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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, migraines, attention-deficit hyperactivity disorder (ADHD), substance abuse and sleep disorders. They can be used 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) and monoamine oxidase inhibitors (MAOIs). Other drugs used or proposed for the treatment of depression include buprenorphine, low-dose antipsychotics, and St John's wort.

Medical uses

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.

Clinical guidelines

The UK National Institute for Health and Care Excellence (NICE) 2004 guidelines indicate that antidepressants should not be used for the initial treatment of mild depression, because the risk-benefit ratio is poor. The guidelines recommend that antidepressants treatment in combination with psychosocial interventions should be considered for:

• People with a past 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 continued for at least 6 months to reduce the risk of relapse, and that SSRIs are better tolerated than tricyclic antidepressants.

American Psychiatric Association treatment guidelines recommend that initial treatment should be individually tailored based on factors including 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. Antidepressant medication is recommended as an initial treatment choice in people with mild, moderate, or severe major depression, and should be given to all patients with severe depression unless ECT is planned.

Systematic Reviews

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.

Researchers Irving Kirsch and Thomas Moore have contested the pharmacological activity of antidepressants in the relief of depression, and state that the evidence is most consistent a role as active placebos. Their study consisted of a meta analysis incorporating data from both published studies and unpublished data obtained from the FDA via a Freedom of Information Act request. Overall, antidepressant pills worked 18% better than placebos, a statistically significant difference, but not one that is clinically significant. In a later publication, Kirsch concluded that the overall effect of new-generation antidepressant medication is below recommended criteria for clinical significance.

Another study focusing on paroxetine (Paxil) and imipramine found that antidepressant drugs were only slightly better than placebo in cases of mild or moderate depression they surveyed but offered "substantial" benefit in those with severe depression.

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 review commissioned by the National Institute for Health and Care Excellence concluded that there is strong evidence that 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 modalities.

The Cochrane Collaboration recently performed a systematic review of clinical trials of the generic antidepressant amitriptyline. 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.

A study published in the Journal of the American Medical Association (JAMA) 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 antidepressant use.

The STAR*D Trial

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 Hamiliton Depression Scale (HAM-D17) in order to be enrolled in the trial. Generally accepted cutoffs are 7-17 points for mild depression, 8-24 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%. Tweny six percent dropped out.
• 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 stages. Relapse was higher in those who responded to medication but did not achieve remission (59-83%) than in those who achieved remission.

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.

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 weeks.

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. 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

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 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 newer anticonvulsants.

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.

Long-term use

The therapeutic effects of antidepressants typically do not continue once the course of medication ends, resulting in a high rate of relapse. A recent 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 studies.

Comparative efficacy and tolerability

Where:

For adverse effects/overdose toxicity

4 means very strong effect/extreme toxicity.

3 strong effect; efficacious/high toxicity.

2 moderate effect/moderately toxic.

1 weak effect/weakly toxic.

v very weak/negligible effect

For tolerability

4 extremely tolerable. These drugs have proven to be better tolerated than the SSRIs.

3 very tolerable ? few, mild and transient side effects. These are drugs such as the SSRIs.

2 moderately tolerable. Some of the more tolerable of TCAs.

1 poor tolerability. TCAs and MAOIs mostly.

For efficacy

3 Superior efficacy drug, according to at least one review article.

2 Ordinary efficacy drug. Maybe some primary sources indicate superior efficacy relative to superior efficacy agents (e.g. agomelatine has shown superior efficacy to venlafaxine in one clinical trial) but insufficient data to say with much confidence.

1 Inferior efficacy compared to ordinary efficacy drugs, according to at least one review article.

Acronyms/terms used in the above table:

Activating effects – adverse effects such as agitation, anxiety, insomnia and tremor.

AMH – Australian Medicines Handbook.

GI – Gastrointestinal.

Inactivating effects – sedating effects such as drowsiness, somnolence and sedation.

IR – Immediate release tablets.

ND – No data.

Ortho hypot – Orthostatic hypotension

QTc i. p. – QTc interval prolongation

SD – Sexual dysfunction.

XR – Extended release tablets.

PER DRUG NOTES:

Tricyclic antidepressants (TCAs)

Amitriptyline: Preferentially (8x over norepinephrine) inhibits the reuptake of serotonin but norepinephrine reuptake inhibition is clinically significant. Listed as a more hepatotoxic antidepressant in a recent review article.

Amoxapine: Sometimes classed with the tetracyclic antidepressants. Has atypical antipsychotic actions too. Not available in Australia, Canada or the UK but available in the US. May be faster acting. Antidopaminergic, which means that it can cause extrapyramidal side effects, tardive dyskinesia and neuroleptic malignant syndrome. Causes kidney failure and seizures in overdose, although it usually does not cause cardiotoxic effects in overdose.

Clomipramine: Highly selective (~120x) for serotonin reuptake inhibition. More epileptogenic than other TCAs.

Desipramine: Preferentially inhibits the reuptake of norepinephrine (22x over serotonin).

Dosulepin (Dothiepin): Not available in the US. Available in Australia (where it is still commonly referred to as dothiepin) and the UK.
Weight gain: probably 2
Danger in overdose: 4

Doxepin: Somewhat selective for inhibiting norepinephrine reuptake (2.3x over serotonin).

Imipramine: First marketed TCA. Somewhat selective for serotonin reuptake (26x over norepinephrine).
Relative efficacy: 3 More hepatotoxic than most other antidepressants.

Lofepramine: Not licensed in Australia, US or Canada. Licensed in the UK and other European countries.
QTc i. p.: 1 (dose-dependent)

Maprotiline: Fairly selective (~90x over dopamine) norepinephrine reuptake inhibitor.

Nortriptyline: Active metabolite of amitriptyline. Somewhat selective (4.2x) for norepinephrine reuptake inhibition.

Protriptyline: Relatively (14x over serotonin) selective norepinephrine reuptake inhibition.

Tianeptine: Enhances the reuptake of serotonin and increases dopaminergic and glutamatergic neurotransmission. Not approved for clinical use in Australia, Canada, the UK, the US and Ireland. More hepatotoxic than most other antidepressants.

Trimipramine: Has antidopaminergic effects and hence can cause extrapyramidal side effects, tardive dyskinesia and neuroleptic malignant syndrome.

Monoamine oxidase inhibitors (MAOIs)

Isocarboxazid: Not licensed for use in Australia.

Moclobemide: Only clinically utilized reversible inhibitor of monoamine oxidase A (RIMA). Not approved for use in the US. Approved for clinical use in Australia, Canada, Ireland, New Zealand, Singapore, South Africa and the UK.
Activating effects: ? (insomnia common according to the AMH)

Phenelzine: Phenelzine is more prone than tranylcypromine and most other antidepressant to causing liver damage.

Seligiline: Originally used a treatment for Parkinson's disease due to its selective, irreversible inhibition of MAO-B but at higher doses MAO-A inhibition occurs.

Tranylcypromine: Metabolized into amphetamine analogues in vivo. Can cause liver damage.

Selective serotonin reuptake inhibitors (SSRIs)

Citalopram: Most likely of the SSRIs to prolong the QT interval. Also the most toxic SSRI in overdose. Less hepatotoxic than most other antidepressants.
QTc i. p.: 2 (dose dependent; doses >40 mg/day are particularly dangerous)

Escitalopram: The more active S-enantiomer of citalopram. May be the most efficacious of the SSRIs (although no statistically significant difference between the efficacy of sertraline and escitalopram have been teased out to date). Based on the available evidence it is less toxic than its racemic counterpart, (R,S)-citalopram, in overdose. Less hepatotoxic than most other antidepressants.

Fluoxetine: First SSRI to receive FDA approval in 1987. Some studies have shown slight (often statistically insignificant) weight reductions in those on fluoxetine. Has the longest net half-life (taking into account the effects of its active metabolite, norfluoxetine) of any antidepressant clinically used, and consequently, when abruptly stopped, withdrawal effects are usually mild and rare. Dermatologic reactions are more common than with sertraline.

Fluvoxamine: Not FDA approved for major depression; FDA approved for OCD. Has the highest affinity of any SSRI towards the sigma-1 receptor at which it serves as an agonist. Less hepatotoxic than most other antidepressants.

Paroxetine: Only SSRI that's not Australian pregnancy category C but is rather category D due to an increased risk of Persistent Pulmonary Hypertension of the Newborn. The FDA of the US has placed it in category D. It is associated with a higher risk of sexual dysfunction, weight gain, anticholinergic side effects and drowsiness than the other SSRIs. Has a short half life compared to other SSRIs and hence is the most prone to causing withdrawal effects whenever a dose is missed. Paroxetine has the lowest affinity for the sigma-1 receptors of all the SSRIs. It also possesses the highest propensity of any SSRI for causing extrapyramidal symptoms. Less hepatotoxic than most other antidepressants.

Sertraline: Highest risk of psychiatric side effects (e.g. mania, suicidal behavior/ideation, psychosis, etc.) Has slight (but clinically significant) inhibitory effects on dopamine reuptake. Has the second highest affinity of the SSRIs towards the sigma-1 receptor where it may serve as a sigma-1 receptor antagonist.
GI toxicity: 2 (mostly
diarrhoea)

Serotonin-norepinephrine reuptake inhibitors (SNRIs)

Desvenlafaxine: Active metabolite of venlafaxine.

Duloxetine: Unlike the other SNRIs listed here duloxetine does not cause dose-dependent hypertension as a common adverse effect. Used to relieve neuropathic pain too. More hepatotoxic than most other antidepressants.

Milnacipran: Primarily used as a treatment for neuropathic pain.
Danger in overdose: ? (No single-drug fatal overdoses reported yet)

Venlafaxine: Relatively selective (116x) for serotonin reuptake inhibition over norepinephrine.
GI toxicity: 2 (IR) / 1 (XR)

Noradrenergic and specific serotonergic antidepressants (NaSSAs)

Mianserin: Not licensed for use in the US and Canada. Licensed for use in Australia and the UK. Can cause blood dyscrasias (including agranulocytosis) and consequently both the BNF and AMH recommend regular complete blood count monitoring.

Mirtazapine: Licensed for use in the US, UK, Australia and Canada. Mianserin's successor and analogue.

Serotonin antagonist and reuptake inhibitors (SARIs)

Nefazodone: Risk of hepatotoxicity. Available in the US but not in Canada, Australia or Europe.

Trazodone: Not available in Australia. More hepatotoxic than other antidepressants.
Relative efficacy: 2

Serotonin modulator and stimulators (SMSs)

Vilazodone: Potential for serotonin syndrome as an adverse effect.
Danger in overdose: ? (probably low aside from an increased risk of serotonin syndrome)

Vortioxetine: Introduced to the US market in September 2013 and hence data on its adverse effects may be lagging behind. Serotonin syndrome is a possible (rare) adverse effect.

Other

Agomelatine: Not licensed in the US or Canada. Licensed in Australia and the UK.
Relative efficacy: 2

Bupropion: Only licensed in the UK and Australia as a smoking cessation aid, but in the US it is licensed for the treatment of major depressive disorder. More hepatotoxic than most other antidepressants.

Reboxetine: Not licensed in the US or Canada. Licensed in Australia and the UK.

Anxiety Disorders

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.

Obsessive compulsive disorder

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 adverse effects. 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.

Eating Disorders

Anti-depressants 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 anti-depressants 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.

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 SSRI's 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 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.

Pain

Fibromyalgia

A 2012 meta analysis concluded that antidepressants treatment favorably affects pain, health-related quality of life, depression, and sleep in fibromylgia 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% vs 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. 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".

Neuropathic Pain

A 2014 meta analysis from the Cochrane Collaboration found the antidepressant duloxetine effective for the treatment of pain resulting from diabetic neuropathy. The same group reviewed data for amitryptyline in the treatment of neuropathic pain and found limited useful randomized clinical trial data, but concluded that the long history of successful use in the community for the treatment of fibromyalgia and neuropathic pain justified its continued use.

Adverse effects

Difficulty tolerating adverse effects is the most common reason for antidepressant discontinuation.

General

For bipolar depression, antidepressants (most frequently SSRIs) can exacerbate or trigger symptoms of hypomania and mania.

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 as SSRIs and tricyclics in treating depressive disorders.

Pregnancy

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 SSRI treatment, 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 SSRI exposed pregnancies. The FDA advises for the risk of birth defects with the use of paroxetine and the MAOI should be avoided.

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.

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.

Antidepressant-induced mania

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.

Suicide

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 Drug Administration (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

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 induced by SSRIs by the same mechanism.

Bupropion, a weak NDRI and nicotinic antagonist, may be useful in treating reduced libido as a result of SSRI treatment. However, these results are preliminary, and as such must be taken cum grano salis.

Changes in weight

Changes in appetite or weight are common among antidepressants, but largely drug-dependent and are related to which neurotransmitters they affect. 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 effect.

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

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 paroxetine.

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.

Pharmacology

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. Further evidence to the contrary of the monoamine hypothesis are the recent findings that a single intravenous infusion with ketamine, an antagonist of the NMDA receptor — a type of glutamate receptor — produces rapid (within 2 hours), robust and sustained (lasting for up to a fortnight) antidepressant effects. To overcome these flaws with the monoamine hypothesis a number of alternative hypotheses have been proposed, including the glutamate, neurogenic, epigenetic, cortisol hypersecretion and inflammatory hypotheses.

Types

Adjuncts

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 is may be attempted when depression treatments have not been successful in the past.

Types of adjunct medication techniques generally fall into the following categories:

• 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)
• A stimulant with an antidepressant (e.g., amphetamine and fluoxetine)
• An antipsychotic, particularly atypical antipsychotics, for reasons not clearly understood

A review article published in 2007 found psychostimulants may be effective in treatment-resistant depression with concomitant antidepressant therapy. 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.

Chronic nicotine intake via nicotine patches results in an increased response to standard antidepressants. Similarly varenicline has been shown to augment sub-therapeutic doses of SSRIs to produce an antidepressant effect.

Atypical antipsychotics such as aripiprazole (Abilify), quetiapine (Seroquel), olanzapine, and risperidone are also popular adjuncts and appear to be an effective adjunctive treatment option in this indication. Lithium may also be used as an adjunct in major depressive disorder. Triiodothyronine (T₃) has also been successfully used as an adjunct in major depressive disorder.

Ketamine

Ketamine has been clinically tested for treatment-resistant bipolar depression, major depressive disorder, and people in a suicidal crisis in emergency rooms, and is being used this way off-label. The drug is given by a single intravenous infusion at doses less than those used in anesthesia, and preliminary data have indicated it produces a rapid (within 2 hours) and relatively sustained (about 1–2 weeks long) significant reduction in symptoms in some patients. Initial studies with ketamine have sparked scientific and clinical interest due to its rapid onset, and because it appears to work by blocking NMDA receptors for glutamate, a different mechanism from most modern antidepressants that operate on other targets.

Nutrition

Omega-3 fatty acids have been proposed as a treatment for depression, alone or in combination with other treatments. One small pilot study of childhood depression (ages 6–12) suggested omega 3 fatty acids may have therapeutic benefits for treating childhood depression. A 2005 review article that included double-blind studies, randomized control trials, and epidemiological studies linking omega-3 fatty acids consumption and depression found that low fish consumption (the primary source of omega-3 fatty acids) correlated to increased rates of depression. Additionally, case-control and cohort studies of unipolar and postpartum depression indicated low blood levels of omega-3 fatty acids in depressed patients.

A 2008 review of clinical studies of the effectiveness of omega-3 fatty acids on depression has shown somewhat inconsistent results: "Of the evaluated studies, 13 showed a significant positive association between omega-3 and depression, while six studies did not show a relationship between the referred variables." To be read with caution because of limited data, a 2008 Cochrane systematic review found in the one eligible study that omega-3 fatty acids are an effective adjunctive therapy for depressed but not manic symptoms in bipolar disorder. The authors found an "acute need" for more randomized, controlled trials.

History

Before the 1950s, opioids, amphetamine, and methamphetamine 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 had been used as a "nerve tonic" to alleviate depression.

Isoniazid, iproniazid, and imipramine

In 1951, 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 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 and flamboyant head of research at Rockland State Hospital, began to popularize it in the medical and popular press as a "psychic energizer". Roche put a significant marketing effort behind iproniazid. Its sales grew until it was recalled in 1961, due to reports of lethal hepatotoxicity.

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

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

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 uses. Imipramine remained in common use and numerous successors were introduced. The use of monoamine oxidase inhibitors (MAOI) increased after the development and introduction of "reversible" forms affecting only the MAO-A subtype of inhibitors, making this drug safer to use.

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

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 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 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

Prescription trends

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.

The number of antidepressants prescribed by the National Health Service (NHS) in the UK almost doubled during one decade, authorities reported in 2010. Furthermore the number increased sharply in 2009 when 39.1 million prescriptions were issued, compared to 20.1 million issued in 1999. Also, physicians issued 3.18 million more prescriptions in 2009 than in 2008. Health authorities believed the increase was partly linked to the recession. However, other reasons include a diagnosis improvement, a reduction of the stigma on mental ill-health, and more distress caused by the economic crisis. Furthermore, physicians' concern is that some people who exhibit milder symptoms of depression are being prescribed drugs unnecessarily due to the lack of other options including talk therapies, counseling and cognitive behavioral therapy. One more factor that may be increasing the consumption of antidepressants is the fact that these medications now are used for other conditions including social anxiety and post traumatic stress.

Most commonly prescribed

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

Netherlands: In the Netherlands, paroxetine, marketed as Seroxat among generic preparations, is the most prescribed antidepressant, followed by the tricyclic antidepressant amitriptyline, citalopram and venlafaxine.

MAOIs can be as effective as tricyclic antidepressants, although they generally are used less frequently because they have a higher incidence of dangerous side effects and interactions.

Litigation

• 2012 GlaxoSmithKline 3 billion dollars (US) – Paxil, The company touted Paxil for off-label use in children and adolescents, despite data that failed to show it was effective for these age groups, – Wellbutrin for marketing its antidepressant for off-label uses, including weight loss, substance abuse and sexual dysfunction and the seizure drug Lamictal.
• 2007 Bristol-Myers Squibb $515 million for off-label marketing of Abilify for children and adolescents, and geriatric patients suffering from dememtia.
• Ely Lilly In one of the only three cases to ever go to trial for SSRI indication in suicide, Eli Lilly and Company is alleged to have the judicial process by making a deal with the plaintiff's attorney to throw the case, in part by not disclosing damaging evidence to the jury. The case, known as the Fentress Case, involved a Kentucky man, Joseph Wesbecker, on Prozac, who went to his workplace and opened fire with an assault rifle, killing 8 people (including Fentress), and injuring 12 others before turning the gun on himself. The jury returned a 9-to-3 verdict in favor of Lilly. The judge, in the end, took the matter to the Kentucky Supreme Court, which found that "there was a serious lack of candor with the trial court and there may have been deception, bad faith conduct, abuse of judicial process and, perhaps even fraud." The judge later revoked the verdict and instead recorded the case as settled.

Publication of research findings

• Publication bias. Trials for which results were unfavorable were less likely to be published. Published data suggest a favorable risk-benefit profile for some SSRIs; however, addition of unpublished data indicates that risks could outweigh benefits of these drugs to treat depression in children and young people. Of 90 drugs approved by the FDA between 1998 and 2000, trials that did not show statistically significant results were 34% less likely to have been published; on the other hand, positive results are often published more than once.
• Demands on access to data has been met by resistance on the part of industry.

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 often 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 themself into society through their use, a view and association not observed in the West.

Environmental impacts

Somewhat less than 10% of orally administered fluoxetine is excreted from humans unchanged or as glucuronide. 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.

Exposure to fluoxetine has been demonstrated to increase serotonergic activity in fish, subsequently reducing aggressive behavior. Artificially increasing serotonin levels in crustaceans can temporarily reverse social status and turn subordinates into aggressive and territorial dominant males. 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.

See also

• Antidepressants in Japan
• Atypical depression
• Depression and natural therapies
• Discovery and development of dual serotonin and norepinephrine reuptake inhibitors
• The Emperor's New Drugs
• Side Effects (book)
• Listening to Prozac
• Peter Breggin
• David Healy (psychiatrist)
• Peter D. Kramer
• Anatomy of an epidemic by Robert Whittaker

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Additional reading

• Stahl, Stephen M. (1997). Psychopharmacology of Antidepressants. Informa Healthcare. ISBN 978-1-85317-513-8.

• Antidepressants
• Pharmacology
• Psychiatric instruments: depression