managing side effects of psychiatric medications

Managing Side Effects of Psychiatric Medications

ARS PRE QUESTIONS

Managing Side Effects of Psychiatric Medications

Adverse Drug Effects: Key Issues• Common:

– Among patients taking an SSRI, 52% had >3 adverse effects– Psychiatric adverse drug events account for 90,000 annual ER visits

• Contributor to nonadherence• Risk/benefit considerations:

– Transient vs. persistent? – Dose-related?– Dangerous vs. merely annoying?– Distinguish adverse drug effects from 1º illness symptoms (e.g.,

suicidality, sexual dysfunction, lethargy)– Paradoxical drug effects (e.g., nausea from ondansetron)– When is a drug’s efficacy unique (e.g., clozapine) vs. feasibility of

changing medications?– Pharmacokinetic interactions (eg, grapefruit juice and CYP450 3A4)– Are there viable management strategies

Hu et al. J Clin Psychiatry. 2004; 65: 959-965; Hampton et al.JAMA Psychiatry 2014; 71: 1006-1014.

Adverse Effects: Time Course Considerations

Goldberg & Ernst. Psych Clin N Amer. 2016; 39: 375-385.

Headache Nausea Sedation Insomnia Sexual Dysfxn

Weight Gain or ↑ Appetite

Weight Loss or↓ Appetite

EPS or tremor

SSRIs X X X X X X X

SNRIs X X X VEN

Bupropion X X X X X X

Lithium X X

DVPX X X

CBZ X X

LTG X X

AAPs ARI, PAL X X X X

Stimulants X X

* Occurring in >10% of subjects in FDA registration trials

Abbreviations: AAPs=Atypical antipsychotics; ARI=aripiprazole; CBZ=carbamazepine; DVPX=divalproex; LTG=lamotrigine; PAL=paliperidone; SNRIs=serotonin-norepinephrine reuptake inhibitors; SSRIs=selective serotonin reuptake inhibitors; VEN=venlafaxineAdapted from Goldberg & Ernst, Managing the Side Effects of Psychotropic Medications. Am Psych Press. 2012.

Common* Adverse Effects of Psychotropic Drugs

Psychotropics and Sexual Dysfunction

Antidepressants: wide variability (25-80%)Antidepressants with least risk for sexual dysfunction:

Serretti & Chiason, J Clin Psychopharmacol 2009; 29(3): 259-66; Clayton et al. J Clin Psychiatry. 2002;63(4):357-366; Boyarsky et al. Depress Anxiety. 1999;9(4):175-179; Clayton et al. J Clin Psychiatry. 2007;68(12):1860-1866; Clayton et al. J Sex Med 2013; 10(10):2465-2476;

Clayton et al. Int Clin Psychopharmacol 2015;30(4):216-223; Clayton et al. Int Clin Psychopharmacol 2015;30(6):307-315; Clayton et al. J Sex Med 2013;10(3):768-776;. Clayton et al. J Sex Med. 2007;4(4 Pt 1):917-929; Jacobsen et al. J Sex Med 2015; 12(10):2036-2048; Serretti & Chiason, Int Clin Psychopharmacol 2011; 26: 130-140.

• vilazodone• desvenlafaxine• vortioxetine

• bupropion• mirtazapine• seligiline transdermal system

Antipsychotics: meta-analysis (N=7,975):thioridazine > clozapine > haloperidol > risperidone > olanzapine > aripiprazole > perphenazine > ziprasidone > quetiapine

Strategies to Counter Iatrogenic Sexual DysfunctionStrategy Pro’s Con’sDopamine agonists (amantadine, bromocriptine, pramipexole)

May reverse antipsychotic-associated ↑ prolactin

No large controlled trials, may not help other mechanisms

Bupropion 1 (+) placebo-controlled trial, 150 mg BID

2 (-) placebo-controlled trials

Buspirone 1 small (+) randomized placebo-controlled trial

1 (-) small placebo-controlled trial

Phosphodiesterase inhibitors (+) placebo-controlled trials in men and women

Non-ideal long-term solution

Testosterone gel or transdermal

1 (+) placebo-controlled trial in men and women

Androgenizing effects in women?

Methylphenidate Open label case series (only) Abuse potential

Switch agents Escitalopram→vortioxetine: significant global improvement

Replacement agents may be less effective or have own AEs

Safarinejad, BJU Int 2010; 106: 840-847; Masand et al., Am J Psychiatr 2001; 158: 06-807 ; DeBattista et al., J Clin Psychiatry 2005; 66: 844-848; Landén et al., J Clin Psychopharmacol 1998; 19: 268-271; Michelson et al., Am J Psychiatry 2000; 157: 239-243; Nurnberger et al., JAMA 2003; 289: 56-64;

Fava et al., J Clin Psychiatry 2006; 67: 240-246; Nurnberg et al., JAMA 2008; 300: 395-404; Amiaz et al., J Sex Marital Therapy 2011; 37: 243-254; Fooladi et al., J Sex Med 2014; 11: 831-839; Roeloffs et al., J Clin Psychiatry 1996; 57: 548; Jacobsen et al., J Sex Med 2015; 12: 2036-2048

Nausea: Incidence (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: Initial Management Strategies

• Gradual instead of rapid titration of serotonergic antidepressants, or divalproex, may minimize nausea

• Take medication after food• Sustained-release/ divided dosing/ with separate meals• High fat, e.g., spoonful of peanut butter• Ginger root 550 mg - two pills three times a day• Treat GERD/ gastritis with PPIs

*Whitmyer et al. (2007). **Dunner et al. (2006).

Nausea: Pharmacological Management

• Ondansetron 4 mg PO q 4-6o PRN or granisetron transdermal patch

• Add mirtazapine 15 to 30 mg/day (5HT-3 blockade, similar to setrons)

• Trimethobenzamide 300 mg PO q 4-6o PRN• Promethazine 12.5-25 mg PO BID PRN• Prochlorperazine 5-10 mg PO or 25 mg PR 1-2x/day • Metoclopramide (D2/5HT-3 antagonist) 10 mg PO q 8o

PRN

Dry Mouth (Xerostomia)

• Caused by anticholinergic effects, adrenergic effects, serotonergic effects, lithium

• May cause dental caries, oral ulcers• Management:

– Increased oral hygiene– Sugarless/xylitol-containing chewing gum or candy– Biotene (gel, oral rinse, gum, toothpaste, etc)– Other saliva substitutes/oral moisturizers like cellulose gum, glycerin

(e.g. Oasis moisturizing mouth spray) – If severe: procholinergics (e.g., pilocarpine 5-10 mg PO 1-3x/day;

cevimeline 30 mg PO qDay)

Hypersalivation (Sialorrhea)

• Assure not a sign of laryngeal dystonia• Associated with clozapine (non-dose-dependent,

presumably related to M4 agonism and/or alpha-2 antagonism)

• May be associated with DRD4 polymorphism• Management:

– Glycopyrrolate 1 mg PO BID– Biperiden 2 mg PO 1-2x/day– Trihexyphenidyl 2 mg PO qDay– Oxybutinin 5 mg PO 1-3x/day– Clonidine 0.05 – 0.1 mg/day– Sublingual atropine 1% ophthalmic drops q6o

Rajagopal et al., Psychiatry Genet 2014; 24: 273-276.

Antidepressant-Associated Sweating

• Prominent in the upper body, face, scalp, neck, and chest

• Tends to occur in bursts that may also be superimposed on a baseline increase in sweating

• Nearly half - tended to sweat more than others even before the antidepressant

• Management:– Terazosin: 1 mg HS, can increase at weekly intervals to 4 to 6 mg at

bedtime• Can cause: Dizziness/lightheadedness, hypotension, dry mouth

– Glycopyrrolate does not cross the blood-brain barrier to a significant extent

Mago et al. (2013). Ann Clin Psychiatry. PMID: 23638448.Ghaleiha et al. (2013). Int J PsychiatryClin Pract. PMID: 22731399.**Mago (2013). J Clin Psychopharmacol. PMID: 23422382.

Cardiovascular Adverse Effects: Orthostatic Hypotension

• Causes: alpha-1 blockers, MAOIs, dehydration• Management:

– Dosage reductions– ↑ hydration and salt intake (but may not reliably help if already

euvolemic)– TED stockings– Fludrocortisone (begun at 0.1-0.2 mg/day, may increase to 0.4-0.6

mg/day; monitor for low K+) or midrodine 5 mg PO TID (watch for headache, flushing, dry mouth)

Adapted from Goldberg & Ernst, Managing the Side Effects of Psychotropic Medications, Am Psych Press 2012.

Cardiovascular Adverse Effects: ECG Changes

Medication ↑ Heart Rate

↑ QTc/ Ventricular

Arrhythmias

Quinidine-like Effects

↑PR, ↑QRS

ST-T Changes

AEDs (Carbamazepine, Lamotrigine)

X X

Lithium X (>1.2mmol/L) X

Tricyclics X X X

SNRIs X X (in OD)

SSRIs X (rare)Antipsychotics X X

Stimulants X ?

Trazodone X X

Buproprion X X (in OD) X (in OD) X (in OD)

Adapted from Goldberg & Ernst, Managing the Side Effects of Psychotropic Medications, Am Psych Press 2012

N= 212 trials, 43,049 participants

Leucht et al. Lancet 2013; 382: 951–62.

QTc Prolongation: Meta-analysis Across Antipsychotics

Weight Gain & Psychiatric Meds• Presumed mechanisms:

– Appetite stimulation (5HT2C, H1 blockade)– Insulin resistance/metabolic dysfunction (atypical antipsychotics)

• Predictors:– Weight gain >2 kg in first 2-3 weeks (predicts eventual gain >10 kg w/olanzapine)– Younger age– Nonwhite– Low baseline BMI– Female– Pharmacogenetics: 5HT2C, MTHFR

• Use Pooled Cohort Equations to calculate individual cardiac risk based on:

– Age, gender, race, total cholesterol, HDL cholesterol, systolic BP,– Use of antihypertensive medications, smoking status, diabetes status

Degenhardt et al., J Clin Psychopharmacol 2011; 31: 337-340; Lipkovich et al., J Clin Psychopharmacol 2006; 26: 316-320; Kinon et al., J Clin Psychiatry 2001; 62; 92-100; Gebhardt et al., 2009 J Psych Res 2009; 43: 620-626; Stone et al., J Am Coll Cardiol 2014 Jul 1;63(25 Pt B):2889-934.

Medication* Weight Gain ≥ 7%SZ BM MD BD

Iloperidone 10 - - -Asenapine 35 19 - -Lurasidone 67 - - 58Brexpiprazole 17 - 52 -

Cariprazine (to 6 mg/d) 34 ND - -Aripiprazole 21 ND 22 -Olanzapine 6 3 6Paliperidone 35 - - -Quetiapine IR 6 8 -

16Quetiapine XR 22 20 29Risperidone (to 8 mg/d) 18 - -Ziprasidone 16 58 - -

* Reported for monotherapies, except for adjunctive use for major depressive disorder and olanzapine-fluoxetine combination for bipolar depressionNNH for quetiapine for bipolar depression calculated from product labelling

BD - bipolar depression; BM – bipolar mania; MD –major depressive disorder; NA – not available; ND – no difference; NNH – number needed to harm; SZ – schizophrenia; Akathisia- AE

Citrome L. Int J Clin Pract. 2015;69:1211-20.Citrome L. CNS Spectr. 2014;19 (Suppl 1):4-11.Citrome L. Expert Opin Pharmacother. 2011; 12: 2751–8.

Weight Gain with Atypical Antipsychotics: NNH

Medications Used to Attenuate Antipsychotic-Related Weight Gain and Metabolic

Abnormalities

Weighted Mean Difference with 95% confidence interval of weight change in kilograms between pharmacologic treatment and placebo. Shaded boxes indicate agents that separated from placebo.

withdrawn for safety reasons

Maayan et al. Neuropsychopharmacol 2010; 35:1520-1530.

Strategies to Counter Iatrogenic Weight GainStrategy Pro’s Con’sMetformin Meta-analysis of 7 RCTs (N=398):

4.8% ↓ in body weight GI upset; relevant for non-AAP weight gain?

Topiramate * Meta-analysis of 8 trials (N=336): -2.83 kg mean weight loss

Cognitive adverse effects, renal calculi, metabolic acidosis, paresthesias

Zonisamide 1 RCT, 57% lost >5% of initial weight

Amantadine 2 RCTs: amantadine co-therapy w/olanzapine = no weight gain

Bupropion + Naltrexone Half of obese healthy adults lose 5-6% of initial weight

Björkhem-Bergman et al., J Psychopharmacol 2011; 25: 299-305; Mahmood et al., J Clin Psychopharmacol 2013; 33: 90-94; Gadde et al., JAMA 2003; 289: 1820-1825;

Deberdt et al., Eur Neuropsychopharmacol 2005; 15: 13-21;Graham et al., Am J Psychiatry 2005; 162: 1744-1746 ; Greenway et al., Lancet 2010; 376: 595-605

Additional options: topiramate + phentermine; lamotrigine; orlistat; nizatidine; amphetamine; lorcaserin

AAP=atypical antipsychotic; RCT=randomized controlled trial

Somnolence and Sedation: Management

• Often dose-related• Night-time dosing• Avoid additive sedating co-therapies if unnecessary• Most common offenders (all > 20% incidence in FDA

registration trials): – carbamazepine ≈ oxcarbazepine > gabapentin, fluvoxamine,– mirtazapine > fluvoxamine > paroxetine – clozapine > olanzapine> asenapine > lurasidone

Goldberg & Ernst, Managing the Side Effects of Psychotropic Medications, Am Psych Press 2012.

Somnolence with Atypical Antipsychotics: NNH

Medication* Somnolence AEs

SZ BM MD BD

Iloperidone 16 - - -

Asenapine 17 6 - -

Lurasidone 11 - - 25

Brexpiprazole 50 - 34 -

Cariprazine (to 6 mg/d)

100 25 - -

Aripiprazole 20 50 -

Olanzapine 7 11 12

Paliperidone 42 - - -

Quetiapine IR 103

Quetiapine XR 7 3 4

Risperidone (to 8 mg/d)

13 34 - -

Ziprasidone 15 6 - -


BD - bipolar depression; BM – bipolar mania; MD – major depressive disorder; NA – not available; ND – no difference; NNH – number needed to harm; SZ –schizophrenia; Akathisia- AE


Akathisia with Atypical Antipsychotics Across Diagnoses: NNH

BD - bipolar depression; BM – bipolar mania; MD –major depressive disorder; NA – not available; ND – no difference; NNH – number needed to harm; SZ – schizophrenia; Akathisia- AE


Medication* Akathisia AEsSZ BM MD BD

Iloperidone ND - - -Asenapine 34 50 - -Lurasidone 10 - - 15Brexpiprazole 112 - 15 -

Cariprazine (to 6 mg/d) 15 7 - -Aripiprazole 25 12 5 -Olanzapine 25 NA 167 NAPaliperidone 39 - - -Quetiapine IR ND ND -

34Quetiapine XR 188 143 91Risperidone (to 8 mg/d) 15 17 - -Ziprasidone 100 20 - -


AkathisiaAgent Incident Rates

Across IndicationsAripiprazole 10-13%

Asenapine 4-11%

Brexpiprazole 4-14%

Cariprazine 9-21%

Clozapine 3%

Iloperidone 1-2%

Lurasidone 6-22%

Olanzapine 3%

Paliperidone 6-9%

Quetiapine 1-4%

Risperidone 5-9%

Ziprasidone 8-10%

Dose related

Goldberg & Ernst, Managing the Side Effects of Psychotropic Medications, Am Psych Press 2012

Akathisia: Management

• Dosage reductions if feasible• If appropriate, consider change from higher risk (e.g.,

aripiprazole) to lower risk (e.g., iloperidone) agent• Centrally-acting beta-blockers (e.g., propranolol 30-90

mg/day in divided doses; betaxolol 10-20 mg/day)– NOT cardioselective beta-blockers like metoprolol

• Dopamine agonists (amantadine 100-200 mg BID, rotigotine 2-8 mg/day), and benzodiazepines (clonazepam 0.5 – 1.0 mg at hs)

• 5HT2A antagonists (e.g., mirtazapine, trazodone)• Antocholinergics (e.g., benztropine) less helpful for

akathisia than for parkinsonism Goldberg & Ernst. Managing the Side Effects of Psychotropic Medications, Am Psych Press 2012;Poyurovsky. Br J Psychiatry. 2010; 196: 89-91.

Tremor: Management

• Most common: lithium, divalproex, bupropion• Assure tremor does not reflect broader neurotoxicity

(e.g., check lithium or valproate serum levels)• May be dose-related• Differentiate iatrogenic from benign essential tremor• Management:

– Propranolol 10-120 mg/day in divided doses• Beware risk for bradycardia, hypotension, asthma exacerbation;

assure absence of heart block on ECG– Primidone 100-300 mg/day– Acetazolamide 125-500 mg/day

Goldberg & Ernst, Managing the Side Effects of Psychotropic Medications, Am Psych Press 2012

Tetrabenazine and Related Compounds

• Currently FDA-approved for Huntington’s Chorea• Reversible inhibitor of vesicular monoamine transporter-

2 (VMAT-2), which packages neurotransmitters (preferentially dopamine) from cytosol into vesicles for release into synapse– Rapid absorption and metabolism, multiple daily doses– ß-enantiomer and its 2 active metabolites block postsynaptic DA

receptors, can worsen parkinsonism– May cause depression, suicidal ideation

• Deutetrabenazine (SD-809) – requires less frequent dosing than tetrabenazine

• Valbenazine – t1/2 ≈ 20o (qDay dosing)– Response (>50% reduction on AIMS); NNT=4

O’Brien et al. Movement Disorders. 2015; 30: 1681-1687.

Take Home Points

• Side effects - common, distressing, and a leading cause of non-adherence

• Proactively assess suspected adverse drug effects, recognize plausibility, dose effects, drug interactions, time course, persistence, dangerousness, degree of subjective distress, and manageability

• Collaborative approach with patients• Favor medications with more modest adverse effects

when feasible, treat adverse effects when a drug's benefits are unique and substantial

ARS POST QUESTIONS

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managing side effects of psychiatric medications

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