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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)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
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
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