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

In the paper

“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.”

In the paper

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

In the paper

“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.”

In the paper

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

In the paper

“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”

What the sources say

• Not checked yetcites [2] Peretti, 2000, Acta Psychiatr Scand Suppl source

In the paper

“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).”

What the sources say

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

In the paper

“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”

What the sources say

• Not checked yetcites [12] de Abajo, 1999, BMJ source

In the paper

“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).”

In the paper

“It has been hypothesized that antidepressants might affect primary hemostasis by interfering with the uptake mechanism of blood serotonin by platelets.”

What the sources say

• Not checked yetcites [10] Andrade, 2010, J Clin Psychiatry source

In the paper

“For example, SSRIs were suspected to have the potential to induce QTc interval prolongation, and therefore increase the risk of ventricular arrhythmia.23”

What the sources say

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

In the paper

“Thus, the FDA has put forth a recommendation regarding citalopram and the risk of abnormal heart rhythms.25”

What the sources say

• Not checked yetcites [25] Wang, 2013, Expert Rev Neurother source

In the paper

“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.”

In the paper

“Unfortunately, all antidepressants, except for SSRIs, were associated with increases in heart rate. They also decreased heart rate variability (HRV).28”

What the sources say

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

In the paper

“SSRIs were initially considered to have safer cardiac profiles than TCAs.22”

What the sources say

• Not checked yetcites [22] Glassman, 1998, Int Clin Psychopharmacol source

In the paper

“Increases in resting-state heart rate and decreases in its variability are associated with substantial morbidity and mortality.27”

What the sources say

• Not checked yetcites [27] Boudoulas, 2015, Cardiology source

In the paper

“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”

What the sources say

• Not checked yetcites [13] van Walraven, 2001, BMJ source
• Not checked yetcites [14] Ziegelstein, 2007, Am J Med source
• Not checked yetcites [15] Targownik, 2009, Am J Gastroenterol source

In the paper

“Serotonin causes platelet aggregation, but SSRIs inhibit the uptake of serotonin into platelets.10”

What the sources say

• Not checked yetcites [10] Andrade, 2010, J Clin Psychiatry source

In the paper

“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).”

What the sources say

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

In the paper

“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”

What the sources say

• Not checked yetcites [33] Scully, 2003, Oral Dis source

In the paper

“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”

What the sources say

• Not checked yetcites [46] Voican, 2014, Am J Psychiatry source

In the paper

“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”

What the sources say

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

In the paper

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

What the sources say

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

In the paper

“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”

What the sources say

• Not checked yetcites [46] Voican, 2014, Am J Psychiatry source
• Not checked yetcites [47] DeSanty, 2007, Ann Pharmacother source

In the paper

“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”

What the sources say

• Not checked yetcites [30] Watts, 2012, Pharmacol Rev source
• Not checked yetcites [31] Hong, 1994, Gac Med Mex

In the paper

“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).”

What the sources say

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

In the paper

“Classical studies showed that epileptogenic potential is higher for TCAs than for bupropion, so TCAs are still contraindicated for individuals with seizure disorders.53”

What the sources say

• Not checked yetcites [53] Haddad, 2008, Hum Psychopharmacol source

In the paper

“Depression is the most prevalent psychiatric disorder in people who die by committing a suicide.59”

What the sources say

• Not checked yetcites [59] Cavanagh, 2003, Psychol Med source

In the paper

“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.”

What the sources say

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

In the paper

“Amoxapine (292), maprotiline (211), and desipramine (187) had the highest hazard indices.”

What the sources say

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

In the paper

“However, more importantly, it is also obvious that the newer antidepressants are not necessarily more beneficial.”

In the paper

“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”

What the sources say

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

In the paper

“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.”

In the paper

“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”

What the sources say

• Not checked yetcites [60] Dumais, 2005, Am J Psychiatry source

In the paper

“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”

What the sources say

• Not checked yetcites [57] Stone, 2014, N Engl J Med source

In the paper

“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).”

What the sources say

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

In the paper

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

What the sources say

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

In the paper

“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.”

What the sources say

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

In the paper

“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”

What the sources say

• Not checked yetcites [58] Friedman, 2014, N Engl J Med source

In the paper

“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”

What the sources say

• Not checked yetcites [52] Alper, 2007, Biol Psychiatry source

In the paper

“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.”

What the sources say

• Not checked yetcites [72] De Picker, 2014, Psychosomatics source

In the paper

“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”

What the sources say

• Not checked yetcites [72] De Picker, 2014, Psychosomatics source

In the paper

“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”

What the sources say

• Not checked yetcites [72] De Picker, 2014, Psychosomatics source

In the paper

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

In the paper

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

What the sources say

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

In the paper

“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”

What the sources say

• Not checked yetcites [67] Fava, 2000, J Clin Psychiatry

In the paper

“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”

What the sources say

• Not checked yetcites [68] Vanina, 2002, Psychiatr Serv source

In the paper

“Although imipramine showed significantly higher sexual dysfunction than placebo, the rate was lower than the previous 5 antidepressants.65”

What the sources say

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

In the paper

“Benztropine, cyproheptadine, and terazosin could be used to alleviate antidepressant-induced sweating, but its effects have not yet been confirmed.838485”

What the sources say

• Not checked yetcites [83] Mago, 2013, Ann Clin Psychiatry
• Not checked yetcites [84] Kolli, 2013, Innov Clin Neurosci
• Not checked yetcites [85] Butt, 1989, J Clin Psychiatry

In the paper

“Thus, it is not wise to simply conclude whether or not newer antidepressants Are safer in terms of sleep.”

In the paper

“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”

What the sources say

• Not checked yetcites [79] Ng, 2017, J Child Adolesc Psychopharmacol source
• Not checked yetcites [80] Rye, 1998, Depress Anxiety source

In the paper

“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”

What the sources say

• Not checked yetcites [76] Houghton, 2004, Sleep Med Rev source

In the paper

“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”

What the sources say

• Not checked yetcites [95] Pae, 2015, J Psychiatr Res source

In the paper

“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.”

What the sources say

• Not checked yetcites [87] Maslej, 2017, Psychother Psychosom source
• Not checked yetcites [89] Sharma, 2016, BMJ source

In the paper

“The two had a similar discontinuation rate in general and from adverse events.”

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

“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”

What the sources say

• Not checked yetcites [90] Cuijpers, 2013, Br J Psychiatry source
• Not checked yetcites [91] Almeida, 2015, J Am Med Dir Assoc source
• Not checked yetcites [92] Holwerda, 2016, Br J Psychiatry source

In the paper

“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”

What the sources say

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

In the paper

“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”

What the sources say

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

In the paper

“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”

What the sources say

• Not checked yetcites [87] Maslej, 2017, Psychother Psychosom source
• Not checked yetcites [89] Sharma, 2016, BMJ source

In the paper

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

In the paper

“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”

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

What the sources say

• Not checked yetcites [104] Every-Palmer, 2014, J Eval Clin Pract source

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [109] Hillhouse, 2015, Exp Clin Psychopharmacol source

In the paper

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

What the sources say

• Not checked yetcites [108] Davidson, 2000, J Appl Psychol source

In the paper

“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.”

What the sources say

• Not checked yetcites [107] John, 2016, Indian J Surg source