Antidepressant

The UK National Institute for Health and Care Excellence (NICE) 2009 guidelines indicate that antidepressants should not be routinely used for the initial treatment of mild depression, because the risk to benefit ratio is poor. The guidelines recommended that antidepressant treatment be considered:

• For people with a history of moderate or severe depression
• For people with mild depression that has been present for a long period
• As a first-line treatment for moderate or severe depression
• As a second-line treatment for mild depression that persists after other interventions

The guidelines further note that antidepressant treatment should be used in combination with psychosocial interventions in most cases, should be continued for at least six months to reduce the risk of relapse, and that selective serotonin reuptake inhibitor (SSRIs) are typically better tolerated than other antidepressants.[22]

American Psychiatric Association treatment guidelines recommend that initial treatment be individually tailored based on factors including severity of symptoms, co-existing disorders, prior treatment experience, and the person's preference. Options may include pharmacotherapy, psychotherapy, electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS) or light therapy. They recommended antidepressant medication as an initial treatment choice in people with mild, moderate, or severe major depression, that should be given to all people with severe depression unless ECT is planned.[23]

Reviews of antidepressants generally find that they benefit adults with depression.[20][13] On the other hand, some contend that most studies on antidepressant medication are confounded by several biases: the lack of an active placebo, which means that many people in the placebo arm of a double-blind study may figure out that they are not getting any true treatment, thus destroying double-blindness; a short follow up after termination of treatment; non-systematic recording of adverse effects; very strict exclusion criteria in samples of patients; studies being paid for by the industry; selective publication of results. That means that the small beneficial effects that are found may not be statistically significant.[24][25][26][27][14]

Antidepressants are recommended by the National Institute for Health and Care Excellence (NICE) for the treatment of generalized anxiety disorder (GAD) that has failed to respond to conservative measures such as education and self-help activities. GAD is a common disorder of which the central feature is excessive worry about a number of different events. Key symptoms include excessive anxiety about multiple events and issues, and difficulty controlling worrisome thoughts that persists for at least 6 months.

Antidepressants provide a modest-to-moderate reduction in anxiety in GAD.[28] The efficacy of different antidepressants is similar.[28]

Some antidepressants are used as a treatment for social anxiety disorder, but their efficacy is not entirely convincing, as only a small proportion of antidepressants showed some efficacy for this condition. Paroxetine was the first drug to be FDA-approved for this disorder. Its efficacy is considered beneficial, although not everyone responds favorably to the drug. Sertraline and fluvoxamine extended release were later approved for it as well, while escitalopram is used off-label with acceptable efficacy. However, there isn't enough evidence to support citalopram for treating social phobia, and fluoxetine was no better than placebo in clinical trials. SSRIs are used as a first-line treatment for social anxiety, but they don't work for everyone. One alternative would be venlafaxine, which is a SNRI. It showed benefits for social phobia in five clinical trials against placebo, while the other SNRIs are not considered particularly useful for this disorder as many of them didn't undergo testing for it. As of now, it is unclear if duloxetine and desvenlafaxine can provide benefits for people with social anxiety. However, another class of antidepressants called MAOIs are considered effective for social anxiety, but they come with many unwanted side effects and are rarely used. Phenelzine was shown to be a good treatment option, but its use is limited by dietary restrictions. Moclobemide is a RIMA and showed mixed results but still received approval in some European countries for social anxiety disorder. TCA antidepressants, such as clomipramine and imipramine, are not considered effective for this anxiety disorder in particular. This leaves out SSRIs such as paroxetine, sertraline and fluvoxamine CR as acceptable and tolerated treatment options for this disorder.[29][30]

SSRIs are a second-line treatment of adult obsessive–compulsive disorder (OCD) with mild functional impairment and as first-line treatment for those with moderate or severe impairment. In children, SSRIs are considered as a second-line therapy in those with moderate-to-severe impairment, with close monitoring for psychiatric adverse effects.[31] Efficacy has been demonstrated both in short-term treatment trials of 6 to 24 weeks and in discontinuation trials of 28 to 52 weeks duration.[32][33][34][35] Clomipramine, a TCA drug, is considered effective and useful for OCD, however it is used as a second line treatment because it is less well tolerated than the SSRIs. Despite this, it has not shown superiority to fluvoxamine in trials. All SSRIs can be used effectively for OCD. SNRI use may also be attempted, though no SNRIs have been approved for treatment of OCD. Despite these treatment options, many patients remain symptomatic after initiating the medication, and less than half achieve remission.[36]

Antidepressants are one of the treatment options for PTSD, however their efficacy is not well established. Paroxetine and sertraline, both of the serotonin reuptake inhibitors class, have been FDA approved for the treatment of PTSD. Paroxetine has slightly higher response and remission rates than sertraline for this condition, however neither drug is considered very helpful for a broad patient demographic. Fluoxetine and venlafaxine are used off label. Fluoxetine has produced unsatisfactory mixed results. Venlafaxine showed response rates of 78%, which is significantly higher than what paroxetine and sertraline achieved. However, it did not address as many symptoms of PTSD as paroxetine and sertraline, in part due to the fact the venlafaxine is an SNRI. This class of drugs inhibits the reuptake of norepinephrine, which may cause anxiety in some patients. Fluvoxamine, escitalopram and citalopram were not well tested in this disorder. MAOIs, while some of them may be helpful, are not used much because of their unwanted side effects. This leaves paroxetine and sertraline as acceptable treatment options for some people, although more effective antidepressants are needed.[37]

Panic disorder is treated relatively well with medications compared to other disorders. Several classes of antidepressants have shown efficacy for this disorder, however SSRIs and SNRIs are used first-line. Paroxetine, sertraline, fluoxetine are FDA approved for panic disorder, while fluvoxamine, escitalopram and citalopram are also considered effective for it. The SNRI venlafaxine is also approved for this condition. Unlike with social anxiety and PTSD, some TCAs antidepressants, like clomipramine and imipramine have shown efficacy for panic disorder. Moreover, the MAOI phenelzine is considered useful too. Panic disorder has many drugs for its treatment, however, the starting dose must be lower than the one used for major depressive disorder because people, have reported an increase in anxiety as a result of starting the medication. In conclusion, while panic disorder's treatment options seem acceptable and useful for this condition, many people are still symptomatic after treatment with residual symptoms.[38][39][40]

Antidepressants are recommended as an alternative or additional first step to self-help programs in the treatment of bulimia nervosa.[41] SSRIs (fluoxetine in particular) are preferred over other antidepressants due to their acceptability, tolerability, and superior reduction of symptoms in short-term trials. Long-term efficacy remains poorly characterized. Bupropion is not recommended for the treatment of eating disorders due to an increased risk of seizure.[42]

Similar recommendations apply to binge eating disorder.[41] SSRIs provide short-term reductions in binge eating behavior, but have not been associated with significant weight loss.[43]

Clinical trials have generated mostly negative results for the use of SSRIs in the treatment of anorexia nervosa.[44] Treatment guidelines from the National Institute of Health and Care Excellence[41] recommend against the use of SSRIs in this disorder. Those from the American Psychiatric Association note that SSRIs confer no advantage regarding weight gain, but that they may be used for the treatment of co-existing depressive, anxiety, or obsessive–compulsive disorders.[43]

A 2012 meta-analysis concluded that antidepressants treatment favorably affects pain, health-related quality of life, depression, and sleep in fibromyalgia syndrome. Tricyclics appear to be the most effective class, with moderate effects on pain and sleep and small effects on fatigue and health-related quality of life. The fraction of people experiencing a 30% pain reduction on tricyclics was 48% versus 28% for placebo. For SSRIs and SNRIs the fraction of people experiencing a 30% pain reduction was 36% (20% in the placebo comparator arms) and 42% (32% in the corresponding placebo comparator arms). Discontinuation of treatment due to side effects was common.[45] Antidepressants including amitriptyline, fluoxetine, duloxetine, milnacipran, moclobemide, and pirlindole are recommended by the European League Against Rheumatism (EULAR) for the treatment of fibromyalgia based on "limited evidence".[46]

A 2014 meta-analysis from the Cochrane Collaboration found the antidepressant duloxetine to be effective for the treatment of pain resulting from diabetic neuropathy.[47] The same group reviewed data for amitriptyline in the treatment of neuropathic pain and found limited useful randomized clinical trial data. They concluded that the long history of successful use in the community for the treatment of fibromyalgia and neuropathic pain justified its continued use.[48] The group was concerned about the potential for overestimating the amount of pain relief provided by amitriptyline, and highlighted that only a small number of people will experience significant pain relief by taking this medication.[48]

Antidepressants may be modestly helpful for treating people who have both depression and alcohol dependence, however the evidence supporting this association is of low quality.[49] Buproprion is used to help people stop smoking. Antidepressants are also used to control some symptoms of narcolepsy.[50] Antidepressants may be used to relieve pain in people with active rheumatoid arthritis however, further research is required.[51] Antidepressants have been shown to be superior to placebo in treating depression in individuals with physical illness, although reporting bias may have exaggerated this finding.[52]

Between 30% and 50% of individuals treated with a given antidepressant do not show a response.[53][54] Approximately one-third of people achieve a full remission, one-third experience a response and one-third are nonresponders. Partial remission is characterized by the presence of poorly defined residual symptoms. These symptoms typically include depressed mood, anxiety, sleep disturbance, fatigue and diminished interest or pleasure. It is currently unclear which factors predict partial remission. However, it is clear that residual symptoms are powerful predictors of relapse, with relapse rates 3–6 times higher in people with residual symptoms than in those who experience full remission.[55] In addition, antidepressant drugs tend to lose efficacy over the course of treatment.[56] According to data from the Centers for Disease Control and Prevention, less than one-third of Americans taking one antidepressant medication have seen a mental health professional in the previous year.[57] A number of strategies are used in clinical practice to try to overcome these limits and variations.[58] They include switching medication, augmentation, and combination.

The American Psychiatric Association 2000 Practice Guideline advises that where no response is achieved following six to eight weeks of treatment with an antidepressant, to switch to an antidepressant in the same class, then to a different class of antidepressant. A 2006 meta-analysis review found wide variation in the findings of prior studies; for people who had failed to respond to an SSRI antidepressant, between 12% and 86% showed a response to a new drug. However, the more antidepressants an individual had already tried, the less likely they were to benefit from a new antidepressant trial.[54] However, a later meta-analysis found no difference between switching to a new drug and staying on the old medication; although 34% of treatment resistant people responded when switched to the new drug, 40% responded without being switched.[59]

For a partial response, the American Psychiatric Association guidelines suggest augmentation, or adding a drug from a different class. These include lithium and thyroid augmentation, dopamine agonists, sex steroids, NRIs, glucocorticoid-specific agents, or the newer anticonvulsants.[60]

A combination strategy involves adding another antidepressant, usually from a different class so as to have effect on other mechanisms. Although this may be used in clinical practice, there is little evidence for the relative efficacy or adverse effects of this strategy.[61] Other tests conducted include the use of psychostimulants as an augmentation therapy. Several studies have shown the efficacy of combining modafinil for treatment-resistant people. It has been used to help combat SSRI-associated fatigue.[62]

The effects of antidepressants typically do not continue once the course of medication ends. This results in a high rate of relapse. A 2003 meta-analysis found that 18% of people who had responded to an antidepressant relapsed while still taking it, compared to 41% whose antidepressant was switched for a placebo.[63]

A gradual loss of therapeutic benefit occurs in a minority of people during the course of treatment.[64][65] A strategy involving the use of pharmacotherapy in the treatment of the acute episode, followed by psychotherapy in its residual phase, has been suggested by some studies.[66][67] For patients who wish to stop their antidepressants, engaging in brief psychological interventions such as Preventive Cognitive Therapy[68] or Mindfulness-based Cognitive Therapy while tapering down has been found to diminish the risk for relapse.[69]

SSRI use in pregnancy has been associated with a variety of risks with varying degrees of proof of causation. As depression is independently associated with negative pregnancy outcomes, determining the extent to which observed associations between antidepressant use and specific adverse outcomes reflects a causative relationship has been difficult in some cases.[80] In other cases, the attribution of adverse outcomes to antidepressant exposure seems fairly clear.

SSRI use in pregnancy is associated with an increased risk of spontaneous abortion of about 1.7-fold,[81][82] and is associated with preterm birth and low birth weight.[83]

A systematic review of the risk of major birth defects in antidepressant-exposed pregnancies found a small increase (3% to 24%) in the risk of major malformations and a risk of cardiovascular birth defects that did not differ from non-exposed pregnancies.[84] A study of fluoxetine-exposed pregnancies found a 12% increase in the risk of major malformations that did not reach statistical significance.[85] Other studies have found an increased risk of cardiovascular birth defects among depressed mothers not undergoing SSRI treatment, suggesting the possibility of ascertainment bias, e.g. that worried mothers may pursue more aggressive testing of their infants.[86] Another study found no increase in cardiovascular birth defects and a 27% increased risk of major malformations in SSRI exposed pregnancies.[82] The FDA advises for the risk of birth defects with the use of paroxetine[87] and the MAOI should be avoided.

A 2013 systematic review and meta-analysis found that antidepressant use during pregnancy was statistically significantly associated with some pregnancy outcomes, such as gestational age and preterm birth, but not with other outcomes. The same review cautioned that because differences between the exposed and unexposed groups were small, it was doubtful whether they were clinically significant.[88]

A neonate (infant less than 28 days old) may experience a withdrawal syndrome from abrupt discontinuation of the antidepressant at birth. Antidepressants have been shown to be present in varying amounts in breast milk, but their effects on infants are currently unknown.[89]

Moreover, SSRIs inhibit nitric oxide synthesis, which plays an important role in setting vascular tone. Several studies have pointed to an increased risk of prematurity associated with SSRI use, and this association may be due to an increase risk of pre-eclampsia of pregnancy.[90]

Another possible problem with antidepressants is the chance of antidepressant-induced mania or hypomania in people with or without a diagnosis of bipolar disorder. Many cases of bipolar depression are very similar to those of unipolar depression. Therefore, the person can be misdiagnosed with unipolar depression and be given antidepressants. Studies have shown that antidepressant-induced mania can occur in 20–40% of people with bipolar disorder.[91] For bipolar depression, antidepressants (most frequently SSRIs) can exacerbate or trigger symptoms of hypomania and mania.[92]

Studies have shown that the use of antidepressants is correlated with an increased risk of suicidal behavior and thinking (suicidality) in those aged under 25.[93] This problem has been serious enough to warrant government intervention by the US Food and Drug Administration (FDA) to warn of the increased risk of suicidality during antidepressant treatment.[94] According to the FDA, the heightened risk of suicidality occurs within the first one to two months of treatment.[95][96] The National Institute for Health and Care Excellence (NICE) places the excess risk in the "early stages of treatment".[97] A meta-analysis suggests that the relationship between antidepressant use and suicidal behavior or thoughts is age-dependent.[93] Compared with placebo, the use of antidepressants is associated with an increase in suicidal behavior or thoughts among those 25 or younger (OR=1.62). A review of RCTs and epidemiological studies by Healy and Whitaker found an increase of suicidal acts by a factor of 2.4.[98] There is no effect or possibly a mild protective effect among those aged 25 to 64 (OR=0.79). Antidepressant treatment has a protective effect against suicidality among those aged 65 and over (OR=0.37).[93][99]

Sexual side effects are also common with SSRIs, such as loss of sexual drive, failure to reach orgasm, and erectile dysfunction.[100] Although usually reversible, these sexual side-effects can, in rare cases, continue after the drug has been completely withdrawn.[101][102]

In a study of 1022 outpatients, overall sexual dysfunction with all antidepressants averaged 59.1%[103] with SSRI values between 57% and 73%, mirtazapine 24%, nefazodone 8%, amineptine 7% and moclobemide 4%. Moclobemide, a selective reversible MAO-A inhibitor, does not cause sexual dysfunction,[104] and can actually lead to an improvement in all aspects of sexual function.[105]

Biochemical mechanisms suggested as causative include increased serotonin, particularly affecting 5-HT₂ and 5-HT₃ receptors; decreased dopamine; decreased norepinephrine; blockade of cholinergic and α₁adrenergic receptors; inhibition of nitric oxide synthetase; and elevation of prolactin levels.[106] Mirtazapine is reported to have fewer sexual side effects, most likely because it antagonizes 5-HT₂ and 5-HT₃ receptors and may, in some cases, reverse sexual dysfunction induced by SSRIs by the same mechanism.[107]

Bupropion, a weak NDRI and nicotinic antagonist, may be useful in treating reduced libido as a result of SSRI treatment.[108]

Certain antidepressants may cause emotional blunting, characterized by reduced intensity of both positive and negative emotions as well as symptoms of apathy, indifference, and amotivation.[109][110][111][112][113][114][115][116][117] It may be experienced as either beneficial or detrimental depending on the situation.[118] This side effect has been particularly associated with serotonergic antidepressants like SSRIs and SNRIs, but may be less with atypical antidepressants like bupropion, agomelatine, and vortioxetine.[110][116][119][120] Higher doses of antidepressants seem to be more likely to produce emotional blunting than lower doses.[110] It can be decreased by reducing dosage, discontinuing the medication, or switching to a different antidepressant that may have less propensity for causing this side effect.[110]

Changes in appetite or weight are common among antidepressants, but are largely drug-dependent and related to which neurotransmitters they affect. Mirtazapine and paroxetine, for example, may be associated with weight gain and/or increased appetite,[121][122][123] while others (such as bupropion and venlafaxine) achieve the opposite effect.[124][125]

The antihistaminic properties of certain TCA- and TeCA-class antidepressants have been shown to contribute to the common side effects of increased appetite and weight gain associated with these classes of medication.

A 2017 meta-analysis found that antidepressants were associated with significantly increased risk of death (+33%) and new cardiovascular complications (+14%) in the general population.[126] Conversely, risks were not greater in people with existing cardiovascular disease.[126]

Antidepressant discontinuation syndrome, also called antidepressant withdrawal syndrome, is a condition that can occur following the interruption, reduction, or discontinuation of antidepressant medication.[127] The symptoms may include flu-like symptoms, trouble sleeping, nausea, poor balance, sensory changes, and anxiety.[127][12][128] The problem usually begins within three days and may last for several months.[127][128] Rarely psychosis may occur.[127]

A discontinuation syndrome can occur after stopping any antidepressant including selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs).[127][12] The risk is greater among those who have taken the medication for longer and when the medication in question has a short half-life.[127] The underlying reason for its occurrence is unclear.[127] The diagnosis is based on the symptoms.[127]

Methods of prevention include gradually decreasing the dose among those who wish to stop, though it is possible for symptoms to occur with tapering.[127][11][128] Treatment may include restarting the medication and slowly decreasing the dose.[127] People may also be switched to the long acting antidepressant fluoxetine which can then be gradually decreased.[11]

Approximately 20–50% of people who suddenly stop an antidepressant develop an antidepressant discontinuation syndrome.[127][12][128] The condition is generally not serious.[127] Though about half of people with symptoms describe them as severe.[128] Some restart antidepressants due to the severity of the symptoms.[128]

Blister pack of Prozac (fluoxetine), a selective serotonin reuptake inhibitor

Selective serotonin reuptake inhibitors (SSRIs) are believed to increase the extracellular level of the neurotransmitter serotonin by limiting its reabsorption into the presynaptic cell, increasing the level of serotonin in the synaptic cleft available to bind to the postsynaptic receptor. They have varying degrees of selectivity for the other monoamine transporters, with pure SSRIs having only weak affinity for the norepinephrine and dopamine transporters.

SSRIs are the most widely prescribed antidepressants in many countries.[168] The efficacy of SSRIs in mild or moderate cases of depression has been disputed.[169][170][171][172]

The chemical structure of venlafaxine (Effexor), an SNRI

Serotonin–norepinephrine reuptake inhibitors (SNRIs) are potent inhibitors of the reuptake of serotonin and norepinephrine. These neurotransmitters are known to play an important role in mood. SNRIs can be contrasted with the more widely used selective serotonin reuptake inhibitors (SSRIs), which act mostly upon serotonin alone.

The human serotonin transporter (SERT) and norepinephrine transporter (NET) are membrane proteins that are responsible for the reuptake of serotonin and norepinephrine. Balanced dual inhibition of monoamine reuptake can possibly offer advantages over other antidepressants drugs by treating a wider range of symptoms.[173]

SNRIs are sometimes also used to treat anxiety disorders, obsessive–compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), chronic neuropathic pain, and fibromyalgia syndrome (FMS), and for the relief of menopausal symptoms.

Serotonin modulator and stimulators (SMSs), sometimes referred to more simply as "serotonin modulators", are a type of drug with a multimodal action specific to the serotonin neurotransmitter system. To be precise, SMSs simultaneously modulate one or more serotonin receptors and inhibit the reuptake of serotonin. The term was coined in reference to the mechanism of action of the serotonergic antidepressant vortioxetine, which acts as a serotonin reuptake inhibitor (SRI), partial agonist of the 5-HT_1A receptor, and antagonist of the 5-HT₃ and 5-HT₇ receptors.[174][175][176] However, it can also technically be applied to vilazodone, which is an antidepressant as well and acts as an SRI and 5-HT_1A receptor partial agonist.[177]

An alternative term is serotonin partial agonist/reuptake inhibitor (SPARI), which can be applied only to vilazodone.[178]

Serotonin antagonist and reuptake inhibitors (SARIs) while mainly used as antidepressants, are also anxiolytics and hypnotics. They act by antagonizing serotonin receptors such as 5-HT_2A and inhibiting the reuptake of serotonin, norepinephrine, and/or dopamine. Additionally, most also act as α₁-adrenergic receptor antagonists. The majority of the currently marketed SARIs belong to the phenylpiperazine class of compounds. They include trazodone and nefazodone.

Norepinephrine reuptake inhibitors (NRIs or NERIs) are a type of drug that acts as a reuptake inhibitor for the neurotransmitter norepinephrine (noradrenaline) by blocking the action of the norepinephrine transporter (NET). This in turn leads to increased extracellular concentrations of norepinephrine.

NRIs are commonly used in the treatment of conditions like ADHD and narcolepsy due to their psychostimulant effects and in obesity due to their appetite suppressant effects. They are also frequently used as antidepressants for the treatment of major depressive disorder, anxiety and panic disorder. Additionally, many drugs of abuse such as cocaine and methylphenidate possess NRI activity, though it is important to mention that NRIs without combined dopamine reuptake inhibitor (DRI) properties are not significantly rewarding and hence are considered to have a negligible abuse potential.[179][180] However, norepinephrine has been implicated as acting synergistically with dopamine when actions on the two neurotransmitters are combined (e.g., in the case of NDRIs) to produce rewarding effects in psychostimulant drugs of abuse.[181]

Norepinephrine–dopamine reuptake inhibitors (NDRIs) inhibit the reuptake of norepinephrine and dopamine.[182] The only medication of this class widely used for depression is bupropion (Wellbutrin).[108] However, while often described as an NDRI, the dopaminergic actions of bupropion are very weak and it appears to be more of a noradrenergic agent.[183][184][185][186][187] In the past, NDRIs such as amineptine (Survector) and nomifensine (Merital) have also been used as antidepressants, but these medications were both discontinued due to toxicity.[182] Methylphenidate (Ritalin), a stimulant most commonly used in the treatment of attention deficit hyperactivity disorder (ADHD), is sometimes used off-label in the treatment of depression.[188][189][190]

The majority of the tricyclic antidepressants (TCAs) act primarily as serotonin–norepinephrine reuptake inhibitors (SNRIs) by blocking the serotonin transporter (SERT) and the norepinephrine transporter (NET), respectively, which results in an elevation of the synaptic concentrations of these neurotransmitters, and therefore an enhancement of neurotransmission.[191][192] Notably, with the sole exception of amineptine, the TCAs have weak affinity for the dopamine transporter (DAT), and therefore have low efficacy as dopamine reuptake inhibitors (DRIs).[191]

Although TCAs are sometimes prescribed for depressive disorders, they have been largely replaced in clinical use in most parts of the world by newer antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs) and norepinephrine reuptake inhibitors (NRIs). Adverse effects have been found to be of a similar level between TCAs and SSRIs.[193]

Tetracyclic antidepressants (TeCAs) are a class of antidepressants that were first introduced in the 1970s. They are named after their chemical structure, which contains four rings of atoms, and are closely related to the tricyclic antidepressants (TCAs), which contain three rings of atoms.

Monoamine oxidase inhibitors (MAOIs) are chemicals which inhibit the activity of the monoamine oxidase enzyme family. They have a long history of use as medications prescribed for the treatment of depression. They are particularly effective in treating atypical depression.[194] They are also used in the treatment of Parkinson's disease and several other disorders.

Because of potentially lethal dietary and drug interactions, MAOIs have historically been reserved as a last line of treatment, used only when other classes of antidepressant drugs (for example selective serotonin reuptake inhibitors and tricyclic antidepressants) have failed.[195]

MAOIs have been found to be effective in the treatment of panic disorder with agoraphobia,[196] social phobia,[197][198][199] atypical depression[200][201] or mixed anxiety and depression, bulimia,[202][203][204][205] and post-traumatic stress disorder,[206] as well as borderline personality disorder.[207] MAOIs appear to be particularly effective in the management of bipolar depression according to a retrospective-analysis.[208] There are reports of MAOI efficacy in obsessive–compulsive disorder (OCD), trichotillomania, dysmorphophobia, and avoidant personality disorder, but these reports are from uncontrolled case reports.[209]

MAOIs can also be used in the treatment of Parkinson's disease by targeting MAO-B in particular (therefore affecting dopaminergic neurons), as well as providing an alternative for migraine prophylaxis. Inhibition of both MAO-A and MAO-B is used in the treatment of clinical depression and anxiety disorders.

NMDA receptor antagonists like ketamine and esketamine are rapid-acting antidepressants and seem to work via blockade of the ionotropic glutamate NMDA receptor.[210]

See the list of antidepressants and management of depression for other drugs that are not specifically characterized.

Lithium has been used to augment antidepressant therapy in those who have failed to respond to antidepressants alone.[214] Furthermore, lithium dramatically decreases the suicide risk in recurrent depression.[215] There is some evidence for the addition of a thyroid hormone, triiodothyronine, in patients with normal thyroid function.[216]

Psychopharmacologists have also tried adding a stimulant, in particular, d-amphetamine.[217] However, the use of stimulants in cases of treatment-resistant depression is relatively controversial.[218][219] A review article published in 2007 found psychostimulants may be effective in treatment-resistant depression with concomitant antidepressant therapy, but a more certain conclusion could not be drawn due to substantial deficiencies in the studies available for consideration, and the somewhat contradictory nature of their results.[219]

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."[227] 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 refer to its action.[228] 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.[229] 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.[230]

Selikoff and Robitzek also experimented with another anti-tuberculosis drug, iproniazid; it showed a greater psychostimulant effect, but more pronounced toxicity.[231] 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.[232] 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".[232][233] Roche put a significant marketing effort behind iproniazid.[232] Its sales grew until it was recalled in 1961, due to reports of lethal hepatotoxicity.[232]

The antidepressant effect of a tricyclic, 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 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 in 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.[234]

Antidepressants became prescription drugs in the 1950s. It was estimated that no more than 50 to 100 individuals per million had the kind of depression that these new drugs would treat, and pharmaceutical companies were not enthusiastic in marketing for this small market. Sales through the 1960s remained poor compared to the sales of tranquilizers,[235] which were being marketed for different uses.[236] 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.[236][237]

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.

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.[238][239] SSRIs became known as "novel antidepressants" along with other newer drugs such as SNRIs and NRIs with various selective effects.[240]

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.[210]

A 2016 randomized controlled trial evaluated the rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression with positive outcome.[241][242]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.[243]

In the United States, antidepressants were the most commonly prescribed medication in 2013.[244] Of the estimated 16 million "long term" (over 24 months) users, roughly 70 percent are female.[244] As of 2017, about 16.5% of white people in the United States took antidepressants compared with 5.6% of black people in the United States.[245]

In the UK, figures reported in 2010 indicated that the number of antidepressants prescribed by the National Health Service (NHS) almost doubled over a decade.[246] Further analysis published in 2014 showed that number of antidepressants dispensed annually in the community went up by 25 million in the 14 years between 1998 and 2012, rising from 15 million to 40 million. Nearly 50% of this rise occurred in the four years after the 2008 banking crash, during which time the annual increase in prescriptions rose from 6.7% to 8.5%.[247] These sources also suggest that aside from the recession, other factors that may influence changes in prescribing rates may include: improvements in diagnosis, a reduction of the stigma surrounding mental health, broader prescribing trends, GP characteristics, geographical location and housing status. Another factor that may contribute to increasing consumption of antidepressants is the fact that these medications now are used for other conditions including social anxiety and posttraumatic stress disorder.

Structural formula of the SSRI sertraline

United States: The most commonly prescribed antidepressants in the US retail market in 2010 were:[248]

Netherlands: In the Netherlands, paroxetine is the most prescribed antidepressant, followed by amitriptyline, citalopram and venlafaxine.[249]

As of 2003, worldwide, 30 to 60% of people didn't follow their practitioner's instructions about taking their antidepressants,[250] and as of 2013 in the US, it appeared that around 50% of people did not take their antidepressants as directed by their practitioner.[251]

When people fail to take their antidepressants, there is a greater risk that the drug won't help, that symptoms get worse, that they miss work or are less productive at work, and that the person may be hospitalized.[252] This also increases costs for caring for them.[252]

Some academics have highlighted the need to examine the use of antidepressants and other medical treatments in cross-cultural terms, due to the fact that various cultures prescribe and observe different manifestations, symptoms, meanings and associations of depression and other medical conditions within their populations.[253][254] These cross-cultural discrepancies, it has been argued, then have implications on the perceived efficacy and use of antidepressants and other strategies in the treatment of depression in these different cultures.[253][254] In India, antidepressants are largely seen as tools to combat marginality, promising the individual the ability to reintegrate into society through their use—a view and association not observed in the West.[253]

Because most antidepressants function by inhibiting the reuptake of neurotransmitters serotonin, dopamine, and norepinephrine[255] these drugs can interfere with natural neurotransmitter levels in other organisms impacted by indirect exposure.[256] Antidepressants fluoxetine and sertraline have been detected in aquatic organisms residing in effluent dominated streams.[257] The presence of antidepressants in surface waters and aquatic organisms has caused concern because ecotoxicological effects to aquatic organisms due to fluoxetine exposure have been demonstrated.[258]

Coral reef fish have been demonstrated to modulate aggressive behavior through serotonin.[259] Artificially increasing serotonin levels in crustaceans can temporarily reverse social status and turn subordinates into aggressive and territorial dominant males.[260]

Exposure to fluoxetine has been demonstrated to increase serotonergic activity in fish, subsequently reducing aggressive behavior.[261] Perinatal exposure to fluoxetine at relevant environmental concentrations has been shown to lead to significant modifications of memory processing in 1-month-old cuttlefish.[262] This impairment may disadvantage cuttlefish and decrease their survival. Somewhat less than 10% of orally administered fluoxetine is excreted from humans unchanged or as glucuronide.[263][264]