Antidepressant

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Fluoxetine (Prozac), an SSRI
chemical structure of the SNRI drug venlafaxine
The chemical structure of venlafaxine (Effexor), an SNRI

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,[1] tryptophan,[2] low-dose antipsychotics,[3] and St John's wort.[4]

Efficacy[edit]

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.[5] 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.[6]

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.[7]

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.[8] The study was dubbed "The Sequenced Treatment Alternatives to Relieve Depression" (STAR*D) Study. The results[9][10] are summarized here.

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.[13] These included bupropion sustained release, bupropion, citalopram, lithium, mirtazapine, nortriptyline, sertraline, triiodothyronine, tranylcypromine, and venlafaxine extended release.[medical citation needed]

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.[14]

A 2002 review concluded that there was no evidence that antidepressants reduce the risk of recurrence of depression when their use is terminated. The authors of this review advocated that antidepressants be combined with therapy, and pointed to interpersonal psychotherapy (IPT) and cognitive behavioral therapy (CBT).[15]

Clinical guidelines[edit]

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.[16]

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.[17]

Limitations and strategies[edit]

Between 30% and 50% of individuals treated with a given antidepressant do not show a response.[18][19] 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.[20] In addition, antidepressant drugs tend to lose efficacy over the course of treatment.[21] A number of strategies are used in clinical practice to try to overcome these limits and variations.[22] They include switching medication, augmentation, and combination.

"Trial and error" switching[edit]

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.[medical citation needed]

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.[19] 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.[23] Thus, the clinical response to the new drug might be a placebo effect associated with the belief that one is receiving a different medication.[medical citation needed]

Augmentation and combination[edit]

For a partial response, the American Psychiatric Association guidelines suggest augmentation, or adding a drug from a different class. These include: lithium and thyroid augmentation, dopamine agonists, sex steroids, NRIs, glucocorticoid-specific agents, or the newer anticonvulsants.[24]

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.[25]

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.[26]

Long-term use[edit]

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.[27]

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.[28] In addition, gradual loss of therapeutic benefit occurs during the course of treatment.[29] 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.[30][31]

Antidepressant-induced mania[edit]

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.[32]

Mild depression[edit]

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.[33] The difference in effect between active placebos and several antidepressants appeared small and strongly affected by publication bias.[33]

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.[34]

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.[35][36]

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.[37] 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.[38]

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.[39]

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.[40]

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.[41]

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.[42]

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.[43]


Comparative efficacy and tolerability[edit]

Adverse effects[edit]

Difficulty tolerating adverse effects is the most common reason for antidepressant discontinuation.[medical citation needed]

General[edit]

For bipolar depression, antidepressants (most frequently SSRIs) can exacerbate or trigger symptoms of hypomania and mania.[62]

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.[63][64] 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.[65][66]

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.[67]

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.[68]

Pregnancy[edit]

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[69] 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,[70] birth defects,[71] and developmental delays.[72] Antidepressants have been shown to be present in varying amounts in breast milk, but their effects on infants are currently unknown.[73]

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.[74]

Suicide[edit]

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.[75] 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.[76] The circumstances under which this can happen are not clear, and other studies show that antidepressants treat suicidal ideation.

Sexual[edit]

Sexual side-effects are also common with SSRIs, such as loss of sexual drive, failure to reach orgasm, and erectile dysfunction.[77] 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.[78]

In a study of 1022 outpatients, overall sexual dysfunction with all antidepressants averaged 59.1%[79] 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,[80] and can actually lead to an improvement in all aspects of sexual function.[81]

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.[82] 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.[83]

Bupropion, a weak NDRI and nicotinic antagonist, may be useful in treating reduced libido as a result of SSRI treatment.[84] However, these results are preliminary, and as such must be taken cum grano salis.

REM Sleep[edit]

All major antidepressant drugs – except trimipramine, bupropion,[85] 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.[86] Mirtazapine either has no effect on REM sleep or increases it slightly.[87] 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.[88]

Changes in weight[edit]

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,[89][90][91] while others (such as bupropion and venlafaxine) achieve the opposite effect.[92][93]

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[edit]

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.[94]

Withdrawal syndromes have been reported with TCAs,[95] MOAIs,[96] SNRIs,[97] 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[98] 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.[99]

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.[29]

Some of the withdrawal symptoms of SSRI discontinuation include: nausea, chills, muscles aches, dizziness, anxiety, irritability, insomnia, fatigue,[100] and, in some patients, electric shock sensations.[101][102]

Moreover, when changes in antidepressant dosage occur, whether up or down, a doubling of the risk of suicide is seen.[103]

To minimize the intensity of withdrawal and rebound effects[104] 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.[100] 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.[105] Paroxetine and venlafaxine[96][101][106][107][108][109][110] seem to be particular difficult to discontinue and prolonged withdrawal syndrome lasting over 18 months have been reported with paroxetine.[94] Peer-support groups exist to help patients taper off of their antidepressants.[111]

Pharmacology[edit]

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).[44] 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.[44] 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.[44] 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.[112][113] 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.[113] 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.[112][113][114][115]

Types[edit]

Adjuncts[edit]

Adjunct medications are an umbrella term used to describe substances that increase the potency or "enhance" antidepressants.[116] 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:

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.[117]

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.[118]

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.[119] Lithium may also be used as an adjunct in major depressive disorder.[119][120][121] Triiodothyronine (T3) has also been successfully used as an adjunct in major depressive disorder.[119][122]

Nicotine[edit]

Nicotine is believed to act as an antidepressant,[123] 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.[124] 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.[118]

Caffeine[edit]

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.[125]

Ketamine[edit]

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.[126][127] It produces a rapid antidepressant effect, acting within two hours as opposed to the several weeks taken by typical antidepressants to work.[128]

Some research has attributed the effect to ketamine being an NMDA receptor antagonist,[129][130] 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.[131][132]

Nutrition[edit]

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.[133] 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.[134]

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."[135] 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.[136]

History[edit]

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.[137] Extracts from the herb St John's wort had been used as a "nerve tonic" to alleviate depression.[138]

Isoniazid, iproniazid, and imipramine[edit]

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."[139] 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.[140] 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.[141] For reasons unrelated to its efficacy, isoniazid as an antidepressant was soon overshadowed by the more toxic iproniazid,[140] 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.[142]

Selikoff and Robitzek also experimented with another anti-tuberculosis drug, iproniazid; it showed a greater psychostimulant effect, but more pronounced toxicity.[143] 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.[144] 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".[144][145] Roche put a significant marketing effort behind iproniazid, including promoting its off-label use for depression.[144] Its sales grew until it was recalled in 1961, due to reports of lethal hepatotoxicity.[144]

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

Attempting to improve the effectiveness of chlorpromazine, Kuhn – in conjunction with the Geigy Pharmaceutical Company – discovered the compound "G 22355", later renamed imipramine. Imipramine had a beneficial effect in patients with depression who showed mental and motor retardation. Kuhn described his new compound as a "thymoleptic" "taking hold of the emotions," in contrast with neuroleptics, "taking hold of the nerves" in 1955-56. These gradually became established, resulting in the patent and manufacture in the US in 1951 by Häfliger and SchinderA.[146]

Second generation antidepressants[edit]

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,[147] which were being marketed for different uses.[148] 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.[148][149]

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

Researchers began a process of rational drug design to isolate antihistamine-derived compounds that would selectively target these systems. The first such compound to be patented was zimelidine in 1971, while the first released clinically was indalpine. Fluoxetine was approved for commercial use by the US Food and Drug Administration (FDA) in 1988, becoming the first blockbuster SSRI. Fluoxetine was developed at Eli Lilly and Company in the early 1970s by Bryan Molloy, Klaus Schmiegel, David Wong and others.[150][151] SSRIs became known as "novel antidepressants" along with other newer drugs such as SNRIs and NRIs with various selective effects.[152]

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.[153] 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.[154][155]

Society and culture[edit]

Prescription trends[edit]

In the United Kingdom, the use of antidepressants increased by 234% in the 10 years up to 2002.[156] In the US a 2005 independent report stated that 11% of women and 5% of men in the non-institutionalized population (2002) take antidepressants.[157] A 1998 survey found that 67% of patients diagnosed with depression were prescribed an antidepressant.[158] A 2007 study suggested that 25% of Americans were overdiagnosed with depression, regardless of any medical intervention.[159] 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.[160] Between 1996 and 2004 in British Columbia, antidepressant use increased from 3.4% to 7.2% of the population.[161] Data from 1992 to 2001 from the Netherlands indicated an increasing rate of prescriptions of SSRIs, and an increasing duration of treatment.[162] 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.[163] 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.[medical citation needed]

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.[164]

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).[165] 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.[166] A survey in the UK found that male general physicians were more likely to prescribe antidepressants than female doctors.[167]

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.[168]

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.[169]

Most commonly prescribed[edit]

Structural formula of the SSRI escitalopram, in its free base form.

United States: The most commonly prescribed antidepressants in the US retail market in 2010[170] were:

SertralineZoloftSSRI33,409,838
CitalopramCelexaSSRI27,993,635
FluoxetineProzacSSRI24,473,994
EscitalopramLexaproSSRI23,000,456
TrazodoneDesyrelSARI18,786,495
DuloxetineCymbaltaSNRI14,591,949
ParoxetinePaxilSSRI12,979,366
AmitriptylineElavilTCA12,611,254
Venlafaxine XREffexor XRSNRI7,603,949
Bupropion XLWellbutrinNDRI7,317,814
MirtazapineRemeronTeCA6,308,288
Venlafaxine EREffexorSNRI5,526,132
Bupropion SRNDRI4,588,996
DesvenlafaxinePristiqSNRI3,412,354
NortriptylineSensovalTCA3,210,476
Bupropion ERNDRI3,132,327
VenlafaxineEffexorSNRI2,980,525
BupropionWellbutrin XLNDRI753,516

Germany: The most commonly prescribed antidepressant in Germany is reported to be (concentrated extracts of) Hypericum perforatum (St John's wort).[171]

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.[172]

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[edit]

Publication of research findings[edit]

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.[191] Wyeth pointed out that the data were good enough for FDA approval of the drugs.[192]

See also[edit]

References[edit]

  1. ^ Bodkin, JA; Zornberg, GL; Lukas, SE; Cole, JO (1995). "Buprenorphine Treatment of Refractory Depression". Journal of Clinical Psychopharmacology 15 (1): 49–57. doi:10.1097/00004714-199502000-00008. PMID 7714228. 
  2. ^ Ghadirian, AM; Murphy, BE; Gendron, MJ (1998). "Efficacy of light versus tryptophan therapy in seasonal affective disorder". Journal of Affective Disorders 50 (1): 23–7. doi:10.1016/S0165-0327(98)00053-6. PMID 9716275. 
  3. ^ Vega, JAW; Mortimer, AM; Tyson, PJ (2003). "Conventional Antipsychotic Prescription in Unipolar Depression, I". The Journal of Clinical Psychiatry 64 (5): 568–74. doi:10.4088/JCP.v64n0512. PMID 12755661. 
  4. ^ Linde, K; Berner, MM; Kriston, L (2008). "St John's wort for major depression". In Linde, Klaus. Cochrane Database of Systematic Reviews (4): CD000448. doi:10.1002/14651858.CD000448.pub3. PMID 18843608. 
  5. ^ Hamilton, M (1960). "A Rating Scale for Depression". Journal of Neurology, Neurosurgery & Psychiatry 23 (1): 56–62. doi:10.1136/jnnp.23.1.56. PMC 495331. PMID 14399272. 
  6. ^ Khan, A; Faucett, J; Lichtenberg, P; Kirsch, I; Brown, WA (2012). "A Systematic Review of Comparative Efficacy of Treatments and Controls for Depression". In Holscher, Christian. PLoS ONE 7 (7): e41778. Bibcode:2012PLoSO...741778K. doi:10.1371/journal.pone.0041778. PMC 3408478. PMID 22860015. 
  7. ^ Gartlehner, G; Hansen, RA; Morgan, LC; Thaler, K; Lux, L; Van Noord, M; Mager, U; Thieda, P; Gaynes, BN et al. (2011). "Comparative Benefits and Harms of Second-Generation Antidepressants for Treating Major Depressive Disorder: An Updated Meta-analysis". Annals of Internal Medicine 155 (11): 772–85. doi:10.7326/0003-4819-155-11-201112060-00009. PMID 22147715. 
  8. ^ "Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study". National Institute of Mental Health. Retrieved 28 November 2012. 
  9. ^ Fava, M; Rush, AJ; Wisniewski, SR; Nierenberg, AA; Alpert, JE; McGrath, PJ; Thase, ME; Warden, D; Biggs, M et al. (2006). "A Comparison of Mirtazapine and Nortriptyline Following Two Consecutive Failed Medication Treatments for Depressed Outpatients: A STAR*D Report". The American Journal of Psychiatry 163 (7): 1161–72. doi:10.1176/appi.ajp.163.7.1161. PMID 16816220. 
  10. ^ a b Trivedi, MH; Fava, M; Wisniewski, SR; Thase, ME; Quitkin, F; Warden, D; Ritz, L; Nierenberg, AA; Lebowitz, BD et al. (2006). "Medication Augmentation after the Failure of SSRIs for Depression". New England Journal of Medicine 354 (12): 1243–52. doi:10.1056/NEJMoa052964. PMID 16554526. 
  11. ^ Trivedi, MH; Rush, AJ; Wisniewski, SR; Nierenberg, AA; Warden, D; Ritz, L; Norquist, G; Howland, RH; Lebowitz, B et al. (2006). "Evaluation of Outcomes with Citalopram for Depression Using Measurement-Based Care in STAR*D: Implications for Clinical Practice". American Journal of Psychiatry 163 (1): 28–40. doi:10.1176/appi.ajp.163.1.28. PMID 16390886. 
  12. ^ Rush, AJ; Trivedi, MH; Wisniewski, SR; Stewart, JW; Nierenberg, AA; Thase, ME; Ritz, L; Biggs, MM; Warden, D et al. (2006). "Bupropion-SR, Sertraline, or Venlafaxine-XR after Failure of SSRIs for Depression". New England Journal of Medicine 354 (12): 1231–42. doi:10.1056/NEJMoa052963. PMID 16554525. 
  13. ^ Warden, D; Rush, AJ; Trivedi, MH; Fava, M; Wisniewski, SR (2007). "The STAR*D Project results: A comprehensive review of findings". Current psychiatry reports 9 (6): 449–59. doi:10.1007/s11920-007-0061-3. PMID 18221624. 
  14. ^ Taylor, MJ; Freemantle, N; Geddes, JR; Bhagwagar, Z (2006). "Early Onset of Selective Serotonin Reuptake Inhibitor Antidepressant Action: Systematic Review and Meta-analysis". Archives of General Psychiatry 63 (11): 1217–23. doi:10.1001/archpsyc.63.11.1217. PMC 2211759. PMID 17088502. 
  15. ^ Hollon, SD; Thase, ME; Markowitz, JC (2002). "Treatment and Prevention of Depression". Psychological Science in the Public Interest 3 (2): 39–77. doi:10.1111/1529-1006.00008. 
  16. ^ "Depression". National Institute for Health and Clinical Excellence. December 2004. Archived from the original on 15 November 2008. Retrieved 20 March 2013. 
  17. ^ "Practice guideline for the treatment of patients with major depressive disorder". National Guideline Clearinghouse. 2010. Archived from the original on 28 October 2008. Retrieved 20 March 2013. 
  18. ^ Baghai, Thomas; Möller, Hans-Jurgen; Rupprecht, Rainer (2006). "Recent Progress in Pharmacological and Non-Pharmacological Treatment Options of Major Depression". Current Pharmaceutical Design 12 (4): 503–15. doi:10.2174/138161206775474422. PMID 16472142. 
  19. ^ a b Ruhé, HG; Huyser, J; Swinkels, JA; Schene, AH (2006). "Switching Antidepressants After a First Selective Serotonin Reuptake Inhibitor in Major Depressive Disorder". The Journal of Clinical Psychiatry 67 (12): 1836–55. doi:10.4088/JCP.v67n1203. PMID 17194261. 
  20. ^ Tranter, R; O'Donovan, C; Chandarana, P; Kennedy, S (2002). "Prevalence and outcome of partial remission in depression". Journal of psychiatry & neuroscience 27 (4): 241–7. PMC 161658. PMID 12174733. 
  21. ^ Byrne, SE; Rothschild, AJ (1998). "Loss of Antidepressant Efficacy During Maintenance Therapy". The Journal of Clinical Psychiatry 59 (6): 279–88. doi:10.4088/JCP.v59n0602. PMID 9671339. 
  22. ^ Mischoulon, D; Nierenberg, AA; Kizilbash, L; Rosenbaum, JF; Fava, M (2000). "Strategies for managing depression refractory to selective serotonin reuptake inhibitor treatment: A survey of clinicians". Canadian journal of psychiatry 45 (5): 476–81. PMID 10900529. 
  23. ^ Bschor, T; Baethge, C (2010). "No evidence for switching the antidepressant: Systematic review and meta-analysis of RCTs of a common therapeutic strategy". Acta Psychiatrica Scandinavica 121 (3): 174–9. doi:10.1111/j.1600-0447.2009.01458.x. PMID 19703121. 
  24. ^ Debattista, C; Lembke, A (2005). "Update on augmentation of antidepressant response in resistant depression". Current Psychiatry Reports 7 (6): 435–40. doi:10.1007/s11920-005-0064-x. PMID 16318821. 
  25. ^ Lam, RW; Wan, DDC; Cohen, NL; Kennedy, SH (2002). "Combining Antidepressants for Treatment-Resistant Depression". The Journal of Clinical Psychiatry 63 (8): 685–93. doi:10.4088/JCP.v63n0805. PMID 12197448. 
  26. ^ Chouinard, G; Chouinard, Virginie-Anne (2008). "Atypical Antipsychotics: CATIE Study, Drug-Induced Movement Disorder and Resulting Iatrogenic Psychiatric-Like Symptoms, Supersensitivity Rebound Psychosis and Withdrawal Discontinuation Syndromes". Psychotherapy and Psychosomatics 77 (2): 69–77. doi:10.1159/000112883. PMID 18230939. 
  27. ^ Geddes, JR; Carney, SM; Davies, C; Furukawa, TA; Kupfer, DJ; Frank, E; Goodwin, GM (2003). "Relapse prevention with antidepressant drug treatment in depressive disorders: A systematic review". The Lancet 361 (9358): 653–61. doi:10.1016/S0140-6736(03)12599-8. PMID 12606176. 
  28. ^ Gardarsdottir, H; Van Geffen, ECG; Stolker, JJ; Egberts, TCG; Heerdink, ER (2009). "Does the Length of the First Antidepressant Treatment Episode Influence Risk and Time to a Second Episode?". Journal of Clinical Psychopharmacology 29 (1): 69–72. doi:10.1097/JCP.0b013e31819302b1. PMID 19142111. 
  29. ^ a b Fava, Giovanni A.; Offidani, Emanuela (2011). "The mechanisms of tolerance in antidepressant action". Progress in Neuro-Psychopharmacology and Biological Psychiatry 35 (7): 1593–602. doi:10.1016/j.pnpbp.2010.07.026. PMID 20728491. 
  30. ^ Fava, GA; Park, SK; Sonino, N (2006). "Treatment of recurrent depression". Expert Review of Neurotherapeutics 6 (11): 1735–40. doi:10.1586/14737175.6.11.1735. PMID 17144786. 
  31. ^ Petersen, TJ (2006). "Enhancing the efficacy of antidepressants with psychotherapy". Journal of Psychopharmacology 20 (3 suppl): 19–28. doi:10.1177/1359786806064314. PMID 16644768. 
  32. ^ Goldberg, JF; Truman, CJ (2003). "Antidepressant-induced mania: An overview of current controversies". Bipolar Disorders 5 (6): 407–20. doi:10.1046/j.1399-5618.2003.00067.x. PMID 14636364. 
  33. ^ a b Turner, EH; Matthews, AM; Linardatos, E; Tell, RA; Rosenthal, R (2008). "Selective Publication of Antidepressant Trials and Its Influence on Apparent Efficacy". New England Journal of Medicine 358 (3): 252–60. doi:10.1056/NEJMsa065779. PMID 18199864. 
  34. ^ Kirsch, I; Moore, TJ; Scoboria, A; Nicholls, SS (2002). "The emperor's new drugs: An analysis of antidepressant medication data submitted to the U.S. Food and Drug Administration". Prevention & Treatment 5. doi:10.1037/1522-3736.5.1.523a. 
  35. ^ "Study: Antidepressant barely better than placebo". USA Today. 7 July 2002. Retrieved 6 November 2008. [unreliable medical source?]
  36. ^ a b Kirsch, I; Deacon, BJ; Huedo-Medina, TB; Scoboria, A; Moore, TJ; Johnson, BT (2008). "Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration". PLoS Medicine 5 (2): e45. doi:10.1371/journal.pmed.0050045. PMC 2253608. PMID 18303940. 
  37. ^ Walsh, BT; Seidman, SN; Sysko, R; Gould, M (2002). "Placebo Response in Studies of Major Depression: Variable, Substantial, and Growing". JAMA 287 (14): 1840–7. doi:10.1001/jama.287.14.1840. PMID 11939870. 
  38. ^ Langreth, Robert (5 January 2010). "Study Undermines Case for Antidepressants". Forbes. Archived from the original on 8 December 2012. Retrieved 1 July 2010. 
  39. ^ Leucht, C; Huhn, M; Leucht, S (2012). "Amitriptyline versus placebo for major depressive disorder". In Leucht, C. Cochrane Database of Systematic Reviews 12: CD009138. doi:10.1002/14651858.CD009138.pub2. PMID 23235671. 
  40. ^ "Depression in Adults (update)" (PDF). National Collaborating Centre for Mental Health Commissioned by the National Institute for Health and Clinical Excellence. www.nice.org.uk. pp. 282–292. Retrieved 20 November 2013. 
  41. ^ "CDC: Antidepressants most prescribed drugs in U.S". CNN. 9 July 2007. Retrieved 21 May 2011. 
  42. ^ "'Remembering' prior antidepressant use affects the brain's response to new drugs". Yahoo! India News. ANI. 27 March 2012. 
  43. ^ Gueorguieva, R; Mallinckrodt, C; Krystal, JH (2011). "Trajectories of Depression Severity in Clinical Trials of Duloxetine: Insights into Antidepressant and Placebo Responses". Archives of General Psychiatry 68 (12): 1227–37. doi:10.1001/archgenpsychiatry.2011.132. PMC 3339151. PMID 22147842. 
  44. ^ a b c d e f g h i j Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (in English) (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8.  edit
  45. ^ a b c d e f g h i j k "Side effects of antidepressant medications". UpToDate. Wolters Kluwer Health. Retrieved 24 October 2013. 
  46. ^ a b c d e f g h i j k l m n o Royal Pharmaceutical Society of Great Britain. MARTINDALE - The Complete Drug Reference. Pharmaceutical Press. Retrieved 31 October 2013. 
  47. ^ a b c Cipriani, A; Furukawa, TA; Salanti, G; Geddes, JR; Higgins, JP; Churchill, R; Watanabe, N; Nakagawa, A; Omori, IM; McGuire, H; Tansella, M; Barbui, C (February 2009). "Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis" (PDF). Lancet 373 (9665): 746–758. doi:10.1016/S0140-6736(09)60046-5. PMID 19185342.  edit
  48. ^ a b c d e f g h i j k l Taylor, D; Paton, C; Shitij, K (2012). The Maudsley prescribing guidelines in psychiatry (in English). West Sussex: Wiley-Blackwell. ISBN 978-0-470-97948-8.  edit
  49. ^ a b White, N; Litovitz, T; Clancy, C (December 2008). "Suicidal antidepressant overdoses: a comparative analysis by antidepressant type". Journal of Medical Toxicology 4 (4): 238–250. doi:10.1007/BF03161207. PMC 3550116. PMID 19031375.  edit
  50. ^ a b c d e f g h Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.  edit
  51. ^ a b van Moffaert, M; de Wilde, J; Vereecken, A; Dierick, M; Evrard, JL; Wilmotte, J; Mendlewicz, J (March 1995). "Mirtazapine is more effective than trazodone: a double-blind controlled study in hospitalized patients with major depression". Int Clin Psychopharmacol 10 (1): 3?9. doi:10.1097/00004850-199503000-00001. PMID 7622801. 
  52. ^ "AMOXAPINE tablet [Watson Laboratories, Inc.]". DailyMed. Watson Laboratories, Inc. August 2010. Retrieved 30 October 2013. 
  53. ^ a b Walker, R; Whittlesea, C, ed. (2007) [1994]. Clinical Pharmacy and Therapeutics (4th ed.). Edinburgh: Churchill Livingstone Elsevier. ISBN 978-0-7020-4293-5.  edit
  54. ^ Bruijn, JA; Moleman, P; Mulder, PG; van den Broek, WW; van Hulst, AM; van der Mast, RC; van de Wetering, BJ (October 1996). "A double-blind, fixed blood-level study comparing mirtazapine with imipramine in depressed in-patients". Psychopharmacology (Berl.) 127 (3): 231?7. doi:10.1007/BF02246131. PMID 8912401. 
  55. ^ Bruijn, JA; Moleman, P; Mulder, PG; van den Broek, WW (May 1999). "Depressed in-patients respond differently to imipramine and mirtazapine". Pharmacopsychiatry 32 (3): 87?92. doi:10.1055/s-2007-979200. PMID 10463374. 
  56. ^ a b Fishback, JA; Robson, MJ; Xu, YT; Matsumoto, RR (September 2010). "Sigma receptors: Potential targets for a new class of antidepressant drug". Pharmacology & Therapeutics 127 (3): 271?282. doi:10.1016/j.pharmthera.2010.04.003. PMID 20438757. 
  57. ^ a b Kishimoto, Akira; Todani, Ayako; Miura, Junko; Kitagaki, Tetsuno; Hashimoto, Kenji (May 2010). "The opposite effects of fluvoxamine and sertraline in the treatment of psychotic major depression: a case report". Annals of General Psychiatry 9 (1): 23?25. doi:10.1186/1744-859X-9-23. PMC 2881105. PMID 20492642. 
  58. ^ Borkowska, A; Pilaczy?ska, E; Araszkiewicz, A; Rybakowski, J (November?December 2002). "[The effect of sertraline on cognitive functions in patients with obsessive-compulsive disorder]". Psychiatria Polska (in Polish) 36 (6 suppl): 289?295. PMID 12647451. 
  59. ^ Schmitt, JAJ; Ramaekers, JG; Kruizinga, MJ; Van Boxtel, MPJ; Vuurman, EFPM; Riedel, WJ (September 2002). "Additional dopamine reuptake inhibition attenuates vigilance impairment induced by serotonin reuptake inhibition in man". Journal of Psychopharmacology 16 (3): 207?214. doi:10.1177/026988110201600303. PMID 12236626. 
  60. ^ Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8.  edit
  61. ^ Goodwin, GM (2009). "Clinical Studies on the Efficacy of Agomelatine on Depressive Symptoms". CNS Drugs 23 (Suppl. 2): 35?39. doi:10.2165/11318650-000000000-00000. PMID 19708724. (subscription required (help)). 
  62. ^ Benazzi, F (1997). "Antidepressant-associated hypomania in outpatient depression: A 203-case study in private practice". Journal of Affective Disorders 46 (1): 73–7. doi:10.1016/S0165-0327(97)00082-7. PMID 9387089. 
  63. ^ Birmes, P; Coppin, D; Schmitt, L; Lauque, D (2003). "At the Bedside: Serotonin syndrome: a brief review". Canadian Medical Association Journal 168 (11): 1439–1442. PMC 155963. PMID 12771076. Retrieved 29 November 2013. 
  64. ^ Boyer, EW; Shannon, M (2005). "Current Concepts: The Serotonin Syndrome" (PDF). New England Journal of Medicine 352 (11): 1112–1120. doi:10.1056/NEJMra041867. PMID 15784664. Retrieved 29 November 2013. 
  65. ^ Mason, PJ; Morris, VA; Balcezak, TJ (2000). "Serotonin syndrome. Presentation of 2 cases and review of the literature". Medicine (Baltimore) 79 (4): 201–209. doi:10.1097/00005792-200007000-00001. PMID 10941349. (subscription required (help)). 
  66. ^ Sampson, E; Warner, JP (1999). "Serotonin syndrome: potentially fatal but difficult to recognize". British Journal of General Practice 49 (448): 867–868. doi:10.1097/00005792-200007000-00001. PMC 1313553. PMID 10941349. 
  67. ^ Yeragani, V; Yeragani, TS (2009). "Hypertensive crisis and cheese". Indian Journal of Psychiatry 51 (1): 65–66. doi:10.4103/0019-5545.44910. PMC 2738414. PMID 2738414. 
  68. ^ Paykel, E S. (1995). "Clinical efficacy of reversible and selective inhibitors of monoamine oxidase a in major depression". Acta Psychiatrica Scandinavica 91: 22–7. doi:10.1111/j.1600-0447.1995.tb05920.x. PMID 7717091. 
  69. ^ "FDA Advising of Risk of Birth Defects with Paxil" (Press release). U.S. Food and Drug Administration. Retrieved 29 November 2012. 
  70. ^ Nakhai-Pour, HR; Broy, P; Bérard, A (2010). "Use of antidepressants during pregnancy and the risk of spontaneous abortion". Canadian Medical Association Journal 182 (10): 1031–7. doi:10.1503/cmaj.091208. PMC 2900326. PMID 20513781. 
  71. ^ Louik, C; Lin, AE; Werler, MM; Hernández-Díaz, Sonia; Mitchell, Allen A. (2007). "First-Trimester Use of Selective Serotonin-Reuptake Inhibitors and the Risk of Birth Defects". New England Journal of Medicine 356 (26): 2675–83. doi:10.1056/NEJMoa067407. PMID 17596601. 
  72. ^ Pedersen, L H.; Henriksen, T B.; Olsen, J (2010). "Fetal Exposure to Antidepressants and Normal Milestone Development at 6 and 19 Months of Age". Pediatrics 125 (3): e600–8. doi:10.1542/peds.2008-3655. PMID 20176667. 
  73. ^ Lanza Di Scalea, T; Wisner, KL (2009). "Antidepressant Medication Use During Breastfeeding". Clinical Obstetrics and Gynecology 52 (3): 483–97. doi:10.1097/GRF.0b013e3181b52bd6. PMC 2902256. PMID 19661763. 
  74. ^ Sivagnanam, G (2012). "Antidepressants". Journal of Pharmacology and Pharmacotherapeutics 3 (3): 287–8. 
  75. ^ Cox, G. R.; Callahan, P.; Churchill, R.; Hunot, V.; Merry, S. N.; Parker, A. G.; Hetrick, S. E. (2012). "Psychological therapies versus antidepressant medication, alone and in combination for depression in children and adolescents". In Cox, Georgina R. Cochrane Database of Systematic Reviews. doi:10.1002/14651858.CD008324.pub2.  edit
  76. ^ Friedman, R. A.; Leon, A. C. (2007). "Expanding the Black Box — Depression, Antidepressants, and the Risk of Suicide". New England Journal of Medicine 356 (23): 2343–2346. doi:10.1056/NEJMp078015. PMID 17485726.  edit
  77. ^ Potenza, edited by Jon E. Grant, Marc N. (2012). The Oxford handbook of impulse control disorders. Oxford: Oxford University Press. ISBN 9780195389715. 
  78. ^ Csoka, AB; Bahrick, A; Mehtonen, OP (2008 Jan). "Persistent sexual dysfunction after discontinuation of selective serotonin reuptake inhibitors.". The journal of sexual medicine 5 (1): 227–33. PMID 18173768. 
  79. ^ Montejo, AL; Llorca, G; Izquierdo, JA; Rico-Villademoros, F (2001). "Incidence of sexual dysfunction associated with antidepressant agents: A prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction". The Journal of clinical psychiatry 62 (Suppl 3): 10–21. PMID 11229449. 
  80. ^ Serretti, Alessandro; Chiesa, Alberto (2009). "Treatment-Emergent Sexual Dysfunction Related to Antidepressants". Journal of Clinical Psychopharmacology 29 (3): 259–66. doi:10.1097/JCP.0b013e3181a5233f. PMID 19440080. 
  81. ^ Chebili, S; Abaoub, A; Mezouane, B; Le Goff, JF (1998). "Antidepressants and sexual stimulation: The correlation". L'Encephale 24 (3): 180–4. PMID 9696909. 
  82. ^ Keltner, Norman L.; McAfee, Kelly M.; Taylor, Carey L. (2009). "Biological Perspectives". Perspectives in Psychiatric Care 38 (3): 111–6. doi:10.1111/j.1744-6163.2002.tb00665.x. PMID 12385082. 
  83. ^ Ozmenler, NK; Karlidere, T; Bozkurt, A; Yetkin, S; Doruk, A; Sutcigil, L; Cansever, A; Uzun, O; Ozgen, F et al. (2008). "Mirtazapine augmentation in depressed patients with sexual dysfunction due to selective serotonin reuptake inhibitors". Human Psychopharmacology: Clinical and Experimental 23 (4): 321. doi:10.1002/hup.929. 
  84. ^ Labbate, LA; Grimes, JB; Hines, A; Pollack, MH (1997 Dec). "Bupropion treatment of serotonin reuptake antidepressant-associated sexual dysfunction.". Annals of clinical psychiatry : official journal of the American Academy of Clinical Psychiatrists 9 (4): 241–5. PMID 9511948. 
  85. ^ Ott, GE; Rao, U; Lin, KM; Gertsik, L; Poland, RE (2004 Sep). "Effect of treatment with bupropion on EEG sleep: relationship to antidepressant response.". The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP) 7 (3): 275–81. PMID 15122973. 
  86. ^ Vertes, Robert P.; Eastman, Kathleen E. (2000). "The case against memory consolidation in REM sleep". Behavioral and Brain Sciences 23 (6): 867–76; discussion 904–1121. doi:10.1017/S0140525X00004003. PMID 11515146. 
  87. ^ "Mirtazapine Regulates Stress Hormones, Improves Sleep In Depressed Patients: Presented at ISP". Pharmaclub.com. [unreliable medical source?]
  88. ^ Cohen, RM; Pickar, D; Garnett, D; Lipper, S; Gillin, JC; Murphy, DL (1982). "REM sleep suppression induced by selective monoamine oxidase inhibitors.". Psychopharmacology 78 (2): 137–40. PMID 6817370. 
  89. ^ Stimmel, GL; Dopheide, JA; Stahl, SM (1997). "Mirtazapine: An antidepressant with noradrenergic and specific serotonergic effects". Pharmacotherapy 17 (1): 10–21. PMID 9017762. 
  90. ^ "mirtazapine (Rx) - Remeron, Remeron SolTab". Medscape. WebMD. Retrieved 19 November 2013. 
  91. ^ Papakostas, GI (2008). "Tolerability of modern antidepressants". J Clin Psychiatry 69 (Suppl E1): 8–13. PMID 18494538. 
  92. ^ Li Z, Maglione M, Tu W, Mojica W, Arterburn D, Shugarman LR, Hilton L, Suttorp M, Solomon V, Shekelle PG, Morton SC (April 2005). "Meta-analysis: pharmacologic treatment of obesity". Ann. Intern. Med. 142 (7): 532–46. doi:10.7326/0003-4819-142-7-200504050-00012. PMID 15809465. 
  93. ^ "Effexor Medicines Data Sheet". Wyeth Pharmaceuticals Inc. 2006. Archived from the original on 17 September 2006. Retrieved 17 September 2006. 
  94. ^ a b Tamam, L; Ozpoyraz, N (2002). "Selective serotonin reuptake inhibitor discontinuation syndrome: A review". Advances in Therapy 19 (1): 17–26. doi:10.1007/BF02850015. PMID 12008858. 
  95. ^ Kramer, JC; Klein, DF; Fink, M (1961). "Withdrawal symptoms followingdicontin of imipramine therapy". The American Journal of Psychiatry 118: 549–50. PMID 14459296. 
  96. ^ a b Haddad, Peter M. (2001). "Antidepressant Discontinuation Syndromes". Drug Safety 24 (3): 183–97. doi:10.2165/00002018-200124030-00003. PMID 11347722. 
  97. ^ Parker, G; Blennerhassett, J (1998). "Withdrawal reactions associated with venlafaxine". Aust N Z J Psychiatry 32 (2): 291–4. doi:10.3109/00048679809062742. PMID 9588310. 
  98. ^ Nielsen, Margrethe; Hansen, Ebba Holme; Gøtzsche, Peter C. (2012). "What is the difference between dependence and withdrawal reactions? A comparison of benzodiazepines and selective serotonin re-uptake inhibitors". Addiction 107 (5): 900–8. doi:10.1111/j.1360-0443.2011.03686.x. PMID 21992148. 
  99. ^ Medawar, C (2004). Medicines out of Control. The Netherlands: Aksant. [page needed]
  100. ^ a b "Depressive Disorders". Merck Manual Online. Retrieved 9 January 2014. "Continued therapy with an antidepressant for 6 to 12 mo (up to 2 yr in patients > 50) is usually needed to prevent relapse. Most antidepressants, especially SSRIs, should be tapered off (by decreasing the dose by about 25%/wk) rather than stopped abruptly; stopping SSRIs abruptly may result in discontinuationsyndrome [sic] (nausea, chills, muscles aches, dizziness, anxiety, irritability, insomnia, fatigue). The likelihood and severity of withdrawal varies inversely with the half-life of the SSRI." [not in citation given]
  101. ^ a b Baboolal, Nelleen S. (2004). "Venlafaxine Withdrawal Syndrome". Journal of Clinical Psychopharmacology 24 (2): 229–31. doi:10.1097/01.jcp.0000117427.05703.f2. PMID 15206672. 
  102. ^ Reeves, RR; Mack, JE; Beddingfield, JJ (2003). "Shock-Like Sensations During Venlafaxine Withdrawal". Pharmacotherapy 23 (5): 678–81. doi:10.1592/phco.23.5.678.32198. PMID 12741444. 
  103. ^ Valuck, Robert J.; Orton, Heather D.; Libby, Anne M. (2009). "Antidepressant Discontinuation and Risk of Suicide Attempt". The Journal of Clinical Psychiatry 70 (8): 1069–77. doi:10.4088/JCP.08m04943. PMID 19758520. 
  104. ^ "Antidepressants and Addiction". Biopsychiatry.com. Retrieved 30 November 2012. 
  105. ^ Fava, Giovanni A.; Bernardi, Manuela; Tomba, Elena; Rafanelli, Chiara (2007). "Effects of gradual discontinuation of selective serotonin reuptake inhibitors in panic disorder with agoraphobia". The International Journal of Neuropsychopharmacology 10 (6): 835–8. doi:10.1017/S1461145706007462. PMID 17224089. 
  106. ^ Fava, M; Mulroy, R; Alpert, J; Nierenberg, AA; Rosenbaum, JF (1997). "Emergence of adverse events following discontinuation of treatment with extended-release venlafaxine". The American Journal of Psychiatry 154 (12): 1760–2. PMID 9396960. 
  107. ^ Parker, Gordon; Blennerhassett, Jenny (1998). "Withdrawal reactions associated with venlafaxine". Australian and New Zealand Journal of Psychiatry 32 (2): 291–4. doi:10.3109/00048679809062742. PMID 9588310. 
  108. ^ Van Noorden, MS; Vergouwen, AC; Koerselman, GF (2002). "Delirium during withdrawal of venlafaxine". Nederlands tijdschrift voor geneeskunde 146 (26): 1236–7. PMID 12132141. 
  109. ^ Nissen, C; Feige, B; Nofzinger, E; Riemann, D; Berger, M; Voderholzer, U (2005). "Transient narcolepsy-cataplexy syndrome after discontinuation of the antidepressant venlafaxine". Journal of Sleep Research 14 (2): 207–8. doi:10.1111/j.1365-2869.2005.00447.x. PMID 15910521. 
  110. ^ "Paxil Progress". Paxilprogress.org. Retrieved 27 November 2012. 
  111. ^ a b Maes, M; Yirmyia, R; Noraberg, J; Brene, S; Hibbeln, J; Perini, G; Kubera, M; Bob, P; Lerer, B; Maj, M (March 2009). "The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression". Metabolic Brain Disease 24 (1): 27–53. doi:10.1007/s11011-008-9118-1. PMID 19085093. </ref> edit
  112. ^ a b c Sanacora, G; Treccani, G; Popoli, M (January 2012). "Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders" (PDF). Neuropharmacology 62 (1): 63–77. doi:10.1016/j.neuropharm.2011.07.036. PMID 21827775.  edit
  113. ^ Menke A, Klengel T, Binder EB (2012). "Epigenetics, depression and antidepressant treatment". Current Pharmaceutical Design 18 (36): 5879–5889. doi:10.2174/138161212803523590. PMID 22681167.  edit
  114. ^ Vialou, V; Feng, J; Robison, AJ; Nestler, EJ (January 2013). "Epigenetic mechanisms of depression and antidepressant action". Annual Review of Pharmacology and Toxicology 53 (1): 59–87. doi:10.1146/annurev-pharmtox-010611-134540. PMID 23020296.  edit
  115. ^ "Depressive Disorders". Merck Manual. Retrieved 30 November 2012. 
  116. ^ Orr, Katy; Taylor, David (2007). "Psychostimulants in the Treatment of Depression". CNS Drugs 21 (3): 239–57. doi:10.2165/00023210-200721030-00004. PMID 17338594. 
  117. ^ a b Mineur, Yann S.; Picciotto, Marina R. (2010). "Nicotine receptors and depression: Revisiting and revising the cholinergic hypothesis". Trends in Pharmacological Sciences 31 (12): 580–6. doi:10.1016/j.tips.2010.09.004. PMC 2991594. PMID 20965579. 
  118. ^ a b c Taylor, D; Carol, P; Shitij, K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. ISBN 9780470979693. 
  119. ^ Australian Medicines Handbook 2013. Adelaide: Australian Medicines Handbook Pty Ltd. 2013. ISBN 9780980579093. 
  120. ^ Bauer, M; Dopfmer, S (October 1999). "Lithium augmentation in treatment-resistant depression: meta-analysis of placebo-controlled studies". Journal of Clinical Psychopharmacology 19 (5): 427–434. doi:10.1097/00004714-199910000-00006. PMID 10505584. 
  121. ^ Aronson, R; Offman, HJ; Joffe, RT; Naylor, CD (September 1996). "Triiodothyronine augmentation in the treatment of refractory depression. A meta-analysis". Archives of General Psychiatry 53 (9): 842–848. doi:10.1001/archpsyc.1996.01830090090013. PMID 8792761. 
  122. ^ Ischaki, E; Gratziou, C (2009). "Smoking and depression: Is smoking cessation effective?". Therapeutic Advances in Respiratory Disease 3 (1): 31–8. doi:10.1177/1753465809102662. PMID 19293201. 
  123. ^ Benowitz, Neal L. (2009). "Pharmacology of Nicotine: Addiction, Smoking-Induced Disease, and Therapeutics". Annual Review of Pharmacology and Toxicology 49: 57–71. doi:10.1146/annurev.pharmtox.48.113006.094742. PMC 2946180. PMID 18834313. 
  124. ^ Lara, Diogo R. (2010). "Caffeine, Mental Health, and Psychiatric Disorders". Journal of Alzheimer's Disease 20 (Suppl 1): S239–48. doi:10.3233/JAD-2010-1378 (inactive 19 March 2013). PMID 20164571. 
  125. ^ Rush, A John (2013). "Ketamine for Treatment-Resistant Depression: Ready or Not for Clinical Use?". American Journal of Psychiatry 170 (10): 1079–81. doi:10.1176/appi.ajp.2013.13081034. ISSN 0002-953X. PMID 23982324. 
  126. ^ Diazgranados, N (August 2010). "A Randomized Add-on Trial of an N-methyl-d-aspartate Antagonist in Treatment-Resistant Bipolar Depression". Archives of General Psychiatry 67 (8): 793–802. doi:10.1001/archgenpsychiatry.2010.90. PMC 3000408. PMID 20679587. 
  127. ^ Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, Kavalali ET, Monteggia LM (7 July 2011). "NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses". Nature 475 (7354): 91–95. doi:10.1038/nature10130. PMC 3172695. PMID 21677641. 
  128. ^ Zarate CA, Singh JB, Carlson PJ, et al. (August 2006). "A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression". Archives of General Psychiatry 63 (8): 856–64. doi:10.1001/archpsyc.63.8.856. PMID 16894061. 
  129. ^ Berman RM, Cappiello A, Anand A, et al. (February 2000). "Antidepressant effects of ketamine in depressed patients". Biological Psychiatry 47 (4): 351–4. doi:10.1016/S0006-3223(99)00230-9. PMID 10686270. 
  130. ^ Koike, H.; Iijima, M.; Chaki, S. (2011). "Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression". Behavioural Brain Research 224 (1): 107–111. doi:10.1016/j.bbr.2011.05.035. PMID 21669235.  edit
  131. ^ "Faster-Acting Antidepressants Closer to Becoming a Reality". NIMH. 25 July 2007. 
  132. ^ Nemets, H; Nemets, B; Apter, A; Bracha, Z; Belmaker, RH (2006). "Omega-3 Treatment of Childhood Depression: A Controlled, Double-Blind Pilot Study". American Journal of Psychiatry 163 (6): 1098–100. doi:10.1176/appi.ajp.163.6.1098. PMID 16741212. 
  133. ^ Sontrop, Jessica; Campbell, M Karen (2006). "Ω-3 polyunsaturated fatty acids and depression: A review of the evidence and a methodological critique". Preventive Medicine 42 (1): 4–13. doi:10.1016/j.ypmed.2005.11.005. PMID 16337677. 
  134. ^ Rocha Araujo, Daniele Marano; Vilarim, Marina Machado; Nardi, Antonio E (2010). "What is the effectiveness of the use of polyunsaturated fatty acid omega-3 in the treatment of depression?". Expert Review of Neurotherapeutics 10 (7): 1117–29. doi:10.1586/ern.10.77. PMID 20586692. 
  135. ^ Montgomery, Paul; Richardson, Alexandra J (2008). "Omega-3 fatty acids for bipolar disorder". In Montgomery, Paul. Cochrane Database of Systematic Reviews (2): CD005169. doi:10.1002/14651858.CD005169.pub2. PMID 18425912. 
  136. ^ Weber, MM; Emrich, HM (1988). "Current and Historical Concepts of Opiate Treatment in Psychiatric Disorders". International Clinical Psychopharmacology 3 (3): 255–66. doi:10.1097/00004850-198807000-00007. PMID 3153713. 
  137. ^ Czygan, Franz-C. (2003). "Kulturgeschichte und Mystik des Johanniskrauts: Vom 2500 Jahre alten Apotropaikum zum aktuellen Antidepressivum" [From a 2500 year old apotropic comes a current antidepressive. The cultural history and mistique of St. John's wort]. Pharmazie in unserer Zeit (in German) 32 (3): 184–90. doi:10.1002/pauz.200390062. PMID 12784538. 
  138. ^ Selikoff, Irving J.; Robitzek, EH (1952). "Tuberculosis Chemotherapy with Hydrazine Derivatives of Isonicotinic Acid". CHEST Journal 21 (4): 385–438. doi:10.1378/chest.21.4.385. PMID 14906149. 
  139. ^ a b Healy, D (2001). "The Antidepressant Drama". In Weissman, M.M. The treatment of depression: bridging the 21st century. American Psychiatric Pub. pp. 10–11. ISBN 978-0-88048-397-1. Retrieved 28 May 2009. 
  140. ^ Healy, David (1996). The psychopharmacologists: interviews. London: Chapman and Hall. p. 8. ISBN 978-1-86036-008-4. 
  141. ^ Healy, David (1998). The Psychopharmacologists: Volume 2. A Hodder Arnold Publication. pp. 132–4. ISBN 978-1-86036-010-7. 
  142. ^ Robitzek, EH; Selikoff, IJ; Mamlok, E; Tendlau, A (1953). "Isoniazid and Its Isopropyl Derivative in the Therapy of Tuberculosis in Humans: Comparative Therapeutic and Toxicologic Properties". CHEST Journal 23 (1): 1–15. doi:10.1378/chest.23.1.1. PMID 12998444. 
  143. ^ a b c d López-Muñoz, Francisco; Alamo, Cecilio; Juckel, Georg; Assion, Hans-Jörg (2007). "Half a Century of Antidepressant Drugs". Journal of Clinical Psychopharmacology 27 (6): 555–9. doi:10.1097/jcp.0b013e3181bb617. PMID 18004120. 
  144. ^ "Psychic Energizer". Time. 15 April 1957. Retrieved 28 May 2009. 
  145. ^ Kuhn, R (1958). "The treatment of depressive states with G 22355 (imipramine hydrochloride)". The American Journal of Psychiatry 115 (5): 459–64. PMID 13583250. 
  146. ^ "Tranquilizers". Cumberland Moutain Community Services. www.cmcsb.com. Archived from the original on 16 September 2012. Retrieved 20 November 2013. [unreliable medical source?]
  147. ^ a b Healy, David (1999). "The Three Faces of the Antidepressants: A Critical Commentary on the Clinical-Economic Context of Diagnosis". The Journal of Nervous & Mental Disease 187 (3): 174–80. doi:10.1097/00005053-199903000-00007. PMID 10086474. 
  148. ^ Pletscher, A (1991). "The discovery of antidepressants: A winding path". Experientia 47 (1): 4–8. doi:10.1007/BF02041242. PMID 1999242. 
  149. ^ Domino, EF (1999). "History of modern psychopharmacology: A personal view with an emphasis on antidepressants". Psychosomatic Medicine 61 (5): 591–8. PMID 10511010. 
  150. ^ Wong, DT; Bymaster, FP; Horng, JS; Molloy, BB (1975). "A new selective inhibitor for uptake of serotonin into synaptosomes of rat brain: 3-(p-trifluoromethylphenoxy). N-methyl-3-phenylpropylamine". The Journal of Pharmacology and Experimental Therapeutics 193 (3): 804–11. PMID 1151730. 
  151. ^ Freeman, H (1996). "Tolerability and safety of novel antidepressants". European Psychiatry 11: 206s. doi:10.1016/0924-9338(96)88597-X. 
  152. ^ Linde, K; Ramirez, G; Mulrow, CD; Pauls, A; Weidenhammer, W; Melchart, D (1996). "St John's wort for depression--an overview and meta-analysis of randomised clinical trials". BMJ 313 (7052): 253–8. doi:10.1136/bmj.313.7052.253. PMC 2351679. PMID 8704532. 
  153. ^ Müller, W (2003). "Current St. John's wort research from mode of action to clinical efficacy". Pharmacological Research 47 (2): 101–9. doi:10.1016/S1043-6618(02)00266-9. PMID 12543057. 
  154. ^ Nathan, P J. (2001). "Hypericum perforatum (St John's Wort): A non-selective reuptake inhibitor? A review of the recent advances in its pharmacology". Journal of Psychopharmacology 15 (1): 47–54. doi:10.1177/026988110101500109. PMID 11277608. 
  155. ^ (National Institute for Clinical Excellence, 2004)
  156. ^ Stagnitti, M (2005) [study done in 2002]. "Antidepressant Use in the US Civilian Non-Institutionalised Population". US Department of Health and Human Services. Rockville(MD): Medical Expenditure Panel, Agency for Healthcare Research and Quality. 
  157. ^ Sleath, B; Tina Shih, Ya-Chen (2003). "Sociological influences on antidepressant prescribing". Social Science & Medicine 56 (6): 1335–44. doi:10.1016/S0277-9536(02)00132-6. PMID 12600369. 
  158. ^ "Depression could be overdiagnosed". HeraldNet. The Washington Post. April 2007. Retrieved 28 May 2009. [unreliable medical source?]
  159. ^ Olié, JP; Elomari, F; Spadone, C; Lépine, JP (2002). "Résultats d'une enquête sur l'usage des antidépresseurs en population générale française" [Antidepressants consumption in the global population in France]. L'Encephale (in French) 28 (5 Pt 1): 411–7. PMID 12386542. 
  160. ^ Raymond, CB; Morgan, SG; Caetano, PA (2007). "Antidepressant Utilization in British Columbia from 1996 to 2004: Increasing Prevalence but Not Incidence". Psychiatric Services 58 (1): 79–84. doi:10.1176/appi.ps.58.1.79. PMID 17215416. 
  161. ^ Meijer, WEE; Heerdink, ER; Leufkens, HGM; Herings, RMC; Egberts, ACG; Nolen, WA (2004). "Incidence and determinants of long-term use of antidepressants". European Journal of Clinical Pharmacology 60 (1): 57–61. doi:10.1007/s00228-004-0726-3. PMID 14985889. 
  162. ^ McManus, Peter; Mant, Andrea; Mitchell, Philip B; Montgomery, William S; Marley, John; Auland, Merran E (2000). "Recent trends in the use of antidepressant drugs in Australia, 1990-1998". The Medical journal of Australia 173 (9): 458–61. PMID 11149300. 
  163. ^ Zimmerman, M; Posternak, M; Friedman, M; Attiullah, N; Baymiller, S; Boland, R; Berlowitz, S; Rahman, S; Uy, K et al. (2004). "Which Factors Influence Psychiatrists' Selection of Antidepressants?". American Journal of Psychiatry 161 (7): 1285–9. doi:10.1176/appi.ajp.161.7.1285. PMID 15229063. 
  164. ^ Petersen, T; Dording, C; Neault, NB; Kornbluh, R; Alpert, JE; Nierenberg, AA; Rosenbaum, JF; Fava, M (2002). "A survey of prescribing practices in the treatment of depression". Progress in Neuro-Psychopharmacology and Biological Psychiatry 26 (1): 177–87. doi:10.1016/S0278-5846(01)00250-0. PMID 11853110. 
  165. ^ Barbui, C; Hotopf, M; Freemantle, N; Boynton, J; Churchill, R; Eccles, MP; Geddes, JR; Hardy, R; Lewis, G et al. (2000). "Treatment discontinuation with selective serotonin reuptake inhibitors (SSRIs) versus tricyclic antidepressants (TCAs)". In Barbui, Corrado. Cochrane Database of Systematic Reviews (3): CD002791. doi:10.1002/14651858.CD002791. PMID 17636706. [unreliable medical source?]
  166. ^ "Male GPs depression pills 'bias'". BBC News. 21 July 2005. Retrieved 29 May 2009. 
  167. ^ Davis, Rowenna (11 June 2010). "Antidepressant Use Rises as Recession Feeds Wave of Worry". The Guardian (London). Archived from the original on 15 June 2010. Retrieved 1 July 2010. 
  168. ^ "Antidepressant Use Doubles in U.S., Study Finds". Reuters. 4 August 2009. Archived from the original on 3 July 2010. Retrieved 1 July 2010. 
  169. ^ "Top 200 generic drugs by units in 2010" (PDF). "Top 200 brand drugs by units in 2010" (PDF). 
  170. ^ Tyler, VE (1999). "Herbs Affecting the Central Nervous System". In Janick J. Perspectives on New Crops and New Uses. ASHS Press. p. 528. ISBN 978-0-9615027-0-6. Archived from the original on 27 April 2009. Retrieved 29 May 2009. 
  171. ^ "GIPdatabank". Gipdatabank.nl. Archived from the original on 6 December 2008. Retrieved 6 November 2008. 
  172. ^ "USDOJ: GlaxoSmithKline to Plead Guilty and Pay $3 Billion to Resolve Fraud Allegations and Failure to Report Safety Data". Justice.gov. 2 July 2012. Retrieved 30 November 2012. 
  173. ^ "USDOJ: Abbott Laboratories Sentenced for Misbranding Drug". Justice.gov. 2 October 2012. Retrieved 30 November 2012. 
  174. ^ "Pharmaceutical Company Eli Lilly To Pay Record $1.415 Billion For Off-label Drug Marketing" (PDF). United States Department of Justice. www.justice.gov. 15 January 2009. Archived from the original on 30 August 2010. Retrieved 20 November 2013. 
  175. ^ "Pharmaceutical Giant AstraZeneca to Pay $520 Million for Off-label Drug Marketing". Justice.gov. 27 April 2010. Retrieved 30 November 2012. 
  176. ^ "Pharmaceutical Company Pfizer, Inc. To Pay $301 Million For Off-label Drug Marketing" (PDF). United States Department of Justice. www.justice.gov. 2 September 2009. Archived from the original on 20 November 2013. Retrieved 20 November 2013. 
  177. ^ "#07-782: 09-28-07 Bristol-Myers Squibb to Pay More Than $515 Million to Resolve Allegations of Illegal Drug Marketing and Pricing". Justice.gov. 28 September 2007. Retrieved 30 November 2012. 
  178. ^ "#322: 05-13-04 WARNER-LAMBERT TO PAY $430 MILLION TO RESOLVE CRIMINAL & CIVIL HEALTH CARE LIABILITY RELATING TO OFF-LABEL PROMOTION". Justice.gov. 13 May 2004. Retrieved 30 November 2012. 
  179. ^ Zitrin, Richard; Langford, Carol M. (1999). "Hide and Secrets in Louisville". The Moral Compass of the American Lawyer. Ballantine Books. [page needed]
  180. ^ Gøtzsche, PC; Hróbjartsson, A; Johansen, HK; Haahr, MT; Altman, DG; Chan, An-Wen (2007). "Ghost Authorship in Industry-Initiated Randomised Trials". PLoS Medicine 4 (1): e19. doi:10.1371/journal.pmed.0040019. PMC 1769411. PMID 17227134. 
  181. ^ Steinman, Michael A.; Bero, Lisa A.; Chren, Mary-Margaret; Landefeld, C Seth (2006). "Narrative Review: The Promotion of Gabapentin: An Analysis of Internal Industry Documents". Annals of Internal Medicine 145 (4): 284–93. doi:10.7326/0003-4819-145-4-200608150-00008. PMID 16908919. 
  182. ^ Healy, David; Cattell, Dinah (2003). "Interface between authorship, industry and science in the domain of therapeutics". The British Journal of Psychiatry 183: 22–7. doi:10.1192/bjp.02-235 (inactive 20 March 2013). PMID 12835239. (subscription required (help)). 
  183. ^ McHenry, L; Jureidini, J (2008). "Industry-Sponsored Ghostwriting in Clinical Trial Reporting: A Case Study". Accountability in Research 15 (3): 152–67. doi:10.1080/08989620802194384. PMID 18792536. 
  184. ^ Mundy, A (2001). Dispensing with the truth: the victims, the drug companies, and the dramatic story behind the battle over Fen-Phen. New York: St. Martin's Press. ISBN 0-312-25324-9. [page needed]
  185. ^ Whittington, Craig J; Kendall, Tim; Fonagy, Peter; Cottrell, David; Cotgrove, Andrew; Boddington, Ellen (2004). "Selective serotonin reuptake inhibitors in childhood depression: Systematic review of published versus unpublished data". The Lancet 363 (9418): 1341–5. doi:10.1016/S0140-6736(04)16043-1. PMID 15110490. 
  186. ^ Lee, Kirby; Bacchetti, Peter; Sim, Ida (2008). "Publication of Clinical Trials Supporting Successful New Drug Applications: A Literature Analysis". In Clarke, Mike. PLoS Medicine 5 (9): e191. doi:10.1371/journal.pmed.0050191. PMC 2553819. PMID 18816163. 
  187. ^ Duggan, L; Fenton, M; Dardennes, J; El-Dosoky, R; Indran, A; Indran, S (2005). "Olanzapine for schizophrenia". In Duggan, Lorna. Cochrane Database of Systematic Reviews (2): CD001359. doi:10.1002/14651858.CD001359.pub2. PMID 10796640. 
  188. ^ Bian, Zhao-Xiang; Wu, Tai-Xiang (2010). "Legislation for trial registration and data transparency". Trials 11: 64. doi:10.1186/1745-6215-11-64. PMC 2882906. PMID 20504337. 
  189. ^ "Antidepressants do they work? A Review of the Review". Doctors Lounge. 21 September 2009. Retrieved 30 November 2012. [self-published source?]
  190. ^ Nutt, D; Malizia, A (2008). "Why does the world have such a 'down' on antidepressants?". Journal of Psychopharmacology 22 (3): 223–6. doi:10.1177/0269881108091877. PMID 18541622. 
  191. ^ Blue, L (26 February 2008). "Antidepressants Hardly Help". Time. 

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