Selective serotonin reuptake inhibitor

 Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor (SSRIs) are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed. A 2010 meta-analysis states that "The magnitude of benefit of antidepressant medication compared with placebo ... may be minimal or nonexistent, on average, in patients with mild or moderate symptoms. For patients with very severe depression, the benefit of medications over placebo is substantial." This analysis discarded a great majority of FDA-approved antidepressant studies, including those that used placebo washout periods typically used as controls.

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. They are the most widely prescribed antidepressants in many countries.

Medical uses
The main indication for SSRIs is clinical depression. SSRIs are frequently prescribed for anxiety disorders, such as social anxiety, panic disorders, obsessive–compulsive disorder (OCD), eating disorders, chronic pain and occasionally, for posttraumatic stress disorder (PTSD). Though not specifically indicated by the manufacturers, they are sometimes prescribed to treat irritable bowel syndrome (IBS), Lichen simplex chronicus and premature ejaculation.

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.. In Canada, the drug approval process is carried out by Health Canada.

A general disadvantage of SSRIs in treating premature ejaculation is that they require continuous daily treatment to delay ejaculation significantly. For the occasional "on-demand" treatment, a few hours before coitus, clomipramine gave better results than paroxetine in one study, while in another study both sertraline and clomipramine were indistinguishable from the pause–squeeze technique and inferior to paroxetine. 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, with on-demand sertraline, paroxetine or clomipramine, and with the pause–squeeze technique.

Efficacy
Efficacy of SSRIs for the treatment of depression compared to placebo is disputed. Two meta-analyses of clinical trials found that in mild and moderate depression, which constitute the vast majority of depression cases, the effect of SSRI is very small or none compared to placebo, while in very severe depression the effect of SSRIs is clinically significant. However, treatment by either placebo or SSRI may have a significant effect in lower-severity depression vs. no treatment at all.

A widely-reported 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, and two non-SSRI antidepressants nefazodone and venlafaxine). The authors found that although the effect of antidepressants vs placebos was statistically significant, it did not exceed the NICE criteria for a clinically significant effect. In particular they found that the effect size was very small for moderate depression but increased with severity reaching 'clinical significance' for very severe depression. The relationship between severity and efficacy was attributed to a reduction of the placebo effect in severely depressed patients, rather than an increase in the effect of the medication. Some researchers have questioned the statistical basis of this study suggesting that it underestimates the effect size of antidepressants but even when they re-analyse the data they find that this is still below the NICE threshold for 'clinical significance' when all results are combined (although individually paroxetine and venflafaxine exceed this threshold).

A 2010 meta-analysis 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.

List of agents
Drugs in this class include (trade names in parentheses):
 * citalopram (Celexa, Cipramil, Cipram, Dalsan, Recital, Emocal, Sepram, Seropram, Citox, Cital)
 * dapoxetine (Priligy)
 * escitalopram (Lexapro, Cipralex, Seroplex, Esertia)
 * fluoxetine (Prozac, Fontex, Seromex, Seronil, Sarafem, Ladose, Motivest, Flutop, Fluctin (EUR), Fluox (NZ), Depress (UZB), Lovan (AUS))
 * fluvoxamine (Luvox, Fevarin, Faverin, Dumyrox, Favoxil, Movox)
 * indalpine (Upstene) (discontinued)
 * paroxetine (Paxil, Seroxat, Sereupin, Aropax, Deroxat, Divarius, Rexetin, Xetanor, Paroxat, Loxamine, Deparoc)
 * sertraline (Zoloft, Lustral, Serlain, Asentra)
 * vilazodone (Viibryd)
 * zimelidine (Zelmid, Normud) (discontinued)

Related agents
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.

Adverse effects
General side effects are mostly present during the first 1–4 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 6–8 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:
 * anhedonia
 * apathy
 * nausea/vomiting
 * drowsiness or somnolence
 * headache
 * bruxism
 * tinnitus
 * extremely vivid or strange dreams
 * dizziness
 * fatigue
 * mydriasis (pupil dilation)
 * urinary retention
 * changes in appetite
 * insomnia and/or changes in sleep
 * weight loss/gain (measured by a change in bodyweight of 7 pounds)
 * increased risk of bone fractures and injuries
 * changes in sexual behaviour (see the next section)
 * increased feelings of depression and anxiety (which may sometimes provoke panic attacks)
 * tremors (and other symptoms of Parkinsonism in vulnerable elderly patients)
 * autonomic dysfunction including orthostatic hypotension, increased or reduced sweating
 * akathisia
 * renal impairment
 * suicidal ideation (thoughts of suicide)
 * photosensitivity
 * Paresthesia
 * Syndrome of inappropriate antidiuretic hormone hypersecretion

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.

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 diagnosis.

Sexual side effects
SSRIs can cause various types of sexual dysfunction such as anorgasmia, erectile dysfunction, and diminished libido. Initial studies found sexual side effects not significantly different than 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% of patients, although the lack of placebo control in these studies means they are likely overestimates.

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 and maprotiline, some of which are also not associated with weight gain). As a result, sexual dysfunction caused by SSRIs can sometimes be mitigated by several different drugs. These include:
 * bupropion (norepinephrine and dopamine reuptake inhibitor)
 * buspirone (serotonin 5-HT1A receptor partial agonist)
 * cyproheptadine (5-HT2 antagonist)
 * methylphenidate (stimulant)
 * mirtazapine (noradrenergic and specific serotonergic antidepressant (NaSSA))
 * amphetamine (stimulant)
 * amantadine (antiviral drug)
 * pramipexole (dopamine agonist) and
 * ropinirole (dopamine agonist)

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.

Cardiovascular side effects
Cardiovascular side effects are very rare with SSRI use, with a reported incidence of less than 0.0003 percent. SSRIs inhibit cardiac and vascular sodium, calcium and potassium channels and prolong QT intervals. However, a number of large studies of patients without known pre-existing heart disease have reported no EKG changes related to SSRI use. 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.

Discontinuation syndrome
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. 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.

Post-SSRI sexual dysfunction
According to one source, Post-SSRI sexual dysfunction (PSSD) is an iatrogenic type of sexual dysfunction caused directly by the previous use of SSRI antidepressants.

While apparently uncommon, it can last for months, years, or sometimes indefinitely after the discontinuation of SSRIs.

One or more of the following sexual symptoms may persist or begin after the discontinuation of SSRIs:


 * Decreased or absent libido
 * Impotence or reduced vaginal lubrication
 * Difficulty initiating or maintaining an erection or becoming aroused
 * Persistent genital arousal disorder despite absence of desire
 * Muted, delayed or absent orgasm (anorgasmia)
 * Reduced or no experience of pleasure during orgasm (ejaculatory anhedonia)
 * Premature ejaculation
 * Weakened penile, vaginal or clitoral sensitivity
 * Genital anesthesia
 * Loss or decreased response to sexual stimuli
 * Reduced semen volume
 * Priapism (persistent erectile state of the penis or clitoris)

Children and adolescents
Several studies have found that SSRI can cause a higher risk of suicidal behavior in children and adolescents. 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%. More infrequently, studies have been inconclusive. 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.

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. 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, despite having a favorable risk-benefit ratio for use with depression in adolescents and children, is not licensed for this use.

Adults
It is unclear whether or not SSRIs affect the risk of suicidal behavior for adults.
 * A 2005 meta-analysis of drug company data found no evidence that SSRIs increased the risk of suicide; however, important protective or hazardous effects could not be excluded. Also among high-risk adult patients, antidepressant drug treatment does not seem related to suicide attempts and death.
 * A 2005 review observed that suicide attempts are increased in those who use SSRIs as compared to placebo and compared to therapeutic interventions other than tricyclic antidepressants. No difference risk of suicide attempts was detected between SSRIs versus tricyclic antidepressants.
 * On the other hand, a 2006 review suggests that the widespread use of antidepressants in the new “SSRI-era” appear to have led to highly significant decline in suicide rates in most countries with traditionally high baseline suicide rates. The decline is particularly striking for women who, compared with men, seek more help for depression. Recent clinical data on large samples in the US too have revealed a protective effect of antidepressant against suicide.
 * A 2006 meta analysis of random controlled trials suggests that SSRIs increase suicide ideation compared with placebo. However, the observational studies suggests that SSRIs did not increase suicide risk more than older antidepressants. The researchers stated that if SSRIs increase suicide risk in some patients, the number of additional deaths is very small because ecological studies have generally found that suicide mortality has declined (or at least not increased) as SSRI use has increased.
 * An additional meta-analysis by the FDA in 2006 found an age-related effect of SSRI's. Among adults younger than 25 years, results indicated that there was a higher risk for suicidal behavior. For adults between 25 and 64, the effect appears neutral on suicidal behavior but possibly protective for suicidal behavior for adults between the ages of 25 and 64. For adults older than 64, SSRI's seem to reduce the risk of both suicidal behavior.

Suicide warnings
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. Similar precautionary notice revisions were implemented by the Japanese Ministry of Health. 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.

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. 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.

Aggression
Analyses of the risks of SSRIs by governing bodies in the United States and United Kingdom have produced warnings about aggression when the medications are used with children and adolescents.

Compulsive lying and other OCD related behavior
Analyses of the risks of SSRIs by governing bodies in China and United Kingdom have produced warnings about an increase in the development of OCD related behaviour. Pathological lying and social anxiety disorder are amongst those behaviors.

Pregnancy and breastfeeding
SSRIs are not considered major teratogens. They do, however, cross the placenta and may thus affect the newborn. Sertraline and paroxetine, and SSRI as a group have been associated with congenital malformations, in particular, septal defects. Some evidence suggests that SSRIs are associated with neonatal complications such as neonatal abstinence syndrome (NAS) and persistent pulmonary hypertension (PPHN).

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.

Neonatal abstinence syndrome
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.

Permanent neuropsychological changes
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. 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. Later it was found that neonatal citalopram and escitalopram makes persistent changes in the serotonergic transmission of the brain resulting in behavioral changes, which are reversed by treatment with antidepressants. 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.

But when young mice were treated with the SNRI desimipramine they developed to normal adults, which suggests that serotonin and noradrenaline 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.

The mechanism is currently unknown, but it seems that early life overstimulation of the 5HT-1 receptor that regulates serotonin production results in low serotonin production after puberty.

Persistent pulmonary hypertension
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.

Interaction with carbohydrate metabolism
Serotonin is also involved in regulation of carbohydrate metabolism. Few analyses of the role of SSRIs in treating depression cover the effects on carbohydrate metabolism from intervening in serotonin handling by the body.

Bleeding tendencies
Many reports have been published incriminating SSRIs with increased bleeding tendencies. SSRIs are known to cause platelet dysfunction. SSRIs, fluoxetine and sertraline have also been found to increase gastric acid secretion in rats and so can be ulcerogenic particularly when combined with NSAIDs. Though the overall risk may be very small but case reports of life threatening bleeding have also been reported.

Overdose
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. However, case reports of SSRI poisoning have indicated that severe toxicity can occur and deaths have been reported following massive single ingestions, although this is exceedingly uncommon when compared to the tricyclic antidepressants.

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. Other reported significant effects include coma, seizures, and cardiac toxicity.

Treatment for SSRI overdose is mainly based on symptomatic and supportive care. Medical care may be required for agitation, maintenance of the airways, and treatment for serotonin syndrome. ECG monitoring is usually indicated to detect any cardiac abnormalities.

Contraindications and drug interaction
One major contraindication of SSRIs is the concomitant use of MAOIs (monoamine oxidase inhibitors). This is likely to cause severe serotonin syndrome/toxidrome.

People taking SSRIs should also avoid taking pimozide (an antipsychotic diphenylbutylpiperidine derivative). Tramadol hydrochloride (or Ultram, Ultracet) can, in rare cases, produce seizures when taken in conjunction with an SSRI or tricyclic antidepressant. Liver impairment is another contraindication for medications of this type.

SSRIs may increase blood levels and risk of toxicities of certain medications:
 * 1) highly protein-bound medications like warfarin (coumadin) and digoxin
 * 2) antiarrhythmic agents like propafenone (Rythmol) or flecainide (Tambocor)
 * 3) beta blockers like metoprolol (Toprol xl) or propranolol (Inderal)
 * 4) Tricyclic antidepressants like amitriptyline (Elavil, Endep) etc.
 * 5) triptans like sumatriptan (Imitrex, Imigran) etc.
 * 6) benzodiazepines like alprazolam (Xanax) or diazepam (Valium)
 * 7) carbamazepine (Tegretol)
 * 8) cisapride (Propulsid)
 * 9) clozapine (Clozaril)
 * 10) ciclosporin (Neoral)
 * 11) haloperidol (Haldol)
 * 12) phenytoin (Dilantin)
 * 13) pimozide (Orap)
 * 14) theophylline (Theo-dur)

Certain drugs may increase toxicities of SSRIs:
 * 1) alcohol and other CNS depressants
 * 2) methylene blue dye
 * 3) diuretics (water pills)
 * 4) MAOIs – possibly fatal serotonin syndrome/toxidrome
 * 5) sympathomimetic drugs like pseudoephedrine (Sudafed)
 * 6) lithium
 * 7) sibutramine (Meridia)
 * 8) MDMA (ecstasy)
 * 9) zolpidem (ambien)
 * 10) dextromethorphan (cough suppressant) – increased risk of serotonin syndrome/toxidrome
 * 11) tramadol (synergistic serotoninergic effect said to increase risk of seizure or serotonin syndrome/toxidrome)
 * 12) pethidine/meperidine – increased risk of serotonin syndrome/toxidrome
 * 13) herbal Saint John's wort or yohimbe – increased risk of serotonin syndrome/toxidrome

SSRIs also directly interfere with ligands of 5-HT receptors, like the psychedelics and entactogens. SSRIs strongly attenuate the effects of tryptamine psychedelics like psilocybin and LSD, and almost completely eliminate the serotonergic effects of phenethylamine psychedelics like mescaline and MDMA. The exact mechanism that causes this interaction is still unclear.

Mechanism of action
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
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 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
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 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.

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.

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, and why increased anxiety is a common side effect in the first few days or weeks of use.

Role in BDNF release
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.

Pharmacogenetics
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. 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.

Neuroprotection
Studies have suggested that SSRIs may promote the growth of new neural pathways or neurogenesis in rats. 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.

Anti-inflammatory and immunomodulation
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.

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.

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.

SSRIs versus TCAs
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. 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
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. In addition, hope for breaching the blood-brain barrier for causes such as severe depression is underway. 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
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.

Criticism
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.

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.

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.

One possible mechanism is by inhibition of dopaminergic neurotransmission.

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 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. 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.

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%.

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.

Lawsuits
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. The inclusion of the black box warning may have led to a decrease in prescriptions of SSRIs and an increase in suicide.