Major depressive disorder: Validated treatments and future challenges

Table 1 Main classes of antidepressants with their date of approval, contributions, and disadvantages

Product		Date of FDA1 approval	Contributions	Disadvantages
MAOI2	Iproniazid	1958	Confirmed the role of monoaminergic transmission in depression	Drug interactions, dietary restrictions
			Led to a new search methodologies to develop new antidepressants	Hepatotoxicity and hypertensive crises
TC3	Imipramine	1959	Efficacy in patients with more severe symptoms of MDD	Cardiovascular toxicity and anticholinergic side effects. Risk of lethal toxicity from overdoses
	Desipramine
	Nortriptyline	1992
	Amitriptyline	1961
	Clomipramine	Not approved
	First tetracyclicmaprotiline
SSRI4	Fluoxetine	1987	Improved tolerability	Several minor side effects (sexual dysfunction, loss of appetite, vomiting, nausea, irritability, anxiety, insomnia, and headache). Paroxetine had the highest rate of sexual dysfunction. Fluvoxamine is associated with the most overall adverse events
	Citalopram	1998
	Fluvoxamine	2007
	Paroxetine	1992
	Escitalopram	2002
	Sertraline	1999
SNRI5	Venlafaxine	2008	Commonly recommended for patients who do not respond to SSRIs	No improvement in efficacy. Lower tolerability (highest rates of nausea, vomiting, and sexual dysfunction)
	Duloxetine	2004
	Reboxetine	Not approved
Other antidepressants	Trazodone	1981	Comparable efficacy to SSRIs	High rate of somnolence
	Nefazodone	2003		Rare but fatal hepatotoxicity
	Bupropion	2003	A better tolerability profile (minimal weight gain or even weight loss). Likely to improve symptoms of fatigue and sleepiness	May increase risk for seizures (low evidence)
	Vortioxetine	2013	Efficacy in elderly patients. Supposed cognitive-enhancing properties. Safety profile is similar to SSRIs	The most commonly reported adverse effect was nausea
	Vilazodone	2011	Less sexual dysfunction (low evidence). Safety profile is similar to SSRIs	The most commonly reported adverse effects were diarrhea and nausea
	Mirtazapine	1997	Comparable efficacy to SSRIs. Low risk of sexual dysfunction	Weight gain
Ketamine and related drugs	Ketamine	Not approved	Rapid effects on resistant depression and acute suicidal ideation	Short antidepressant effect. Possible neurotoxicity and drug dependence
	Esketamine	2019	Treatment-resistant depression. Greater affinity for NMDA receptor than ketamine	Potential risk of abuse. Lack of hindsight

¹United States Food and Drug Administration.

²Monoamine oxidase inhibitors.

³Tricyclic antidepressant.

⁴Selective serotonin reuptake inhibitors.

⁵Serotonin-norepinephrine reuptake inhibitors.

NMDA: N-methyl-D-aspartate; SSRI: DSelective serotonin reuptake inhibitors; MDD: Major depressive disorder; MAOI: Monoamine oxidase inhibitor.