Because of dietary restrictions and the associated serious medical complications of MAOIs, TCAs quickly became the antidepressants of choice following the FDA approval of imipramine. This was followed by the FDA approval of a large number of TCAs with variations in structure that provided a spectrum of differing binding affinities to the 5 TCA targets: the norepinephrine transport pump, the serotonin transport pump, the histamine-1 receptor, the cholinergic muscarinic receptor, and the alpha-1 adrenergic receptor.
Related to TCAs came the tetracyclic antidepressants, including amoxapine, maprotiline, and mirtazapine. Uniquely, mirtazapine lacks any clinically relevant monoamine reuptake inhibition; rather it is an antagonist at alpha-2 adrenergic, 5HT-2A, 5HT-2C, 5HT-3, and histamine receptors.
Although safer than MAOIs, TCAs still have a significant adverse-effect profile as well as lethality in overdose. The adverse effects of MAOIs and TCAs led to the development of novel molecules that target the same 3 monoamines. The structural modifications lessened the collateral receptor affinities that contribute to many of the burdensome and dangerous adverse effects.
Bupropion was the first and remains the only norepinephrine-dopamine reuptake inhibitor. In the US, fluoxetine was the first of many SSRIs that proved to be safe in overdose. Following the SSRIs, the SNRIs (venlafaxine, duloxetine, desvenlafaxine, and levomilnacipran) varied widely in their potencies to the serotonin and norepinephrine transport pumps.
Other novel antidepressants were developed that could target both the serotonin transport pump along with specific serotonin sub-receptors:
• Serotonin reuptake inhibition and 5HT-2A antagonism, as well as other receptors: trazodone, nefazodone
• SRI and 5HT-1A partial agonism: vilazodone
• SRI and 5HT-1A agonism; 5HT-1B partial agonism; and 5HT-1D, 5HT-3, and 5HT-7 antagonism: vortioxetine
Peer-reviewed analysis: no medication shows superiority
There is no lack of research attempting to differentiate the current armamentarium of antidepressants. Two studies provide credible conclusions about antidepressant efficacy, although both have significant limitations and biases.
The STAR*D study remains the largest prospective study in history to evaluate a series of 4 alternative treatment options in a cohort of 3671 patients with a unipolar major depressive episode, with the primary outcome of achieving remission. Patients could move along the algorithm through 4 steps, each of which had a defined menu of options including changing the monotherapy antidepressant, augmentation of the antidepressant, and changing to or adding cognitive therapy (Table 4).2
One of the most remarkable findings from the STAR*D study was that when a patient moved on to step 2 after failing to achieve remission or having poor tolerability with citalopram, he or she had an equal likelihood in step 2 to achieve remission with 3 different classes of antidepressants: bupropion SR, sertraline, or venlafaxine ER. This finding highlights the challenge of choosing which medication to change to after a patient does not respond to, or cannot tolerate, the first antidepressant. The mechanism of action did not have an impact on overall treatment response to a second antidepressant after failure to respond to the first. The likelihood of achieving symptom remission was almost the same at steps 1 and 2, but significantly lower at steps 3 and 4, despite what might have been more aggressive treatment. STAR*D has generated countless studies, many of which remain ongoing.
Cipriani and colleagues8 reviewed 117 randomized controlled trials (N = 25,928) from 1991 through 2007. They compared the effectiveness and tolerability of bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, mirtazapine, paroxetine, reboxetine, sertraline, and venlafaxine. Primary outcome was defined as the “proportion of patients who responded to or dropped out of the allocated treatment.” Escitalopram and sertraline had the overall best outcomes of efficacy and tolerability. Not surprisingly, many subsequent letters to the editor provided criticism and differing opinions in response to this study’s design and conclusions.
Dr. Miller is Medical Director, Brain Health, Exeter, NH.
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