Antipsychotic

PolypharmacyJordanne 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:

1. Examine the the benefits and the concerns of using

more than one antipsychotic in the treatment of

schizophrenia

1. Evaluate the use of antipsychotics in combination with

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

● 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.

Current Guidelines reviewed

(Foster & King, submitted, 2020)

Consolidated Treatment Algorithm

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 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.

Clozapine

(Kar, Barreto, & Chandavarkar, 2016; Nielsen, Dahm,

Lublin, & Taylor, 2010; Tiihonen et al., 2019)

• Clozapine with a second antipsychotic currently have the

best, although limited, evidence in terms of antipsychotic

polypharmacy.

Clozapine (Continued)

• Improvements in Global impression, body weight and

cholesterol levels

• Some evidence for improved somnolence and

hypersomnia.

Clozapine and Aripiprazole

(Kar, Barreto, & Chandavarkar,

2016; Nielsen, Dahm, Lublin, &

Taylor, 2010; Tiihonen et al., 2019)

• 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.

Clozapine and Aripiprazole

(Tiihonen et al., 2019)

(Tiihonen et al., 2019)

ConclusionsEvidence on antipsychotic

combinations’ effectiveness is

limited:

Patients maintained on a

combination antipsychotics longer

than 10 weeks

Antipsychotic combinations

including clozapine

Treatment simultaneously initiated

with two antipsychotics

Patients with refractory

schizophrenia and no practical

access to clozapine

Managing antipsychotic

combinations:

Watch for:

● Drug interactions

● Metabolic syndrome

● Motor side effects

● Hyperprolactinemia

Work closely with primary care to

monitor patient

Switching back to

monotherapy:

(Re)Consider clozapine; resolve

barriers preventing access

Consider the risk of symptom

relapse

Monitor all domains of illness

Anticipate medication

discontinuation

ReferencesCitrome, L. (2009). Adjunctive lithium and anticonvulsants for the treatment of schizophrenia: What is

the evidence? Expert Review of Neurotherapeutics, 9(1), 55-71.

Correll, C. U., MD, & Gallego, Juan A., MD, MS. (2012). Antipsychotic polypharmacy. Psychiatric

Clinics of North America, 35(3), 661-681. doi:10.1016/j.psc.2012.06.007

Correll, C. U., Rummel-Kluge, C., Corves, C., Kane, J. M., & Leucht, S. (2008). Antipsychotic

combinations vs monotherapy in schizophrenia: A meta-analysis of randomized controlled trials.

Schizophrenia Bulletin, 35(2), 443-457.

Essock, S. M., Schooler, N. R., Stroup, T. S., McEvoy, J. P., Rojas, I., Jackson, C., . . . Schizophrenia

Trials Network. (2011). Effectiveness of switching from antipsychotic polypharmacy to monotherapy.

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37(5), 595-599.

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References (continued)

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