Selective serotonin reuptake inhibitor

From Wikipedia, the free encyclopedia - View original article

Selective serotonin reuptake inhibitor
Drug class

UseDepression anxiety disorders, and some personality disorders.
Biological targetSerotonin transporter
ATC codeN06AB
External links
MeSHD017367
AHFS/Drugs.comDrug Classes
Consumer ReportsBest Buy Drugs
 
Jump to: navigation, search
Selective serotonin reuptake inhibitor
Drug class

UseDepression anxiety disorders, and some personality disorders.
Biological targetSerotonin transporter
ATC codeN06AB
External links
MeSHD017367
AHFS/Drugs.comDrug Classes
Consumer ReportsBest Buy Drugs

Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor[1] (SSRIs) are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders.

SSRIs are believed to increase the extracellular level of the neurotransmitter serotonin by inhibiting its reuptake 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 noradrenaline and dopamine transporter.

SSRIs are the first class of psychotropic drugs discovered using the process called rational drug design, a process that starts with a specific biological target and then creates a molecule designed to affect it.[2] They are the most widely prescribed antidepressants in many countries.[2] The efficacy of SSRIs in mild or moderate cases of depression has been disputed.[3][4][5]

Medical uses[edit]

The main indication for SSRIs is major depressive disorder (also called "major depression", "clinical depression" and often simply "depression"). SSRIs are frequently prescribed for anxiety disorders, such as social anxiety disorder, panic disorders, obsessive–compulsive disorder (OCD), eating disorders, chronic pain and occasionally, for posttraumatic stress disorder (PTSD). They are also frequently used to treat depersonalization disorder, although generally with poor results.[6]

Depression[edit]

Antidepressants are recommended by the National Institute for Clinical Excellence (NICE) as a first-line treatment of severe depression and for the treatment of mild-to-moderate depression that persists after conservative measures such as cognitive therapy.[7] They recommend against their routine use in those who have chronic health problems and mild depression.[7] There has been controversy regarding the efficacy of antidepressants in treating depression depending on its severity and duration. A comprehensive review conducted by NICE concluded that antidepressants have no advantage over placebo in the treatment of short term mild depression, but that the available evidence supported the use of antidepressants in the treatment of dysthymia and other forms of chronic mild depression.[8] Two meta-analyses of clinical trials published in 2008 and 2011 found that in mild and moderate depression, the effect of SSRIs is small or none compared to placebo, while in very severe depression the effect of SSRIs is between "relatively small " and "substantial".[3][9] Unlike the NICE study, these studies did not discriminate between the acutely and chronically depressed. The 2008 meta-analysis combined 35 clinical trials submitted to the U.S. Food and Drug Administration (FDA) before licensing of four newer antidepressants (including the SSRIs paroxetine and fluoxetine, the non-SSRI antidepressant nefazodone, and the SNRI (serotonin and norepinephrine reuptake inhibitor) venlafaxine). The authors attributed the relationship between severity and efficacy to a reduction of the placebo effect in severely depressed patients, rather than an increase in the effect of the medication.[9] Some researchers have questioned the statistical basis of this study suggesting that it underestimates the effect size of antidepressants.[10][11] A 2010 review reached similar conclusions: in mild and moderate depression, specifically that the effect of SSRI is very small or none compared to placebo, while it is clinically significant in very severe depression.[3][12] However, this analysis included only 6 studies out of the over 2,000 that have been done, involved just 2 medications, and did not involve studies with placebo washout periods typically used as controls.[4][5]

SSRIs are recommended by NICE over tricyclics due to their superior tolerability.[13] One study showed that SSRIs have greater adverse effects than TCAs in the elderly, though the authors caution that more research is needed.[14] There does not appear to be a substantial difference in efficacy among the various second generation antidepressants (SSRIs and SNRIs).[15]

Generalized anxiety disorder[edit]

SSRIs are recommended by the National Institute for Health and Clinical 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,[16] and are superior to placebo in treating GAD.[17] The efficacy of different antidepressants is similar.[16][17]

Obsessive compulsive disorder (OCD)[edit]

SSRIs are recommended for the second line treatment of adult obsessive compulsive disorder patients 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.[18] 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.[19][20]

Eating disorders[edit]

Anti-depressants are recommended as an alternative or additional first step to self-help programs in the treatment of bulimia nervosa.[16] SSRIs (fluoxetine in particular) are preferred over other anti-depressants due to their acceptability, tolerability, and superior reduction of symptoms in short term trials. Long term efficacy remains poorly characterized.

Similar recommendations apply to binge eating disorder.[16] SSRIs provide short term reductions in binge eating behavior, but have not been associated with significant weight loss.[21]

Clinical trials have generated mostly negative results for the use of SSRI's in the treatment of anorexia nervosa.[22] Treatment guidelines from the National Institute of Health and Clinical Excellence[16] 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.[21]

Stroke recovery[edit]

SSRIs have been used in the treatment of stroke patients, including those with and without symptoms of depression. A recent meta analysis of randomized, controlled clinical trials found a statistically significant effect of SSRIs on dependence, neurological deficit, depression, and anxiety. There was no statistically significant effect on death, motor deficits, or cognition.[23]

Premature ejaculation[edit]

A general disadvantage of SSRIs in treating premature ejaculation is that they require continuous daily treatment to delay ejaculation significantly.[24] For the occasional "on-demand" treatment, a few hours before coitus, clomipramine gave better results than paroxetine in one study,[25] while in another study both sertraline and clomipramine were indistinguishable from the pause–squeeze technique and inferior to paroxetine.[26] The most recent research, conducted in 2007, suggests that on-demand treatment with sildenafil (Viagra) offers a dramatic improvement in ejaculation delay and sexual satisfaction as compared with daily paroxetine,[27] with on-demand sertraline, paroxetine or clomipramine,[26] and with the pause–squeeze technique.[26][27]

Adverse effects[edit]

General side effects are mostly present during the first one to four weeks while the body adapts to the drug (with the exception of sexual side effects, which tend to occur later in treatment). In fact, it often takes six to eight weeks for the drug to begin reaching its full potential (the slow onset is considered a downside to treatment with SSRIs). Almost all SSRIs are known to cause one or more of these symptoms:

Many side effects disappear after the adaptation phase, when the antidepressant effects begin to come to prominence. However, despite being called general, the side effects and their durations are highly individual and drug-specific. Usually the treatment is begun with a small dose to see how the patient's body reacts to the drug, after that either the dose can be adjusted (e.g. Prozac in the UK is begun at a 20 mg dose, and then adjusted as necessary to 40 mg or 60 mg). Should the drug prove ineffective, or the side effects intolerable to the patient, another common route is to switch treatment to either another SSRI, or an SNRI.[34]

Mania or hypomania is a possible side effect. Users with some type of bipolar disorder are at a much higher risk, however SSRI-induced mania in patients previously diagnosed with unipolar depression can trigger a bipolar episode; however, according to DSM IV-TR, the diagnosis of bipolar disorder requires that the individuals symptoms must not stem from medication side effects, toxins, drug abuse, or another general medical condition.

Sexual dysfunction[edit]

SSRIs can cause various types of sexual dysfunction such as anorgasmia, erectile dysfunction, and diminished libido.[35] It can last for months, years, or sometimes indefinitely after the discontinuation of SSRIs. Initial studies found sexual side effects not significantly different from placebo, but since these studies relied on unprompted reporting, the frequency was probably underestimated. In more recent studies, doctors have specifically asked about sexual difficulties, and found that they are present in between 17% and 41%[36][37] of patients, although the lack of placebo control in these studies means they are likely underestimates. This is because release of extracellular concentrations of serotonin in the brain decreases dopamine and norepinephrine leading to erectile and/or sexual dysfunction.

Stimulation of postsynaptic 5-HT2 and 5-HT3 receptors decreases dopamine and norepinephrine release from the substantia nigra. A number of drugs are not associated with sexual side effects (such as bupropion, mirtazapine, tianeptine, agomelatine and moclobemide,[38][39] some of which are also not associated with weight gain).

A small number of case reports have appeared in the literature suggesting that in rare cases, sexual dysfunction may persist after discontinuing treatment.[40]

On the other hand, the effect of SSRIs to slow down sexual stimulation may be used as treatment; SSRIs have been proposed as a drug to treat premature ejaculation.[41] The Andean herbaceous biennial plant Lepidium meyenii (also known as "maca") was found to be effective for alleviating SSRI-induced sexual dysfunction on a small double-blind, randomized, parallel group dose-finding pilot study.[42]

There is no FDA-approved treatment for SSRI-induced sexual dysfunction and there has been a lack of randomized, placebo-controlled, double-blind studies of potential treatments. There is evidence for the following management strategies: for erectile dysfunction, the addition of a PDE5 inhibitor such as sildenafil; for decreased libido, possibly adding or switching to bupropion; and for overall sexual dysfunction, switching to nefazodone.[43]

Cardiovascular[edit]

Cardiovascular side effects are very rare with SSRI use, with a reported incidence of less than 0.0003 percent.[44] SSRIs inhibit cardiac and vascular sodium, calcium and potassium channels and prolong QT intervals.[45] A number of large studies of patients without known pre-existing heart disease have reported no EKG changes related to SSRI use.[46] More recently, however, concerns about cardiac problems have led to a reduction in the recommended maximum dose of two types of SSRI's. The recommended maximum daily dose of citalopram was reduced to 40 mg for most people and 20 mg for those older than age 60 and some others.[47] The recommended maximum daily dose of escitalopram was reduced to 10 mg for those older than age 65; the maximum daily dose for most other people remained unchanged at 20 mg.[48][49] In overdose, fluoxetine has been reported to cause sinus tachycardia, myocardial infarction, junctional rhythms and trigeminy. Some authors have suggested electrocardiographic monitoring in patients with severe pre-existing cardiovascular disease who are taking SSRI's.[50]

Discontinuation syndrome[edit]

Antidepressants such as SSRIs have some dependence producing effects, most notably a withdrawal syndrome. Their dependence producing properties (depending on the antidepressant) may not be as significant as other psychotropic drugs such as benzodiazepines; however, withdrawal symptoms nonetheless may be quite severe and even debilitating. SSRIs have little abuse potential, but discontinuation can produce disturbing withdrawal symptoms that may be indistinguishable from a reoccurrence of the original illness.[51] Since physical dependence is a reality, discontinuation should be discussed with a medical practitioner before beginning treatment with this class of drugs.

When discontinuing an SSRI or SNRI some doctors may switch the patient to fluoxetine due to its much longer half-life. This may avoid many of the severe withdrawal symptoms associated with SSRI/SNRI discontinuation. This can be done either by administering a single 20 mg dose of fluoxetine or by beginning on a low dosage of fluoxetine and slowly tapering down. Any SSRI or SNRI may be requested in liquid form, which allows very gradual tapering. Alternatively, a patient wishing to stop taking an SSRI/SNRI may visit a compounding pharmacy where his or her prescription may be re-arranged into progressively smaller dosages. For example the lowest dose of cymbalta that can normally be prescribed is 20 mg in gel capsules; a compounding pharmacist may divide this into doses of 20, 15, 10, 5 and 2.5 mg so that a proper tapered reduction may take place.

Suicide risk[edit]

Children and adolescents[edit]

Several studies have found that SSRI use is related to a higher risk of suicidal behavior in children and adolescents.[52][53][54] For instance, a 2004 U.S. Food and Drug Administration (FDA) analysis of clinical trials on children with major depressive disorder found statistically significant increases of the risks of "possible suicidal ideation and suicidal behavior" by about 80%, and of agitation and hostility by about 130%;[55] More infrequently, studies have been inconclusive.[56] However, a recent comparison of aggression and hostility occurring during treatment with fluoxetine to placebo in children and adolescents found that no significant difference between the fluoxetine group and a placebo group.[57] There is also evidence that higher rates of SSRI prescriptions are associated with lower rates of suicide in children, though since the evidence is correlational, the true nature of the relationship is unclear.[58]

In 2004, the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom judged fluoxetine (Prozac) to be the only antidepressant that offered a favorable risk-benefit ratio in children with depression, though it was also associated with a slight increase in the risk of self-harm and suicidal ideation.[59] Only two SSRIs are licensed for use with children in the UK, sertraline (Zoloft) and fluvoxamine (Luvox), and only for the treatment of obsessive–compulsive disorder. Fluoxetine is not licensed for this use.[60]

Adults[edit]

It is unclear whether or not SSRIs affect the risk of suicidal behavior for adults.

Suicide warnings[edit]

The FDA findings resulted in a black box warning on SSRI and other antidepressant medications regarding the increased risk of suicidal behavior in patients younger than 24.[65] Similar precautionary notice revisions were implemented by the Japanese Ministry of Health.[66] In 2004 the Medicines and Healthcare products Regulatory Agency in the United Kingdom issued a warning about increases in 'insomnia, agitation, weight loss, headache, tremor, loss of appetite, self-harm and suicidal thoughts' when the medications are used with children and adolescents.[67]

The introduction of a warning regarding the association between SSRIs and suicide by the FDA in 2004 led to a dramatic decrease in prescriptions of these medications to young people. Originally, there were concerns that the decrease in prescriptions caused by the warnings could increase the number of teenage suicides in the US.[68] However, the most recent data from the US National Center for Health Statistics put these concerns to rest. The suicide rates for persons younger than 25 has actually decreased between 2004 and 2007.[original research?] [69][70]

Pregnancy and breastfeeding[edit]

Administration during pregnancy of SSRI is associated with an increased rate of miscarriages, birth defects, persistent pulmonary hypertension of the newborn, newborn behavioral syndrome, and possibly long term behavioral problems.[71] The risk of spontaneous abortion is increased about 1.7 fold.[72]

The FDA issued a statement on July 19, 2006 stating nursing mothers on SSRIs must discuss treatment with their physicians. However, the medical literature on the safety of SSRIs has determined that some SSRIs like Sertraline and Paroxetine are considered safe for breastfeeding.[73][74][75]

Maternal SSRI use may be associated with autism.[76] A large cohort study published 2013 found no significant association between SSRI use and autism in offspring.[77]

Neonatal abstinence syndrome[edit]

Neonatal abstinence syndrome is a withdrawal syndrome in newborn babies. It has been documented in SSRI treatment. By November 2003, a total of 93 cases of SSRI use associated with either neonatal convulsions or withdrawal syndrome had been reported. Subsequently, the authors of a Lancet study concluded that doctors should avoid or cautiously manage the prescribing of these drugs to pregnant women with psychiatric disorders.[78]

Neuropsychological changes due to SSRI use in infancy[edit]

Since the early 80's scientists have used a technique called neonatal clomipramine to produce animals used in depression research. If rats are given the tricyclic antidepressant clomipramine when 8–21 days old, they develop behavioural changes in adulthood that resemble depression in humans.[79][80] In 1997 Lundbeck found that treatment with the SSRI LU-10-134-C, which only differs from their product citalopram by two atoms could give similar results as clomipramine.[81] Later it was found that neonatal citalopram and escitalopram makes persistent changes in the serotonergic transmission of the brain resulting in behavioral changes,[82][83] which are reversed by treatment with antidepressants.[84] By treating normal and knockout mice lacking the serotonin transporter with fluoxetine scientists showed that normal emotional reactions in adulthood, like a short latency to escape foot shocks and inclination to explore new environments were dependent on active serotonin transporters during the neonatal period.[85][86]

But when young mice were treated with the SNRI desimipramine they developed to normal adults, which suggests that serotonin and norepinephrine have different effects in the developing brain. For humans, the developmental stage sensitive to SSRI:s corresponds with the last trimester to the first years of life. A study showed that 4-year old children perinatally exposed to SSRIs behave normally. However, the young mice and rats also seem normal until they reach puberty and develop behavioural disturbances.[87][88]

The mechanism is currently unknown, but it seems that early life overstimulation of the 5-HT1 receptor that regulates serotonin production results in low serotonin production after puberty.[89]

Persistent pulmonary hypertension[edit]

Persistent pulmonary hypertension (PPHN) is a serious and life-threatening, but rare, lung condition that occurs soon after birth of the newborn. Newborn babies with PPHN have high pressure in their lung blood vessels and are not able to get enough oxygen into their bloodstream. About 1 to 2 babies per 1000 babies born in the U.S. develop PPHN shortly after birth, and often they need intensive medical care. One study has found that PPHN is six times more common in babies whose mothers take an SSRI antidepressant after the 20th week of the pregnancy compared to babies whose mothers do not take an antidepressant.[90]

A population-based cohort study, which included 1.6 million live births in five Nordic countries, of women with filled SSRI prescriptions later than the 20th week gestation by last menstrual period demonstrated an increased risk of persistent pulmonary hypertension (PPHN) compared to control infants (adjusted RR 2.1, 95% CI 1.5-3). The increased risk of PPHN was of similar magnitude for the SSRI class of drugs (Fluoxetine, Citalopram, Paroxetine, Sertraline, Escitalopram). This study showed that the absolute risk of PPHN would only increase the incidence from 0.1 to 0.3 percent of live-births with late prenatal SSRI exposure.[91]

Bleeding tendencies[edit]

SSRIs appear to increase the risk of bleeding.[92][93][94][95] This includes an increased risk of GI bleeding, post operative bleeding,[92] and intracranial bleeding.[96] SSRIs are known to cause platelet dysfunction.[97][98]

Overdose[edit]

SSRIs appear safer in overdose when compared with traditional antidepressants, such as the tricyclic antidepressants. This relative safety is supported both by case series and studies of deaths per numbers of prescriptions.[99] However, case reports of SSRI poisoning have indicated that severe toxicity can occur[100] and deaths have been reported following massive single ingestions,[101] although this is exceedingly uncommon when compared to the tricyclic antidepressants.[99]

Because of the wide therapeutic index of the SSRIs, most patients will have mild or no symptoms following moderate overdoses. The most commonly reported severe effect following SSRI overdose is serotonin syndrome; serotonin toxicity is usually associated with very high overdoses or multiple drug ingestion.[102] Other reported significant effects include coma, seizures, and cardiac toxicity.[99]

The SSRIs, in decreasing toxicity in overdose, can be listed as follows:[103]

Contraindications and drug interaction[edit]

The following drugs may precipitate serotonin syndrome in people on SSRIs:[104][105]

Painkillers of the NSAIDs drug family may interfere and reduce efficiency of SSRIs and may compound the increased risk of gastrointestinal bleeds caused by SSRI use.[93][95][106] NSAIDs include:

There are a number of potential pharmacokinetic interactions between the various individual SSRIs and other medications. Most of these arise from the fact that every SSRI has the ability to inhibit certain P450 cytochromes.[107][108]

Drug NameCYP1A2CYP2C9CYP2C19CYP2D6CYP3A4CYP2B6
Citalopram+00+00
Escitalopram000+00
Fluoxetine++++/+++++++
Fluvoxamine+++++++++++
Paroxetine++++++++++
Sertraline+++/+++++

Legend:
0 — no inhibition.
- — no data available.
+ — mild inhibition.
++ — moderate inhibition.
+++ — strong inhibition.

List of agents[edit]

Drugs in this class include (trade names in parentheses):

Selective serotonin reuptake inhibitors (SSRIs)
Citalopram structure.svg

Citalopram

Dapoxetine Structural Formulae V.1.svg

Dapoxetine

Escitalopram.svg

Escitalopram

Fluoxetine-2D-skeletal.svg

Fluoxetine

Fluvoxamine2DACS.svg

Fluvoxamine

Indalpine.png

Indalpine

Paroxetine.svg

Paroxetine

Sertraline Structural Formulae.png

Sertraline

Zimelidine Structural Formulae V.1.svg

Zimelidine

Related agents[edit]

SSRIs form a subclass of serotonin uptake inhibitors, which includes other non-selective inhibitors as well. Serotonin-norepinephrine reuptake inhibitors, serotonin-norepinephrine-dopamine reuptake inhibitors and selective serotonin reuptake enhancers are also serotonergic antidepressants.

Mechanism of action[edit]

SSRIs are believed to act by inhibiting the reuptake of serotonin after being released in synapses. How much an individual will respond to this, however, also depends on genetics. In addition, several other mechanisms are suggested for the desired effect, e.g. neuroprotection and anti-inflammatory and immunomodulatory factors. Taken together, SSRI has several advantages compared with tricyclic antidepressants (TCA)s and 5-HT-prodrugs. However, the latter might be required in addition to SSRIs in certain situations.

Basic understanding[edit]

In the brain, messages are passed between two nerve cells via a chemical synapse, a small gap between the cells. The (presynaptic) cell that sends the information releases neurotransmitters (including serotonin) into that gap. The neurotransmitters are then recognized by receptors on the surface of the recipient (postsynaptic) cell, which upon this stimulation, in turn, relays the signal. About 10% of the neurotransmitters are lost in this process; the other 90% are released from the receptors and taken up again by monoamine transporters into the sending (presynaptic) cell (a process called reuptake).

To stimulate the recipient cell, SSRIs inhibit the reuptake of serotonin. As a result, the serotonin stays in the synaptic gap longer than it normally would, and may repeatedly stimulate the receptors of the recipient cell. The current model of SSRIs (the Monoamine Hypothesis) assumes that a lower homeostatic level of serotonin is primarily responsible for depression. While this holds in cases of major depression, minor to moderate cases are not as clear cut, and may in fact be caused by excess serotonin in specific areas of the brain.

Some current research points to more than just a single type of chemical signaling - the classic synapse model - involving serotonin. Astrocytes are "helper cells" in the brain that do not participate directly in chemical signaling, but play a part in homeostasis for many chemical levels in the brain. Recent research[109] suggests that serotonin is one of the hormones regulated by astrocytes, and that astrocytes actually uptake, package, and resend serotonin in a way similar to neuronal axons, but do not have corresponding post-synaptic terminals, therefore appearing to function only to control the local levels of serotonin in the cerebrospinal fluid.

Still more research illustrates that the current model for the antidepressant activity of SSRIs may be misdirected, as a drug that works entirely opposite to SSRIs - Tianeptine, a selective serotonin reuptake enhancer - also exhibits antidepressant activity, especially in patients resistant to SSRI therapy. The effect of an SSRE in comparison to an SSRI requires that the nature of serotonin signaling in the areas of the brain related to mood and cognition needs further elucidation. If serotonin firing is regularly phasic (related to brain waves), or rapid and discrete, then SSRIs simply compress the signal potential at affected receptors (bringing down the maximum potential and bring up the minimum) by causing a constant leftover signal (serotonin left in the synaptic gap) coupled with weaker subsequent signals (due to the decrease in presynaptic serotonin available to send new signals). By this hypothetical model, SSREs increase the signal potential separation (min to max) at affected 5-HT sites by reducing the level of free cerebrospinal serotonin and increasing the amount uptaken into axons to send new signals.

Pharmacodynamics[edit]

SSRIs inhibit the reuptake of the neurotransmitter serotonin (5-hydroxytryptamine or 5-HT) into the presynaptic cell, increasing levels of 5-HT within the synaptic cleft.

However, there is one counteracting effect: high serotonin levels will not only activate the postsynaptic receptors, but also flood presynaptic autoreceptors, which serve as a feedback sensor for the cell. Activation of the autoreceptors (by agonists like serotonin) triggers a throttling back of serotonin production. The resulting serotonin deficiency persists for some time, as the transporter inhibition occurs downstream to the cause of the deficiency and therefore, is not able to counterbalance the serotonin deficiency. The body adapts gradually to this situation by lowering (downregulating) the sensitivity of the autoreceptors.[110][dubious ]

Another adaptive process provoked by SSRIs is the downregulation of postsynaptic serotonin 5-HT2A receptors. After the use of an SSRI, since there is more serotonin available, the response is to decrease the number of postsynaptic receptors over time and in the long run, this modifies the serotonin/receptor ratio. This downregulation of 5-HT2A occurs when the antidepressant effects of SSRIs become apparent. Also, deceased suicidal and otherwise depressed patients have had more 5-HT2A receptors than normal patients. These considerations suggest that 5-HT2A overactivity is involved in the pathogenesis of depression.[111]

Most of the serotonin receptors on the surface of the cell are coupled to a G-protein inside it. These proteins activate or inhibit second messengers, which in turn affect transcription factors. Transcription factors are proteins that fit to the beginning of a gene and tell the cell to start using it.

These (slowly proceeding) neurophysiological adaptations of the brain tissue are the reason why usually several weeks of continuous SSRI use is necessary for the antidepressant effect to become fully manifested,[111] and why increased anxiety is a common side effect in the first few days or weeks of use.

Role in BDNF release[edit]

SSRIs act on signal pathways such as cAMP (Cyclic AMP) on the postsynaptic neuronal cell, which leads to the release of Brain Derived Neurotrophic Factor (BDNF). BDNF enhances the growth and survival of cortical neurons and synapses.[112]

Pharmacogenetics[edit]

Large bodies of research are devoted to using genetic markers to predict whether patients will respond to SSRIs or have side effects that will cause their discontinuation, although these tests are not yet ready for widespread clinical use.[113] Single-nucleotide polymorphisms of the 5-HT(2A) gene correlated with paroxetine discontinuation due to side effects in a group of elderly patients with major depression, but not mirtazapine (a non-SSRI antidepressant) discontinuation.[114]

Neuroprotection[edit]

Studies have suggested that SSRIs may promote the growth of new neural pathways or neurogenesis in rats.[115] Also, SSRIs may protect against neurotoxicity caused by other compounds (for instance fenfluramine) as well as from depression itself. SSRIs have been found to induce programmed cell death in Burkitt lymphoma and the brain tumors neuroblastoma and glioma with minimal effect on normal tissue.[116][117]

Anti-inflammatory and immunomodulation[edit]

Recent studies show pro-inflammatory cytokine processes take place during depression, mania and bipolar disorder, in addition to somatic disease (such as autoimmune hypersensitivity) and it is possible that symptoms manifest in these psychiatric illnesses are being attenuated by pharmacological effect of antidepressants on the immune system.[118][119][120][121][122]

SSRIs have demonstrated immunomodulatory and anti-inflammatory effects 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.[123][124][125][126]

Future serotonergic 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.[127]

SSRIs versus TCAs[edit]

SSRIs are described as 'selective' because they affect only the reuptake pumps responsible for serotonin, as opposed to earlier antidepressants, which affect other monoamine neurotransmitters as well, and as a result, SSRIs have fewer side effects.

There appears no significant difference in effectiveness between SSRIs and tricyclic antidepressants, which were the most commonly used class of antidepressants before the development of SSRIs.[128] However, SSRIs have the important advantage that their toxic dose is high, and, therefore, they are much more difficult to use as a means to commit suicide. Further, they have fewer and milder side effects. Tricyclic antidepressant also have a higher risk of serious cardiovascular side effects, which SSRIs lack.

SSRIs versus 5-HT-Prodrugs[edit]

Serotonin cannot be administered directly because when ingested orally, it will not cross the blood–brain barrier, and therefore would have no effect on brain functions. Also, serotonin would activate every synapse it reaches, whereas SSRIs only enhance a signal that is already present, but too weak to come through. The selectivity of the membrane can be reduced for a drug by injecting it in a concentrated sugar solution. The high osmotic pressure of the sugar solution causes the endothelial cells of the capillaries to shrink, which opens gaps between their tight junctions and makes the barrier more permeable. As a result the drug can enter the brain tissue.

SSRIs together with 5-HT-Prodrugs[edit]

Biosynthetic serotonin is made from tryptophan, an amino acid. In 1989, the Food and Drug Administration made tryptophan available by prescription only, in response to an outbreak of eosinophilia-myalgia syndrome caused by impure L-tryptophan supplements sold over-the-counter. With current standards, L-tryptophan is again available over the counter in the US as well as supplement 5-HTP, which is a direct precursor to serotonin.

Society and culture[edit]

Criticism[edit]

A recent international review article, says that the idea that antidepressants might contribute to suicide in depressed patients was first raised in 1958. For 30 years antidepressants were primarily used in severely depressed and often hospitalised patients. The issue of suicidality on selective serotonin reuptake inhibitors (SSRIs) became one of public concern with reports in 1990 that Prozac could lead to suicidality in patients.[129] Fourteen years later, warning labels were put on antidepressants suggesting particular difficulties "during the early phase of treatment, during treatment discontinuation, and when the dose of treatment is being changed, and that treatment related risks may be present in patients being treated for syndromes other than depression, such as anxiety or smoking cessation".[129]

In late 2004 media attention was given to a proposed link between SSRI use and juvenile suicide. For this reason, the use of SSRIs in pediatric cases of depression is now recognized by the United States FDA as warranting a cautionary statement to the parents of children who may be prescribed SSRIs by a family doctor. The FDA's currently required packaging insert for SSRIs includes a warning (known as a "black box warning") that a pooled analysis of placebo controlled trials of 9 antidepressant drugs (including multiple SSRIs) resulted in a risk of suicidal behavior that was twice that of placebo. At the same time, in adults SSRIs do not increase the risk of suicide.[130]

Critics of SSRIs claim that the widely disseminated television and print advertising of SSRIs promotes an inaccurate message, oversimplifying what these medications actually do and deceiving the public.[131]

The criticism stems from questions about the validity of claims that SSRIs work by 'correcting' chemical imbalances. Without accurately measuring patients' neurotransmitter levels to allow for continuous monitoring during treatment, it is impossible to know if one is correctly targeting a deficient neurotransmitter (i.e. correcting an imbalance), reaching a desirable level, or even introducing too much of a particular neurotransmitter. Thus it has been argued that SSRIs can actually cause chemical imbalances and abnormal brain states, as evidenced by the fact that many report problems of sexual dysfunction, whose effects last long after the medication has been discontinued. Hence, it is purported that when a patient discontinues an SSRI, they may have a chemical imbalance due to the rapid cessation of the drug that causes the discontinuation syndrome.[132]

One possible mechanism is by inhibition of dopaminergic neurotransmission.[133]

Biopsychiatrists believe that, among other factors, the balance of neurotransmitters in the brain is a biological regulator of mental health. In this theory, emotions within a "normal" spectrum reflect a proper balance of neurochemicals, but abnormally extreme emotions, such as clinical depression, reflect an imbalance. Psychiatrists[who?] claim that medications regulate neurotransmitters, and many if not most psychiatrists also claim they treat abnormal personalities by removing a neurochemical excess or replenishing a deficit.[citation needed] On the other hand, Elliot Valenstein, a psychologist and neuroscientist, claims that the broad biochemical assertions and assumptions of mainstream psychiatry are not supported by evidence.[134]

One controversial critic of antidepressants, Peter Breggin, a physician who opposes the overuse of prescription medications to treat patients for mental health issues, predicted iatrogenic issues that SSRIs incur on a significant percentage of patients. Another prominent SSRI critic is David Healy.

A widely reported meta-analysis combined 35 clinical trials submitted to the U.S. Food and Drug Administration (FDA) before licensing of four newer antidepressants (including the SSRIs paroxetine and fluoxetine, and two non-SSRI antidepressants nefazodone and venlafaxine). The authors found that although the antidepressants were statistically superior to placebo they did not exceed the NICE criteria for a 'clinically significant' effect. For more detail, see the section "Efficacy".

A study in The New England Journal of Medicine on a possible publication bias regarding the efficacy of SSRI medications in the treatment of depression suggests that their effectiveness and risk-benefit ratios may be greatly exaggerated. Of 74 studies registered with the United States FDA, 37 with positive results were published in academic journals, while 22 studies with negative results were not published and 11 with negative results were published in a way that conveyed a positive outcome (one positive study was not published and three negative studies were published with results that were portrayed as negative). Overall, 94% of studies actually published were positive outcomes; when published and unpublished studies were included for analysis, the percentage of positive outcomes was 51%.[135]

Although controversial, the existence of an SSRI-related withdrawal syndrome mimicking depression may inflate the therapeutic effect size reported in long-term (more than 6 months) placebo controlled trials of SSRI’s, due to a reliance on randomized discontinuation designs. Discontinuation trials are a variant of the classic 2-arm placebo controlled randomized controlled trials used in shorter placebo controlled studies of SSRI’s.[136][137]

Regulation[edit]

All SSRIs are approved in the U.S. for use with psychiatric disorders as outlined in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV).

Approved uses for SSRIs vary by country and are determined by the overseeing branch of government in charge of regulating drugs. In the U.S., the Food and Drug Administration (FDA) approves drugs after trial results have been submitted by the pharmaceutical companies. In Europe, drugs can be approved either by the European Medicines Agency for human consumption throughout the European Union or by the regulatory agencies of individual countries for use within those countries.[citation needed]. In Canada, the drug approval process is carried out by Health Canada.

Lawsuits[edit]

Hundreds of lawsuits have been filed against drug manufacturers seeking compensation for harm attributed to the use of SSRIs. Suits based on product liability, for example, often allege failure to adequately warn users of potential side effects. Manufacturers have defended many suits on the merits and settled many others. In 2005, the U.S. FDA asked manufacturers to include black box warnings on antidepressant drug packaging.[138] Though a 2007 study[139] purportedly showed that the black box "warnings discouraged use of antidepressants in children and adolescents and... led to increases in suicide rates as a result of untreated depression" an article in the New York Times[140] that ran two weeks later questioned the results of the study, claiming that the data did not support a causal link between the black box warning and increased rates of suicide.

See also[edit]

References[edit]

  1. ^ Barlow, David H. Durand, V. Mark (2009). "Chapter 7: Mood Disorders and Suicide". Abnormal Psychology: An Integrative Approach (Fifth ed.). Belmont, CA: Wadsworth Cengage Learning. p. 239. ISBN 0-495-09556-7. OCLC 192055408. 
  2. ^ a b Preskorn SH, Ross R, Stanga CY (2004). "Selective Serotonin Reuptake Inhibitors". In Sheldon H. Preskorn, Hohn P. Feighner, Christina Y. Stanga and Ruth Ross. Antidepressants: Past, Present and Future. Berlin: Springer. pp. 241–62. ISBN 978-3-540-43054-4. 
  3. ^ a b c Jay C. Fournier, MA; Robert J. DeRubeis, PhD; Steven D. Hollon, PhD; Sona Dimidjian, PhD; Jay D. Amsterdam, MD; Richard C. Shelton, MD; Jan Fawcett, MD (January 2010). "Antidepressant Drug Effects and Depression Severity". The Journal of the American Medical Association 303 (1): 47–53. doi:10.1001/jama.2009.1943. PMC 3712503. PMID 20051569. 
  4. ^ a b Kramer, Peter (7 Sep 2011). "In Defense of Antidepressants". The New York Times. Retrieved 13 July 2011. 
  5. ^ a b Ronald Pies, MD (April 2010). "Antidepressants Work, Sort of-Our System of Care Does Not". Journal of Clinical Psychopharmacology 30 (2): 101–104. doi:10.1097/JCP.0b013e3181d52dea. PMID 20520282. 
  6. ^ Medford, Nick. "Understanding and treating depersonalization disorder". Advances in Psychiatric Treatment (2005). Retrieved 2011-11-11. 
  7. ^ a b "www.nice.org.uk". 
  8. ^ Depression: The NICE Guideline on the Treatment and Management of Depression in Adults (Updated Edition). RCPsych Publications. 2010. ISBN 1-904671-85-3. 
  9. ^ a b Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT (February 2008). "Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration". PLoS Medicine 5 (2): e45. doi:10.1371/journal.pmed.0050045. PMC 2253608. PMID 18303940. 
  10. ^ Horder J, Matthews P, Waldmann R (June 2010). "Placebo, Prozac and PLoS: significant lessons for psychopharmacology". Journal of Psychopharmacology 25 (10): 1277–88. doi:10.1177/0269881110372544. PMID 20571143. 
  11. ^ Fountoulakis KN, Moller H-J (August 2010). "Efficacy of antidepressants: a re-analysis and re-interpretation of the Kirsch data". International Journal of Neuropsychopharmacology 14 (3): 1–8. doi:10.1017/S1461145710000957. PMID 20800012. 
  12. ^ John Kelley (March 2, 2010). "Antidepressants: Do They "Work" or Don't They?". Scientific American. 
  13. ^ "www.nice.org.uk". 
  14. ^ Coupland CA, Dhiman P, Barton G, et al. (August 2011). "A study of the safety and harms of antidepressant drugs for older people: a cohort study using a large primary care database". Health Technol Assess 15 (28): 1–202, iii–iv. doi:10.3310/hta15280. PMID 21810375. 
  15. ^ Gartlehner G, Hansen RA, Morgan LC, et al. (December 2011). "Comparative benefits and harms of second-generation antidepressants for treating major depressive disorder: an updated meta-analysis". Ann. Intern. Med. 155 (11): 772–85. doi:10.7326/0003-4819-155-11-201112060-00009. PMID 22147715. 
  16. ^ a b c d e "www.nice.org.uk". Retrieved 2013-02-20. 
  17. ^ a b Kapczinski F, Lima MS, Souza JS, Schmitt R (2003). "Antidepressants for generalized anxiety disorder". In Kapczinski, Flavio FK. Cochrane Database Syst Rev (2): CD003592. doi:10.1002/14651858.CD003592. PMID 12804478. 
  18. ^ "www.nice.org.uk". 
  19. ^ Arroll B, Elley CR, Fishman T, et al. (2009). "Antidepressants versus placebo for depression in primary care". In Arroll, Bruce. Cochrane Database Syst Rev (3): CD007954. doi:10.1002/14651858.CD007954. PMID 19588448. 
  20. ^ "Medscape Log In". 
  21. ^ a b "National Guideline Clearinghouse | Practice guideline for the treatment of patients with eating disorders". 
  22. ^ Flament MF, Bissada H, Spettigue W (March 2012). "Evidence-based pharmacotherapy of eating disorders". Int. J. Neuropsychopharmacol. 15 (2): 189–207. doi:10.1017/S1461145711000381. PMID 21414249. 
  23. ^ Mead GE, Hsieh CF, Lee R, et al. (2012). "Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery". In Mead, Gillian E. Cochrane Database Syst Rev 11: CD009286. doi:10.1002/14651858.CD009286.pub2. PMID 23152272. 
  24. ^ Waldinger MD (November 2007). "Premature ejaculation: state of the art". The Urologic Clinics of North America 34 (4): 591–9, vii–viii. doi:10.1016/j.ucl.2007.08.011. PMID 17983899. 
  25. ^ Waldinger MD, Zwinderman AH, Olivier B (October 2004). "On-demand treatment of premature ejaculation with clomipramine and paroxetine: a randomized, double-blind fixed-dose study with stopwatch assessment". European Urology 46 (4): 510–5; discussion 516. doi:10.1016/j.eururo.2004.05.005. PMID 15363569. 
  26. ^ a b c Abdel-Hamid IA, El Naggar EA, El Gilany AH (February 2001). "Assessment of as needed use of pharmacotherapy and the pause-squeeze technique in premature ejaculation". International Journal of Impotence Research 13 (1): 41–5. doi:10.1038/sj.ijir.3900630. PMID 11313839. 
  27. ^ a b Wang WF, Wang Y, Minhas S, Ralph DJ (April 2007). "Can sildenafil treat primary premature ejaculation? A prospective clinical study". International Journal of Urology 14 (4): 331–5. doi:10.1111/j.1442-2042.2007.01606.x. PMID 17470165. 
  28. ^ Wu Q, Bencaz AF, Hentz JG, Crowell MD (January 2012). "Selective serotonin reuptake inhibitor treatment and risk of fractures: a meta-analysis of cohort and case-control studies". Osteoporos Int 23 (1): 365–75. doi:10.1007/s00198-011-1778-8. PMID 21904950. 
  29. ^ (English) Stahl SM, Lonnen AJ. « The Mechanism of Drug-induced Akathsia » CNS Spectr. 2011. pii: Stahl. PMID 21406165
  30. ^ (English) Lane RM. « SSRI-induced extrapyramidal side-effects and akathisia: implications for treatment. » J Psychopharmacol. 1998;12(2):192-214 PMID 9694033
  31. ^ (English) Koliscak LP, Makela EH. « Selective serotonin reuptake inhibitor-induced akathisia. » J Am Pharm Assoc. (2003). 2009 Mar-Apr;49(2):e28-36; quiz e37-8 PMID 19289334
  32. ^ (English) Leo RJ. « Movement disorders associated with the serotonin selective reuptake inhibitors. » J Clin Psychiatry. 1996 Oct;57(10):449-54 PMID 8909330
  33. ^ September 23, 2012. "SSRIs and Depression". Emedicinehealth.com. Retrieved 2012-09-23. 
  34. ^ A landmark study in the use of anti-depressants and their role in step-therapy can be found in the STAR*D trial.
  35. ^ Coleman, E. (2011). "Chapter 28. Impulsive/compulsive sexual behavior: Assessment and treatment". In Grant, Jon E.; Potenza, Marc N. The Oxford Handbook of Impulse Control Disorders. New York: Oxford University Press. p. 385. ISBN 9780195389715. 
  36. ^ Hu XH, Bull SA, Hunkeler EM, et al. (July 2004). "Incidence and duration of side effects and those rated as bothersome with selective serotonin reuptake inhibitor treatment for depression: patient report versus physician estimate". The Journal of Clinical Psychiatry 65 (7): 959–65. doi:10.4088/JCP.v65n0712. PMID 15291685. 
  37. ^ Landén M, Högberg P, Thase ME (January 2005). "Incidence of sexual side effects in refractory depression during treatment with citalopram or paroxetine". The Journal of Clinical Psychiatry 66 (1): 100–6. doi:10.4088/JCP.v66n0114. PMID 15669895. 
  38. ^ Clayton, Anita H. (2003). "Antidepressant-Associated Sexual Dysfunction: A Potentially Avoidable Therapeutic Challenge". Primary Psychiatry 10 (1): 55–61. 
  39. ^ Kanaly KA, Berman JR (December 2002). "Sexual side effects of SSRI medications: potential treatment strategies for SSRI-induced female sexual dysfunction". Current Women's Health Reports 2 (6): 409–16. PMID 12429073. 
  40. ^ Csoka AB, Bahrick AS, Mehtonen O-P (2008). "Persistent Sexual Dysfunction after Discontinuation of Selective Serotonin Reuptake Inhibitors (SSRIs)". J Sex Med. 5 (1): 227–33. doi:10.1111/j.1743-6109.2007.00630.x. PMID 18173768. 
  41. ^ Waldinger MD, Olivier B (July 2004). "Utility of selective serotonin reuptake inhibitors in premature ejaculation". Current Opinion in Investigational Drugs 5 (7): 743–7. PMID 15298071. 
  42. ^ Dording CM, Fisher L, Papakostas G, et al. (2008). "A double-blind, randomized, pilot dose-finding study of maca root (L. meyenii) for the management of SSRI-induced sexual dysfunction". CNS Neurosci Ther 14 (3): 182–91. doi:10.1111/j.1755-5949.2008.00052.x. PMID 18801111. 
  43. ^ Balon R (2006). "SSRI-Associated Sexual Dysfunction". The American Journal of Psychiatry 163 (9): 1504–9; quiz 1664. doi:10.1176/appi.ajp.163.9.1504. PMID 16946173. 
  44. ^ Huffman, Grace Brooke (August 1997). "Cardiac effects in patients using SSRI antidepressants - selective serotonin reuptake inhibitor - Tips from Other Journals". American Family Physician. 
  45. ^ Pacher P, Kecskemeti V (2004). "Cardiovascular Side Effects of New Antidepressants and Antipsychotics: New Drugs, old Concerns?". Current Pharmaceutical Design 10 (20): 2463–75. doi:10.2174/1381612043383872. PMC 2493295. PMID 15320756. 
  46. ^ Goldberg RJ (1998). "Selective serotonin reuptake inhibitors: infrequent medical adverse effects". Archives of Family Medicine 7 (1): 78–84. doi:10.1001/archfami.7.1.78. PMID 9443704. 
  47. ^ FDA. "FDA Drug Safety". 
  48. ^ [ref1]
  49. ^ "ref2" (PDF). Retrieved 2012-09-23. 
  50. ^ Pacher P, Ungvari Z, Nanasi PP, Furst S, Kecskemeti V (June 1999). "Speculations on difference between tricyclic and selective serotonin reuptake inhibitor antidepressants on their cardiac effects. Is there any?". Current Medicinal Chemistry 6 (6): 469–80. PMID 10213794. 
  51. ^ van Broekhoven F, Kan CC, Zitman FG (June 2002). "Dependence potential of antidepressants compared to benzodiazepines". Prog. Neuropsychopharmacol. Biol. Psychiatry 26 (5): 939–43. doi:10.1016/S0278-5846(02)00209-9. PMID 12369270. 
  52. ^ a b Stone MB, Jones ML (2006-11-17). "Clinical review: relationship between antidepressant drugs and suicidal behavior in adults" (PDF). Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC). FDA. pp. 11–74. Retrieved 2007-09-22. 
  53. ^ Levenson M, Holland C (2006-11-17). "Statistical Evaluation of Suicidality in Adults Treated with Antidepressants" (PDF). Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC). FDA. pp. 75–140. Retrieved 2007-09-22. 
  54. ^ a b Olfson M, Marcus SC, Shaffer D (August 2006). "Antidepressant drug therapy and suicide in severely depressed children and adults: A case-control study". Archives of General Psychiatry 63 (8): 865–72. doi:10.1001/archpsyc.63.8.865. PMID 16894062. 
  55. ^ Hammad TA (2004-08-116). "Review and evaluation of clinical data. Relationship between psychiatric drugs and pediatric suicidal behavior" (PDF). FDA. pp. 42; 115. Retrieved 2008-05-29. 
  56. ^ Hetrick S, Merry S, McKenzie J, Sindahl P, Proctor M (2007). "Selective serotonin reuptake inhibitors (SSRIs) for depressive disorders in children and adolescents". In Hetrick, Sarah E. Cochrane Database Syst Rev (3): CD004851. doi:10.1002/14651858.CD004851.pub2. PMID 17636776. 
  57. ^ Meta-Analysis of Aggression and/or Hostility-Related Events in Children and Adolescents Treated with Fluoxetine Compared with Placebo Journal of Child and Adolescent Psychopharmacology. October 2007; 17(5) 713-718. doi:10.1089/cap.2006.0138.
  58. ^ Gibbons RD, Hur K, Bhaumik DK, Mann JJ (November 2006). "The relationship between antidepressant prescription rates and rate of early adolescent suicide". The American Journal of Psychiatry 163 (11): 1898–904. doi:10.1176/appi.ajp.163.11.1898. PMID 17074941. 
  59. ^ "Report of the CSM expert working group on the safety of selective serotonin reuptake inhibitor antidepressants" (PDF). MHRA. 2004-12-01. Retrieved 2007-09-25. 
  60. ^ "Selective Serotonin Reuptake Inhibitors (SSRIs): Overview of regulatory status and CSM advice relating to major depressive disorder (MDD) in children and adolescents including a summary of available safety and efficacy data". MHRA. 2005-09-29. Retrieved 2008-05-29. 
  61. ^ Gunnell D, Saperia J, Ashby D (February 2005). "Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults: meta-analysis of drug company data from placebo controlled, randomised controlled trials submitted to the MHRA's safety review". BMJ 330 (7488): 385. doi:10.1136/bmj.330.7488.385. PMC 549105. PMID 15718537. 
  62. ^ Fergusson D, Doucette S, Glass KC, et al. (February 2005). "Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomised controlled trials". BMJ 330 (7488): 396. doi:10.1136/bmj.330.7488.396. PMC 549110. PMID 15718539. 
  63. ^ Rihmer Z, Akiskal H (August 2006). "Do antidepressants t(h)reat(en) depressives? Toward a clinically judicious formulation of the antidepressant-suicidality FDA advisory in light of declining national suicide statistics from many countries". J Affect Disord 94 (1–3): 3–13. doi:10.1016/j.jad.2006.04.003. PMID 16712945. 
  64. ^ Hall WD, Lucke J (2006). "How have the selective serotonin reuptake inhibitor antidepressants affected suicide mortality?". Aust N Z J Psychiatry 40 (11–12): 941–50. doi:10.1111/j.1440-1614.2006.01917.x. PMID 17054562. 
  65. ^ "FDA Proposes New Warnings About Suicidal Thinking, Behavior in Young Adults Who Take Antidepressant Medications". FDA. 2007-05-02. Retrieved 2008-05-29. 
  66. ^ "www1.mhlw.go.jp" (PDF). Japanese Ministry of Health (in Japanese). 
  67. ^ "Questions and answers: Advice on SSRIs in children from the Committee on Safety of Medicine" (PDF). Medicines and Healthcare products Regulatory Agency. 
  68. ^ Gibbons RD, Brown CH, Hur K, et al. (September 2007). "Early evidence on the effects of regulators' suicidality warnings on SSRI prescriptions and suicide in children and adolescents". The American Journal of Psychiatry 164 (9): 1356–63. doi:10.1176/appi.ajp.2007.07030454. PMID 17728420. 
  69. ^ Xu J, Kochanek KD, Tejada-Vera B (August 2009). "Deaths: Preliminary Data for 2007" (PDF). National Vital Statistics Reports 58 (1): 29–30. Retrieved 2009-09-20. 
  70. ^ Heron M, Hoyert DL, Murphy SL,et al. (April 2009). "Deaths: Final Data for 2006" (PDF). National Vital Statistics Reports 57 (14): 30. Retrieved 2009-09-20. 
  71. ^ Domar, A. D.; Moragianni, V. A.; Ryley, D. A.; Urato, A. C. (31 October 2012). "The risks of selective serotonin reuptake inhibitor use in infertile women: a review of the impact on fertility, pregnancy, neonatal health and beyond". Human Reproduction 28 (1): 160–71. doi:10.1093/humrep/des383. PMID 23117129. 
  72. ^ Rahimi, Roja; Shekoufeh Nikfar, Mohammad Abdollahi (2006). "Pregnancy outcomes following exposure to serotonin reuptake inhibitors: a meta-analysis of clinical trials". Reproductive Toxicology 22 (4): 571–575. doi:10.1016/j.reprotox.2006.03.019. PMID 16720091. 
  73. ^ "Breastfeeding Update: SDCBC's quarterly newsletter". Breastfeeding.org. Retrieved 2010-07-10. [dead link]
  74. ^ "Using Antidepressants in Breastfeeding Mothers". kellymom.com. Retrieved 2010-07-10. 
  75. ^ Gentile S, Rossi A, Bellantuono C (2007). "SSRIs during breastfeeding: spotlight on milk-to-plasma ratio". Archives of Women's Mental Health 10 (2): 39–51. doi:10.1007/s00737-007-0173-0. PMID 17294355. 
  76. ^ USA (2012-05-24). "Antidepressant use during pregnancy and ... [Arch Gen Psychiatry. 2011] - PubMed - NCBI". Ncbi.nlm.nih.gov. Retrieved 2012-09-23. 
  77. ^ Hviid, Anders; Mads Melbye and Björn Pasternak (19 December 2013). "Use of selective serotonin reuptake inhibitors during pregnancy and risk of autism". The New England Journal of Medicine 369: 2406–2415. doi:10.1056/NEJMoa1301449. Retrieved 18 December 2013. 
  78. ^ Medicalnewstoday.com Medical News Today - Lancet Press Release. Feb 05 2005
  79. ^ Vogel G, Neill D, Hagler M, Kors D (1990). "A new animal model of endogenous depression: a summary of present findings". Neuroscience and Biobehavioral Reviews 14 (1): 85–91. doi:10.1016/S0149-7634(05)80164-2. PMID 2183099. 
  80. ^ Velazquez-Moctezuma J, Aguilar-Garcia A, Diaz-Ruiz O (September 1993). "Behavioral effects of neonatal treatment with clomipramine, scopolamine, and idazoxan in male rats". Pharmacology, Biochemistry, and Behavior 46 (1): 215–7. doi:10.1016/0091-3057(93)90343-R. PMID 7902983. 
  81. ^ Hansen HH, Sánchez C, Meier E (December 1997). "Neonatal administration of the selective serotonin reuptake inhibitor Lu 10-134-C increases forced swimming-induced immobility in adult rats: a putative animal model of depression?". The Journal of Pharmacology and Experimental Therapeutics 283 (3): 1333–41. PMID 9400008. 
  82. ^ Popa D, Léna C, Alexandre C, Adrien J (April 2008). "Lasting syndrome of depression produced by reduction in serotonin uptake during postnatal development: evidence from sleep, stress, and behavior". The Journal of Neuroscience 28 (14): 3546–54. doi:10.1523/JNEUROSCI.4006-07.2008. PMID 18385313. 
  83. ^ Maciag D, Simpson KL, Coppinger D, et al. (January 2006). "Neonatal Antidepressant Exposure has Lasting Effects on Behavior and Serotonin Circuitry". Neuropsychopharmacology 31 (1): 47–57. doi:10.1038/sj.npp.1300823. PMC 3118509. PMID 16012532. 
  84. ^ Maciag D, Williams L, Coppinger D, Paul IA (February 2006). "Neonatal citalopram exposure produces lasting changes in behavior which are reversed by adult imipramine treatment". European Journal of Pharmacology 532 (3): 265–9. doi:10.1016/j.ejphar.2005.12.081. PMC 2921633. PMID 16483567. 
  85. ^ Holden C (October 2004). "Neuroscience. Prozac treatment of newborn mice raises anxiety". Science 306 (5697): 792. doi:10.1126/science.306.5697.792. PMID 15514122. 
  86. ^ Ansorge MS, Zhou M, Lira A, Hen R, Gingrich JA (October 2004). "Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice". Science 306 (5697): 879–81. doi:10.1126/science.1101678. PMID 15514160. 
  87. ^ Ansorge MS, Morelli E, Gingrich JA (January 2008). "Inhibition of serotonin but not norepinephrine transport during development produces delayed, persistent perturbations of emotional behaviors in mice". The Journal of Neuroscience 28 (1): 199–207. doi:10.1523/JNEUROSCI.3973-07.2008. PMID 18171937. 
  88. ^ Misri S, Reebye P, Kendrick K, et al. (June 2006). "Internalizing behaviors in 4-year-old children exposed in utero to psychotropic medications". The American Journal of Psychiatry 163 (6): 1026–32. doi:10.1176/appi.ajp.163.6.1026. PMID 16741203. 
  89. ^ Maciag D, Coppinger D, Paul IA (December 2006). "Evidence that the deficit in sexual behavior in adult rats neonatally exposed to citalopram is a consequence of 5-HT1 receptor stimulation during development". Brain Research 1125 (1): 171–5. doi:10.1016/j.brainres.2006.10.009. PMC 1762094. PMID 17101120. 
  90. ^ FDA.gov, FDA Public Health Advisory - Treatment Challenges of Depression in Pregnancy
  91. ^ [1], Kieler H, Artama M, Engeland A, Ericsson O, Furu K, Gissler M, Nielsen RB, Norgaard M, Stephansson O, Valdimarsdottir U, Zoega H, Haglund B." Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn: population based cohort study from the five Nordic countries" BMJ 2012;344:d8012
  92. ^ a b Weinrieb, RM; Auriacombe, M; Lynch, KG; Lewis, JD (March 2005). "Selective serotonin re-uptake inhibitors and the risk of bleeding". Expert opinion on drug safety 4 (2): 337–44. doi:10.1517/14740338.4.2.337. PMID 15794724. 
  93. ^ a b Taylor, D; Carol, P; Shitij, K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. ISBN 9780470979693. 
  94. ^ Andrade, C; Sandarsh, S; Chethan, KB; Nagesh, KS (December 2010). "Serotonin Reuptake Inhibitor Antidepressants and Abnormal Bleeding: A Review for Clinicians and a Reconsideration of Mechanisms". The Journal of Clinical Psychiatry 71 (12): 1565–1575. doi:10.4088/JCP.09r05786blu. PMID 21190637. 
  95. ^ a b de Abajo, FJ; García-Rodríguez, LA (July 2008). "Risk of upper gastrointestinal tract bleeding associated with selective serotonin reuptake inhibitors and venlafaxine therapy: interaction with nonsteroidal anti-inflammatory drugs and effect of acid-suppressing agents". Archives of General Psychiatry 65 (7): 795–803. doi:10.1001/archpsyc.65.7.79. PMID 18606952. 
  96. ^ http://www.neurology.org/content/early/2012/10/17/WNL.0b013e318271f848.abstract Selective serotonin reuptake inhibitors and brain hemorrhage
  97. ^ Serebruany VL (February 2006). "Selective serotonin reuptake inhibitors and increased bleeding risk: are we missing something?". The American Journal of Medicine 119 (2): 113–6. doi:10.1016/j.amjmed.2005.03.044. PMID 16443409. 
  98. ^ Halperin D, Reber G (2007). "Influence of antidepressants on hemostasis". Dialogues in Clinical Neuroscience 9 (1): 47–59. PMC 3181838. PMID 17506225. 
  99. ^ a b c Isbister G, Bowe S, Dawson A, Whyte I (2004). "Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose". J Toxicol Clin Toxicol 42 (3): 277–85. doi:10.1081/CLT-120037428. PMID 15362595. 
  100. ^ Borys D, Setzer S, Ling L, Reisdorf J, Day L, Krenzelok E (1992). "Acute fluoxetine overdose: a report of 234 cases". Am J Emerg Med 10 (2): 115–20. doi:10.1016/0735-6757(92)90041-U. PMID 1586402. 
  101. ^ Oström M, Eriksson A, Thorson J, Spigset O (1996). "Fatal overdose with citalopram". Lancet 348 (9023): 339–40. doi:10.1016/S0140-6736(05)64513-8. PMID 8709713. 
  102. ^ Sporer K (1995). "The serotonin syndrome. Implicated drugs, pathophysiology and management". Drug Saf 13 (2): 94–104. doi:10.2165/00002018-199513020-00004. PMID 7576268. 
  103. ^ White, N; Litovitz, T; Clancy, C (December 2008). "Suicidal antidepressant overdoses: a comparative analysis by antidepressant type". Journal of Medical Toxicology 4 (4): 238–250. doi:10.1007/BF03161207. PMC 3550116. PMID 19031375.  edit
  104. ^ Ener, RA; Meglathery, SB; Decker, WAV; Gallagher, RM (March 2003). "Serotonin Syndrome and Other Serotonergic Disorders". Pain Medicine 4 (1): 63–74. doi:10.1046/j.1526-4637.2003.03005.x. PMID 12873279. 
  105. ^ Boyer, EW; Shannon, M (2005). "The serotonin syndrome". The New England Journal of Medicine 352 (11): 1112–1120. doi:10.1056/NEJMra041867. PMID 15784664. 
  106. ^ Solomon H. Snyder. "J.L. Warner-Schmidt et.al "Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans" PNAS 2011". Pnas.org. Retrieved 2012-09-23. 
  107. ^ Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman’s The Pharmacological Basis of Therapeutics (12th ed.). McGraw Hill Professional. ISBN 978-0071624428. 
  108. ^ Ciraulo, DA; Shader, RI (2011). Pharmacotherapy of Depression (2nd ed.). Springer. p. 49. doi:10.1007/978-1-60327-435-7. ISBN 978-1-60327-435-7. 
  109. ^ Watson, Cheryl et al. "Serotonin Regulation by Astrocytes". The FASEB Journal. 
  110. ^ Gobbi M, Crespi D, Foddi MC, et al. (July 1997). "Effects of chronic treatment with fluoxetine and citalopram on 5-HT uptake, 5-HT1B autoreceptors, 5-HT3 and 5-HT4 receptors in rats". Naunyn-Schmiedeberg's Archives of Pharmacology 356 (1): 22–8. doi:10.1007/PL00005024. PMID 9228186. 
  111. ^ a b Eison AS, Mullins UL (1996). "Regulation of central 5-HT2A receptors: a review of in vivo studies". Behavioural Brain Research 73 (1–2): 177–81. doi:10.1016/0166-4328(96)00092-7. PMID 8788498. 
  112. ^ Kolb, Bryan and Wishaw Ian. An Introduction to Brain and Behavior. New York: Worth Publishers 2006, Print.
  113. ^ Rasmussen-Torvik LJ, McAlpine DD (2007). "Genetic screening for SSRI drug response among those with major depression: great promise and unseen perils". Depression and Anxiety 24 (5): 350–7. doi:10.1002/da.20251. PMID 17096399. 
  114. ^ Murphy GM, Kremer C, Rodrigues HE, Schatzberg AF (October 2003). "Pharmacogenetics of antidepressant medication intolerance". The American Journal of Psychiatry 160 (10): 1830–5. doi:10.1176/appi.ajp.160.10.1830. PMID 14514498. 
  115. ^ Malberg JE, Eisch AJ, Nestler EJ, Duman RS (December 2000). "Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus". The Journal of Neuroscience 20 (24): 9104–10. PMID 11124987. 
  116. ^ Levkovitz Y, Gil-Ad I, Zeldich E, Dayag M, Weizman A (2005). "Differential induction of apoptosis by antidepressants in glioma and neuroblastoma cell lines: evidence for p-c-Jun, cytochrome c, and caspase-3 involvement". Journal of Molecular Neuroscience 27 (1): 29–42. doi:10.1385/JMN:27:1:029. PMID 16055945. 
  117. ^ Serafeim A, Holder MJ, Grafton G, et al. (April 2003). "Selective serotonin reuptake inhibitors directly signal for apoptosis in biopsy-like Burkitt lymphoma cells". Blood 101 (8): 3212–9. doi:10.1182/blood-2002-07-2044. PMID 12515726. 
  118. ^ O'Brien SM, Scully P, Scott LV, Dinan TG (February 2006). "Cytokine profiles in bipolar affective disorder: focus on acutely ill patients". Journal of Affective Disorders 90 (2–3): 263–7. doi:10.1016/j.jad.2005.11.015. PMID 16410025. 
  119. ^ Obuchowicz E, Marcinowska A, Herman ZS (2005). "[Antidepressants and cytokines--clinical and experimental studies]". Psychiatria Polska (in Polish) 39 (5): 921–36. PMID 16358592. 
  120. ^ Hong CJ, Yu YW, Chen TJ, Tsai SJ (2005). "Interleukin-6 genetic polymorphism and Chinese major depression". Neuropsychobiology 52 (4): 202–5. doi:10.1159/000089003. PMID 16244501. 
  121. ^ Elenkov IJ, Iezzoni DG, Daly A, Harris AG, Chrousos GP (2005). "Cytokine dysregulation, inflammation and well-being". Neuroimmunomodulation 12 (5): 255–69. doi:10.1159/000087104. PMID 16166805. 
  122. ^ Kubera M, Maes M, Kenis G, Kim YK, Lasoń W (April 2005). "Effects of serotonin and serotonergic agonists and antagonists on the production of tumor necrosis factor alpha and interleukin-6". Psychiatry Research 134 (3): 251–8. doi:10.1016/j.psychres.2004.01.014. PMID 15892984. 
  123. ^ Diamond M, Kelly JP, Connor TJ (October 2006). "Antidepressants suppress production of the Th1 cytokine interferon-gamma, independent of monoamine transporter blockade". European Neuropsychopharmacology 16 (7): 481–90. doi:10.1016/j.euroneuro.2005.11.011. PMID 16388933. 
  124. ^ Kubera M, Lin AH, Kenis G, Bosmans E, van Bockstaele D, Maes M (April 2001). "Anti-Inflammatory effects of antidepressants through suppression of the interferon-gamma/interleukin-10 production ratio". Journal of Clinical Psychopharmacology 21 (2): 199–206. doi:10.1097/00004714-200104000-00012. PMID 11270917. 
  125. ^ Maes M (January 2001). "The immunoregulatory effects of antidepressants". Human Psychopharmacology 16 (1): 95–103. doi:10.1002/hup.191. PMID 12404604. 
  126. ^ Maes M, Kenis G, Kubera M, De Baets M, Steinbusch H, Bosmans E (March 2005). "The negative immunoregulatory effects of fluoxetine in relation to the cAMP-dependent PKA pathway". International Immunopharmacology 5 (3): 609–18. doi:10.1016/j.intimp.2004.11.008. PMID 15683856. 
  127. ^ O'Brien SM, Scott LV, Dinan TG (August 2004). "Cytokines: abnormalities in major depression and implications for pharmacological treatment". Human Psychopharmacology 19 (6): 397–403. doi:10.1002/hup.609. PMID 15303243. 
  128. ^ Anderson IM (April 2000). "Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability". Journal of Affective Disorders 58 (1): 19–36. doi:10.1016/S0165-0327(99)00092-0. PMID 10760555. 
  129. ^ a b Healy D, Aldred G (2005). Antidepressant drug use and the risk of suicide. International Review of Psychiatry 17, 163–172.
  130. ^ Gunnell D, Saperia J, Ashby D (2005). "Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults: meta-analysis of drug company data from placebo controlled, randomised controlled trials submitted to the MHRA's safety review". BMJ 330 (7488): 385. doi:10.1136/bmj.330.7488.385. PMC 549105. PMID 15718537. 
  131. ^ Lacasse JR, Leo J (December 2005). "Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature". PLoS Medicine 2 (12): e392. doi:10.1371/journal.pmed.0020392. PMC 1277931. PMID 16268734. 
  132. ^ Moncrieff J, Cohen D (July 2006). "Do Antidepressants Cure or Create Abnormal Brain States?". PLoS Medicine 3 (7): e240. doi:10.1371/journal.pmed.0030240. PMC 1472553. PMID 16724872. 
  133. ^ Damsa C, Bumb A, Bianchi-Demicheli F, et al. (August 2004). "'Dopamine-dependent' side effects of selective serotonin reuptake inhibitors: a clinical review". The Journal of Clinical Psychiatry 65 (8): 1064–8. doi:10.4088/JCP.v65n0806. PMID 15323590. 
  134. ^ Valenstein, Elliot S. (1998). Blaming the brain: the truth about drugs and mental health. New York: Free Press. ISBN 0-684-84964-X. [page needed]
  135. ^ Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R (January 2008). "Selective publication of antidepressant trials and its influence on apparent efficacy". The New England Journal of Medicine 358 (3): 252–60. doi:10.1056/NEJMsa065779. PMID 18199864. 
  136. ^ Deshauer D, Moher D, Fergusson D, Moher E, Sampson M, Grimshaw J (May 2008). "Selective serotonin reuptake inhibitors for unipolar depression: a systematic review of classic long-term randomized controlled trials". CMAJ 178 (10): 1293–301. doi:10.1503/cmaj.071068. PMC 2335186. PMID 18458261. 
  137. ^ Geddes JR, Carney SM, Davies C, et al. (February 2003). "Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review". Lancet 361 (9358): 653–61. doi:10.1016/S0140-6736(03)12599-8. PMID 12606176. 
  138. ^ Center for Drug Evaluation and Research Antidepressant Use in Children, Adolescents, and Adults. Retrieved September 30, 2008.
  139. ^ "Early Evidence on the Effects of Regulators' Suicidality Warnings on SSRI Prescriptions and Suicide in Children and Adolescents". Am J Psychiatry. 2007-09-01. Retrieved 2012-06-19. 
  140. ^ "Experts Question Study on Youth Suicide Rates". New York Times. 2007-09-14. Retrieved 2012-06-19. 

External links[edit]