Upload
others
View
8
Download
0
Embed Size (px)
Citation preview
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.
American Journal of Psychiatry, 168(7), 702-708.
Foster, A., Buckley, P., Lauriello, J., Looney, S., & Schooler, N. (2017). Combination antipsychotic
therapies: An analysis from a longitudinal pragmatic trial. Journal of Clinical Psychopharmacology,
37(5), 595-599.
Ganguly, R., Kotzan, J. A., Miller, L. S., Kennedy, K., & Martin, B. C. (2004). Prevalence, trends, and
factors associated with antipsychotic polypharmacy among medicaid-eligible schizophrenia patients,
1998-2000. Journal of Clinical Psychiatry, 65(10), 1377-1388.
Guideline Writing Group.The american psychiatric association practice guideline for the treatment of
patients with schizophrenia
References (continued)Heckers, S., Barch, D. M., Bustillo, J., Gaebel, W., Gur, R., Malaspina, D., . . . Carpenter, W. (2013). Structure of the
psychotic disorders classification in DSM‐5. Schizophrenia Research, 150(1), 11-14. doi:10.1016/j.schres.2013.04.039
Helfer, B., Samara, M. T., Huhn, M., Klupp, E., Leucht, C., Zhu, Y., . . . Leucht, S. (2016). Efficacy and safety of
antidepressants added to antipsychotics for schizophrenia: A systematic review and meta-analysis. American Journal of
Psychiatry, 173(9), 876-886. doi:10.1176/appi.ajp.2016.15081035
Kar, N., Barreto, S., & Chandavarkar, R. (2016). Clozapine monitoring in clinical practice: Beyond the mandatory
requirement. Clinical Psychopharmacology and Neuroscience : The Official Scientific Journal of the Korean College of
Neuropsychopharmacology, 14(4), 323-329. doi:10.9758/cpn.2016.14.4.323
Kreyenbuhl, J., Valenstein, M., McCarthy, J. F., Ganoczy, D., & Blow, F. C. (2006). Long-term combination
antipsychotic treatment in VA patients with schizophrenia. Schizophrenia Research, 84(1), 90-99.
doi:10.1016/j.schres.2006.02.023
Leucht, S., Helfer, B., Dold, M., Kissling, W., & McGrath, J. J. (2015). Lithium for schizophrenia. Cochrane Database of
Systematic Reviews,
McCutcheon, R. A., Reis Marques, T., & Howes, O. D. (2020). Schizophrenia—An overview. JAMA Psychiatry, 77(2),
201-10. doi:10.1001/jamapsychiatry.2019.3360
Nielsen, J., Dahm, M., Lublin, H., & Taylor, D. (2010). Psychiatrists’ attitude towards and knowledge of clozapine
treatment. Journal of Psychopharmacology, 24(7), 965-971. doi:10.1177/0269881108100320
Stahl, S. M. (2008). Stahl's essential psychopharmacology online (4th ed.) Cambridge in collaboration with
Neuroscience Education Institute.
Stroup, T. S., Gerhard, T., Crystal, S., Huang, C., Tan, Z., Wall, M. M., . . . Olfson, M. (2019). Comparative
effectiveness of adjunctive psychotropic medications in patients with schizophrenia. JAMA Psychiatry, 76(5), 508.
doi:10.1001/jamapsychiatry.2018.4489
References (continued)
Tiihonen, J., Suokas, J. T., Suvisaari, J. M., Haukka, J., & Korhonen, P. (2012). Polypharmacy with
antipsychotics, antidepressants, or benzodiazepines and mortality in schizophrenia. Archives of
General Psychiatry, 69(5), 476-483. doi:10.1001/archgenpsychiatry.2011.1532
Tiihonen, J., Taipale, H., Mehtälä, J., Vattulainen, P., Correll, C. U., & Tanskanen, A. (2019).
Association of antipsychotic polypharmacy vs monotherapy with psychiatric rehospitalization among
adults with schizophrenia. JAMA Psychiatry, 76(5), 499-507.
Tseng, P., Chen, Y., Chung, W., Tu, K., Wang, H., Wu, C., & Lin, P. (2016). Significant effect of
valproate augmentation therapy in patients with schizophrenia: A meta-analysis study. Medicine,
95(4)