Considerations when selecting an antidepressant: a narrative review for primary care providers treating adults with depression

Figures & data

Figure 1. Growth in number of patients prescribed antidepressants for MDD: 1996–2015 [19].

Reproduced from Luo Y, Kataoka Y, Ostinelli EG, Cipriani A and Furukawa TA. National prescription patterns of antidepressants in the treatment of adults with major depression in the US between 1996 and 2015: a population representative survey based analysis. Front Psychiatry. 2020;11:35. doi: 10.3389/fpsyt.2020.00035; under the terms of the Creative Commons Attribution License (CCBY). https://creativecommons.org/licenses/by/4.0/. The SE of number of adults with MDD is shown by error bars.^aPatients with multiple antidepressants: referring to patients who were prescribed >1 antidepressant during that year, i.e. both patients with combination therapy and patients who changed previous monotherapy into a new drug in that year. MDD: major depressive disorder.

Table 1. Antidepressant profiles by class.

Class	Mechanism of antidepressant effect	Examples	Symptoms/Clinical profile^a	AEs	Additional considerations
SSRIs	Targeted and selective serotonin reuptake inhibition [32]	Fluoxetine Paroxetine Fluvoxamine Sertraline Citalopram Escitalopram [32]	Some are also specifically approved to treat [32]: Panic disorder Social anxiety disorder OCD PTSD Bulimia nervosa Premenstrual dysphoric disorder	Headaches, GI distress, insomnia, fatigue, anxiety, sexual dysfunction, weight gain, falls/fractures, coagulopathy [32,34–36] Prolongation of QT interval with citalopram and escitalopram [32,35]	Avoid many of the anticholinergic and cardiac AEs of the TCAs [32] Do not require dietary and drug-related restrictions [32] Often prescribed first-line because of a more targeted MOA and safer AE profile. Subtle AE differences must be weighed by the prescriber May not be suited for patients with sleep disturbances [8,12,32] Risk of GI bleeding may be doubled with concomitant NSAID use [32,36] May be associated with increased risk of falls and fractures with long-term use (may be less suited to elderly patients) [8,34,107,108] Associated with emotional blunting [20,22] Associated with discontinuation syndrome [12]
SNRIs	Dual inhibition of serotonin and norepinephrine reuptake May have an effect on other neurotransmitters [12,37]	Venlafaxine Desvenlafaxine Duloxetine Levomilnacipran [37]	Venlafaxine may be suitable for comorbid anxiety Duloxetine may be suited to treat depression with pain [33,37]	Nausea, insomnia, dry mouth, headache, increased blood pressure, sexual dysfunction, weight gain [12,33,37]	Side effects are similar to SSRIs, but may reflect noradrenergic activity [8] May not be suited for patients with sleep disturbances [33]
Serotonin modulator	Multimodal SSRI and a partial 5-HT1A receptor agonist [52,53] Partial agonist activity at 5-HT1A receptors [48,109]	Vilazodone		Nausea, diarrhea, headache, insomnia [48,53]	Better side-effect profile than most antidepressants with lower risk of sexual dysfunction or weight gain [12,52,53]
	Multimodal; thought to be mediated through antagonist effect on the 5-HT3, 5-HT7, and 5-HT1D receptors; partial agonist activity on the 5-HT1B receptor; agonist effect on the 5-HT1A receptor; and inhibition of the 5-HT transporter [51] Also enhances the extracellular concentration of dopamine, histamine, norepinephrine, and acetylcholine [109]	Vortioxetine	Older patients (aged 64–88 years) TESD Deficits in cognitive processing speed Comorbid anxiety [106]	Nausea, diarrhea, dizziness [52,55]	Better side-effect profile than most antidepressants with lower risk of sexual dysfunction or weight gain [55] Excellent for avoiding emotional blunting and cognitive blunting in most patients. Enhances speed of cognitive processing [54,55]
Atypical	Norepinephrine-dopamine reuptake inhibitor [8,12] No direct effects on serotonin, histamine, acetylcholine, or adrenaline receptors [50]	Bupropion	Fatigue Anxious distress [8]	Headache, agitation, insomnia, loss of appetite, weight loss, sweating, hypertension [8]	Increased seizure risk in patients with epilepsy No sexual dysfunction or weight gain Contraindicated in eating disorder due to weight loss May also help patients quit smoking [8] Commonly used for augmentation [50]
	Targets both melatonin and serotonin receptors [43,110]	Agomelatine^b	Comorbid insomnia [48]	Toxic hepatitis (rare, sporadic) [48]	The first melatonergic antidepressant designed to restore perturbed biological rhythms [47,110] Requires monitoring of liver function [48] Possibly lower risk of sexual side effects [110]
	Inhibits norepinephrine alpha-2 autoreceptors, allowing more norepinephrine to be released from presynaptic nerve terminals [12] Potent agonist of histaminergic H1 receptors [43] Also blocks serotonergic 5-HT2A/2C and 5-HT3 receptors [42,43]	Mirtazapine	Comorbid insomnia, GAD, OCD, PTSD, social anxiety disorder, headaches/migraine [42]	Sedation, increased appetite, weight gain [8] Potential increase in cholesterol [8,43]	Reduced sexual dysfunction compared with SSRIs/SNRIs [42] Some risk of reduced WBC count [42] May have fast onset of action compared with SSRIs [41]
	Serotonin antagonist and reuptake inhibitor; combined effect on serotonin reuptake pumps and 5-HT2A/2C receptors via both receptor agonist and antagonist activities [44]	Trazodone Nefazodone	Comorbid insomnia or GAD [44,45]	Sedation, nausea, priapism (rare), orthostatic hypotension [8]	Reduced risk of sexual dysfunction, but may cause priapism [44] Often used to induce sleep as a positive effect; slow-release formulation may be less sedating [8,46] Concerns with hepatotoxicity and liver function monitoring limit the use of nefazodone [12,44]
MAOIs	Inhibit the activity of the enzyme monoamine oxidase, preventing the breakdown of monoamine neurotransmitters [8,27,28]	Isocarboxazid Phenelzine Tranylcypromine Selegiline Moclobemide [8,12,28]	MDD with atypical features, or patients with poor response to other antidepressants [8,28,29]	Weight gain, fatigue, orthostatic hypotension, sexual side effects [8]	Generally, not prescribed first-line due to food and drug-drug interactions that may cause serotonin syndrome and hypertensive crises [8,12,28,29] Selegiline and moclobemide may be considered safer and more suitable for use earlier in treatment
TCAs	Elevate extracellular serotonin and norepinephrine levels via uptake inhibition [12] Antagonize muscarinic acetylcholine receptors	Imipramine Amitriptyline Doxepin Desipramine Nortriptyline Amoxapine Clomipramine Maprotiline Trimipramine Protriptyline [3,8,12]	Amitriptyline for pain, melancholia (psychomotor slowing, diurnal mood variation) Comorbid insomnia Pain Social anxiety disorder Severely depressed with melancholic features [8,19]	Weight gain, sedation, dry mouth, nausea, blurred vision, constipation, tachycardia, orthostatic hypotension [8,19]	Generally, not prescribed first-line due to increased anticholinergic and cardiotoxic side effects, risk of falls [8]
NMDA receptor antagonists	Ketamine is a noncompetitive NMDA and glutamate receptor antagonist, predicted to mediate its effect by a secondary increase in structural synaptic connectivity [111] Esketamine, like ketamine, is postulated to inhibit NMDA receptor on gamma-aminobutyric acid interneurons to restore synaptic function [112] Dextromethorphan/bupropion increases norepinephrine availability by inhibiting reuptake and acting as alpha-4-beta-2 nicotinic antagonists [56] Dextromethorphan is an uncompetitive antagonist of the NMDA receptor and a sigma-1 receptor agonist. Bupropion increases plasma levels of dextromethorphan by inhibiting CYP2D6, and may be related to noradrenergic and/or dopaminergic mechanisms [56,59]	Ketamine Esketamine Dextromethorphan/bupropion	Ketamine and esketamine: TRD with ≥2 failed antidepressants treatment, or for MDD patients with acute suicidality [23,57]	Ketamine and esketamine: Treatment-emergent adverse events generally include, but are not limited to, psychiatric (psychotomimetic effects and dissociation), neurologic/cognitive (dizziness, drowsiness and light-headedness), hemodynamic, genitourinary, and abuse liability [23] Dextromethorphan/ bupropion: Dizziness, nausea, headache, diarrhea, somnolence, dry mouth [24]	Ketamine and esketamine: Have rapid-onset efficacy in TRD [23] Intranasal esketamine and intravenous ketamine are effective routes of administration [23] To be administered only in settings with multidisciplinary trained personnel [23] Esketamine administration may require REMS in some countries (e.g. the United States) [23] Some treatment-emergent adverse events with ketamine are dose dependent In cases of discontinuation, a transitions-of-care plan is necessary for ongoing surveillance of depressive symptoms [23] Dextromethorphan/ bupropion: Rapid efficacy compared to antidepressant monotherapy [56] May increase seizure risk in patients taking higher doses, and with certain other medicines and medical conditions [59] To be avoided for patients who have or had seizure disorder or eating disorder, and if a MAOI is used in the last 14 days [59] May increase risk of hypertension [59]

^aNot all are on-label. Consult the prescribing guide for the specific antidepressant.

^bNot currently available for use in the United States.

5-HT: serotonin, AE: adverse event, GAD: generalized anxiety disorder, GI: gastrointestinal, CYP2D6: cytochrome P450 2D6, MAOI: monoamine oxidase inhibitor, MDD: major depressive disorder, MOA: mechanism of action, NMDA receptor: N-methyl-D-aspartate receptor, NSAID: nonsteroidal anti-inflammatory drug, OCD: obsessive-compulsive disorder, PTSD: posttraumatic stress disorder, REMS: Risk Evaluation and Mitigation Strategy, SNRI: serotonin-norepinephrine reuptake inhibitor, SSRI: selective serotonin reuptake inhibitor, TCA: tricyclic antidepressant, TESD: treatment-emergent sexual dysfunction, TRD: treatment-resistant depression, WBC: white blood cell

Figure 2. Treating MDD in primary care: factors influencing initial antidepressant selection [3,8,84].

Figure 3. Summary algorithm for selecting an antidepressant [3,8,48,88].

Table

5-HT	serotonin
ADHD	attention deficit/hyperactivity disorder
AE	adverse event
APA	American Psychiatric Association
BPD	bipolar disorder
CANMAT	Canadian Network for Mood and Anxiety Treatments
CNS	central nervous system
CYP2D6	cytochrome P450 2D6
FDA	US Food and Drug Administration
GAD	generalized anxiety disorder
GI	gastrointestinal
MAOI	monoamine oxidase inhibitor
MDD	major depressive disorder
MDE	major depressive episode
MOA	mechanism of action
NMDA	N-methyl-D-aspartate
NSAID	nonsteroidal anti-inflammatory drug
OCD	obsessive-compulsive disorder
PTSD	posttraumatic stress disorder
RANZP	Royal Australian and New Zealand College of Psychiatrists
RCT	randomized controlled trial
REM	rapid eye movement
REMS	Risk Evaluation and Mitigation Strategy
SDS	Sheehan Disability Scale
SIADH	syndrome of inappropriate antidiuretic hormone secretion
SNRI	serotonin-norepinephrine reuptake inhibitor
SSRI	selective serotonin reuptake inhibitor
TCA	tricyclic antidepressant
TESD	treatment-emergent sexual dysfunction
TRD	treatment-resistant depression
US	United States
WBC	white blood cell

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