Polypharmacy: To Avoid or

to Embrace?
Michael P. Sionzon, MD
December 6, 2013
Philippine College of Psychopharmacology
Crowne Plaza Hotel
Disclosure
› Part-time consultant for Janssen
› Given lectures for Janssen, Medichem, Zydus, and Torrent
TO P OR NOT TO P. THAT IS THE QUESTION.
These are the questions:
› How widespread is polypharmacy in clinical practice?
› What are the rationale and risks of polypharmacy?
› What is the evidence for the efficacy of polypharmacy in the
different psychiatric conditions?
› How do we practice rational polypharmacy?
What are the trends of
polypharmacy in psychiatry?
Antipsychotic mono- and polypharmacy in the naturalistic
treatment of schizophrenia with atypical AP
› Prospective naturalistic study of patients treated for
schizophrenia-spectrum disorders from 1997-2003 (n=796)
Medication Status on Initiation

30%
34%
70%

66%
In transition between 2
agents
Stable polypharmacy

Polypharmacy Monotherapy Faries D, et al. BMC Psychiatry 2005; 5(26):

 Antipsychotic mono- and polypharmacy in the naturalistic
treatment of schizophrenia with atypical AP

Percent of patients in monotherapy /

polypharmacy in a 1-year period 45
40.7
40
0.6 5 1.9
35
35.7 30 26.9

% of Patients
25
30.4
20
15
10.3 9.9
10
6.3 6.1
5
26.9 0
< 60 61-120 121-180 181-240 241-300 >300

Monotherapy Polypharmacy
Mix: Mono/Poly No AP
Mix: No AP/Mono Mix: No AP/Poly Days of Polypharmacy

Faries D, et al. BMC Psychiatry 2005; 5(26):

Drug Treatment Patterns in Bipolar Disorder
› Patient self-report of drugs taken daily for 6 months
› 450 patients, mean of 222.0 days
– 78.4% of patients took a stable drug combination for > 50% of days
 Majority of patients were taking polypharmacy
– Patients were more likely to take a mood stabilizer than any other
drug
– No predominant drug regimen pattern

Bauer M, et al. Int J of Bipolar Disorders 2013; 1(5):

Polypharmacy prevalence rates in the treatment
of unipolar depression
› Retrospective chart review of 126 patients from one
institution
– Patients were prescribed a mean of:
› 1.98 (SD 0.94) psychotropic medications
› 1.15 (SD 0.52) antidepressants
› 0.64 (SD0.5) full dosed antidepressants
 Majority of patients were taking monotherapy

Glaezer A, et al., J of Affective Disorders 2009; 117: 18-23

National Trends in Psychotropic Polypharmacy in
Office-Based Psychiatry (US)
› Annual data from 1996 – 2006 cross-sectional National Ambulatory Medical
Care survey
– 13,079 visits to office-based psychiatrists
– Number of medications prescribed in each visit and specific medication combinations

59.8%*

42.6% 33.2%*

16.9%

Mojtabai R, et al. Arch Gen Psychaitry. 2010: 67(1): 26-36

*p<0.001
 Odds Ratio of Psychotropic Polypharmacy per
Diagnosis (1996-2006 ) – Same Class
Combination
> 2 Anti-depressants > 2 Antipsychotics > 2 Mood Stabilizers > 2 Sedative-
Hypnotics
Diagnosis
Major Depression 3.44 - - -
Other Depressive
2.02 - - -
Disorders
Bipolar Disorders 1.56 - 15.46
Anxiety Disorders 1.35 - - 2.13
Schizophrenia - 6.75 - -

Higher odds of polypharmacy (same class):

Bipolar > Schizophrenia > Major depression

Mojtabai R, et al. Arch Gen Psychaitry. 2010: 67(1): 26-36

 Odds Ratio of Psychotropic Polypharmacy per
Diagnosis (1996-2006 ) – Different Class
Combination Antipsychotic Mood Mood
Antidepressan Antipsychotic Antipsychotic
+ stabilizer+ t + Sedative- + Mood + Sedative stabilizer +
Antidepressan Antidepressan Sedative-
hypnotic Stabilizer Hypnotic
Diagnosis t t hypnotic
Major 1.53 2.09
Depression
Other Depressive
Disorders
Bipolar Disorders 2.27 10.26 7.36 2.33 11.21
Anxiety Disorders 2.39
Schizophrenia 4.46 1.82 3.49 4.05 2.26

Higher odds of polypharmacy:

Bipolar (MS + AD/SH/AP) > Schizophrenia (AP+ AD/SH/MS)> Major depression and Anxiety
disorders (AD+SH) Mojtabai R, et al. Arch Gen Psychaitry. 2010: 67(1): 26-36
Trends in Drug Development
› Antidepressants: Multiple to solitary neurotransmitters

› Antipsychotics: Solitary to multiple neurotransmitters

Images from Stahl SM, Stahl’s Essential Psychopharmacology, 3rd ed.

What are the rationale and
risks of polypharmacy?
Arguments against using polypharmacy

The likelihood of
There is not much The likelihood of problematic
evidence to support the problematic side effects pharmacokinetic and
efficacy of this practice is increased pharmacodynamic
interactions is increased

Patients are less The clinician often has

adherent to complex no basis for deciding
The costs are greater
medical regimens than what dose adjustments
simplier regimens in which ingredient

Miller AL. et al. Schizophrenia Bull 2002; 28(1):105-109

 Reasons for Rational Polypharmacy

To treat two To treat an adverse effect

pathophysiologically distinct produced by the primary drug
but comorbid illness (e.g. adding anticholinergic
(e.g. major depression plus when a patient develops
panic disorder) dystonia on a neuroleptic)

To provide amelioration To treat intervening phases To boost or augment the

while awaiting the delayed
effect of another medication
(e.g. Using benzodiazepines
for mania while waiting for
anti-manic effects of lithium)
of an illness efficacy of the primary
(e.g. adding antidepressant treatment
to a mood stabilizer when a (e.g. combining 2
bipolar patient develops a antipsychotics to treat
depressive episode) schizophrenia)

Presekorn SH, J of Psychiatric Practice 2007; 13: 97-105

What is the evidence for the
efficacy of polypharmacy in the
different psychiatric conditions?
What is the evidence for the
efficacy of polypharmacy?
SCHIZOPHRENIA
Antipsychotic combinations vs monotherapy in
Schizophrenia: Meta-analysis of RCTs
› Meta-analysis of 19 RCTs comparing antipsychotic
monotherapy to cotreatment with a second antipsychotic
– 1,229 patients
– 28 monotherapy arms: 14 FGA arms and 14 SGA arms
– 19 co-treatment arms: 2 FGAs (n=6), FGA+SGA (n=7), 2 SGAs (n=6)
– APs used
› Clozapine (n=11)
› Chlorpromazine (n=6)
› Risperidone (n=6)
› Sulpiride (n=5)
› Pimozide, Thioridazine, Fluphenazine, Trifluoperazine, Reserpine, Haloperidol,
Olanzapine, Levomepromazine (n=1 each)

Correll CU, et al. Schizophrenia Bull 2009; 35(2): 443-457

Efficacy – AP co-treatment was superior to monotherapy
(less study-specific defined inefficacy)

Correll CU, et al. Schizophrenia Bull 2009; 35(2): 443-457

Tolerability – AP co-treatment was superior to
monotherapy (drop-out rates / all-cause discontinuation)

Correll CU, et al. Schizophrenia Bull 2009; 35(2): 443-457

Other findings
› No group differences in AEs, except higher prolactin levels if
risperidone or sulpiride added to clozapine
› Meta-regression analysis:
– Significant moderators of superior efficacy of AP co-treatment:
1. Similar doses in the mono- and polytherapy arms
2. SGA + FGA combinations
3. Concurrent polypharmacy initiation
– Other moderators that trended towards significance
1. Study duration (> 10 weeks)
2. Blinding
3. Clozapine combinations

Correll CU, et al. Schizophrenia Bull 2009; 35(2): 443-457

What is the evidence for the
efficacy of polypharmacy?
BIPOLAR DISORDER
Combination therapy for Acute Mania
› Review of 20 double-blind RTCs of monotherapy or combined
therapy for acute mania

+ 20%
+ 21%

*Response rate defined as > 50% decrease in mania rating

Ketter TA, J Clin Psychiatry 2008; 69[suppl 5]: 9-15
Combination Therapy for Maintenance
› BALANCE Study (Bipolar Affective Disorder: Lithium /
Anticonvulsant Evaluation)
– Randomized, open-label, 3-group trial of maintenance therapy (24 mos)
› Lithium monotherapy
› Valproate monotherapy
› Combination lithium + valproate
– Primary efficacy outcome – Time to new intervention for an emerging
mood episode
› New drug treatment (commencement of a new drug, increase in dose of concurrent
drug, restarting of a discontinued drug, or increasing the dose of investigational
drug in response to an emergent mood episode)
› Admission to a hospital

BALANCE Investigators and collaborators. Lancet 2010; 375: 385-395.

Efficacy and Lithium levels
Combination (n=110) Lithium (n=110) Valproate (n=110)
New intervention to mood event
No. of patients with 59 (54%) 65 (59%) 76 (69%)
mood event (%)
Adjusted HR (95% CI) 1.00 0.80 (0.58-1.17) 0.59 (0.42-0.83)
p value - 0.23 0.0014
Lithium blood concentrations at randomization (mmol/L)
Unknown 18 (16%) 19 (17%)
< 0.4 8 (7%) 7 (6%)
0.4 – 0.6 36 (33%) 28 (25%)
0.6 – 0.8 38 (35%) 75% 31 (28%) 59%
0.8 – 1.0 10 (9%) 23 (21%)
>1.0 0 9% 2 (2%) 23%

BALANCE Investigators and collaborators. Lancet 2010; 375: 385-395.

Time to first admission or adjuvant treatment

› Median survival time (months; 95% CI)

– Combination: 15.5 (10.4 - *)
– Lithium: 10.5 (7.7 – 18.3)
– Valproate: 7.1 (4.6 – 12.2)

* Survival curve does not extend sufficiently far to allow calculation of upper limit of 95% CI
BALANCE Investigators and collaborators. Lancet 2010; 375: 385-395.
What is the evidence for the
efficacy of polypharmacy?
DEPRESSION
Depression: STAR-D

Monotherapy Combination

Huynh NN and McIntyre R. Primary Care Companion J Clin Psychiatry 2008; 10(2): 91-96
STAR*D Results

Poly Mono

SSRI NDRI SNRI SSRI TCA MAOI

5HT1A Partial NaSSA

agonist
Farah A. CNS Spectrums 14:1 (Suppl 2), Jan 2009
TO P OR NOT TO P. ISTHAT
THATISTHE
THEQUESTION?
QUESTION.
Tailor the medication regimen based on the
clinical presentation of each patient

RISKS

BENEFITS
How do we practice rational
polypharmacy?
Dimensional View of Polypharmacy

DIAGNOSTIC HIERARCHY HIERARCHY OF EVIDENCE FOR MULTIPLE

MEDICATION USE (MMU)/POLYPHARMACY
Etio
logi
c

Pathophysiologic

Syndromic
MDD

Schiz Bipolar

Symptomatic

Kahn AY and Preskorn SH in Polypharmacy in Psychiatry Practice Vol 1.

Ritsner M (ed)., Springer 2013
Rationale for Rational Polypharmacy in Psychiatry

When drug combinations are used as part of augmentation

strategy

Treating patients suffering from complex psychiatric disorders

Adapted from Kahn AY and Preskorn SH in Polypharmacy in Psychiatry Practice Vol 1. Ritsner M (ed)., Springer 2013
Principles for Rational Polypharmacy in Psychiatry

Drug combinations should not pose greater safety or

tolerability risks than monotherapy unless offset
substantially by sufficient better efficacy
• Use only those drug combinations that do not interact both
pharmacokinetically or pharmacodynamically
• Avoid Fluoxetine, Fluvoxamine, Paroxetine, Carbamazepine
• Use apps such as Medscape or ePocrates
• Scientific evidence that combination is more effective than
monotherapy

Adapted from Kahn AY and Preskorn SH in Polypharmacy in Psychiatry Practice Vol 1. Ritsner M (ed)., Springer 2013
Strategies for Schizophrenia
When Several Antipsychotic Monotherapies Fail

Divalproex
Atypical antipsychotic
High dose Lamotrigine
Antidepressant
Dose
Atypical antipsychotic
Usual top
dose

OPTION 1 – High-dose atypical OPTION 2 – Augmentation

TIme

Images from Stahl SM, Stahl’s Essential Psychopharmacology, 3rd ed.

Strategies for Schizophrenia
When All Else Fails

Conventional Atypical
antipsychotic antipsychotic #2

High dose Atypical

Atypical
antipsychotic antipsychotic #1
Dose
Usual top
dose

OPTION 1 – Conventional add-on OPTION 1 – Combine

OPTION 2 SDA/DPAs
2 – Augmentation
Time

Images from Stahl SM, Stahl’s Essential Psychopharmacology, 3rd ed.

Strategies for Depression
Notes:
– Buspirone : Serotonin partial agonist - Buspar
1st line agent lithium
– BZD - Benzodiazepine
– Mirtazapine – NaSSA (Noradrenergic and
1st line agent T3/T4 Specific Serotonergic Antidepressant)
– SARI: Serotonin 2A antagonist/reuptake
inhibitors - Trazodone
1st line agent buspirone – SDA: Serotonin-Dopamine Antagonist - Atypical
AP
– DPA: Dopamine partial agonist - Aripiprazole
1st line agent zolpidem/BZD
– NDRI: Norepinephrine and Dopamine Reuptake
Inhibitors – Bupropion (Wellbutrin/Zyban)
1st line agent SARI mirtazapine
– NRI: (Selective) Norepinephrine Reuptake
SDA/DPA
Inhibitors – Atomoxetine (Straterra)
– Modafinil – Stimulant; May be a dopamine
stimulant DA agonist transport inhibitor
NDRI/NRI modafinil
(e.g. pramipexole)

Images from Stahl SM, Stahl’s Essential Psychopharmacology, 3rd ed.

Strategies for Bipolar
Evidence-Based Bipolar Combos › Notes:
– Caution: Divalproex increases levels of
lamotrigine be decreasing hepatic clearance
Atypical DPA lithium

Atypical DPA Vaproate

Practice-Based Bipolar Combos

lithium divalproex

lamotrigine divalproex

lamotrigine lithium

lamotrigine lithium divalproex

Images from Stahl SM, Stahl’s Essential Psychopharmacology, 3rd ed.
Summary
Polyphamacy
› Avoid it if you can.
› Do it if you must.
› But do it rationally.
We are inviting everyone to attend …
Thank you very much for
your attention.