Antidepressant

The opposite is depressogenic, not depressant.

Fluoxetine (Prozac), an SSRI

The chemical structure of venlafaxine (Effexor), an SNRI

Antidepressants are drugs for the treatment of depression. Despite their name, they are often used to treat a wide range of other conditions, on- or off-label, for conditions such as anxiety disorders, obsessive compulsive disorder, eating disorders, chronic pain, neuropathic pain, and some hormone-mediated disorders such as dysmenorrhea, and for snoring, migraines, attention-deficit hyperactivity disorder (ADHD), substance abuse, and occasionally even insomnia or other sleep disorders. Antidepressants can be used both alone or combination with other medications. Most antidepressants have a delayed onset of action (2–6 weeks) but for those who respond well to a given drug, some degree of efficacy is often seen after one week.

Many off-label or recreational drugs can produce an antidepressant effect, but their use is controversial. Opioids were used to treat major depression until the late 1950s. Amphetamines were used until the mid-1960s.^{[citation needed]} Scant research on the use of opioids limit their use for the treatment of depression, 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 antidepressants. In a small study published in 1995, the opioid buprenorphine was shown to have potential for treating severe, treatment-resistant depression. The nutritional supplement tryptophan is also used in treating some forms of seasonal depression or in combination with use of bright light exposure.

Low dose antipsychotics are also sometimes used, and St John's wort. Benzodiazepines can improve the short-term response of antidepressants when used together, but also carry a risk of physical dependence with reduced effect over time as well as withdrawal symptoms. Antipsychotics can have severe long term negative effects, such as tardive dyskinesia, brain atrophy, and metabolic syndrome Inert placebos can also have significant antidepressant effects.

Non pharmaceutical approaches to the treatment of depression include psychotherapy, cognitive-behavioural therapy, electro-convulsive therapy, acupuncture, exercise, sleep deprivation, or bright light exposure.

History

St John's wort

Before the 1950s, opioids and amphetamines were commonly used as antidepressants. Their use was later restricted due to their addictive nature and side-effects. Extracts from the herb St John's wort had been used as a "nerve tonic" to alleviate depression.

Isoniazid, iproniazid, and imipramine

In 1951, Irving Selikoff and Edward Robitzek, working out of Sea View Hospital on Staten Island, began clinical trials on two new anti-tuberculosis agents developed by Hoffman-LaRoche, isoniazid and iproniazid. Only patients with a poor prognosis were initially treated; nevertheless, their condition improved dramatically. Selikoff and Robitzek noted "a subtle general stimulation... the patients exhibited renewed vigor and indeed this occasionally served to introduce disciplinary problems." The promise of a cure for tuberculosis in the Sea View Hospital trials was excitedly discussed in the mainstream press.

In 1952, learning of the stimulating side-effects of isoniazid, the Cincinnati psychiatrist Max Lurie tried it on his patients. In the following year, he and Harry Salzer reported that isoniazid improved depression in two thirds of their patients and coined the term antidepressant to describe its action. A similar incident took place in Paris, where Jean Delay, head of psychiatry at Sainte-Anne Hospital, heard of this effect from his pulmonology colleagues at Cochin Hospital. In 1952, before Lurie and Salzer, Delay, with the resident Jean-Francois Buisson, reported the positive effect of isoniazid on depressed patients. For reasons unrelated to its efficacy, isoniazid as an antidepressant was soon overshadowed by the more toxic iproniazid, although it remains a mainstay of tuberculosis treatment. The mode of antidepressant action of isoniazid is still unclear. It is speculated that its effect is due to the inhibition of diamine oxidase, coupled with a weak inhibition of monoamine oxidase A.

Selikoff and Robitzek also experimented with another anti-tuberculosis, iproniazid; it showed a greater psychostimulant effect, but more pronounced toxicity. Later, Jackson Smith, Gordon Kamman, George Crane, and Frank Ayd, described the psychiatric applications of iproniazid. Ernst Zeller found iproniazid to be a potent monoamine oxidase inhibitor. Nevertheless, iproniazid remained relatively obscure until Nathan Kline, the influential and flamboyant head of research at Rockland State Hospital, began to popularize it in the medical and popular press as a "psychic energizer". Roche put a significant marketing effort behind iproniazid, including promoting its off-label use for depression. Its sales grew until it was recalled in 1961, due to reports of lethal hepatotoxicity.

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

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

Second generation antidepressants

Antidepressants became prescription drugs in the 1950s. It was estimated that no more than 50 to 100 individuals per million suffered from the kind of depression that these new drugs would treat, and pharmaceutical companies were not enthusiastic in marketing for this small market. Sales through the 1960s remained poor compared to the sales of tranquilizers, which were being marketed for different uses. Imipramine remained in common use and numerous successors were introduced. The use of monoamine oxidase inhibitors (MAOI) increased after the development and introduction of "reversible" forms affecting only the MAO-A subtype of inhibitors, making this drug safer to use.

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

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

St John's wort fell out of favor in most countries through the 19th and 20th centuries, except in Germany, where Hypericum extracts were eventually licensed, packaged and prescribed. Small-scale efficacy trials were carried out in the 1970s and 1980s, and attention grew in the 1990s following a meta-analysis. It remains an over-the-counter drug (OTC) supplement in most countries. Research continues to investigate its active component hyperforin and to elucidate its mode of action.

Classes of antidepressants

For a more complete list of antidepressants, see

Main article: List of antidepressants

Selective serotonin reuptake inhibitors

Selective serotonin reuptake inhibitors, SSRIs are thought to prevent the reuptake of serotonin (also known as 5-hydroxytryptamine, or 5-HT) by the presynaptic neuron, thus initially maintaining higher levels of 5-HT in the synapse. Like all anti-depressants their mechanism of action remains unknown.

SSRI antidepressants includes:

• Citalopram (Celexa)
• Escitalopram (Lexapro, Cipralex)
• Paroxetine (Paxil, Seroxat)
• Fluoxetine (Prozac)
• Fluvoxamine (Luvox)
• Sertraline (Zoloft, Lustral)

Norepinephrine reuptake inhibitors

Selective norepinephrine reuptake inhibitors (NRIs) inhibit the reuptake of norepinephrine. The NRIs include:

• Atomoxetine (Strattera)
• Reboxetine (Edronax)
• Viloxazine (Vivalan)

Noradrenergic and specific serotonergic antidepressants (NaSSA)

Noradrenergic and specific serotonergic antidepressants NaSSA inhibit reuptake of serotonin, and noradrenaline at the presynaptic alpha-2 adrenergic receptors. Examples include:

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

Serotonin–norepinephrine reuptake inhibitors

Serotonin–norepinephrine reuptake inhibitors (SNRIs) inhibit reuptake of serotonin and norepinephrine. These include:

• Desvenlafaxine (Pristiq)
• Duloxetine (Cymbalta)
• Milnacipran (Ixel, Savella)
• Venlafaxine (Effexor)

Serotonin antagonist and reuptake inhibitors

The Serotonin antagonist and reuptake inhibitors (SARIs) include:

• Etoperidone (Axiomin, Etonin)
• Nefazodone (Serzone, Nefadar)
• Trazodone (Desyrel)

Norepinephrine-dopamine reuptake inhibitors

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

• Bupropion (Wellbutrin, Zyban)

Selective serotonin reuptake enhancers

• Tianeptine (Stablon, Coaxil, Tatinol)
• Amineptine

Norepinephrine-dopamine disinhibitors

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

Tricyclic antidepressants block the reuptake of norepinephrine and serotonin.

The tricyclics 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

Irreversible monoamine oxidase inhibitors (MAOIs) inhibit the enzyme monoamine oxidase, which breaks down the neurotransmitters dopamine, serotonin, and norepinephrine. As 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 any more. 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.

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

Nicotine

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

Caffeine

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

Adjunct medication

Other medications are used to "augment" the effect of antidepressants with mixed results. Some of the drugs used include

Psychostimulants such as

• amphetamine (Adderall)
• methylphenidate (Ritalin)
• modafinil (Provigil, Alertec)

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. 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. A review article published in 2007 found psychostimulants "may" be effective in treatment-resistant depression with concomitant antidepressant therapy. A more certain conclusion could not be drawn due to substantial deficiencies in the studies available for consideration, and the "somewhat" contradictory nature of their results. However, the authors claim psychostimulants are likely to have a higher level of clinical effectiveness under circumstances in which the patient will probably die soon, so rapid relief is of great importance. In this situation, the patient is likely to die before dependence on, or tolerance of, the medication interferes with their care.

• nicotine

Chronic nicotine intake via nicotine patches results in an increased response to standard antidepressants. Similarly varenicline has been shown to augment subtherapeutic dose levels of SSRIs to produce an antidepressant effect.

• lithium

Lithium remains the standard treatment for bipolar disorder and is often used in conjunction with other medications. Lithium's potential side effects include thirst, tremors, light-headedness, nausea, diarrhea. Long term use is associated with kidney failure.

Anticonvulsants are also used, particularly in bipolar disorder. They include:

• carbamazepine (Tegretol)
• sodium valproate (Epilim, Depakote)
• lamotrigine (Lamictal)
• clonazepam(Klonopin)
• oxcarbazepine(Trileptal)

Benzodiazepines also play a prominent role in the treatment of bipolar disorder. The are used to counteract the often nervous or "jittery" effects of psychostimulant medications can produce. For example a common side effect of Prozac is insomnia thus a tranquilizer such as Valium maybe prescribe to offset this effect. Additionally, benzodiazepines have been proven to augment and compliment the effects of antidepressants giving the patient the optimum results of the drug. Due to their potential for dependency however most patients over the course of their treatment take benzodiazepines on an "as needed" (PRN) basis.

The most commonly used benzodiazepines are:

• diazepam(Valium)
• clonazepam(Klonopin)
• lorazepam(Ativan)
• alprazolam(Xanax)
• temazepam(Restoril)

Alternative therapies

Herbalism

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.^{[citation needed]}

In a small (30-patient), double-blind, randomized clinical trial, saffron (Crocus sativus L.) was to be equally effective with imipramine for treating mild to moderate depression. However, no other researchers have confirmed these results, nor has a larger population study been published. Another small (40-patient), eight-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. Neither study has been confirmed in larger trials at other centers.

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.

Nutrition

Poor nutrition has been proposed as a risk factor for developing depression. In a study of older adults, poor nutrition was a strong predictor of depressive symptoms.

Omega 3 fatty acids have been proposed as a treatment for depression, alone or in combination with other treatments. One small pilot study of childhood depression (ages six to 12) suggested omega 3 fatty acids may have therapeutic benefits for treating childhood depression. A 2005 review article included double-blind studies, randomized control trials, epidemiological studies linking omega 3 fatty acids consumption and depression found that low fish consumption (the primary source of omega 3 fatty acids) correlated to increased rates of depression, and case-control and cohort studies of unipolar and postpartum depression indicating low blood levels of omega-3 fatty acids in depressed patients.

A 2008 review of clinical studies of the effectiveness of omega-3 fatty acids on depression has shown somewhat inconsistent results: "Of the evaluated studies, 13 showed a significant positive association between omega-3 and depression, while six studies did not show a relationship between the referred variables." To be read with caution because of limited data, a 2008 Cochrane systematic review found in the one eligible study that omega 3 fatty acids are an effective adjunctive therapy for depressed but not manic symptoms in bipolar disorder. The authors found an "acute need" for more randomised, controlled trials.

Mechanisms of Action

For depression, the mechanism of action of antidepressants is unknown.

Neurogenic Adaptations

The neurogenic hypothesis states that molecular and cellular mechanisms underlying the regulation of adult neurogenesis is required for remission from depression and that neurogenesis is mediated by the action of antidepressants. Chronic use of antidepressant increased neurogenesis in the hippocampus of rats. Other animal research suggests that long term drug-induced antidepressants effects modulate the expression of genes mediated by clock genes, possibly by regulating the expression of a second set of genes (i.e. clock-controlled genes).

The 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).

Hypothalamic-Pituitary-Adrenal Axis

One manifestation of depression is an altered hypothalamic-pituitary-adrenal axis (HPA axis) that resembles the neuro-endocrine (cortisol) response to stress, that of increased cortisol production and a subsequent impaired negative feedback mechanism. It is not know whether this HPA axis disregulation is reactive or causative for depression. This briefing suggest that the mode of action of antidepressants may be in regulating HPA axis function.

Monomine Hypothesis

In 1965, Joseph Schildkraut postulated the Monoamine Hypothesis when he posited an association between low levels of neurotransmitters and depression. By 1985, the monoamine hypothesis was mostly dismissed until it was revived with the introduction of SSRIs through the successful direct-to-consumer advertising, often revolving around the claim that SSRIs correct a chemical imbalance caused by a lack of serotonin within the brain.

To date, there is no evidence to support serotonin dysfunction in the pathophysiology of this disorder.

Serotonin levels in human brain is measured indirectly by sampling cerebrospinal fluid for its main metabolite, 5-hydroxyindole-acetic acid, or by measuring the serotonin precursor, tryptophan. In one placebo controlled study funded by the National Institute of Health, tryptophan depletion was achieved, but they did not observe the anticipated depressive response. Similar studies aimed at increasing serotonin levels did not relieve symptoms of depression. At this time, decreased serotonin level in the brain and symptoms of depression have not been linked

Although there is evidence that antidepressants inhibit the reuptake of serotonin, norepinephrine, and to a lesser extent dopamine, the significance of this phenomenon in the amelioration of psychiatric symptoms is not known. Given the low overall response rates of antidepressants, and the poorly understood causes of depression, it is premature to assume a putative mechanism of action of antidepressants.

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.^{[citation needed]}

Antidepressant Receptor Affinity

A number of antidepressants have been compared below:

Compound	SERT	NET	DAT	H1	M1-5	α1	α2	5-HT1A	5-HT2C	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	1.38	5100	28000	380	1800	1550	?	?	?	?
Clomipramine	0.28	<1	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	1.55	11.2	240	2300	3000	8300	?	?	?	?
Escitalopram	1.1	7840	10000	1970	1240	3870	?	?	?	?
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	2.22	1300	9100	10000	240000	7700	?	?	?	?
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	58.5	7.14	11500	312	6700	11900	?	?	?	?
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 smaller dissociation constant indicates more efficacy. 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. Note that desmethylclomipramine, a metabolite of clomipramine, has a comparably high affinity for the NET as clomipramine has for the SERT.^{[citation needed]}

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

To establish efficacy, an antidepressant must show that it can produce a therapeutic effect for the condition for which it is taken. An antidepressant should be more efficacious than placebo to justify the risk associated with side effects. For depression, the Hamilton Depression Rating Scale (HAM-D) is often used to measure the severity of depression. The maximum score for the 17-item HAM-D questionnaire is 52; the higher the score, the more severe the depression. What constitute a sufficient response to a drug has not been well established, but total remission or virtual elimination of all depression symptoms is the goal, however, remission rates are rarely published. For placebo, the percentage of symptom reduction is approximately 31 to 38%, compared to 46 to 54% for antidepressants.

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

The largest and most expensive study conducted to date, on the effectiveness of pharmacological treatment for depression, was commissioned by the National Institute of Mental Health. The study was dubbed "The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study. The results are summarized here.

• After the first course of treatment, 27.5% of the 2,876 participants reached remission with a HAM-D score of 7 or less. 21% dropped out.
• After the second course of treatment, 21 to 30% of the remaining 1,439 participants remitted. Only 310 participants were willing or available to continue the study., Switching medications can achieve remission in about 25% of patients.
• After the third course of treatment, 17.8% of the remaining 310 participants remitted.
• After the fourth and last course of treatment, 10.1% of the remaining 109 participants remitted.
• After a one year follow-up, of the 1085 remitted participants, 93% participants had either relapsed or dropped out of the study.

There were no statistical or meaningful clinical differences in remission rates, response rates, or times to remission or response among any of the medications compared in this study. These included bupropion sustained release, bupropion, citalopram, lithium, mirtazapine, nortriptyline, sertraline, triiodothyronine, tranylcypromine, venlafaxine extended release.^{[citation needed]}

A 2008 review of randomized controlled trials concluded that symptomatic improvement with SSRIs was greatest by the end of the first week of use, but that some improvement continued for at least 6 weeks.

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

Some clinical reviews include:

• (2007) A review of the use of antidepressants for childhood depression
• (2004) An assessment of antidepressants compared with an "active placebo"
• (2001) A comparison of the relative efficacy of different classes of antidepressants in different settings and in regard to different kinds of depression
• (1999) An assessment of the newer types of the MAOI class

Clinical guidelines

The UK National Institute for Clinical Excellence (NICE) 2004 guidelines indicate that antidepressants should not be used for the initial treatment of mild depression, because the risk-benefit ratio is poor; that for moderate or severe depression an SSRI is more likely to be tolerated than a tricyclic; and that antidepressants for severe depression should be combined with a psychological treatment such as Cognitive Behavioural Therapy.

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

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. They include switching medication, augmentation, and combination.

"Trial and error" switching

The American Psychiatric Association 2000 Practice Guideline advises that where no response is achieved following six to eight weeks of treatment with an antidepressant, to switch to an antidepressant in the same class, then to a different class of antidepressant. The remission rate reported by the STAR*D study was 21% using this method.^{[citation needed]}

A 2006 meta-analysis review found wide variation in the findings of prior studies; for patients who had failed to respond to an SSRI antidepressant, between 12% and 86% showed a response to a new drug. However, the more antidepressants an individual had already tried, the less likely they were to benefit from a new antidepressant trial. However, a later meta-analysis found no difference between switching to a new drug and staying on the old medication; although 34% of treatment resistant patients responded when switched to the new drug, 40% responded without being switched. Thus, the clinical response to the new drug might be a placebo effect associated with the belief that one is receiving a different medication.^{[citation needed]}

Augmentation and combination

For a partial response, the American Psychiatric Association guidelines suggest augmentation, or adding a drug from a different class. These include: lithium and thyroid augmentation, dopamine agonists, sex steroids, NRI's, glucocorticoid-specific agents, or the newer anticonvulsants The STAR*D project reported a remission rate of 30% with this method.^{[citation needed]}

A combination strategy involves adding an additional antidepressant, usually from different class so as to have effect other mechanisms. Although this may be used in clinical practice, there is little evidence for the relative efficacy or adverse effects of this strategy. The STAR*D project reported similar remission rates as with augmentation strategy.^{[citation needed]}

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

Long-term use

The therapeutic effects of antidepressants typically do not continue once the course of medication ends, resulting in a high rate of relapse. A recent meta-analysis of 31 placebo-controlled antidepressant trials, mostly limited to studies covering a period of one year, found that 18% of patients who had responded to an antidepressant relapsed while still taking it, compared to 41% whose antidepressant was switched for a placebo. 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.^{[citation needed]}

In a five-year follow up, relapse rates was 23% greater for users greater than one year, but not different for 6 or 12 months users. In addition, gradual loss of therapeutic benefit occurs during the course of treatment. A strategy involving the use of pharmacotherapy in the treatment of the acute episode, followed by psychotherapy in its residual phase, has been suggested by some studies.

Antidepressant-induced Mania

Another possible problem with antidepressants is the chance of antidepressant-induced mania in patients with bipolar depression or manic depression. Many cases of bipolar depression are very similar to those of unipolar depression. Therefore, the patient can be misdiagnosed with unipolar depression and be given antidepressants. Studies have shown that antidepressant-induced mania can occur in 20-40% of bipolar patients.

Controversy

• Ghost writing of studies for industry-sponsored drug trials is common. Of all 44 trial which was approved between 1994 and 1995 by the ethics committees of Copenhagen and Frederiksberg in Denmark, up to 91%, that is 40 of the 44 trials, has some form of ghostwriting, and for the most part, the ghost was a statistician. Cases relating to gabapentin, paroxetine, sertraline, fenfluramine/phentermine (fen-phen) are well documented, while many others, relating to olanzapine, quetiapine,remain under seal by the courts.^{[citation needed]}
• Publication bias. Trials for which results were unfavourable were less likely to be published. Published data suggest a favourable risk-benefit profile for some SSRIs; however, addition of unpublished data indicates that risks could outweigh benefits of these drug to treat depression in children and young people. Of 90 drugs approved by the FDA between 1998 and 2000,the trials which did not show statistically significant results were 34% less likely to have been published, on the other hand, positive results are often published more than once. Based on Healy's examination of the data produced from the Cochrane study of Olanzapine for schizophrenia, the four initial trials of Zyprexa gave rise to 234 publications, most of which were ghost written.
• Lack of access to raw data, data suppression, misrepresentation, and manipulation has eroded value of trial results. Demands on access to data has been met by resistance on the part of industry.
• A meta-analysis by UK, US and Canadian researchers was published in 2008, surveying all pharmaceutical-company-sponsored drug trials on the six most widely prescribed new-generation antidepressants submitted for approval to the FDA between 1987 and 1999. The results showed that the difference in efficacy between antidepressants and placebo was minimal, but that it increased from virtually no difference at moderate levels of initial depression to a relatively small difference for patients with very severe depression. The difference reached conventional criteria for clinical significance for patients at the upper end of the very severely depressed category, due to a reduction in the efficacy of placebo. The study received widespread media coverage in some countries, but was met with criticism from the professional community.

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

Controversy Regarding Placebo Effects and Efficacy in Mild Depression

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

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

A study published in JAMA demonstrated that the magnitude of the placebo effect in clinical trials of depression have been growing over time, while the effect size of tested drugs has remained relatively constant. The authors suggest that one possible explanation for the growing placebo effect in clinical trials is the inclusion of larger number of participants with shorter term, mild, or spontaneously remitting depression as a result of decreasing stigma associated with antidepressant use.

An 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..."

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 psychologist Irving Kirsch, lead author of the study. He and co-author Thomas Moore released their findings in "Prevention and Treatment", an e-journal of the American Psychological Association. In a later publication, Kirsch concluded that the overall effect of new-generation antidepressant medication is below recommended criteria for clinical significance.

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 paroxetine (Paxil) from GlaxoSmithKline and imipramine.

The Cochrane Collaboration recently performed a systematic review of clinical trials of the generic antidepressant amitriptyline. The study concluded that in spite of moderate evidence for publication bias, there is strong evidence that the efficacy of amitriptyline is superior to placebo.

A review commissioned by the National Institute for Clinical excellence concluded that there there is strong evidence that SSRIs have greater efficacy than placebo on achieving a 50% reduction in depression scores in moderate and severe major depression, and that there is some evidence for a similar effect in mild depression. The treatment guidelines developed in conjunction with this review suggest that antidepressants should be considered in patients with moderate to severe depression and those with mild depression that is persistent or resistant to other treatment modalities.

In 2005, 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.

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

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

Adverse effects

Difficulty tolerating adverse effects is the most common reason for antidepressant discontinuation.^{[citation needed]} Over 1500 side effects have been cataloged for the SSRI alone.

General

SSRI side effects include but are not limited to: Serotonin syndrome, nausea, diarrhea, increased blood pressure, agitation, headaches, anxiety, nervousness, emotional lability, increased suicidal ideation, suicide attempts, insomnia, drug interactions, neonate adverse reactions, anorexia, dry mouth, somnolence, tremors, sexual dysfunction decreased libido, asthenia, dyspepsia, dizziness, sweating, personality disorder, epistaxis, urinary frequency, menorrhagia, mania/hypomania, chills, palpitations, taste perversion, and micturition disorder drowsiness, GI irregularities,muscle weakness, long term weight gain.^{[citation needed]}

SSRIs inhibit serotonin-mediated platelet activation. This leads to increased risk of gastrointestinal bleeding; at times as high as 57% increase in risk. This is especially important in the elderly, those with a history of peptic ulcer disease or previous gastrointestinal bleeding, and those on blood thinners, such as aspirin and clopidogrel. A recent observational study shows that SSRIs may increase the risk of transient ischemic attacks and strokes compared with tricyclic antidepressants.

Side-effects of an Noradrenergic and specific serotonergic antidepressant may include drowsiness, increased appetite, and weight gain.

Tricyclic antidepressants common side effects include: dry mouth, blurred vision, drowsiness, dizziness, tremors, sexual problems, skin rash, and weight gain or loss.^{[citation needed]} Toxicity occurs at about 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, their favorable price, and off label uses.^{[citation needed]}

MAOIs (monoamine oxidase inhibitors) side effects include:^{[citation needed]} MAOI 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 MAOI. 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.^{[citation needed]}

Other side effects of MAOI include: hepatitis, heart attack, stroke, and seizures. Serotonin syndrome is a side-effect of MAOIs when combined with certain medications. Moclobemide may be preferred in the elderly as its pharmacokinetics are not affected by age, is well tolerated by the elderly as well as younger adults, has few serious adverse events, and, in addition, it is as effective as other antidepressants that have more side-effects; moclobemide also has beneficial effects on cognition. A new generation of MAOIs has been introduced; moclobemide (Manerix), known as a reversible inhibitor of monoamine oxidase A (RIMA), which is as effective as SSRIs and tricyclic antidepressants, in depressive disorders, acts in a more short-lived and selective manner and does not require a special diet.

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.

For bipolar depression, anti-depressant, most frequently SSRIs, can exacerbate or trigger symptoms of hypomania and mania.

Pregnancy

Pregnancy can trigger a range of emotions that make it more difficult to cope with depression. The risk of medication discontinuation and relapse have to be weighed against the risk to the developing fetus and baby. Some antidepressants have lower risk for the baby during pregnancy, but the FDA advises for the risk of birth defects with the use of Paxil and the MAOI should be avoided. A neonate may experience a withdrawal syndrome from abrupt discontinuation of the antidepressant at birth. The use of antidepressants during pregnancy is associated with an increased risk of spontaneous abortion, birth defects, and developmental delays. Antidepressants is present in varying amounts in breast milk but the effect on the baby is unknown.

Moreover, SSRIs inhibit nitric oxide synthesis, which leads to vasoconstriction. This is significant in pregnancy as SSRIs have been associated with the development of hypertension and pre-eclampsia of pregnancy. This in turn can lead to fetal prematurity. A 2006 industry based publication in the Journal of the American Medical Association (JAMA) found that discontinuing anti-depressive medication during pregnancy led to more frequent relapse. The JAMA later published a correction noting the financial ties and possible conflict of interest, however, the authors maintained 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.

Suicide

Whenever changes in antidepressant dosage occur, whether up or down, a doubling of the risk of suicide is seen. A study of 159,810 users of either amytriptyline, fluoxetine, paroxetine or dothiepin found that the risk of suicidal behavior is increased in the first month after starting antidepressants, especially during the first 1 to 9 days.

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. although it's controversial whether this is due to the medication or as part of the depression itself (i.e. efficacious antidepressant effect can cause those that are severely depressed, to the point of severe psychomotor inhibition, are rendered more alert and thus have increased capacity to carry out suicide even though they are relatively improved in state). The increased risk for suicidality and suicidal behaviour among adults under 25 approaches that seen in children and adolescents.

Young patients should be closely monitored for signs of suicidal ideation or behaviors, especially in the first eight weeks of therapy.^{[citation needed]}

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 warns against the use of Paxil for children and teens depression in favor of Prozac.

SSRI prescriptions for children and adolescents decreased after U.S. and European regulatory agencies issued warnings about a possible suicide risk with antidepressant use in pediatric patients, and these decreases were associated with increases in suicide rates in children and adolescents in both the United States with a 14% increase, and 50% increase in the Netherlands.

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.Jon Jureidini, a critic of this study, says 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.^{[citation needed]}

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 unsupported given the plethora of confounding variables.

Another study was taken the overall rate of suicidal acts was 27 per 1000 person-years, and most events occurred within 6 months of medication initiation. According to this study, no commonly used antidepressant medication has an advantage in regard to suicide-related safety. It remains a question as to whether other therapeutic maneuvers, such as ongoing counseling, provide a protective counter-effect to children's and adolescents' antidepressant-associated risk of suicidal thoughts or behaviour.

Sexual

Sexual side-effects are also common with SSRIs, such as loss of sexual drive, failure to reach orgasm, and erectile dysfunction. Although usually reversible, these sexual side-effects can, in rare cases, last for months or years after the drug has been completely withdrawn. This is known as Post SSRI Sexual Dysfunction.^{[citation needed]}

In a study of 1022 outpatients, overall sexual dysfunction with all antidepressants averaged 59.1% with SSRIs values between 57 and 73%, mirtazapine 24%, nefazodone 8%, amineptine 7% and moclobemide 4%. Moclobemide, a selective reversible MAO-A inhibitor does not cause sexual dysfunction, and can actually lead to an improvement in all aspects of sexual function.

Biochemical mechanisms suggested as causative include increased serotonin, particularly affecting 5-HT₂ and 5-HT₃ receptors; decreased dopamine; decreased norepinephrine; blockade of cholinergic and α₁ adrenergic receptors; inhibition of nitric oxide synthetase; and elevation of prolactin levels. Mirtazapine is reported to have fewer sexual side-effects, most likely because it antagonizes 5-HT₂ and 5-HT₃ receptors and may, in some cases, reverse sexual dysfunction induced by SSRIs by the same mechanism.

Bupropion, a 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.^{[citation needed]}

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.^{[citation needed]}

Weight gain

Many antidepressants (TCA, TecA, paroxetine from the group of SSRI's) 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.^{[citation needed]}

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.

Withdrawal symptoms

If a SSRI is suddenly discontinued, it frequently produces a SSRI discontinuation syndrome that has a both a somatic and psychological withdrawal component.

Withdrawal syndromes have been reported with tricyclic antidepressants, monoamine oxidase inhibitors and with SSRI's. Researchers from the Nordic Cochrane Center in Denmark compared the signs and symptoms of SSRI discontinuation to those of the benzodiazepine withdrawal syndrome and concluded that the withdrawal reactions were so similar that both withdrawal reactions indicated a dependence syndrome. Elsewhere, concerns have been raised that SSRIs cause dependence. Antidepressans 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. When treatment is prolonged over 6–9 months, processes oppose the initial acute effects of antidepressant drugs (loss of clinical effects). When drug treatment ends, these processes may be unopposed and yield withdrawal symptoms and increased vulnerability to relapse. Such processes are not necessarily reversible. The more antidepressants are switched or potentiated, the more likely oppositional tolerance can take place.

Some of the withdrawal symptoms of SSRI discontinuation include: Anger, anxiety, panic, depression, depersonalization, detachment, confusion, decreased concentration, memory problems, bouts of crying, hallucinations, mania, delirium, headache, sweating, convulsion, myalgias, lethargy, fatigue, sleep disturbances, nightmares, gastrointestinal, balance problems, visual disturbances, electric shock sensations, numbness, parasthesia, restless legs, tingling, tinnitus, tremors, shaking, parkinsonism, aggression, and catatonia.^{[citation needed]}

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

To minimize the intensity of withdrawal and rebound effects antidepressants should be discontinued over a period of several weeks or months depending on a person's response to reductions. The Ashton protocol for discontinuation suggest reducing 10% of the remaining dose every week or two Most cases of discontinuation syndrome last between one and four weeks but a substantial minority, perhaps up to 15% of users, have persistent withdrawal symptoms evident one year post-withdrawal. Paroxetine and venlafaxine seem to be particular difficult to discontinue and prolonged withdrawal syndrome lasting over 18 months have been reported with paroxetine. Several peer-support groups help patients to taper off of their antidepressants.

Society and culture

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.^{[citation needed]}

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). Currently, the most commonly prescribed antidepressants are selective serotonin reuptake inhibitors (SSRIs), even though a Cochrane systematic review found no major difference in efficacy between SSRIs and tricyclic antidepressants. A survey in the UK found that male general physicians were more likely to prescribe antidepressants than female doctors.

The number of antidepressants prescribed by the 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

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

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

Sertraline	Zoloft	SSRI	33,409,838
Citalopram	Celexa	SSRI	27,993,635
Fluoxetine	Prozac	SSRI	24,473,994
Escitalopram	Lexapro	SSRI	23,000,456
Trazodone	Desyrel	SARI	18,786,495
Duloxetine	Cymbalta	SNRI	14,591,949
Paroxetine	Paxil	SSRI	12,979,366
Amitriptyline	Elavil	TCA	12,611,254
Venlafaxine XR	Effexor XR	SNRI	7,603,949
Bupropion XL	Wellbutrin	NDRI	7,317,814
Mirtazapine	Remeron	TeCA	6,308,288
Venlafaxine ER	Effexor	SNRI	5,526,132
Bupropion SR		NDRI	4,588,996
Desvenlafaxine	Pristiq	SNRI	3,412,354
Nortriptyline	Sensoval	TCA	3,210,476
Bupropion ER		NDRI	3,132,327
Venlafaxine	Effexor	SNRI	2,980,525
Bupropion	Wellbutrin XL	NDRI	753,516

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

Netherlands: In the Netherlands, paroxetine, marketed as Seroxat among generic preparations, is the most prescribed antidepressant, followed by the tricyclic antidepressant amitriptyline, citalopram and venlafaxine.

MAOIs can be as effective as tricyclic antidepressants, although they are generally used less frequently because they have a higher incidence of dangerous side effects and interactions.

Litigation

• 2012 GlaxoSmithKline 3 billion dollars (US) - Paxil, The company touted Paxil for off-label use in children and adolescents, despite data that failed to show it was effective for these age groups, –Wellbutrin for marketing its antidepressant for off-label uses, including weight loss, substance abuse and sexual dysfunction and the seizure drug Lamictal.
• 2012 Johnson & Johnson $1.6 and $2.2 billion Risperdal off label marketing
• 2012 Abbott Laboratories $698 million for off label marketing Depakote for use in dementia patients who became agitated or aggressive despite lack of evidence that the drug was effective for that use.
• 2009 Eli Lilly $1.4 billion for marketing Zyprexa for children and the elderly dementia patients, both off-label uses. It is only approved to treat two disorders, schizophrenia and bipolar disorder.
• 2010 AstraZeneca $520 for off-label marketing of Seroquel.
• 2009 Pfizer $301 million for off label marketing of Geodon.
• 2007 Bristol-Myers Squibb $515 million for off-label marketing of Abilify for children and adolescent, and geriatric patients suffering from dememtia.
• 2004 Pfizer $430 million for off-label marketing of Neurontin.
• Ely Lilly In one of the only three cases to ever go to trial for SSRI indication in suicide, Eli Lilly and Company was caught corrupting the judicial process by making a deal with the plaintiff's attorney to throw the case, in part by not disclosing damaging evidence to the jury. The case, known as the Fentress Case involved a Kentucky man, Joseph Wesbecker, on Prozac, who went to his workplace and opened fire with an assault rifle killing 8 people (including Fentress), and injuring 12 others before turning the gun on himself. The jury returned a 9-to-3 verdict in favor of Lilly. The judge, in the end, took the matter to the Kentucky Supreme Court, which found that "there was a serious lack of candor with the trial court and there may have been deception, bad faith conduct, abuse of judicial process and, perhaps even fraud." The judge later revoked the verdict and instead, recorded the case as settled. The value of the secret settlement deal has never been disclosed, but was reportedly "tremendous".

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. 
• Lint, Don (2011). "Antidepressants and spontaneous abortion". Canadian Medical Association Journal 183 (11): 1283. doi:10.1503/cmaj.111-2056. PMC 3153521. PMID 21825057.