Psychiatric Polypharmacy: Etiology and Consequences

1. Sonali Sarkar MD, MPH, DrPH Psychiatric Polypharmacy, Etiology and Potential Consequences

2. Acknowledgement • United States Army Institute of Surgical Research (USAISR) • Oak Ridge Associated Universities (ORAU) • University of Texas Health Science Center at San Antonio (UTHSCSA)

3. Presentation Overview • Definition of psychiatric polypharmacy • Introduction • Methods • Epidemiology • Etiologic factors • Potential consequences • Harmful polypharmacy with examples • Beneficial polypharmacy with examples • Practice guidelines

4. Psychiatric Polypharmacy • Two or more drugs used in the treatment of a psychiatric condition [1] • Referred to as [2-4] - Potentially inappropriate medication (PIM) - Antipsychotic polypharmacy (APP) - Hyper-pharmacotherapy - Co-medication / co-prescription - Multiple medication use

5. Introduction • Psychiatric polypharmacy is a major public health problem • Rising trend of polypharmacy in the U.S is growing at an alarming rate [5] • Polypharmacy trend also observed in other parts of the world [5]

6. Methods • Review of online databases (PubMed, Medline, EBSCO, Psychinfo) was conducted • Time period: 2000-2016 • Population: Adults + child/ adolescents • Key words were searched using “And” “Or” - Search terms: psychiatry, polypharmacy, multiple medication, epidemiology, prevalence, antidepressant, antipsychotic, adverse reaction, side-effect, interaction, practice, guidelines, recommendation

7. Methods • Search yielded approx. 1000 articles • Initial review: included 289 articles • Articles were reviewed one by one • Final review: included 250 articles that were recent & relevant to the topic

8. Epidemiology • Prevalence is increasing globally [5] • Common in patients with schizophrenia [6] • Noted in 30-50% of adult schizophrenics [7,8] • Prevalence of polypharmacy with second gen antipsychotics (SGA) is rising (3.9-50%) [9] • Commonly co-prescribed SGA are risperidal and olanzapine [10]

9. Epidemiology • Polypharmacy is noted not only with antipsychotics but also with antidepressants, mood stabilizers, and sedative-hypnotics [11] • National trends in polypharmacy in an office setting indicate common drugs prescribed [12] • Antidepressants (61.7%) • Antidepressants + sedative hypnotics (23.1%) • Antidepressants + antipsychotics (12.9%) • Antidepressants + antidepressants (12.6%)

10. Epidemiology • Noted in adults with psychosis, borderline personality d/o, affective and mood d/o[13-14] • In adults with affective/bipolar disorder, prevalence rate of one or more antidepressant or antipsychotic is approximately 36-85% [15,16] • Silent epidemic of polypharmacy is seen not only in adults but also in children & adolescents [17]

11. Epidemiology • Among youths, prevalence rate is 8-12% [17] • Combinations of SGA+SGA are common [18] • Aripiprazole/quetiapine(23% and 17%) • Risperidal/quetiapine(18% and 15%) • Aripiprazole/ risperidone (17% and 11%) • Risperidal/olanzapine (5% and 6%) • Quetiapine/olanzapine (4% and 7%)

12. Epidemiology • In youths, antidepressants are co-prescribed with stimulants & antipsychotics [19] • Youth antidepressant (SSRIs) prescription prevalence rate is approximately 2-5% [20] • In youth ADHD, psychostimulant (Ritalin) prescription rate with antipsychotic is 3.9% [21]

13. Polypharmacy Etiology • Rationale for polypharmacy is not clear • Prior studies are limited as they are [22-24] -Observational vs. interventional -Lack tools to assess polypharmacy efficacy -Rely on prescriber autonomy -Poor response rate -Lack power: small sample size -Inadequate control of confounders

14. Polypharmacy Etiology • Demographic factors • Psychiatric condition • Comorbidity • Substance abuse • Prescribing practice • Patient determinants

15. Demographic factors (adult) • Age (18-25 yrs) [8] • Age advancement [8] • Gender: Male (majority)/female gender [25,26] • Low education, poor SES, Medicaid/public insurance [26, 27] • Race: mixed findings reported • AA: cumulative higher dose, older drugs & depot formulations [28, 29] • CATIE trial: Coprescription less likely in AA [25] • No differences by race/ethnicity [30,31]

16. Demographic factors (youth) Among children & adolescents [32, 33] • Age children (13-15 yrs) • Male gender • Caucasian race • Low socio-economic status • Medicaid/public insurance • Disability status • Child custody outside/ foster care

17. Psychiatric Condition (adult) • Schizophrenia/psychosis [8] • Treatment refractory/difficult to treat [35] • Negative symptoms/depressive d/o [36] • Violence, hostility, suicidality [36] • Severity of condition[35] • Inpatient status (majority)/ outpatient [12] • Longer hospitalization/shorter follow up[12,35]

18. Psychiatric Condition (youth) • Child clinical correlates [21, 37] • Autism spectrum disorder (ASD) • Attention deficit hyperactivity d/o (ADHD) • Conduct d/o (CD) • Oppositional defiant d/o (ODD) • Adolescent clinical correlates [39] • Schizophrenia spectrum disorder • Mood d/o, Bipolar illness • Anxiety d/o, CD/ODD

19. Comorbidity • Adult: obesity, dyslipidemia, metabolic syndrome, somatic pain, dementia, MR, Alzheimer’s disease, personality d/o [38] • Pediatric: enuresis, encopresis, neurological d/o, motor tics, developmental d/o, obsessive compulsive personality d/o [37] • Higher comorbidity score/index is associated with polypharmacy [32]

20. Substance abuse • Substance abuse: predictor of polypharmacy [40] • Polysubstance abuse: nicotine, alcohol, drugs (marijuana/cocaine) is prevalent [40] • Youth substance abuse: h/o abuse, MDD, Mania, CD, ADHD [41] • Youth ADHD: Antipsychotic + stimulants [40,41] • Intoxication/withdrawal need Rx with CNS drugs • Benzodiazepines + antipsychotics [42]

21. Prescribing practice • Perception, attitude, prescriber knowledge[43] • Child psychiatrists prescribe more meds [32,34] • Prescribers’ deviate from routine algorithm[23] • Lack of adequate monotherapy trials [23,24] • Polypharmacynoted at treatment initiation phase: explains the rising prevalence [24] • Prescribers are under pressure, focus on drug Rx instead of global improvement [44] • Prescriber bias: qualitative/quantitative diff. in prescribing practice to minority pt. [28,29]

22. Patient determinants • Attitude, cultural beliefs, family influence, racial/ethnic diff: polypharmacy [45] • Behaviors: doctor shopping, multiple providers, request for meds, early med refill, prescription drug abuse [46] • Health disparities, indiv variablity in genetic polymorphisms, drug metabolism, pharmacogenetics/pharmacokinetics: polypharmacy determinants [47]

23. Patient determinants • In youths, parental/child perception, parental request for meds, attitude & belief towards psychiatric Rx [48] • Youth violent behavior, impulsivity, aberrant behaviors are associated with polypharmacy [21, 32, 33]

24. Consequences • Adverse effects: weight gain, sexual dysfunction, anticholinergic side-effect [49] • SGA’s : metabolic syndrome, hyperlipidemia, type 2 D.M, glucose intolerance [50] • In youth: Rx emergent type 2 D.M w SGA [51] • Drug to drug interactions: effect on Cyt P450 • Elderly: cognitive impairment, falls, fracture [52] • Cumulative toxicity, mortality & morbidity [53] • Rx complexity: non-compliance/adherence [54] • Mental health cost/economic burden [55]

25. Beneficial Polypharmacy • Concept: Synergistic action of drugs w diff mechanism of action on multiple neurochemical pathway [56] • Improve therapeutic outcome & clinical s/o [56] - Ex:Venlafaxine(mood d/o) + amitryptiline(pain) - Ac. Psychosis: FGA(haldol) + SGA (risperdal) • Approach is used to target two diff psych cond • Psychosis (risperdal) + Anxiety (quetiapine) • Depression (SSRI) + Seizure (gabapentin)

26. Beneficial Polypharmacy • Affective d/o (rec. cyclic manic episodes) -Lithium (add on) + SSRI/Bupropion (depression) [57, 58] • Bipolar d/o: Lithium (maintenance) + anticonvulsants (divalproate, carbamazepine, lamotrigine) [59] • Lithium as add on: clinical efficacy, antisuicidal effect (decreased aggression/impulsivity) [60]

27. Beneficial Polypharmacy • Rx resistant depression: drugs targeting inhibition (5HT) + NE receptors [61] • SSRI (prozac) + NE uptake inhibitor (desipramine) is effective than monotherapy • Combination w 3 diff antidepressants was more effective than Fluoxetine monotherapy [62, 63] • Mirtazapine + SSRI (Paxil) • Mirtazapine + Venlafaxine • Mirtazapine + Bupropion

28. Beneficial polypharmacy • Newer antidepressants(multitarget agents) [64] • Fewer & milder side-effects • Provide complimentary strategy for psych Rx • To reduce risk of EPS, anticholinergic effects, • Proven beneficial in ameliorating symptom[65] • Thus, rational polypharmacy improves clinical outcome & GAF score.

29. Harmful Polypharmacy • Some drug combinations: none to low clinical response; proven futile/harmful [66] • Ex: SGA (risperdal) + SGA (clozapine) [67] • RCT: Combining Meds to Enhance Depression Outcomes (CO-MED) study= No diff in remission/response rate in 12 wks in grps [68] • Escitalopram + Placebo • Escitalopram + Bupropion • Venlafaxine + Mirtazapine

30. Harmful Polypharmacy • Sudden cardiac death: QT prolongation (Torsade de Pointes) with polypharmacy [69] • Haldol/Thorazine + Ziprasidone/quetiapine • Need cardiac eval, EKG, monitoring of vitals • Pediatric SGA for behavioral d/o in absence of evidence based indication= med side-effect, wt. gain, metabolic syndrome [70]

31. Practice Guidelines • Prior studies have listed in detail [71-75] • These include: • Initiate polypharmacy only when monotherapy fails. • Synergism in drugs mechanism of action • FGA + SGA block dopaminergic+serotonergic • Used in Ac. Psychosis, agitation • Ex: Haldol (FGA) in pt. w risperdal (SGA)

32. Practice guideline • Specific targeting of Rx emergent symptom clusters • Ex: Rx emergent anxiety, positive/neg s/o of schizophrenia benefit from add on SGA/benzo • Augmentation in Rx refractory psych cond • Sec antipsychotic can be added if failed antipsychotic trial/suboptimal response w clozapine • Noncompliance: Maintenance (Inj.depot) continued + antipsychotics to prevent relapse

33. Practice guidelines • Continue antipsychotic combinations if therapeutic efficacy & safety is noted • Ex: Beneficial neurocog. effects noted with SGA (olanzapine + risperdal) vs haldol alone • Personality d/o (OCD) in schizophrenia can be Rx w SGA • Aripiprazole/amisulpride + SGA (5HT2) • Diff. class of antidepressants (synergistic effect): Refractory depression

34. Practice guideline • For affective/mood d/o follow these steps • If partial benefit noted; side-effect is mild, then • Increase the dose of first medication • Switch to another class of antidepressant • Augment the first med w second antidepressant w diff mech of action (improves clinical outcome w no increase in side-effect)

35. Practice guidelines • Multimodal Rx approach w 2 or 3 drugs for Rx resistance (MDD/Bipolar d/o) • Ex: SSRIs can be used w augmentation agents that have synergistic action • Anticonvulsants (valproate/lamotrigine) • Lithium (mood stabilizer) • Atypical antipsychotics • Melatonin, Buspirone, Thyroxine

36. Practice guidelines • Adjunct meds (antiparkinsonian, sedative-hypnotics, anticholinergic drugs) + FGA • To reduce EPS symptoms and side-effects • Ex: Haldol + ativan + benadryl • Child Psychiatrists’ need to obtain detailed h/o, diff bet. behav & psych d/o before prescribing meds in youths.

37. Questions?

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