Antidepressants are drugs used for the treatment of major depressive
disorder and other conditions, including dysthymia, anxiety disorders,
obsessive–compulsive disorder, eating disorders, chronic pain,
neuropathic pain and, in some cases, dysmenorrhoea, snoring, migraine,
attention-deficit hyperactivity disorder (ADHD), addiction,
dependence, and sleep disorders. They may be prescribed alone or in
combination with other medications.
The most important classes of antidepressants are the selective
serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine
reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs),
monoamine oxidase inhibitors (MAOIs), reversible inhibitors of
monoamine oxidase A (RIMAs), tetracyclic antidepressants (TeCAs), and
noradrenergic and specific serotonergic antidepressant (NaSSAs). St
John's wort is also used in the treatment of depression.
One theory regarding the cause of depression is that it is
characterized by an overactive hypothalamic–pituitary–adrenal axis
(HPA axis) that resembles the neuro-endocrine response to stress.
These HPA axis abnormalities participate in the development of
depressive symptoms, and antidepressants may serve to regulate HPA
There has been a long debate in the medical community about the
effectiveness of antidepressants, centering around whether the
observed results in patients can be attributed to the placebo effect.
1 Medical uses
1.1 Major depressive disorder
1.1.1 Clinical guidelines
1.1.2 Systematic reviews
1.1.4 Limitations and strategies
1.1.5 "Trial and error" switching
1.1.6 Augmentation and combination
1.1.7 Long-term use
1.2 Anxiety disorders
1.2.1 Generalized anxiety disorder
1.2.2 Obsessive–compulsive disorder
1.3 Eating disorders
1.4.2 Neuropathic pain
2 Adverse health effects
2.3 Antidepressant-induced mania
2.6 Changes in weight
2.7 Discontinuation syndrome
2.8 Emotional blunting
4.1 Selective serotonin reuptake inhibitors
4.2 Serotonin–norepinephrine reuptake inhibitors
Serotonin modulators and stimulators
Serotonin antagonists and reuptake inhibitors
Norepinephrine reuptake inhibitors
4.7 Tetracyclic antidepressants
Monoamine oxidase inhibitors
5.1 Less common adjunct medication
6.1 Isoniazid, iproniazid, and imipramine
6.2 Second generation antidepressants
7 Society and culture
7.1 Prescription trends
7.2 Most commonly prescribed
7.4 Social science perspective
7.5 Environmental impacts
8 See also
10 Additional reading
11 External links
See also: Comparative efficacy and tolerability of antidepressants
For depression, the
Hamilton Depression Rating Scale (HAM-D) is often
used to measure the severity of depression. The maximum score for
the 17-item HAM-D questionnaire is 52; the higher the score, the more
severe the depression.
Major depressive disorder
This section needs to be updated. Please update this article to
reflect recent events or newly available information.
National Institute for Health and Care Excellence
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
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
American Psychiatric Association
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 patient 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 patients with severe depression unless ECT is
Conflicting results have arisen from studies analyzing the efficacy of
antidepressants by comparisons to placebo in people with acute mild to
moderate depression. Stronger evidence supports the usefulness of
antidepressants in the treatment of depression that is chronic
(dysthymia) or severe.
A 2018 meta-analysis of trials found that in adults with major
depressive disorder antidepressants were more efficacious than placebo
 Effect sizes measured at 8-weeks after treatment onset were modest
with a summary standard mean difference of 0.3.
A 2017 meta analysis comparing the efficacy of
SSRIs against placebo
found the mean reduction in
Hamilton Depression Rating Scale (HDRS) to
be -1.94 points over 49 studies. This was statistically significant,
but failed to meet the clinical significance threshold, predefined
according to the National Institute for Health and Care Excellence
recommended standard mean difference of 0.5, equivalent to a 3-point
reduction in HDRS. A high risk of bias was found, which could possibly
explain the statistically significant effect of SSRI, and the authors
concluded that the frequency of adverse events outweighed the small
A 2015 systematic review of add-on therapies for treatment-resistant
depression concluded that quetiapine and aripiprazole have the
strongest evidence-base supporting their efficacy, but they are
associated with additional treatment-related side effects when used as
an add-on therapy.
In 2014 the U.S. FDA published a systematic review of all
antidepressant maintenance trials submitted to the agency between 1985
and 2012. The authors concluded that maintenance treatment reduced the
risk of relapse by 52% compared to placebo, and that this effect was
primarily due to recurrent depression in the placebo group rather than
a drug withdrawal effect.
A 2012 meta-analysis found that fluoxetine and venlafaxine were
effective for major depression in all age groups. The authors also
found no evidence of a relationship between baseline severity of
depression and degree of benefit of antidepressants over placebo.
A review published in 2012 found a negative correlation between study
year and efficacy of antidepressants as measured by response rate. The
change in response rate was largely driven by increase in placebo
response. However the authors still concluded that antidepressants
were effective in treating depression. The authors found that TCAs
were the most effective drug, followed by SNRIs, MAOIs,
Cochrane Collaboration published a systematic review of clinical
trials of the tricyclic antidepressant amitriptyline in 2012. The
study concluded that in spite of moderate evidence for publication
bias, there is strong evidence that the efficacy of amitriptyline is
superior to placebo.
The efficacy of paroxetine (Paxil) and imipramine was observed in a
2010 meta analysis to be dependent upon the baseline severity, as
measured by the HDRS. Antidepressants in patients with a score less
than 23(indicating mild to moderate depression) demonstrated a small
benefit over placebo. However, antidepressants in those with a score
>25 exhibited an advantage over placebo that cross the NICE
threshold for clinical significance.
A review commissioned by the National Institute for Health and Care
Excellence that published in 2009 concluded that there is strong
SSRIs have greater efficacy than placebo on achieving a
50% reduction in depression scores in moderate and severe major
depression, and that there is some evidence for a similar effect in
mild depression. The treatment guidelines developed in conjunction
with this review suggest that antidepressants should be considered in
patients with moderate to severe depression and those with mild
depression that is persistent or resistant to other treatment
Cochrane Collaboration review on
St John's wort
St John's wort (specifically,
any extracts which contain
Hypericum perforatum), and a 2015
meta-analytic systematic review by some of the same authors, both
concluded that it: has superior efficacy to placebo in treating
depression; is as effective as standard antidepressant pharmaceuticals
for treating depression; and has fewer adverse effects than other
antidepressants. The 2015 meta analysis concluded that it is difficult
to assign a place for St. John's wort in the treatment of depression
owing to limitations in the available evidence base, including large
variations in efficacy seen in trials performed in German-speaking
relative to other countries. Reversible inhibitors of monoamine
oxidase A (RIMAs) have also been shown to be an effective drug therapy
with greater tolerability than other antidepressants; however, the
efficacy of SSRIs, tricyclic, and tetracyclic antidepressants in
treating depression is supported by a much larger evidence base
compared to other antidepressant drug therapies (i.e., St John's wort,
rMAO-A inhibitors, serotonin–norepinephrine reuptake inhibitor,
serotonin antagonist and reuptake inhibitors, noradrenaline reuptake
inhibitors, and noradrenergic and specific serotonergic
In a 2008 publication,
Irving Kirsch and Thomas Moore concluded that
the overall effect of new-generation antidepressant medication is
below recommended criteria for clinical significance. This updated
work they had first published in 2002 in which they stated that the
evidence is most consistent a role as active placebos.
A 2004 review concluded that antidepressant studies that failed to
support efficacy claims were dramatically less likely to be published
than those that did support favorable efficacy claims. Similar
results were obtained for a study of publication of clinical trials of
antidepressants in children. A 2015 investigation of meta-analyses
of antidepressant studies found that 79% of them had "sponsorship or
authors who were (pharmaceutical) industry employees and/or had
conflicts of interest".
A study published in the Journal of the American Medical Association
(JAMA) in 2002 demonstrated that the magnitude of the placebo effect
in clinical trials of depression have been growing over time, while
the effect size of tested drugs has remained relatively constant. The
authors suggest that one possible explanation for the growing placebo
effect in clinical trials is the inclusion of larger number of
participants with shorter term, mild, or spontaneously remitting
depression as a result of decreasing stigma associated with
Placebo response rates in clinical trials of
complementary and alternative (CAM) therapies are significantly lower
than those in clinical trials of traditional antidepressants.
The largest and most expensive study conducted to date, on the
effectiveness of pharmacological treatment for depression, was
commissioned by the National Institute of Mental Health. The study
was dubbed "The Sequenced Treatment Alternatives to Relieve
Depression" (STAR*D) Study. The results are summarized here.
Participants in the trial were recruited when they sought medical care
at general medical or psychiatric clinics. No advertising was used to
recruit subjects in order to maximize the generalizability of the
study results. Participants were required to have a minimum score of
14 point on the Hamilton Depression Scale (HAM-D17) in order to be
enrolled in the trial. Generally accepted cutoffs are 7–17 points
for mild depression, 18–24 points for moderate depression, and ≥
24 for severe depression. The average participant baseline HAM-D17
score was 22. The pre-specified primary endpoint of this trial was
remission as determined by the HAM-D score, with all patients with
missing scores rated as non-responders. In the aftermath of the trial,
the investigators have presented the results mainly using the
secondary endpoint of remission according to the QIDS-SR16 Score,
which tend to be somewhat higher.
After the first course of treatment, 27.5% of the 2,876 participants
reached remission with a HAM-D score of 7 or less and 33% achieved
remission according to the QIDS-SR scale. The response rate according
to the QIDS-SR16 score was 47%. Twenty-six percent dropped
After the second course of treatment, 21 to 30% of the remaining 1,439
participants remitted. Switching medications can achieve remission
in about 25% of patients.
After the third course of treatment, 17.8% of the remaining 310
participants remitted.
After the fourth and last course of treatment, 10.1% of the remaining
109 participants remitted.
Relapse within 12 months was 33% in those who achieved remission in
the first stage, and 42% to 50% in those achieving remission in later
Relapse was higher in those who responded to medication but
did not achieve remission (59–83%) than in those who achieved
There were no statistical or meaningful clinical differences in
remission rates, response rates, or times to remission or response
among any of the medications compared in this study. These
included bupropion sustained release, bupropion, citalopram, lithium,
mirtazapine, nortriptyline, sertraline, triiodothyronine,
tranylcypromine, and venlafaxine extended release.[medical citation
A 2008 review of randomized controlled trials concluded that
symptomatic improvement with
SSRIs was greatest by the end of the
first week of use, but that some improvement continued for at least 6
Limitations and strategies
Between 30% and 50% of individuals treated with a given antidepressant
do not show a response. In clinical studies, approximately
one-third of patients 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, psychic 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 patients with residual
symptoms than in those who experience full remission. In addition,
antidepressant drugs tend to lose efficacy over the course of
treatment. 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. A number of strategies are used in clinical
practice to try to overcome these limits and variations. They
include switching medication, augmentation, and combination.
"Trial and error" switching
American Psychiatric Association
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 patients 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.
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 patients responded when switched to the new drug,
40% responded without being switched.
Augmentation and combination
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
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. Other tests recently conducted include the use of
psychostimulants as an augmentation therapy. Several studies have
shown the efficacy of combining modafinil to treatment-resistant
patients. It has been used to help combat SSRI-associated fatigue.
The therapeutic 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 of 31 placebo-controlled antidepressant
trials, mostly limited to studies covering a period of one year, found
that 18% of patients who had responded to an antidepressant relapsed
while still taking it, compared to 41% whose antidepressant was
switched for a placebo.
A gradual loss of therapeutic benefit occurs in a minority of people
during the course of treatment. 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
Generalized anxiety disorder
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, and are superior to placebo in treating GAD. The efficacy
of different antidepressants is similar.
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 can be considered as a second-line therapy in those with
moderate-to-severe impairment, with close monitoring for psychiatric
SSRIs are efficacious in the treatment of OCD;
patients treated with
SSRIs are about twice as likely to respond to
treatment as those treated with placebo. 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.
Antidepressants are recommended as an alternative or additional first
step to self-help programs in the treatment of bulimia nervosa.
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
Bupropion is not recommended for the treatment
of eating disorders due to an increased risk of seizure.
Similar recommendations apply to binge eating disorder. SSRIs
provide short-term reductions in binge eating behavior, but have not
been associated with significant weight loss.
Clinical trials have generated mostly negative results for the use of
SSRIs in the treatment of anorexia nervosa. Treatment guidelines
from the National Institute of Health and Care Excellence
recommend against the use of
SSRIs in this disorder. Those from the
American Psychiatric Association
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
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
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. 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".
A 2014 meta-analysis from the
Cochrane Collaboration found the
antidepressant duloxetine to be effective for the treatment of pain
resulting from diabetic neuropathy. 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. 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.
Adverse health effects
Difficulty tolerating adverse effects is the most common reason for
antidepressant discontinuation.[medical citation needed]
Serotonin syndrome and MAOIs
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. 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.
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 be bothered by only
a headache due to an increase in blood pressure.
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
SSRIs and tricyclics in treating depressive disorders.
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. 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, and is associated with
preterm birth and low birth weight.
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. A study
of fluoxetine-exposed pregnancies found a 12% increase in the risk of
major malformations that just missed statistical significance.
Other studies have found an increased risk of cardiovascular birth
defects among depressed mothers not undergoing
suggesting the possibility of ascertainment bias, e.g. that worried
mothers may pursue more aggressive testing of their infants.
Another study found no increase in cardiovascular birth defects and a
27% increased risk of major malformations in
pregnancies. The FDA advises for the risk of birth defects with
the use of paroxetine 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.
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
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
Another possible problem with antidepressants is the chance of
antidepressant-induced mania in patients with bipolar disorder. Many
cases of bipolar depression are very similar to those of unipolar
depression. Therefore, the patient can be misdiagnosed with unipolar
depression and be given antidepressants. Studies have shown that
antidepressant-induced mania can occur in 20–40% of bipolar
patients. For bipolar depression, antidepressants (most frequently
SSRIs) can exacerbate or trigger symptoms of hypomania and mania.
Main article: Antidepressants and suicide risk
Studies have shown that the use of antidepressants is correlated with
an increased risk of suicidal behaviour and thinking (suicidality) in
those aged under 25. This problem has been serious enough to
warrant government intervention by the US Food and
(FDA) to warn of the increased risk of suicidality during
antidepressant treatment. According to the FDA, the heightened
risk of suicidality is within the first one to two months of
treatment. The National Institute for Health and Care
Excellence (NICE) places the excess risk in the "early stages of
treatment". A meta-analysis suggests that the relationship between
antidepressant use and suicidal behavior or thoughts is
age-dependent. Compared to placebo the use of antidepressants is
associated with an increase in suicidal behavior or thoughts among
those aged under 25 (OR=1.62). This increase in suicidality approaches
that observed in children and adolescents. 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).
Sexual side-effects are also common with SSRIs, such as loss of sexual
drive, failure to reach orgasm, and erectile dysfunction. Although
usually reversible, these sexual side-effects can, in rare cases, last
for months or years after the drug has been completely withdrawn.
In a study of 1022 outpatients, overall sexual dysfunction with all
antidepressants averaged 59.1% with
SSRIs 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, and can actually lead to an improvement in all
aspects of sexual function.
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.
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
SSRIs by the same mechanism.
Bupropion, a weak NDRI and nicotinic antagonist, may be useful in
treating reduced libido as a result of
Changes in weight
Changes in appetite or weight are common among antidepressants, but
largely drug-dependent and are related to which neurotransmitters they
Mirtazapine and paroxetine, for example, have the effect of
weight gain and/or increased appetite, while others
(such as bupropion and venlafaxine) achieve the opposite
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.
Antidepressant discontinuation syndrome
Antidepressant discontinuation symptoms were first reported with
imipramine, the first tricyclic antidepressant (TCA), in the late
1950s, and each new class of antidepressants has brought reports of
similar conditions, including monoamine oxidase inhibitors (MAOIs),
SSRIs, and SNRIs. As of 2001, at least 21 different antidepressants,
covering all the major classes, were known to cause discontinuation
syndromes. The problem has been poorly studied, and most of the
literature has been case reports or small clinical studies; incidence
is hard to determine and controversial.
People with discontinuation syndrome have been on an antidepressant
for at least four weeks and have recently stopped taking the
medication, either abruptly or after a fast taper. Common
symptoms include flu-like symptoms (nausea, vomiting, diarrhea,
headaches, sweating), sleep disturbances (insomnia, nightmares,
constant sleepiness), sensory/movement disturbances (imbalance,
tremors, vertigo, dizziness, electric-shock-like experiences), mood
disturbances (dysphoria, anxiety, agitation) and cognitive
disturbances (confusion and hyperarousal). Over fifty
symptoms have been reported.
Most cases of discontinuation syndrome last between one and four
weeks, are relatively mild, and resolve on their own; in rare cases
symptoms can be severe or extended.
Paroxetine and venlafaxine
seem to be particularly difficult to discontinue and prolonged
withdrawal syndrome lasting over 18 months have been reported with
With the explosion of use and interest in
SSRIs in the late 1980s and
early 1990s, focused especially on Prozac, interest grew as well in
discontinuation syndromes. In the late 1990s, some investigators
thought that symptoms that emerged when antidepressants were
discontinued, might mean that antidepressants were causing addiction,
and some used the term "withdrawal syndrome" to describe the symptoms.
Addictive substances cause physiological dependence, so that drug
withdrawal causes suffering. These theories were abandoned, since
addiction leads to drug-seeking behavior, and people taking
antidepressants do not exhibit drug-seeking behavior. The term
"withdrawal syndrome" is no longer used with respect to
antidepressants, to avoid confusion with problems that arise from
addiction. There are case reports of antidepressants
being abused, but these are rare and are mostly limited to
antidepressants with stimulant effects and to people who already had a
substance use disorder. A 2012 comparison of the effects of
stopping therapy with benzodiazepines and
SSRIs argued that because
the symptoms are similar, it makes no sense to say that
benzodiazepines are addictive while
SSRIs are not. Responses to
that review noted that there is no evidence that people who stop
SSRIs exhibit drug-seeking behavior while people who stop
taking benzodiazepines do, and that the drug classes should be
Antidepressants can cause emotional blunting, or numbness. This is a
reduction in extremes of emotion, both positive and negative. While
the patient may feel less depressed, they may also feel less happiness
or empathy in some situations. This may be cause for a dose reduction
or medication change. The exact mechanism is unknown.
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). 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. 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. 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. A number of alternative hypotheses have
been proposed, including the glutamate, neurogenic, epigenetic,
cortisol hypersecretion and inflammatory
See also: List of antidepressants
Selective serotonin reuptake inhibitors
Blister pack of Prozac (fluoxetine), a selective serotonin reuptake
Selective serotonin reuptake inhibitors
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. The efficacy of
SSRIs in mild or moderate cases of
depression has been disputed.
Serotonin–norepinephrine reuptake inhibitors
The chemical structure of venlafaxine (Effexor), an SNRI
Serotonin–norepinephrine reuptake inhibitors
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.
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
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 created to
describe 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. 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.
An alternative term is serotonin partial agonist/reuptake inhibitor
(SPARI), which can be applied only to vilazodone.
Serotonin antagonists and reuptake inhibitors
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
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.
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.
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. 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).
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.
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
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. 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.
MAOIs have been found to be effective in the treatment of panic
disorder with agoraphobia, social phobia, atypical
depression or mixed anxiety and depression,
bulimia, and post-traumatic stress disorder,
as well as borderline personality disorder.
MAOIs appear to be
particularly effective in the management of bipolar depression
according to a recent[when?] retrospective-analysis. 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.
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.
See the list of antidepressants for other drugs which are not
Adjunct medications are an umbrella term used to describe substances
that increase the potency or "enhance" antidepressants. 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
Common types of adjunct medication techniques generally fall into the
Two or more antidepressants taken together
From the same class (affecting the same area of the brain, often at a
much higher level)
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), olanzapine (Zyprexa), and risperidone (Risperdal).
It is unknown if undergoing psychological therapy at the same time as
taking anti-depressants enhances the anti-depressive effect of the
Less common adjunct medication
Lithium has been used to augment antidepressant therapy in those who
have failed to respond to antidepressants alone. Furthermore,
lithium dramatically decreases the suicide risk in recurrent
depression. There is some evidence for the addition of a thyroid
hormone, triiodothyronine, in patients with normal thyroid
Psychopharmacologists have also tried adding a stimulant, in
particular, d-amphetamine. However, the use of stimulants in
cases of treatment-resistant depression is relatively
controversial. 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
St John's wort
Before the 1950s, opioids and amphetamines were commonly used as
antidepressants. Their use was later restricted due to their
addictive nature and side effects. Extracts from the herb St
John's wort have been used as a "nerve tonic" to alleviate
Isoniazid, iproniazid, and imipramine
Irving Selikoff and Edward Robitzek, working out of Sea View
Hospital on Staten Island, began clinical trials on two new
anti-tuberculosis agents developed by Hoffman-LaRoche, isoniazid and
iproniazid. Only patients with a poor prognosis were initially
treated; nevertheless, their condition improved dramatically. Selikoff
and Robitzek noted "a subtle general stimulation … the patients
exhibited renewed vigor and indeed this occasionally served to
introduce disciplinary problems." The promise of a cure for
tuberculosis in the
Sea View Hospital
Sea View Hospital trials was excitedly discussed
in the mainstream press.
In 1952, learning of the stimulating side effects of isoniazid, the
Cincinnati psychiatrist Max Lurie tried it on his patients. In the
following year, he and Harry Salzer reported that isoniazid improved
depression in two thirds of their patients and coined the term
antidepressant to describe its action. A similar incident took
place in Paris, where Jean Delay, head of psychiatry at Sainte-Anne
Hospital, heard of this effect from his pulmonology colleagues at
Cochin Hospital. In 1952 (before Lurie and Salzer), Delay, with the
resident Jean-Francois Buisson, reported the positive effect of
isoniazid on depressed patients. The mode of antidepressant
action of isoniazid is still unclear. It is speculated that its effect
is due to the inhibition of diamine oxidase, coupled with a weak
inhibition of monoamine oxidase A.
Selikoff and Robitzek also experimented with another anti-tuberculosis
drug, iproniazid; it showed a greater psychostimulant effect, but more
pronounced toxicity. Later, Jackson Smith, Gordon Kamman, George
Crane, and Frank Ayd, described the psychiatric applications of
iproniazid. Ernst Zeller found iproniazid to be a potent monoamine
oxidase inhibitor. Nevertheless, iproniazid remained relatively
obscure until Nathan Kline, the influential head of research at
Rockland State Hospital, began to popularize it in the medical and
popular press as a "psychic energizer". Roche put a
significant marketing effort behind iproniazid. Its sales grew
until it was recalled in 1961, due to reports of lethal
The antidepressant effect of a tricyclic, a three ringed compound, was
first discovered in 1957 by
Roland Kuhn in a Swiss psychiatric
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
Company – discovered the compound "G 22355", later renamed
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.
Second generation antidepressants
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, which were being marketed for different
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
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
(FDA) in 1988, becoming the first blockbuster SSRI.
Eli Lilly and Company
Eli Lilly and Company in the early 1970s by Bryan Molloy,
Klaus Schmiegel, David Wong and others.
SSRIs became known
as "novel antidepressants" along with other newer drugs such as SNRIs
and NRIs with various selective effects.
St John's wort
St John's wort fell out of favor in most countries through the 19th
and 20th centuries, except in Germany, where
Hypericum extracts were
eventually licensed, packaged and prescribed. Small-scale efficacy
trials were carried out in the 1970s and 1980s, and attention grew in
the 1990s following a meta-analysis. It remains an
over-the-counter drug (OTC) supplement in most countries. Research
continues to investigate its active component hyperforin, and to
further understand its mode of action.
Society and culture
In the United States, antidepressants were the most commonly
prescribed medication in 2013. Of the estimated 16 million "long
term" (over 24 months) users, roughly 70 percent are female.
In the UK, figures reported in 2010 indicated that the number of
antidepressant prescribed by the
National Health Service
National Health Service (NHS) almost
doubled over a decade. 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%. 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 post
Most commonly prescribed
Structural formula of the
United States: The most commonly prescribed antidepressants in the US
retail market in 2010 were:
Venlafaxine (all formulations)
Effexor (IR, ER, XR)
Bupropion (all formulations)
Wellbutrin (IR, ER, SR, XL)
Netherlands: In the Netherlands, paroxetine, marketed as Seroxat among
generic preparations, is the most prescribed antidepressant, followed
by amitriptyline, citalopram and venlafaxine.
Main article: Adherence (medicine)
As of 2003, worldwide, 30 to 60% of people didn't follow their
practitioner's instructions about taking their antidepressants,
and as of 2013 in the US, it appeared that around 50% of people did
not take their antidepressants as directed by their practitioner.
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. This also increases costs for caring for them.
Social science perspective
In looking at the issue of antidepressant use, 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. 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. In
India antidepressants are largely seen as tools to combat marginality,
promising the individual the ability to re-integrate into society
through their use—a view and association not observed in the
Because most antidepressants function by inhibiting the reuptake of
neurotransmitters serotonin, dopamine, and norepinepherine these
drugs can interfere with natural neurotransmitter levels in other
organisms impacted by indirect exposure. Antidepressants
fluoxetine and sertraline have been detected in aquatic organisms
residing in effluent dominated streams. 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.
Coral reef fish have been demonstrated to modulate aggressive behavior
through serotonin. Artificially increasing serotonin levels in
crustaceans can temporarily reverse social status and turn
subordinates into aggressive and territorial dominant males.
Exposure to fluoxetine has been demonstrated to increase serotonergic
activity in fish, subsequently reducing aggressive behavior.
Perinatal exposure to fluoxetine at relevant environmental
concentrations has been shown to lead to significant modifications of
memory processing in 1-month-old cuttlefish. 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.
Wikimedia Commons has media related to Antidepressants.
Antidepressants in Japan
Depression and natural therapies
Discovery and development of dual serotonin and norepinephrine
Listening to Prozac
Listening to Prozac by Peter Kramer
Anatomy of an Epidemic
Anatomy of an Epidemic by Robert Whittaker
List of investigational antidepressants
Drug classes defined by psychological effects
► Drugs by psychological effects
► Psychoactive drugs
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Look up antidepressant in Wiktionary, the free dictionary.
Media related to Antidepressants at Wikimedia Commons
Specific reuptake inhibitors and/or receptor modulators
Tricyclic and tetracyclic antidepressants
Monoamine oxidase inhibitors
Atypical antipsychotics (aripiprazole, brexpiprazole, lurasidone,
olanzapine, quetiapine, risperidone)
Lithium (lithium carbonate, lithium citrate)
Thyroid hormones (triiodothyronine (T3), levothyroxine (T4))
Hypericum perforatum (St. John's Wort)
Rubidium chloride (RbCl)
‡Withdrawn from market
§Never to phase III
Pharmacology: major drug groups
Proton pump inhibitors
Blood and blood
forming organs (B)
Calcium channel blockers
Angiotensin II receptor antagonists
Bile acid sequestrants
Thyroid hormones/Antithyroid agents
infestations (J, P, QI)
Antimicrobials: Antibacterials (Antimycobacterials)
and joints (M)
nervous system (N)
Sensory organs (S)
Other ATC (V)