Antidepressant

refer to caption
Blister pack of Prozac (fluoxetine), a selective serotonin reuptake inhibitor
chemical structure of the SNRI drug venlafaxine
The chemical structure of venlafaxine (Effexor), an SNRI

Antidepressants are drugs used for the treatment of major depressive disorder and other conditions, including dysthymia, anxiety disorders, obsessive compulsive disorder, eating disorders, chronic pain, neuropathic pain and, in some cases, dysmenorrhoea, snoring, migraine, attention-deficit hyperactivity disorder (ADHD), addiction, dependence, and sleep disorders. They can be used alone or in combination with other medications but only when prescribed.

The most important classes of antidepressants are the selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), reversible monoamine oxidase A inhibitors (rMAO-A inhibitors), tetracyclic antidepressants (TeCAs), and noradrenergic and specific serotonergic antidepressant (NaSSAs).[1] St John's wort is also used in the treatment of depression.[1][2]

Medical uses

For depression, the Hamilton Depression Rating Scale (HAM-D) is often used to measure the severity of depression.[3] The maximum score for the 17-item HAM-D questionnaire is 52; the higher the score, the more severe the depression.

Major depressive disorder

Clinical guidelines

The UK National Institute for Health and Care Excellence (NICE) 2009 guidelines indicate that antidepressants should not be routinely used for the initial treatment of mild depression, because the risk-benefit ratio is poor. The guidelines recommend that antidepressant treatment should be considered for:

The guidelines further note that antidepressant treatment should be used in combination with psychosocial interventions in most cases, should be continued for at least 6 months to reduce the risk of relapse, and that SSRIs are typically better tolerated than other antidepressants.[4]

American Psychiatric Association treatment guidelines recommend that initial treatment should be individually tailored based on factors that include severity of symptoms, co-existing disorders, prior treatment experience, and patient preference. Options may include pharmacotherapy, psychotherapy, electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS) or light therapy. Antidepressant medication is recommended as an initial treatment choice in people with mild, moderate, or severe major depression, and should be given to all patients with severe depression unless ECT is planned.[5]

Systematic reviews

Conflicting results have arisen from studies analyzing the efficacy of antidepressants by comparisons to placebo in people with acute mild to moderate depression. Stronger evidence supports the usefulness of antidepressants in the treatment of depression that is chronic (dysthymia) or severe.

Researchers Irving Kirsch and Thomas Moore have contested the pharmacological activity of antidepressants in the relief of depression, and state that the evidence is most consistent a role as active placebos.[6] Their study consisted of a meta analysis incorporating data from both published studies and unpublished data obtained from the FDA via a Freedom of Information Act request. Overall, antidepressant pills worked 18% better than placebos, a statistically significant difference, but not one that is clinically significant.[7] In a later publication, Kirsch concluded that the overall effect of new-generation antidepressant medication is below recommended criteria for clinical significance.[8]

Another study focusing on paroxetine (Paxil) and imipramine found that antidepressant drugs were only slightly better than placebo in cases of mild or moderate depression they surveyed but offered "substantial" benefit in those with severe depression.[9]

In 2014 the U.S. FDA published a systematic review of all antidepressant maintenance trials submitted to the agency between 1985 and 2012. The authors concluded that maintenance treatment reduced the risk of relapse by 52% compared to placebo, and that this effect was primarily due to recurrent depression in the placebo group rather than a drug withdrawal effect.[10]

A review commissioned by the National Institute for Health and Care Excellence concluded that 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.[11]

The Cochrane Collaboration recently performed a systematic review of clinical trials of the tricyclic 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.[12]

A 2015 systematic review of add-on therapies for treatment-resistant depression concluded that quetiapine and aripiprazole have the strongest evidence-base supporting their efficacy, but they are associated with additional treatment-related side effects when used as an add-on therapy.[13]

A 2008 Cochrane Collaboration review on St John's wort (specifically, any extracts which contain hypericum perforatum), and a 2015 meta-analytic systematic review by some of the same authors, both concluded that it: has superior efficacy to placebo in treating depression; is as effective as standard antidepressant pharmaceuticals for treating depression; and has fewer adverse effects than other antidepressants. The 2015 meta analysis concluded that it is difficult to assign a place for St. John's wort in the treatment of depression owing to limitations in the available evidence base, including large variations in efficacy seen in trials performed in German-speaking relative to other countries.[1][2] Reversible monoamine oxidase A inhibitors (rMAO-A inhibitors) have also been shown to be an effective drug therapy with greater tolerability than other antidepressants;[1] however, the efficacy of SSRIs, tricyclic, and tetracyclic antidepressants in treating depression is supported by a much larger evidence base compared to other antidepressant drug therapies (i.e., St John's wort, rMAO-A inhibitors, serotonin–norepinephrine reuptake inhibitor, serotonin antagonist and reuptake inhibitors, noradrenaline reuptake inhibitors, and noradrenergic and specific serotonergic antidepressants).[1]

A study published in the Journal of the American Medical Association (JAMA) demonstrated that the magnitude of the placebo effect in clinical trials of depression have been growing over time, while the effect size of tested drugs has remained relatively constant. The authors suggest that one possible explanation for the growing placebo effect in clinical trials is the inclusion of larger number of participants with shorter term, mild, or spontaneously remitting depression as a result of decreasing stigma associated with antidepressant use.[14] Placebo response rates in clinical trials of complementary and alternative (CAM) therapies are significantly lower than those in clinical trials of traditional antidepressants.[15]

A 2004 review concluded that antidepressant studies that failed to support efficacy claims were dramatically less likely to be published than those that did support favorable efficacy claims.[16] Similar results were obtained for a study of publication of clinical trials of antidepressants in children.[17] A 2015 investigation of meta-analyses of antidepressant studies found that 79% of them had "sponsorship or authors who were (pharmacutical) industry employees and/or had conflicts of interest".[18]

A 2012 meta-analysis found that fluoxetine and venlafaxine were effective for major depression in all age groups. The authors also found no evidence of a relationship between baseline severity of depression and degree of benefit of antidepressants over placebo.[19]

The STAR*D Trial

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.[20] The study was dubbed "The Sequenced Treatment Alternatives to Relieve Depression" (STAR*D) Study. The results[21][22] are summarized here. Participants in the trial were recruited when they sought medical care at general medical or psychiatric clinics. No advertising was used to recruit subjects in order to maximize the generalizability of the study results. Participants were required to have a minimum score of 14 point on the Hamilton Depression Scale (HAM-D17) in order to be enrolled in the trial. Generally accepted cutoffs are 7–17 points for mild depression, 18–24 points for moderate depression, and ≥ 24 for severe depression.[23] The average participant baseline HAM-D17 score was 22.[24] The pre-specified primary endpoint of this trial was remission as determined by the HAM-D score, with all patients with missing scores rated as non-responders. In the aftermath of the trial, the investigators have presented the results mainly using the secondary endpoint of remission according to the QIDS-SR16 Score, which tend to be somewhat higher.

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.[29] These included bupropion sustained release, bupropion, citalopram, lithium, mirtazapine, nortriptyline, sertraline, triiodothyronine, tranylcypromine, and venlafaxine extended release.

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.[30]

Limitations and strategies

Between 30% and 50% of individuals treated with a given antidepressant do not show a response.[31][32] In clinical studies, approximately one-third of patients achieve a full remission, one-third experience a response and one-third are nonresponders. Partial remission is characterized by the presence of poorly defined residual symptoms. These symptoms typically include depressed mood, psychic anxiety, sleep disturbance, fatigue and diminished interest or pleasure. It is currently unclear which factors predict partial remission. However, it is clear that residual symptoms are powerful predictors of relapse, with relapse rates 3–6 times higher in patients with residual symptoms than in those who experience full remission.[33] In addition, antidepressant drugs tend to lose efficacy over the course of treatment.[34] According to data from the Centers for Disease Control and Prevention, less than one-third of Americans taking one antidepressant medication have seen a mental health professional in the previous year.[35] A number of strategies are used in clinical practice to try to overcome these limits and variations.[36] 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. 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.[32] 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.[37]

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, NRIs, glucocorticoid-specific agents, or the newer anticonvulsants.[38]

A combination strategy involves adding another antidepressant, usually from a different class so as to have effect on other mechanisms. Although this may be used in clinical practice, there is little evidence for the relative efficacy or adverse effects of this strategy.[39] Other tests recently conducted include the use of psychostimulants as an augmentation therapy. Several studies have shown the efficacy of combining modafinil to treatment-resistant patients. It has been used to help combat SSRI-associated fatigue.[40]

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.[41]

A gradual loss of therapeutic benefit occurs in a minority of people during the course of treatment.[42][43] 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.[44][45]

Comparative efficacy and tolerability

Anxiety disorders

Generalized anxiety disorder

Antidepressants are recommended by the National Institute for Health and Care Excellence (NICE) for the treatment of generalized anxiety disorder (GAD) that has failed to respond to conservative measures such as education and self-help activities. GAD is a common disorder of which the central feature is excessive worry about a number of different events. Key symptoms include excessive anxiety about multiple events and issues, and difficulty controlling worrisome thoughts that persists for at least 6 months.

Antidepressants provide a modest-to-moderate reduction in anxiety in GAD,[66] and are superior to placebo in treating GAD.[67] The efficacy of different antidepressants is similar.[66][67]

Obsessive-compulsive disorder

SSRIs are a second-line treatment of adult obsessive-compulsive disorder (OCD) with mild functional impairment and as first-line treatment for those with moderate or severe impairment. In children, SSRIs can be considered as a second-line therapy in those with moderate-to-severe impairment, with close monitoring for psychiatric adverse effects.[68] SSRIs are efficacious in the treatment of OCD; patients treated with SSRIs are about twice as likely to respond to treatment as those treated with placebo.[69][70] Efficacy has been demonstrated both in short-term treatment trials of 6 to 24 weeks and in discontinuation trials of 28 to 52 weeks duration.[71][72][73]

Eating disorders

Antidepressants are recommended as an alternative or additional first step to self-help programs in the treatment of bulimia nervosa.[74] SSRIs (fluoxetine in particular) are preferred over other antidepressants due to their acceptability, tolerability, and superior reduction of symptoms in short-term trials. Long-term efficacy remains poorly characterized. Bupropion is not recommended for the treatment of eating disorders due to an increased risk of seizure.[75]

Similar recommendations apply to binge eating disorder.[74] SSRIs provide short-term reductions in binge eating behavior, but have not been associated with significant weight loss.[76]

Clinical trials have generated mostly negative results for the use of SSRIs in the treatment of anorexia nervosa.[77] Treatment guidelines from the National Institute of Health and Care Excellence[74] recommend against the use of SSRIs in this disorder. Those from the American Psychiatric Association note that SSRIs confer no advantage regarding weight gain, but that they may be used for the treatment of co-existing depressive, anxiety, or obsessive-compulsive disorders.[76]

Pain

Fibromyalgia

A 2012 meta-analysis concluded that antidepressants treatment favorably affects pain, health-related quality of life, depression, and sleep in fibromyalgia syndrome. Tricyclics appear to be the most effective class, with moderate effects on pain and sleep and small effects on fatigue and health-related quality of life. The fraction of people experiencing a 30% pain reduction on tricyclics was 48% versus 28% for placebo. For SSRIs and SNRIs the fraction of people experiencing a 30% pain reduction was 36% (20% in the placebo comparator arms) and 42% (32% in the corresponding placebo comparator arms). Discontinuation of treatment due to side effects was common.[78] Antidepressants including amitriptyline, fluoxetine, duloxetine, milnacipran, moclobemide, and pirlindole are recommended by the European League Against Rheumatism (EULAR) for the treatment of fibromyalgia based on "limited evidence".[79]

Neuropathic pain

A 2014 meta-analysis from the Cochrane Collaboration found the antidepressant duloxetine effective for the treatment of pain resulting from diabetic neuropathy.[80] The same group reviewed data for amitryptyline in the treatment of neuropathic pain and found limited useful randomized clinical trial data, but concluded that the long history of successful use in the community for the treatment of fibromyalgia and neuropathic pain justified its continued use.[81]

Adverse effects

Difficulty tolerating adverse effects is the most common reason for antidepressant discontinuation.

General

Main articles: Serotonin syndrome and MAOIs

Almost any medication involved with serotonin regulation has the potential to cause serotonin toxicity (also known as serotonin syndrome) – an excess of serotonin that can induce mania, restlessness, agitation, emotional lability, insomnia and confusion as its primary symptoms.[82][83] Although the condition is serious, it is not particularly common, generally only appearing at high doses or while on other medications. Assuming proper medical intervention has been taken (within about 24 hours) it is rarely fatal.[84][85]

MAOIs tend to have pronounced (sometimes fatal) interactions with a wide variety of medications and over-the-counter drugs. If taken with foods that contain very high levels of tyramine (e.g., mature cheese, cured meats, or yeast extracts), they may cause a potentially lethal hypertensive crisis. At lower doses the person may be bothered by only a headache due to an increase in blood pressure.[86]

In response to these adverse effects, a different type of MAOI has been developed: the reversible inhibitor of monoamine oxidase A (RIMA) class of drugs. Their primary advantage is that they do not require the person to follow a special diet, while being purportedly effective as SSRIs and tricyclics in treating depressive disorders.[87]

Pregnancy

SSRI use in pregnancy has been associated with a variety of risks with varying degrees of proof of causation. As depression is independently associated with negative pregnancy outcomes, determining the extent to which observed associations between antidepressant use and specific adverse outcomes reflects a causative relationship has been difficult in some cases.[88] In other cases, the attribution of adverse outcomes to antidepressant exposure seems fairly clear.

SSRI use in pregnancy is associated with an increased risk of spontaneous abortion of about 1.7-fold,[89][90] and is associated with preterm birth and low birth weight.[91]

A systematic review of the risk of major birth defects in antidepressant-exposed pregnancies found a small increase (3% to 24%) in the risk of major malformations and a risk of cardiovascular birth defects that did not differ from non-exposed pregnancies.[92] A study of fluoxetine-exposed pregnancies found a 12% increase in the risk of major malformations that just missed statistical significance.[93] Other studies have found an increased risk of cardiovascular birth defects among depressed mothers not undergoing SSRI treatment, suggesting the possibility of ascertainment bias, e.g. that worried mothers may pursue more aggressive testing of their infants.[94] Another study found no increase in cardiovascular birth defects and a 27% increased risk of major malformations in SSRI exposed pregnancies.[90] The FDA advises for the risk of birth defects with the use of paroxetine[95] and the MAOI should be avoided.

A neonate (infant less than 28 days old) may experience a withdrawal syndrome from abrupt discontinuation of the antidepressant at birth. Antidepressants have been shown to be present in varying amounts in breast milk, but their effects on infants are currently unknown.[96]

Moreover, SSRIs inhibit nitric oxide synthesis, which plays an important role in setting vascular tone. Several studies have pointed to an increased risk of prematurity associated with SSRI use, and this association may be due to an increase risk of pre-eclampsia of pregnancy.[97]

Antidepressant-induced mania

Another possible problem with antidepressants is the chance of antidepressant-induced mania in patients with bipolar disorder. Many cases of bipolar depression are very similar to those of unipolar depression. Therefore, the patient can be misdiagnosed with unipolar depression and be given antidepressants. Studies have shown that antidepressant-induced mania can occur in 20–40% of bipolar patients.[98] For bipolar depression, antidepressants (most frequently SSRIs) can exacerbate or trigger symptoms of hypomania and mania.[99]

Suicide

Studies have shown that the use of antidepressants is correlated with an increased risk of suicidal behaviour and thinking (suicidality) in those aged under 25.[100] This problem has been serious enough to warrant government intervention by the US Food and Drug Administration (FDA) to warn of the increased risk of suicidality during antidepressant treatment.[101] According to the FDA, the heightened risk of suicidality is within the first one to two months of treatment.[102][103][104] The National Institute for Health and Care Excellence (NICE) places the excess risk in the "early stages of treatment".[105] A meta-analysis suggests that the relationship between antidepressant use and suicidal behavior or thoughts is age-dependent.[100] Compared to placebo the use of antidepressants is associated with an increase in suicidal behavior or thoughts among those aged under 25 (OR=1.62). This increase in suicidality approaches that observed in children and adolescents. There is no effect or possibly a mild protective effect among those aged 25 to 64 (OR=0.79). Antidepressant treatment has a protective effect against suicidality among those aged 65 and over (OR=0.37).[100][106]

Sexual

Sexual side-effects are also common with SSRIs, such as loss of sexual drive, failure to reach orgasm, and erectile dysfunction.[107] Although usually reversible, these sexual side-effects can, in rare cases, last for months or years after the drug has been completely withdrawn.[108]

In a study of 1022 outpatients, overall sexual dysfunction with all antidepressants averaged 59.1%[109] 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,[110] and can actually lead to an improvement in all aspects of sexual function.[111]

Biochemical mechanisms suggested as causative include increased serotonin, particularly affecting 5-HT2 and 5-HT3 receptors; decreased dopamine; decreased norepinephrine; blockade of cholinergic and α1adrenergic receptors; inhibition of nitric oxide synthetase; and elevation of prolactin levels.[112] 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.[113]

Bupropion, a weak NDRI and nicotinic antagonist, may be useful in treating reduced libido as a result of SSRI treatment.[114]

Changes in weight

Changes in appetite or weight are common among antidepressants, but largely drug-dependent and are related to which neurotransmitters they affect. Mirtazapine and paroxetine, for example, have the effect of weight gain and/or increased appetite,[115][116][117] while others (such as bupropion and venlafaxine) achieve the opposite effect.[118][119]

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.

Discontinuation syndrome

Antidepressant discontinuation symptoms were first reported with imipramine, the first tricyclic antidepressant (TCA), in the late 1950s, and each new class of antidepressants has brought reports of similar conditions, including monoamine oxidase inhibitors (MAOIs), SSRIs, and SNRIs. As of 2001, at least 21 different antidepressants, covering all the major classes, were known to cause discontinuation syndromes.[120] The problem has been poorly studied, and most of the literature has been case reports or small clinical studies; incidence is hard to determine and controversial.[120]

People with discontinuation syndrome have been on an antidepressant for at least four weeks and have recently stopped taking the medication, either abruptly or after a fast taper.[121] Common symptoms include flu-like symptoms (nausea, vomiting, diarrhea, headaches, sweating), sleep disturbances (insomnia, nightmares, constant sleepiness), sensory/movement disturbances (imbalance, tremors, vertigo, dizziness, electric-shock-like experiences), mood disturbances (dysphoria, anxiety, agitation) and cognitive disturbances (confusion and hyperarousal).[121][122][123] Over fifty symptoms have been reported.[124]

Most cases of discontinuation syndrome last between one and four weeks, are relatively mild, and resolve on their own; in rare cases symptoms can be severe or extended.[121] Paroxetine and venlafaxine seem to be particularly difficult to discontinue and prolonged withdrawal syndrome lasting over 18 months have been reported with paroxetine.[120][125][126]

With the explosion of use and interest in SSRIs in the late 1980s and early 1990s, focused especially on Prozac, interest grew as well in discontinuation syndromes.[127] In the late 1990s, some investigators thought that symptoms that emerged when antidepressants were discontinued, might mean that antidepressants were causing addiction, and some used the term "withdrawal syndrome" to describe the symptoms. Addictive substances cause physiological dependence, so that drug withdrawal causes suffering. These theories were abandoned, since addiction leads to drug-seeking behavior, and people taking antidepressants do not exhibit drug-seeking behavior. The term "withdrawal syndrome" is no longer used with respect to antidepressants, to avoid confusion with problems that arise from addiction.[121][128][129] There are case reports of antidepressants being abused, but these are rare and are mostly limited to antidepressants with stimulant effects and to people who already had a substance use disorder.[130] A 2012 comparison of the effects of stopping therapy with benzodiazepines and SSRIs argued that because the symptoms are similar, it makes no sense to say that benzodiazepines are addictive while SSRIs are not.[131] Responses to that review noted that there is no evidence that people who stop taking SSRIs exhibit drug-seeking behavior while people who stop taking benzodiazepines do, and that the drug classes should be considered differently.[132][133]

Pharmacology

The earliest and probably most widely accepted scientific theory of antidepressant action is the monoamine hypothesis (which can be traced back to the 1950s), which states that depression is due to an imbalance (most often a deficiency) of the monoamine neurotransmitters (namely serotonin, norepinephrine and dopamine).[46] It was originally proposed based on the observation that certain hydrazine anti-tuberculosis agents produce antidepressant effects, which was later linked to their inhibitory effects on monoamine oxidase, the enzyme that catalyses the breakdown of the monoamine neurotransmitters.[46] All currently marketed antidepressants have the monoamine hypothesis as their theoretical basis, with the possible exception of agomelatine which acts on a dual melatonergic-serotonergic pathway.[46] Despite the success of the monoamine hypothesis it has a number of limitations: for one, all monoaminergic antidepressants have a delayed onset of action of at least a week; and secondly, there are a sizeable portion (>40%) of depressed patients that do not adequately respond to monoaminergic antidepressants.[134][135] A number of alternative hypotheses have been proposed, including the glutamate, neurogenic, epigenetic, cortisol hypersecretion and inflammatory hypotheses.[134][135][136][137]

Types

Selective serotonin reuptake inhibitors

Selective serotonin reuptake inhibitors (SSRIs) are believed to increase the extracellular level of the neurotransmitter serotonin by limiting its reabsorption into the presynaptic cell, increasing the level of serotonin in the synaptic cleft available to bind to the postsynaptic receptor. They have varying degrees of selectivity for the other monoamine transporters, with pure SSRIs having only weak affinity for the norepinephrine and dopamine transporters.

SSRIs are the most widely prescribed antidepressants in many countries.[138] The efficacy of SSRIs in mild or moderate cases of depression has been disputed.[139][140][141]

Serotonin-norepinephrine reuptake inhibitors

Serotonin-norepinephrine reuptake inhibitors (SNRIs) are potent inhibitors of the reuptake of serotonin and norepinephrine. These neurotransmitters are known to play an important role in mood. SNRIs can be contrasted with the more widely used selective serotonin reuptake inhibitors (SSRIs), which act upon serotonin alone.

The human serotonin transporter (SERT) and norepinephrine transporter (NET) are membrane proteins that are responsible for the reuptake of serotonin and norepinephrine. Balanced dual inhibition of monoamine reuptake can possibly offer advantages over other antidepressants drugs by treating a wider range of symptoms.[142]

SNRIs are sometimes also used to treat anxiety disorders, obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), chronic neuropathic pain, and fibromyalgia syndrome (FMS), and for the relief of menopausal symptoms.

Serotonin modulators and stimulators

Serotonin modulator and stimulators (SMSs), sometimes referred to more simply as serotonin modulators, are a type of drug with a multimodal action specific to the serotonin neurotransmitter system. To be precise, SMSs simultaneously modulate one or more serotonin receptors and inhibit the reuptake of serotonin. The term was created to describe the mechanism of action of the serotonergic antidepressant vortioxetine (Brintellix/Trintellix), which acts as a serotonin reuptake inhibitor (SRI), partial agonist of the 5-HT1A receptor, and antagonist of the 5-HT3 and 5-HT7 receptors.[143][144][145] However, it can also technically be applied to vilazodone (Viibryd), which is an antidepressant as well and acts as an SRI and 5-HT1A receptor partial agonist.[146]

An alternative term is serotonin partial agonist/reuptake inhibitor (SPARI), which can be applied only to vilazodone.[147]

Serotonin antagonists and reuptake inhibitors

Serotonin antagonist and reuptake inhibitors (SARIs) while mainly used as antidepressants, are also anxiolytics and hypnotics. They act by antagonizing serotonin receptors such as 5-HT2A and inhibiting the reuptake of serotonin, norepinephrine, and/or dopamine. Additionally, most also act as α1-adrenergic receptor antagonists. The majority of the currently marketed SARIs belong to the phenylpiperazine class of compounds.

Norepinephrine reuptake inhibitors

Norepinephrine reuptake inhibitors (NRIs or NERIs) are a type of drug that acts as a reuptake inhibitor for the neurotransmitter norepinephrine (noradrenaline) by blocking the action of the norepinephrine transporter (NET). This in turn leads to increased extracellular concentrations of norepinephrine.

NRIs are commonly used in the treatment of conditions like ADHD and narcolepsy due to their psychostimulant effects and in obesity due to their appetite suppressant effects. They are also frequently used as antidepressants for the treatment of major depressive disorder, anxiety and panic disorder. Additionally, many drugs of abuse such as cocaine and methylphenidate possess NRI activity, though it is important to mention that NRIs without combined dopamine reuptake inhibitor (DRI) properties are not significantly rewarding and hence are considered to have a negligible abuse potential.[148][149] However, norepinephrine has been implicated as acting synergistically with dopamine when actions on the two neurotransmitters are combined (e.g., in the case of NDRIs) to produce rewarding effects in psychostimulant drugs of abuse.[150]

Tricyclic antidepressants

The majority of the tricyclic antidepressants (TCAs) act primarily as serotonin-norepinephrine reuptake inhibitors (SNRIs) by blocking the serotonin transporter (SERT) and the norepinephrine transporter (NET), respectively, which results in an elevation of the synaptic concentrations of these neurotransmitters, and therefore an enhancement of neurotransmission.[151][152] Notably, with the sole exception of amineptine, the TCAs have negligible affinity for the dopamine transporter (DAT), and therefore have no efficacy as dopamine reuptake inhibitors (DRIs).[151] Both serotonin and norepinephrine have been highly implicated in depression and anxiety, and it has been shown that facilitation of their activity has beneficial effects on these mental disorders.[153]

Although TCAs are sometimes prescribed for depressive disorders, they have been largely replaced in clinical use in most parts of the world by newer antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs) and norepinephrine reuptake inhibitors (NRIs). Adverse effects have been found to be of a similar level between TCAs and SSRIs.[154]

Tetracyclic antidepressants

Tetracyclic antidepressants (TeCAs) are a class of antidepressants that were first introduced in the 1970s. They are named after their chemical structure, which contains four rings of atoms, and are closely related to the tricyclic antidepressants (TCAs), which contain three rings of atoms.

Monoamine oxidase inhibitors

Monoamine oxidase inhibitors (MAOIs) are chemicals which inhibit the activity of the monoamine oxidase enzyme family. They have a long history of use as medications prescribed for the treatment of depression. They are particularly effective in treating atypical depression.[155] They are also used in the treatment of Parkinson's disease and several other disorders.

Because of potentially lethal dietary and drug interactions, monoamine oxidase inhibitors have historically been reserved as a last line of treatment, used only when other classes of antidepressant drugs (for example selective serotonin reuptake inhibitors and tricyclic antidepressants) have failed.[156]

MAOIs have been found to be effective in the treatment of panic disorder with agoraphobia,[157] social phobia,[158][159][160] atypical depression[161][162] or mixed anxiety and depression, bulimia,[163][164][165][166] and post-traumatic stress disorder,[167] as well as borderline personality disorder.[168] MAOIs appear to be particularly effective in the management of bipolar depression according to a recent retrospective-analysis.[169] There are reports of MAOI efficacy in obsessive-compulsive disorder (OCD), trichotillomania, dysmorphophobia, and avoidant personality disorder, but these reports are from uncontrolled case reports.[170]

MAOIs can also be used in the treatment of Parkinson's disease by targeting MAO-B in particular (therefore affecting dopaminergic neurons), as well as providing an alternative for migraine prophylaxis. Inhibition of both MAO-A and MAO-B is used in the treatment of clinical depression and anxiety.

Others

See the list of antidepressants for other drugs which are not specifically characterized.

Adjuncts

Adjunct medications are an umbrella term used to describe substances that increase the potency or "enhance" antidepressants.[171] They work by affecting variables very close to the antidepressant, sometimes affecting a completely different mechanism of action. This may be attempted when depression treatments have not been successful in the past.

Common types of adjunct medication techniques generally fall into the following categories:

Less common adjunct medication

Lithium has been used to augment antidepressant therapy in those who have failed to respond to antidepressants alone.[173] Furthermore, lithium dramatically decreases the suicide risk in recurrent depression.[174] There is some evidence for the addition of a thyroid hormone, triiodothyronine, in patients with normal thyroid function.[175] Stephen M. Stahl, renowned academician in psychopharmacology, has stated resorting to a dynamic psychostimulant, in particular, d-amphetamine is the "classical augmentation strategy for treatment-refractory depression".[176] However, the use of stimulants in cases of treatment-resistant depression is relatively controversial.[177][178] A review article published in 2007 found psychostimulants may be effective in treatment-resistant depression with concomitant antidepressant therapy, but 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.[178]

History

refer to caption
St John's wort

Before the 1950s, opioids and amphetamines were commonly used as antidepressants.[179][180] Their use was later restricted due to their addictive nature and side effects.[179] Extracts from the herb St John's wort had been used as a "nerve tonic" to alleviate depression.[181]

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."[182] 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.[183] 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.[184] 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.[185]

Selikoff and Robitzek also experimented with another anti-tuberculosis drug, iproniazid; it showed a greater psychostimulant effect, but more pronounced toxicity.[186] 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.[187] 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".[187][188] Roche put a significant marketing effort behind iproniazid.[187] Its sales grew until it was recalled in 1961, due to reports of lethal hepatotoxicity.[187]

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.

Attempting to improve the effectiveness of chlorpromazine, Kuhn – in conjunction with the Geigy Pharmaceutical Company – discovered the compound "G 22355", later renamed imipramine. Imipramine had a beneficial effect in patients with depression who showed mental and motor retardation. Kuhn described his new compound as a "thymoleptic" "taking hold of the emotions," in contrast with neuroleptics, "taking hold of the nerves" in 1955–56. These gradually became established, resulting in the patent and manufacture in the US in 1951 by Häfliger and SchinderA.[189]

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,[190] which were being marketed for different uses.[191] 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.[191][192]

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.

Researchers began a process of rational drug design to isolate antihistamine-derived compounds that would selectively target these systems. The first such compound to be patented was zimelidine in 1971, while the first released clinically was indalpine. Fluoxetine was approved for commercial use by the US Food and Drug Administration (FDA) in 1988, becoming the first blockbuster SSRI. Fluoxetine was developed at Eli Lilly and Company in the early 1970s by Bryan Molloy, Klaus Schmiegel, David Wong and others.[193][194] SSRIs became known as "novel antidepressants" along with other newer drugs such as SNRIs and NRIs with various selective effects.[195]

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.[196] It remains an over-the-counter drug (OTC) supplement in most countries. Research continues to investigate its active component hyperforin, and to further understand its mode of action.[197][198]

Society and culture

Prescription trends

In the United States, antidepressants were the most commonly prescribed medication in 2013.[199] Of the estimated 16 million "long term" (over 24 months) users, roughly 70 percent are female.[199]

In the UK, figures reported in 2010 indicated that the number of antidepressant prescribed by the National Health Service (NHS) almost doubled over a decade.[200] Further analysis published in 2014 showed that number of antidepressants dispensed annually in the community went up by 25 million in the 14 years between 1998 and 2012, rising from 15 million to 40 million. Nearly 50% of this rise occurred in the four years after the 2008 banking crash, during which time the annual increase in prescriptions rose from 6.7% to 8.5%.[201] These sources also suggest that aside from the recession, other factors that may influence changes in prescribing rates may include: improvements in diagnosis, a reduction of the stigma surrounding mental health, broader prescribing trends, GP characteristics, geographical location and housing status. Another factor that contribute to increasing consumption of antidepressants is the fact that these medications now are used for other conditions including social anxiety and post traumatic stress.

Most commonly prescribed

Structural formula of the SSRI sertraline

United States: The most commonly prescribed antidepressants in the US retail market in 2010 were:[202]

Drug name Commercial name Drug class Total prescriptions
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
Venlafaxine (all formulations) Effexor (IR, ER, XR) SNRI 16,110,606
Bupropion (all formulations) Wellbutrin (IR, ER, SR, XL) NDRI 15,792,653
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 XL NDRI 7,317,814
Mirtazapine Remeron TeCA 6,308,288
Venlafaxine ER Effexor XR SNRI 5,526,132
Bupropion SR Wellbutrin SR NDRI 4,588,996
Desvenlafaxine Pristiq SNRI 3,412,354
Nortriptyline Sensoval TCA 3,210,476
Bupropion ER Wellbutrin XL NDRI 3,132,327
Venlafaxine Effexor SNRI 2,980,525
Bupropion Wellbutrin IR NDRI 753,516

Netherlands: In the Netherlands, paroxetine, marketed as Seroxat among generic preparations, is the most prescribed antidepressant, followed by amitriptyline, citalopram and venlafaxine.[203]

Social science perspective

In looking at the issue of antidepressant use, some academics have highlighted the need to examine the use of antidepressants and other medical treatments in cross-cultural terms, due to the fact that various cultures prescribe and observe different manifestations, symptoms, meanings and associations of depression and other medical conditions within their populations.[204][205] These cross-cultural discrepancies, it has been argued, then have implications on the perceived efficacy and use of antidepressants and other strategies in the treatment of depression in these different cultures.[204][205] In India antidepressants are largely seen as tools to combat marginality, promising the individual the ability to re-integrate into society through their use—a view and association not observed in the West.[204]

Environmental impacts

Somewhat less than 10% of orally administered fluoxetine is excreted from humans unchanged or as glucuronide.[206][207] Because most antidepressants function by inhibiting the reuptake of neurotransmitters serotonin, dopamine, and norepinepherine[208] these drugs can interfere with natural neurotransmitter levels in other organisms impacted by indirect exposure.[209] Antidepressants fluoxetine and sertraline have been detected in aquatic organisms residing in effluent dominated streams.[210] The presence of antidepressants in surface waters and aquatic organisms has caused concern because ecotoxicological effects to aquatic organisms due to fluoxetine exposure have been demonstrated.[211] Coral reef fish have been demonstrated to modulate aggressive behavior through serotonin.[212]

Exposure to fluoxetine has been demonstrated to increase serotonergic activity in fish, subsequently reducing aggressive behavior.[213] Artificially increasing serotonin levels in crustaceans can temporarily reverse social status and turn subordinates into aggressive and territorial dominant males.[214] Perinatal exposure to fluoxetine at relevant environmental concentrations has been shown to lead to significant modifications of memory processing in 1-month-old cuttlefish.[215] This impairment may disadvantage cuttlefish and decrease their survival.

See also

Wikimedia Commons has media related to Antidepressants.
Look up antidepressant in Wiktionary, the free dictionary.

References

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