for biological treatment of schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World J Biol Psychiatry. 2012; 13:318- 378.

6. Lehman AF, Lieberman JA, Dixon LB, McGlashan TH, Miller AL, Perkins DO, et al; American Psychiatric Association; Steering Committee on Practice Guidelines. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161(2 Suppl): 1-56.

7. Ahn YM, Kwon JS, Bahk WM, Kim CE, Park JI, Lee SY, et al. The feasibility test of Korean medication algorithm for the treatment with schizophrenic patients (II): the problem for applying algorithm to the real clinical situation and opinion of revision. Korean J Psychopharmacol. 2006;17: 35-49.

8. Paton C, Lelliott P, Harrington M, Okocha C, Sensky T, Duffett R. Patterns of antipsychotic and anticholinergic prescribing for hospital inpatients. J Psychopharmacol. 2003; 17: 223-229.

9. Procyshyn RM, Honer WG, Wu TK, Ko RW, McIsaac SA, Young AH, et al. Persistent antipsychotic polypharmacy and excessive dosing in the community psychiatric treatment setting: a review of medication profiles in 435 Canadian outpatients. J Clin Psychiatry. 2010; 71: 566-573.

10. Santone G, Bellantuono C, Rucci P, Picardi A, Preti A, de Girolamo G. Patient characteristics and process factors associated with antipsychotic polypharmacy in a nationwide sample of psychiatric inpatients in Italy. Pharmacoepidemiol Drug Saf. 2011; 20: 441-449.

11. Sim K, Su A, Fujii S, Yang SY, Chong MY, Ungvari GS, et al. Antipsychotic polypharmacy in patients with schizophrenia: a multicentre comparative study in East Asia. Br J Clin Pharmacol. 2004; 58:178-183.

12. Suokas JT, Suvisaari JM, Haukka J, Korhonen P, Tiihonen J. Description of long-term polypharmacy among schizophrenia outpatients. Soc Psychiatry Psychiatr Epidemiol. 2013; 48: 631-638.

13. Stahl SM, Grady MM. A critical review of atypical antipsychotic utilization: comparing monotherapy with polypharmacy and augmentation. Curr Med Chem. 2004;11: 313-327.

14. Shim IH, Woo YS, Jun TY, Kim KS, Bahk WM. Changes in antipsychotic drug usage in the psychiatric inpatients at a university hospital between 1997, 2003-2004 and 2009- 2010. Korean J Psychopharmacol. 2012 ;23: 57-64.

15. Fourrier A, Gasquet I, Allicar MP, Bouhassira M, Lepine JP, Begaud B. Pattern of neuroleptic drug prescription: A national cross sectional survey of a random sample of French psychiatrists. Br J Clin Pharmacol. 2000; 49: 80-86.

16. Centorrino F, Eakin M, Bahk W, Kelleher JP, Goren J, Salvatore P et al. Inpatient antipsychotic drug use in 1998, 1993, and 1989. Am J Psychiatry. 2002;159(11): 1932-35.

17. Andor E, Peter M, Hess L, Valterio C. Antipsychotic use in patients with schizophrenia treated in private psychiatry. Swiss Med Wkly. 2005; 135: 109-115.

18. Burns T, Christova L, Cooper S, Harrison L, Mckendrick J, Laugharne R et al. Maintenance antipsychotic medication pattern in outpatients Schizophrenia patients: a naturalistic cohort study. Acta Psychiatr Scand. 2006; 113(2): 126-134.

19. Dutta SB, Dhasmana DC, Bhardwaj R. Psychotropic drug utilization pattern among patients with schizophrenia. Indian J Psychiatry. 2005; 47(4): 243 – 44.

20. Chaudhary PK, Deka K, Chetai D. Disability associated with mental disorders. Indian J Psychiatry. 2006; 48: 95-101.

21. Padmavati R., Rajkumar S, Srinivasan TN. Schizophrenic patients who were never treated – a study in an Indian urban community. Psychological Medicine. 1998; 28: 1113-117.

22. Meltzer HY, Rabinowitz J, Lee MA, Philip A, Cola PA, Rajan R et al. Age at onset and gender of schizophrenic patients in relation to neuroleptic resistance. Am J Psychiatry. 1997; 154(4): 475-82.

23. Welham JL, Richard J, Thomis RJ, McGrath JJ. Age-at-first-registration for affective psychosis and schizophrenia. Schizophrenia Bulletin. 2004; 30(4): 849-53.

24. Malinger JB, Fisher SG, Brown T, Lamberti JS. Racial disparities in the use of second- generation antipsychotics for the treatment of schizophrenia. Psychiatric services. 2006; 57(1): 133-36.

25. Rosenheck R, Stroup S, Keefe RS, Mcevoy J, Swartz M, Perkins D et al. Measuring outcome priorities and preferences in people with schizophrenia. British J Psychiatry. 2005: 187: 529 – 36.

26. Ren X S, Kazis L E, Lee A F, Hamed A, Huang YH, Chunninghamg F et al. Patient characteristics and prescription pattern of atypical antipsychotics among patients with Schizophrenia. J Clin Pharm Ther. 2002; 27: 441-451.

27. Ritsner M, Sherina O, Ginath Y. Genetic epidemiological study of schizophrenia: Reproductive behaviour. Acta Psychiatr Scand. 1992; 85: 423-9.

28. Lane A, Byrne M, Mulvany F, Kinsella A, Waddington JL, Walsh D et al. Reproductive behaviour in schizophrenia relative to other mental disorders: Evidence for increased fertility in men despite reduced marital rate. Acta Psychiatr Scand. 1995; 91: 222-8.

29. Nanko S, Moridaira J. Reproductive rate in schizophrenic outpatients. Acta Psychiatr Scand 1993; 87: 400-4.

30. Odegaard O. Fertility of psychiatric first admissions in Norway. Acta Psychiatr Scand. 1980; 62: 212-20.

31. Thara R, Srinivasan TN. Marriage and gender in schizophrenia. Indian J Psychiatry. 1997; 39: 64-9.

32. Thara R, Padmavathi R, Lakshmi A, karpagavalli P. Family education in schizophrenia: A comparison of two approaches. Indian J Psychiatry. 2005;47(4):218 – 21.

33. Ponnudurai R, Jayakar J, Sekar BS. Assessment of mortality and marital status of schizophrenic patients over a period of 13 years. Indian J Psychiatry. 2006; 48: 84-87.

34. Acquaviva E, Gansquet L, Falissard B. Psychotropic combination in schizophrenia. Eur J Clin Pharmacol. 2005; 61: 855-61.

35. Ungavari GS, Chung YG, Chee YK, Fung N, Kwong TW. The pharmacological treatment of Schizophrenia in Chinese patients: A comparison of prescription pattern between 1996 and 1999. Br J Clin Pharmacol. 2002; 54: 437-444.

36. Volz A, Khorsand V, Gillies D, Leucht S. Benzodiazepines for schizophrenia. (Cochrane Review) In: The Cochrane Library, Issue 1;2007.

37. Magliano L, Fiorillo A, Guarneri M, Marasco C, Rosa CD, Malangone C. Prescription of psychotropic drugs to patients with schizophrenia: An Italian national survey. Eur J Clin Pharmacol. 2004; 60: 513–22.

38. Kingsbury SJ, Yi D, Simpson GM. Rational and irrational polypharmacy. Psychiatric Services. 2001; 52(8): 1033-36.

39. Covell NC, Carlos T, Jackson T, Evans C, Essock SM. Antipsychotic prescribing practices in Connecticut's public mental health system: Rates of changing medications and prescribing styles. Schizophrenia Bulletin. 2002; 28(1): 17-29.

40. Clark RE, Bartels SJ, Mellman TA, Peacock WA. Recent trends in antipsychotic combination therapy of schizophrenia and schizoaffective disorders: Implications for state mental health policy. Schizophrenia Bulletin. 2002; 28(1): 75-84.

41. Mccue RE, Waheed R, Urcuyo L. Polypharmacy in patients with schizophrenia. J Clin Psychiatry. 2003; 64: 984 – 89.

Received on 17.01.2020 Modified on 01.03.2020

Research J. Pharm. and Tech. 2021; 14(8):4265-4269.

DOI: 10.52711/0974-360X.2021.00740

Anxiolytics n(%)	Antidepressants n(%)	Mood Stabilizers n (%)	Anticholinergics n(%)
T. Lorazepam 68 (48.92)	T. Fluoxetine 7(5.04)	T. Lithium 6(4.32)	T. Benzhexo l 78(56.12)
Inj. Lorazepam 16(11.51)	T. Sertraline 7(5.04)	T. Phenytoin 5(3.60)	Inj. Promethazine 12(8.63)
T. Clonazepam 13(9.3)	T. Escitalopram 5(3.60)	T. Sod valproate 3(2.16)	T. Triheixphenidy l 4(2.88)
T. Zolpidem11(7.91)	T. Amitriptyline 4(2.88)	T. Topiramate 2(1.44)	T. Metoclopramide 1(0.72)
T. Nitrazepam7(5.04)	T. Citalopram 2(1.44)	T. Carbamazepine 2(2.88)	T. Procyclidine 1(0.72)
Inj. Diazepam 6(4.32)	T. Dosulepin 1(0.72)
T. Diazepam 2(1.44)	T. Venlafaxine 1(0.72)
T. Alprazolam 1(0.72)	T. Mirtazapine 1(0.72)
T. Flurazepam 1(0.72)	T. Bupropion 1(0.72)
	T. Seligilin 1(0.72)