An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia. Drugs including the monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs) are most commonly associated with the term. These medications are among those most commonly prescribed by psychiatrists and other physicians, and their effectiveness and adverse effects are the subject of many studies and competing claims. Many drugs produce an antidepressant effect, but restrictions on their use have caused controversy and off-label prescription a risk, despite claims of superior efficacy.
Most typical antidepressants have a delayed onset of action (2–6 weeks) and are usually administered for anywhere from months to years. Despite the name, antidepressants are often used to treat other conditions, such as anxiety disorders, obsessive compulsive disorder, eating disorders, chronic pain, and some hormone-mediated disorders such as dysmenorrhea. Alone or together with anticonvulsants (e.g., Tegretol or Depakote), these medications can be used to treat attention-deficit hyperactivity disorder (ADHD) and substance abuse by addressing underlying depression. Also, antidepressants have been used for hypercytorism, with mixed reviews, and are sometimes used to treat snoring and migraines.
Other medications that are not usually called antidepressants, including antipsychotics in low doses and benzodiazepines, may be used to manage depression, although benzodiazepines may cause physical dependence if treatment is not properly monitored by a doctor. Stopping benzodiazepine treatment abruptly can cause unpleasant withdrawal symptoms. An extract of the herb St John's Wort is commonly used as an antidepressant, although it is labeled as a dietary supplement in some countries. The term antidepressant is sometimes applied to any therapy (e.g., psychotherapy, electro-convulsive therapy, acupuncture) or process (e.g., sleep disruption, increased light levels, regular exercise) found to improve a clinically depressed mood.
Inert placebos can have significant antidepressant effects, and so to establish a substance as an "antidepressant" in a clinical trial it is necessary to show superior efficacy to placebo.
History
Various opiates and amphetamines were commonly used as antidepressants until the mid-1950s, when they fell out of favor due to their addictive nature and side effects. Extracts from the herb St John's Wort have long been used (as a "nerve tonic") to alleviate depression.
Isoniazid and iproniazid
In 1951, two physicians from Sea View Hospital on Staten Island, Irving Selikoff and Edward Robitzek, began clinical trials on two new anti-tuberculosis agents from 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 and coined the term antidepressant to describe its action. A similar incident took place in Paris, where Jean Delay, head of psychiatry at Sainte-Anne Hospital, found out from his pulmonology colleagues at Cochin Hospital about the side effects of isoniazid. In 1952, before Lurie and Salzer, Delay, with the resident Jean-Francois Buisson, reported the positive effect of isoniazid on depressed patients. For reasons unrelated to its efficacy, isoniazid as an antidepressant was soon overshadowed by the more toxic iproniazid, although it remains a mainstay of tuberculosis treatment. 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.
Another anti-tuberculosis drug tried at the same time by Selikoff and Robitzek, iproniazid, showed a greater "psychostimulant" effect, but more pronounced toxicity. After the publications on isoniazid, papers by Jackson Smith, Gordon Kamman, George Crane, and Frank Ayd appeared, describing the psychiatric applications of iproniazid. Ernst Zeller found iproniazid to be a potent monoamine oxidase inhibitor. Nevertheless, iproniazid remained relatively obscure until Nathan Kline, the influential and flamboyant 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, including promoting its off-label use for depression. Its sales grew massively in the following years, until it was recalled from the market in 1961 due to cases of lethal hepatotoxicity.
Imipramine
The discovery that a tricyclic ("three ringed") compound had a significant antidepressant effect was first made in 1957 by Roland Kuhn in a Swiss psychiatric hospital. By that time antihistamine derivatives were increasingly used to treat surgical shock and then as psychiatric neuroleptics. Although in 1955 reserpine was shown to be more effective than placebo in alleviating anxious depression, neuroleptics (literally, "to seize the neuron") were being developed as sedatives and antipsychotics.
Attempting to improve the effectiveness of chlorpromazine, Kuhn, in conjunction with the Geigy pharmaceutical company, discovered that compound "G 22355" (manufactured and patented in the US in 1951 by Häfliger and Schinder) had a beneficial effect in patients with depression accompanied by mental and motor retardation. Kuhn first reported his findings on what he called a "thymoleptic" (literally, "taking hold of the emotions," in contrast with neuroleptics, "taking hold of the nerves") in 1955-56. These gradually became established, resulting in marketing of the first tricyclic antidepressant, imipramine, soon followed by variants.
Later history
These new drug therapies became prescription drugs in the 1950s. It was estimated that no more than 50 to 100 people per million suffered from the kind of depression that these new drugs would treat, and pharmaceutical companies were not enthusiastic. Sales through the 1960s remained poor compared to the major tranquilizers (neuroleptics/antipsychotics) and minor tranquilizers (such as benzodiazepines), which were being marketed for different uses. Imipramine remained in common use and numerous successors were introduced. The field of MAO inhibitors remained quiet for many years until "reversible" forms affecting only the MAO-A subtype were introduced, avoiding some of the adverse effects.
Most pharmacologists by the 1960s thought the main therapeutic action of tricyclics was to inhibit norepinephrine reuptake, but it was gradually observed that this action was associated with energizing and motor stimulating effects, while some antidepressant compounds appeared to have differing effects through action on serotonin systems (notably proposed in 1969 by Carlsson and Lindqvist as well as Lapin and Oxenkrug).
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 Food and Drug Administration (United States) in 1988, becoming the first blockbuster SSRI. Fluoxetine was developed at Eli Lilly in the early 1970s by Bryan Molloy, David Wong and others.
While it had fallen out of favor in most countries through the 19th and 20th centuries, the herb St John's Wort became increasingly popular in Germany, where Hypericum extracts were eventually licensed, packaged and prescribed by doctors. Small-scale efficacy trials were carried out in the 1970s and 1980s, and attention grew in the 1990s following a meta-analysis of these. It remained an over-the-counter drug (OTC) or supplement in most countries and research continued to investigate its neurotransmitter effects and active components, particularly hyperforin
SSRIs became known as "novel antidepressants" along with other newer drugs such as SNRIs and NRIs with various different selective effects, such as venlafaxine, duloxetine, nefazodone and mirtazapine.
Types of Antidepressants
Main article: List of antidepressantsSelective serotonin reuptake inhibitors (SSRIs)
Selective serotonin reuptake inhibitors (SSRIs) are a family of antidepressants considered the current standard of drug treatment. A possible cause of depression is an inadequate amount of serotonin, a chemical used in the brain to transmit signals between neurons. SSRIs are said to w
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