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Selective serotonin reuptake inhibitor

Selective serotonin reuptake inhibitors (SSRIs) are a class of antidepressants used in the treatment of depression, anxiety disorders, and some personality disorders. They are also typically effective and used in treating premature ejaculation problems as well as some cases of insomnia.

SSRIs increase the extracellular level of the neurotransmitter serotonin by inhibiting its reuptake into the presynaptic cell, increasing the level of serotonin available to bind to the postsynaptic receptor. They have varying degrees of selectivity for the other monoamine transporters, having little binding affinity for the noradrenaline and dopamine transporters.

The first class of psychotropic drugs to be rationally designed, SSRIs are the most widely prescribed antidepressants in many countries.

List of SSRIs

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

citalopram (Celexa, Cipramil, Dalsan, Recital, Emocal, Sepram, Seropram)
dapoxetine (no trade name yet; not yet approved by the FDA)
escitalopram (Lexapro, Cipralex, Esertia)
fluoxetine (Prozac, Fontex, Seromex, Seronil, Sarafem, Fluctin (EUR), Fluox (NZ), Depress (UZB), Lovan (AUS))
fluvoxamine (Luvox, Fevarin, Faverin, Dumyrox, Favoxil, Movox)
paroxetine (Paxil, Seroxat, Sereupin, Aropax, Deroxat, Rexetin, Xetanor, Paroxat)
sertraline (Zoloft, Lustral, Serlain)
zimelidine (Zelmid, Normud)

Related antidepressants

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

Medical indications

The main indication for SSRIs is clinical depression. SSRIs are frequently prescribed for anxiety disorders like 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 US for use with psychiatric disorders as outlined in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV).

The uses for which SSRIs are approved vary by country and is determined by the overseeing medical branch of government in charge of regulating drugs. In the United States, the Food and Drug Administration (FDA) makes these approvals after trials have been submitted by pharmaceutical companies. In Europe, drugs can be approved either by the European Medicines Agency for human consumption throughout the EU 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", a few hours before coitus, treatment, 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.

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.

People taking SSRIs should also avoid taking pimozide (an antipsychotic diphenylbutylpiperidine derivative). The atypical opioid analgesic 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:

highly protein-bound medications like warfarin (coumadin) and digoxin
antiarrhythmic agents like propafenone (Rythmol) or flecainide (Tambocor)
beta blockers like metoprolol (Toprol xl) or propranolol (Inderal)
tricyclic antidepressants like amitriptyline (Elavil) (may increase risk of serotonin syndrome)
benzodiazepines like alprazolam (Xanax) or diazepam (Valium)
carbamazepine (Tegretol)
cisapride (Propulsid)
clozapine (Clozaril)
ciclosporin (Neoral)
haloperidol (Haldol)
phenytoin (Dilantin)
pimozide (Orap)
theophylline (Theo-dur)

Certain drugs may increase toxicities of SSRIs:

alcohol and other CNS depressants
diuretics (water pills)
MAOIs
sympathomimetic drugs like pseudoephedrine (Sudafed)
lithium
sibutramine (Meridia)
MDMA (ecstasy)
zolpidem (ambien)
Dextromethorphan

Mode of action

SSRIs 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 synapse, a small gap between the cells. The cell that sends the information releases neurotransmitters (of which serotonin is one) 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).

Some theories link depression to a lack of stimulation of the recipient neuron at a synapse . 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 be recognized again (and again) by the receptors of the recipient cell, stimulating it.

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.

But there is one counteracting effect: high serotonin levels will not only activate the postsynaptic receptors, but also flood presynaptic autoreceptors, that 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 is therefore not able to counterbalance it. The body adapts gradually to this situation by lowering (downregulating) the sensitivity of the autoreceptors .

Of greater importance is another adaptive process: the downregulation of postsynaptic serotonin 5-HT_2A receptors. After the use of an SSRI, since there is more serotonin available, the response is to lower (to normal levels or less) the number of postsynaptic receptors over time, and in the long run, this modifies the serotonin/receptor ratio. Since a larger percentage of available receptors become activated by serotonin, transmission is enhanced or restored .

These (slowly proceeding) neurophysiological adaptions of the brain tissue are the reason why usually several weeks of continuous SSRI use are 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.

Pharmacogenetics

Large bodies of research are devoted to using genetic markers to predict whether patients will respond to SSRIs or have side effects which will cause their discontinuation, although these tests are not yet ready for widespread clinical use. Single nucleotide polymorphisms of the 5-HT(2A) gene correlates with increased paroxetine discontinuation, 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 MDMA and 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 is possible that symptoms manifest in these psychiatric illnesses are being attenuated by pharmacological effect of antidepressants on the immune system.

SSRIs have been shown to be immunomodulatory and anti-inflammatory against pro-inflammatory cytokine processes, specifically on the regulation of Interferon-gamma (IFN-gamma) and Interleukin-10 (IL-10), as well as TNF-alpha and Interleukin-6 (IL-6). Antidepressants have also been shown to suppress TH1 upregulation.

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. Because of this, SSRIs lack some of the side effects of the more general drugs.

There appears to be 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.

SSRIs together with 5-HT-Prodrugs

Biosynthetically serotonin is made from tryptophan, an amino acid. If depression is caused by lack of serotonin, rather than insensitivity to it, SSRIs alone will not work well, whereas supplementing with tryptophan will. 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. Combining 5-HTP with SSRIs may lead to serotonin syndrome, as a result of too much serotonin activity in the brain. A doctor should be consulted before combining the two.

Adverse effects

General side 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
drowsiness or somnolence
headache
clenching of teeth
extremely vivid and strange dreams
dizziness
changes in appetite
weight loss/gain (measured by a change in bodyweight of 7 pounds)
may result in a double 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
autonomic dysfunction including orthostatic hypotension, increased or reduced sweating
akathisia
liver or renal impairment
suicidal ideation (thoughts of suicide)
Photosensitivity (increased risk of sunburn) (Use protective clothing, such as long sleeves and hats, and sunscreen to decrease the risk of sunburn.)

Common gastrointestinal side effects include nausea, vomiting, and diarrhea, which are brought about by the actions of serotonin on the gastrointestinal tract.

Most side effects usually disappear after the adaptation phase, when the antidepressive effects begin to show. 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 (eg. Prozac in the UK is begun at a 20mg dose, and then adjusted as necessary to 40mg or 60mg). Should the drug prove not to be effective, 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 that such side effects occur in less than 10% of patients, 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. This dysfunction occasionally disappears spontaneously without stopping the SSRI, and in most cases resolves after discontinuation. In some cases, however, it does not; this is known as Post SSRI Sexual Dysfunction (PSSD).

It is believed that sexual dysfunction is caused by an SSRI induced reduction in dopamine. Stimulation of postsynaptic 5-HT2 and 5-HT3 receptors decreases dopamine release from the Substantia Nigra. A number of drugs are not associated with sexual side-effects (bupropion, mirtazapine (Remeron), maprotiline (Ludiomil), tianeptine (Stablon) (some of these 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 receptor agonist)
methylphenidate (stimulant)
mirtazapine (noradrenergic and specific serotonergic antidepressant (NaSSA))
amphetamine (stimulant)
amantadine (antiviral)
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

SSRIs are addictive as discontinuing their use is known to produce both somatic and psychological withdrawal symptoms. Since Physical Dependence is a reality, discontinuation should be discussed with a medical practitioner before beginning treatment with this class of drugs.

Suicidality and aggression

Similarly to other antidepressants, SSRIs can cause suicidality in children. Analyses of the risks of SSRIs by governing bodies in the United States and United Kingdom have produced warnings about suicidality and aggression when the medications are used with children and adolescents.

A 2004 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%. An additional analysis by the FDA also indicated 1.5-fold increase of suicidality in the 18–24 age group. This resulted in a black box warning on SSRI and other antidepressant medications regarding the increased risk of suicidality in patients younger than 24.

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.

Other studies on SSRIs and suicide among adolescents are equivocal; rates of suicide attempts in high-risk populations appear to be unaffected by SSRI prescriptions in adults. 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. The introduction of a warning regarding the association between SSRIs and suicide led to a decrease in prescriptions for the medications in 2003 and 2004, and these decreases in prescriptions were associated with an increase in actual number of teenage suicide.

SSRIs and Pregnancy

The FDA issued a warning on July 19, 2006 stating nursing mothers on SSRIs must discuss treatment with their physicians.

When taken by pregnant women, selective serotonin reuptake inhibitors (SSRIs) cross the placenta and have the potential to affect newborns. Sertraline and paroxetine have been associated with congenital malformations. Some evidence suggests that SSRIs are associated with neonatal complications such as neonatal abstinence syndrome (NAS) and persistent pulmonary hypertension (PPHN).

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 they are 8-21 days old they will develop behavioural changes in adulthood which resembles 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 unblocked 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 has different effects in the developing brain.

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.

Overdose

SSRIs appear to be 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.

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 suicidality 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. 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 which is causing 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 (though the efficacy of antidepressants and antipsychotics is not undisputed). 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 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. 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.

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%.

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. Food and Drug Administration (FDA) asked manufacturers to include black box warnings on antidepressant drug packaging.