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Cited by 299Treatment of Major DepressionElectroconvulsive Therapy StudiesPharmacovigilance and Adverse Drug Reactions

Addressing the Side Effects of Contemporary Antidepressant Drugs: A Comprehensive Review

Open access
Wang, Sheng-Min, Han, Changsu, Bahk, Won-Myoung, Lee, Soo-Jung, Patkar, Ashwin A., Masand, Prakash S., Pae, Chi-Un·2018·Chonnam Medical Journal
DOI 10.4068/cmj.2018.54.2.101PMC PMC5972123
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Abstract

Randomized trials have shown that selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) have better safety profiles than classical tricyclic antidepressants (TCAs). However, an increasing number of studies, including meta-analyses, naturalistic studies, and longer-term studies suggested that SSRIs and SNRIs are no less safe than TCAs. We focused on comparing the common side effects of TCAs with those of newer generation antidepressants including SSRIs, SNRIs, mirtazapine, and bupropion. The main purpose was to investigate safety profile differences among drug classes rather than the individual antidepressants, so studies containing comparison data on drug groups were prioritized. In terms of safety after overdose, the common belief on newer generation antidepressants having fewer side effects than TCAs appears to be true. TCAs were also associated with higher drop-out rates, lower tolerability, and higher cardiac side-effects. However, evidence regarding side effects including dry mouth, gastrointestinal side effects, hepatotoxicity, seizure, and weight has been inconsistent, some studies demonstrated the superiority of SSRIs and SNRIs over TCAs, while others found the opposite. Some other side effects such as sexual dysfunction, bleeding, and hyponatremia were more prominent with either SSRIs or SNRIs.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review compares side effects of tricyclic antidepressants (TCAs) with newer-generation agents (SSRIs, SNRIs, mirtazapine, bupropion), concluding that newer drugs are clearly safer in overdose and better tolerated, but that evidence for many other side effects (dry mouth, GI effects, hepatotoxicity, seizure, weight) is inconsistent. Side effects tied to high serotonin selectivity — sexual dysfunction, bleeding, hyponatremia — appear more prominent with SSRIs/SNRIs than TCAs.

Key findings

  • Tolerability: a meta-analysis of 3 head-to-head studies found SSRIs had significantly lower dropout rates (OR=0.41; 95% CI 0.19–0.86) and adverse events (OR=0.48; 95% CI 0.32–0.70; p<0.001) than TCAs; a network meta-analysis found fluoxetine (OR=0.23), citalopram (OR=0.27), and paroxetine (OR=0.22) better tolerated than imipramine in children/adolescents with MDD.
  • Overdose safety: hazard indices were highest for amoxapine (292), maprotiline (211), and desipramine (187), with newer antidepressants (except bupropion) much lower; case fatality rate ratio was 0.5 (95% CI 0.4–0.7) for SSRIs vs 13.8 (95% CI 13.0–14.7) for TCAs, with venlafaxine 2.5 and mirtazapine 1.9.
  • Cardiovascular: SSRIs prolonged QTc by 6 ms more than placebo (dose-dependent), with citalopram prolonging most; overall cardiovascular adverse reactions were 0.15% for TCAs, 0.08% for SSRIs, 0.07% for mirtazapine, and SNRIs showed significantly higher hypertension risk (p<0.001), with venlafaxine incidence 0.05%.
  • Serotonergic side effects: SSRI bleeding risk RR=3.0 vs RR=0.8 for non-serotonergic antidepressants; dry mouth risk was RR 1.64 for SSRIs, 2.24 for SNRIs, and 2.0 for bupropion (all p<0.001); hyponatremia ORs were 1.5–21.6 for SSRIs vs 1.1–4.9 for TCAs, with older age (OR 6.3) and thiazide diuretics (OR 11.2–13.5) raising risk.
  • Seizure and weight evidence was contradictory: bupropion IR >450 mg raised seizure incidence ~10-fold, while SR formulation showed 0.1% in 3,094 patients; in a UK cohort of 238,963 patients trazodone had the highest risk (HR 5.41, NNH 65), TCAs HR 2.32 vs SSRIs HR 1.92, while a separate nested case-control study found SSRIs OR 1.98 vs TCAs OR 0.99. An EHR study of 22,610 patients found all antidepressants caused weight gain, with bupropion, amitriptyline, and nortriptyline gaining significantly less than citalopram.

Methods

  • Narrative/comprehensive review; articles identified from PubMed, Embase, Medline, PsycINFO, CINAHL, and Web of Science using the keywords "antidepressant," "side-effects," and "tolerability."
  • Prioritized large-scale observational studies, well-designed RCTs, and prior reviews/meta-analyses, with studies containing class-level comparison data (e.g., SSRIs vs TCAs) favored over individual-drug comparisons; multimodal antidepressants (vilazodone, vortioxetine) covered in a separate section.
  • Searches and verification handled by lead authors (C-U Pae and C Han) and independently reassessed by coauthors (S-J Lee and S-M Wang).

Limitations

  • Stated: the volume of studies on antidepressant side effects could not all be included "due to space limitations"; the authors also note that evidence on dry mouth, GI side effects, hepatotoxicity, seizure, and weight is inconsistent, and that short-term RCTs and long-term naturalistic/pharmacovigilance studies yield discrepant results.
  • Stated: adverse-effect reporting is prone to systematic expectation influences — a meta-analysis found significantly more adverse effects reported in TCA-placebo groups than SSRI-placebo groups (e.g., dry mouth OR 3.5, drowsiness OR 2.7, constipation OR 2.7, sexual problems OR 2.3), which the authors attribute to possible investigator expectation (Golem effect).
  • Evident from the text: no systematic search dates, inclusion/exclusion criteria, study-quality appraisal, or quantitative synthesis are reported, so the review's conclusions rest on selected evidence rather than a reproducible systematic protocol.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.4068/cmj.2018.54.2.101

Cites

112 of 112 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 169 cited sources checked · 0 supported · 0 flagged

  • Findingnone given

    QTc interval prolongation was consistently shown to be a problem for citalopram.

    “QTc interval prolongation was consistently shown to be a problem for citalopram.”
    Quote in the paperNot a substantial claim
  • Findingnone given

    TCAs were associated with higher cardiovascular risk, such as acute toxicity.

    “TCAs were associated with higher cardiovascular risk, such as acute toxicity”
    Quote in the paperSubstantial claim
  • Findingnone given

    Sexual dysfunction, bleeding, and hyponatremia were more prominent in antidepressants with high serotonin selectivity (SSRIs>SNRIs>TCAs).

    “sexual dysfunction, bleeding, and hyponatremia were more prominent in antidepressants with high serotonin selectivity (SSRIs>SNRIs>TCAs).”
    Quote in the paperNot a substantial claim
  • Findingreasoning

    SSRIs and SNRIs were not entirely risk-free.

    “SSRIs and SNRIs were not entirely risk-free.”
    Quote in the paperSubstantial claim
  • Findingown data

    The benefit of SSRIs over TCAs in seizures has not been confirmed.

    “the benefit of SSRIs over TCAs in seizures has not been confirmed.”
    Quote in the paperSubstantial claim
  • May combine two claims. 53
  • Classified as probably not a substantial claim. 18
  • The quote only partly states this claim. 2

  • May combine two claims.

    Findingnone given

    Studies regarding SSRIs and SNRIs in dry mouth, gastrointestinal side effect, hepatotoxicity, and weight were contradictory, some showing their superior over TCAs and some illustrating the opposite.

    “studies regarding SSRIs and SNRIs in dry mouth, gastrointestinal side effect, hepatotoxicity, and weight were contradictory, some showing their superior over TCAs and some illustrating the opposite.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    TCAs were associated with higher drop-out rates and lower tolerability.

    “TCAs were also associated with higher drop-out rates and lower tolerability.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Evidence regarding side effects including dry mouth, gastrointestinal side effects, hepatotoxicity, seizure, and weight has been inconsistent; some studies demonstrated the superiority of SSRIs and SNRIs over TCAs, while others found the opposite.

    “However, evidence regarding side effects including dry mouth, gastrointestinal side effects, hepatotoxicity, seizure, and weight has been inconsistent, some studies demonstrated the superiority of SSRIs and SNRIs over TCAs, while others found the opposite.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    TCAs are associated with higher drop-out rates, lower tolerability, and higher cardiac side-effects.

    “TCAs were also associated with higher drop-out rates, lower tolerability, and higher cardiac side-effects.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Studies initially supported that SSRIs do not differ from TCAs in efficacy but have superior side effect profiles such as less anticholinergic symptoms.

    “Studies initially supported this hypothesis suggesting that, although SSRIs do not differ from TCAs in efficacy, they have superior side effect profiles such as less anticholinergic symptoms.2”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Peretti, 2000, Acta Psychiatr Scand Suppl source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Negative effects on heart rate were highest in TCAs (mean=73.94 bpm, p<0.001, Cohen's d, 0.72-0.81) followed by SNRIs (mean=71.00 bpm, Cohen's d, 0.42-0.95) compared to those not on antidepressants (mean=66.87 bpm).

    “These negative effects were highest in TCAs (mean=73.94 bpm, p<0.001, Cohen's d, 0.72–0.81) followed by SNRIs (mean=71.00 bpm, Cohen's d, 0.42–0.95) compared to those not on antidepressants (mean=66.87 bpm).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Kemp, 2014, Am J Psychiatry source

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  • May combine two claims.

    Premisecitation

    A study showed that the risk of GI bleeding increased with SSRIs (RR=3.0), but not in those with antidepressants having no serotonin reuptake inhibitor property (RR=0.8).

    “A study showed that the risk of GI bleeding increased with SSRIs (Risk ratio (RR)=3.0), but not in those with antidepressants having no serotonin reuptake inhibitor property (RR=0.8).12”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] de Abajo, 1999, BMJ source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The data searches and verifications were handled by lead authors and independently reassessed by coauthors.

    “The data searches and verifications were handled by lead authors (C-U Pae and C Han) and independently reassessed by coauthors (S-J Lee and S-M Wang).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Antidepressants might affect primary hemostasis by interfering with the uptake mechanism of blood serotonin by platelets.

    “It has been hypothesized that antidepressants might affect primary hemostasis by interfering with the uptake mechanism of blood serotonin by platelets.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Andrade, 2010, J Clin Psychiatry source

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  • May combine two claims.

    Premisecitation

    SSRIs were suspected to have the potential to induce QTc interval prolongation, and therefore increase the risk of ventricular arrhythmia.

    “For example, SSRIs were suspected to have the potential to induce QTc interval prolongation, and therefore increase the risk of ventricular arrhythmia.23”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Mago, 2014, Expert Rev Neurother source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    The FDA has put forth a recommendation regarding citalopram and the risk of abnormal heart rhythms.

    “Thus, the FDA has put forth a recommendation regarding citalopram and the risk of abnormal heart rhythms.25”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Wang, 2013, Expert Rev Neurother source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A meta-analysis of 3 head-to-head studies showed SSRIs had significantly lower dropout rates (OR=0.41; 95% CI: 0.19-0.86) and adverse events (OR=0.48; 95% CI: 0.32-0.70; p<0.001) than TCAs.

    “The results showed that SSRIs had significantly lower dropout rates (OR=0.41; 95% CI: 0.19–0.86) and adverse events (adverse event: OR=0.48; 95% CI: 0.32–0.70; p<0.001) than TCAs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    All antidepressants, except for SSRIs, were associated with increases in heart rate and decreased heart rate variability.

    “Unfortunately, all antidepressants, except for SSRIs, were associated with increases in heart rate. They also decreased heart rate variability (HRV).28”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Kemp, 2014, Am J Psychiatry source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    SSRIs were initially considered to have safer cardiac profiles than TCAs.

    “SSRIs were initially considered to have safer cardiac profiles than TCAs.22”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Glassman, 1998, Int Clin Psychopharmacol source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Increases in resting-state heart rate and decreases in its variability are associated with substantial morbidity and mortality.

    “Increases in resting-state heart rate and decreases in its variability are associated with substantial morbidity and mortality.27”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Boudoulas, 2015, Cardiology source

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  • May combine two claims.

    Premisecitation

    Numerous studies reported the risk of bleeding associated with SSRIs and venlafaxine, the most potent serotonergic drug among SNRIs, was associated with degree of serotonin reuptake inhibition property.

    “Thereafter, numerous studies reported the risk of bleeding associated with SSRIs and venlafaxine, the most potent serotonergic drug among SNRIs,131415 was associated with degree of serotonin reuptake inhibition property.16”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [13] van Walraven, 2001, BMJ source

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    • cites [14] Ziegelstein, 2007, Am J Med source

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    • cites [15] Targownik, 2009, Am J Gastroenterol source

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  • May combine two claims.

    Premisecitation

    Serotonin causes platelet aggregation, but SSRIs inhibit the uptake of serotonin into platelets.

    “Serotonin causes platelet aggregation, but SSRIs inhibit the uptake of serotonin into platelets.10”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Andrade, 2010, J Clin Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Significant risk of dry mouth was associated with SSRIs (Relative risk: 1.64, p<0.001), SNRIs (Relative risk: 2.24, p<0.001), and, to some degree, atypical antidepressant bupropion (Relative risk: 2.0, p<0.001).

    “The study further demonstrated that significant risk of dry mouth was associated with SSRIs (Relative risk: 1.64, p<0.001), SNRIs (Relative risk: 2.24, p<0.001), and, to some degree, atypical antidepressant bupropion (Relative risk: 2.0, p<0.001).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Cappetta, 2018, Prog Neuropsychopharmacol Biol Psychiatry source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Traditionally, TCAs were known to decrease salivary flow rate by blocking the effects of acetylcholine on muscarinic M3 receptors, which can lead to dry mouth.

    “Traditionally, TCAs were known to decrease salivary flow rate by blocking the effects of acetylcholine on muscarinic M3 receptors, which can lead to dry mouth.33”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Scully, 2003, Oral Dis source

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  • May combine two claims.

    Premisecitation

    Recent research supported the early hypothesis and showed that among new antidepressants nefazodone, bupropion, duloxetine, and agomelatine have higher risk of liver damage whereas citalopram, escitalopram, paroxetine, and fluvoxamine had lower risks.

    “Recent research supported this early hypothesis, and further showed that among new antidepressants nefazodone, bupropion, duloxetine, and agomelatine have higher risk of liver damage whereas citalopram, escitalopram, paroxetine, and fluvoxamine had lower risks.46”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] Voican, 2014, Am J Psychiatry source

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    Premisecitation

    TCAs were found to be less often associated with nausea, anorexia and weight loss, but more with constipation and weight gain, in comparison with fluoxetine, which may be due to anticholinergic side effects.

    “TCAs were found to be less often associated with nausea, anorexia and weight loss, but more with constipation and weight gain, in comparison with fluoxetine, which may be due to anticholinergic side effects.38”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Brambilla, 2005, Pharmacopsychiatry source

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  • May combine two claims.

    Premisecitation

    Among antidepressants, SNRIs had a higher risk of dry mouth than SSRIs, and fluvoxamine and vortioxetine were not associated with an increased risk of dry mouth.

    “Among them, SNRIs had a higher risk than SSRIs, and fluvoxamine and vortioxetine were not associated with an increased risk of dry mouth.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Cappetta, 2018, Prog Neuropsychopharmacol Biol Psychiatry source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Experts believe that it is impossible to prevent idiopathic drug induced liver injury, but the severity of the reaction may be minimized with prompt recognition and early withdrawal of the agent.

    “More importantly, experts believe that it is impossible to prevent idiopathic drug induced liver injury, but the severity of the reaction may be minimized with prompt recognition and early withdrawal of the agent.4647”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [46] Voican, 2014, Am J Psychiatry source

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    • cites [47] DeSanty, 2007, Ann Pharmacother source

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  • May combine two claims.

    Interpretationcitation

    Newer antidepressants have greater cardiovascular safety, but they are not entirely without risk, because blockade of serotonin and norepinephrine transporters with or without monoamine receptor contributes to cardiovascular problems.

    “While newer antidepressants have greater cardiovascular safety, they are not entirely without risk, because blockade of serotonin and norepinephrine transporters with or without monoamine receptor contributes to cardiovascular problems.3031”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [30] Watts, 2012, Pharmacol Rev source

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    • cites [31] Hong, 1994, Gac Med Mex

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    Premisecitation

    For the first 5 years of prescription, trazodone (HR 5.41, 95% CI 3.05 to 9.61, NNH 65) had the highest risk compared with no antidepressant, followed by lofepramine (HR 3.09), venlafaxine (HR 2.84), and combined treatment (HR 2.73).

    “For the first 5 years of prescription, trazodone (Hazard Ratio 5.41, 95 % confidence interval (CI) 3.05 to 9.61, number needed to harm (NNH) 65) had the highest risk compared with no antidepressant, followed by lofepramine (HR 3.09), venlafaxine (HR 2.84), and combined treatment (HR 2.73).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Hill, 2015, BMC Psychiatry source

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    Premisecitation

    Classical studies showed that epileptogenic potential is higher for TCAs than for bupropion, so TCAs are still contraindicated for individuals with seizure disorders.

    “Classical studies showed that epileptogenic potential is higher for TCAs than for bupropion, so TCAs are still contraindicated for individuals with seizure disorders.53”
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    • cites [53] Haddad, 2008, Hum Psychopharmacol source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Depression is the most prevalent psychiatric disorder in people who die by committing a suicide.

    “Depression is the most prevalent psychiatric disorder in people who die by committing a suicide.59”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Cavanagh, 2003, Psychol Med source

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    Premisecitation

    Venlafaxine (2.5, 95% CI 2.0-3.1) and mirtazapine (1.9, 95% CI 1.1-2.9) were also safer than TCAs, but the case fatality rate ratio was higher than that of SSRIs.

    “Venlafaxine (2.5, 95% CI 2.0–3.1) and Mirtazapine (1.9, 95% CI 1.1–2.9) were also safer than TCAs, but the case fatality rate ratio was higher than that of SSRIs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] Hawton, 2010, Br J Psychiatry source

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    Premisecitation

    A study done in the US investigated poison control data of 25 antidepressants from 2000 to 2004 and found amoxapine (292), maprotiline (211), and desipramine (187) had the highest hazard indices.

    “Amoxapine (292), maprotiline (211), and desipramine (187) had the highest hazard indices.”
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    • cites [61] White, 2008, J Med Toxicol source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    It is obvious that the newer antidepressants are not necessarily more beneficial.

    “However, more importantly, it is also obvious that the newer antidepressants are not necessarily more beneficial.”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    A network meta-analysis including 34 trials with 5260 participants and 14 antidepressants found a significantly increased risk of suicidal behavior or ideation with the use of venlafaxine than placebo (OR 0·13, 95% CI: 0·00-0·55) and five other antidepressants (escitalopram, imipramine, duloxetine, fluoxetine, and paroxetine).

    “A significantly increased risk of suicidal behavior or ideation was found with the use of venlafaxine than placebo (OR 0·13, 95% CI: 0·00–0·55) and five other antidepressants (escitalopram, imipramine, duloxetine, fluoxetine, and paroxetine).9”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Cipriani, 2016, Lancet source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The FDA has issued a black box warning concerning the risk of suicidality associated with the use of antidepressants in children and adolescents from 2004.

    “The FDA has issued a black box warning concerning the risk of suicidality associated with the use of antidepressants in children and adolescents from 2004.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    It has been estimated that a quarter of patients diagnosed with major depression attempt suicide in their lifetime, and 15% of those patients ultimately die from suicide.

    “It has been estimated that a quarter of patients diagnosed with major depression attempt suicide in their lifetime, and 15% of those patients ultimately die from suicide.60”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Dumais, 2005, Am J Psychiatry source

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    Premisecitation

    Whether or not antidepressants truly increase suicidality is up for debate because depression itself is associated with an increased risk of suicide.

    “Despite this fact, whether or not antidepressants truly increase suicidality is up for debate because depression itself is associated with an increased risk of suicide.57”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Stone, 2014, N Engl J Med source

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    Premisecitation

    Within the case-control analysis, relative risk estimates for seizures were increased in current users of SSRIs (OR: 1.98) and SNRIs (OR: 1.99), but not in TCAs (OR: 0.99).

    “Furthermore, within the case-control analysis, relative risk estimates for seizures were increased in current users of SSRIs (OR: 1.98) and SNRIs (OR: 1.99), but not in TCAs (OR: 0.99).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Bloechliger, 2016, Drug Saf source

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  • May combine two claims.

    Premisecitation

    Among SSRIs, paroxetine and citalopram had a higher risk whereas escitalopram and sertraline had a lower risk of seizure.

    “Among SSRIs, paroxetine and citalopram had a higher risk whereas escitalopram and sertraline had a lower risk of seizure.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Hill, 2015, BMC Psychiatry source

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  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Although TCAs as a class had higher risk (HR: 2.32) than SSRIs (HR: 1.92), the study included trazodone as a TCA; if trazodone was not included as TCAs, then HR for SSRIs and TCAs might be very similar.

    “Although TCAs as a class had higher risk (HR: 2.32) than SSRIs (HR: 1.92), the study included trazodone as a TCAs. Thus, if trazodone was not included as TCAs, then HR for SSRIs and TCAs might be very similar.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Hill, 2015, BMC Psychiatry source

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  • May combine two claims.

    Premisecitation

    The meta-analysis which led to the black box warning showed that rate of suicidal thinking or suicidal behavior was 4% among patients being prescribed an antidepressant, as compared with 2% among those being taken placebo.

    “Moreover, the meta-analysis which lead to the black box warning in fact showed that rate of suicidal thinking or suicidal behavior was 4% among patients being prescribed an antidepressant, as compared with 2% among those being taken placebo.58”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] Friedman, 2014, N Engl J Med source

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  • May combine two claims.

    Premisecitation

    The seizure incidence with bupropion SR was similar to that of the general population (0.07-0.09%) as well as that of other antidepressants including SSRIs (0.1%).

    “The seizure incidence was similar to that of the general population (0.07–0.09%) as well as that of other antidepressants including SSRIs (0.1%).52”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Alper, 2007, Biol Psychiatry source

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    Premisecitation

    Older age (OR: 6.3) and concomitant use of (thiazide) diuretics (OR: 11.2-13.5) increased the risk of antidepressant induced hyponatremia.

    “Above all, older age (OR: 6.3) and concomitant use of (thiazide) diuretics (OR: 11.2–13.5) increased the risk of antidepressant induced hyponatremia.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] De Picker, 2014, Psychosomatics source

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  • May combine two claims.

    Premisecitation

    The first reports of antidepressant-induced hyponatremia concerned the tricyclic antidepressant class, but most studies suggested SSRIs (OR: 1.5-21.6) have a higher risk than TCAs (OR: 1.1-4.9).

    “The first reports of antidepressant-induced hyponatremia concerned the tricyclic antidepressant class, but most studies suggested SSRIs (OR: 1.5–21.6) have a higher risk than TCAs (OR: 1.1–4.9).72”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] De Picker, 2014, Psychosomatics source

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  • May combine two claims.

    Premisecitation

    Studies suggested that hyponatremia incidence with venlafaxine was equal to or higher than that of SSRIs, but studies regarding duloxetine are yet to be defined.

    “Studies also suggested that hyponatremia incidence with venlafaxine was equal to or higher than that of SSRIs, but studies regarding duloxetine are yet to be defined.72”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] De Picker, 2014, Psychosomatics source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The effect of antidepressants on sleep is very complicated, and patients with depression may experience both decreased and/or increased sleep.

    “The effect of antidepressants on sleep is very complicated, and patients with depression may experience both decreased and / or increased sleep.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Weight losing effects disappeared with longer term (>4 months) therapy, and paroxetine conversely caused significant weight gain.

    “However, weight losing effects disappeared with longer term (>4 months) therapy, and paroxetine conversely caused significant weight gain.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [70] Serretti, 2010, J Clin Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Early studies have suggested that newer antidepressants, SSRIs and SNRIs, still have a risk of weight gain, but mirtazapine have less risk of causing weight gain than TCAs.

    “Early studies have suggested that newer antidepressants, SSRIs and SNRIs still have a risk of weight gain, but mirtazapine have less risk of causing weight gain than TCAs.67”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Fava, 2000, J Clin Psychiatry

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    It was generally accepted that paroxetine has a higher risk of weight gain amongst the SSRIs, and amitriptyline was thought to cause the most potent weight gain among TCAs.

    “It was generally accepted that paroxetine has a higher risk of weight gain amongst the SSRIs, and amitriptyline was thought to cause the most potent weight gain among TCAs.68”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] Vanina, 2002, Psychiatr Serv source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Although imipramine showed significantly higher sexual dysfunction than placebo, the rate was lower than the previous 5 antidepressants.

    “Although imipramine showed significantly higher sexual dysfunction than placebo, the rate was lower than the previous 5 antidepressants.65”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Serretti, 2009, J Clin Psychopharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Benztropine, cyproheptadine, and terazosin could be used to alleviate antidepressant-induced sweating, but its effects have not yet been confirmed.

    “Benztropine, cyproheptadine, and terazosin could be used to alleviate antidepressant-induced sweating, but its effects have not yet been confirmed.838485”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [83] Mago, 2013, Ann Clin Psychiatry

      Not checked in the free run.

    • cites [84] Kolli, 2013, Innov Clin Neurosci

      Not checked in the free run.

    • cites [85] Butt, 1989, J Clin Psychiatry

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    It is not wise to simply conclude whether or not newer antidepressants are safer in terms of sleep.

    “Thus, it is not wise to simply conclude whether or not newer antidepressants Are safer in terms of sleep.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Bupropion is well known to cause insomnia, but it is also effective in patients with attention deficit hyperactivity disorder (ADHD) or atypical depression (patients with hypersomnia).

    “Bupropion is well known to cause insomnia, but it is also effective in patients with attention deficit hyperactivity disorder (ADHD) or atypical depression (patients with hypersomnia).7980”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [79] Ng, 2017, J Child Adolesc Psychopharmacol source

      Not checked in the free run.

    • cites [80] Rye, 1998, Depress Anxiety source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Venlafaxine is associated with increased rapid eye-movement (REM) sleep latency and a reduction in the overall time spent in the REM phase while sleeping, which is why it is one of the first line drugs for cataplexy and narcolepsy with or without depression.

    “For example, venlafaxine is associated with increased rapid eye-movement (REM) sleep latency and a reduction in the overall time spent in the REM phase while sleeping, which is why it is one of the first line drugs for cataplexy and narcolepsy with or without depression.76”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [76] Houghton, 2004, Sleep Med Rev source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Vortioxetine has an antagonistic property on 5-HT3, 5-HT7 and 5-HT1D receptors, while it shows agonist activity at the 5-HT1A receptor as well as presenting a partial agonist profile at the 5-HT1B receptor.

    “vortioxetine has an antagonistic property on 5-HT3, 5-HT7 and 5-HT1D receptors, while it shows agonist activity at the 5-HT1A receptor as well as presenting a partial agonist profile at the 5-HT1B receptor.95”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [95] Pae, 2015, J Psychiatr Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some studies have found that antidepressant use was associated with a small increase in all-cause mortality, while other meta-analysis has suggested potential differences based on population characteristics.

    “Some studies have found that antidepressant use was associated with a small increase in all-cause mortality, while other meta-analysis has suggested potential differences based on population characteristics.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [87] Maslej, 2017, Psychother Psychosom source

      Not checked in the free run.

    • cites [89] Sharma, 2016, BMJ source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Vilazodone and citalopram had a similar discontinuation rate in general and from adverse events.

    “The two had a similar discontinuation rate in general and from adverse events.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [96] Mathews, 2015, Int Clin Psychopharmacol source

      Not checked in the free run.

    • cites [97] Wagner, 2018, J Affect Disord source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MDD itself is well-known to increase the mortality of patients regardless of disease severity (relative risk of MDD=1.58 vs. subthreshold depression=1.33), continuously supported by a number of cohort studies.

    “However, MDD itself is also-well-known to increase the mortality of patients regardless of disease severity (relative risk of MDD=1.58 vs. subthreshold depression= 1.33)90 continuously supported by a number of cohort studies.919293”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [90] Cuijpers, 2013, Br J Psychiatry source

      Not checked in the free run.

    • cites [91] Almeida, 2015, J Am Med Dir Assoc source

      Not checked in the free run.

    • cites [92] Holwerda, 2016, Br J Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Antidepressant use may have an increased risk of all cause mortality related to myocardial infarction, stroke, falls, upper gastrointestinal bleeding, seizures, bold dyscrasia, and adverse drug reactions.

    “Therefore we have to keep in mind that the use of antidepressants may have an increased risk of all cause mortality related to myocardial infarction, stroke, falls, upper gastrointestinal bleeding, seizures, bold dyscrasia, and adverse drug reactions”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] Coupland, 2011, BMJ source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The class effects of antidepressants on all cause mortality are still elusive, although the widespread use of SSRIs is partly based on the belief that they are safer than the older TCAs.

    “Similarily, the class effects of antidepressants on all cause mortality are also still elusive, although the widespread use of SSRIs is partly based on the belief that they are safer than the older TCAs.87”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [87] Maslej, 2017, Psychother Psychosom source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Antidepressants may be hazardous in the general population, but are less so in cardiovascular patients, perhaps owing to the positive effects in the clotting process involving platelet cell activation.

    “Antidepressants may be hazardous in the general population, but are less so in cardiovascular patients, perhaps owing to the positive effects in the clotting process involving platelet cell activation.8789”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [87] Maslej, 2017, Psychother Psychosom source

      Not checked in the free run.

    • cites [89] Sharma, 2016, BMJ source

      Not checked in the free run.

  • The quote only partly states this claim.

    Interpretationreasoning

    The common belief that newer generation antidepressants have fewer side effects than TCAs appears to be true.

    “the common belief that newer generation antidepressants have fewer side effects than TCAs appears to be true.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Significantly more patients treated with vilazodone experienced diarrhea (26.5% vs. 10.6%; RR 2.49, 95% CI 1.69-3.67) and vomiting (6.6% vs. 1.8%; RR 3.73, 95% CI 1.41-9.86) than patients treated with citalopram.

    “However, significantly more patients treated with vilazodone experienced diarrhea (26.5% vs. 10.6%; RR 2.49, 95% CI 1.69–3.67) and vomiting (6.6% vs. 1.8%; RR 3.73, 95% CI 1.41–9.86) than patients treated with citalopram.9697”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [96] Mathews, 2015, Int Clin Psychopharmacol source

      Not checked in the free run.

    • cites [97] Wagner, 2018, J Affect Disord source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The ethical and feasibility aspects of the use of placebo in clinical trials are increasingly being debated.

    “the ethical and feasibility aspects of the use of placebo in clinical trials are increasingly being debated.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [104] Every-Palmer, 2014, J Eval Clin Pract source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Patients taking MAOI had to change their diets to limit or avoid foods and beverages containing tyramine, which largely decreased the tolerability and compliance related with antidepressant treatment.

    “patients taking MAOI had to change their diets to limit or avoid foods and beverages containing tyramine which largely decreased the tolerability and compliance related with antidepressant treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Many SSRIs and SNRIs have lost their patency, so they are starting to be replaced with even more expensive drugs such as multimodal drugs (i.e. vilazodone and vortioxetine).

    “many SSRIs and SNRIs have lost their patency, so they are starting to be replaced with even more expensive drugs such as multimodal drugs (i.e. vilazodone and vortioxetine).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Hillhouse, 2015, Exp Clin Psychopharmacol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The researchers may have expected the placebo group within the TCA group to have a poorer safety profile, which is called the Golem effect.

    “the researchers may have expected the placebo group within the TCA group to have a poorer safety profile which is called the Golem effect.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [108] Davidson, 2000, J Appl Psychol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The clinicians or investigators may have expected a better safety profile for SSRIs than TCAs, causing the placebo group within the SSRIs study to have less reported side effects.

    “The clinicians or investigators may have expected a better safety profile for SSRIs than TCAs causing the placebo group within the SSRIs study to have less reported side effects.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [107] John, 2016, Indian J Surg source

      Not checked in the free run.

65 of 65

  • The paper relies on this without support.

    The drug classes compared (SSRIs, SNRIs, TCAs, etc.) are sufficiently homogeneous that class-level safety comparisons are meaningful.

    “We aimed to compare safety among different drug classes (i.e. SSRIs vs TCAs) rather than the individual antidepressants (i.e. fluoxetine vs imipramine).”

  • The paper relies on this without support.

    The literature search identified the relevant body of evidence on antidepressant side effects.

    “Published articles were identified from PubMed, Embase, Medline, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Web of Science using the key words “antidepressant,” “side-effects,” and “tolerability.””

  • The paper relies on this without support.

    Classically, TCAs were known to have a higher risk of seizure than bupropion.

    “Classically, TCAs were known to have a higher risk of seizure than bupropion.”

  • The paper relies on this without support.

    There is a large discrepancy in patient characteristics between subjects enrolled in RCT and in real clinical practice.

    “There is a large discrepancy in patient characteristics between subjects enrolled in RCT and in real clinical practice.”

  • The paper relies on this without support.

    In the industry's perspective, conducting such studies would result in more loss than gain.

    “In the industry's perspective, conducting such studies would result in more loss than gain.”

  • The paper relies on this without support.

    Such studies will represent a large financial and chronological burden, so it is almost impossible for investigators to undertake such studies without industry's support.

    “However, such studies will represent a large financial and chronological burden, so it is almost impossible for investigators to undertake such studies without industry's support.”

  • The paper relies on this without support.

    The ethical burden is another important obstacle.

    “The ethical burden is another important obstacle.”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • SSRIs and SNRIs are associated with a range of side effects, including loss of appetite, weight loss, drowsiness, dizziness, fatigue, headaches, increased suicidal thoughts, nausea/vomiting, sexual dysfunction, and increased risk of cardiovascular and cerebrovascular events.

    “However, SSRIs and SNRIs are associated with a range of side effects, including loss of appetite, weight loss, drowsiness, dizziness, fatigue, headaches, increased suicidal thoughts, nausea/vomiting, sexual dysfunction, and increased risk of cardiovascular and cerebrovascular events [3–5].”

    From Antidepressant side effects and their impact on treatment outcome in people with major depressive disorder: an iSPOT-D report (2021) · cites this paper as [3]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Dry-mouth finding conflicts with stated exceptions

    Minor

    The paper says all antidepressants in the cited meta-analysis increased dry mouth compared with placebo, then says fluvoxamine and vortioxetine were not associated with an increased risk.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 6

  1. Hong, 1994, Gac Med Mex, 130, 131
  2. Fava, 2000, J Clin Psychiatry, 61, 37
  3. Degner, 2004, Pharmacopsychiatry, 37, S39
  4. Mago, 2013, Ann Clin Psychiatry, 25, 186
  5. Kolli, 2013, Innov Clin Neurosci, 10, 10
  6. Butt, 1989, J Clin Psychiatry, 50, 146

Cited by

Sorted by citations

Related

Authors
Wang, S.-M., Han, C., Bahk, W.-M., Lee, S.-J., Patkar, A. A., Masand, P. S., & Pae, C.-U.
Affiliations
  • The Catholic University of Korea Seoul St. Mary's Hospital (KR)
  • Korea University (KR)
  • Catholic University of Korea (KR)
  • Duke Medical Center (US)
  • Global Medical Education, New York, NY, USA.
Corresponding author
Pae, Chi-Un
ORCID
Venue
Chonnam Medical Journal
Publisher
Chonnam National University Medical School
Published
2018
Volume
54
Issue
2
Pages
101
ISSN
  • 0377-9564 (ISSN-L)
  • 2233-7385
  • 2233-7393
DOI
10.4068/cmj.2018.54.2.101
PMC
PMC5972123
OpenAlex
W2804876758
Cited by
299
References
111
Citations by year
2026: 31 · 2025: 45 · 2024: 41 · 2023: 43 · 2022: 55 · 2021: 34 · 2020: 28 · 2019: 20 · 2018: 2
FWCI
2.45
Type
journal article
Language
en
Open access
Licence
Locations
  • Chonnam Medical Journal (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
Keywords
antidepressant side effects, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, mirtazapine, bupropion, drug safety comparison, antidepressant overdose, cardiac side effects, sexual dysfunction, hyponatremia, hepatotoxicity, gastrointestinal adverse effects, drug tolerability

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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