Antipsychotic Polypharmacy Jordanne King, MD , PGY-III Psychiatry Resident Adriana Foster, MD, Professor and Vice-Chair of Clinical and Research Programs, FIU Department of Psychiatry and Behavioral Health
Disclosures • Jordanne King: Nothing to disclose. • Adriana Foster: HRSA, NIMH research funding
Objectives After viewing this presentation, participants will be able to: Examine the the benefits and the concerns of using 1. more than one antipsychotic in the treatment of schizophrenia Evaluate the use of antipsychotics in combination with 1. other psychotropics in the treatment of schizophrenia
Will Discuss • The pharmacology and pathology underlying treatment in schizophrenia • The reasons for concern as well as the benefits with the use of more than one antipsychotic concomitantly • The evidence for the use of antipsychotics with other psychotropics or treatment modalities • Use of clozapine
Background: Schizophrenia ● More than 23 million people worldwide are affected with Schizophrenia ● 30% of patients with schizophrenia experience a poor long- term prognosis ○ Residual psychotic symptoms ○ Poor social functioning and a poor quality of life ● People with schizophrenia die on average 20 years earlier ○ Metabolic syndrome such as diabetes, hypertension and hyperlipidemia contribute to morbidity and mortality Mercer & Reynolds, 2002
Background: Schizophrenia ● How do we decide on Treatment? ● Dimensional assessments of not only the dimensions of psychosis but also the fields of cognition and affect can capture meaningful variation in the severity of symptoms and may guide treatment planning
Dimensional analysis of psychosis (Heckers et al., 2013)
(Stahl, 2008)
(Stahl, 2008)
(McCutcheon, Reis Marques, & Howes, 2020)
Receptor D1 D2 D3 5HT2B 5HT2A 5HT1A MI H1 1ALPHA Second Generation Clozapine + + + +++ ++ + +++ +++ +++ Olanzapine ++ ++ ++ ++ +++ ++ +++ ++ Quetiapine + + + ++ ++ + ++ +++ +++ Asenapine +++ +++ +++ +++ ++++ ++ + +++ +++ Zotepine ++ +++ ++ +++ + +++ +++ Risperidone + +++ +++ ++ ++++ + ++ +++ Paliperidone ++ +++ +++ ++ +++ + ++ +++ Ziprasidone + +++ +++ ++ ++++ ++ ++ ++ Iloperidone + +++ ++ +++ ++ ++ ++++ Lurasidone +++ +++ +++ ++ Aripiprazole +++ +++ ++++ ++ +++ ++ ++ Brexpiprazole + ++++ ++ ++ ++++ ++++ ++ ++ Cariprazine ++++ ++++ ++++ ++ +++ ++ + Sulpiride ++ ++ Receptor D2 5HT2 Muscarinic Histaminic Adrenergic First Generation Chlorpromazine ++++ ++++ ++++ ++++ ++++ Thioridazine ++++ ++++ ++++ ++++ ++++ Perphenazine ++++ ++++ + +++ ++ Trifluoperazine ++++ +++ + ++ ++ Fluphenazine ++++ ++ + ++ + Thiothixene ++++ + + +++ ++ Haloperidol ++++ ++ + + + Loxapine +++ ++++ ++ ++++ +++
Background: Antipsychotic Polypharmacy • Antipsychotic polypharmacy = simultaneous prescribing of more than one antipsychotic at a time • Duration: undefined
Background: Antipsychotic Polypharmacy Though an active area of interest: • Data and quality of reviews is limited • Lack of uniformity makes it difficult to interpret data • No data from a primary care setting
Current Guidelines reviewed ● American Psychiatric Association ● Texas Medication Algorithm Project Schizophrenia treatment guidelines ● Florida Best Practice Psychotherapeutic Medication Guidelines ● Clinical Practice Guidelines for Management of Schizophrenia in India ● The Royal Australian and New Zealand College of Psychiatrists clinical guideline. ● The National Institute of Health and Care Excellence guidelines.
Consolidated Treatment Algorithm (Foster & King, submitted, 2020)
Prevalence of the use of 2 or more antipsychotics (Ganguly, et al, 2004; Kreyenbuhl et al, 2006; Tiihonen et al., 2019)
Why is this an issue?
Motor Side Effects ● Extra pyramidal symptoms: ○ Combinations of 1st with 2nd generation antipsychotics lead to increased anticholinergic use, ○ The low propensity of extrapyramidal side effects found with 2nd generation monotherapy does not persist when 2nd generation antipsychotic drugs are combined ● Neuroleptic malignant syndrome has been found to be associated with antipsychotic combinations in case reports ● Tardive dyskinesia and akathisia have not been clearly associated with combinations antipsychotics
Hyperprolactinemia • It appears that adding an antipsychotic drug with high D2 blockage potential to a drug with low D2 propensity increases the risk of hyperprolactinemia • The exception to this case is the use of concomitant aripiprazole
Metabolic syndrome • Long term use of antipsychotics in schizophrenia increases the risk for metabolic syndrome (i.e. the state of hyperlipidemia, obesity, hypertension and glucose intolerance) • Currently there is insufficient data on the potential harm of antipsychotic polypharmacy in regards to metabolic syndrome,
Metabolic syndrome • Aripiprazole may be protective for dyslipidemia and glucose metabolism compared to other antipsychotic combinations and monotherapy • A rationale is to use a second antipsychotic with a higher D2 receptor affinity to address the persisting psychotic symptoms while lowering the dose of the antipsychotic with higher liability of metabolic syndrome.
Are there potential benefits to antipsychotic combinations?
Evidence of potential benefits Correll , Schizophrenia Bulletin , Vol. 35, Issue 2, March 2009, Pp 443 – 457 Lack of Efficacy as Defined in Each Study.
Evidence of potential benefits Time to Medication Change for Any Reason Among Patients Randomly Assigned Either to Stay on Antipsychotic Polypharmacy or to Switch to Monotherapy (Essock et al., 2011)
Evidence of potential benefits (Foster, Buckley, Lauriello, Looney, & Schooler, 2017)
Combinations of antipsychotics and other psychotropics
Mood Stabilizers • Evidence for use in Schizophrenia is limited • Lithium augmentation- better clinical response than antipsychotic alone until schizoaffective disorder and not double blinded studies was excluded • Divalproex augmentation - found to decrease psychiatric symptoms but only in open, not randomized clinical trials or trials lasting less than 4 weeks • Gabapentin - some evidence may be associated with higher mortality that may be more due to its side effects profile • (Citrome, 2009; Leucht, Helfer, Dold, Kissling, & McGrath, 2015; Tseng et al., 201, Stroup et al., 2019)
Benzodiazepines • No evidence that is beneficial when compared to adjunctive antidepressant or mood stabilizer • Associated with higher mortality • Possibly due to: • withdrawal • discontinuation after long term use may increase anxiety and suicidal behaviour (Tiihonen et al., 2019, Stroup et al., 2019)
Neuromodulation • ECT: • Still holds as a very effective treatment for psychosis in recent reviews of the treatment. • Particular evidence that clozapine + ECT is of particular effectiveness in TRS or those who have not responded to clozapine • TMS: • Less invasive • Some evidence of efficacy in refractory positive symptoms • No evidence for negative or cognitive symptoms
Antidepressants • Effective for negative symptoms as well as depressive symptoms • Safe without changes in dropout rates, exacerbations of psychosis or adverse effects • May reduce ER visits and hospitalizations • Particularly helpful in patients with comorbid substance abuse • Lower risk of diabetes and reduced mortality and possible reduce suicide deaths (Helfer et al., 2016) (Stroup et al., 2019) (Tiihonen, Suokas, Suvisaari, Haukka, & Korhonen, 2012)
Antidepressants (Helfer et al., 2016)
(Stroup et al., 2019)
The elephant in the room....
Clozapine • Clozapine is scarcely prescribed (15% - US and 54% - UK) • Why? • the mandatory monitoring of white blood/absolute neutrophil count • other potentially serious adverse effect warnings • 40-60% of patients respond incompletely to clozapine monotherapy. (Kar, Barreto, & Chandavarkar, 2016; Nielsen, Dahm, Lublin, & Taylor, 2010; Tiihonen et al., 2019)
Clozapine (Continued) • Clozapine with a second antipsychotic currently have the best, although limited, evidence in terms of antipsychotic polypharmacy.
Clozapine and Aripiprazole • Improvements in Global impression, body weight and cholesterol levels • Some evidence for improved somnolence and hypersomnia. (Kar, Barreto, & Chandavarkar, 2016; Nielsen, Dahm, Lublin, & Taylor, 2010; Tiihonen et al., 2019)
Clozapine and Aripiprazole • Tiihonen et al. 2019 • The lowest risk of hospitalization was observed for clozapine plus aripiprazole (7-14% lower than any antipsychotic monotherapy). • Better outcome in terms of both psychiatric hospital readmission as well as all-cause hospitalization than any other monotherapy or combination of antipsychotics. (Tiihonen et al., 2019)
(Tiihonen et al., 2019)
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