Antidepressants

There are distinct differences between the different classes of antidepressants available because they all work in a different way. In addition, within each class, there are differences between individual antidepressants with regards to how long they remain in the body, how they are metabolized, and how much they interact with other medications.

Monoamine oxidase inhibitors (MAOIs)

MAOIs block the effects of monoamine oxidase enzymes, thereby increasing the concentration of dopamine, norepinephrine, and serotonin in the brain.

• Isocarboxazid (Marplan)

• Phenelzine (Nardil)

• Tranylcypromine (Parnate)

Norepinephrine and dopamine reuptake inhibitors (NDRIs)

NDRIs block the reuptake of norepinephrine and dopamine, increasing the concentration of these two neurotransmitters in the nerve synapse.

• Bupropion (Wellbutrin)

Selective serotonin reuptake inhibitors (SSRIs)

SSRIs increase levels of serotonin in the brain by preventing the reuptake of serotonin by nerves.

• Citalopram (Celexa)

• Escitalopram (Lexapro)

• Fluoxetine (Prozac)

• Fluvoxamine (Luvox)

• Paroxetine (Brisdelle)

• Sertraline (Zoloft)

• Vilazodone (Viibrid)

Serotonin and norepinephrine reuptake inhibitors (SNRIs)

SNRIs block the reuptake of both serotonin and norepinephrine, increasing the concentration of these two neurotransmitters in the nerve synapse.

• Duloxetine (Cymbalta)

• Desvenlafaxine (Khedezla)

• Levomilnacipran (Fetzima)

• Venlafaxine (Effexor)

Serotonin antagonist and reuptake inhibitors (SARIs)

SARIs prevent the reuptake of serotonin and affect the binding of serotonin to certain receptors

• Nefazodone (Serzone)

• Trazodone (Desyrel)

Tricyclic antidepressants (TCA) and tetracyclic antidepressants (TeCAs)

TCAs and TeCAs work by increasing levels of norepinephrine and serotonin. They may also block the actions of other neurotransmitters, such as acetylcholine and histamine.

Tricyclics

• Amitriptyline

• Clomipramine (Anafranil)

• Desipramine (Norpramin)

• Doxepin (Sinequan)

• Imipramine (Tofranil)

• Nortriptyline (Pamelor)

• Protriptyline (Vivactil)

• Trimipramine (Surmontil)

Tetracyclics

• Amoxapine (Asendin)

• Maprotiline (Ludiomil)

• Mirtazapine (Remeron)

Miscellaneous antidepressants

Increase levels of neurotransmitters by an unknown mechanism of action that is different from other pre-existing classes of antidepressant.

• Vortioxetine (Trintellix)

• See also: Discovery and development of dual serotonin and norepinephrine reuptake inhibitors

The idea of an antidepressant, if melancholy is thought synonymous with depression, existed at least as early as the 1599 pamphlet A pil to purge melancholie or, A preparative to a pvrgation: or, Topping, copping, and capping: take either or whether: or, Mash them, and squash them, and dash them, and diddle come derrie come daw them, all together... Thomas d'Urfey's Wit and Mirth: Or Pills to Purge Melancholy, the title of a large collection of songs, was published between 1698 and 1720.

Before the 1950s, opioids and amphetamines were commonly used as antidepressants. Amphetamine has been described as the first antidepressant. Use of opioids and amphetamines for depression was later restricted due to their addictive nature and side effects. Extracts from the herb St John's wort have been used as a "nerve tonic" to alleviate depression.

St John's wort fell out of favor in most countries through the 19th and 20th centuries, except in Germany, where Hypericum extracts were eventually licensed, packaged, and prescribed. Small-scale efficacy trials were carried out in the 1970s and 1980s, and attention grew in the 1990s following a meta-analysis. It remains an over-the-counter (OTC) supplement in most countries. Lead contamination associated with its usage has been seen as concerning, as lead levels in women in the United States taking St. John's wort are elevated by about 20% on average. Research continues to investigate its active component hyperforin, and to further understand its mode of action.

Isoniazid, iproniazid, and imipramine In 1951, Irving Selikoff and Edward H. Robitzek, working out of Sea View Hospital on Staten Island, began clinical trials on two new anti-tuberculosis agents developed by Hoffman-LaRoche, isoniazid, and iproniazid. Only patients with a poor prognosis were initially treated. Nevertheless, their condition improved dramatically. Selikoff and Robitzek noted "a subtle general stimulation ... the patients exhibited renewed vigor and indeed this occasionally served to introduce disciplinary problems." The promise of a cure for tuberculosis in the Sea View Hospital trials was excitedly discussed in the mainstream press.

In 1952, learning of the stimulating side effects of isoniazid, the Cincinnati psychiatrist Max Lurie tried it on his patients. In the following year, he and Harry Salzer reported that isoniazid improved depression in two-thirds of their patients, so they then coined the term antidepressant to refer to its action. A similar incident took place in Paris, where Jean Delay, head of psychiatry at Sainte-Anne Hospital, heard of this effect from his pulmonology colleagues at Cochin Hospital. In 1952 (before Lurie and Salzer), Delay, with the resident Jean-Francois Buisson, reported the positive effect of isoniazid on depressed patients. The mode of antidepressant action of isoniazid is still unclear. It is speculated that its effect is due to the inhibition of diamine oxidase, coupled with a weak inhibition of monoamine oxidase A.

Selikoff and Robitzek also experimented with another anti-tuberculosis drug, iproniazid; it showed a greater psychostimulant effect, but more pronounced toxicity. Later, Jackson Smith, Gordon Kamman, George E. Crane, and Frank Ayd, described the psychiatric applications of iproniazid. Ernst Zeller found iproniazid to be a potent monoamine oxidase inhibitor. Nevertheless, iproniazid remained relatively obscure until Nathan S. Kline, the influential head of research at Rockland State Hospital, began to popularize it in the medical and popular press as a "psychic energizer". Roche put a significant marketing effort behind iproniazid. Its sales grew until it was recalled in 1961, due to reports of lethal hepatotoxicity.

The antidepressant effect of a tricyclic antidepressant, a three-ringed compound, was first discovered in 1957 by Roland Kuhn in a Swiss psychiatric hospital. Antihistamine derivatives were used to treat surgical shock and later as neuroleptics. Although in 1955, reserpine was shown to be more effective than a placebo in alleviating anxious depression, neuroleptics were being developed as sedatives and antipsychotics.

Attempting to improve the effectiveness of chlorpromazine, Kuhn — in conjunction with the Geigy Pharmaceutical Company — discovered the compound "G 22355", later renamed imipramine. Imipramine had a beneficial effect on patients with depression who showed mental and motor retardation. Kuhn described his new compound as a "thymoleptic" "taking hold of the emotions," in contrast with neuroleptics, "taking hold of the nerves" in 1955–56. These gradually became established, resulting in the patent and manufacture in the US in 1951 by Häfliger and SchinderA.

Antidepressants became prescription drugs in the 1950s. It was estimated that no more than fifty to one hundred individuals per million had the kind of depression that these new drugs would treat, and pharmaceutical companies were not enthusiastic about marketing for this small market. Sales through the 1960s remained poor compared to the sales of tranquilizers, which were being marketed for different uses. Imipramine remained in common use and numerous successors were introduced. The use of monoamine oxidase inhibitors (MAOI) increased after the development and introduction of "reversible" forms affecting only the MAO-A subtype of inhibitors, making this drug safer to use.

By the 1960s, it was thought that the mode of action of tricyclics was to inhibit norepinephrine reuptake. However, norepinephrine reuptake became associated with stimulating effects. Later tricyclics were thought to affect serotonin as proposed in 1969 by Carlsson and Lindqvist as well as Lapin and Oxenkrug.

Second-generation antidepressants

• Main article: Second-generation antidepressants Researchers began a process of rational drug design to isolate antihistamine-derived compounds that would selectively target these systems. The first such compound to be patented was zimelidine in 1971, while the first released clinically was indalpine. Fluoxetine was approved for commercial use by the US Food and Drug Administration (FDA) in 1988, becoming the first blockbuster SSRI. Fluoxetine was developed at Eli Lilly and Company in the early 1970s by Bryan Molloy, Klaus Schmiegel, David T. Wong, and others. SSRIs became known as "novel antidepressants" along with other newer drugs such as SNRIs and NRIs with various selective effects.

Rapid-acting antidepressants Esketamine (brand name Spravato), the first rapid-acting antidepressant to be approved for clinical treatment of depression, was introduced for this indication in March 2019 in the United States.

Research A 2016 randomized controlled trial evaluated the rapid antidepressant effects of the psychedelic Ayahuasca in treatment-resistant depression with a positive outcome. In 2018, the FDA granted Breakthrough Therapy Designation for psilocybin-assisted therapy for treatment-resistant depression and in 2019, the FDA granted Breakthrough Therapy Designation for psilocybin therapy treating major depressive disorder.

Publication bias and aged research A 2018 systematic review published in The Lancet comparing the efficacy of 21 different first and second generation antidepressants found that antidepressant drugs tended to perform better and cause less adverse events when they were novel or experimental treatments compared to when they were evaluated again years later. Unpublished data was also associated with smaller positive effect sizes. However, the review did not find evidence of bias associated with industry funded research.