Antidepressant

Fluoxetine (Prozac), an SSRI

Venlafaxine, an SNRI

An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes (2005) people with a depressive illness will experience a therapeutic effect to their mood, however this will not be experienced in healthy individuals. 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.

The efficacy of modern thymoleptic anti-depressants has never been conclusively demonstrated to be greater than that of active placebo, according to two Cochrane Collaboration reviews. A review of all studies of anti-depressants ever submitted to the FDA, published and unpublished, was submitted to the FDA in 2004. In the published literature, anti-depressants had 94% success in treating depression. In the withheld literature, they had below 50% success. Combined, all studies showed 51% efficacy - only two points better than that of placebo. This increased the apparent efficacy of different anti-depressants from 11% to 69% over placebo. Possible exceptions are mirtazepine - a norepinephrine and serotonin antagonist, with effects opposite that of the SSRIs and SNRIS - and venlafaxine, an SNRI with substantial similarity in chemical structure to the opioid derivative tramadol.

Opioids were used to treat major depression until the late 1950s. Amphetamines were used until the mid 1960s. Prescribing opioids or amphetamines for depression falls into a legal grey area. Research has only rarely been conducted in to the therapeutic potential of opioid derivatives for depression in the past sixty years, whereas amphetamines have found a thriving market for conditions as widely arrayed as attention deficit disorder, narcolepsy, and obesity, and continue to be studied for myriad applications. Both opioids and amphetamines induce a therapeutic response very quickly, showing results within twenty-four to forty-eight hours; the therapeutic ratios for both opioids and amphetamines are greater than those of the tricyclic anti-depressants. In some of this little, heavily restricted research, the opioid buprenorphine has shown the greatest potential for treating severe, treatment-resistant depression of any known pharmaceutical in a small study that is generally recognized and was published in 1995, but has never been pursued due to the social stigma attached to opioids in addition to that attached to mental illness in America.

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 controversially, and with a dearth of empirical evidence to support their indication, off-label 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 sometimes to treat snoring and migraines.

Other medications that are not usually called antidepressants, including antipsychotics in low doses and benzodiazepines, may be used to manage depression, although benzodiazepines - along with all drugs called "anti-depressants" - cause a physical dependence to form. Stopping benzodiazepine (or SSRI) 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

St John's Wort

Various opiates (via the µ-opioid receptor and κ-opioid receptor) 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 people 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 nerves" or "to take hold of nerves") 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

Main article: List of antidepressants

Selective serotonin reuptake inhibitors (SSRIs)

Selective serotonin reuptake inhibitors (SSRIs) are a class 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 class of drugs includes:

• Citalopram (Celexa, Cipramil)
• Escitalopram (Lexapro, Cipralex, Seroplex, Lexamil)
• Fluoxetine (Prozac, Sarafem, Symbyax)
• Fluvoxamine (Luvox)
• Paroxetine (Paxil, Aropax)
• Sertraline (Zoloft)

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, long-term weight gain 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, 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 blocking certain serotonin receptors. Side effects may include drowsiness, increased appetite, and weight gain. Examples include:

• Mianserin (Tolvon)
• Mirtazapine (Remeron, Avanza, Zispin)

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:

• Atomoxetine (Strattera)
• Mazindol (Mazanor, Sanorex)
• Reboxetine (Edronax)
• Viloxazine (Vivalan)

Norepinephrine-dopamine reuptake inhibitors (NDRIs)

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

• Bupropion (Wellbutrin, Zyban)

Selective serotonin reuptake enhancers (SSREs)

• Tianeptine (Stablon, Coaxil, Tatinol)

Norepinephrine-dopamine disinhibitors (NDDIs)

Norepinephrine-dopamine disinhibitors (NDDIs) act by antagonizing the serotonin 5-HT_2C receptor which normally acts to inhibit norepinephrine and dopamine release, thereby promoting outflow of these neurotransmitters.

• Agomelatine (Valdoxan, Melitor, Thymanax)

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:

• Amitriptyline (Elavil, Endep)
• Clomipramine (Anafranil)
• Doxepin (Adapin, Sinequan)
• Imipramine (Tofranil)
• Trimipramine (Surmontil)

Secondary amine tricyclic antidepressants

• Desipramine (Norpramin)
• Nortriptyline (Pamelor, Aventyl, Noritren)
• Protriptyline (Vivactil)

Monoamine oxidase inhibitor (MAOIs)

Monoamine oxidase inhibitors (MAOIs) may be used if other antidepressant medications are ineffective. MAOIs work by blocking the enzyme monoamine oxidase which breaks down the neurotransmitters dopamine, serotonin, and norepinephrine (noradrenaline). Because there are potentially fatal interactions between this class of medication and certain foods (particularly those containing tyramine), as well as certain drugs, classic MAOIs are rarely prescribed anymore. However, this does not apply to Emsam, the transdermal patch form of selegiline, which due to its bypassing of the stomach has a lesser propensity to induce such events. MAOIs can be as effective as tricyclic antidepressants, although they are generally used less frequently due to the fact that they have a higher incidence of dangerous side effects and interactions. 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. The MAOI group of medicines include:

• Isocarboxazid (Marplan)
• Moclobemide (Aurorix, Manerix)
• Phenelzine (Nardil)
• Selegiline (Eldepryl, Emsam)
• Tranylcypromine (Parnate)

Augmenter drugs

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

• Buspirone (Buspar)
• Gepirone (Ariza)
• Nefazodone (Serzone)
• Tandospirone (Sediel)
• Trazodone (Desyrel)
• Bupropion (Wellbutrin/Zyban)

Tranquillizers and sedatives, typically the benzodiazepines, are prescribed to ease anxiety with cats 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), methylphenidate (Ritalin) or modafinil (Provigil, Alertec), as these chemicals can enhance motivation and social behavior, and suppress appetite and sleep. Modafinil is unique in its effect on sleep: it increases alertness and reduces drowsiness while the patient is active, but does not inhibit normal sleep. These medications can also restore sexual drive, although this is a negative side effect and not a reason for the prescription of psychostimulants. 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.

Herbal antidepressants

St. John's Wort is by far the most widely-used and well-studied herbal antidepressant. A number of other herbs have been used traditionally to treat depression and related ailments like anxiety, but the research on most of these treatments is sparse.

Saffron (Crocus sativus L.) has been found in a double-blind randomized clinical trial to be equally effective with imipramine for treating mild to moderate depression; the study also remarked that anticholinergic side effects were more frequent in the imipramine treatment group. Another 8-week double-blind randomized trial found saffron to have a similar effect to fluoxetine (Prozac) in the treatment of mild to moderate depression, including a similar remission rate and similar rate of side effects.

Lavender, Lavandula angustifolia, has been traditionally used to treat depression, although until recently there was little research on this plant. A 2003 double-blind, randomized clinical trial compared lavender to imipramine in the treatment of mild to moderate depression, testing both each treatments individually, and a combination of the two. Lavender was found to be less effective than imipramine, but the combination of both treatments was found to be more effective than either alone.

Several plants in the Salvia genus have been studied for antidepressant properties, although most of the research conducted so far has only been from mice and rat studies. Salvia elegans, also known as pineapple sage, is widely used in Mexican traditional medicine, and has been found in single study in mice to have antidepressant and antianxiety properties. Salvia sclarea, also known as clary, is known to have an antidepressant-like effect in rats, which is thought to be explained by modulation of dopamine.

Ocimum tenuiflorum, also known as Tulsi or holy basil, has been used in Ayurveda to treat anxiety and depression, and was shown in a clinical study to be effective at treating generalized anxiety disorder and depression.

Wormwood, Artemisia absinthium, has shown antidepressant effects in mice, similar activity to imipramine.

Nutrients and nutritional supplements as antidepressants

Nutrition has been implicated as one of the causes and risk factors for depression, and accordingly, one approach to depression involves the use of nutritional supplements or changes in diet. A study of older adults found that poor nutrition was a strong predictor of depressive symptoms a year later. A few nutrients have been studied directly for their antidepressant properties, both to treat and prevent depression, as well as related conditions such as anxiety.

Omega-3

Omega 3 fatty acids have been proposed as a treatment for depression, often suggested to be combined with other treatments. One small pilot study of childhood depression (ages 6-12) suggested that omega 3 may have therapeutic benefits for treating childhood depression. A 2005 review of the scientific literature concluded that there were several different independent lines of evidence suggesting that omega-3 fatty acids play a role in depression, and that the theory of omega-3's role in depression was biologically plausible. The evidence includes a few double-blind randomized control trials, epidemiological studies linking low fish consumption (the primary source of omega-3) to increased rates of depression, and case-control and cohort studies of unipolar and postpartum depression indicating low blood levels of omega-3 in depressed patients.

Other essential nutrients

Folic acid and Vitamin B12 have also been proposed as a treatment for depression, especially when used in conjunction with other treatments. In particular, folic acid has been shown to improve the treatment response to other antidepressants.

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. The findings were based on a national survey of 8,098 people.

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

The choice of 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). A survey in the UK found that male general physicians were more likely to prescribe antidepressants than female doctors.

The number of antidepressants prescribed by the NHS in the United Kingdom almost doubled during one decade, authorities reported in 2010. Furthermore the number highly increased in 2009 when 39.1 million prescriptions were issued compared with 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 talking therapies, counseling and cognitive behavior therapy. One more factor that may be increasing the consumption of antidepressants is the fact that these medications now are used for other conditions including social anxiety and post traumatic stress.

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

Most commonly prescribed 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	SARI	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.

The Monoamine Hypothesis is a biological theory stating that depression is caused by the underactivity in the brain of monoamines, such as dopamine, serotonin, and norepinephrine. In the 1950s the monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants were accidentally discovered to be effective in the treatment of depression. These findings and other supporting evidence led Joseph Schildkraut to publish his paper called "The Catecholamine Hypothesis of Affective Disorders" in 1965. Schildkraut associated low levels of neurotransmitters with depression. Research into other mental impairments such as schizophrenia also found that too little activity of certain neurotransmitters were connected to these disorders. The hypothesis has been a major focus of research in the fields pathophysiology and pharmacotherapy for over 25 years.

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-HT_2A 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-HT_2A receptors evolved as a saturation signal (people who use 5-HT_2A 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-HT_2A 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-HT_2A 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-HT_2A 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:

Compound	SERT	NET	DAT	H1	M1-5	α1	α2	5-HT1A	5-HT2	D2
Agomelatine	?	?	?	?	?	?	?	?	270	?
Amitriptyline	4.3	35	3250	0.95	9.6	24	690	450	18	1460
Amoxapine	58	16	4310	25	1000	50	2600	?	?	?
Atomoxetine	8.9	2.03	1080	5500	2060	3800	8800	10900	940	35000+
Bupropion	45026	1389	2784	11800	35000+	4200	35000+	35000+	35000+	35000+
Buspirone	?	?	?	?	?	138	?	5.7	174	362
Butriptyline	1360	5100	3940	?	?	?	?	?	?	?
Citalopram	1.16	4070	28100	?	?	?	?	?	?	?
Clomipramine	0.28	38	2190	31	37	38	3200	?	?	?
Desipramine	17.6	0.83	3190	60	66	100	5500	6400	350	3500
Dosulepin	8.6	46	5310	?	?	?	?	?	?	?
Doxepin	68	29.5	12100	0.17	23	23.5	1270	276	27	360
Duloxetine	0.8	7.5	240	?	?	?	?	?	?	?
Etoperidone	890	20000	52000	3100	35000+	38	570	85	36	2300
Femoxetine	11	760	2050	4200	184	650	1970	2285	130	590
Fluoxetine	0.81	240	3600	5400	590	3800	13900	32400	280	12000
Fluvoxamine	0.81	240	3600	?	?	?	?	?	?	?
Imipramine	1.4	37	8500	37	46	32	3100	5800	150	620
Lofepramine	70	5.4	18000	360	67	100	2700	4600	200	2000
Maprotiline	5800	11.1	1000	2	570	90	9400	?	?	?
Mazindol	100	1.4	11	?	?	?	?	?	?	?
Mianserin	4000	71	9400	?	?	?	?	?	?	?
Milnacipran	123	200	10000+	?	?	?	?	?	?	?
Mirtazapine	1500+	1250~	1500+	1~	1000~	500~	100~	1500+	10~	1500+
Nefazodone	200	360	360	24000	11000	48	640	80	26	910
Nisoxetine	383	5.1	477	?	?	?	?	?	?	?
Nomifensine	1010	15.6	56	?	?	?	?	?	?	?
Nortriptyline	18	4.37	1140	6.3	37	55	2030	294	41	2570
Oxaprotiline	3900	4.9	4340	?	?	?	?	?	?	?
Paroxetine	0.13	40	490	22000	108	4600	17000	35000+	19000	32000
Protriptyline	19.6	1.41	2100	25	25	130	6600	?	?	?
Reboxetine	720	11	10000+	?	?	?	?	?	?	?
Sertraline	0.29	420	25	24000	630	380	4100	35000+	9900	10700
Trazodone	160	8500	7400	1100	35000+	42	320	96	25.0	35000+
Trimipramine	149	2450	3780	0.27	58	24	680	?	?	?
Venlafaxine	82	2480	7647	35000+	35000+	35000+	35000+	35000+	35000+	35000+
Viloxazine	17300	155	100000+	?	?	?	?	?	?	?
Zimelidine	152	9400	11700	?	?	?	?	?	?	?

The values above are expressed as equilibrium dissociation constants. It should be noted that less is more. SERT, NET, and DAT correspond to the abilities of the compounds to inhibit the reuptake of serotonin, norepinephrine, and dopamine, respectively. The other values correspond to their affinity for various receptors.

Anti-inflammatory and immunomodulation

Recent studies show pro-inflammatory cytokine processes take place during clinical depression, mania and bipolar disorder, and it is possible that symptoms of these conditions are attenuated by the pharmacological effect of antidepressants on the immune system.

Studies also show that the chronic secretion of stress hormones as a result of disease, including somatic infections or autoimmune syndromes, may reduce the effect of neurotransmitters or other receptors in the brain by cell-mediated pro-inflammatory pathways, thereby leading to the dysregulation of neurohormones. SSRIs, SNRIs and tricyclic antidepressants acting on serotonin, norepinephrine and dopamine receptors have been shown to be immunomodulatory and anti-inflammatory against pro-inflammatory cytokine processes, specifically on the regulation of Interferon-gamma (IFN-gamma) and Interleukin-10 (IL-10), as well as TNF-alpha and Interleukin-6 (IL-6). Antidepressants have also been shown to suppress TH1 upregulation.

Antidepressants, specifically TCAs and SNRIs (or SSRI-NRI combinations), have also shown analgesic properties.

These studies warrant investigation for antidepressants for use in both psychiatric and non-psychiatric illness and that a psycho-neuroimmunological approach may be required for optimal pharmacotherapy. Future antidepressants may be made to specifically target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines.

Therapeutic efficacy

There is a large amount of research evaluating the potential therapeutic effects of antidepressants, whether through efficacy studies under experimental conditions (including randomized clinical trials) or through studies of "real world" effectiveness. A sufficient response to a drug is often defined as at least a 50% reduction in self-reported or observed symptoms, with a partial response often defined as at least a 25% reduction. The term remission indicates a virtual elimination of depression symptoms, albeit with the risk of a recurrence of symptoms or complete relapse. Full remission or recovery signifies a full sustained return to a "normal" psychological state with full functioning.

There has also been a great deal of study about whether antidepressants address the underlying causes of depression. 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).

Review studies

Recent clinical reviews include:

• A comparison of the relative efficacy of different classes of antidepressants in different settings and in regard to different kinds of depression
• An assessment of antidepressants compared with an "active placebo"
• An assessment of the newer types of the MAOI class
• A meta-analysis of randomized trials of St John's Wort
• A review of the use of antidepressants for childhood depression
• A review of all antidepressant trials submitted to the U.S. Food and Drug Administration (FDA) from 1987 to 2004 has shown that around half of the trials failed to show any benefit over placebo. All but one of the successful trial results were published in scientific journals, while nearly all the unsuccessful trials were either not published or were presented in a misleadingly positive light (compared to the FDA's own evaluation of the data). This arose because whilst studies are required for medical approval, studies showing adverse findings are not necessarily required to be published or (if published) given similar prominence. As a result, while it appeared in the research literature that 94 percent of trials had positive outcomes, in the actual data submitted to the Food and Drug Administration, only 51 percent did. This publication bias inflated the apparent statistical effect of every antidepressant studied, by between 11% and 69%.
• A meta-analysis by UK, US and Canadian researchers, published in 2008, surveyed all pharmaceutical-company-sponsored drug trials on the six most widely prescribed new-generation antidepressants submitted for approval to the FDA between 1987 and 1999. The results showed, consistent with a prior metaanalysis, that the difference in efficacy between antidepressants and placebo was minimal, but that it increased from virtually no difference at moderate levels of initial depression to a relatively small difference for patients with very severe depression. The difference reached conventional criteria for clinical significance for patients at the upper end of the very severely depressed category, due to a reduction in the efficacy of placebo. The study received widespread media coverage in some countries, but was met with criticism from the professional community. Eli Lilly and Company responded by highlighting that the study did not take into account more recent studies on its product, Prozac, and that it was proud of the difference Prozac has made to millions of people. GlaxoSmithKline warned that this one study should not be used to cause unnecessary alarm and concern for patients. Wyeth pointed out that the data were good enough for FDA approval of the drugs. 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 ones are 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" have "a down on antidepressants" and that the media does not appreciate the seriousness of depression and blames and stigmatizes sufferers in a manner rooted in medieval religious attitudes.
• A May 7, 2002 article in The Washington Post titled "Against Depression, a Sugar Pill Is Hard to Beat" stated, "A new analysis has found that in the majority of trials conducted by drug companies in recent decades, sugar pills have done as well as—or better than—antidepressants. Companies have had to conduct numerous trials to get two that show a positive result, which is the Food and Drug Administration's minimum for approval. What's more, the sugar pills, or placebos, cause profound changes in the same areas of the brain affected by the medicines, according to research published last week... the makers of Prozac had to run five trials to obtain two that were positive, and the makers of Paxil and Zoloft had to run even more... When Leuchter compared the brain changes in patients on placebos, he was amazed to find that many of them had changes in the same parts of the brain that are thought to control important facets of mood... Once the trial was over and the patients who had been given placebos were told as much, they quickly deteriorated. People's belief in the power of antidepressants may explain why they do well on placebos..."

Clinical guidelines

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.

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 Behavioural Therapy.

Efficacy limitations and strategies

Between 30% and 50% of individuals treated with a given antidepressant do not show a response. Even where there has been a robust response, significant continuing depression and dysfunction is common, with relapse rates 3 to 6 times higher in such cases. In addition, antidepressant drugs tend to lose efficacy over the course of treatment. A number of strategies are used in clinical practice to try to overcome these limits and variations.

"Trial and error" switching

The American Psychiatric Association 2000 Practice Guideline advises that where no response is achieved following six to eight weeks of treatment with an antidepressant, to switch to an antidepressant in the same class, then to a different class of antidepressant.

A recent 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, with between 5% and 39% ending treatment due to adverse effects. The more antidepressants an individual had already tried, the less likely they were to benefit from a new antidepressant trial.

Augmentation and combination

For a partial response, the American Psychiatric Association guidelines advise adding a different kind of pharmaceutical agent to the antidepressant. Studies suggest that most patients fail to achieve remission on a given antidepressant, and augmentation strategies used in clinical practice include the use of lithium and thyroid augmentation, but there is not a good evidence base for these practices or for more novel strategies such as the use of selective dopamine agonists, sex steroids, NRI's, glucocorticoid-specific agents, or the newer anticonvulsants

A combination strategy involves adding one or more additional antidepressants, usually from different classes so as to have a diverse neurochemical effect. Although this may be used in clinical practice, there is little evidence for the relative efficacy or adverse effects of this strategy.

Long-term use

The therapeutic effects of antidepressants typically do not continue once the course of medication ends, resulting in a high rate of relapse. A recent meta-analysis of 31 placebo-controlled antidepressant trials, mostly limited to studies covering a period of one year, found that 18% of patients who had responded to an antidepressant relapsed while still taking it, compared to 41% whose antidepressant was switched for a placebo. The American Psychiatric Association guidelines advise four to five months of continuation treatment on an antidepressant following the resolution of symptoms. For patients with a history of depressive episodes, the British Association for Psychopharmacology's 2000 Guidelines for Treating Depressive Disorders with Antidepressants advise remaining on an antidepressant for at least six months and as long as five years or indefinitely.

Whether or not someone relapses after stopping an antidepressant does not appear to be related to the duration of prior treatment, however, and gradual loss of therapeutic benefit during the course also occurs. 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.

Medication failure

Approximately 30% of patients have remission of depression with medications. For patients with inadequate response, either adding sustained-release bupropion (initially 200 mg per day then increase by 100 mg up to total of 400 mg per day) or buspirone (up to 60 mg per day) for augmentation as a second drug can cause remission in approximately 30% of patients, while switching medications can achieve remission in about 25% of patients.

By pregnancy

There is uncertainty whether pregnancy contributes to medication failure, because the only report so far has drawn much controversy on itself:

In 2006, a widely reported study published in the Journal of the American Medical Association (JAMA) challenged the common assumption that hormonal changes during pregnancy protected expectant mothers against depression, finding that discontinuing anti-depressive medication during pregnancy led to more frequent relapse. The JAMA article did not disclose that several authors had financial ties to pharmaceutical companies making antidepressants. The JAMA later published a correction noting the ties and the authors maintain that the ties have no bearing on their research work. Obstetrician and perinatologist Adam Urato told the Wall Street Journal that patients and medical professionals need advice free of industry influence.

Withdrawal symptoms

If an SSRI medication is suddenly discontinued, it may produce both somatic and psychological withdrawal symptoms, a phenomenon known as "SSRI discontinuation syndrome" (Tamam & Ozpoyraz, 2002). When the decision is made to stop taking antidepressants it is common practice to "wean" off of them by slowly decreasing the dose over a period of several weeks. Most cases of discontinuation syndrome last between one and four weeks.

The selection of an antidepressant and dosage suitable for a certain case and a certain person is a lengthy and complicated process, requiring the knowledge of a professional. Certain antidepressants can initially make depression worse, can induce anxiety, or can make a patient aggressive, dysphoric or acutely suicidal. In rare cases, an antidepressant can induce a switch from depression to mania or hypomania.

Side effects

Antidepressants often cause adverse effects, and difficulty tolerating these is the most common reason for discontinuing an effective medication.

Side effects of SSRIs include: nausea, diarrhea, agitation, headaches. Sexual side effects are also common with SSRIs, such as loss of sexual drive, failure to reach orgasm and erectile dysfunction. Serotonin syndrome is also a worrying condition associated with the use of SSRIs. The Food and Drug Administration requires Black Box warnings on all SSRIs, which state that they double suicidal rates (from 2 in 1,000 to 4 in 1,000) in children and adolescents. The increased risk for suicidality and suicidal behaviour among adults under 25 approaches that seen in children and adolescents.

Side effects of TCAs (tricyclic antidepressants): Fairly common side effects include dry mouth, blurred vision, drowsiness, dizziness, tremors, sexual problems, skin rash, and weight gain or loss.

Side effects of MAOIs (monoamine oxidase inhibitors): Rare side effects of MAOIs like phenelzine (Nardil) and tranylcypromine (Parnate) include hepatitis, heart attack, stroke, and seizures. Serotonin syndrome is a side effect of MAOIs when combined with certain medications.

General

MAO inhibitors can produce a potentially lethal hypertensive reaction if taken with foods that contain excessively high levels of tyramine, such as mature cheese, cured meats or yeast extracts. Likewise, lethal reactions to both prescription and over the counter medications have occurred. Patients undergoing therapy with MAO inhibiting medications are monitored closely by their prescribing physicians, who are consulted before taking an over the counter or prescribed medication. Such patients must also inform emergency room personnel and keep information with their identification indicating that they are on MAO inhibitors. Some doctors suggest the use of medical identification tags. Although these reactions may be lethal, the total number of deaths due to interactions and dietary concerns is comparable to over-the-counter medications.

Antidepressants are used with care, usually in conjunction with mood stabilisers, in the treatment of bipolar disorder, as they can exacerbate symptoms of mania. They can also trigger mania or hypomania in some patients with bipolar disorder and in a small percentage of patients with depression. SSRIs are the antidepressants most frequently associated with this side effect.

Breast cancer survivors risk having their disease come back if they use certain antidepressants while also taking the cancer prevention drug tamoxifen, according to research released in May 2009.

Anti-depressants are not psychologically addictive in most people, but cause a physical dependency in nearly all patients with sustained use. SNRI drugs tend to cause a greater degree of physical dependency than SSRIs, and thus have a more difficult withdrawal syndrome. However, all anti-depressants, with the possible exception of the NaSSA drugs, cause a physical dependency to form and have a withdrawal syndrome that can be anywhere from mild to severe in intensity given the unique factors of each patient and drug when discontinuing the drug. Anti-depressants need to be tapered slowly when being discontinued to avoid a severe withdrawal; however, discontinuing an anti-depressant quickly if the need is great can be very uncomfortable, but is very unlikely to be harmful to a non-impregnated female, unlike benzodiazepines, which must be tapered slowly under all circumstances for risk of status epilepticus and possible fatality. Harm can come to the foetus by means of spontaneous abortion due to the over-rapid discontinuation of some anti-depressants; however, most anti-depressants are harmful to the foetus, and should not be taken by those who are impregnate or attempting to become impregnated unless the benefit is judged to outweigh the risk. If impregnated, it is necessary to consult with a medical doctor who can counsel one on the best course of action in continuing, tapering, or abruptly discontinuing psychiatric medication. One should never attempt to discontinue psychiatric medication without the knowledge and supervision of a medical practitioner.

Suicide

Patients with depression are at greatest risk for suicide immediately after treatment has begun, as antidepressants can reduce the symptoms of depression such as psychomotor retardation or lack of motivation before mood starts to improve. Although this appears paradoxical, studies indicate that suicidal ideation is a relatively common at the start of antidepressant therapy, and it may be especially common in younger patients such as pre-adolescents and teenagers. Manufacturers and physicians often recommend that other family members and loved ones monitor the young patient's behavior for any signs of suicidal ideation or behaviors, especially in the first eight weeks of therapy.

Until the black box warnings on these drugs were issued by FDA and equivalent agencies in other nations, side effects and alerting families to risk were largely ignored and downplayed by manufacturers and practitioners. This may have resulted in some deaths by suicide although direct proof for such a link is largely anecdotal. The higher incidence of suicide ideation reported in a number of studies has drawn attention and caution in how these drugs are used.

People under the age of 24 who suffer from depression are warned that the use of antidepressants could increase the risk of suicidal thoughts and behaviour. Federal health officials unveiled proposed changes to the labels on antidepressant drugs in December 2006 to warn people of this danger.

The FDA states that Paxil should be avoided in children and teens and that in cases of pediatric cases of depressive disorder the antidepressant drug to be used is Prozac.

On September 6, 2007, the Centers for Disease Control and Prevention reported that the suicide rate in American adolescents, (especially girls, 10 to 24 years old), increased 8% (2003 to 2004), the largest jump in 15 years, to 4,599 suicides in Americans ages 10 to 24 in 2004, from 4,232 in 2003, giving a suicide rate of 7.32 per 100,000 people that age. The rate previously dropped to 6.78 per 100,000 in 2003 from 9.48 per 100,000 in 1990.

Psychiatrists found that the increase is due to the decline in prescriptions of antidepressant drugs like Prozac to young people since 2003, leaving more cases of serious depression untreated. In a December 2006 study, The American Journal of Psychiatry said that a decrease in antidepressant prescriptions to minors of just a few percentage points coincided with a 14 percent increase in suicides in the United States; in the Netherlands, the suicide rate was 50% up after a fall in antidepressant prescriptions.

Critics of this study say that the US "2004 suicide figures were compared simplistically with the previous year, rather than examining the change in trends over several years". The pitfalls of such attempts to infer a trend using just two data points (years 2003 and 2004) are further demonstrated by the fact that, according to the new epidemiological data, the suicide rate in 2005 in children and adolescents actually declined despite the continuing decrease of SSRI prescriptions. "It is risky to draw conclusions from limited ecologic analyses of isolated year-to-year fluctuations in antidepressant prescriptions and suicides.

One promising epidemiological approach involves examining the associations between trends in psychotropic medication use and suicide over time across a large number of small geographic regions. Until the results of more detailed analyses are known, prudence dictates deferring judgment concerning the public health effects of the FDA warnings." Subsequest follow-up studies have supported the hypothesis that antidepressant drugs reduce suicide risk. However, the conclusion that societal suicide rate decreases are due to antidepressant prescription is extraordinarily dubious given the plethora of confounding variables.

Sexual

Sexual dysfunction is a very common side effect, especially with SSRIs. Common sexual side effects include problems with sexual desire, lack of interest in sex, and anorgasmia (trouble achieving orgasm). 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 known as Post SSRI Sexual Dysfunction.

SSRI-induced sexual dysfunction affects 30% to 50% or more of individuals who take these drugs for depression. Biochemical mechanisms suggested as causative include increased serotonin, particularly affecting 5HT2 and 5HT3 receptors; decreased dopamine; decreased norepinephrine; blockade of cholingeric and alpha-1 adrenergic receptors; inhibition of nitric oxide synthetase; and elevation of prolactin levels.

Bupropion, a dual reuptake inhibitor (NE and DA), often causes a moderate increase in sexual drive, due to increased dopamine activity. This effect is also seen with dopamine reuptake inhibitors, CNS stimulants and dopamine agonists, and is due to increases in testosterone production (due to inhibition of prolactin) and nitric oxide synthesis. Mirtazapine (Remeron) is reported to have fewer sexual side effects, most likely because it antagonizes 5-HT2 and 5-HT3 receptors. Mirtazapine can in some cases reverse sexual dysfunction induced by SSRIs, which is also likely due to its antagonisation of 5-HT2 and 5-HT3 receptors

Apomorphine, nefazodone and nitroglycerin have been shown to reverse some sexual dysfunction via increased nitric oxide activity. MAOIs are reported to have fewer negative effects on sexual function and sexual drive, particularly moclobemide at a 1.9% rate of occurrence. Bethanechol has been reported to reverse MAOI-induced sexual dysfunction via its cholinergic agonist properties.

Parnate has been anecdotally shown to make one hypersexual with increased libido and very hard erections.

Love

Dr. Helen Fisher, an anthropologist from Rutgers University, has theorized that based on the proposed actions of certain neurotransmitters, SSRIs may alter the perception of some emotions related to love such as desire and arousal. A psychological study showed a small effect to back up this hypothesis but the study has not been reproduced and no clinical evidence exists to lend support to this theory.

Thymoanesthesia

Closely related to sexual side effects is the phenomenon of emotional blunting, or mood anesthesia. Many users of SSRIs complain of apathy, lack of motivation, emotional numbness, feelings of detachment, and indifference to surroundings. They may describe this as a feeling of "not caring about anything anymore." All SSRIs, SNRIs, and serotonergic TCAs can cause this to varying degrees, especially at high doses.

REM Sleep

All major antidepressant drugs, except trimipramine, 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, monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), profoundly suppress REM sleep. Mirtazapine either has no effect on REM sleep or increases it slightly. The MAOIs almost completely suppress REM sleep, while the TCAs and SSRIs have been shown to produce immediate (40-85%) and sustained (30-50%) reductions in REM sleep. This effect often causes increased fatigue in patients who take large doses of antidepressants for extended periods of time. Such fatigue can occasionally interfere with a patient's everyday activities. Abrupt discontinuation of MAOIs can cause a temporary phenomenon known as "REM rebound" in which the patient experiences extremely vivid dreams and nightmares.

Weight gain

Many antidepressants are associated with weight gain usually in the range of 5–25 kg (11–55 lb) but rarely upwards of 50 kg (110 lb). The specific cause is unknown, but antidepressants are associated with increased cravings, an inability to feel full despite consuming enough calories, low energy levels and increased daytime sleepiness, which can lead to overeating and a lack of desire to exercise, and dry mouth, which can lead to ingestion of calorie-laden beverages. 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. Eating low fat, low protein carbohydrate snacks and carbohydrate-rich dinners allows the brain to make serotonin which then controls appetite and balances mood. Carbohydrates thus eaten, as part of a balanced diet, by virtue of their effect on brain serotonin levels, can support weight loss in the setting of antidepressant weight gain.

Controversy

Several studies have stimulated doubt about the effectiveness of antidepressants. A 2002 study cited that the difference between antidepressants and placebo is close to negligible.

Through a Freedom of Information Act request, two psychologists obtained 47 studies used by the FDA for approval of the six antidepressants prescribed most widely between 1987-99. Overall, antidepressant pills worked 18% better than placebos, a statistically significant difference, "but not meaningful for people in clinical settings", says University of Connecticut psychologist Irving Kirsch. He and co-author Thomas Moore released their findings in "Prevention and Treatment", an e-journal of the American Psychological Association.

Another study by psychologists at the University of Pennsylvania, Vanderbilt University, the University of Colorado, and the University of New Mexico also found that antidepressant drugs hardly have better effects than a placebo in those cases of mild or moderate depression. The study was published in the Journal of the American Medical Association. The study focused on Paxil from GlaxoSmithKline and imipramine.

In 2005, anti-depressants 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 anti-depressants.

Lawsuits

In many cases SSRI drug manufacturers have withheld information from the FDA and the public to play down the risks and adverse effects associated with SSRIs. This had led to litigation against many of the pharmaceutical manufacturers of SSRI anti-depressants in cases covering suicidality, SSRI withdrawal and birth defects in neonates from nursing mothers on SSRIs.

In one of the only three cases to ever go to trial for SSRI indication in suicide, Eli Lilly and Company was caught corrupting the judicial process by making a deal with the plaintiff's attorney to throw the case, in part by not disclosing damaging evidence to the jury. The case, known as the Fentress Case involved a Kentucky man, Joseph Wesbecker, on Prozac, who went to his workplace and opened fire with an assault rifle killing 8 people (including Fentress), and injuring 12 others before turning the gun on himself. The jury returned a 9-to-3 verdict in favor of Lilly. The judge, in the end, took the matter to the Kentucky Supreme Court, which found that "there was a serious lack of candor with the trial court and there may have been deception, bad faith conduct, abuse of judicial process and, perhaps even fraud." The judge later revoked the verdict and instead, recorded the case as settled. The value of the secret settlement deal has never been disclosed, but was reportedly "tremendous".

On December 22, 2006, a US court decided in Hoorman, et al. v. SmithKline Beecham Corp. that individuals who purchased Paxil or Paxil CR (paroxetine) for a minor child may be eligible for benefits under a $63.8 million Proposed Settlement. The lawsuit won the claim that pharmaceutical maker GlaxoSmithKline (GSK) promoted Paxil or Paxil CR for prescription to children and adolescents while withholding and concealing material information about the medication's safety and effectiveness for minors.

The lawsuit stemmed from a consumer advocate protest against Paroxetine manufacturer GSK. Since the FDA approved paroxetine in 1992, approximately 5,000 U.S. citizens – and thousands more worldwide – have sued GSK. Most of these people feel they were not sufficiently warned in advance of the drug's side effects and addictive properties.

According to the Paxil Protest website, hundreds more lawsuits have been filed against GSK. The Paxil Protest website was launched August 8, 2005 to offer both information about the protest and information on Paxil previously unavailable to the public. Just three weeks after its launch, the site received more than a quarter of a million hits.

The original Paxil Protest website is no longer available. It is understood that the action to remove the site from the internet was undertaken as part of a confidentiality agreement or 'gagging order' which the owner of the site entered into as part of a settlement of his action against GlaxoSmithKline. (However, in March 2007, the website Seroxat Secrets discovered that an archive of Paxil Protest site was still available on the internet via Archive.org) Gagging orders are common in such cases and can extend to documents that defendants wish to remain hidden from the public. However, in some cases, such documents can become public at a later date, such as those made public by Peter Breggin in February 2006. A press release from Dr. Breggin can be seen here:

In January 2007, according to the Seroxat Secrets website, the national group litigation in the United Kingdom, on behalf of several hundred people who allege withdrawal reactions after use of the drug Seroxat, against GlaxoSmithKline plc, moved a step closer to the High Court in London, with the confirmation that Public Funding had been reinstated following a decision by the Public Interest Appeal Panel. The issue at the heart of this particular action claims Seroxat is a defective drug in that it has a propensity to cause a withdrawal reaction. Hugh James Solicitors confirm this news on their website

On January 29, 2007, the BBC in the UK aired a fourth documentary in its 'Panorama' series about the controversial drug Seroxat. This programme, entitled Secrets of the Drug Trials, focuses on three GSK paediatric clinical trials on depressed children and adolescents.

See also

• Antidepressants in Japan
• Depression and natural therapies

Additional reading

• Healy, David (1997). The antidepressant era. Cambridge: Harvard University Press. ISBN 0-674-03958-0.
• Kramer, Peter D. (1997). Listening to Prozac. New York: Penguin Books. ISBN 0-14-026671-2.
• Baumel, Syd (1999). Natural Antidepressants. New York: McGraw-Hill. ISBN 0-87983-900-7.
• Stahl, Stephen M. (1997). Psychopharmacology of Antidepressants. Informa Healthcare. ISBN 1-85317-513-7.
• Pacher P, Kecskemeti V (2004). "Trends in the development of new antidepressants. Is there a light at the end of the tunnel?". Curr. Med. Chem. 11 (7): 925–43. doi:10.2174/0929867043455594. PMC 2495050. PMID 15078174. {{cite journal}}: Unknown parameter |month= ignored (help)
• Pacher P, Kohegyi E, Kecskemeti V, Furst S (2001). "Current trends in the development of new antidepressants". Curr. Med. Chem. 8 (2): 89–100. PMID 11172668. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

External links

• Creation of New Neurons Critical to Antidepressant Action in Mice
• Do Antidepressants Cure or Create Abnormal Brain States? - Article by Joanna Moncrieff and David Cohen in PLoS Medicine.
• NIH Expert Panel Report on the reproductive and developmental toxicology of Prozac (Fluoxetine)
• NIH Monograph on the potential human reproductive and developmental effects of Prozac (Fluoxetine)
• American Psychiatric Association 1995 Practice Guideline for the Treatment of Patients with Major Depressive Disorder
• Children and Medication - a multimodal presentation
• British Association for Psychopharmacology 2000 Evidence Based Guidelines for Treating Depressive Disorders with Antidepressants
• The Good Drug Guide: new mood-brighteners and antidepressants
• Video of Loren Mosher, M.D. (first Chief of Schizophrenia Studies at NIMH and founding editor of the Schizophrenia Bulletin)
• Joanna Moncrieff: Evidence base for older antidepressants is shaky too. BMJ 2005;330:420 (19 February)
• Introduction to Let Them Eat Prozac by David Healy
• An information leaflet from the Royal College of Psychiatrists
• Barry Yeoman, Putting Science in the Dock, The Nation
• Bibliography on antidepressants in the history of psychology
• Instant insight outlining how a small change in an antidepressant can dramatically change its target in the brain. From the Royal Society of Chemistry
• Collection of 3100+ news stories with the full media article available, mainly criminal in nature, in which antidepressants are mentioned.
• Antidepressants work instantly - BBC News