Stacy Miller, PharmD, BCPS, BCPP
Assistant Professor, Pharmacy Practice
Gatton College of Pharmacy
East Tennessee State University
Johnson City, Tennessee
April 27, 2012
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Consulting fees/honoraria: None
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Speaker’s bureau: None
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Ownership/partnership/principal: None
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Research grants: None
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Salary: None
Upon completion of this session, the learner will be able to:
1.
Define the term polypharmacy
2.
Describe instances of rational and irrational
polypharmacy
3.
Summarize causes and consequences of
polypharmacy in psychiatry
4.
Recommend potential alternatives to irrational
polypharmacy in psychiatry
≥ 2 psychiatric medications
≥ 2 medications for the same indication
≥ 2 medications in the same class or with same
mechanism
≥ 3 medications for the same indication
Hoffman et al. Neuropsych Dis Treat 2001; 7: 639.
Kingsbury et al. Psychiatr Serv 2001; 52: 1033.
Greil et al. J Affect Disord 2012; 136: 534.
Rational
• Unusual/severe clinical presentation
• Pharmacological combinations with
proven synergistic effects
Irrational
• Haphazard combinations
• No distinguishable rationale
Hoffman et al. Neuropsych Dis Treat 2001; 7: 639.
Polypharmacy in Psychiatry
Risks
Causes
Polypharmacy in Psychiatry
Risks
Causes
> 80% D2 occupancy  EPS
Kapur et al. Am J Psychiatr 2000; 157: 514.
Gomberg. J Clin Psychopharmacol 1999; 19: 272.
Koreen et al. Am J Psychiatr 1995; 152: 1690.
Thioridazine (35.6 ms)
Chlorpromazine (23 ms)
Ziprasidone (20.3 ms)
Citalopram (18 ms)
Quetiapine (14.5 ms)
Risperidone (11.6 ms)
Iloperidone (9.1 ms)
Olanzapine (6.8 ms)
Haloperidol (4.7 ms)
Pfizer Briefing Document for Zeldox® Capsule (2000).
Marino et al. Ann Pharmacother 2010; 44: 863-870.
Reilly et al. Lancet 2000; 355: 1048-1052.
Asenapine
Iloperidone
Paliperidone
Richelson E. J Clin Psychiatr 2010; 71(9): 1243.
Stahl. J Clin Psych PCC 2003; 5 (suppl 3): 9.
Low
Intermediate
• Chlorpromazine
• Thioridazine
•
•
•
•
High
Potency
Low
Potency
High
Thiothixene
Trifluoperazine
Perphenazine
Loxapine
• Haloperidol
• Fluphenazine
More EPS
Less histaminergic, alpha
adrenergic,
anticholinergic
Less EPS
More histaminergic, alpha
adrenergic,
anticholinergic
Not just antipsychotics
Metoclopramide
Lithium
TCAs
SSRIs
Ananth et al. Acta Neuropsychiatr 2004; 16: 219.
Margetić et al. Pharmacoepidemiol Saf 2010; 19: 429.
Nardil®
(phenelzine)
Parnate®
(tranylcypromine)
Marplan®
(isocarboxazid)
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Avoid combination with or within 2 weeks of:
◦ SSRIs (wait 5 weeks for fluoxetine)
◦ Amphetamine
◦ Illicit substances – methamphetamine or MDMA (ecstasy)
Sun-Edelstein et al. Expert Opin Drug Saf 2008; 7: 587.
Sola et al. Mayo Clin Proc 2006; 81: 330.
High-potency tricyclic antidepressants
(clomipramine, imipramine)
Meperidine, tramadol, methadone,
fentanyl, propoxyphene
Dextromethorphan
Sun-Edelstein et al. Expert Opin Drug Saf 2008; 7: 587.
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Reversible monoamine oxidase inhibitor (MAO-I)
Contraindicated with SSRI/SNRI unless patient
is advised of risk
Contraindicated with irreversible MAO-I
◦ Nardil® (phenelzine)
◦ Parnate® (tranylcypromine)
◦ Marplan® (isocarboxazid)
Sola et al. Mayo Clin Proc 2006; 81: 330.
Micromedex.
Tricyclic
Antidepressants
• Substrates of CYP 1A2,
2C19, 2D6, 3A4
• Narrow therapeutic index
Micromedex Healthcare Series: Thompson Reuters Healthcare, Inc.
Drug-Drug Interactions Antidepressants
Fluoxetine inhibits CYP 2D6 and
2C9
Decreased metabolism of:
Tricyclic antidepressants
Clozapine
Phenytoin
Warfarin
Tamoxifen (decreased efficacy)
Micromedex Healthcare Series: Thompson Reuters Healthcare, Inc.
Drug-Drug Interactions Antidepressants
Paroxetine inhibits CYP 2D6
Decreased metabolism of:
Tricyclic antidepressants
Tamoxifen (decreased efficacy)
Micromedex Healthcare Series: Thompson Reuters Healthcare, Inc.
Drug-Drug Interactions Antidepressants
Fluvoxamine inhibits CYP 1A2, 2C19, 2C9
and 3A4
Decreased metabolism of:
Tricyclic antidepressants
Clozapine
Methadone
Theophylline
Warfarin
Micromedex Healthcare Series: Thompson Reuters Healthcare, Inc.
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Divalproex Sodium inhibits metabolism of
lamotrigine via glucuronidation
◦ Can increase risk of toxic side effects of lamotrigine
◦ Will impact how lamotrigine is dosed
Micromedex Healthcare Series: Thompson Reuters Healthcare, Inc.
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CYP 3A4 Auto-induction*
◦ Causes its own metabolism
◦ Occurs after each dose increase or initiation
◦ May need higher doses to reach goal serum
concentration after first month of treatment
Also induces 1A2, 2C9/10
 Increases metabolism of oral
contraceptives
 Be cautious when combining with
clozapine (risk for agranulocytosis)
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Micromedex Healthcare Series: Thompson Reuters Healthcare, Inc.
Drug
Substrate
Inhibition
Haloperidol
1A2, 2D6, 3A4
2D6
Fluphenazine
None
None
Thiothixene
None
None
Trifluoperazine
None
None
Perphenazine
2D6
2D6
Loxapine
None
None
Chlorpromazine
2D6
2D6
Thioridazine
2D6
None
Micromedex Healthcare Series: Thompson Reuters Healthcare, Inc.
Drug
Substrate
Inhibition
Clozapine (Clozaril®)
1A2 (major), 3A4, 2D6,
2C19
None
Olanzapine (Zyprexa®)
1A2 (major), 3A4, 2D6
None
Quetiapine (Seroquel®)
3A4
None
Risperidone
(Risperdal®)
2D6 (major), 3A4
Mild-moderate 2D6
Paliperidone (Invega®)
None
None
Ziprasidone (Geodon®)
3A4
None
Asenapine (Saphris®)
1A2
Mild 2D6
Aripiprazole (Abilify®)
2D6, 3A4
None
Iloperidone (Fanapt®)
1A2
None
Over-sedation
Respiratory depression
Additive anti-cholinergic effects
Drug-Induced Delirium
COST
Non-adherence
Polypharmacy in Psychiatry
Risks
Causes
TIMA Depression Algorithm 2000.
TIMA Schizophrenia 2000.
Tamblyn et al. CMAJ 1996; 154: 1177.
Caught in cross-taper
Multiple diagnoses
Fear of relapse
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SC is a 37 year old female with treatment resistant
major depressive disorder. She is prescribed
paroxetine 10 mg daily, lithium 600 mg HS and
aripiprazole 2.5 mg daily. She has never reported
adverse effects from her medications. Is this
rational or irrational polypharmacy and why? What
could be done to avoid this?
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Sally Jo is a 26-year-old female with a diagnosis
of major depressive disorder. Her HAM-D score
before treatment was 23 and now, on her current
regimen, her score is 10. Her medications include
fluoxetine 60 mg daily and venlafaxine XR 150 mg
daily. Is this regimen appropriate? What can be
done to improve it?
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Zach is a 42 year old male with a long history of
schizophrenia. He is being hospitalized for the
fourth time this year for his symptoms of
psychosis.
His current medications are citalopram 40 mg,
lithium 600 mg BID, olanzapine 20 mg HS,
aripiprazole 10 mg daily.
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Zach’s past medical history is significant for
psoriasis, and his condition worsened when
lithium was started.
Zach is also complaining of cogwheel rigidity,
over-sedation and akathisia.
What should be done for Zach?
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Critically evaluate the need for every psychotropic
medication
Consider a washout?
Comparative estimates of complications of washout versus polypharmacy
Treatment Modality
Estimates of Intolerance
Washout
5.9%-7.8%
Polypharmacy
9.1%-34.1%
Hoffman et al. Neuropsych Dis Treat 2001; 7: 639.
The Cost of
Polypharmacy
Libby Zion
1965-1984
Psychiatrist Mohammed Saaed
stopped haloperidol 16 days
before Yates killed her children.
Andrea Yates
http://articles.cnn.com/2002-0304/justice/yates.trial_1_andrea-yatessuicide-defenseattorneys?_s=PM:LAW
Upon completion of this session, the learner will be able to:
1.
Define the term polypharmacy
2.
Describe instances of rational and irrational
polypharmacy
3.
Summarize causes and consequences of
polypharmacy in psychiatry
4.
Recommend potential alternatives to irrational
polypharmacy in psychiatry
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Ananth, J, Aduri K, Parameswaran S, et al. Neuroleptic malignant
syndrome: Risk factors, pathophysiology, and treatment. Acta
Neuropsychiatr 2004; 16: 219-228.
FDA Psychopharmacological Drugs Advisory Committee. Briefing
document for Zeldox® Capsules (Ziprasidone). 19 July 2000.
Gomberg RF. Interaction between olanzapine and haloperidol. J Clin
Psychopharm 1999; 19(3): 272-273.
Greil W, Häberle A, Haueis P, et al. Pharmacotherapeutic trends in
2231 psychiatric inpatients with bipolar depression from the
International AMSP Project between 1994 and 2009. J Affect Disord
2012; 136: 534-542.
Hoffman DA, Schiller M, Greenblatt JM, Iosifescu DV. Polypharmacy or
medication washout: An old tool revisited. Neuropsych Dis Treat 2011;
7: 639-648.
Kapur S, Zipursky R, Jones C. Relationship between Dopamine D2
occupancy, clinical response, and side effects: A double-blind PET
student of first episode schizophrenia. Am J Psychiatr 2000; 157: 514520.
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Kingsbury SJ, Yi D, Simpson GM. Psychopharmacology: rational and
irrational polypharmacy. Psychiatr Serv 2001; 52(8): 1033-1036.
Koreen AR, Lieberman JA, Kronig M, Cooper TB. Cross-tapering
clozapine to risperidone. Am J Psychiatr 1995; 152(11): 1690.
Margetrić B, Margetrić BA. Neuroleptic malignant syndrome and its
controversies. Pharmacoepidemiol Saf 2010; 19: 429-435.
Marino J, Caballero J. Iloperidone for the treatment of
schizophrenia. Ann Pharmacother 2010; 44: 863-870.
Reilly JG, Aiyas SA, Ferrier IN, et al. QTc-interval abnormalities and
psychotropic drug therapy in psychiatric patients. Lancet 2000; 355
(9209): 1048-1052.
Richelson E. New antipsychotic drugs: How do their receptorbinding profiles compare? J Clin Psychiatr 2010; 71(9): 1243-1244.
Sola CL, Bostwick JM, Hart DA, Lineberry TW. Anticipating potential
linezolid-SSRI interactions in the general hospital setting: An MAOI
in disguise. Mayo Clin Proc 2006; 81: 330-334.
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Stahl SM. Describing an atypical antipsychotic: Receptor binding
and its role in pathophysiology. J Clin Psych Primary Care
Companion 2003; 5 (suppl 3): 9-13.
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Sun-Edelstein C, Tepper SJ, Shapiro RE. Drug-induced
serotonin syndrome: A review. Expert Opin Drug Saf 2008;
7: 587-596.
Tamblyn RM, McLeod PJ, Abrahamowicz M, Laprise R. Do
too many cooks spoil the broth? Multiple physician
involvement in medical management of elderly patients and
potentially inappropriate drug combinations. CMAJ 1996;
154(8): 1177-1184.
Trivedi MH, Shon S, Crismon ML, Key T. Texas
Implementation of Medical Algorithms (TIMA): Guidelines
for treating major depressive disorder. 2000.
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