Selective serotonin reuptake inhibitor

"SSRI" redirects here; for other uses, see SSRI (disambiguation).

Selective serotonin reuptake inhibitors (SSRIs) are a class of antidepressants used in the treatment of depression, anxiety disorders and some personality disorders. Studies have also found that SSRIs, as a side effect of their action, may cause in many people either a delay of sexual climax or anorgasmia, so they can be used to develop drugs specifically targeted to treat premature ejaculation.

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.

List of SSRIs

Many drugs in this class are familiar in the USA through advertising, including the following:
(Trade names in parentheses)

• citalopram (Celexa, Cipramil, Emocal, Sepram, Seropram)
• escitalopram oxalate (Lexapro, Cipralex, Esertia)
• fluoxetine (Prozac, Fontex, Seromex, Seronil, Sarafem, Fluctin (EUR))
• fluvoxamine maleate (Luvox, Faverin)
• paroxetine (Paxil, Seroxat, Aropax, Deroxat, Paroxat)
• sertraline (Zoloft, Lustral, Serlain)
• dapoxetine (no known trade name)

Escitalopram is simply the left-handed s-enantiomer of the racemic citalopram. It had been introduced to the market just before the patent protection for citalopram had expired.

It is commonly thought that that the primary action of St. John's wort is as an MAOI.

Note that trazodone is not a typical member of the SSRIs - while it is a serotonin reuptake inhibitor, it is believed that its anti-depressant properties may be due to some of its other pharmacokinetic properties rather than its effect on serotonin reuptake inhibition. That said, it does still share many properties of the typical SSRIs, especially the possibility of the so-called 'discontinuation syndrome' (see the section on this below).

Medical indications

The main indication for SSRIs is clinical depression. Apart from this, SSRIs are frequently prescribed for anxiety disorders like social anxiety, panic disorders, obsessive-compulsive disorder (OCD) and eating disorders. Though not specifically indicated by the manufacturers, they are also sometimes prescribed to treat irritable bowel syndrome (IBS). Additionally, SSRIs have been found to be effective in treating premature ejaculation in up to 60% of men.

Contraindications / drug interaction

SSRIs are contraindicated with concomitant use of MAOIs (monoamine oxidase inhibitors). This can lead to increased serotonin levels which could cause a serotonin syndrome. People taking SSRIs should also avoid taking pimozide (a diphenylbutylpiperidine derivative). The non-opioid analgesic tramadol hydrochloride (or Ultram, Ultracet) can, in rare cases, produce seizures when taken in conjunction with an SSRI or tricyclic antidepressant.

Mode of action

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 has the chance to be recognized again (and again) by the receptors of the recipient cell, which can finally be stimulated fully.

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.

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.

Interaction with carbohydrate metabolism

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

Neuroprotection

Studies have suggested that SSRIs may promote the growth of new neural pathways. Also, SSRIs may protect against neurotoxicity caused by other compounds (for instance MDMA and Fenfluramine) as well as from depression itself.

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 were initially claimed to have fewer and milder side effects.

SSRIs versus 5-HT-Prodrugs

Serotonin cannot be administered directly because when ingested orally, it will not cross the blood-brain barrier, and therefore won't have an 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.

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.

Adverse effects

General side effects

General side effects are mostly present during the first 1-4 weeks while the body adapts to the drug. Almost all SSRIs are known to cause either one or more of these symptoms:

• nausea
• drowsiness
• headache
• changes in weight and appetite
• changes in sexual behaviour (see the next section)
• increased feelings of depression and anxiety
• tremors
• increased sweating

It is not recommended to quit the medication because of the side effects, as they usually disappear after the adaptation phase and at the same time the antidepressive effects begin to show. However, despite being called general, the side effects and their duration is highly individual and drug-specific, so 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 increased or the drug can be changed to some other if the side effects won't disappear or the patient feels they are too uncomfortable.

Suicidality

Over the years there have been many accusations by patients and their families of SSRIs causing suicidal ideation and behavior, but as there is little scientific support for this claim, judicial evidence is piling up that patients committed suicide after using SSRIs. Manufactures of SSRIs historically have vehemently denied any such link and have always blamed the disease rather than the treatment. In 2003 the UKs Committee on Safety of Medicines banned the use of paroxetine (known in that country as Seroxat) in the use of children due to evidence of increased harm and potentially suicidal behaviour. In early 2006 GlaxoSmithKline issued a press release stating that new meta-analysis of their clinical trial data has revealed a statistically significant higher frequency of suicidality in patients treated with their SSRI, paroxetine (Paxil) than with placebo. An October 2006 study revealed SSRIs may decrease youth suicide overall. A more recent study released in November 2006 reinforced the efficacy of SSRIs in depressed adolescents, concluding that SSRIs low suicide rates in children.

In the United States there is a required box warning for suicide risk in children but not for adults.

Sexual side effects

It is well known that the selective serotonin reuptake inhibitors (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 those studies relied on unprompted reporting, so the frequency of such problems was underestimated. In more recent studies, doctors have specifically asked about sexual difficulties, and found that they are present in between 41% and 83% of patients. This dysfunction occasionally disappears spontaneously without stopping the SSRI, and in most cases resolves after discontinuance. In some cases, however, it does not; this is known as 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. Sexual dysfunction caused by SSRI's can sometimes be mitigated by several different drugs. These include bupropion, buspirone, methylphenidate, mirtazapine, amphetamine, pramipexole and ropinirole.

Because of these sexual side effects, the SSRI fluoxetine (Prozac) was recently classified as a reproductive and developmental toxin by the Center for the Evaluation of Risks to Human Reproduction (CERHR), an expert panel at the National Institute of Environmental Health Sciences at the National Institutes of Health.

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In 1970 a simple chemical mechanism of sexual stimulation was published as a research article in the British Journal of Neuro-Psychology.

One of the "side effects" of high doses of L-dopa used at that time in about 10% of Parkinson patients was an increased sexual activity caused by L-dopa being a serotonin antagonist. We independently did the same experiment by injecting rats with para-chlorophenylalanine and measuring the reduction in serotonin levels. We also observed the rats' behavior and correlated the reduced serotonin level to a greatly increased level of sexual activity.

When we completed the experiment, we was stunned to discover that it had been published that month in England. Our work was never published because I failed to realize the value of independent corroboration, and my impending graduation made my being shipped off to Vietnam a much higher priority.

Discontinuation syndrome

Main article: SSRI discontinuation syndrome

SSRIs are not addictive in the conventional medical use of the word (i.e. animals given free access to the drug do not actively seek it out and do not seek to increase the dose), but suddenly discontinuing their use is known to produce both somatic and psychological withdrawal symptoms.

PANES

Persistent Adverse Neurological Effects following SSRI discontinuation (PANES) are serious side-effects induced by an SSRI that remain or worsen after both the medicine has been completely eliminated from the body, and after SSRI discontinuation syndrome (if it occurs) ends.

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 of SSRIs

SSRIs have been the focus of controversy. Some feel that SSRIs are prescribed by overzealous doctors or psychiatrists in cases where their use is only marginally indicated. In late 2004 much 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 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. Other studies have shown no increase in rates of suicide but a small increase of non-fatal self-harm and even of reduced incidence of suicide.

Critics have also alleged that the widely disseminated television and print advertising of SSRI drugs promotes an inaccurate message, oversimplifying what these medications actually do and perhaps misinforming the public, contributing to the problems listed above. Much of the criticism stems from questions about the validity of claims that such drugs work by correcting chemical imbalances.

Other medications to treat depression

The majority of medications most recently approved to treat depression work on multiple neurotransmitters. Venlafaxine and duloxetine (Cymbalta) are both members of the SNRI class of antidepressant medication. SNRIs (serotonin-norepinephrine reuptake inhibitors) work on the norepinephrine and serotonin neurotransmitters. Mirtazapine also increases levels of norepinephrine and serotonin, but it is a tetracyclic antidepressant, not a SSRI or SNRI. The arrival of these new drugs suggest that future antidepressants will not work on serotonin exclusively. Since the expiration of Eli Lilly's Prozac patent, Lilly has been promoting their new SNRI, duloxetine. Natural healing professionals often recommend 5-HTP supplements instead of standard SSRI/MAOI prescriptions as 5-HTP allegedly accomplishes the same goal without resorting to disturbing the brain's natural metabolic procedures, although this has not been scientifically proven.

External links

• MEDLINEplus drug information database
• The FDA Ban of L-Tryptophan
• FDA "black box" warning for SSRIs
• FDA list of SSRIs receiving the "black box" warning
• NIH Expert Panel Report on the reproductive and developmental toxicology of Prozac (Fluoxetine)
• NIH Monograph on the potential human reproductive and developmental effects of Prozac (Fluoxetine)
• PROZAC Product/Prescribing Information