Antipsychotic polypharmacy and augmentation strategies prior to clozapine initiation: a historical cohort study of 310 adults with treatment-resistant schizophrenic disorders

Abstract

Rationale:

Antipsychotic polypharmacy (APP) is commonly used in schizophrenia despite a lack of robust evidence for efficacy, as well as evidence of increased rates of adverse drug reactions and mortality.

Objectives:

We sought to examine APP and the use of other adjunctive medications in patients with treatment-resistant schizophrenic disorders (ICD-10 diagnoses F20–F29) immediately prior to clozapine initiation, and to investigate clinical and sociodemographic factors associated with APP use in this setting.

Methods:

Analysis of case notes from 310 patients receiving their first course of clozapine at the South London and Maudsley NHS Trust (SLaM) was undertaken using the Clinical Record Interactive Search (CRIS) case register. Medication taken immediately prior to clozapine initiation was recorded, and global clinical severity was assessed at time points throughout the year prior to medication assessment using the Clinical Global Impression – Severity scale (CGI-S). Logistic regression was used to investigate factors associated with APP.

Results:

The point prevalence of APP prior to clozapine initiation was 13.6% (n=42), with 32.6% of subjects prescribed adjuvant psychotropic medications. APP was associated with increasing number of adjuvant medications (odds ratio (OR) 1.97, 95% confidence interval (CI) 1.27–3.06), concurrent depot antipsychotic prescription (OR 2.64, CI 1.24–5.62), concurrent antidepressant prescription (OR 4.40, CI 1.82–10.63) and a CGI-S over the previous year within the two middle quartiles (Quartile 2 vs 1 OR 6.19, CI 1.81–21.10; Quartile 3 vs 1 OR 4.45, CI 1.29–15.37; Quartile 4 vs 1 OR 1.88, CI 0.45–7.13).

Conclusions:

APP and augmentation of antipsychotics with antidepressants, mood stabilizers and benzodiazepines are being employed in treatment-resistant schizophrenia prior to clozapine. The conservative APP rate observed may have been influenced by an initiative within SLaM that reduced APP rates during the study window. Efforts to reduce the use of poorly evidenced prescribing should focus on adjuvant medications as well as APP.

Keywords

Schizophrenia polypharmacy antipsychotic clozapine treatment resistant augmentation adjunctive antidepressant mood stabilizer benzodiazepine

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References

Centorrino

Goren

Hennen

. (2004) Multiple versus single antipsychotic agents for hospitalized psychiatric patients: case-control study of risks versus benefits. Am J Psychiat 161: 700–706.

Chakos

Glick

Miller

. (2006) Baseline use of concomitant psychotropic medications to treat schizophrenia in the CATIE trial. Psychiat Serv 57: 1094–1101.

Connolly

Taylor

(2014) Factors associated with non evidence-based prescribing of antipsychotics. Ther Adv Psychopharmacol 4: 247–256.

Correll

Rummel-Kluge

Corves

. (2009) Antipsychotic combinations vs monotherapy in schizophrenia: a meta-analysis of randomized controlled trials. Schizophrenia Bull 35: 443–457.

Englisch

Enning

Grosshans

. (2010) Quetiapine combined with amisulpride in schizophrenic patients with insufficient responses to quetiapine monotherapy. Clin Neuropharmacol 33: 227–229.

Grech

Taylor

(2012) Long-term antipsychotic polypharmacy: how does it start, why does it continue? Ther Adv Psychopharmacol 2: 5–11.

Henderson

Kunkel

Nguyen

. (2006) An exploratory open-label trial of aripiprazole as an adjuvant to clozapine therapy in chronic schizophrenia. Acta Psychiatr Scand 113: 142–147.

Howes

Vergunst

Gee

. (2012) Adherence to treatment guidelines in clinical practice: study of antipsychotic treatment prior to clozapine. Br J Psychiat 201: 481–485.

Josiassen

Joseph

Koheqyi

. (2005) Clozapine augmented with risperidone in the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial. Am J Psychiat 162: 130–136.

10.

Kadra

Stewart

Shetti

. (2015) Extracting antipsychotic polypharmacy data from electronic health records: develoing and evaluating a novel process. BMC Psychiat 15: 166.

11.

Kane

Correll

Goff

. (2009) A multicenter, randomized, double-blind, placebo-controlled, 16-week study of adjunctive aripiprazole for schizophrenia or schizoaffective disorder inadequately treated with quetiapine or risperidone monotherapy. J Clin Psychiat 70: 1348–1357.

12.

Lerner

Chudakova

Kravets

. (2000) Combined use of risperidone and olanzapine in the treatment of patients with resistant schizophrenia: a preliminary case series report. Clin Neuropharmacol 23: 284–286.

13.

Lerner

Bergman

Borokhov

. (2005) Augmentation with amisulpride for schizophrenic patients nonresponsive to antipsychotic monotherapy. Clinical Neuropharmacology 28(2): 66–71.

14.

Leucht

Kissling

McGrath

(2007) Lithium for schizophrenia. Cochrane Db Syst Rev 2007: CD003834.

15.

Lewis

Barnes

Davies

. (2006) Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophrenia Bull 32: 715–723.

16.

Mace

Taylor

(2015) Reducing the rates of prescribing high-dose antipsychotics and polypharmacy on psychiatric inpatient and intensive care units: results of a 6-year quality improvement programme. Ther Adv Psychopharmacol 5: 4–12.

17.

Martin

Park

Langan

. (2014) Socioeconomic status and prescribing for schizophrenia: analysis of 3200 cases from the Glasgow Psychosis Clinical Information System (PsyCIS). Psychiat Bull 38: 54–57.

18.

McEvoy

Lieberman

Stroup

. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiat 163: 600–610.

19.

Muscatello

Bruno

Pandolfo

. (2011) Effect of aripiprazole augmentation of clozapine in schizophrenia: a double-blind, placebo-controlled study. Schizophrenia Research 127: 93–99.

20.

Patel

(2012) Clinician hesitation prior to clozapine initiation: is it justifiable? Br J Psychiat 201: 425–442.

21.

Patel

Bishara

Jayakumar

. (2014) Quality of prescribing for schizophrenia: evidence from a national audit in England and Wales. Eur Neuropsychopharmacol 24: 499–509.

22.

Paton

Barnes

Cavanagh

M-R

. (2008) High-dose and conbination antipsychotic prescribing in actue adult wards in the UK: the challenges posed by p.r.n. prescribing. Br J Psychiat 192: 435–439.

23.

Perkins

Boteva

. (2005) Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: a critical review and meta-analysis. Am J Psychiat 162 1785–1804)

24.

Potkin

Thyrum

Alva

. (2002) The safety and pharmacokinetics of quetiapine when coadministered with haloperidol, risperidone, or thioridazine. J Clin Psychopharmacol 22: 121–130.

25.

Ritmannsberger

Meise

Schauflinger

. (1999) Polypharmacy in psychiatric treatment. Patterns of psychotropic drug use in Austrian psychiatric clinics. Eur Psychiat 14: 33–40.

26.

Roh

Chang

Kim

. (2014) Antipsychotic polypharmacy and high-dose prescription in schizophrenia: a 5-year comparison. Aust NZ J Psychiat 48: 52–60.

27.

Rummel

Kissling

Leucht

(2006) Antidepressants for the negative symptoms of schizophrenia. Cochrane Db Syst Rev 2006: CD005581.

28.

Sepehry

Potvin

Elie

. (2007) Selective serotonin reuptake inhibitor (SSRI) add-on therapy for the negative symptoms of schizophrenia: a meta-analysis. J Clin Psychiat 68: 604–610.

29.

Schmidt-Kraepelin

Puschner

Loos

. (2013) Antipsychotic polypharmacy in high-utilising patients with schizophrenia. Psychiat Prax 40: 380–384.

30.

Schwarz

Volz

. (2008) Valproate for schizophrenia. Cochrane Db Syst Rev 2008: CD004028.

31.

Seeman

(1982) Gender differences in schizophrenia. Can JPsychiat 27: 107–112.

32.

Sneider

Pristed

Correll

. (2015) Frequency and correlates of antipsychotic polypharmacy among patients with schizophrenia in Denmark: A nation-wide pharmacoepidemiological study. Eur Neuropsychopharmacol 25: 1669–1676.

33.

Stewart

Soremekun

Perera

. (2009) The South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLAM BRC) case register: development and descriptive data. BMC Psychiat 9: 51.

34.

Suokas

Suvisaari

Haukka

. (2013) Description of long-term polypharmacy among schizophrenia outpatients. Soc Psych Psych Epid 48: 631–638.

35.

Tani

Uchida

Suzuki

. Interventions to reduce antipsychotic polypharmacy: a systematic review. Schizophrenia Res 143:215–220.

36.

Taylor

Young

Paton

. (2003) Prior antipsychotic prescribing in patients currently receiving clozapine – a case note review. J Clin Psychiat 64: 30–39.

37.

Volz

Khorsand

Gillies

. (2007) Benzodiazepines for schizophrenia. Cochrane Db Syst Rev 2007: CD006391.

38.

Waddington

Youssef

Kinsella

(1998) Mortality in schizophrenia. Antipsychotic polypharmacy and absence of adjunctive anticholinergics over the course of a 10-year prospective study. Br J Psychiat 173: 325–329.

39.

Wahlbeck

Cheine

Essali

. (1999) Evidence of clozapine’s effectiveness in schizophrenia: a systematic review and meta-analysis of randomized trials. Am J Psychiat 156: 990–999.

40.

Zink

Henn

Thome

(2004) Combination of amisulpride and olanzapine in treatment-resistant schizophrenic psychoses. Eur Psychiat 19: 56–58.