An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia. Drugs including the monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs) are most commonly associated with the term. These medications are among those most commonly prescribed by psychiatrists and other physicians, and their effectiveness and adverse effects are the subject of many studies and competing claims. Many drugs produce an antidepressant effect, but restrictions on their use have caused controversy and off-label prescription a risk, despite claims of superior efficacy.

Most typical antidepressants have a delayed onset of action (2–6 weeks) and are usually administered for anywhere from months to years. Despite the name, antidepressants are often used to treat other conditions, such as anxiety disorders, obsessive compulsive disorder, eating disorders, chronic pain, and some hormone-mediated disorders such as dysmenorrhea. Alone or together with anticonvulsants (e.g., Tegretol or Depakote), these medications can be used to treat attention-deficit hyperactivity disorder (ADHD) and substance abuse by addressing underlying depression. Also, antidepressants have been used for hypercytorism, with mixed reviews. Sometimes in snoring and migraine.

Other medications that are not usually called antidepressants, including antipsychotics in low doses and benzodiazepines,may be used to manage depression, although benzodiazepines may cause physical dependence if treatment is not properly monitored by a doctor. Stopping benzodiazepine treatment abruptly can cause unpleasant withdrawal symptoms. An extract of the herb St John's Wort is commonly used as an antidepressant, although it is labeled as a dietary supplement in some countries. The term antidepressant is sometimes applied to any therapy (e.g., psychotherapy, electro-convulsive therapy, acupuncture) or process (e.g., sleep disruption, increased light levels, regular exercise) found to improve a clinically depressed mood.

Inert placebos can have significant antidepressant effects, and so to establish a substance as an "antidepressant" in a clinical trial it is necessary to show superior efficacy to placebo.


History

Various opiates and amphetamines were commonly used as antidepressants until the mid-1950s, when they fell out of favor due to their addictive nature and side effects.[Extracts from the herb St John's Wort have long been used (as a "nerve tonic") to alleviate depression.

 Isoniazid and iproniazid

In 1951, two physicians from Sea View Hospital on Staten Island, Irving Selikoff and Edward Robitzek, began clinical trials on two new anti-tuberculosis agents from 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, found out from his pulmonology colleagues at Cochin Hospital about the side effects of isoniazid. 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.

Another anti-tuberculosis drug tried at the same time by Selikoff and Robitzek, iproniazid, showed a greater "psychostimulant" effect, but more pronounced toxicity.After the publications on isoniazid, papers by Jackson Smith, Gordon Kamman, George Crane, and Frank Ayd appeared, describing 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 massively in the following years, until it was recalled from the market in 1961 due to cases of lethal hepatotoxicity.

Imipramine

The discovery that a tricyclic ("three ringed") compound had a significant antidepressant effect was first made in 1957 by Roland Kuhn in a Swiss psychiatric hospital. By that time antihistamine derivatives were increasingly used to treat surgical shock and then as psychiatric neuroleptics. Although in 1955 reserpine was shown to be more effective than placebo in alleviating anxious depression, neuroleptics (literally, "to seize the neuron") were being developed as sedatives and antipsychotics.

Attempting to improve the effectiveness of chlorpromazine, Kuhn, in conjunction with the Geigy pharmaceutical company, discovered that compound "G 22355" (manufactured and patented in the US in 1951 by Häfliger and Schinder) had a beneficial effect in patients with depression accompanied by mental and motor retardation.Kuhn first reported his findings on what he called a "thymoleptic" (literally, "taking hold of the emotions," in contrast with neuroleptics, "taking hold of the nerves") in 1955-56. These gradually became established, resulting in marketing of the first tricyclic antidepressant, imipramine, soon followed by variants.

Later history

These new drug therapies became prescription drugs in the 1950s. It was estimated that no more than 50 to 100 people per million suffered from the kind of depression that these new drugs would treat, and pharmaceutical companies were not enthusiastic. Sales through the 1960s remained poor compared to the major tranquilizers (neuroleptics/antipsychotics) and minor tranquilizers (such as benzodiazepines), which were being marketed for different uses.Imipramine remained in common use and numerous successors were introduced. The field of MAO inhibitors remained quiet for many years until "reversible" forms affecting only the MAO-A subtype were introduced, avoiding some of the adverse effects.

Most pharmacologists by the 1960s thought the main therapeutic action of tricyclics was to inhibit norepinephrine reuptake, but it was gradually observed that this action was associated with energizing and motor stimulating effects, while some antidepressant compounds appeared to have differing effects through action on serotonin systems (notably 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 Food and Drug Administration (United States) in 1988, becoming the first blockbuster SSRI. Fluoxetine was developed at Eli Lilly in the early 1970s by Bryan Molloy, David Wong and others.

While it had fallen out of favor in most countries through the 19th and 20th centuries, the herb St John's Wort became increasingly popular in Germany, where Hypericum extracts were eventually licensed, packaged and prescribed by doctors. Small-scale efficacy trials were carried out in the 1970s and 1980s, and attention grew in the 1990s following a meta-analysis of these.It remained an over-the-counter drug (OTC) or supplement in most countries and research continued to investigate its neurotransmitter effects and active components, particularly hyperforin[

SSRIs became known as "novel antidepressants" along with other newer drugs such as SNRIs and NRIs with various different selective effects, such as venlafaxine, duloxetine, nefazodone and mirtazapine

Types of Antidepressants

Selective serotonin reuptake inhibitors (SSRIs)

Selective serotonin reuptake inhibitors (SSRIs) are a family of antidepressants considered the current standard of drug treatment. A possible cause of depression is an inadequate amount of serotonin, a chemical used in the brain to transmit signals between neurons. SSRIs are said to work by preventing the reuptake of serotonin (also known as 5-hydroxytryptamine, or 5-HT) by the presynaptic neuron, thus maintaining higher levels of 5-HT in the synapse. Chemists Klaus Schmiegel and Bryan Molloy of Eli Lilly discovered the first SSRI, fluoxetine. This family of drugs includes:

These antidepressants typically have fewer adverse effects than the tricyclics or the MAOIs, although such effects as drowsiness, dry mouth, nervousness, anxiety, insomnia, decreased appetite, and decreased ability to function sexually may occur. Some side effects may decrease as a person adjusts to the drug, but other side effects may be persistent. Though safer than first generation antidepressants, SSRIs may not work on as many patients as previous classes of antidepressants,[citation needed] suggesting the role of norepinephrine in depression is still important.

Work by two researchers has called into question the link between serotonin deficiency and symptoms of depression, noting that the efficacy of SSRIs as treatment does not in itself prove the link. Research indicates that these drugs may interact with transcription factors known as "clock genes,"which may play a role in the addictive properties of drugs (drug abuse), and possibly in obesity.

Randomized controlled trials published in the Archives of General Psychiatry showed that up to one-third of the effect of SSRI Treatment can be seen in the first week. These early effects have also been shown to increase the absolute reduction in HRSD scores by 50%.

Serotonin-norepinephrine reuptake inhibitors (SNRIs)

Serotonin-norepinephrine reuptake inhibitors (SNRIs) are a newer form of antidepressant that work on both norepinephrine and 5-HT. They typically have similar side effects to the SSRIs, though there may be a withdrawal syndrome on discontinuation that may necessitate dosage tapering. These include:

Noradrenergic and specific serotonergic antidepressants (NaSSAs)

Noradrenergic and specific serotonergic antidepressants (NaSSAs) form a newer class of antidepressants which purportedly work to increase norepinephrine (noradrenaline) and serotonin neurotransmission by blocking presynaptic alpha-2 adrenergic receptors while at the same time certain serotonin receptors. Side effects may include drowsiness, increased appetite, and weight gain Examples include:

 Norepinephrine (noradrenaline) reuptake inhibitors (NRIs)

Norepinephrine (noradrenaline) reuptake inhibitors (NRIs) act via norepinephrine (also known as noradrenaline). NRIs are thought to have a positive effect on the concentration and motivation in particular. These include:

Norepinephrine-dopamine reuptake inhibitors (NDRIs)

Norepinephrine-dopamine reuptake inhibitors inhibit the neuronal reuptake of dopamine and norepinephrine (noradrenaline). These include:

Selective serotonin reuptake enhancers (SSREs)

Melatonergic agonists

Tricyclic antidepressants (TCAs)

Tricyclic antidepressants are the oldest class of antidepressant drugs. Tricyclics block the reuptake of certain neurotransmitters such as norepinephrine (noradrenaline) and serotonin. They are used less commonly now due to the development of more selective and safer drugs. Side effects include increased heart rate, drowsiness, dry mouth, constipation, urinary retention, blurred vision, dizziness, confusion, and sexual dysfunction. Toxicity occurs at approximately ten times normal dosages; these drugs are often lethal in overdoses, as they may cause a fatal arrhythmia. However, tricyclic antidepressants are still used because of their effectiveness, especially in severe cases of major depression. These include:

Tertiary Amine Tricyclic Antidepressants:

Secondary Amine Tricyclic Antidepressants

Monoamine oxidase inhibitor (MAOIs)

Monoamine oxidase inhibitors (MAOIs) may be used if other antidepressant medications are ineffective. Because there are potentially fatal interactions between this class of medication and certain foods (particularly those containing Tyramine), red wine, as well as certain drugs, classic MAOIs are rarely prescribed anymore. MAOIs work by blocking the enzyme monoamine oxidase which breaks down the neurotransmitters dopamine, serotonin, and norepinephrine (noradrenaline). MAOIs can be as effective as tricyclic antidepressants, although they can have a higher incidence of dangerous side effects (as a result of inhibition of cytochrome P450 in the liver). A new generation of MAOIs has been introduced; moclobemide (Manerix), known as a reversible inhibitor of monoamine oxidase A (RIMA), acts in a more short-lived and selective manner and does not require a special diet. Additionally, (selegiline) marketed as Emsam in a transdermal form is not a classic MAOI in that at moderate dosages it tends to affect MAO-B which does not require any dietary restrictions. As one of the side effects is weight gain and could be extreme. These include:

Augmenter drugs

Some antidepressants have been found to work better in some patients when used in combination with another drug. Such "augmenter" drugs include:

Tranquillizers and sedatives, typically the benzodiazepines, are prescribed to ease anxiety and promote sleep. Because of the high risk of dependency, these medications are intended only for short-term or occasional use. Medications are often used not for their primary functions, but to exploit what are normally side effects. Quetiapine fumarate (Seroquel) is designed primarily to treat schizophrenia and bipolar disorder, but frequently causes somnolence because of its affinity for histamine (H1 and H2) receptors, exploiting the same side effects as diphenhydramine (Benadryl).

Antipsychotics such as risperidone (Risperdal), olanzapine (Zyprexa), and quetiapine (Seroquel) are prescribed as mood stabilizers and to treat anxiety. Their use as mood stabilizers is a recent phenomenon, and controversial among some patients. Antipsychotics, whether typical or atypical, may also be prescribed to augment an antidepressant, to increase the blood concentration of another drug, or to relieve the psychotic or paranoid symptoms that often accompany clinical depression. However, they can cause serious side effects, particularly at high dosages, including blurred vision, muscle spasms, restlessness, tardive dyskinesia, and weight gain.

Psychostimulants are sometimes added to an antidepressant regimen if the patient suffers from anhedonia, hypersomnia and/or excessive eating as well as low motivation. These symptoms are common in atypical depression, and can be resolved by adding low to moderate doses of amphetamine (Adderall) or methylphenidate (Ritalin) as these chemicals can enhance motivation and social behavior, and suppress appetite and sleep. They can also restore sex drive. Extreme caution must be used however with certain populations. Stimulants are known to trigger manic episodes in people suffering from bipolar disorder. Close supervision of those with substance abuse disorders is urged. Emotionally labile patients should avoid stimulants, as they exacerbate mood shifting.

Lithium remains the standard treatment for bipolar disorder and is often used in conjunction with other medications, depending on whether mania or depression is being treated. Lithium's potential side effects include thirst, tremors, light-headedness, nausea, and diarrhea. Some of the anticonvulsants, such as carbamazepine (Tegretol), sodium valproate (Epilim), and lamotrigine (Lamictal), are also used as mood stabilizers, particularly in bipolar disorder. Both lithium and lamotrigine have also been studied and used to augment antidepressants in treatment-resistant unipolar depression.

Prescription trends

In the United Kingdom the use of antidepressants increased by 234% in the 10 years up to 2002.In the United States 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.he 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 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).

Most commonly prescribed antidepressants

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

The most commonly prescribed antidepressants in the US retail market in 2007 were:

Drug  ↓ Brand  ↓ Class  ↓ 2007 Prescriptions (in millions)  ↓
Sertraline Zoloft SSRI 29.652
Escitalopram Lexapro SSRI 27.023
Fluoxetine Prozac SSRI 22.266
Bupropion Wellbutrin NDRI 20.184
Paroxetine Paxil SSRI 18.141
Venlafaxine Effexor SNRI 17.200
Citalopram Celexa SSRI 16.246
Trazodone Desyrel
15.473
Amitriptyline Elavil TCA 13.462
Duloxetine Cymbalta SNRI 12.551
Mirtazapine Remeron TeCA 5.129
Nortriptyline Pamelor TCA 3.105
Imipramine Tofranil TCA 1.524

The most commonly prescribed antidepressant in Germany is reported to be (concentrated extracts of) hypericum perforatum (St John's Wort). In the Netherlands, paroxetine, marketed as Seroxat among generic preparations, is the most prescribed antidepressant, followed by the tricyclic antidepressant amitriptyline, citalopram and venlafaxine.

Mechanisms of action

The therapeutic effects of antidepressants are believed to be caused by their effects on neurotransmitters and neurotransmission.

Monoamine oxidase inhibitors (MAOIs) block the degradation of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine by inhibiting the enzyme monoamine oxidase, leading to increased concentrations of these neurotransmitters in the brain and an increase in neurotransmission.

Tricyclic antidepressants (TCAs) prevent the reuptake of various neurotransmitters, including serotonin, norepinephrine, and to a much less extent, dopamine. Nowadays the most common antidepressants are selective serotonin reuptake inhibitors (SSRIs), which prevent the reuptake of serotonin (thereby increasing the level of active serotonin in synapses of the brain). Other novel antidepressants affect norepinephrine reuptake, or different receptors on the nerve cell.

While MAOIs, TCAs and SSRIs increase serotonin levels, others prevent serotonin from binding to 5-HT2A receptors, suggesting it is too simplistic to say serotonin is a happy hormone. In fact, when the former antidepressants build up in the bloodstream and the serotonin level is increased, it is common for the patient to feel worse for the first weeks of treatment. One explanation of this is that 5-HT2A receptors evolved as a saturation signal (people who use 5-HT2A antagonists often gain weight), telling the animal to stop searching for food, a mate, etc., and to start looking for predators. In a threatening situation it is beneficial for the animal not to feel hungry even if it needs to eat. Stimulation of 5-HT2A receptors will achieve that. But if the threat is long lasting the animal needs to start eating and mating again - the fact that it survived shows that the threat was not so dangerous as the animal felt. So the number of 5-HT2A receptors decreases through a process known as downregulation and the animal goes back to its normal behavior. This suggests that there are two ways to relieve anxiety in humans with serotonergic drugs: by blocking stimulation of 5-HT2A receptors or by overstimulating them until they decrease via tolerance.

The stimulation or blocking of different receptors on a cell affects its genetic expression. Recent findings have shown that neurogenesis, and thus, changes in brain morphogenesis, mediate the effects of antidepressant drugs.

Another hypothesis is that antidepressants may have some longer-term effects due to the promotion of neurogenesis in the hippocampus, an effect found in mice. Other animal research suggests that antidepressants can affect the expression of genes in brain cells, by influencing "clock genes".

Other research suggests that delayed onset of clinical effects from antidepressants indicates involvement of adaptive changes in antidepressant effects. Rodent studies have consistently shown upregulation of the 3, 5-cyclic adenosine monophosphate (cAMP) system induced by different types of chronic but not acute antidepressant treatment, including serotonin and norepinephrine uptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, lithium and electroconvulsions. cAMP is synthesized from adenosine 5-triphosphate (ATP) by adenylyl cyclase and metabolized by cyclic nucleotide phosphodiesterases (PDEs). Data also suggest that antidepressants can modulate neural plasticity in longterm administration.

One theory regarding the cause of depression is that it is characterized by an overactive hypothalamic-pituitary-adrenal axis (HPA axis) that resembles the neuro-endocrine response to stress. These HPA axis abnormalities participate in the development of depressive symptoms, and antidepressants serve to regulate HPA axis function.

Comparison

A number of antidepressants have been compared below:[49][50][51][52]



Compound SERT NET DAT H1 M1-5 α1 α2 5-HT1A 5-HT2 D2
Amitriptyline 4.3 35 3,250 0.95 9.6 24 690 450 18 1,460
Amoxapine 58 16 4,310 25 1,000 50 2,600  ?  ?  ?
Atomoxetine 8.9 2.03 1,080 5,500 2,060 3,800 8,800 10,900 940 >35,000
Bupropion 45,026 1,389 2,784 11,800 >35,000 4,200 >35,000

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