Polypharmacy in Psychiatry

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Poly-pharmacy in Psychiatry

Introduction

• Historically, Poly-pharmacy for psychiatric disorders has been frowned upon.

• Seen as evidence of poor clinical judgment.

• Seen as either overmedicated or improperly diagnosed.

Definition

• It can be defined as-– Use of two or more medications to treat

the same condition, – Use of two or more drugs of the same

chemical class,– Use of two or more drugs with the same

or similar pharmacologic actions to treat different conditions.

Ref- Kingsbury SJ, Donna Yi, Simpson GM. Rational and Irrational Polypharmacy. PSYCHIATRIC SERVICES ♦ August 2001 Vol. 52 No. 8

What is the impact ???

• Kukreja et al (2013)- reported prevalence rates of poly-pharmacy in psychiatry to vary between 13-90%.

• Rittmannsberger et al (2002)- mono-therapy in psychiatry patients– <1980 in 48%, – 1981-1990 in 31% &– 1991-2000 in 20%.

Socio-Demographic factors

• De las Cuevas & Sanz ( 2004)- – Adult men > women,– Antidepressants were the most common

co-prescribed followed by ADHD medications, antipsychotics.

– More common with ICD-10 diagnosis of Schizophrenia, Schizotypal & Delusional disorders.

Impact in Geriatric population…

• In geriatric group it is often a rule rather than exception !!!...

• In adults >65yrs-– Over 90%- atleast 1 medication/ week.– Over 57%- >5 medications/ week.– Over 12%- >9 medications/ week.

• Cohort study comparing medicine use b/n 98-03→ >5 medications ↑ from 54% to 67%.

• Beers criteria, provides a list of medications that should be avoided in geriatric patients.

Ref: Bryan D et al. polypharmacy and geriatric patient. Clin geratric med 23 (2007) 371- 390.

Geriatric poly-pharmacy

• Adverse drug events (ADEs)- approx. 10% in emergency department.

• Risk factors for ADEs- poly-pharmacy, comorbid conditions, prior ADEs, dementia.

• Drugs implicated in ADEs- Anti-cholinergics, BZDs, TCAs.

• Common ADEs- electrolyte, renal, GI, hemorrhagic & endocrine abnormalities.

• Drug-drug interactions ↑ with ↑ in medications.• Drugs with narrow therapeutic index are frequently

involved like digoxin, CCBs, TCAs, warfarin etc..,

Geriatric pharmacokinetics

• ↑ Sensitivity to drug effects→ due to alterations in renal, hepatic, endocrine, cardiovascular, neurologic functions.

• Exaggerated responses to centrally acting drugs like barbiturates, opioids, TCAs, BZDs, central α agonists.

• ↓ Baroreceptor responsiveness and sensitivity leading to ↑ risk of hypotension.

• Alterations in absorption and distribution, fat to lean body mass ratio, plasma albumin levels contribute to variations.

• Changes in drug metabolism in turn lead to exaggerated responses.

Types of poly-pharmacy

1. Same-Class Poly-pharmacy- Use of more than one medication from the same class ( 2 SSRI’s).

2. Multi-Class Poly-pharmacy - Use of more than one medication from different classes for the same symptom cluster (Val + Olan).

3. Adjunctive Poly-pharmacy- Use of one medication to treat the side effects of another medication from a different class (Risp + THP).

4. Augmentation Poly-pharmacy- – Use of one medication at a lower dose along with another

medication from a different class in full therapeutic dose for the same symptom cluster (Risp + low dose Hal),

– Addition of a medication that would not be used alone for the same symptom cluster (Li + T3).

Ref- Medical Directors Council and State Medicaid Directors. Alexandria, Virginia: 2001.NASMH Program Directors: Technical Report on Psychiatric Polypharmacy.

Is Poly-pharmacy required ???

• Stahl's Essential Psycho-pharmacology & Doran's The Practitioner's Guide, promote synergistic drug combinations.

• Majority of psychiatric patients benefit from synergistic drugs, they also are essential for achieving and maintaining recovery.

• In clinical practice it is very difficult to achieve a full remission or recovery with mono-therapy.

• So poly-pharmacy of mental health medications should be rather a rule than an exception.

Ref: Jakovljević M. How to increase treatment effectiveness & efficacy in psychiatry: Creative psychopharmacotherapy Part 1. Psychiatria Danubina, 2013; Vol. 25, No. 3, pp 269-273

Reasons for Poly-pharmacy…

1. Treat two patho-physiologically distinct but co-morbid illnesses in the same patient (Parkinson’s dis +Psychosis).

2. To treat an adverse effect produced by the primary drug (Risp + THP).

3. To provide acute amelioration while awaiting the delayed effect of another medication (AD + BZD).

4. To treat intervening phases of an illness ( In treatment of Post psychotic depression).

5. To boost/ augment the efficacy of primary treatment (AD + L methyl folate, AP + AD in –ve schiz).

Ref: Preskorn SH, Lacey RL. Polypharmacy: when is it rational? J Psychiatr Pract. 2007;13:97–105.

What Poly-pharmacy is not…

• Irrational poly-pharmacy-1. Clinician’s fear about poor and unstable

state of patient.

2. Sloppy diagnosis.

3. Stuck in cross-titration of drugs.

4. Blind adherence to specifications in guidelines.

5. Inadequate knowledge of receptor pharmacology or a lack of attention to it.

Ref- Kingsbury SJ, Donna Yi, Simpson GM. Rational and Irrational Polypharmacy. PSYCHIATRIC SERVICES ♦ August 2001 Vol. 52 No. 8

Creative/ Rational Poly-pharmacy

• Ghaemi et al (2001)- It is the skillful & rational combination of mental health drugs.

• Combining drugs with synergistic therapeutic effect between the drugs.

• Joseph et al (1997)- – Multiple drugs with each for a specific target

symptom, – Each evaluated individually for efficacy and side

effects and adjusted optimally, – Elimination of each one that is no longer

necessary.

Ref: Jakovljević M. How to increase treatment effectiveness & efficacy in psychiatry: Creative psychopharmacotherapy Part 1. Psychiatria Danubina, 2013; Vol. 25, No. 3, pp 269-273

Poly-pharmacy in Depression


• AD + Li-– Li is the best-studied augmenter to AD.– Addition of Li to a TCA resulted in clinical

improvement <72 hrs in pts who had failed to respond to a TCA alone.

– Addition of Li also appears to prevent relapses in unipolar depression more effectively than an AD alone.

– Pts are likely to improve with Li, if they exhibit significant psychomotor retardation, anorexia, weight loss, and low serum cortisol levels.


• AD + Thyroid supplement– As effective as Li augmentation.– Studies have suggested that T3 at 25-50 mcg/d,

when added to various SSRIs, potentiate their effects.

– In STAR*D trial, pts who had failed with mono-therapy & when augmented with T3, 25% had attained remission.

– Pt likely to respond include females, h/o thyroid abnormalities, females >50 yrs (perhaps more susceptibility to hypothyroidism).


• AD + Stimulant like agents– Include Amphetamines, Pramipexole,

Bupropion, Modafinil.– Amphetamines to target fatigue, hypersomnia

and cognitive difficulties.– Pramipexole + SSRIs has role in treatment

resistant depression at doses 1 mg/d.– Modafinil to target fatigue and hypersomnia.– In STAR*D trial, Bupropion had a remission rate

of 30% in patients who had failed in mono-therapy.


• AD + AP– Augmenters & Adjuncts in Unipolar & Bipolar

depression.– 5-HT2 antagonism of AP has long been thought

to produce antidepressant properties.– They clearly help in symptoms like sleep,

appetite & agitation.– Olanzapine is among the most studied for the

augmentation in resistant depression. – 10-20 mg/day of Olan + Flx effective in

treatment of resistant depression.


• AD + AD– STAR*D trail, found 30% remission with

addition of Buspirone/ Bupropion to Citalopram.

– STAR*D trial, combination of Venlafaxine & Mirtazapine showed improvement in depressive symptoms.

– H1 blocking of mirtazapine may make it a useful augmentor to SSRIs in insomnia.

Poly-pharmacy in Schizophrenia


• AP + AD– To alleviate affective symptoms, like

inter-current major depressive episode.– Studies confirmed efficacy of citalopram

& duloxetine in treatment of depression in schizophrenia.

– SSRIs have showed beneficial impact on negative symptoms.

– Bupropion (NDRI) successful in smoking cessation in schizophrenia.


• AP + Li/ Anticonvulsants– Most common add on strategy.– Valproic acid had beneficial impact on

aggression & tardive dyskinesia.– Carbamazepine proved improvement in

global psychopathology.– Topiramate showed weight loss, pro-

glutamatergic effects & affective stabilization.

– But not supported by strong evidence.


• AP + AP– Clozapine- Anti-suicidal effect & lower

mortality rates than other AP.– For agonistic effects-

• 5HT & Adr system- Ziprasidone.• Differential agonistic and antagonistic effects

in the D- Aripiprazole.• D receptor blockade- sulpride/ Amisulpride.

– Evidence for Risp + Clozapine supported by RCTs.


Anti-Psychotic combination

Study population Results

Olanzapine + Aripiprazole

Overweight, Obese ↓ Weight, BMI, TAG.

Olanzapine + Amisulpride

Partial response to Olanzapine

Improvement in symptoms.

Clozapine + Aripiprazole

On treatment with Clozapine

Improvement in glucose tolerance, ↓ LDL.

Clozapine + SGAs

Analysis of 14 double blind studies

Modest benefit.

Quetiapine/ Risperidone + Aripiprazole

Patients stabilized on Quetiapine/ Rispeidone

↓ PRL levels.

Certain combinations of Antipsychotics


• Amelioration of AP side effects– Akathisia- add on Mirtazapine/ switch to

better tolerated AP.– Weight gain- Reboxetine (AD)/

Metformin.– Add on Aripiprazole to Clozapine to

reduce- mean body weight, waistline, BMI, fasting total & LDL cholestrol.

Ref: Zink M, Englisch S, Lindenberg AM. Polypharmacy in schizophrenia. CurrentOpinioninPsychiatry2010,23:103–111


Effect on receptors

Consequences of blockade

AP with high affinity

D2 antagonism in striatal area

EPS Fluphenazine, haloperidol, risperidone

D2 antagonism in Infudibular system

Hyperprolactinemia Amisulpride, haloperidol, sulpride, riperidone, paliperidone, zotepine

H1 antagonism Weight gain, sedation Clozapine, olanzapine, quetiapine

M1 antagonism Dry mouth, constipation, cognitive impairment

Clozapine, olanzapine, quetiapine

α1 antagonism Orthostatic hypotension, tachycardia

Asenapine, chlorpromazine, clozapine, risperidone, sertindole, ziprasidone

Interactions potentially causing adverse events

Sagud M et al. antipsychotic: to combine or not to combine. Psychiatria Danubina, 2013; Vol. 25, No. 3, pp 306-310

Poly-pharmacy in Geriatric


• Anti-depressants– Sproule et al noted drug interactions of SSRIs

are secondary cytP450 induction.– SSRI + Warfarin is associated with enhanced

anticoagulation.– COPD pts on theophylline, can develop toxicity

if on Flx or Fluvoxamine.– Alzheimer’s pts on Tacrine, can develop toxicity

due to ↑ tacrine if on Fluvoxamine.– Toxicity of terfenadine, astemizole,

carbamezapine are ↑ with SSRIs.

Ref: Katona CLE. Psychotropics and drug interactions. Int J Geriatr Pscyhiatry 2001; 16: S86-90.


• Mood stabilizers– Prone for Li toxicity due to ↓ renal

capacity→ alteration in consciousness and tremors.

– Li + Verapamil→ neurotoxicity and bradycardia.

– Carbamazepine may reduce anticoagulant effects of warfarin when co-administered.

– Cimetidine, Dextropropaxyphene may cause carbamezapine toxicity.


• Anti-psychotics– Phenothiazines + Cimetidine→ enhanced

sedative effect due reduced metabolism.

– Haloperidol + Li→ ↑ Li neurotoxicity.

– SSRI + Clozapine→ ↑ Clozapine toxicity.

– Clozapine ↑ neurotoxicity of Li, BZDs (sedation, hypertension, resp arrest).

– Cigarette smoking ↑ metabolism of Clozapine & Olanzapine→ reduction in effects.

In simple terms…

• Physicians prescribing psychiatric drugs must be aware of the existence and high prevalence of poly-pharmacy.

• Poly-pharmacy suggests two or more medications are being used to treat the same/ different conditions in a patient.

• Poly-pharmacy may be necessary and justified particularly when there are co-morbidities & when mono-therapy provides insufficient improvement

• One can deal with polypharmacy with SAIL and TIDE approaches:– SAIL: Simple drug regimen, Adverse effects knowledge, clear Indication, keep List

of drug name and dosage in patient's chart.

– TIDE: Allow Time to address medication issues, understand Individual variability, avoid potential dangerous Drug-drug interactions, and Educate patients regarding treatment.

• Education, proper clinical titration aided by guidelines and protocols are effective ways to avoid irrational poly-pharmacy.

Questions???

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Department of Psychiatry

Date post:	03-Jun-2015
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Polypharmacy in Psychiatry

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