ChiChi--Un Pae, MD, PhD Un Pae, MD, PhD

Associate ProfessorDepartment of PsychiatryThe Catholic University of Korea College of Medicine

Adjunct Associate ProfessorDepartment of Psychiatry and Behavioral SciencesDuke University Medical Center

Antidepressants:Side effects and and Management

Outline

• General points• Serotonin syndrome• Sexual dysfunction• Affectivity switch• Discontinuation syndrome• Management

Reasons for Discontinuation of Antidepressants

• Side effects, especially decreased libido 42.9%• Aim to deal with symptoms “naturally” 23.1%• Unwillingness to use this type of drug 19.8%• Fear of drug dependence 18.7%• Wanted to find out if symptoms disappeared 17.6%• No improvement or deterioration 17.6%• Bad publicity of antidepressants in media 5.5%• Lack of information 4.4%• Other 31.9%

Sundstrom et al., 2000

Patient Dropout Rates are really problematicDropout rates of patients treated with

antidepressants by week are disappointing

51%

44%39%

0%

35%

21%

32%

50%

28%

0%

10%

20%

30%

40%

50%

60%

Pre-Tx Week 2

Week 4

Week 6

Week 8

Week 10

Week 12

Week 14

Week 16

Lin EH, et al. Med Care 1995;33:67-74.

Potential Neurotransmitter-Specific Effects

• Serotonergic

– Sexual dysfunction

– Weight gain (with long-term enhancement)

– GI upset

– Sleep disturbance

– Suppression of dopamine neurotransmission, which may result in: Decreased ability to

experience pleasure

Apathy and decreased motivation

Decreased attention

Cognitive slowing

• Noradrenergic

– Tremor

– Tachycardia

– Dry mouth

– Insomnia

• Dopaminergic

– Psychomotor activation

– Aggravation of psychosis

Stahl SM. Essential Psychopharmacology. Third Edition, 2008

Consideration of Tolerability

Serotonin Syndrome

Toxicity from excess serotonin in the CNS

Observed in:

•overdose of single drug

•simultaneous use of two or more drugs that increase serotonin

Clinical features of serotonin syndrome

Cognitive Confusion, agitation, hypomania, hyperactivity, restlessness

Autonomic Hyperthermia, sweating, tachycardia, hypertension, mydriasis, flushing, shivering

Neuromuscular Clonus (spontaneous/inducible/ocular), hyperreflexia, hypertonia, ataxia, tremor

Hall M, Buckley N. Serotonin syndrome. Aust Prescr 2003;26:62-3.

Boyer, Shannon. NEJM 2005

Antidepressants SSRIs, monoamine oxidase inhibitors (including moclobemide), tricyclics, mirtazapine, venlafaxine

Antiparkinsonians Amantadine, bromocriptine, levodopa, selegiline, carbergoline, pergolide

Illicit drugs Cocaine, hallucinogenic amphetamines such as MDMA (ecstasy), LSD, etc

Migraine therapy Dihydroergotamine, naratriptan, sumatriptan, zolmitriptan

Other agents Tramadol, pethidine, fentanyl, dextromethorphan, carbamazepine, lithium, reserpine, sibutramine, St John’s wort, bupropion, pethidine, tryptophan, panax ginseng

Isbister et al. MJA 2007;187(6)361-365

Drugs Associated with Serotonin Syndrome

Management

• Supportive care

• Discontinuation of serotonergic medication

• Prevention: awareness of coprescribing serotonergic drugs, patient education

Weight Gain

Weight loss Weight Gain

Bupropion

Duloxetine

Venlafaxine

MAOIs

SSRIs

Mirtazapine

TCAs

Agent dosage; intervention group, n; outcome

Nizatidine 150 mg twice daily; n = 18; .6.8 kg (-7.9 to -5.7 kg)

300 mg twice daily; n = 58; less weight gain at 3 and 4 weeks, effect lost at 16 weeks.

150 mg twice daily; n = 57; no effect

150 mg twice daily; n = 14;

.2.2 kg (-2.9 to -1.5 kg)

Fluoxetine 20 mg daily; n = 15; no effect

Roboxetine 4 mg daily; n = 13; .3.0 kg (-5.6 to -0.5 kg)

Famotidine 40 mg daily; n = 7; no effect

Amantadine 100.300 mg; n = 35; .1.7 kg (-3.9 to 0.5 kg)

Sibutramine 15 mg; n = 19; .4.6 kg (-5.2 to -4.0 kg)

15 mg; no effect

Topiramate 200 mg daily; n = 17; .5.1 kg ( -7.4 to -2.7 kg)

100 mg daily; n = 16; .1.4 kg ( -4.2 to -1.5 kg)

Pharmacologic interventions for weight gain

Sexual dysfunctionCommon side effect of SSRIs and newer

antidepressants

Management strategies:

• Wait - may remit spontaneously in time

• Dose related - reduced dose may improve

• Drug holidays – dosing 3 days a week

- relapse/discontinuation symptoms

• Adjunctive therapy – e.g., sildenafil

• Switching antidepressants- bupropion, moclobemide,

mirtazapine, reboxetine less dysfunction

Braddon J, RGH Pharmacy E-Bulletin:14(11): July 2004

Incidence of Sexual Dysfunction Reported with Various SSRIs*

All studies include direct questioning about sexual function.*SSRIs included fluoxetine, paroxetine, and sertraline.

1. Jacobsen FM. J Clin Psychiatry. 1992;53:119-122.2. Coleman CC et al. Ann Clin Psychiatry. 1999;11:205-215.3. Croft H et al. Clin Ther. 1999;21:643-658.

34 3641 41

61 5967

Patie

nts

(%)

Jacobsen Coleman Croft Kavoussi(female)

Kavoussi(male)

Montejo Feiger

4. Kavoussi RJ et al. J Clin Psychiatry.1997;58:532-537.5. Montejo AL et al. J Clin Psychiatry. 2001;62:10-21. 6. Feiger A et al. J Clin Psychiatry. 1996;57(suppl 2):53-62.

0

10

50

60

70

20

30

40

Wellbutrin as an antidote for SSRIs-induced sexual dysfunction (Changes in

Sexual Functioning Questionnaire)

Clayton et al., J Clin Psychiatry 2004;65:62-67

40.847 48

38.842.8 43.5

0

10

20

30

40

50

60

Baseline Week 2 Week 4

BupropionPlacebo

* *

* P < 0.05

• Possible at 1st day of antidepressants• Unipolar depression: about 60 days• Recurrent depression: about 60 days• Bipolar depression: about 30 days

• Risk increased – with past history of polarity switch/cycle acceleration– female– hypothyroidism– Bipolar II > bipolar I– Earlier age at first treatment

Affectivity switch & Cycle acceleration

Ratio of Threshold Switches to Subthreshold Brief Hypomanias

Leverich GS, et al. Am J Psychiatry. 2006;163:232-239.

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AcuteAntidepressant

Trials (10 weeks)

ContinuationAntidepressantTrials (≤ 1 year)

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1.5

2.0

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BupropionSertralineVenlafaxine

Discontinuation of antidepressants

• When discontinuing, taper doses over several weeks ( eg SSRIs – reduce dose by half, no faster than weekly)

• drugs with shorter half-lives give more discontinuation effects

e.g., paroxetine, venlafaxine–taper more slowly

• Flu-like symptoms• Peak day 5, can last up 3 weeks• Can mimic anxiety/depression

• A Discontinuation of or reduction in dose of SSRI after use of >1 Month

• B 2 of following Symptoms developing within 1-7 days of A:

dizziness, light-headedness, vertigo

shock-like sensations, paresthesia

anxiety headache

diarrhea insomnia

fatigue irritability

gait instability N/V

tremors visual disturbances

• C Symptoms in B cause clinically significant distress or impairment in social, occupational, or functioning

• D Symptoms not due to general medical condition, or recurrence of symptoms for which the SSRI was originally prescribed

Proposed Diagnostic Criteria

for Discontinuation Syndrome

Discontinuation syndrome : SSRI

• All patients treated > 1 month• 23/44 (52%) patients on tapering doses;• 48% abruptly stopped therapy• 10/42 (24%) developed symptoms during• Taper; 76% after therapy discontinued• 81% patients developed symptoms in 1-3 days;

93.8% within 1 week• 53 different symptoms reported

J Psych & Neuroscience 2000;25:255-61

Discontinuation syndrome after tapering off SSRIs

SSRIs Dose DS frequency

Paroxetine 10-60 mg 30/46 (65.2%)

Sertraline 50-150 mg 8/46 (17%)

Fluoxetine 40 mg 5/46 (11%)

Fluvoxamine 100-300 mg 3/46 (7%)

J Psych & Neuroscience 2000;25:255-61

Drug Rationale Recommendation

Category A

Fluoxetine, Phenelzine, Tranylcypromine

drug (or metabolites) with long half-life or persistent effect

•gradual withdrawal generally unnecessary

•withdrawal symptoms very unlikely wait for>10–14 days before starting next antidepressant

(Fluoxetine → phenelzine/tranylcypromine 5 weeks)

Category B

TCAs, SSRIs (except fluoxetine), mianserin, mirtazapine

drug (or metabolites) with intermediate half-life of 24–48 hours

•withdraw gradually to prevent withdrawal symptoms (particularly if higher dose or long term use)

•usually reduce dose by 25% per day (when switching)

•wait for 2–4 days before starting next antidepressant

Category C

Duloxetine, Moclobemide, Reboxetine, Venlafaxine,

Desvenlafaxine

drug (or metabolites) with short half-life of <18 hours

•venlafaxine, withdraw gradually to prevent withdrawal symptoms

•moclobemide, withdrawal symptoms not reported

•wait for 1–2 days before starting next antidepressant

Other safety issues

• SSRIs/SNRIs - Hyponatraemia / SIADH - ↑ risk elderly, female, onset usually within 1st month treatment

• SSRIs - Directly reduce bone mass /strength and may increase falls/fractures

• SSRIs - Abnormal platelet aggregation and GI bleeding risks: greatest risk elderly, NSAID use and previous GI bleeding

• Cardiac effects - TCAs, SNRIs, reboxetine

Richards J et al: Arch Intern Med, 2007: 167:188-194

ADRAC: 22 (3) June 2003

The most likely specific adverse effects on specific antidepressants above and

beyond the parallel placebo condition

Antidepressant

>7.5% >10% >15% >20% >25% >30%

>35% >40%

>45%

Bupropion Dry mouth Constipation Sweating

Tremors Nervousness

- - - - - -

Imipramine Fatigue Tremors Sweating

Constipation Dizziness - - - - Dry mouth

Mirtazapine - Weight gain Dry mouth

Appetite - - - somnolence - -

Nefazodone Confusion Respiratory

Drowsiness Vision

disturbance Nausea Dry

mouth

- Dizziness - - - - -

Venlafaxine-IR

Insomnia Anorexia

Constipation Sweating

Nervousness Dizziness Dry

mouth

Drowsiness - Nausea - - - -

Venlafaxine-XR

Nervousness

Drowsiness

Sweating Dizziness

- Nausea - - - - -

Adherence

• Almost 50% patient stop taking antidepressant within first 2 months

• Warn about adverse effects/ drug interactions

• Reinforce time to improvement and duration of therapy (at least 6 months)

• May need to try > 1 treatment• Do not stop suddenly• Provide written information - NPS leaflet

Improving Compliance

• Educate when and how to take meds• Delay in response – 2-4 wks• Continue meds even if better• Consult w/ Dr before discontinuing• Educate family• Simplify regimen• Effective communication (Listen!)• Medication assistance if $$ issue• Side effects and complicated dosing regimen

can lead to noncompliance

Strategies to Manage S/E’s

• Watch and wait (if no immediate medical risk)

• Alter dosage, frequency, timing of administration –

(SSRI sedation change hs dosing)

• Provide specific treatment for SEs

• Consider switching medication