Antidepressants

While antidepressants may be the drug of choice for depression, they also have FDA approval as treatments for other medical disorders. For example, antidepressants are useful in the treatment of obsessive-compulsive disorder, social phobia, panic disorder, generalized anxiety disorder (GAD), and post-traumatic stress disorder (PTSD).[1] Antidepressants also have non-FDA approved, off-label indications. For example, tricyclic antidepressants are prescribed for pain, insomnia, and migraine. Trazodone, a serotonin modulator, is used off-label for insomnia.[2]

The different classes of antidepressants all work in slightly different ways and target certain neurotransmitters to modulate mood and behavior. All currently licensed antidepressants are believed to work by increasing the neurotransmitters serotonin or norepinephrine, or both, in the synapse. The mechanisms to increase these neurotransmitters vary, though antidepressant drugs target reuptake by the nerve terminals.[3] For example, selective serotonin reuptake inhibitors (SSRIs) work by inhibiting 5-HT reuptake by the presynaptic cleft in a synapse, thus increasing available serotonin levels.[4] Serotonin and norepinephrine reuptake inhibitors (SNRIs) block serotonin reuptake, like SSRIs, however, they also block norepinephrine reuptake in the synapse.[5]

Atypical antidepressants have different mechanisms of action. Bupropion, for example, works by inhibiting the reuptake of dopamine and norepinephrine at the presynaptic cleft.[6] Another atypical antidepressant, agomelatine, works by agonizing melatonin receptors MT1 and MT2 while antagonizing serotonergic 5-HT2C receptors, promoting dopamine and norepinephrine release.[7] Serotonin modulators, like nefazodone, may work by down-regulating postsynaptic serotonin 5-HT2A receptors.[6]

Tricyclic antidepressants, like amitriptyline, are thought to work by inhibiting the reuptake of serotonin and norepinephrine.[8]

Lastly, monoamine oxidase inhibitors (MAOIs), work by inhibiting the monoamine oxidase enzyme, which catabolizes serotonin, norepinephrine, and dopamine.[9] Another antidepressant drug that does not work by blocking reuptake is mirtazapine. Mirtazapine works by blocking alpha-2 adrenergic receptors on the cell bodies and nerve terminals, promoting the release of norepinephrine into the synapse. Furthermore, mirtazapine antagonizes 5-HT and 5-HT receptors, which has been shown to increase norepinephrine and dopamine in the cortical regions of the brain.[3]

Currently, commercially available antidepressants are available to be administered in the form of oral tablets, oral extended-release tablets, oral suspensions, topical creams, and transdermal patches. Studies are examining alternative administration routes, via inhalation, intranasal, sublingual, and rectal forms. These alternative routes are not yet commercially available for antidepressant therapy.[10]

Among the most prevalent side effects of antidepressants include sexual dysfunction, drowsiness, weight gain, insomnia, anxiety, dizziness, headache, dry mouth, blurred vision, nausea, rash, and tremor. Patients may also describe asthenia and malaise while on antidepressant therapy. Clinicians may note symptoms of hyperprolactinemia, syndrome of inappropriate antidiuretic hormone (SIADH), and hyponatremia in patients taking antidepressants.[11]

There are several scenarios where antidepressant use may be contraindicated. These scenarios vary between and within classes. Antidepressants should be used with caution in patients with known hypersensitivities or who are taking other psychotropic medications. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), for example, should not be taken with other SSRIs, monoamine oxidase inhibitors, tricyclic antidepressants, and other psychotropics; this is due to the risk of serotonin syndrome, which can lead to severe neuromuscular and autonomic symptoms.[12]

Tricyclic antidepressants can provide another good example of relative contraindications in antidepressant therapy. Clinicians should be mindful when prescribing tricyclic antidepressants to individuals with cardiovascular disease. Tricyclic antidepressants have been shown to cause orthostatic hypotension. Additionally, in patients with preexisting bundle-branch disease, tricyclic antidepressants may lead to heart block.[13] Buproprion, an atypical antidepressant, has seizure disorder listed as a major contraindication. This contraindication applies to patients with an active seizure diagnosis or with a history of prior seizure activity. Like other antidepressants, bupropion should not be used in patients taking monoamine oxidase inhibitors, or drugs that can lower the seizure threshold.[14]