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Antidepressant
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Antidepressant

Drug class

The skeleton structure of the SNRI venlafaxine, a typical example of an

antidepressant.

Class identifiers

Use Depressive disorders

ATC code N06A

Clinical data
 Drugs.com Drug Classes

Consumer Reports Best Buy Drugs

WebMD MedicineNet  RxList

External links

MeSH D000928

In Wikidata

Antidepressants are medications used to treat major depressive disorder,

some anxiety disorders, some chronic pain conditions, and to help manage
some addictions.[1] Common side-effects of antidepressants include dry mouth, weight
gain, dizziness, headaches, sexual dysfunction,[2][3][4][5][6] and emotional blunting.[7][8][9] Most
types of antidepressants are typically safe to take, but may cause increased thoughts of
suicide when taken by children, adolescents, and young adults. [10] A discontinuation
syndrome can occur after stopping any antidepressant which resembles recurrent
depression.[11][12]
Some reviews of antidepressants for depression in adults find benefit [13] while others do
not.[14] Evidence of benefit in children and adolescents is unclear. [15] There is debate in
the medical community about how much of the observed effects of antidepressants can
be attributed to the placebo effect.[16][17] Most research on whether antidepressant drugs
work is done on people with very severe symptoms, [18] so the results cannot be
extrapolated to the general population. [19]
There are methods for managing depression which do not involve medications or may
be used in conjunction with medications.

Contents

 1Medical uses
o 1.1Major depressive disorder
o 1.2Anxiety disorders
o 1.3Eating disorders
o 1.4Pain
o 1.5Other
o 1.6Limitations and strategies
o 1.7Switching antidepressants
o 1.8Augmentation and combination
o 1.9Long-term use
  2Adverse effects
o 2.1Pregnancy
o 2.2Antidepressant-induced mania
o 2.3Suicide
o 2.4Sexual
o 2.5Changes in weight
o 2.6Discontinuation syndrome
o 2.7Emotional blunting
 3Pharmacology
 4Types
o 4.1Selective serotonin reuptake inhibitors
o 4.2Serotonin–norepinephrine reuptake inhibitors
o 4.3Serotonin modulators and stimulators
o 4.4Serotonin antagonists and reuptake inhibitors
o 4.5Norepinephrine reuptake inhibitors
o 4.6Norepinephrine-dopamine reuptake inhibitors
o 4.7Tricyclic antidepressants
o 4.8Tetracyclic antidepressants
o 4.9Monoamine oxidase inhibitors
o 4.10NMDA receptor antagonists
o 4.11Others
 5Adjuncts
o 5.1Less common adjuncts
 6History
o 6.1Isoniazid, iproniazid, and imipramine
o 6.2Second generation antidepressants
o 6.3Rapid-acting antidepressants
 7Society and culture
o 7.1Prescription trends
o 7.2Adherence
o 7.3Social science perspective
o 7.4Environmental impacts
 8See also
 9References
 10Further reading
 11External links

Medical uses[edit]
Antidepressants are used to treat major depressive disorder and of other conditions,
including some anxiety disorders, some chronic pain conditions, and to help manage
some addictions. Antidepressants are often used in combinations with one another.
[1]
 The proponents of the monoamine hypothesis of depression recommend choosing the
antidepressant with the mechanism of action impacting the most prominent symptoms—
for example, they advocate that people with MDD who are also anxious or irritable
should be treated with SSRIs or norepinephrine reuptake inhibitors, and the ones with
the loss of energy and enjoyment of life—with norepinephrine and dopamine enhancing
drugs.[20]
Major depressive disorder[edit]
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-benefit ratio is poor. The guidelines recommended that
antidepressant treatment be considered for:

 People with a history of moderate or severe

depression,
 Those with mild depression that has been present
for a long period,
 As a second-line treatment for mild depression that
persists after other interventions,
 As a first-line treatment for moderate or severe
depression.
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 SSRIs are typically better tolerated than
other antidepressants.[21]
American Psychiatric Association treatment guidelines recommend that initial treatment
should be individually tailored based on factors that include 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.[22]
Some reviews of antidepressants in adults with depression find benefits [19][13] while others
do not.[14]
Anxiety disorders[edit]
Generalized anxiety disorder[edit]
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. [23] The
efficacy of different antidepressants is similar. [23]
Social anxiety disorder[edit]
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 social anxiety sufferers.
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 got 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. [24][25]
Obsessive–compulsive disorder[edit]
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.
[26]
 SSRIs appear useful for OCD, at least in the short term. [27] 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.[28][29][30] 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, and in some cases,
SNRIs can also be tried even though none of them is approved specifically for OCD.
However, even with all these treatment options, many people remain symptomatic after
initiating the medication, and less than half of them do achieve remission. [31]
Post traumatic stress disorder[edit]
Antidepressants are one of the treatment options for PTSD, however their efficacy is not
well established. Two antidepressants are FDA approved for
it, paroxetine and sertraline, they belong to the serotonin reuptake inhibitors class.
Paroxetine has slightly higher response and remission rates than sertraline for this
condition, however both drugs are not considered very helpful for every person that
takes them. Fluoxetine and venlafaxine are used off label, with fluoxetine producing
unsatisfactory mixed results and venlafaxine, while having a response rates of 78%,
which is significantly higher than what paroxetine and sertraline achieved, but it did not
address all the symptoms of ptsd like the two drugs did, which is in part due to the fact
the venlafaxine is an SNRI, this class of drugs inhibit the reuptake of norepinephrine
too, this could cause some anxiety in some people. 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. [32]
Panic disorder[edit]
Panic disorder is relatively treated well with medications compared with 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, although fluvoxamine, escitalopram and citalopram are
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, in the initiation of treatment, 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. [33][34][35]
Eating disorders[edit]
Antidepressants are recommended as an alternative or additional first step to self-help
programs in the treatment of bulimia nervosa.[36] 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.[37]
Similar recommendations apply to binge eating disorder.[36] SSRIs provide short-term
reductions in binge eating behavior, but have not been associated with significant
weight loss.[38]
Clinical trials have generated mostly negative results for the use of SSRIs in the
treatment of anorexia nervosa.[39] Treatment guidelines from the National Institute of
Health and Care Excellence[36] 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. [38]
Pain[edit]
Fibromyalgia[edit]
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.
[40]
 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". [41]
Neuropathic pain[edit]
A 2014 meta-analysis from the Cochrane Collaboration found the antidepressant
duloxetine to be effective for the treatment of pain resulting from diabetic neuropathy.
[42]
 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.[43] 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.[43]
Other[edit]
Antidepressants may be modestly helpful for treating people who both have depression
and alcohol dependence, however the evidence supporting this association is of low
quality.[44] Buproprion is used to help people stop smoking. Antidepressants are also
used to control some symptoms of narcolepsy.[45] Antidepressants may be used to
relieve pain in people with active rheumatoid arthritis however, further research is
required.[46] 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.[47]
Limitations and strategies[edit]
Between 30% and 50% of individuals treated with a given antidepressant do not show a
response.[48][49] 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.[50] In addition, antidepressant drugs tend to lose efficacy over
the course of treatment.[51] 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. [52] A number of strategies are
used in clinical practice to try to overcome these limits and variations. [53] They include
switching medication, augmentation, and combination.
Switching antidepressants[edit]
See also: Treatment-resistant depression §  Switching antidepressants
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.[49] 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.[54]
Augmentation and combination[edit]
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.[55]
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.[56] 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.[57]
Long-term use[edit]
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.[58]
A gradual loss of therapeutic benefit occurs in a minority of people during the course of
treatment.[59][60] 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.[61][62]

Adverse effects[edit]
Difficulty tolerating adverse effects is the most common reason for antidepressant
discontinuation.[63]
Almost any medication involved with serotonin regulation has the potential to
cause serotonin toxicity (also known as serotonin syndrome) — an excess of serotonin
that can induce mania, restlessness, agitation, emotional lability, insomnia and
confusion as its primary symptoms.[64][65] Although the condition is serious, it is not
particularly common, generally only appearing at high doses or while on other
medications. Assuming proper medical intervention has been taken (within about
24 hours) it is rarely fatal.[66][67] Antidepressants appear to increase the risk of diabetes by
about 1.3 fold.[68]
MAOIs tend to have pronounced (sometimes fatal) interactions with a wide variety of
medications and over-the-counter drugs. If taken with foods that contain very high levels
of tyramine (e.g., mature cheese, cured meats, or yeast extracts), they may cause a
potentially lethal hypertensive crisis. At lower doses, the person may only experience a
headache due to an increase in blood pressure. [69]
In response to these adverse effects, a different type of MAOI has been developed:
the reversible inhibitor of monoamine oxidase A (RIMA) class of drugs. Their primary
advantage is that they do not require the person to follow a special diet, while being
purportedly effective as SSRIs and tricyclics in treating depressive disorders. [70]
Tricyclics and SSRI can cause the so-called drug-induced QT prolongation, especially
in older adults;[71] this condition can degenerate into a specific type of abnormal heart
rhythm called torsades de points which can potentially lead to sudden cardiac arrest.[72]
Pregnancy[edit]
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.[73] 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,[74][75] and is associated with preterm birth and low birth weight. [76]
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.
[77]
 A study of fluoxetine-exposed pregnancies found a 12% increase in the risk of major
malformations that just missed statistical significance. [78] 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. [79] Another study found no
increase in cardiovascular birth defects and a 27% increased risk of major
malformations in SSRI exposed pregnancies. [75] The FDA advises for the risk of birth
defects with the use of paroxetine[80] 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. [81]
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.[82]
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.[83]
Antidepressant-induced mania[edit]
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. [84] For bipolar depression, antidepressants (most
frequently SSRIs) can exacerbate or trigger symptoms of hypomania and mania.[85]
Suicide[edit]
Main article: Antidepressants and suicide risk
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. [86] 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.[87] According to the FDA, the heightened risk of suicidality occurs within the
first one to two months of treatment.[88][89] The National Institute for Health and Care
Excellence (NICE) places the excess risk in the "early stages of treatment". [90] A meta-
analysis suggests that the relationship between antidepressant use and suicidal
behavior or thoughts is age-dependent. [86] 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). 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). [86][91]
Sexual[edit]
Sexual side effects are also common with SSRIs, such as loss of sexual drive, failure to
reach orgasm, and erectile dysfunction.[92] Although usually reversible, these sexual side-
effects can, in rare cases, continue after the drug has been completely withdrawn. [93][94]
In a study of 1022 outpatients, overall sexual dysfunction with all antidepressants
averaged 59.1%[95] 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, [96] and can actually lead
to an improvement in all aspects of sexual function. [97]
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.[98] Mirtazapine is
reported to have fewer sexual side effects, most likely because it antagonizes 5-HT 2 and
5-HT3 receptors and may, in some cases, reverse sexual dysfunction induced by SSRIs
by the same mechanism.[99]
Bupropion, a weak NDRI and nicotinic antagonist, may be useful in treating reduced
libido as a result of SSRI treatment.[100]
Changes in weight[edit]
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,[101][102][103] while others (such as bupropion and venlafaxine)
achieve the opposite effect.[104][105]
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.
Discontinuation syndrome[edit]
Main article: Antidepressant discontinuation syndrome
Antidepressant discontinuation syndrome, also called antidepressant withdrawal
syndrome, is a condition that can occur following the interruption, reduction,
or discontinuation of antidepressant medication.[106] The symptoms may include flu-like
symptoms, trouble sleeping, nausea, poor balance, sensory changes, and anxiety.[106][12]
[107]
 The problem usually begins within three days and may last for several months. [106]
[107]
 Rarely psychosis may occur.[106]
A discontinuation syndrome can occur after stopping any antidepressant
including selective serotonin re-uptake inhibitors (SSRIs), serotonin–norepinephrine
reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs).[106][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.[106] The underlying reason for its occurrence is unclear.
[106]
 The diagnosis is based on the symptoms.[106]
Methods of prevention include gradually decreasing the dose among those who wish to
stop, though it is possible for symptoms to occur with tapering. [106][11][107] Treatment may
include restarting the medication and slowly decreasing the dose. [106] 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.[106][12][107] The condition is generally not serious.
[106]
 Though about half of people with symptoms describe them as severe. [107] Some restart
antidepressants due to the severity of the symptoms. [107]
Emotional blunting[edit]
SSRIs appear to cause emotional blunting, or numbness in some people who take
them. This is a reduction in extremes of emotion, both positive and negative. While the
person may feel less depressed, they may also feel less happiness or empathy. This
may be cause for a dose reduction or medication change. The mechanism is unknown.
[108][109]

Pharmacology[edit]
Main article: Pharmacology of antidepressants
The earliest and probably most widely accepted scientific theory of antidepressant
action is the monoamine hypothesis (which can be traced back to the 1950s), which
states that depression is due to an imbalance (most often a deficiency) of
the monoamine neurotransmitters (namely serotonin, norepinephrine and dopamine).
[110]
 It was originally proposed based on the observation that certain hydrazine anti-
tuberculosis agents produce antidepressant effects, which was later linked to their
inhibitory effects on monoamine oxidase, the enzyme that catalyses the breakdown of
the monoamine neurotransmitters.[110] All currently marketed antidepressants have the
monoamine hypothesis as their theoretical basis, with the possible exception
of agomelatine which acts on a dual melatonergic-serotonergic pathway.[110] Despite the
success of the monoamine hypothesis it has a number of limitations: for one, all
monoaminergic antidepressants have a delayed onset of action of at least a week; and
secondly, there are a sizeable portion (>40%) of depressed patients that do not
adequately respond to monoaminergic antidepressants. [111][112] A number of alternative
hypotheses have been proposed, including the glutamate, neurogenic, epigenetic,
cortisol hypersecretion and inflammatory hypotheses.[111][112][113][114]

Types[edit]
See also: List of antidepressants
Selective serotonin reuptake inhibitors[edit]

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. [115] The efficacy
of SSRIs in mild or moderate cases of depression has been disputed. [116][117][118][119]
Serotonin–norepinephrine reuptake inhibitors[edit]

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. [120]
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 modulators and stimulators[edit]
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-HT1A receptor, and antagonist of the 5-HT3 and 5-HT7 receptors.[121][122]
[123]
 However, it can also technically be applied to vilazodone, which is an antidepressant
as well and acts as an SRI and 5-HT1A receptor partial agonist.[124]
An alternative term is serotonin partial agonist/reuptake inhibitor (SPARI), which can be
applied only to vilazodone.[125]
Serotonin antagonists and reuptake inhibitors[edit]
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-HT2A 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[edit]
This section needs to be updated. Please update this article to reflect recent
events or newly available information.
Last update: PMID 26411968 (January 2018)

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.[126]
[127]
 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. [128]
Norepinephrine-dopamine reuptake inhibitors[edit]
The only drug used of this class for depression is bupropion.[100]
Tricyclic antidepressants[edit]
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.[129][130] Notably, with the sole exception
of amineptine, the TCAs have negligible affinity for the dopamine transporter (DAT), and
therefore have no efficacy as dopamine reuptake inhibitors (DRIs).[129]
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. [131]
Tetracyclic antidepressants[edit]
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[edit]
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.[132] They are also used in the treatment of Parkinson's
disease and several other disorders.
Because of potentially lethal dietary and drug interactions, monoamine
oxidase inhibitors 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.[medical citation needed]
MAOIs have been found to be effective in the treatment of panic
disorder with agoraphobia,[133] social phobia,[134][135][136] atypical depression[137][138] or mixed
anxiety and depression, bulimia,[139][140][141][142] and post-traumatic stress disorder,[143] as well
as borderline personality disorder.[144] MAOIs appear to be particularly effective in the
management of bipolar depression according to a retrospective-analysis.[145] 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. [146]
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[edit]
NMDA receptor antagonists like ketamine and esketamine are rapid-acting
antidepressants and seem to work via blockade of the ionotropic glutamate NMDA
receptor.[147]
Others[edit]
See the list of antidepressants and management of depression for other drugs that are
not specifically characterized.

Adjuncts[edit]
Adjunct medications are an umbrella category of substances that increase the potency
or "enhance" antidepressants.[148] They work by affecting variables very close to the
antidepressant, sometimes affecting a completely different mechanism of action. This
may be attempted when depression treatments have not been successful in the past.
Common types of adjunct medication techniques generally fall into the following
categories:
  Two or more antidepressants taken together
o From the same class (affecting the same
area of the brain, often at a much higher
level)
o From different classes (affecting multiple
parts of the brain not covered
simultaneously by either drug alone)
 An antipsychotic combined with an antidepressant,
particularly atypical antipsychotics such
as aripiprazole (Abilify), quetiapine (Seroquel), olanz
apine (Zyprexa), and risperidone (Risperdal).[149]
It is unknown if undergoing psychological therapy at the same time as taking anti-
depressants enhances the anti-depressive effect of the medication. [150]
Less common adjuncts[edit]
Lithium has been used to augment antidepressant therapy in those who have failed to
respond to antidepressants alone.[151] Furthermore, lithium dramatically decreases the
suicide risk in recurrent depression.[152] There is some evidence for the addition of a
thyroid hormone, triiodothyronine, in patients with normal thyroid function.[153]
Psychopharmacologists have also tried adding a stimulant, in particular, d-
amphetamine.[154] However, the use of stimulants in cases of treatment-resistant
depression is relatively controversial.[155][156] 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.[156]

History[edit]
See also: Discovery and development of dual serotonin and norepinephrine reuptake
inhibitors

St John's wort

Before the 1950s, opioids and amphetamines were commonly used as antidepressants.

[157][158]
 Their use was later restricted due to their addictive nature and side effects.
[157]
 Extracts from the herb St John's wort have been used as a "nerve tonic" to alleviate
depression.[159]
Isoniazid, iproniazid, and imipramine[edit]
In 1951, Irving Selikoff and Edward H. Robitzek [de], 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."[160] 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.[161] 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 [fr], reported the positive effect
of isoniazid on depressed patients.[162] 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.[163]
Selikoff and Robitzek also experimented with another anti-tuberculosis drug, iproniazid;
it showed a greater psychostimulant effect, but more pronounced toxicity.
[164]
 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.[165] 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".[165][166] Roche put a significant marketing effort behind iproniazid. [165] Its sales
grew until it was recalled in 1961, due to reports of lethal hepatotoxicity.[165]
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.[medical citation needed]
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. [167]
Second generation antidepressants[edit]
Main article: Second-generation antidepressants
Antidepressants became prescription drugs in the 1950s. It was estimated that no more
than 50 to 100 individuals per million suffered from 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,[168] which were being marketed for different uses.[169] 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.[169][170]
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. [medical citation needed]
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.[171][172] SSRIs became known as "novel
antidepressants" along with other newer drugs such as SNRIs and NRIs with various
selective effects.[173]
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.[174] It remains an over-the-counter
drug (OTC) supplement in most countries. Of concern are lead contaminant; on
average, lead levels in women in the United States taking St. John's wort are elevated
about 20%.[175] Research continues to investigate its active component hyperforin, and to
further understand its mode of action.[176][177]
Rapid-acting antidepressants[edit]
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.[147]
Research[edit]
A 2016 placebo randomized controlled trial evaluated the rapid antidepressant effects of
the psychedelic ayahuasca in treatment-resistant depression with positive outcome. [178]
[179]
 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. [180]

Society and culture[edit]

Prescription trends[edit]
In the United States, antidepressants were the most commonly prescribed medication in
2013.[181] Of the estimated 16 million "long term" (over 24 months) users, roughly 70
percent are female.[181] 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. [182]
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.
[183]
 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%.[184] 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:[185]

Drug name Drug class Total prescriptions

Sertraline SSRI 33,409,838

Citalopram SSRI 27,993,635

Fluoxetine SSRI 24,473,994

 Drug name Drug class Total prescriptions

Escitalopram SSRI 23,000,456

Trazodone SARI 18,786,495

Venlafaxine (all
SNRI 16,110,606
formulations)

Bupropion (all formulations) NDRI 15,792,653

Duloxetine SNRI 14,591,949

Paroxetine SSRI 12,979,366

Amitriptyline TCA 12,611,254

Venlafaxine XR SNRI 7,603,949

Bupropion XL NDRI 7,317,814

Mirtazapine TeCA 6,308,288

Venlafaxine ER SNRI 5,526,132

Bupropion SR NDRI 4,588,996

Desvenlafaxine SNRI 3,412,354

Nortriptyline TCA 3,210,476

 Drug name Drug class Total prescriptions

Bupropion ER NDRI 3,132,327

Venlafaxine SNRI 2,980,525

Bupropion NDRI 753,516

Netherlands: In the Netherlands, paroxetine is the most prescribed antidepressant,

followed by amitriptyline, citalopram and venlafaxine.[186]
Adherence[edit]
Main article: Adherence (medicine)
As of 2003, worldwide, 30 to 60% of people didn't follow their practitioner's instructions
about taking their antidepressants,[187] and as of 2013 in the US, it appeared that around
50% of people did not take their antidepressants as directed by their practitioner. [188]
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.[189] This also increases costs for caring for them.[189]
Social science perspective[edit]
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. [190][191] 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.[190][191] 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. [190]
Environmental impacts[edit]
Because most antidepressants function by inhibiting the reuptake of neurotransmitters
serotonin, dopamine, and norepinepherine [192] these drugs can interfere with natural
neurotransmitter levels in other organisms impacted by indirect exposure.
[193]
 Antidepressants fluoxetine and sertraline have been detected in aquatic organisms
residing in effluent dominated streams. [194] 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. [195]
Coral reef fish have been demonstrated to modulate aggressive behavior through
serotonin.[196] Artificially increasing serotonin levels in crustaceans can temporarily
reverse social status and turn subordinates into aggressive and territorial dominant
males.[197]
Exposure to fluoxetine has been demonstrated to increase serotonergic activity in fish,
subsequently reducing aggressive behavior.[198] Perinatal exposure to fluoxetine at
relevant environmental concentrations has been shown to lead to significant
modifications of memory processing in 1-month-old cuttlefish. [199] 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.[200][201]

See also[edit]
Wikimedia Commons has
media related
to Antidepressants.

 Management of depression
 Antidepressants in Japan
 Atypical antidepressant
 Depression and natural therapies
 Listening to Prozac by Peter Kramer
 Anatomy of an Epidemic by Robert Whittaker
 List of investigational antidepressants

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Further reading[edit]
 Stahl SM (1997). Psychopharmacology of
Antidepressants. Informa Healthcare. ISBN 978-1-
85317-513-8.

External links[edit]
Look up antidepressant in
Wiktionary, the free
dictionary.

  Media related to Antidepressants at Wikimedia

Commons
► Antidepressants
► Drug classes defined by psychological effects
► Drugs by psychological effects
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Antidepressants (N06A)

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Major chemical drug groups

GND: 4002263-8
LCCN: sh85005661

NDL: 01140705
Categories: 
 Antidepressants
 Major depressive disorder
 Drug classes defined by psychological effects
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