Category:Antidepressants: Difference between revisions

'''Antidepressants''' (a term whose accuracy is sometimes questioned — see [[#Terminology|Terminology]] below) are a class of medicines used principally in the treatment of major depressive disorder, and also in a range of other conditions including anxiety disorders, post-traumatic stress disorder, obsessive–compulsive disorder, and certain chronic pain syndromes. For post-traumatic stress disorder, selective serotonin reuptake inhibitors are recommended as first-line pharmacotherapy in major treatment guidelines, and two — [[sertraline]] and [[paroxetine]] — carry specific regulatory approval for that problem.<ref name="williams2022">Williams T, Phillips NJ, Stein DJ, Ipser JC (2022). Pharmacotherapy for post traumatic stress disorder (PTSD). ''Cochrane Database Syst Rev'' 3(3):CD002795. PMID 35234292.</ref>

The first two medicines specifically recognized as antidepressants were both introduced in the 1950s, and both were discovered by accident. Iproniazid had been developed as a treatment for tuberculosis; clinicians observed that it elevated mood in some patients, and in 1957 Nathan Kline's group reported its effect in depressed patients without tuberculosis. It became the first of the monoamine oxidase inhibitors (MAOIs).<ref name="lopezmunoz2009">López-Muñoz F, Alamo C (2009). Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today. ''Curr Pharm Des'' 15(14):1563–86. PMID 19442174.</ref> At roughly the same time, [[imipramine]] — tested without success as an antipsychotic — was found by the Swiss psychiatrist Roland Kuhn to relieve depression, and became the first of the tricyclic antidepressants (TCAs).<ref name="lopezmunoz2009"/>

The word "antidepressant" describes a presumed action — the lifting of depression — rather than an established mechanism. Its accuracy has been questioned on two grounds. First, the medicines grouped under the term are pharmacologically diverse and their mechanisms are not fully understood. Second, the popular explanation that depression results from a "chemical imbalance" — typically a deficiency of serotonin — is not supported by current evidence; a 2022 umbrella review found no consistent association between serotonin and depression, and standard psychopharmacology texts have likewise stated that no clear monoamine deficit has been demonstrated.<ref name="moncrieff2023">Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA (2023). The serotonin theory of depression: a systematic umbrella review of the evidence. ''Mol Psychiatry'' 28(8):3243–56. PMID 35854107.</ref> Some authors have noted that the "chemical imbalance" phrase owed much to pharmaceutical marketing rather than to settled science.<ref name="lacasse2005">Lacasse JR, Leo J (2005). Serotonin and depression: a disconnect between the advertisements and the scientific literature. ''PLoS Med'' 2(12):e392. PMID 16268734.</ref>

Most antidepressants are understood to act on monoamine neurotransmitter systems — serotonin, norepinephrine, and dopamine — for example by inhibiting reuptake or by inhibiting their breakdown. How these immediate pharmacological actions relate to changes in mood is not fully established. One commonly cited puzzle is that the effect on neurotransmitter levels occurs within hours, whereas any improvement in depressive symptoms typically takes weeks; this gap has prompted alternative or supplementary models, including hypotheses centered on neuroplasticity.<ref name="liu2017">Liu B, Liu J, Wang M, Zhang Y, Li L (2017). From Serotonin to Neuroplasticity: Evolvement of Theories for Major Depressive Disorder. ''Front Cell Neurosci'' 11:305. PMID 29033793.</ref> The mechanism of antidepressant action should therefore be regarded as an area of active investigation rather than a settled question.

The antidepressants are conventionally grouped by their primary mechanism. The monoamine oxidase inhibitors (MAOIs) include [[phenelzine]], [[tranylcypromine]], and [[isocarboxazid]]; the tricyclic antidepressants (TCAs) include [[amitriptyline]], [[nortriptyline]], [[imipramine]], and [[clomipramine]]. The selective serotonin reuptake inhibitors (SSRIs) — [[fluoxetine]], [[sertraline]], [[paroxetine]], [[citalopram]], [[escitalopram]], and [[fluvoxamine]] — and the serotonin–norepinephrine reuptake inhibitors (SNRIs) — [[venlafaxine]], [[duloxetine]], [[desvenlafaxine]], and [[levomilnacipran]] — together account for most modern antidepressant prescribing. Further agents act through other mechanisms, including [[bupropion]], [[mirtazapine]], [[trazodone]], [[vilazodone]], [[vortioxetine]], [[agomelatine]], and the recently introduced rapid-acting agents [[esketamine]] and [[zuranolone]]. The list is not exhaustive.