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 – – Antipsychotics – Sedative-hypnotics – -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 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

#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 –

• 5-HT2A antagonist – Bupropion • No serotonergic activity • Add 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 and Naltrexone

#57 Amitriptyline & Naltrexone #73 & 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 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 = . 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 • β(2)-AR antagonist ICI 118,551 – Not affected by • , α(2)-AR antagonist • or • β(3)-AR antagonist SR 59230A – Effect of nortriptyline was also totally absent in β(2)-AR-deficient mice

AR = 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

#12 Amphetamine-Dextroamphetamine & ; #15 Amphetamine- Dextroamphetamine & ; #16 Amphetamine-Dextroamphetamine & ; #27 Amphetamine-Dextroamphetamine & ; #31 Amphetamine-Dextroamphetamine & ; #38 Amphetamine- Dextroamphetamine & Haloperidol; #39 Amphetamine-Dextroamphetamine & ; #48 Amphetamine-Dextroamphetamine + 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 on dose, method, Speed in Healthy Participants and duration

ADHD = attention-deficit/hyperactivity disorder. Bramness JG, et al. BMC Psychiatry. 2012;12:221. Leelahanaj T, et al. J Med Assoc Thai. 2005;88 Suppl 3:S43-S52. Lake JI, et al. Neuropsychologia. 2013;51(2):284-292. Conflicting Mechanism of Action

Equilibrium Constant Interaction at D2 receptors

Ki (nM) Haloperidol Amphetamine • Amphetamine

D1 121 >10,000 – Increases release of D 2.7 >10,000 monoamines from presynaptic 2 storage vesicles D3 5.7 >10,000 – Inhibits reuptake of monoamines DAT >10,000 140 – Facilitates release of cytoplasmic SERT 2000 3000 presynaptic monoamines NET - 50 – Weak MAO inhibitor • Haloperidol is a dopamine antagonist

• D2 receptor is essential for antipsychotic efficacy DAT = dopamine transporter; MAO = monoamine oxidase. Psychoactive Drug Screening Program (PDSP). https://pdsp.unc.edu/databases/pdsp.php. Accessed May 8, 2018. Wang S, et al. Nature. 2018;555(7695):269-273. Studies Confirm Mutual Interaction

• Amphetamine reduced locomotor activity in hyperactive Coloboma mice mutants – Haloperidol blocked this effect • After 7 days of haloperidol, rats showed impaired sustained attention, increased reaction time, and more errors of omission – Amphetamine blocked this effect – Highest dose of amphetamine alone increased errors • Haloperidol blocked this effect • Studies in humans are rare – A single dose of amphetamine increased activity in 21 participants with schizophrenia on haloperidol Fan X, et al. Neurobiol Dis. 2007;26(1):201-211. Brockel BJ, et al. J Pharmacol Exp Ther. 1995;275(3):1090-1098. Cools R, et al. Philos Trans A Math Phys Eng Sci. 2004;362(1825):2871-2888. Goldberg TE, et al. Am J Psychiatry. 1991;148(1):78-84. Insurance Data Confirm Inferior Efficacy of Combination • US medical/pharmacy claims database – 22,622 children started on AAP after Tx with stimulant • Excluded cases with indication for AAP • 2127 cases left after all exclusions – 84,588 children started on non-AAP after stimulant for comparison • Atomoxetine, , • 16,508 cases left after same exclusions – 1857 matched pairs, 81% augmenters • Significantly higher rates of subsequent augmentation, health care resource utilization, and total health care costs AAP = . Sikirica V, et al. J Manag Care Pharm. 2012;18(9):676-689. Risk of Hospitalization after Restarting Stimulants

• Ontario Drug Benefit Database – October 1, 1999 to March 31, 2013 – 12,856 participants < 26 years old were hospitalized for psychosis or mania after starting a stimulant – 119 participants started stimulants < 60 days before first hospitalization – 64 controls between 120 and 180 days before first hospitalization – Odds ratio 1.86 (1.38–3.28) – 34% restarted on stimulants within 100 days of discharge • 45% were re-hospitalized within a median of 18 days Cressman AM, et al. J Clin Psychopharmacol. 2015;35(6):667-671. #34 Donepezil and Oxybutynin

#21 Donepezil & Benztropine; #28 Donepezil & Ranitidine; #34 Donepezil & Oxybutynin; #40 Donepezil & ; #58 Donepezil & Amitriptyline; #59 Donepezil & Diphenhydramine; #60 Donepezil & ; #61 Donepezil & Hydroxyzine Opposing Clinical Actions and Side Effects

Donepezil Oxybutynin FDA indication for FDA indication for Alzheimer’s Disease Bladder Muscle Dysfunction

ACB “definite class” 7% of patients develop associated with 0.33 Urinary Incontinence greater decline in MMSE over 2 years

ACB = anticholinergic cognitive burden; MMSE = Mini-Mental State Examination. Hashimoto M, et al. Lancet. 2000;356(9229):568. Fox C, et al. J Am Geriatr Soc. 2011;59(8):1477-1483. Conflicting Mechanism of Action

Equilibrium Constant Antagonism at Muscarinic Receptors

Ki (nM) Oxybutynin • Donepezil is a reversible acetylcholinesterase

M1 5.9 inhibitor

M2 15 – MOA via an increase in the concentration of

M3 5.3 acetylcholine – Activity at M1 and M2 relevant for cognition • Oxybutynin is an antagonist at muscarinic receptors

– M3 receptors are primarily responsible for detrusor contraction

Psychoactive Drug Screening Program (PDSP). https://pdsp.unc.edu/databases/pdsp.php. Accessed April 14, 2018. US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/. Accessed June 12, 2018. Abrams P, et al. Br J Pharmacol. 2006;148(5):565-578. Prospective Study Confirms Loss of Efficacy

• 3536 Nursing Home Residents – Higher functioning residents lost 1.08 per quarter on a 28-item ADL scale • Donepezil 70.5%, rivastigmine 19.9%, and galantamine 16.5% • No other anticholinergic medications – 376 residents with Tx for urine incontinence • Residents on oxybutynin lost an additional 0.54 per quarter • Similar findings with tolterodine • Combined significance P=.01 ADL = activity of daily living. Sink KM, et al. J Am Geriatr Soc. 2008;56(5):847-853. Avoiding Cognitive Effects in Overactive Bladder

• Agents with low lipid solubility are correlated with less cognitive effects – Darifenacin and trospium have the lowest lipid solubility with poor CNS penetration – Oxybutynin crosses the blood brain barrier freely

• Solifenacin is selective for M3 – Reduced cognitive effects

• is a B3 agonist – No effect on anticholinergic load

CNS = central nervous system. Callegari E, et al. Br J Clin Pharmacol. 2011;72(2):235-246. Oresković S, et al. Coll Antropol. 2012;36(1):243-248. Pagoria D, et al. Curr Urol Rep. 2011;12(5):351-357. Perk S, et al. J Manag Care Spec Pharm. 2016;22(9):1072-1084. #23 Amphetamine-Dextroamphetamine & Alprazolam

#10 Amphetamine-Dextroamphetamine & Clonazepam; #11 Atomoxetine & Clonazepam; #13 Amphetamine-Dextroamphetamine & Lorazepam; #14 Methylphenidate & Lorazepam; #23 Amphetamine-Dextroamphetamine & Alprazolam; #24 Atomoxetine & Lorazepam; #29 Methylphenidate & Alprazolam; #30 Methylphenidate & Clonazepam; #37 Amphetamine- Dextroamphetamine & Diazepam; #45 Atomoxetine & Alprazolam; #46 Methylphenidate & Diazepam Opposing Clinical Actions and Side Effects

Amphetamine Alprazolam FDA indication for ADHD FDA indication for Anxiety

Somnolence in up to 76% Anxiety in 8% leading to Memory Impairment in 33% discontinuation in 2.1% Cognitive Disorder in 29%

US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/. Accessed June 12, 2018. Mechanism of Action

Amphetamine Alprazolam

Tulane University School of Medicine. http://tmedweb.tulane.edu/pharmwiki/doku.php/dextroamphetamine. Accessed June 14, 2018. Griffin CE 3rd, et al. Ochsner J. 2013;13(2):214-223. Opposing Effect on Performance

• Computerized task to assess focus – 18 fully rested human participants – Dextroamphetamine 10 mg induced enhancement on behavioral measures compared to placebo • Also increased tunnel vision – Alprazolam impaired performance compared to placebo

Mills KC, et al. Hum Factors. 2001;43(2):310-327. Persisting Memory Impairment with Alprazolam

• Memory impairment 24 hours after a single 1 mg oral dose of alprazolam – 16 words in 8 practice trials – Alprazolam 9.8 words (1.2) group differed significantly from – Placebo 14.3 (0.7) at 24 hours • Longer trials of alprazolam lead to more persistent impairment – Marked impairment in word recall after 8 weeks of alprazolam vs placebo in patients with panic disorder – Persisting impairment at 24 weeks – No relative impairment at 3.5 years

Greenblatt DJ, et al. Clin Pharmacol Ther. 1988;44(3):326-334. Kiliç C, et al. Psychol Med. 1999;29(1):225-231. Alprazolam Impairs Discriminative Ability in Amphetamine Users • Pretreatment with alprazolam blocked the discriminative ability for dose of amphetamine and some of the self-reported effects – 6 healthy individuals became > 80% accurate on 4 consecutive days in discriminating dose – Amphetamine 0, 2.5, 5,10, and 15 mg – Alprazolam 0.5 mg pretreatment significantly attenuated discriminative ability to detect the highest dose of 15 mg • Pretreatment with alprazolam enhanced self-administration of methamphetamine in rats, shifting inverted “U’” to left

Rush CR, et al. J Clin Psychopharmacol. 2004;24(4):410-420. Spence AL, et al. Drug Alcohol Depend. 2016;166:209-217. Synergistic Impact in Impaired Driving and Accidents • Once alprazolam is detected, the most common additional substance in those pulled over for DUI of drugs is amphetamine – Sweden, 2001–2005 – Alprazolam-amphetamine combination prevalent in fatal accidents • Elevated prevalence of amphetamine- benzodiazepine combination in DUI cases – Finland, 1997–2008 • Amphetamine-benzodiazepine combination commonly found in seriously injured drivers – Denmark, 2007–2010

DUI = driving under the influence. Jones AW, et al. J Psychopharmacol. 2013;27(3):276-281. Blencowe T, et al. Ther Drug Monit. 2011;33(1):64-71. Wiese Simonsen K, et al. Forensic Sci Int. 2013;224(1-3):44-50. In Contrast to the Absence of Clinical Studies Showing Efficacy…

Google search: adderall and xanax reddit. #20 Propranolol and Atomoxetine

#20 Atomoxetine & Propranolol #52 Amphetamine-Dextroamphetamine & Metoprolol #53 Amphetamine-Dextroamphetamine & Propranolol #54 Atomoxetine & #55 Atomoxetine & Metoprolol Opposing Clinical Actions and Side Effects

Propranolol Atomoxetine FDA indication for FDA indication for ADHD Hypertension

22.4% with increase in Heart Rate of 20 bpm, Decreased Performance 12.4% with increase on Neuropsychometrics systolic BP of 20 mm Hg

bpm = beats per minute; BP = blood pressure. US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/. Accessed June 12, 2018. Kostis JB, et al. Psychopharmacology. 1990;102(2):163-170. Conflicting Mechanism of Action

Equilibrium Constant Adrenergic β Receptors

Ki (nM) Propranolol Atomoxetine • Atomoxetine has a preferential effect

B1 1.3 - on reuptake of norepinephrine B 0.33 - – Less affinity for serotonin 2 transporter NET - 5 • Propranolol is a non-cardioselective SERT - 77 lipid soluble noradrenergic antagonist • Contrary action verified in extinction training in rats – Atomoxetine increased strength of learning – Propranolol had opposite effect

Psychoactive Drug Screening Program (PDSP). https://pdsp.unc.edu/databases/pdsp.php. Accessed April 14, 2018. Ding YS, et al. Neuroimage. 2014;86:164-171. Janak PH, et al. Neuropsychopharmacology. 2012;37(4):975-985. Propranolol and Depressive Symptoms

Early Case Studies Suggest Link Meta-Analysis Results Conflict • Depressive symptoms are linked to • Meta-analysis of RPCDB studies of β- starting propranolol or subsequent blockers in the Tx of MI, HF, or HTN dose increases – Increased incidence of fatigue • Depressive symptoms – No increased risk of depression resolved after stopping • An earlier meta-analysis including studies propranolol comparing propranolol to other β-blockers reported contrary results – No recurrence with starting – Organic mood disorder, depressed atenolol as a substitute for type propranolol • Propranolol was associated with more fatigue, decreased energy, decreased libido, anorexia, and poor concentration MI = myocardial infarction; HF = heart failure; HTN = hypertension. Petrie WM, et al. Am J Psychiatry. 1982;139(1):92-94. McNeil GN, et al. Am J Psychiatry. 1982;139(9):1187-1188. Parker WA. Clin Pharm. 1985;4(2):214-218. Ko DT, et al. JAMA. 2002;288(3):351-357. Patten SB. Can J Psychiatry. 1990;35(3):257-259. Propranolol Abolishes Effect of Atomoxetine

• β-adrenoceptor blockade blocks atomoxetine-induced risk taking – Rats performed a probabilistic discounting task as a model for risk taking • 1 lever guaranteed a single pellet • Other lever delivered 4 pellets with decreasing chance from 100% to 12.5% – Atomoxetine increased risk taking • More pulls of risky lever, less likely to pull safe lever after loss – Co-administration of propranolol blocked this effect • did not

Yang FN, et al. Physiol Behav. 2016;153:125-132. Avoiding Cardiac Effects and Polypharmacy

• Dose reduction of atomoxetine • Switch atomoxetine to guanfacine – Less risk of hypertension Lipid Cardio- Non- • Switch propranolol to a non-lipid Solubility selective selective soluble β-blocker Propranolol High - – Atenolol has lower levels in CSF * – Atenolol has been reported to have Intermediate Metoprolol Carvedilol* less impact on cognitive function • Similar to ACE inhibitors Low Atenolol – Other studies have highlighted atenolol’s anticholinergic activity and impact on cognitive function • Blood brain barrier changes with age CSF = cerebrospinal fluid; ACE = angiotensin-converting enzyme. US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/. Accessed June 12, 2018. Posey DJ, et al. CNS Drug Rev. 2007;13(4):465-474. Neil-Dwyer G. Aviat Space Environ Med. 1981;52(11 Pt 2):S19-S22. Bulpitt CJ, et al. J Cardiovasc Pharmacol. 1992;19 Suppl 6:S100-S104. Lanctôt KL, et al. Psychosomatics. 2014;55(1):61-68. #17 Ropinirole and Olanzapine

#17 Ropinirole & Olanzapine #41 Ropinirole & Paliperidone #42 Ropinirole & Risperidone #66 Ropinirole & Opposing Clinical Actions and Side Effects

Olanzapine Ropinirole FDA indication for FDA indication for RLS Schizophrenia

Psychosis in 8% of Parkinson’s Disease 10% on 15 mg patients treated with Case series of qd report Ropinirole RLS Akathisia 2 of 35 treated for RLS

US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/. Accessed June 12, 2018. Stoner SC, et al. Ann Pharmacother. 2009;43(9):1426-1432. Zhao M, et al. J Clin Neurosci. 2014;21(9):1622-1625. Aggarwal S, et al. Curr Drug Saf. 2010;5(2):129-131. Kraus T, et al. J Clin Psychopharmacol. 1999;19(5):478-479. Conflicting Mechanism of Action

Dopamine D2 Receptors Antagonistic Action • D2 receptor is essential for • Olanzapine is a dopamine antipsychotic efficacy antagonist at D2 • Akathisia associated with blockade • Ropinirole is a dopamine agonist of D receptors 2 – Highest affinity for D2, D3, D4 • RLS symptoms • Antagonistic interaction verified via – Absent during the day during recruitment of β-arrestin2 to the hyper-dopaminergic state dopamine D2 receptor – Worse during the evening during hypo-dopaminergic state

Wang S, et al. Nature. 2018;555(7695):269-273. Kumar R, et al. Curr Opin Psychiatry. 2009;22(3):293-299. Khan FH, et al. J Neurol. 2017;264(8):1634-1641. Kvernmo T, et al. Clin Ther. 2006;28(8):1065-1078. Klewe IV, et al. Neuropharmacology. 2008;54(8):1215-1222. Clinical Studies of Combination are Scarce

• Case Study – Onset of RLS with olanzapine • Symptoms resolved with reduction of dose of olanzapine and addition of ropinirole – No long-term follow-up on antipsychotic efficacy

Kang SG, et al. J Psychopharmacol. 2009;23(5):597-601. Alternative Treatments for Monotherapy • RLS – Alternative treatments to consider • Fe replacement at < 75 mcg/L • Pregabalin • Gabapentin enacarbil • Pneumatic compression • Psychosis – Onset of RLS is dose dependent • Often resolves with dose reduction • Resolved with discontinuation – RLS did not recur with switch to different antipsychotic – EPS/RLS modulated by type of AAP EPS = extrapyramidal symptoms. Winkelman JW, et al. Neurology. 2016;87(24):2585-2593. Zhao M, et al. J Clin Neurosci. 2014;21(9):1622-1625. Kang SG, et al. J Psychopharmacol. 2009;23(5):597-601. Leucht S, et al. Lancet. 2013;382(9896):951-962. Aggarwal S, et al. Curr Drug Saf. 2010;5(2):129-131. Kraus T, et al. J Clin Psychopharmacol. 1999;19(5):478-479. #4 Clonidine and Mirtazapine

#4 Mirtazapine & Clonidine #62 Mirtazapine & Guanfacine Opposing Clinical Actions and Side Effects

Clonidine Mirtazapine Off-label treatment for ADHD FDA indication for Inattention Major Depression

Half of studies report increase in incidence of Sedation in 54% Major Depression Half-life of 22 hours —usually 1.5% to 2.3%

Childress AC, et al. Drugs Today. 2012;48(3):207-217. Clonidine/Adverse Effects. www.micromedexsolutions.com. Accessed April 14, 2018. US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/. Accessed June 12, 2018. Conflicting Mechanism of Action

Equilibrium Constant α-2A Adrenoceptors

Ki (nM) Clonidine Mirtazapine • Clonidine’s positive effect on α-2A 43 20 attention is mediated via stimulation α-2B 106 - of postsynaptic α-2A receptors α-2C 233 18 • Mirtazapine enhances serotonergic transmission by blocking presynaptic 5-HT2A >10,000 69 α-2A heteroreceptors H1 - 1.3

Psychoactive Drug Screening Program (PDSP). https://pdsp.unc.edu/databases/pdsp.php. Accessed August 14, 2017 and April 14, 2018. Sallee FR. The Role of Alpha 2 Agonists in the Attention Deficit/Hyperactivity Disorder Treatment Paradigm. 2008. www.medscape.org/viewarticle/577743. Accessed June 12, 2018. Davis R, et al. CNS Drugs. 1996;5(5):389-402. Studies Confirm an Interaction

• Mirtazapine blocks a discriminative stimulus protocol in rats – Clonidine has opposite effect • Mirtazapine blocks the antihypertensive effect of clonidine – 2 case reports of hypertensive urgency

Dekeyne A, et al. Neuropharmacology. 2006;51(4):718-726. Abo-Zena RA, et al. Pharmacotherapy. 2000;20(4):476-478. Strategies for Avoiding Polypharmacy

• For treating HTN, select an anti- hypertensive medication with less association with inducing depressive symptoms – ACE inhibitors – Angiotensin receptor blockers • For treating major depression, select an antidepressant with efficacy for treating inattention – Bupropion

Boal AH, et al. Hypertension. 2016;68(5):1132-1138. Wilens TE, et al. Am J Psychiatry. 2001;158(2):282-288. #2 and Sertraline

#2 Clozapine & Sertraline #5 Clozapine & Citalopram #6 Clozapine & Fluoxetine #9 Clozapine & Paroxetine #19 Clozapine & Escitalopram #26 Clozapine & Fluvoxamine Opposing Clinical Actions and Side Effects

Clozapine FDA indication for Schizophrenia

Sertraline FDA indication for OCD

21% with emergence or worsening of Obsessions vs 1.3% on other antipsychotics

OCD = obsessive-compulsive disorder. de Haan L, et al. J Clin Psychiatry. 1999;60(6):364-365. Conflicting Mechanism of Action

Equilibrium Constant Serotonergic Receptors

Ki (nM) Clozapine Nor Sertraline • 5-HT2A and 5-HT2C are crucial for clozapine efficacy of SSRIs in treating OCD D1 215 14.3 - • Sertraline blocks the reuptake of D2 128 100 - serotonin

D3 240 153 - • Clozapine is an antagonist at

5-HT1A 160 13.9 >10,000 serotonergic receptors

5-HT2A 2.6 10.9 -

5-HT2C 4.8 - - SERT 1600 316 1.5

Psychoactive Drug Screening Program (PDSP). https://pdsp.unc.edu/databases/pdsp.php. Accessed May 10, 2018. Delgado PL, et al. J Psychoactive Drugs. 1998;30(4):359-366. Jenck F, et al. Expert Opin Investig Drugs. 1998;7(10):1587-1599. Case Reports Document Efficacy

• Worsening OCD symptoms in clozapine treated 39-year-old male after augmenting with fluvoxamine – Associated with elevation in clozapine serum levels – OCD symptoms improved after addition of sertraline • No CYP1A2 inhibition • Additional case of treating OCD induced from clozapine with sertraline

Rahman MS, et al. Am J Psychiatry. 1998;155(11):1629-1630. Allen L, et al. Am J Psychiatry. 1994;151(7):1096-1097. Meta-Analysis on Reverse Combination Adding Antipsychotics to SSRIs • Augmentation Strategies for OCD – Antipsychotics added to SSRIs – 12 RPCDB with 394 participants – Percentage of responders – Risperidone with significant effect size • Antipsychotic augmentation shown more effective for comorbidities – Tic-related OCD – Schizotypal symptoms – Poor insight

Dold M, et al. Int J Neuropsychopharmacol. 2013;16(3):557-574. Hirschtritt ME, et al. JAMA. 2017;317(13):1358-1367. #1 Prazosin and Venlafaxine

#1 Venlafaxine & Prazosin #3 Duloxetine & Prazosin #32 Duloxetine & #33 Venlafaxine & Tamsulosin Opposing Clinical Actions and Side Effects

Venlafaxine FDA indication for Major Depression Prazosin Off-label treatment for PTSD and Nightmares 7% of patients treated with Venlafaxine had Nightmares vs 2% on placebo

PTSD = posttraumatic stress disorder. US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/. Accessed June 12, 2018. Singh B, et al. Prim Care Companion CNS Disord. 2016;18(4). Conflicting Mechanism of Action

Equilibrium Constant Antagonism at α-Adrenoceptors

Ki (nM) Prazosin Venlafaxine α-1A 0.37 >10,000 • Venlafaxine is a serotonin and norepinephrine reuptake inhibitor α-1B 0.32 - • Prazosin is a antagonist at α-1 α-1D 0.22 - receptors α-2A 302 >10,000 α-2B 31 - α-2C 11 - SERT - 80 NET - 385

Psychoactive Drug Screening Program (PDSP). https://pdsp.unc.edu/databases/pdsp.php. Accessed April 14, 2018. Weikop P, et al. J Psychopharmacol. 2004;18(3):395-403. Neurophysiological Cancelation

• Prazosin blocks the discriminative stimulus of a specific norepinephrine reuptake inhibitor, reboxetine in rats – Full substitution was attained with venlafaxine • Prazosin attenuates the venlafaxine induced increase in serotonergic activity in the prefrontal cortex of rats

Millan MJ, et al. Int J Neuropsychopharmacol. 2007;10(5):579-593. Weikop P, et al. J Psychopharmacol. 2004;18(3):395-403. Avoiding Nightmares and Polypharmacy • Noradrenergic medications are to be avoided in PTSD • The Best Practices task force of the American Academy of Sleep Medicine for the treatment of nightmare disorder – Prazosin is recommended, level A – Fluvoxamine may be considered, level C – Venlafaxine is not suggested, level B • Based on a large placebo- controlled study in which most symptoms of PTSD improved with a 12-week course, disturbing dreams did not

Boehnlein JK, et al. J Psychiatr Pract. 2007;13(2):72-78. Aurora RN, et al. J Clin Sleep Med. 2010;6(4):389-401. Practical Take-Aways • We have an impressive number of medications in our psychiatric formulary, but a limited number of neurotransmitters of interest to modulate. Often more extensive medication regimens are associated with inferior results • Anticholinergic medications are often prescribed for geriatric patients for numerous indications, but limit the efficacy of acetylcholinesterase inhibitors. Anticholinergics are not all the same. Know which can be safely prescribed • Although stimulants are commonly prescribed to increase focus and improve attention, concurrent prescription of benzodiazepines is associated with increased risk of automobile collisions and other accidents