The FDA approval of Prozac in 1987 marked a revolution in the treatment of depression. Before then, the mainstay of treatment had been talk therapy of the kind originally inspired by Sigmund Freud, and the only medications available were those that had been around since the 1950s—the tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs).
While still prescribed today for certain cases of treatment-refractory depression, these early drugs are often difficult to tolerate due to their frequent and unpleasant side effects. Today, their use has largely been supplanted by the Prozac generation of antidepressants, collectively known as Serotonin Reuptake Inhibitors (SSRIs). SSRIs have been shown to be safe, effective, and generally easy to tolerate.
Since the release of Prozac, additional classes of antidepressants have been introduced that take advantage of their specifically designed function to selectively modulate the main chemical messengers involved in mood, emotion, and cognition: namely, serotonin, norepinephrine, and dopamine. An improved balance of these neurotransmitters (including a correction of abnormally low serotonin levels) typically corresponds to a reduction in depressive symptoms.
While SSRIs comprise the consensus first-line treatment for major depression, the other classes are effective options for 1) treating recurrent episodes, 2) targeting specific symptoms (e.g., insomnia or poor appetite), or 3) augmenting a partial response to an SSRI. Due to slight differences in their mechanisms of action, the antidepressant classes can vary significantly in their side effect profiles (see Table 1). This may allow for individualized treatment selection depending on a patient’s symptom burden, genetics, and personal preference. It should be emphasized that, to date, no oral antidepressant medication has been proven to be “better” at treating depression than any other.
SSRIs
Serotonin Reuptake Inhibitors (SSRIs) include many of the popular brand-name antidepressants that were fixtures on TV commercials in the 1990s and early 2000s. These include fluoxetine (Prozac), sertraline (Zoloft), citalopram (Celexa), escitalopram (Lexapro), paroxetine (Paxil), and fluvoxamine (Luvox). In addition to treating depression, these medications are also first-line treatments for several other conditions, including generalized anxiety, panic attacks, obsessive-compulsive disorder, and post-traumatic stress disorder.
As described in the name itself, this class of medication works by “inhibiting the reuptake” of serotonin—i.e., decreasing the rate at which serotonin is cleared and metabolized. This leaves more serotonin available to stimulate areas of the brain responsible for regulating mood, anxiety, sleep, and even digestion.
Since serotonin is heavily involved in a host of bodily functions, altering its concentration to any significant degree is likely to lead to some unwanted effects outside the realm of mood and emotion. Common side effects noted by patients taking SSRIs include nausea, dry mouth, headache, insomnia or somnolence, loose stools, weight gain, and sexual dysfunction. The latter is typically one of the most bothersome side effects and can affect up to 3 out of every 4 patients treated with SSRIs.
Sexual dysfunction can manifest not only as diminished interest in sex but also as impaired ability to become aroused, sustain arousal, or achieve orgasm. Options to treat sexual dysfunction include switching to a different antidepressant class, taking a drug holiday, or adding another medication to counteract the sexual dysfunction. Because antidepressant side effects are often dose-dependent, lowering the dose can help mitigate sexual dysfunction as well as the other side effects noted above. Except for sexual dysfunction, many side effects are often temporary and go away after a few days or weeks of use.
Although all SSRIs are generally well-tolerated, some are worse offenders of a particular side effect than others. Below is a rough comparison of different SSRIs with respect to drowsiness, insomnia/agitation, gastrointestinal upset, weight gain, and sexual dysfunction
| Drug | Drowsiness | Insomnia/Agitation | GI upset | Weight Gain | Sexual Dysfunction |
| Celexa | — | + | + | + | +++ |
| Lexapro | — | + | + | + | +++ |
| Prozac | — | ++ | + | — | +++ |
| Luvox | + | + | + | + | +++ |
| Paxil | + | + | + | ++ | ++++ |
| Zoloft | — | ++ | ++ | + | +++ |
SNRIs
A separate, yet related class of antidepressants is called the Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs). As the name suggests, these medicines block the reuptake of both serotonin and norepinephrine. In addition to being involved in the regulation of mood, norepinephrine is important in maintaining energy levels, alertness, and concentration—areas often negatively impacted by depression. The main SNRIs are venlafaxine (Effexor), duloxetine (Cymbalta), desvenlafaxine (Pristiq), and levomilnacipran (Fetzima).
Like SSRIs, SNRIs are effective at treating depressive disorders along with anxiety disorders. Since norepinephrine is also important for inhibiting pain signals along the spinal cord, a distinguishing feature of some SNRIs is their utility in chronic pain syndromes, such as diabetic neuropathy, fibromyalgia, and chronic musculoskeletal pain.
The side effects of SNRIs are similar to those reported for SSRIs, including sexual dysfunction, although dizziness and diaphoresis (excessive sweating) appear to be more common with SNRIs. Nausea remains the most frequently cited side effect, reported by up to a third of patients, and gradually diminishes over time. Additionally, SNRIs may increase blood pressure due to their noradrenergic activity. Blood pressure should be assessed prior to starting an SNRI and monitored throughout treatment. Nonetheless, the number of patients who meet the criteria for sustained hypertension is low.
Subtle variations also exist between the SNRIs themselves, related to the fact that these drugs will affect serotonin and norepinephrine levels to differing degrees. For example, at low doses, Effexor will primarily increase serotonin levels (acting like an SSRI) and will only increase norepinephrine levels at higher doses. By contrast, Cymbalta and Fetzima both have greater effects on norepinephrine at all doses, allowing these medications to be particularly useful in the comanagement of chronic pain syndromes. In addition, because the cognitive symptoms of depression (e.g., poor concentration, low energy) may be improved with higher noradrenergic activity, all SNRIs may be good choices for depressed patients with fatigue and brain fog.
The “Atypical” Antidepressants
Several second-generation antidepressants exist that cannot be neatly categorized as either an SSRI or SNRI, yet they still achieve a robust antidepressant effect by directly or indirectly modulating the activity of serotonin, norepinephrine, and dopamine.
Bupropion (Wellbutrin)
Wellbutrin works differently from SSRIs and SNRIs because, rather than affecting serotonin, it selectively blocks the reuptake of norepinephrine and dopamine. That’s why it is sometimes referred to as a NDRI (norepinephrine-dopamine reuptake inhibitor). Like norepinephrine, dopamine plays a key role in promoting attention and motivation, so Wellbutrin can be useful in depressive episodes associated with impaired focus and motivational drive. In fact, Wellbutrin is sometimes used off-label for ADHD to improve attention and concentration.
Because it does not have serotonergic activity, Wellbutrin avoids some main drawbacks of SSRIs, including nausea, weight gain, and sexual dysfunction. More common are insomnia, agitation, headache, and dry mouth. Because Wellbutrin tends to be more activating than serotonergic antidepressants, however, it may worsen anxiety in some patients, and it should be avoided in those with existing insomnia. Mild weight loss has been reported. There is also evidence that Wellbutrin lowers the seizure threshold at high doses, so it is generally not prescribed to those with a history of seizures or eating disorders.
Mirtazapine (Remeron)
Remeron is a sedating antidepressant that possesses a complex mechanism of action, affecting norepinephrine and serotonin differently compared to SSRIs or SNRIs. Because of its direct action on specific receptors, Remeron may have a quicker onset of antidepressant action than other medicines. The main complaint about Remeron is increased weight gain. However, for patients struggling with severe, melancholic depression leading to “vegetative” symptoms (i.e., not eating or sleeping), Remeron can be an excellent first choice. Like Wellbutrin, Remeron is devoid of the sexual side effects common to serotonergic antidepressants. Additionally, because the side effects of weight gain and sedation are dose-dependent, the dosage of Remeron can be adjusted accordingly; at low doses (7.5-15 mg), the sedating effects are high, whereas the risk of weight gain is low. At higher doses (>15 mg), Remeron tends to be slightly less sedating while conferring a greater risk for weight gain.
Trazodone (Desyrel)
Like Remeron, trazodone is a sedating antidepressant with few sexual side effects, and it is often used as a non-addictive option for primary insomnia. It, too, has a complex mechanism of action—increasing serotonin while simultaneously blocking activity at specific serotonin receptors. Unlike Remeron, it does not cause weight gain, making it an appealing choice for treating depression associated with insomnia. Nonetheless, significant daytime somnolence and dizziness can limit its tolerability since high doses are usually required to achieve an antidepressant effect. A serious but very rare side effect of trazodone is priapism (painful erection lasting >6 hours), occurring in less than 1% of patients.
The Newer Atypicals: SSRI-plus
Two of the newer antidepressants on the market are vilazodone (Viibryd) and vortioxetine (Trintellix), both FDA-approved in the 2010s. Both of these drugs possess multimodal serotonergic action, meaning they not only block the reuptake of serotonin (like SSRIs) but they also directly manipulate serotonin receptors, leading to downstream antidepressant effects. As such, these medicines are sometimes referred to as “serotonin modulators” or “SSRI-plus.”
Early marketing data suggested that Viibryd had fewer sexual side effects than typical SSRIs, although these claims remain to be verified. In contrast, for Trintellix, head-to-head data showed greater improvement in treatment-emergent sexual side effects when patients were switched to Trintellix compared to Lexapro. Additional data suggest Trintellix may have pro-cognitive effects (such as improved processing speed) compared to SSRIs. Both appear to have a lower risk of weight gain and sedation. However, a high prevalence of nausea and the expensive brand-name price tag are negative factors to consider for Trintellix, while Viibryd’s slow titration schedule, potential for drug interactions, and requirement to be taken with food have limited its utility.
The “Classical” Antidepressants: TCAs and MAOIs
As mentioned in the introduction, these two classes of compounds were the earliest medications used in the pharmacological treatment of depression. Their use spurred the first biological theories of depression that remain relevant today.
The main TCAs are listed in Table 1. They act primarily by elevating serotonin and norepinephrine levels via reuptake inhibition. However, since they also affect other neurotransmitters (like histamine and acetylcholine), they have a heavy side effect burden, including dry mouth, blurry vision, constipation, and urinary retention. Additionally, TCAs are known to cause prominent weight gain and sedation and can have serious cardiac effects (e.g., arrhythmias), which may be fatal in case of an overdose. Because of this, their use is generally restricted to third-line treatments of depression. Regular ECG monitoring is recommended in those patients with a history of cardiac disease.
The MAOIs, in contrast to TCAs, act by inhibiting the activity of an enzyme (Monoamine Oxidase) involved in metabolizing and breaking down the monoamine neurotransmitters, which include serotonin, norepinephrine, and dopamine. Like TCAs, the early nonselective MAOIs were often limited in their use due to adverse events, including dangerous interactions with tyramine-rich foods (e.g., wine, aged cheese). If tyramine is not sufficiently broken down, it can cause a massive release of norepinephrine, triggering a potentially lethal spike in blood pressure (i.e. hypertensive crisis). Dangerously high serotonin levels (termed “serotonin syndrome”) can also occur when MAOIs are administered along with other agents that increase serotonin, like SSRIs. Consequently, they are often the last pharmacologic alternative after all other antidepressant options have failed. However, some newer MAOIs, like selegiline (Emsam) and the reversible MAOI moclobemide, have proven safer, with fewer adverse interactions, and may be considered for use earlier in treatment.
General considerations:
Idiosyncratic differences in response rate and tolerability can make antidepressant treatment sometimes feel like a “trial-and-error.” However, knowledge about the mechanisms of action and common side effects across the different antidepressant classes can help patients and providers make informed decisions for tailoring treatment. Since antidepressants can differ in their pharmacological profile even within the same class, it’s important to discuss all relevant side effects with your doctor in order to stop, switch, or add medications safely and effectively.
