Side effects of antidepressants during long-term use in a naturalistic setting

Eur Neuropsychopharmacol. 2013 Nov;23(11):1443-51. doi: 10.1016/j.euroneuro.2013.05.001. Epub 2013 May 30.


Side effects of antidepressants are usually underreported in clinical trials and large scale naturalistic studies are restricted to six months of use. We examined the prevalence and nature of patient-perceived side effects and their determinants during long-term antidepressant use in a naturalistic setting. Subjects, aged 19 to 67 years, in the Netherlands Study of Depression and Anxiety were recruited from primary care and specialized mental health care covered 927 cases of single antidepressant use. In 64% of cases, on average, 2.9 side effects were reported. The number of side effects was higher when subjects had higher depression severity (OR=1.28; p=0.002), three or more psychiatric diagnoses (OR=1.97; p=0.02), higher dose (OR=1.44; p=0.006) and was lower when subjects were older (OR=0.83; p=0.02) and had longer duration of use (OR=0.94; p=0.04). Tricyclic antidepressants were associated with more side effects (OR=2.52; p=0.003) and, particularly, more anticholinergic effects, like dry mouth and constipation, as compared to selective serotonin reuptake inhibitors. Venlafaxine showed more profuse sweating (OR=1.79; p=0.007), whereas mirtazapine showed more weight gain and less sexual dysfunction (OR=0.36; p=0.03), as compared to selective serotonin reuptake inhibitors. Weight gain was associated with female gender (OR=1.76; p=0.004) and duration of use (OR=1.06; p=0.03). We show that antidepressant side effect, known from short-term studies, persist during long-term use and are associated with depression severity and antidepressant dose. A novel finding was that venlafaxine is associated with more profuse sweating and that weight gain appeared more specific in female users. Clinicians should be aware that, during long-term antidepressant use, side effects are common and persistent.

Keywords: Antidepressants; Anxiety; Depression; Naturalistic setting; Side effects.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aging / drug effects
  • Antidepressive Agents, Tricyclic / administration & dosage*
  • Antidepressive Agents, Tricyclic / adverse effects*
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Netherlands
  • Serotonin Uptake Inhibitors / administration & dosage*
  • Serotonin Uptake Inhibitors / adverse effects*
  • Severity of Illness Index
  • Time Factors
  • Young Adult


  • Antidepressive Agents, Tricyclic
  • Serotonin Uptake Inhibitors