Antipsychotic Prescribing in the treatment of Schizophrenia Karen Hayhurst ERC, Wythenshawe Hospital

UK Prevalence Antipsychotic Combination Prescribing Inpatients 48%1-day audit (n=3132) Harrington et al % 1-day audit (n=3576) Lelliott et al % 1-month audit (n=107) Chaplin & McGuigan 1996 Community patients 33% (n=52,884) Shepherd et al 2003 Large UK variation12% to 71% Harrington et al 2002 Duration of AP poly mean = 4 years (up to 18 years) Waddington et al 1998

Local Prevalence Combination Antipsychotic Prescribing (1998)

Local Prevalence (2005) Audit of Antipsychotic Prescribing - Oldham Sample size389 patients (majority treated with olanzapine) Rate of AP co-prescribing23% Rate of high dose prescribing (>1000 cpzeq) 14% Receiving anticholinergic medication 29%

Local Prevalence (2005) Audit of Antipsychotic Prescribing - Pennine Care 5 sites pooled together 815 patients AP mono group N=630 Majority treated with olanzapine FGA mono group more likely to be older, have a longer length of illness and to be outpatients Combination AP rate 21% 2/3 rd SGA + FGA together 5% 3 AP drugs together Most common combination = olanzapine + flupenthixol depot Co-prescribed group more likely to be older and to have a longer length of illness High dose rate (>1000 cpzeq) 14% Co-prescribed group received a higher cpzeq dose More patients on combination treatment received a high dose (>1000 CPZeq) High dose group more likely to have a longer length of illness Drug most likely to be prescribed alone > 1000 CPZeq = clozapine Combination most likely to be prescribed > 1000 CPZeq = olanzapine + flupenthixol Treated with adjunctive anticholinergics 25% More co-prescribed patients treated with anticholinergics More high dose patients treated with anticholinergics More depot patients treated with anticholinergics

Link between AP co-prescribing & high dose prescribing AP co-prescribing leads to likelihood of receiving a combined high dose A pt prescribed >1 AP drug has 41x the odds of being prescribed a high dose than a pt prescribed a single AP drug Lelliott et al Mean dose of AP mono = CPZeq - Mean dose of AP poly = CPZeq Bingefors et al US inpatient study = AP dose 78% higher for those on AP combinations than on AP monotherapy Centorrino et al 2004 Incidence = 20% of UK pts receive AP drugs in doses exceeding BNF guidance Bebbington 2001

Adverse events related to Antipsychotic Co-prescribing Prescribers not aware of additive side-effects resulting from AP polypharmacy Maudsley guidelines When FGA and SGAs combined, patients are put at risk for both the old and new adverse effects Yuzda 2000 Atypical AP polypharmacy inc probability of receiving anti-EPS treatment 2-fold Carnahan et al 2006 Patients prescribed FGA + SGA together more likely to be prescribed regular anticholinergic meds compared with patients receiving a SGA alone = higher rates of EPS Taylor et al 2000 No therapeutic advantages & significant increase in adverse reactions with doses > 375 mg CPZeq Bollini et al 1994 Use of high AP doses leads to a high incidence of SEs + may be associated with sudden cardiac death as AP drugs cause QTc lengthening in a dose-related manner Pathare & Paton 1997 Reilly et al 2000 Receiving >1 AP concurrently associated with reduced survival Waddington et al 1998 Patients are less adherent to complex medical regimes than simpler regimes Chen 1991

Treatment Guidelines – UK Royal College of Psychiatrists’ consensus statement on high dose AP prescribing (revised, May 2006) “the efficacy of combining 2 or more FGAs or adding a FGA to a SGA (or vice versa) has not been established + there is evidence for increased risk of adverse effects and pharmacokinetic interactions” “current state of knowledge does not allow for any plausible pharmacological rationale for high-dose AP medication” NICE guidance on the use of newer (atypical) antipsychotic drugs for the treatment of schizophrenia (2002) “atypical & typical AP drugs not to be prescribed concurrently, except for short periods to cover changeover of meds” “high doses may increase likelihood of side effects + thus may limit benefit by reduction in concordance” NICE core interventions in the treatment and management of schizophrenia in primary & secondary care (2002) “best to use a single drug, using doses within BNF dose range and not to use high or loading doses” “the addition of a second AP to clozapine may be considered for people with TRS for whom clozapine has proved insufficiently effective” BNF (British National Formulary 2006) “prescribing of >1 AP at the same time is not recommended; it may constitute a hazard” “consider high-dose therapy to be for a limited period - abandon if no improvement after 3m + return to standard dosage” Maudsley prescribing guidelines ( ) “AP monotherapy is desirable and should be the norm” “polypharmacy should be undertaken only where response to a single AP (including clozapine) has been clearly demonstrated to be inadequate - in such cases, the effect of polypharmacy should be carefully evaluated and documented - where there is no clear benefit, treatment should revert to single AP therapy”

Treatment Guidelines – US APA Practice Guideline (American Psychiatric Association 2 nd Edition 2004) “practitioners should be aware of problems inherent in combination therapies, including increased costs + decreased adherence” “higher doses are no more effective for acute treatment than normal doses, but are associated with greater incidence of side effects” IPAP (CINP-International Psychopharmacology Algorithm Project - Meltzer et al updated 2006) “monotherapy is a core recommendation of this algorithm” “rapid high-dose AP treatment is almost never warranted” TMAP (Texas Medication Algorithm Project, Miller et al 1999; updated 2004) “there is no evidence to support the use of AP polypharmacy before a trial of clozapine has been attempted” “augmentation of clozapine remains the best treatment option for patients whose schizophrenic symptoms fail to respond or only partially respond to an adequate trial of clozapine monotherapy” PORT (Patient Outcomes Research Team, Lehman & Steinwachs 1998) “the dosage of AP medication for an acute symptom episode should be in the range of cpzeq per day for a minimum of 6 weeks - reasons for dosages outside this range should be justified” “massive loading doses of AP medication, referred to as ‘rapid neuroleptization’, should not be used”

Can antipsychotic prescribing be changed? SiGMA (Schizophrenia in Greater Manchester) audits Tameside (1999/ 2000) & South Manchester (2001): – where guidelines used, AP co-prescribing rates 30% in previous audits CUtLASS (cost-utility of the latest antipsychotics in severe schizophrenia) N= % rate of AP co-prescribing at baseline - 14% rate of AP co-prescribing at one year (end of study) Lewis et al 2006 Systematic review - studies which have tried to change prescribing behaviour Wide variation in effect of interventions on AP prescribing Relatively small changes in AP co-prescribing as a result of interventions: - 2.1% decrease Glikman % difference in rates of change between intervention and control groups Thompson 2006 AP drug dose - moderate to large changes as a result of interventions - 30% reduction in mean cpzeq dose Warner 1995

Summary UK prevalence AP co-prescribing - wide variation (30-50%) Local prevalence AP co-prescribing – 1998 audit (30-50%) Oldham audit (N=389) - AP co-prescribing = 23% - high dose AP prescribing = 14% Pennine Care audit (N=815) - link between AP poly & high dose prescribing - indication of pt characteristics associated with AP co-prescribing/ high dose prescribing - association with anticholinergic use as indicative of incidence of SEs Concerns re associated adverse events All available treatment guidelines guard against the use of combination AP prescribing (except for closely monitored addition of a 2 nd AP drug to clozapine in TRS) & high dose prescribing Evidence that AP prescribing can be changed Controlled trials of AP co-prescribing needed so risks vs benefits can be determined Freudenreich & Goff 2002; Miller & Craig 2002; Stahl & Grady 2004; Tapp 2005