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First-line antidepressants escitalopram sertraline bupropion mirtazapine by Dr Jason Cafer MD

For first-episode depression, it is customary to start with an SSRI. For adults, no SSRI is clearly more effective than others, although escitalopram (Lexapro) has a slight advantage over the others for tolerability, and possibly for efficacy. For children, fluoxetine (Prozac) has the best evidence. For adults, escitalopram and sertraline (Zoloft) are preferred because they have fewer drug-drug interactions compared to fluoxetine or paroxetine (Paxil). Although quite safe, citalopram (Celexa) is a bit riskier than the other SSRIs due to mild QT prolongation, for which FDA lowered the recommended maximum from 60 mg to 40 mg.  There is no reason to choose citalopram over escitalopram.


If the patient is not eating or sleeping, consider starting with mirtazapine (Remeron). If insomnia is prominent but weight gain is not desired, consider choosing an SSRI plus trazodone (Desyrel) 50 mg at bedtime, PRN or scheduled ($4). The FDA max for trazodone is 400 mg, but prescribed doses rarely exceed 200 mg.


For depressed patients with fibromyalgia or other types of chronic pain, an SNRI like venlafaxine (Effexor) or duloxetine (Cymbalta) would be a reasonable first-line choice. Effexor XR is dosed 75–225 mg QD. Cymbalta is 30–60 mg QD (FDA max 120 mg). 

Antidepressants and Related Medications

Triclyclic antidepressant table Cafer's Psychopharmacology
SSRI antidepressant table Cafer's Psychopharmacology
Atypical antidepressant table Cafer's Psychopharmacology
MAOI NMDA receptor antigonist antidepressant table Cafer's Psychopharmacology
Cafer's antidepressants rain cloud icons for antidepressants

Treatment-Resistant Depression

Treatment-resistant depression (TRD) is defined as failure of two 6-week antidepressant trials. For TRD, trying a third antidepressant is no more effective than placebo.


Augmenting the antidepressant is twice as effective as placebo (Zhou et al, 2015). Lithium (0.5–0.8 mmol/L) and aripiprazole (Abilify) 5–15 mg are the top choices for augmentation. Other proven options include quetiapine (Seroquel) 100–300 mg HS, risperidone (Risperdal) 0.5–3 mg HS and liothyronine (Cytomel, T3 thyroid hormone) 50 mcg.


There is moderate evidence for adding olanzapine (Zyprexa) 5–15 mg or buspirone (Buspar) 5–15 mg BID–TID. About 50% of TRD cases are actually bipolar disorder (Francesca et al, 2014), for which lithium or lamotrigine (Lamictal) are superior to antidepressants in preventing the next depressive episode.


Intravenous ketamine or intranasal esketamine are quickly effective for TRD. Electroconvulsive therapy (ECT) has the highest rate of response and remission of any form of antidepressant treatment. 


All antidepressants have a black box warning of increased suicidal thoughts and behavior in children, adolescents and young adults. Increased risk of completed suicide has not been established. For adults beyond age 24, incidence of suicidal thoughts does not exceed placebo. For those age 65 and older, antidepressants decrease suicidal thoughts. In reduction of suicide risk, lithium is superior to antidepressants. 


For children and adolescents, antidepressants (SSRIs, SNRIs) show more prominent benefit for anxiety than for depression (Locher et al, 2017).


All antidepressants have the potential to induce a “switch” to mania, usually in the context of undiagnosed bipolar disorder. Patients with known bipolar disorder suffering a depressive episode may be treated with an antidepressant combined with a mood stabilizer or an antipsychotic. Upon successful treatment of a bipolar depressive episode, consider tapering off the antidepressant after a few months to avoid destabilization of mood over the long term.


Following a Mediterranean diet can improve acute depression and prevent future depressive episodes (Jacka et al 2017; Parletta et al, 2017). 30–60 minutes of light therapy every morning can produce benefits comparable to medication for seasonal and non-seasonal depression (Penders et al, 2016). All depressed patients should be screened for hypothyroidism—ordering serum TSH level is sufficient.

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