Antidepressant

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, tryptophan, low-dose antipsychotics, and St John's wort.

Efficacy
To establish efficacy, an antidepressant must show that it can produce a therapeutic effect for the condition for which it is taken. An antidepressant should be more efficacious than placebo to justify the risk associated with side effects. 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. What constitute a sufficient response to a drug has not been well established, but total remission or virtual elimination of all depression symptoms is the goal, however, remission rates are rarely published. For placebo, the percentage of symptom reduction is approximately 31 to 38%, compared to 46 to 54% for antidepressants.

On the basis of 234 studies, no clinically relevant superiority of one antidepressant over another was detected for the treatment of acute, continuation, and maintenance phases of depression, taking into account age, sex, ethnicity, or comorbid conditions. Individual drugs differed in onset of action, adverse events, and some measures of health-related quality of life.

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.
 * After the first course of treatment, 27.5% of the 2,876 participants reached remission with a HAM-D score of 7 or less. 21% dropped out.
 * After the second course of treatment, 21 to 30% of the remaining 1,439 participants remitted. Only 310 participants were willing or available to continue the study. 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.
 * After a one year follow-up, of the 1085 remitted participants, 93% participants had either relapsed or dropped out of the study.

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.

Clinical guidelines
The UK National Institute for Clinical 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; that for moderate or severe depression an SSRI is more likely to be tolerated than a tricyclic; and that antidepressants for severe depression should be combined with a psychological treatment such as Cognitive Behavioral Therapy.

The American Psychiatric Association 2000 Practice Guideline for the Treatment of Patients with major depressive disorder indicates that, if preferred by the patient, antidepressant medications may be provided as an initial primary treatment for mild major depressive disorder; antidepressant medications should be provided for moderate to severe major depressive disorder unless electroconvulsive therapy is planned; and a combination of antipsychotic and antidepressant medications or electroconvulsive therapy should be used for psychotic depression. It states that efficacy is generally comparable between classes and within classes and that the initial selection will largely be based on the anticipated side-effects for an individual patient, patient preference, quantity and quality of clinical trial data regarding the medication, and its cost.

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. The remission rate reported by the STAR*D study was 21% using this method.

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. Thus, the clinical response to the new drug might be a placebo effect associated with the belief that one is receiving a different medication.

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 an additional 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.

Opponents of switching, augmentation and combination argue that treatment may also propel the illness to a malignant and treatment-unresponsive course with iatrogenic psychiatric-like symptoms and treatment resistance or episode acceleration.

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.

In a five-year follow up, relapse rates was 23% greater for users greater than one year, but not different for 6 or 12 months users. In addition, gradual loss of therapeutic benefit occurs 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.

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.

Mild depression
Various researchers have contested the ability of antidepressants to relieve depression, skeptical that the drugs aid patients significantly more than placebo.

A review of antidepressant trials submitted to the FDA by the industry for drug approval revealed that when a trial was successful, the results of the trial was published 94% of the time, however, when the trial was not found to be more effective than placebo, it was only published 50% of the time. This demonstrated a measure of bias in reporting by industry. Combined, 51% of all studies showed efficacy. The difference in effect between active placebos and several antidepressants appeared small and strongly affected by publication bias.

Controversy regarding the efficacy of antidepressants has arisen due to studies showing that antidepressants fail to provide significantly greater efficacy than placebo in some studies. A 2002 study claimed that the difference between antidepressants and placebo is close to negligible.

A meta-analysis done by two psychologists led them to believe that although the drugs did help people, the difference between the pills and placebo was not meaningful for patients; a later publication by the same author concluded newer-generation medicines were below the criteria of clinical significance. Another study focusing on paroxetine (Paxil) and imipramine found that antidepressant drugs were hardly better than placebo in cases of mild or moderate depression they surveyed.

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 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 review commissioned by the National Institute for Clinical Excellence concluded that there 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.

In 2005, antidepressants became the most prescribed drug in the United States, causing more debate over the issue. Some doctors believe this is a positive sign that people are finally seeking help for their issues. Others disagree, saying that this shows that people are becoming too dependent on antidepressants.

In 2012, Aimee Hunter and her team used electroencephalography (EEG) and showed that taking placebo decreased pre-frontal brain activity in those subjects who had prior use of an antidepressants, similar to the expected antidepressant response, but increased brain activity in antidepressant-naive subjects. She attributes this antidepressant response of placebo, in repeat users, to a memory effect.

However, the later experiment conducted by John H. Krystal at Yale University School of Medicine to assess whether growth mixture modeling can provide insights into antidepressant and placebo responses in clinical trials of patients with major depression showed that Duloxetine and SSRI did not differ in efficacy, and compared with placebo they significantly decreased the odds of following the nonresponder trajectory. Antidepressant responders had significantly better Hamilton Depression Rating Scale (HAM-D) scores over time than placebo-treated patients, but antidepressant nonresponders had significantly worse HAM-D scores over time than the placebo-treated patients.

Comparative efficacy and tolerability
Comparative efficacy and tolerability table

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.

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

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.

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 and tranylcypromine can both cause 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. 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.

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.

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.

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.

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. 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.

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

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
Pregnancy can trigger a range of emotions that make it more difficult to cope with depression. The risk of medication discontinuation and relapse have to be weighed against the risk to the developing fetus and baby. Some antidepressants have lower risk for the baby during pregnancy, but the FDA advises for the risk of birth defects with the use of Paxil 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. The use of antidepressants during pregnancy is associated with an increased risk of spontaneous abortion, birth defects, and developmental delays. 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 leads to vasoconstriction. This is significant in pregnancy as SSRIs have been associated with the development of hypertension (high blood pressure) and pre-eclampsia of pregnancy. This in turn can lead to fetal prematurity.

Suicide
The relationship between antidepressant use and suicide risk is uncertain, complicated, and the target of medical research. Some studies have shown that the use of some antidepressants correlate with an increased risk of suicide in some patients and especially youth. This problem has been serious enough to warrant government interventions in some places to label greater likelihood of suicide as a risk of using antidepressants. The circumstances under which this can happen are not clear, and other studies show that antidepressants treat suicidal ideation.

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. This is referred to as Post SSRI Sexual Dysfunction.

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.

REM Sleep
All major antidepressant drugs – except trimipramine, bupropion, mirtazapine, and nefazodone –  suppress REM sleep, and it has been proposed that the clinical efficacy of these drugs largely derives from their suppressant effects on REM sleep. The three major classes of antidepressant drugs (MAOIs, TCAs, and SSRIs), profoundly suppress REM sleep. Mirtazapine either has no effect on REM sleep or increases it slightly. The MAOIs almost completely suppress REM sleep, while the TCAs and SSRIs have been shown to produce immediate (40–85%) and sustained (30–50%) reductions in REM sleep. This effect often causes increased fatigue in patients who take large doses of antidepressants for extended periods of time. Such fatigue can occasionally interfere with a patient's everyday activities. Abrupt discontinuation of MAOIs can cause a temporary phenomenon known as "REM rebound" in which the patient experiences extremely vivid dreams and nightmares.

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.

Withdrawal symptoms
If an SSRI is suddenly discontinued, it frequently produces an event of "SSRI discontinuation syndrome" that has a both a bodily and psychological withdrawal component.

Withdrawal syndromes have been reported with TCAs, MOAIs, SNRIs, and with SSRIs. Researchers from the Nordic Cochrane Center in Denmark compared the signs and symptoms of SSRI discontinuation to those of the benzodiazepine withdrawal syndrome and concluded that the withdrawal reactions were so similar that both withdrawal reactions indicated a dependence syndrome. Elsewhere, concerns have been raised that SSRIs cause dependence.

When treatment is prolonged over 6–9 months, processes oppose the initial effects of antidepressant drugs (loss of clinical effects). When drug treatment ends, these processes may be unopposed and yield withdrawal symptoms and increased vulnerability to relapse. Such processes are not necessarily reversible. The more antidepressants are switched or potentiated, the more likely oppositional tolerance can take place.

Some of the withdrawal symptoms of SSRI discontinuation include: nausea, chills, muscles aches, dizziness, anxiety, irritability, insomnia, fatigue, and, in some patients, electric shock sensations.

Moreover, when changes in antidepressant dosage occur, whether up or down, a doubling of the risk of suicide is seen.

To minimize the intensity of withdrawal and rebound effects antidepressants should be discontinued over a period of several weeks or months depending on a person's response to reductions. A suggested regimen is a decrease in the SSRI by about 25% per week. This is a guideline; the actual amount of time required to withdraw from a given antidepressant is unique to the drug. Certain antidepressants may have long half-lives and remain in the person's system for a period of time long enough to prevent a sudden "drop" in concentration, meaning that withdrawal or rebound effects are unlikely or less pronounced.

Most cases of discontinuation syndrome last between one and four weeks but a substantial minority, perhaps up to 15% of users, have persistent withdrawal symptoms evident one year post-withdrawal. Paroxetine and venlafaxine    seem to be particular difficult to discontinue and prolonged withdrawal syndrome lasting over 18 months have been reported with paroxetine. Peer-support groups exist to help patients taper off of their antidepressants.

Environmental impacts
There is good reason to believe that much of the large amounts of antidepressants consumed end up back into the ecosystem. Michael Thomas of Idaho State University in Pocatello reports that around 80% of these drugs are passed right through our bodies and end up in our water supplies. Fluoxetine is exceted 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 cuddle fish and decrease their survival.

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.

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.

Nicotine
Nicotine is believed to act as an antidepressant, by stimulating the release of dopamine and norepinephrine; in addition, nicotine is believed to exert an antidepressant effect due to the desensitisation of nicotinic receptors, which occurs as a result of tolerance. Clinical trials have demonstrated nicotine (administered using a dermal nicotine patch) exerts an antidepressant effect in both depressed nonsmokers and smokers, and can be considered for treatment-resistant depression. The proposed mechanism of chronic nicotine use causing desensitisation of nicotinic receptors – thereby leading to an antidepressant effect –  is consistent with the theory first proposed over 30 years ago and subsequent research that confirmed excessive acetylcholine activity in the brain leads to depressive symptoms. Varenicline, a nicotinic receptor-acting drug used to wean people off of nicotine dependence, has also demonstrated antidepressant properties.

Caffeine
Individuals using caffeine at moderate doses (fewer than 6 cups of coffee per day), have a reduced incidence of depressive symptoms and an overall reduced risk of suicide. Anxiety is an important side-effect of caffeine that occurs more commonly in individuals suffering from panic disorder or social phobia or when taken in excessive amounts.

Ketamine
Early studies have shown that ketamine may be effective in treatment-resistant depression, though experts have stated that it is not yet ready for clinical practice but rather may lead to the development of novel medications in the future. It produces a rapid antidepressant effect, acting within two hours as opposed to the several weeks taken by typical antidepressants to work.

Some research has attributed the effect to ketamine being an NMDA receptor antagonist, though others have suggested that blocking the NMDA receptor is an intermediate step that increases the activity of another receptor, AMPA, which is what is responsible for ketamine's rapid antidepressant actions.

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. For reasons unrelated to its efficacy, isoniazid as an antidepressant was soon overshadowed by the more toxic iproniazid, although it remains a mainstay of tuberculosis treatment. The mode of antidepressant action of isoniazid is still unclear. It is speculated that its effect is due to the inhibition of diamine oxidase, coupled with a weak inhibition of monoamine oxidase A.

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, including promoting its off-label use for depression. 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.

Prescription trends
In the United Kingdom, the use of antidepressants increased by 234% in the 10 years up to 2002. In the US a 2005 independent report stated that 11% of women and 5% of men in the non-institutionalized population (2002) take antidepressants. A 1998 survey found that 67% of patients diagnosed with depression were prescribed an antidepressant. A 2007 study suggested that 25% of Americans were overdiagnosed with depression, regardless of any medical intervention. The findings were based on a national survey of 8,098 people.

A 2002 survey found that about 3.5% of all people in France were being prescribed antidepressants, compared to 1.7% in 1992, often for conditions other than depression and often not in line with authorizations or guidelines. Between 1996 and 2004 in British Columbia, antidepressant use increased from 3.4% to 7.2% of the population. Data from 1992 to 2001 from the Netherlands indicated an increasing rate of prescriptions of SSRIs, and an increasing duration of treatment. Surveys indicate that antidepressant use, particularly of SSRIs, has increased rapidly in most developed countries, driven by an increased awareness of depression together with the availability and commercial promotion of new antidepressants. Antidepressants are also increasingly used worldwide for non-depressive patients as studies continue to show the potential of immunomodulatory, analgesic and anti-inflammatory properties in antidepressants.

The choice of a particular antidepressant is reported to be based, in the absence of research evidence of differences in efficacy, on seeking to avoid certain side-effects, and taking into account comorbid (co-occurring) psychiatric disorders, specific clinical symptoms and prior treatment history.

It is also reported that, despite equivocal evidence of a significant difference in efficacy between older and newer antidepressants, clinicians perceive the newer drugs, including SSRIs and SNRIs, to be more effective than the older drugs (tricyclics and MAOIs). Currently, the most commonly prescribed antidepressants are selective serotonin reuptake inhibitors (SSRIs), even though a Cochrane systematic review found no major difference in efficacy between SSRIs and tricyclic antidepressants. A survey in the UK found that male general physicians were more likely to prescribe antidepressants than female doctors.

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.

The use of antidepressants in the US doubled over one decade, from 1996 to 2005. Antidepressant drugs were prescribed to 13 million in 1996 and to 27 million people by 2005. In 2008, more than 164 million prescriptions were written. During this period, patients were less likely to undergo psychotherapy.

Most commonly prescribed


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

Germany: The most commonly prescribed antidepressant in Germany is reported to be (concentrated extracts of) Hypericum perforatum (St John's wort).

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.
 * 2012 Johnson & Johnson $1.6 and $2.2 billion Risperdal off-label marketing
 * 2012 Abbott Laboratories $698 million for off-label marketing Depakote for use in dementia patients who became agitated or aggressive, despite lack of evidence that the drug was effective for that use.
 * 2009 Eli Lilly $1.4 billion for marketing Zyprexa for children and the elderly dementia patients, both off-label uses. It is only approved to treat two disorders, schizophrenia and bipolar disorder.
 * 2010 AstraZeneca $520 million for off-label marketing of Seroquel.
 * 2009 Pfizer $301 million for off-label marketing of Geodon.
 * 2007 Bristol-Myers Squibb $515 million for off-label marketing of Abilify for children and adolescents, and geriatric patients suffering from dememtia.
 * 2004 Pfizer $430 million for off-label marketing of Neurontin.
 * Ely Lilly In one of the only three cases to ever go to trial for SSRI indication in suicide, Eli Lilly and Company was caught corrupting 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. The value of the secret settlement deal has never been disclosed, but was reportedly "tremendous".

Publication of research findings

 * Ghost writing of studies for industry-sponsored drug trials is common. Of all 44 trials approved between 1994 and 1995 by the ethics committees of Copenhagen and Frederiksberg in Denmark, up to 91%, that is 40 of the 44 trials, has some form of ghostwriting, and for the most part, the ghost was a statistician. Cases relating to gabapentin, paroxetine, sertraline, fenfluramine/phentermine (fen-phen) are well documented, while many others, relating to olanzapine, quetiapine, remain under seal by the courts.
 * 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. Based on Healy's examination of the data produced from the Cochrane study of Olanzapine for schizophrenia, the four initial trials of Zyprexa gave rise to 234 publications, most of which were ghost written.
 * Lack of access to raw data, data suppression, misrepresentation, and manipulation has eroded value of trial results. Demands on access to data has been met by resistance on the part of industry.
 * A meta-analysis by UK, US and Canadian researchers was published in 2008, surveying all pharmaceutical company-sponsored drug trials on the six most widely prescribed new-generation antidepressants submitted for approval to the FDA between 1987 and 1999. The results showed that the difference in efficacy between antidepressants and placebo was minimal, but that it increased from virtually no difference at moderate levels of initial depression to a relatively small difference for patients with very severe depression. The difference reached conventional criteria for clinical significance for patients at the upper end of the very severely depressed category, due to a reduction in the efficacy of placebo. The study received widespread media coverage in some countries, but was met with criticism from the professional community.


 * Eli Lilly and Company responded by highlighting that the study did not take into account more recent studies on its product, Prozac, and that it was proud of the difference Prozac has made to millions of people. GlaxoSmithKline warned that this one study should not be used to cause unnecessary alarm and concern for patients. Two leading UK psychiatrists/pharmacologists, with financial and professional links to pharmaceutical companies, argued that short-term approval trials are not very suitable for evaluating effectiveness, that the unpublished trials are of poorer quality, that the meta-analysis authors came from a "psychology background" rather than drug testing background, and that the media and "elements of the medico/scientific community [sic]" have "a down on antidepressants" and that the media do not appreciate the seriousness of depression, and blame and stigmatize sufferers. Wyeth pointed out that the data were good enough for FDA approval of the drugs.