Antidepressant Adverse Effects

Aka: Antidepressant Adverse Effects, Antidepressant Side Effects

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II. Adverse Effects: Least Tolerated Agents (early discontinuation)

  1. Most Likely to be discontinued
    1. Tricyclic Antidepressants (e.g. Amitriptyline)
    2. Serotonin Norepinephrine Reuptake Inhibitor (SNRI, e.g. Venlafaxine)
  2. Least Likely to be discontinued
    1. Bupropion
    2. Citalopram (Celexa)
    3. Escitalopram (Lexapro)
    4. Fluoxetine (Prozac)
    5. Sertraline (Zoloft)
    6. Vortioxetine (Trintellix)
    7. Cipriani (2018) Lancet 391(10128): 1357-66 [PubMed]

III. Adverse Effects: Anticholinergic Symptoms

  1. Most Anticholinergic
    1. Tricyclic Antidepressants (Tertiary amines, e.g. Amitriptyline)
  2. Least Anticholinergic
    1. Selective Serotonin Reuptake Inhibitor (SSRI)
    2. Bupropion
    3. Serotonin Antagonist and Reuptake Inhibitor (SARI, e.g. Trazodone)
    4. MAO Inhibitors

IV. Adverse Effects: Weight gain (Histamine H1 receptor blockade)

  1. Weight gain may be >5%
    1. Highest risk in first 2 years (but may continue to increase over the longterm)
  2. Most Weight Gain
    1. Tricyclic Antidepressants (e.g. Amitriptyline)
    2. Mirtazapine (Remeron)
    3. Paroxetine (Paxil)
  3. Least Weight Gain
    1. Bupropion
    2. Fluoxetine (Prozac)

V. Adverse Effects: Orthostatic Hypotension (alpha 1 receptor blockade)

  1. Most Orthostatic Hypotension
    1. Tricyclic Antidepressants (Tertiary amines, e.g. Amitriptyline)
  2. Least Orthostatic Hypotension
    1. Bupropion
    2. Selective Serotonin Reuptake Inhibitor (SSRI)

VI. Adverse Effects: Cardiac Arrhythmia (Type 1A Antiarrhythmic effect)

  1. Most Risk for Cardiac Arrhythmia
    1. Tricyclic Antidepressants (Tertiary amines, e.g. Amitriptyline)
      1. See Tricyclic Antidepressant Overdose
  2. Least Risk for Cardiac Arrhythmia
    1. Bupropion
  3. Other cardiac considerations
    1. Although QTc Prolongation has been reported with Citalopram and Escitalopram, ventricular Arrhythmia risk is very low
      1. FDA recommends Citalopram maximum dose limited to 40 mg (20 mg if age >60 years old)
      2. Prasitlumkum (2021) Med Sci 9(2): 26 [PubMed]
    2. Ischemic Heart Disease
      1. Consider Sertraline (antiplatelet activity, low side effect profile)
      2. Teply (2016) Prog Cardiovasc Dis 58(5): 514-28 [PubMed]

VII. Adverse Effects: Bleeding Risk (Drug Interaction)

  1. SSRI and SNRI agents increase risk of bleeding events when combined with Anticoagulants and antiplatelet agents
    1. Drug Interactions occur primarily with Warfarin
    2. SSRI use may as much as double the risk of Abnormal Bleeding (esp. Gastrointestinal Bleeding)
      1. Avoid combining with NSAIDs and other risk factors for Gastrointestinal Bleeding
      2. Overall Odds Ratio 1.55
        1. Jiang (2015) Clin Gastroenterol Hepatol 13(1): 42-50.e3 [PubMed]
    3. One additional patient on Warfarin for Atrial Fibrillation with SNRI or SSRI will have have a major bleeding event
      1. However, also affect other Anticoagulants such as Pradaxa and antiplatelet agents
  2. Most Bleeding Risk
    1. Fluoxetine (Prozac)
    2. Flovoxamine (especially with Warfarin)
    3. Paroxetine (Paxil)
    4. Sertraline (Zoloft)
  3. Least Bleeding Risk
    1. Mirtazapine (Remeron)
    2. Bupropion
  4. References
    1. (2014) Presc Lett 21(11): 65
    2. Sansone (2009) Psychiatry 6(7): 24–29 [PubMed]

VIII. Adverse Effects: Gastrointestinal Effects (Serotonin reuptake blockade)

  1. Nausea and Vomiting are the most common Antidepressant Adverse Effects (esp. SNRI)
  2. Most adverse effects
    1. Nausea or Vomiting: Venlafaxine (Effexor)
    2. Constipation: Paroxetine (Paxil)
    3. Diarrhea: Sertraline (Zoloft)
  3. Minimal Gastrointestinal adverse Effects
    1. Fluoxetine (Prozac)
    2. MAO Inhibitors
    3. Trazodone
  4. No Significant Gastrointestinal Effects
    1. Tricyclic Antidepressants (e.g. Amitriptyline)
    2. Bupropion

IX. Adverse Effects: Sedation (Histamine H1 receptor blockade)

  1. Most
    1. Tricyclic Antidepressants (e.g. Amitriptyline)
    2. Nefazodone (Serzone)
    3. Trazodone
  2. Moderate
    1. Mirtazapine (Remeron)
    2. Paroxetine (Paxil)
    3. Phenelzine (Nardil)
  3. No Significant Sedation
    1. Bupropion
    2. Venlafaxine (Effexor)
    3. Fluoxetine (Prozac)

X. Adverse Effects: Agitation, Activation or Insomnia

  1. Most Agitation, Activation or Insomnia
    1. Bupropion
    2. Fluoxetine (Prozac)
    3. Sertraline (Zoloft)
  2. Least Agitation, Activation or Insomnia
    1. Tricyclic Antidepressants (e.g. Amitriptyline)
    2. Venlafaxine (Effexor)
    3. Trazodone
    4. Paroxetine (Paxil)

XI. Adverse Effects: Seizure Risk (Lower Seizure threshold)

  1. Most Seizure Risk
    1. Bupropion
    2. Clomipramine (Anafranil)
    3. Tricyclic Antidepressant (e.g. Amitriptyline)
  2. Least Seizure Risk
    1. Selective Serotonin Reuptake Inhibitor (SSRI)
    2. MAO Inhibitor
    3. Serotonin Antagonist and Reuptake Inhibitor (SARI, e.g. Trazodone)
    4. Venlafaxine (Effexor)

XII. Adverse Effects: Sexual Dysfunction (Serotonin reuptake blockade)

  1. See Antidepressant Induced Sexual Dysfunction
  2. Most Sexual Dysfunction
    1. Tricyclic Antidepressants (e.g. Amitriptyline)
    2. MAO Inhibitor
    3. Selective Serotonin Reuptake Inhibitor (SSRI)
      1. Paroxetine (Paxil)
      2. Escitalopram (Lexapro)
  3. Least Sexual Dysfunction
    1. Bupropion
    2. Nefazodone (Serzone)

XIII. Adverse Effects: Hyponatremia (Serum Sodium <130 meq/L)

  1. Typically occurs in the first month of therapy
  2. Overall Odds Ratio (OR) up to 2.6, but SSRIs may have OR as high as 3.3
  3. Highest risk
    1. Selective Serotonin Reuptake Inhibitors or SSRI
    2. Serotonin Norepinephrine Reuptake Inhibitor (SNRI, e.g. Venlafaxine)
    3. Mirtazapine (Remeron)
    4. Tricyclic Antidepressants (e.g. Amitriptyline)
  4. References
    1. De Picker (2014) Psychosomatics 55(6): 536-47 [PubMed]

XIV. Adverse Effects: Suicidality

  1. Primarily increased in age <18 years old (Odds Ratio 2.39)
  2. Selective Serotonin Reuptake Inhibitors (SSRI)
    1. Fluoxetine (Prozac)
    2. Paroxetine (Paxil)
    3. Sertraline (Zoloft)
  3. Serotonin Norepinephrine Reuptake Inhibitor (SNRI, e.g. Venlafaxine)
    1. Venlafaxine (Effexor)
    2. Duloxetine (Cymbalta)
  4. References
    1. Sharma (2016) BMJ 352:i65 [PubMed]

XV. Adverse Effects: Miscellaneous

  1. Hepatotoxicity
    1. Nefazodone (Serzone)
    2. Bupropion
    3. Duloxetine (Cymbalta)
    4. Trazodone
    5. Voican (2014) Am J Psychiatry 171(4): 404-15 [PubMed]
  2. Osteoporosis and Fragility Fracture Risk
    1. Overall Hazard Ratio 1.88 for fragility Fracture typically with prolonged use (>10 years)
    2. Selective Serotonin Reuptake Inhibitors (SSRI)
    3. Serotonin Norepinephrine Reuptake Inhibitor (SNRI, e.g. Venlafaxine)
    4. Moura (2014) Osteoporosis Int 25(5): 1473-81 [PubMed]

XVI. References

  1. Bhatia (1997) Am Fam Physician 55(5):1683-94 [PubMed]
  2. Hansen (2005) Ann Intern Med 143:415-26 [PubMed]
  3. Kovich (2015) Am Fam Physician 92(2): 94-100 [PubMed]
  4. Kovich (2023) Am Fam Physician 107(2): 173-81 [PubMed]

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