ADDRESSING THE INTOLERABLE: PRACTICAL STRATEGIES TO

ADDRESSING THE INTOLERABLE: PRACTICAL STRATEGIES TO MITIGATE PSYCHOTROPIC SIDE EFFECTS

Rajnish Mago, MDClinical Professor, Department of Psychiatry, SUNY Upstate Medical University

Learning Objectives

•Employ strategies to mitigate the risk for psychotropic side effects that impact medication adherence

•Apply evidence-based strategies to the clinical management of troubling side effects, including akathisia, sexual dysfunction, tardive dyskinesia, and metabolic effects

COMMON Adverse Effects

•Nausea

•Dry mouth

•Excessive sweating

•Tremors

•Akathisia

•Sexual dysfunction

•Weight gain

•Tardive dyskinesia

What Sucks Is That…

•Great majority are NUISANCE side effects rather than MEDICALLY serious

•Also, many that lead to discontinuation SUBSIDE after 2 to 4 weeks

Call To Action!

For each adverse effect—a menu of options

Non-pharmacological or pharmacological

Level 1, Level 2, Level 3

Nausea

Nausea: PDR (≥ 2 X Placebo)

> 30% Divalproex ER 48%, Venlafaxine 31%

> 20% Paroxetine 26%, Vortioxetine 26%, Sertraline 25%, Vilazodone 23%,Bupropion 22%, Fluoxetine 22%,Atomoxetine 21%, Citalopram 21%

> 10% Escitalopram 15%, Modafinil 11%, Risperidone 11%

> 5% Lamotrigine 7%, Mixed amphetamine salts 7%, Lisdexamfetamine 6%

Nausea

•Very uncomfortable!•Most frequent cause of discontinuation in antidepressant clinical trials

Nausea: Level 1

Example: Titrate antidepressant up over one week. Nausea on duloxetine Started at 60 mg/day: 33%30 mg/day for one week, then 60 mg/day: 16%

Whitmyer VG et al. J Clin Psychiatry 2007;68(12):1921-30;Dunner DL et al. Curr Ther Res Clin Exp 2005;66(6):522-40.

Nausea: Level 1

Example: Strategies to lower peak levelsSustained-release ORSplit dose and give with separate meals

- Atomoxetine once a day—34%- Atomoxetine twice a day—17%

Camporeale A et al. J Psychopharmacol 2015;29(1):3-14.

Nausea: Level 1

Simple anti-nausea treatmentGinger root 550 mg capsules

One or two capsules three times a day

Giacosa A et al. Eur Rev Med Pharmacol Sci 2015;19(7):1291-6;Marx W et al. Curr Opin Support Palliat Care 2015;9(2):189-95.

Nausea: Level 2

Prescription anti-nausea medications

- Ondansetron (use orally dissolving tablet) 4 to 8 mg every 6 hours, if needed

- Mirtazapine (blocks 5HT-3 receptors, just like the setrons)

Pedersen L, Klysner R. Int Clin Psychopharmacol 1997;12(1):59-60.

Dry Mouth

Dry Mouth: Why Is It Important?

•Common with many psychotropic medications

•May cause dental caries, oral ulcers

Bardow A et al. Arch Oral Biol 2001;46(5):413-23; Cockburn N et al. J Affect Disord 2017;223:184-93;

Fratto G, Manzon L. Int J Psychiatry Med 2014;48(3):185-97; Kisley S. Can J Psychiatry 2016;61(5):277-82;

Rindal DB et al. Community Dent Oral Epidemiol 2005;33(1):74-80.

Dry Mouth: Level 1

Xylitol-containing products (chewing gum, lozenge)

Dry Mouth: Level 1

Saliva substitutes/oral moisturizers e.g., Biotene (gel, oral rinse, gum, toothpaste, etc.)

Jose A et al. (2017). J Clin Dent 2017;28(2):32-8;Mouly SJ et al. J Clin Psychopharmacol 2007;27(5):437-43.

Aliko A et al. Rheumatol Int 2012;32(9):2877-81.

Dry Mouth: Level 2

Medication to stimulate saliva productionExample: Pilocarpine

Masters KJ. Am J Psychiatry 2005;162(5):1023;Salah RS, Cameron OG. Am J Psychiatry 1996;153(4):579.

Dry Mouth: Level 2

Prefer LOCALLY acting medication

Pilocarpine eye drops

Antidepressant-Induced Excessive Sweating (ADIES)

PDR (≥ 2 X placebo)

> 20% Bupropion 22%

> 10% Venlafaxine 14%, Citalopram 11%, Paroxetine 11%

> 5% Levomilnacipran 9%, Fluoxetine 8%, Sertraline 8%, Duloxetine 6%, Escitalopram 5%

< 5% Atomoxetine 4%, Lisdexamfetamine 3% Modafinil 1%, Buspirone 1%

Management?

•Wait-and-watch? •Dose reduction?•Change antidepressant?

Antidotes?

1. Glycopyrrolate:•Anticholinergic•Mostly does not cross blood-brain barrier •1 to 2 mg, up to three times a day•Use PRN

Mago R. J Clin Psychopharmacol 2013;33(2):279-80.

Antidotes?

2. Terazosin: alpha blocker:•Can cause orthostatic hypotension

•Needs titration by 1 mg per week or slower

Mago R et al. Ann Clin Psychiatry 2013;25(3):186-92.

Tremors

Why Is It Important?

•A leading cause of discontinuation, e.g., lithium

Mago R et al. Harv Rev Psychiatry 2014;22(6):363-6.

Tremor: PDR (≥ 2 X Placebo)

> 20% Lithium, Divalproex 25%, Bupropion 21%

> 5% SSRIs 8%, Olanzapine 6%, Aripiprazole 6%

< 5% Lamotrigine 4%, Vilazodone 2%, Quetiapine 2%, Buspirone 1%

Tremor: How to Monitor?

Tremors: Level 1

1. Reduce caffeine (but caution with lithium)2. Sustained-release preparations3. Take medication at bedtime (peak during

sleep)

Tremors: Level 2

1. Antipsychotic-induced tremor:•Anticholinergics (e.g., benztropine 2 to 6 mg/day)

•Amantadine2. Lithium-induced tremor:

Beta-blocker—does not have to be centrally-acting

Metoprolol, atenolol

Akathisia

Incidence

•Ziprasidone 16%•Cariprazine 16%•Aripiprazole 13%•Brexpiprazole? 4–7%•Risperidone 8%•Olanzapine 6%•Quetiapine 4%•Iloperidone 2%•Lumateperone 2%

Akathisia: Levels 1 and 2

•Identify!•Titrate up slowly•Check serum ferritin •Decrease dose if possible (usually dose-dependent)

•Change antipsychotic to one with lower akathisia risk?

Miller CH, Fleischhacker WW. Drug Saf 2000;22(1):73-81.

Akathisia: Level 3

(NOT anticholinergics)1. Propranolol

NOT beta-blockers that do not cross the blood-brain barrier and/or are cardioselective

20 mg twice daily on day 1, then 40 mg twice daily

Consider higher dose

Consider change to long-actingRathbone J, Soares-Weiser K. Cochrane Database Syst Rev 2006;2006(4):CD003727;

Lima AR et al. Cochrane Database Syst Rev 2004;2004(4):CD001946.

Akathisia: Level 3

2. Clonazepam

3. Mirtazapine (a 5-HT2A antagonist)

Important: Not more than 15 mg/day

Praharaj SK et al. Ther Adv Psychopharmacol 2015;5(5):307-13;Poyurovsky M et al. Biol Psychiatry 2006;59(11):1071-7;

Laoutidis ZG, Luckhaus C. Int J Neuropsychopharmacol 2014;17(5):823-32.

Sexual Dysfunction

What Are My Chances of Getting Sexual Dysfunction?

•CANNOT rely on percentages from PDR•Large study of patients on a single antidepressant and no other known cause:

about 25%

Clayton AH et al. J Clin Psychiatry 2002;63(4):357-66; Williams VS et al. J Clin Psychiatry 2006;67(2):204-10;

Montejo-González AL et al. J Sex Marital Ther 1997;23(3):176-94.

More in Men or in Women?

•Incidence is the SAME

Men 34%

Women 33%

•May be more severe in women

Clayton AH et al. J Clin Psychiatry 2002;63(4):357-66; Williams VS et al. J Clin Psychiatry 2006;67(2):204-10;

Montejo-González AL et al. J Sex Marital Ther 1997;23(3):176-94.

Management of Antidepressant-Induced Sexual Dysfunction (ADISD)

1. Wait-and-watch2. Reduce dose3. Drug holidays4. Switch to another antidepressant5. Add an “antidote”

1. Wait-and-Watch?

•Even after waiting for 6 to 18 months:

10%—full improvement

Another 10%—partial improvement•Waiting may be OK if: mild, orgasmic, < 4 to 6 months

Montejo-González AL et al. J Sex Marital Ther 1997;23(3):176-94;Montejo AL et al. J Clin Psychiatry 2001;62(Suppl 3):10-21;.Ashton AK, Rosen RC. J Sex Marital Ther 1998;24(3):191-2;

Zajecka J. J Clin Psychiatry 2001;62(Suppl 3):35-43.

2. Drug Holidays?

•Effective for sertraline & paroxetine in 50%•Not for fluoxetine

Rothschild AJ. Am J Psychiatry 1995;152(10):1514-6.

3. Switch to Another Antidepressant?

•Absent or very low: Bupropion, MirtazapineTransdermal selegilineMoclobemide

4. Add an Antidote: Bupropion?

•All three clinical trials done in the United States: Negative

Masand PS et al. Am J Psychiatry 2001;158(5):805-7;Clayton AH et al. J Clin Psychiatry 2004;65(1):62-7;

DeBattista C et al. J Clin Psychiatry.2005;66(7):844-8.

So, Should We Add Bupropion?

1. SWITCH to bupropion

2. Consider if:

- patient is still depressed, or

- problem is mainly with desire

Add a Phosphodiesterase-5 (PDE-5) Inhibitor

•Work even in antidepressant-induced erectile dysfunction

•Arousal, erectile function, ejaculation, orgasm, and overall satisfaction improved

•Not as effective for women•Tadalafil now ~ $1 per 20 mg pill

Fava M et al. J Clin Psychiatry 2006;67(2):240-6;Nurnberg HG et al. JAMA 2003;289(1):54-64.

Weight Gain

Treatment of Weight Gain

1. Metformin extended release (ER) 1000 to 2000 mg/day

2. Topiramate 100 to 300 mg/day3. Amantadine 100 to 400 mg/day4. Melatonin 5 mg/day5. Medications approved for treatment of

obesity

De Hert M et al. CNS Drugs 2012;26(9):733-59.

Metformin?

•For weight gain on second-generation antipsychotics

•Most effective of several options•In those who had gained >10% of baseline weight•reduced weight by 7.5%

de Silva VA et al. BMC Psychiatry 2016;16(1):341;Zheng W et al. J Clin Psychopharmacol 2015;35(5):499-509;

Maayan L et al. Neuropsychopharmacology 2010;35(7):1520-30.

Who Is Most Likely to Benefit?

•NOT only if serum glucose was increased•Younger/recently started on the antipsychotic/not markedly obese

•Had rapid weight gain

Hasnain M, Vieweg WV. Acta Psychiatr Scand 2013;128(6):488-9;Jarskog LF et al. Am J Psychiatry 2013;170(9):1032-40.

Before Starting Metformin

•NOT in elderly or medically ill (heart failure, hypoxia, etc.)

•Baseline assessment—clinical, hepatic function tests, basic metabolic panel

•Counsel: •Avoid heavy alcohol use•One multivitamin pill per day

•Commonest side effect: diarrhea

Treating With Metformin

•Metformin extended release (ER) 500 mg one per day after largest meal of the day

•Increase every 1 to 2 weeks to 1000 mg twice daily. Higher dose is better!

•Check vitamin B12 level once a year

Tardive Dyskinesia

Management: First-line

1. Taper off anticholinergic medication

2. Stop the causative dopamine-blocking medication, if possible

3. Switch to a second-generation antipsychotic

4. Switch to quetiapine?

5. Prescribe a vesicular monoamine transporter (VMAT) inhibitor

Egan MF et al. Schizophr Bull 1997;23(4):583-609;Bhidayasiri R et al. Neurology 2013;81(5):463-9;Bhidayasiri R et al. J Neurol Sci 2018;389:67-75;

Caroff SN et al. J Clin Psychiatry 2011;72(3):295-303;Emsley R et al. J Clin Psychiatry 2004;65(5):696-701.

VMAT2

1. Vesicular monoamine transporter 2

2. Transports dopamine (and other monoamine neurotransmitters) from the cytoplasm into vesicles

3. So, protects them from being degraded

4. VMAT1 – periphery, VMAT2 – central nervous system

Hauser RA et al. Am J Psychiatry 2017;174(5):476-84.

VMAT2 Inhibitors

1. Tetrabenazine – FDA-approved for Huntington’s chorea

2. Valbenazine – FDA-approved for tardive dyskinesia

3. Deutetrabenazine – FDA-approved for tardive dyskinesia

Ondo WG et al. 1999;156(8):1279-81;Hauser RA et al. Am J Psychiatry 2017;174(5):476-84;

Anderson KE et al. Lancet Psychiatry 2017;4(8):595-604.

Management: Second-line

1. Switch to clozapine?

2. Increase dopamine blockade., e.g., risperidone?

3. Add a benzodiazepine like clonazepam?

4. Add amantadine?

5. Add Ginkgo biloba?

Louzã MR, Bassitt DP. J Clin Psychopharmacol 2005;25(2):180-2; Bai YM et al. J Clin Psychiatry 2003;64(11):1342-8; Thaker GK et al. Am J Psychiatry 1990;147(4):445-51; Bhidayasiri R et al. Neurology

2013;81(5):463-9; Bhidayasiri R et al. J Neurol Sci 2018;389:67-75; Vijayakumar D, Jankovic J. Drugs 2016;76(7):779-87; Angus S et al. J Clin Psychopharmacol 1997;17(2):88-91; Pappa S et al. Clin

Neuropharmacol 2010;33(6):271-5; Zheng W et al. Pharmacopsychiatry 2016;49(3):107-11.

Call to Action!

For each adverse effect – a menu of options

Non-pharmacological or pharmacological

Level 1, Level 2, Level 3

Posttest Question 1

What is one of the most common side effects causing discontinuation of antidepressant clinical trials?

A. Dry mouthB. Excessive sweatingC.NauseaD.Tremors

Posttest Question 2

Of the following atypical antipsychotics, which agent demonstrates the lowest association with akathisia?

A. ZiprasidoneB. QuetiapineC.CariprazineD.Aripiprazole

Posttest Question 3

Which of the following statements about antidepressant-induced sexual dysfunction is correct?

A. Men have a higher incidence of sexual dysfunctionB. Women have a higher incidence of sexual dysfunctionC.Men and women have a similar incidence of sexual

dysfunction, but severity may be worse in menD.Men and women have a similar incidence of sexual

dysfunction, but severity may be worse in women