Antidepressants

Overview
An antidepressant, is a psychiatric medication or other substance (nutrient or herb) used for alleviating depression or dysthymia ('milder' depression). Drug groups known as MAOIs, tricyclics and SSRIs are particularly associated with the term. These medications are now amongst the drugs most commonly prescribed by psychiatrists and general practitioners, and their effectiveness and adverse effects are the subject of many studies and competing claims. An example of an herbal remedy that is an antidepressant is St John's Wort. Nutrients that are antidepressants include phenylalanine, tyrosine, tryptophan, 5-Hydroxytryptophan, and choline.

Most antidepressants have a delayed onset of action and are usually taken over the course of weeks, months or years. They are generally considered distinct from stimulants, and drugs used for an immediate euphoric effect only are not generally considered antidepressants. Despite the name, antidepressants are often used in the treatment of other conditions, including anxiety disorders, bipolar disorder, obsessive compulsive disorder, eating disorders and chronic pain. Some have also become known as lifestyle drugs or "mood brighteners". Other medications not known as antidepressants, including antipsychotics in low doses and benzodiazepines, are also widely used to manage depression.

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 clinically depressed mood. An inert placebo tends to have a significant antidepressant effect, so establishing something as an antidepressant in a clinical trial involves demonstrating a significant additional effect.

History
Opium and St John's Wort (as a "nerve tonic") had long been used to alleviate depression (amongst many other things), but iproniazid was the first synthetic chemical compound generally accepted as an antidepressant. The chemical from which it was derived, isoniazid was independently recognized as having clinically significant effects on depression, in 1952 by Jean-Francois Buisson in France and Max Lurie in the United States, after it had come into widespread use as a treatment for tuberculosis.

Iproniazid was then observed to have a greater "psychostimulant" effect and to inhibit the enzyme Monoamine Oxidase. Nathan Kline and colleagues conducted the first clinical trial to demonstrate a significant effect of iproniazid on depression in psychiatric patients. Kline approached Roche with what he called a "psychic energizer" and the first Monoamine oxidase inhibitor (MAOI) was introduced as Marsilid. Sales grew massively in the following years, and others of the class were introduced by several drug companies, but adverse effects such as hypertension crisis related to food amines, and acute hepatic necrosis, curtailed their use.

The discovery that a tricyclic ("three ringed") compound had a significant antidepressant effect was also first made in the early 1950s, by Roland Kuhn in a Swiss psychiatric hospital. By that time antihistamine derivatives were coming in to use to treat surgical shock and then as psychiatric neuroleptics. Although, in 1955, reserpine was indicated to be more effective than placebo in alleviating anxious depression, neuroleptics (literally "to seize the neuron") were developing for use as sedatives and antipsychotics.

In attempting to improve the effectiveness of one of them, chlorpromazine, in conjunction with the Geigy pharmaceutical company, Kuhn 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 with mental and motor retardation. He first reported his findings on what he called a "thymoleptic" (literally "taking hold of the emotions", by contrast with neuroleptics, "taking hold of the nerves") in 1955/56 and they gradually became established, resulting in the marketing of the first tricyclic antidepressant, imipramine, soon followed by variants.

These new drug therapies became prescription-only medications 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.

The term antidepressant is reported to have been coined by Lurie and to not have been widely adopted until at least the 1960s. 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 whilst some antidepressant compounds appeared to have differing effects through action on serotonin systems (notably proposed by Carlsson and Lindqvist (1969) and Lapin and Oxenkrug (1969)).

Researchers began a process of rational drug design to isolate antihistamine-derived compounds that would 'selectively' (specifically) target these systems. The first such compound to be patented, in 1971, was zimelidine, whilst the first released clinically was indalpine. Fluoxetine (Prozac), FDA approved for commercial use in 1988, became the first blockbuster SSRI. Fluoxetine was developed at Eli Lilly in the early 1970s by Bryan Molloy, Ray Fuller, 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 had become increasingly popular in Germany where Hypericum extracts eventually became licensed, packaged and prescribed by doctors. Small-scale efficacy trials were carried out from 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

Selective serotonin reuptake inhibitors (SSRIs)
Selective serotonin reuptake inhibitors (SSRIs) are a family of antidepressants considered to be the current standard of drug treatment. It is thought that one 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 by the presynaptic nerve, thus maintaining higher levels of 5-HT in the synapse. Recently, however, 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. Recent research indicates that these drugs may interact with transcription factors known as "clock genes", which may be important for the addictive properties of drugs of abuse, and possibly in obesity.

Recent randomized controlled trials in Archives of General Psychiatry showed that up to one-third of effects of SSRI Treatment can be seen in first week. Early effects also shown to have secondary effect of reducing absolute reduction in HDRS score by 50%. Even more recent studies, published by the Archives of General Psychiatry note that 25% of so-called clinical depression does not meet a disease criteria and should be considered to be ordinary sadness and adjustment to the difficulties in life.

This family of drugs includes fluoxetine (Prozac), paroxetine (Paxil), escitalopram (Lexapro, Esipram), citalopram (Celexa), and sertraline (Zoloft). These antidepressants typically have fewer adverse side 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, SSRI's may not work as often, suggesting the role of norepinephrine.

Serotonin-norepinephrine reuptake inhibitors (SNRIs)
Serotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine (Effexor) and duloxetine (Cymbalta) are a newer form of antidepressant that works on both norepinephrine and 5-HT. They typically have similar side effects to the SSRIs, although there may be a withdrawal syndrome on discontinuation that may necessitate dosage tapering.

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 minimizing serotonin related side-effects by blocking certain serotonin receptors. The only example of this class in clinical use is mirtazapine (Avanza, Zispin, Remeron).

Norepinephrine (noradrenaline) reuptake inhibitors (NRIs)
Norepinephrine (noradrenaline) reuptake inhibitors (NRIs) such as reboxetine (Edronax) act via norepinephrine (also known as noradrenaline). NRIs are thought to have a positive effect on concentration and motivation in particular, though they have been known to increase aggression.

Norepinephrine-dopamine reuptake inhibitors
Norepinephrine-dopamine reuptake inhibitors such as bupropion (Wellbutrin, Zyban) inhibit the neuronal reuptake of dopamine and norepinephrine (noradrenaline).

Tricyclic antidepressants (TCAs)
Tricyclic antidepressants are the oldest and include such medications as amitriptyline and desipramine. 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. Several 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. However, tricyclic antidepressants are still used because of their high potency, especially in severe cases of clinical depression.

Monoamine oxidase inhibitor (MAOIs)
Monoamine oxidase inhibitors (MAOIs) such as phenelzine (Nardil) 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), 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 effect MAO-B which does not require any dietary restrictions.

Augmentor drugs
Some antidepressants have been found to work more effectively in some patients when used in combination with another drug. Such "augmentor" drugs include tryptophan (Tryptan) and buspirone (Buspar).

Tranquillizers and sedatives, typically the benzodiazepines, may be prescribed to ease anxiety and promote sleep. Because of their high potential for fostering dependence, these medications are intended only for short-term or occasional use. Medications often are used not for their primary function but to exploit what are normally side effects. Quetiapine fumarate (Seroquel) is designed primarily to treat schizophrenia and bipolar disorder, but a frequently reported side-effect is somnolence. Therefore, this drug can be used in place of an antianxiety agent such as clonazepam (Klonopin, Rivotril).

Antipsychotics such as risperidone (Risperdal), olanzapine (Zyprexa), and Quetiapine (Seroquel) are prescribed as mood stabilizers and are also effective in treating anxiety. Their use as mood stabilizers is a recent phenomenon and is controversial with some patients. Antipsychotics (typical or atypical) may also be prescribed in an attempt to augment an antidepressant, to make antidepressant blood concentration higher, or to relieve psychotic or paranoid symptoms often accompanying clinical depression. However, they may have serious side effects, particularly at high dosages, which may include blurred vision, muscle spasms, restlessness, tardive dyskinesia, and weight gain.

Antidepressants by their nature behave similarly to psychostimulants. Antianxiety medications by their nature are depressants. Close medical supervision is critical to proper treatment if a patient presents with both illnesses because the medications tend to work against each other.

Psycho-stimulants 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 which are common in atypical depression can be quickly resolved with the addition of low to moderate dosages of amphetamine or methylphenidate (brand names Adderall and Ritalin, respectively) as these chemicals enhance motivation and social behavior, as well as suppress appetite and sleep. These chemicals are also known to 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. They are also easily abused as they are effective substitutes for Methamphetamine when used recreationally. 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, and nausea or 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.

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-Insitutionalised population (2002) now take antidepressants A 1998 survey found that 67% of patients diagnosed with depression were prescribed an antidepressant. A 2007 study purports 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 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 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 unequivocal 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.

Most commonly prescribed antidepressants


The most commonly prescribed antidepressants in the US in 2006 were:
 * Escitalopram - of the SSRI class (e.g. Lexapro, Cipralex)
 * Sertraline - of the SSRI class (e.g. Zoloft, Lustral, Apo-Sertral, Asentra, Gladem, Serlift, Stimuloton)
 * Venlafaxine - of the SNRI class (e.g. Effexor XR, Effexor)
 * Bupropion - of the NDRI classes (e.g. Wellbutrin XR, Zyban)
 * Duloxetine - of the SNRI class (e.g. Cymbalta)
 * Paroxetine - of the SSRI class (e.g. Paxil, Seroxat, Aropax)

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 related to their effects on neurotransmitters. Monoamine oxidase inhibitors (MAOIs) block the break-down of monoamine neurotransmitters (serotonin and norepinephrine) by inhibiting the enzymes which oxidize them, thus leaving higher levels still active in the brain (synaptic cleft).

Tricyclic antidepressants (TCAs) prevent the reuptake of various neurotransmitters, including serotonin, norepinephrine, and dopamine. Selective serotonin reuptake inhibitors (SSRIs) more specifically prevent the reuptake of serotonin (thereby increasing the level of active serotonin in synapses of the brain). Other novel antidepressants specifically affect serotonin and other neurotransmitters.

A theory centered on neurotransmitter effects appears to be incomplete, however. Neurotransmitter levels are altered as soon as the antidepressant chemicals build up in the bloodstream, but effects on mood appear to occur several days or weeks later.

One explanation of this holds that the "down-regulation" of neurotransmitter receptors— an apparent consequence of excess signaling and a process that takes several weeks — is actually the mechanism responsible for the alleviation of depressive symptoms. 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 also affect the expression of genes in brain cells, by influencing "clock genes".

New 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 antidepressants to have the ability of modulating neural plasticity in longterm administration.

Anti-inflammatory and immunomodulation
Recent studies show pro-inflammatory cytokine processes take place during depression, mania and bipolar disease, and is possible that symptoms manifest in these psychiatric illnesses are being attenuated by pharmacological affect 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 dual serotonergic-noradrenergic reuptake inhibition by dual SNRIs (or SSRI-NRI combinations), have also shown analgesic properties additionally.

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.

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

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.

Tolerance and dependence
Most antidepressants, including the SSRIs and tricyclics, are known to produce tolerance (i.e. a patient receiving antidepressant therapy for some years will often have to increase the dose over time, or add other drugs, to receive the same therapeutic effect), and withdrawal (particularly if abrupt) may produce adverse effects, which can range from mild to extremely severe.

Antidepressants do not seem to have all of the same addictive qualities as other substances such as nicotine, caffeine, cocaine, or other stimulants - in other words, while antidepressants may cause dependence and withdrawal they do not seem to cause uncontrollable urges to increase the dose due to euphoria or pleasure, and thus do not meet the strict definition of an addictive substance. However, antidepressants do meet the World Health Organisation definition of "dependency-inducing", and indeed the SSRIs are listed by the organisation as among the most strongly dependency-inducing substances in existence.

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 or months, although often this will reduce the severity of the discontinuation reaction, rather than prevent it. Most cases of discontinuation syndrome last between one and four weeks, though there are examples of patients (especially those who have used the drugs for longer periods of time, or at a higher dose) experiencing adverse effects such as impaired concentration, poor short-term memory, elevated anxiety and sexual dysfunction, for months or even years after discontinuation.

It is generally not a good idea to take antidepressants without a prescription. 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 certain cases, an antidepressant can induce a switch from depression to mania or hypomania, can accelerate and shorten a manic cycle (i.e. promote a rapid-cycling pattern), or can induce the development of psychosis (or just the re-activation of latent psychosis) in a patient with depression who was not psychotic before the antidepressant.

Side effects
Antidepressants can often cause side effects, and an inability to tolerate these is the most common cause of discontinuing an otherwise working medication.

Side effects of SSRIs: Nausea, diarrhea, headaches. Sexual side effects are also common with SSRIs, such as loss of libido, failure to reach orgasm and erectile problems. Serotonin syndrome is also a worrying condition associated with the use of SSRIs. The Food and Drug Administration has included Black Box warnings on all SSRIs stating how they double suicidality (from 2 in 1,000 to 4 in 1,000) in children and adolescents who are prescribed these drugs.

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 (brand name: Nardil) and tranylcypromine (brand name: Parnate) include liver inflammation, heart attack, stroke, and seizures.Serotonin syndrome is a side effect of MAOIs and SSRIs when they are combined.

General
Although recent drugs may have fewer side effects, patients sometimes report severe side effects associated with their discontinuation, particularly with paroxetine and venlafaxine. Additionally, a certain percentage of patients do not respond to antidepressant drugs. Another advantage of some newer antidepressants is they can show effects within as few as five days, whereas most take four to six weeks to show a change in mood. However, some studies show that these medications might be even more likely to result in moderate to severe sexual dysfunction. However, there are medications in trials that appear to show an improved profile in regard to sexual dysfunction and other key side effects.

MAO inhibitors can produce a potentially lethal hypertensive reaction if taken with foods that contain 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. Any patient currently undergoing therapy with an MAO inhibiting medication should be monitored closely by the prescribing physician and always consulted before taking an over the counter or prescribed medication. Such patients should also inform emergency room personnel and information should be kept with one's identification indicating the fact that the holder is on MAO inhibiting medications. Some doctors even suggest the use of a medical alert ID bracelet. Although the reactions in question are dramatic when they happen, the total number of deaths due to interactions and dietary concerns are comparable to over-the-counter medications.

Antidepressants should be used with great care, usually in conjunction with mood stabilisers, in the treatment of bipolar disorder, as they can exacerbate symptoms of mania. They have also been known to 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.

Use of antidepressants should be monitored by a psychiatrist, but in countries such as France, New Zealand, the United Kingdom, and the United States, primary care physicians are able to prescribe antidepressants without consulting a psychiatrist.

In particular, it has been noted that the most dangerous period for suicide in a patient with depression is immediately after treatment has commenced, as antidepressants may reduce the symptoms of depression such as psychomotor retardation or lack of motivation before mood starts to improve. Although this appears to be a paradox, studies indicate the suicidal ideation is a relatively common component of the initial phases of antidepressant therapy, and it may be even more prevalent in younger patients such as pre-adolescents and teenagers. It is strongly recommended that other family members and loved ones monitor the young patient's behavior, especially in the first eight weeks of therapy, for any signs of suicidal ideation or behaviors.

Until the black box warnings on these drugs were issued by FDA as well as by 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 the inherent danger.

Sexual
Sexual dysfunction is a very common side effect, especially with SSRIs. Common sexual side effects include problems with libido (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 disorder is known as Post SSRI Sexual Dysfunction.

Bupropion, a dual reuptake inhibitor (NE and DA), in many cases results in a moderately increased libido, 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 increased nitric oxide synthesis. 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 libido, particularly moclobemide at a 1.9% rate of occurrence. Betanechol has been reported to reverse MAOI-induced sexual dysfunction via its cholinergic agonist properties (Gross 1982).

In order for the physician to select the appropriate response, the patient should provide the physician with information to distinguish between reduced libido (little or no desire for sex), reduced sexual function (impotence, vaginal dryness) and anorgasmia, as these have separate causes and prompt different treatment.

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 any more." All SSRIs, SNRIs, and serotonergic TCAs are liable to cause this effect to varying degrees, especially at higher dosages.

REM Sleep
It is well recognized that virtually all major antidepressant drugs but trimipramine suppress REM sleep and it has, in fact, 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. The MAOIs virtually completely abolish REM sleep, while the TCAs and SSRIs have been shown to produce immediate (40-85%) and sustained (30-50%) reductions in REM sleep. 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 in all categories are associated with weight gain usually in the range of 10-50 pounds but not uncommonly upwards of 100 pounds. The specific cause is unknown, but it is known that antidepressants are associated with increased cravings (usually for high fat carbohydrates), an inability to feel full despite ingestion of adequate 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. 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, thus 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.

The paper in question has been severely criticized by independent researchers, however. One reason for this is that it deals almost exclusively with the SSRI class of medication. In leveling criticism against the efficacy of SSRIs, critics state, it is not the best paper, merely the most widely known one. Also, other classes of antidepressants have demonstrated superior efficacy, and it has been argued that this paper is "throwing the baby out with the bathwater", while its thrust should in fact be leveled at the serotonin hypothesis of depression.

Furthermore, not all patients necessarily respond to a given medication, studies do not always address dosage versus drug-placebo differences for those who do. Data submitted to the FDA can also underestimate how a drug will perform in clinic practice, as studies sometimes are designed as much for marketing purposes as they are to estimate the magnitude of a medication's effects.

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.

More than half of the 47 studies found that patients on antidepressants improved no more than those on placebos, Kirsch says. "They should have told the American public about this. The drugs have been touted as much more effective than they are." He says studies finding no benefit have been mentioned only on labeling for Celexa, the most recently approved drug. The others included in his evaluation: Prozac, Paxil, Zoloft, Effexor and Serzone.

Dr Joseph Glenmullen, a Harvard psychiatrist, has written a book on the subject for the layperson; see link below.

In 2007, 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. 

Non-mainstream treatments
There are numerous alternative treatments for depression, whether medications or other kinds of intervention.

Opiates
Various Opiates were commonly used as antidepressants until the mid-1950s, when they fell out of favor with medical orthodoxy due to their addictive nature, tolerance buildup issues and their side-effect profile. Today the use of opioids in treating depression is a large taboo in the medical field due to associations with drug abuse; hence, research has proceeded at a very slow rate. A small clinical trial conducted at Harvard Medical School in 1995, demonstrated that a majority of treatment-refractory, unipolar, non-psychotic, major depression patients could be successfully treated with an opioid medication called Buprenorphine, which is a partial mu agonist and potent kappa antagonist. The exact mechanism of its action in depression is not known, as kappa (κ) antagonists are antidepressants in their own right.

In 2006, The Journal of European Neuropsychopharmacology published a follow-up study to the 1995 Harvard experiment, with results very consistent with the original Harvard findings. Eleven severely depressed patients, refractory to all the conventional depression treatments, were given small doses of buprenorphine. Most of these patients found the buprenorphine to be of significant benefit in relieving their inner torment. The researchers theorized that "Possibly, the response to opiates describes a special subtype of depressive disorders e.g corresponding to a dysregulation of the endogenous opioid system and not of the monaminergic system." 

Yet another relevant scientific paper was published in the American Journal of Psychiatry in 1999, detailing how researchers found Oxycodone/Oxymorphone to help 5 out of 6 'incurable' refractory severe depression patients. 

While opioids have been proven to substantially relieve symptoms of depression for a large class of patients, re-acceptance of this fact has been severely hampered by governmental narcotic prohibition efforts, and the (until buprenorphine) lack of alternatives with low risk of tolerance and addiction. Buprenorphine is generally preferred as the first-line opiate in depression treatment, as managing the tolerance buildup of other opiates can be complicated.

Other treatments

 * Gamma-Hydroxybutyric acid (GHB) has been used by some as an antidepressant. Claude Rifat, a French biologist, conducted some early research into GHB's antidepressant potential. Rifat noted that GHB did not cause the emotional blunting effects caused by conventional antidepressants, but instead intensified pleasurable and rewarding feelings in the user while powerfully suppressing depression. However, GHB has now been outlawed, except for use as a prescription treatment for narcolepsy.
 * Clinical trials have shown the effect of acupuncture to be comparable with amitriptyline; in addition, specifically Electroacupuncture has been found to be more effective in depressive patients with decreased excretion of 3-methyl-4-hydroxy-phenylglycol (the principal metabolite of the central neurotransmitter norepinephrine), while amitriptyline is more effective for those with inhibition in the dexamethasone suppression test. Acupuncture has also been proven to prompt the body to produce greater levels of endorphins.
 * Most studies conclude that St. John's wort is usually as effective against depressions as other modern medication, again with fewer side effects, and it is widely prescribed for depression in Europe. A recent study showed St. John's wort to be no more effective than a placebo in cases of severe depression, although an SSRI was also no more effective on the primary outcome measure.
 * The amino acid derivative SAM-e has been studied in recent years
 * Tryptophan dietary supplements, although banned in many countries due to impurities that caused a blood disease, have also been used as natural antidepressants. Dietary supplements of 5-HTP, a chemical the body forms from tryptophan and uses to make serotonin, have shown some promising research results but need further study.
 * NMDA antagonists such as ketamine and dextromethorphan have recently gained some interest in this field as their apparent ability to reverse opioid tolerance, and can give fast-acting dramatic effects. However, their acute psychoactive effects have been a problem.
 * Memantine, a moderate affinity NMDA antagonist, has been used to avoid tolerance buildup, and has seen use in opioid tolerance reversal. Proglumide is used to induce acute reversal of tolerance prior to this maintenance strategy; it does not work by itself in the long term, due to tolerance to its effects.
 * Opiorphin is a very recently discovered substance that increases the effectiveness of endorphins, meaning that it has effects similar to opioid agonists without the addiction and withdrawal effects. While it has been shown to be extremely effective for analgesia, any ability to treat depression or the presence of an abuse potential are largely informed guesswork at this stage.

Classes and members
The following clickable info-box is from the Anatomical Therapeutic Chemical Classification System published by the World Health Organization. See also Wikipedia's list of antidepressants.

Additional reading

 * David Healy, The Antidepressant Era, Paperback Reprint Edition, Harvard University Press (1999) ISBN 0674039580
 * Peter D. Kramer, Listening to Prozac: The Landmark Book about Anti-Depressants and the Remaking of the Self, Paperback Revised Edition, Penguin (1997) ISBN 0140266712
 * Syd Baumel, Natural Antidepressants, Paperback 1st edition, McGraw-Hill (1999) ISBN 0879839007
 * Stephen M. Stahl, Psychopharmacology of Antidepressants, Paperback 1st Edition, Taylor & Francis (1997) ISBN 1853175137
 * Pacher P, Kecskemeti V. Trends in the development of new antidepressants. Is there a light at the end of the tunnel? Curr Med Chem. 2004 Apr;11(7):925-43. PMID 15078174
 * Pacher P, Kohegyi E, Kecskemeti V, Furst S. Current trends in the development of new antidepressants.Curr Med Chem. 2001 Feb;8(2):89-100. PMID 11172668

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