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

In the paper

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

In the paper

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

In the paper

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

In the paper

“SSRIs and SNRIs were not entirely risk-free.”

In the paper

“the benefit of SSRIs over TCAs in seizures has not been confirmed.”

In the paper

“SNRIs are especially associated with increased incidence of cardiovascular AEs, such as hypertension.”

In the paper

“our review suggested that the risk is the highest for trazodone”

In the paper

“in general many short-term studies, such as RCT, suggested that SSRIs and SNRIs have a better safety profile than the TCAs.”

In the paper

“the long-term studies, such as naturalistic/retrospective and pharmacovigilance studies, showed that the use of SSRIs and SNRIs is likely to yield important side effects.”

What the sources say

• Not checked yetcites [103] Carvalho, 2016, Psychother Psychosom source

In the paper

“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).”

In the paper

“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.”

In the paper

“Some other side effects such as sexual dysfunction, bleeding, and hyponatremia were more prominent with either SSRIs or SNRIs.”

In the paper

“In terms of safety after overdose, the common belief on newer generation antidepressants having fewer side effects than TCAs appears to be true.”

In the paper

“However, safety and tolerability concerns related to the newer generation of antidepressants including SSRIs and selective serotonin-norepinephrine reuptake inhibitors (SNRIs) have increased with recent research.34”

What the sources say

• Not checked yetcites [3] Whiskey, 2013, J Psychopharmacol source
• Not checked yetcites [4] Moret, 2009, J Psychopharmacol source

In the paper

“In terms of hypertension, SNRIs showed a significantly higher risk (p<0.001) than other antidepressants did.”

What the sources say

• Not checked yetcites [26] Spindelegger, 2014, Int J Neuropsychopharmacol source

In the paper

“Among SNRIs, venlafaxine (incidence rate 0.05%, median dosage 150 mg/day) was revealed to have a significantly higher risk of hypertension (p<0.001).”

What the sources say

• Not checked yetcites [26] Spindelegger, 2014, Int J Neuropsychopharmacol source

In the paper

“Two studies even showed that SSRIs, but not TCAs, were associated with an increased risk of bleeding.1718”

What the sources say

• Not checked yetcites [17] Dall, 2009, Clin Gastroenterol Hepatol source
• Not checked yetcites [18] Opatrny, 2008, Br J Clin Pharmacol source

In the paper

“The QTc prolongation was also dose dependent.”

What the sources say

• Not checked yetcites [24] Beach, 2014, J Clin Psychiatry source

In the paper

“Three studies further showed that the bleeding risk increased with low-dose aspirin or NSAID.192021”

What the sources say

• Not checked yetcites [19] Hauta-Aho, 2009, Ann Med source
• Not checked yetcites [20] Dalton, 2003, Arch Intern Med source
• Not checked yetcites [21] Wessinger, 2006, Aliment Pharmacol Ther source

In the paper

“Among SSRIs, citalopram prolonged the QTc to the greatest extent.”

What the sources say

• Not checked yetcites [24] Beach, 2014, J Clin Psychiatry source

In the paper

“Thus, dropout rate and tolerability could be an important indirect hallmark of drug safety.”

In the paper

“Moreover, the study further showed that TCAs prolong the QTc to a greater extent than SSRIs.”

What the sources say

• Not checked yetcites [24] Beach, 2014, J Clin Psychiatry source

In the paper

“The overall cardiovascular adverse reactions were higher for TCAs (0.15%) and SNRIs than SSRIs (0.08%).”

What the sources say

• Not checked yetcites [26] Spindelegger, 2014, Int J Neuropsychopharmacol source

In the paper

“The noradrenergic and specific serotonergic antidepressant mirtazapine (0.07%) had a significantly lower risk of cardiovascular adverse events.”

What the sources say

• Not checked yetcites [26] Spindelegger, 2014, Int J Neuropsychopharmacol source

In the paper

“In addition, side effects which are more specific to serotonin or norepinephrine also have become a concern.56”

What the sources say

• Not checked yetcites [5] Dording, 2002, Ann Clin Psychiatry source
• Not checked yetcites [6] Kirwin, 2005, Pharmacotherapy source

In the paper

“In contrast, hypertension associated with SSRIs was very rare.”

What the sources say

• Not checked yetcites [26] Spindelegger, 2014, Int J Neuropsychopharmacol source

In the paper

“Although tolerability might be considered different from side effects, the two could also be closely related because side effects from antidepressants are some of the most common factors responsible for the treatment discontinuation.7”

What the sources say

• Not checked yetcites [7] Fortney, 2011, J Clin Psychiatry source

In the paper

“Thus, antidepressants with a high degree of inhibition of serotonin uptake might cause more bleeding abnormalities than antidepressants with a low degree of inhibition of serotonin uptake.11”

What the sources say

• Not checked yetcites [11] de Abajo, 2011, Drugs Aging source

In the paper

“In line with this study, a network meta-analysis showed that SSIRs including fluoxetine (OR=0.23; 95% CI: 0.04–0.78), citalopram (OR=0.27; 95% CI: 0.04–0.96), and paroxetine (OR=0.22; 95% CI: 0.08–0.87) were better tolerated than TCAs (imipramine) in children and adolescents with MDD.9”

What the sources say

• Not checked yetcites [9] Cipriani, 2016, Lancet source

In the paper

“In recent years, newer classes of antidepressants were also suggested to have a high risk of cardiovascular adverse effects.”

What the sources say

• Not checked yetcites [23] Mago, 2014, Expert Rev Neurother source

In the paper

“A meta-analysis, which included 16 prospective controlled studies, showed that SSRIs caused significantly greater QTc interval prolongation than did placebo by 6 milliseconds.24”

What the sources say

• Not checked yetcites [24] Beach, 2014, J Clin Psychiatry source

In the paper

“For example, up to 43% of patients with major depressive disorder (MDD) stopped taking antidepressants due to side effects.8”

What the sources say

• Not checked yetcites [8] Hung, 2014, Curr Opin Psychiatry source

In the paper

“The SSRIs might have had less risk of dry mouth because of their lower affinity for muscarinic cholinergic receptors, alpha-2 receptors, and norepinephrine.”

What the sources say

• Not checked yetcites [34] Cappetta, 2018, Prog Neuropsychopharmacol Biol Psychiatry source

In the paper

“The potential for severe hepatotoxicity associated with nefazodone was also stressed.45”

What the sources say

• Not checked yetcites [45] Lucena, 2003, Expert Opin Drug Saf source

In the paper

“The results showed that agomelatine was statistically associated with an increased risk of hepatotoxicity with a reporting odds ratio of 6.4.”

What the sources say

• Not checked yetcites [48] Gahr, 2015, J Clin Pharmacol source

In the paper

“Likewise, higher occurrence of gastrointestinal side effects with fluoxetine than with TCAs have been repeatedly documented in earlier meta-analyses.3839”

What the sources say

• Not checked yetcites [38] Brambilla, 2005, Pharmacopsychiatry source
• Not checked yetcites [39] Wilson, 2004, Int J Geriatr Psychiatry source

In the paper

“However, meta-regression analysis restricted to SSRIs and SNRIs did not indicate a significant association between M3 receptor affinity and risk of dry mouth.34”

What the sources say

• Not checked yetcites [34] Cappetta, 2018, Prog Neuropsychopharmacol Biol Psychiatry source

In the paper

“Among TCAs, clomipramine and amitriptyline also had higher hepatotoxicity than SSRIs.”

What the sources say

• Not checked yetcites [48] Gahr, 2015, J Clin Pharmacol source

In the paper

“Among second generation antidepressants, duloxetine had a higher risk of causing hepatotoxicity.”

What the sources say

• Not checked yetcites [48] Gahr, 2015, J Clin Pharmacol source

In the paper

“Among second generation antidepressants, venlafaxine consistently showed a higher rate of nausea and vomiting than SSRIs.40414243”

What the sources say

• Not checked yetcites [40] Bielski, 2004, J Clin Psychiatry source
• Not checked yetcites [41] Rudolph, 1999, J Affect Disord source
• Not checked yetcites [42] Dierick, 1996, Prog Neuropsychopharmacol Biol Psychiatry source

In the paper

“Thus, gastric motility is significantly influenced by drugs having effects on serotonin receptors or serotonin levels.37”

What the sources say

• Not checked yetcites [37] Janssen, 2010, Aliment Pharmacol Ther source

In the paper

“Classical antidepressants such as monoamine oxidase inhibitors (MAOIs) or TCAs were suspected to have higher potential to induce liver damage than SSRIs.”

In the paper

“Interestingly, the basal heart rate was lower in patients taking SSRIs (mean=65.40 bpm, p=0.003, d=0.161) than in patients taking the placebo (Table 1).”

What the sources say

• Not checked yetcites [28] Kemp, 2014, Am J Psychiatry source

In the paper

“Pharmacovigilance data from Europe also showed similar results demonstrating that agomelatine has the highest risk of hepatotoxicity.49”

What the sources say

• Not checked yetcites [49] Montastruc, 2014, J Clin Psychopharmacol source

In the paper

“The central accumulation of norepinephrine from SNRIs might have activated alpha-2 receptors and concurrent inhibition of parasympathetic salivary neurons in the brainstem, which lead to decreased salivary flow and dry mouth.3435”

What the sources say

• Not checked yetcites [34] Cappetta, 2018, Prog Neuropsychopharmacol Biol Psychiatry source
• Not checked yetcites [35] Abdelmawla, 1999, Br J Clin Pharmacol source

In the paper

“A meta-analysis further showed that the relative risk of nausea and vomiting for venlafaxine was higher than those for SSRIs with RR of 1.53 (95% CI, 1.26–1.86).44”

What the sources say

• Not checked yetcites [44] Gartlehner, 2008, Drug Saf source

In the paper

“Nausea, vomiting, diarrhea, weight loss and anorexia were more frequent in fluoxetine-treated patients than other SSRIs.”

What the sources say

• Not checked yetcites [38] Brambilla, 2005, Pharmacopsychiatry source

In the paper

“SNRIs exhibited a moderately higher risk of dry mouth compared to placebo than SSRIs did.”

What the sources say

• Not checked yetcites [34] Cappetta, 2018, Prog Neuropsychopharmacol Biol Psychiatry source

In the paper

“In summary, evidence suggested TCAs are associated with higher cardiovascular risk even in the therapeutic doses.”

In the paper

“Among newer antidepressants, SNRIs are associated with an increased incidence of cardiovascular AEs, especially hypertension.23”

What the sources say

• Not checked yetcites [23] Mago, 2014, Expert Rev Neurother source

In the paper

“This recent metaanalysis which included 99 RCTs with SSRIs, SNRIs, and atypical antidepressants showed that all antidepressant increased dry mouth compared with placebo.”

What the sources say

• Not checked yetcites [34] Cappetta, 2018, Prog Neuropsychopharmacol Biol Psychiatry source

In the paper

“Recent studies focused on the risk of SSRIs inducing QTc interval prolongation, especially for citalopram.32”

What the sources say

• Not checked yetcites [32] Rao, 2014, Europace source

In the paper

“Mechanism behind cardiovascular side effect is very complicated, but TCAs' higher anticholinergic property may be the major cause.29”

What the sources say

• Not checked yetcites [29] Roose, 2005, Psychosom Med source

In the paper

“Milnacipran showed a higher risk of hepatotoxicity rather than duloxetine.”

What the sources say

• Not checked yetcites [49] Montastruc, 2014, J Clin Psychopharmacol source

In the paper

“The role of serotonin in the gastrointestinal system is very complex, but one thing is very clear: serotonin and its receptors play an important role in gastrointestinal motility.36”

What the sources say

• Not checked yetcites [36] Gershon, 2013, Curr Opin Endocrinol Diabetes Obes source

In the paper

“As a whole both sertraline and venlafaxine (for both, OR: 2.53) had the highest risks.55”

What the sources say

• Not checked yetcites [55] Bloechliger, 2016, Drug Saf source

In the paper

“Among SSRIs, sertraline had the highest risk (OR: 2.53).”

What the sources say

• Not checked yetcites [55] Bloechliger, 2016, Drug Saf source

In the paper

“The study showed that 77 seizure grand mal seizure were identified among 142,090 inpatients under surveillance.”

What the sources say

• Not checked yetcites [56] Köster, 2013, Psychopharmacology (Berl) source

In the paper

“Again, SSRIs did not show significant risk compared with other antidepressants (Table 2).”

What the sources say

• Not checked yetcites [48] Gahr, 2015, J Clin Pharmacol source
• Not checked yetcites [49] Montastruc, 2014, J Clin Psychopharmacol source

In the paper

“The SNRIs and noradrenergic and specific serotonergic antidepressants (NaSSAs) showed the lowest subgroup seizure rates with 0.02 % each56”

What the sources say

• Not checked yetcites [56] Köster, 2013, Psychopharmacology (Berl) source

In the paper

“The results showed that the case fatality rate ratio was significantly less with SSRIs (0.5, 95% CI 0.4–0.7) than with TCAs (13.8, 95% CI 13.0–14.7).”

What the sources say

• Not checked yetcites [62] Hawton, 2010, Br J Psychiatry source

In the paper

“With limited data, it is not possible conclude that newer antidepressants have a higher risk of causing suicidality.”

In the paper

“However, with the development of bupropion sustained release (SR), the incidence of seizure was decreased to 0.1% in a study containing 3,094 patients (50–300 mg).51”

What the sources say

• Not checked yetcites [51] Dunner, 1998, J Clin Psychiatry source

In the paper

“The TCAs had a 2-fold risk to develop a seizure as compared to other antidepressants (0.10%).”

What the sources say

• Not checked yetcites [56] Köster, 2013, Psychopharmacology (Berl) source

In the paper

“Moreover, all newer antidepressants including SSRIs, SNRIs, and mirtazapine (but bupropion) had much lower hazard indices than the TCAs.”

What the sources say

• Not checked yetcites [61] White, 2008, J Med Toxicol source

In the paper

“For SSRIs, the seizure risk was not enhanced relative to our reference population with a seizure rate of 0.05%.”

What the sources say

• Not checked yetcites [56] Köster, 2013, Psychopharmacology (Berl) source

In the paper

“Another retrospective follow-up study, with a nested case-control analysis between 1998 and 2012, further showed that the risk of seizure was higher for SSRIs (odds ratio: 1.98) than for TCAs (OR: 0.99).”

What the sources say

• Not checked yetcites [55] Bloechliger, 2016, Drug Saf source

In the paper

“The use of bupropion immediate release (IR) in dosages more than 450 mg may cause a 10-fold increase of the estimated seizure incidence.50”

What the sources say

• Not checked yetcites [50] Tripp, 2010, Gen Hosp Psychiatry source

In the paper

“A retrospective study containing 238,963 patients extracted from the primary care database of the UK showed that all antidepressants increased risk of seizure.54”

What the sources say

• Not checked yetcites [54] Hill, 2015, BMC Psychiatry source

In the paper

“There are minor individual variations among these drugs, but no studies have confirmed that newer antidepressants have lower rates of sexual dysfunction than TCAs.”

In the paper

“The fatal toxicity index was also greatest for TCAs compared to Venlafaxine, Mirtazapine, and SSRIs (Table 4).”

What the sources say

• Not checked yetcites [62] Hawton, 2010, Br J Psychiatry source

In the paper

“All antidepressants exhibiting serotonin and/or norepinephrine reuptake properties are known to cause sexual dysfunction.”

In the paper

“A meta-analysis further showed that SSRIs including citalopram, escitalopram, fluoxetine, sertraline, paroxetine and SNRIs including venlafaxine and duloxetine were associated with weight loss compared with placebo.”

What the sources say

• Not checked yetcites [70] Serretti, 2010, J Clin Psychiatry source

In the paper

“In contrast, a retrospective study showed that the mean weight change among patients receiving amitriptyline (N=284), sertraline (N=180) and fluoxetine (N=80) did not differ.69”

What the sources say

• Not checked yetcites [69] Sansone, 2000, J Clin Psychopharmacol source

In the paper

“A head-to-head comparison of these two classes in the large population-based Coupland cohort study confirmed this by showing lower HR for TCAs than for SSRIs (1:1.44, p=0.002).73”

What the sources say

• Not checked yetcites [73] Coupland, 2011, BMJ source

In the paper

“Amitriptyline and mirtazapine consistently showed weight gaining effects throughout acute and long-term treatment.”

What the sources say

• Not checked yetcites [70] Serretti, 2010, J Clin Psychiatry source

In the paper

“Among patients who completed the study and had a weight measured at the 12-month point, in addition to the above three antidepressants, escitalopram also caused significantly less weight gain than citalopram.”

What the sources say

• Not checked yetcites [71] Blumenthal, 2014, JAMA Psychiatry source

In the paper

“After adjusting for socio-demographic and clinical features, bupropion, amitriptyline, and nortriptyline caused significantly less weight gain than citalopram.”

What the sources say

• Not checked yetcites [71] Blumenthal, 2014, JAMA Psychiatry source

In the paper

“All antidepressants caused weight gain rather than weight loss.”

What the sources say

• Not checked yetcites [71] Blumenthal, 2014, JAMA Psychiatry source

In the paper

“As controls, they also included weight loss agents including orlistat, phentermine, and sibutramine, which all resulted in decrease in weight (Table 5).71”

What the sources say

• Not checked yetcites [71] Blumenthal, 2014, JAMA Psychiatry source

In the paper

“Within SSRIs, citalopram and escitalopram were constantly noted for higher incidences than other SSRIs.7475”

What the sources say

• Not checked yetcites [74] Degner, 2004, Pharmacopsychiatry
• Not checked yetcites [75] Letmaier, 2012, Int J Neuropsychopharmacol source

In the paper

“In line with this hypothesis, another network meta-analysis showed that bupropion, an antidepressant with no serotonergic effect but dopaminergic effect, had a statistically significantly lower risk of sexual dysfunction than other second generation antidepressants.66”

What the sources say

• Not checked yetcites [66] Reichenpfader, 2014, Drug Saf source

In the paper

“The study included 22,610 patients with 19,244 patients prescribed an antidepressant for at least 3 months.”

What the sources say

• Not checked yetcites [71] Blumenthal, 2014, JAMA Psychiatry source

In the paper

“In contrast, a study showed that the antidepressants with high serotonin selectivity such as citalopram, fluoxetine, paroxetine, sertraline, and venlafaxine showed the highest rates of total sexual dysfunction.”

What the sources say

• Not checked yetcites [65] Serretti, 2009, J Clin Psychopharmacol source

In the paper

“Imipramine and bupropion showed significant weight loss effects for both acute and long term treatment (Table 5).70”

What the sources say

• Not checked yetcites [70] Serretti, 2010, J Clin Psychiatry source

In the paper

“Sexual dysfunction in patients with MDD is very complex because it is associated with both the condition and the antidepressant used.63”

What the sources say

• Not checked yetcites [63] Baldwin, 2004, Expert Opin Drug Saf source

In the paper

“Despite the controversy, antidepressant induced sexual dysfunction is an important concern because up to 80% of depressed patients from randomized clinical trials reported treatment-emergent sexual side effects.64”

What the sources say

• Not checked yetcites [64] Gartlehner, 2011, Ann Intern Med source

In the paper

“Excessive sweating has been associated with antidepressants including TCAs, SSRIs, and SNRIs.”

What the sources say

• Not checked yetcites [81] Marcy, 2005, Ann Pharmacother source

In the paper

“According to the recent metaanalyses, antidepressants' use was associated with a 33% increase in mortality corresponding to estimated additional 2.64 deaths per 1,000 person-years.87”

What the sources say

• Not checked yetcites [87] Maslej, 2017, Psychother Psychosom source

In the paper

“Evidence has been consistent in relation with the increasing risk of all causes of mortality due to antidepressants use.86”

What the sources say

• Not checked yetcites [86] Brouwers, 2016, Int J Cardiol source

In the paper

“Mirtazapine, an antidepressant promoting sleep, may do so not through a sedative action but through resynchronization of the circadian rhythm.78”

What the sources say

• Not checked yetcites [78] Wichniak, 2012, Curr Pharm Des source

In the paper

“Studies showed approximately 10% of patients on SSRIs may develop excessive sweating.81”

What the sources say

• Not checked yetcites [81] Marcy, 2005, Ann Pharmacother source

In the paper

“Venlafaxine and TCAs also showed similar incidence rates.82”

What the sources say

• Not checked yetcites [82] Garber, 1997, J Clin Psychiatry source

In the paper

“Many TCAs, including doxepin, have a very strong sedating effect.”

What the sources say

• Not checked yetcites [77] Yeung, 2015, Sleep Med Rev source

In the paper

“As partly described in previous section, all antidepressants may have some potential to increase mortality in relation to their use.”

What the sources say

• Not checked yetcites [86] Brouwers, 2016, Int J Cardiol source

In the paper

“Thus, low doses of doxepin (3 and 6 mg) were approved by the FDA for the treatment of insomnia.77”

What the sources say

• Not checked yetcites [77] Yeung, 2015, Sleep Med Rev source

In the paper

“Furthermore, mixed evidence suggests that antidepressants may increase the risk of cardiovascular and cerebrovascular events according to metaanalyses.88”

What the sources say

• Not checked yetcites [88] Hansen, 2016, Ann Pharmacother source

In the paper

“For example, in addition to the SSRI activity, vilazodone is a partial agonist at the serotonergic 5-HT1A receptor94”

What the sources say

• Not checked yetcites [94] Wang, 2015, Psychiatry Investig source

In the paper

“In regards to vilazodone, there was only one RCT which compared it with SSRIs (citalopram).”

What the sources say

• Not checked yetcites [96] Mathews, 2015, Int Clin Psychopharmacol source
• Not checked yetcites [97] Wagner, 2018, J Affect Disord source

In the paper

“the high serotonin selectivity may be related to higher risk of bleeding and hyponatremia in SSRIs than in TCAs (Fig. 1).”

What the sources say

• Not checked yetcites [103] Carvalho, 2016, Psychother Psychosom source

In the paper

“patients on vortioxetine experienced a lower risk of decreased appetite, fatigue, sexual dysfunction, and somnolence than patients on duloxetine.”

What the sources say

• Not checked yetcites [9899]

In the paper

“significantly more patients treated with vortioxetine experienced nausea (37.5% vs. 16.7%; RR 2.25, 95% CI 1.12–4.53) than patients treated with paroxetine.”

What the sources say

• Not checked yetcites [97] Wagner, 2018, J Affect Disord source

In the paper

“the available evidence does not indicate fewer negative effects of vilazodone and vortioxetine as compared with other second-generation antidepressants.”

In the paper

“fatal cardio- and neuro-toxicity when over used, could be attributed to the antimuscarinic properties, which still remained as a safety concern.”

What the sources say

• Not checked yetcites 61102

In the paper

“Safety was a big concern with MAOIs because fatal hypertensive crises could occur if large amounts of tyramine was obtained from food.”

What the sources say

• Not checked yetcites [100] Grady, 2012, CNS Spectr source

In the paper

“many side effects related to the antimuscarinic properties arose.”

What the sources say

• Not checked yetcites [101] Remick, 1988, Prog Neuropsychopharmacol Biol Psychiatry source

In the paper

“Thus, there is even less impetus for industry to support such safety studies.”

In the paper

“adverse effect profiles between SSRIs and TCAs are prone to systematic expectation influences.”

What the sources say

• Not checked yetcites [106] Rief, 2009, Drug Saf source

In the paper

“dry mouth (odds ratio [OR] = 3.5; 95% CI: 2.9–4.2), drowsiness (OR = 2.7; 95% CI: 2.2–3.4), constipation (OR= 2.7; 95% CI: 2.1–3.6), sexual problems (OR =2.3; 95% CI 1.5–3.5) were more frequent in the placebo group with the TCAs study than the placebo group or the SSRIs study.”

What the sources say

• Not checked yetcites [106] Rief, 2009, Drug Saf source

In the paper

“significantly more profound adverse effects were reported in TCA-placebo groups compared with SSRI-placebo groups.”

What the sources say

• Not checked yetcites [106] Rief, 2009, Drug Saf source

In the paper

“Various biases could have resulted in discrepancies between results from RCT and naturalistic studies.”

What the sources say

• Not checked yetcites [105] Wang, 2018, Expert Rev Clin Pharmacol source