Doing More by Prescribing Less; Top Ten Drug Interactions that Limit Efficacy Paul Zarkowski, MD Clinical Assistant Professor Harborview Medical Center University of Washington Psychiatrist, Sound Seattle, Washington Disclosure • The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational use(s) of drugs, products, and/or devices (any use not approved by the US Food and Drug Administration). – Dr. Zarkowski will be discussing off-label use of prescription medications in the presentation and will identify those issues. • Applicable CME staff have no relationships to disclose relating to the subject matter of this activity. • This activity has been independently reviewed for balance. Polypharmacy • Increasing incidence of ≥ 2 concurrent prescriptions for – Antidepressants – Antipsychotics – Sedative-hypnotics – Antidepressant-antipsychotic combinations – But not other combinations • Rare RPCDB studies of combinations • Uncertain gains for quality of care and clinical outcomes RPCDB = randomized placebo-controlled double-blind. Mojtabai R, et al. Arch Gen Psychiatry. 2010;67(1):26-36. 3 Types of Evidence • Opposing clinical indications and side FDA Indications, Off-Label Uses, and effects suggest an interaction limiting Side Effects efficacy • Underlying mechanism of action suggests an antagonistic interaction at receptors critical for efficacy • Clinical studies with simultaneous administration of medications confirm decreased efficacy – Humans – Rats – Mice Example of Study Exclusion Pramipexole and Antipsychotic Medication Meets First 2 Criteria But RPCDB Supports Combination • Pramipexole caused psychosis in • Augmenting antipsychotic medications with patients treated for RLS pramipexole to 4.25 mg (0.38 mg) – 24 participants (SC or SA) over 12 • Pramipexole is a dopamine agonist weeks – Significant affinity for D2 – Completion ACT 82% vs PBO 62% • Ki = 3.1 nM – Includes 1 drop out in active arm • Antagonism of D receptor is with disorganization 2 – 3 completers with new or crucial for antipsychotic worsening hallucinations at top efficacy dose – More affinity for D3 – PANSS-Pos • Ki = 0.23 nM • ACT -9.5 (48); PBO +20.9 (60)* • Proposed mechanism of P=.006 action for treating psychosis – PANSS-Neg • ACT -9.2 (28); PBO -15.7 (16) RLS = restless legs syndrome; SC = schizophrenia; SA = schizoaffective disorder; ACT = active; PBO = placebo; PANSS = Positive and Negative Syndrome Scale. Signorelli MS, et al. BMJ Case Rep. 2013;2013. Hollingworth SA, et al. Drugs Real World Outcomes. 2015;2(3):199-203. Sautel F, et al. Neuroreport. 1995;6(2):329-332. Wang S, et al. Nature. 2018;555(7695):269-273. Kelleher JP, et al. Eur Neuropsychopharmacol. 2012;22(6):415-418. Ranking the Prevalence of Interactions that Limit Efficacy • Electronic Chart Review – Genoa Healthcare Database • Largest provider of pharmacy services to behavioral health and addiction treatment communities – Multiple Community Mental Health organizations • All records between January 1, 2016 and May 20, 2018 – Inclusion based on concurrence of 3 types of evidence • Indications and side effects • Mechanism of action • Clinical studies of combination Zarkowski P. 2018; In preparation. #70 Fluoxetine and Cyproheptadine #70 Fluoxetine & Cyproheptadine #71 Sertraline & Cyproheptadine #70 Paroxetine & Cyproheptadine Opposing Clinical Actions and Side Effects Fluoxetine Cyproheptadine FDA indication for Off-label treatment for Major Depression Anorgasmia due to SSRIs Sexual Dysfunction in 36% of Case series of depressive patients on Fluoxetine relapse SSRI = selective serotonin reuptake inhibitor. Benazzi F, et al. Pharmacopsychiatry. 1994;27(6):246. Lauerma H. Acta Psychiatr Scand. 1996;93(1):69-70. Feder R. J Clin Psychiatry. 1991;52(4):163-164. Goldbloom DS, et al. J Clin Psychiatry. 1991;52(6):261-262. Christensen RC. J Clin Psychiatry. 1995;56(9):433-434. Conflicting Mechanism of Action Equilibrium Constant 5-HT1A Serotonin Receptor Ki (nM) Cyproheptadine Fluoxetine • Fluoxetine inhibits the reuptake of H1 0.5 6200 serotonin 5-HT1A 69 > 10,000 • Cyproheptadine is an antagonist at 5-HT 5-HT2A 6.1 196 1A • 5-HT and antidepressant efficacy 5-HT2C 2.2 181 1A SERT - 16 – Shown to be crucial for efficacy in forced swim protocol in rats – Suggested intermediate role in the MOA of antidepressants – Relevance of receptor highlighted by vilazodone and vortioxetine MOA = mechanism of action; SERT = serotonin transporter. Psychoactive Drug Screening Program (PDSP). https://pdsp.unc.edu/databases/pdsp.php. Accessed April 14, 2018. Redrobe JP, et al. Eur J Pharmacol. 1996;318(2-3):213-220. Schreiber S, et al. J Mol Neurosci. 2002;18(1-2):143-149. Navinés R, et al. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(8):1804-1809. Kirilly E, et al. Neuropsychopharmacol Hung. 2015;17(2):81-89. Clinical Interaction Supported by Case Studies • Reversal of antidepressant activity of fluoxetine by cyproheptadine – Case study of 3 males treated for anorgasmia • Loss of response of fluoxetine after addition of cyproheptadine – Case study of 2 patients taking fluoxetine for bulimia nervosa • Interaction not limited to fluoxetine – Case study of cyproheptadine reversing antidepressant effect of paroxetine Feder R. J Clin Psychiatry. 1991;52(4):163-164. Goldbloom DS, et al. J Clin Psychiatry. 1991;52(6):261-262. Christensen RC. J Clin Psychiatry. 1995;56(9):433-434. Suggestions to Try Instead • Dose reduction of fluoxetine • Switch to antidepressant with less sexual side effects – Mirtazapine • 5-HT2A antagonist – Bupropion • No serotonergic activity • Add trazodone to existing SSRI – Open-label study showed improvement in 4 dimensions of sexual function • Possible role of 5-HT2A Benazzi F, et al. Pharmacopsychiatry. 1994;27(6):246. Clayton AH, et al. Postgrad Med. 2014;126(2):91-99. Stryjer R, et al. Clin Neuropharmacol. 2009;32(2):82-84. #57 Amitriptyline and Naltrexone #57 Amitriptyline & Naltrexone #73 Nortriptyline & Naltrexone Clinical Actions Naltrexone Amitriptyline FDA indication for FDA indication for Alcohol and Opioid Use Depression Disorder Off-label use for Pain Rascol O, et al. Clin Neuropharmacol. 1987;10(6):560-564. Mechanism of Action Equilibrium Constant Interaction via Opioid Receptors Ki (nM) Naltrexone Naloxone Amitriptyline • Naltrexone is a long-acting opioid Opioid- 26 52 - blocker, similar to naloxone δ • Amitriptyline inhibits the reuptake Opioid- 1.75 30 - of serotonin and norepinephrine κ • 10 days of amitriptyline blocks Opioid- 0.39 3.7 - mechanically-induced allodynia μ from sciatic nerve cuffing in rats SERT - 39 – No effect from sertraline NET - 68 – Effect reversed by naloxone • μ and κ receptor knock out mice have localized MOA of TCAs to δ NET = norepinephrine transporter; TCA = tricyclic antidepressant. receptors Psychoactive Drug Screening Program (PDSP). https://pdsp.unc.edu/databases/pdsp.php. Accessed April 14, 2018. Benbouzid M, et al. Eur J Pain. 2008;12(8):1008-1017. Bohren Y, et al. Eur J Pain. 2010;14(7):700-704. Megat S, et al. Br J Pharmacol. 2015;172(4):1034-1044. Norepinephrine is the Missing Link • 21 days of nortriptyline blocked mechanically-induced allodynia from sciatic nerve cuffing in rats – Effect was blocked by propranolol • β(2)-AR antagonist ICI 118,551 – Not affected by • Yohimbine, α(2)-AR antagonist • Metoprolol or atenolol • β(3)-AR antagonist SR 59230A – Effect of nortriptyline was also totally absent in β(2)-AR-deficient mice AR = adrenergic receptor. Yalcin I, et al. Ann Neurol. 2009;65(2):218-225. Interaction Verified in Additional Pain Protocol • Acetic acid-induced abdominal constriction assay in mice – Naloxone shifts the dose-response curve of amitriptyline to the right • Studies on interaction in humans are scarce – In one case study 3 challenges of naltrexone caused depressive relapse 3 separate times in a patient that had responded to amitriptyline **P<.01 vs amitriptyline and vehicle regression line. Gray AM, et al. Br J Pharmacol. 1998;124(4):669-674. Schürks M, et al. Pharmacopsychiatry. 2005;38(2):100-102. Not All Pain Medications are Blocked by Naltrexone • NSAIDs – Naloxone had no effect on the dose-response curve of ASA in mice – Pretreatment with naltrexone blocked the analgesic response of codeine but not IBU in patients undergoing dental surgery • AEDs – Naltrexone blocked the antinociceptive properties of morphine but not gabapentin in mice injected with HSV-1 – Replicated in sciatic nerve cuffing NSAID = nonsteroidal anti-inflammatory drug; ASA = aspirin; IBU = ibuprofen; AED = anti-epileptic drug; HSV-1 = herpes simplex virus type-1. Gray AM, et al. Br J Pharmacol. 1998;124(4):669-674. Hersh EV, et al. Oral Surg Oral Med Oral Pathol. 1993;75(5):539-546. Takasaki I, et al. J Pharmacol Exp Ther. 2001;296(2):270-275. Benbouzid M, et al. Eur J Pain. 2008;12(8):1008-1017. #38 Amphetamine-Dextroamphetamine and Haloperidol #12 Amphetamine-Dextroamphetamine & Aripiprazole; #15 Amphetamine- Dextroamphetamine & Quetiapine; #16 Amphetamine-Dextroamphetamine & Risperidone; #27 Amphetamine-Dextroamphetamine & Olanzapine; #31 Amphetamine-Dextroamphetamine & Lurasidone; #38 Amphetamine- Dextroamphetamine & Haloperidol; #39 Amphetamine-Dextroamphetamine & Paliperidone; #48 Amphetamine-Dextroamphetamine + Asenapine Opposing Clinical Actions and Side Effects Haloperidol Dextroamphetamine effective Tx for FDA indication for ADHD Amphetamine-Induced Psychosis Drug-Induced Psychosis in 8% to 46% of regular users Opposite Effect on Clock depending