Selective serotonin reuptake inhibitor

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

Selective Serotonin Reuptake Inhibitors (SSRIs) are a new class of antidepressant medications for treating anxiety disorders. They relieve symptoms by elevating a neurotransmitter called Serotonin by inhibiting the retupake process of the neurotransmitter transport mechanism. They have little or no effect on other neurotransmitters, hence, they are referred to as selective meaning they affect one and only that one neurotransmitter. Their chief advantage over the older antidepressants, MAOIs and TCAs, is not to do with effectiveness rather, it is to do with their safety. Unlike the older depressants, SSRIs have an enormous range of safety in overdose and few drug interactions. Also, because of their selective nature, they have far fewer and much better tolerated side effects for most patients. For these reasons, SSRIs are commonly referred to as The Wonder Drugs.

List of SSRIs

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

• Citalopram (Celexa, Cipramil, Emocal, Sepram)
• Escitalopram oxalate (Lexapro, Cipralex)
• Fluoxetine (Prozac, Fontex, Seromex, Seronil, Sarafem)
• Fluvoxamine maleate (Luvox, Faverin)
• Paroxetine (Paxil, Seroxat, Aropax, Deroxat)
• Sertraline (Zoloft, Lustral)

Escitalopram is simply a variant of citalopram (racemate), of which it is the active enantiomer. It has been introduced to the market after the patent protection for citalopram had expired. The advantages are marginal.

Medical indications

The main indication for SSRIs is the clinical depression. Apart from this, SSRIs are frequently prescribed for anxiety 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.

Way of action

Basic understanding

In the brain, information is passed between two neurons (nerve cells) via a synapse, a small gap between the cells. The neuron that sends the information releases neurotransmitters (with serotonin among them) into that gap. The neurotransmitters are then recognized by receptors on the surface of the recipient 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 in the sending cell (a process called reuptake).

Depression has been linked 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 that way.

Pharmacodynamics

SSRIs inhibit the reuptake of the neurotransmitter serotonin (5-hydroxytryptamine or 5-HT) into the presynaptic cell and by this they elevate the 5-HT level within the synaptic cleft. Paradoxically, at the beginning of the therapy with SSRIs the desired boost of the 5-HT concentration is usually antagonized by another effect.

Usually it takes sevaral weeks of continuous SSRI-application for the antidepressive effects to become fully unfold. Pharmacologically this delay is due to the following reason: The initially high level of serotonin within the synaptic gap not only activate the postsynaptic receptors, but also flood the autoreceptors of the presynaptic cell. Their activation excite the signal within the cell to throttle the serotonin production. The resulting deficiency of serotonin persists in the total sum, since the transporter inhibition is merely downstream (lower-ranking) and is therefore not able to counterbalance the deficiency.

This way, during the (pharmaco)therapy the body has first to adapt to this situation by downregulating the sensitivity of the autoreceptors, what can take up to 3 weeks. From this reason the drugdeveloper currently develop bifunctional SSRIs that additionally occupy the autoreceptors – and thus inactivate this mechanism –, to exert the antidepressant effect undelayed – and this way, to eliminate the currently existing deficits.

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.

The effectiveness of SSRIs does not appear to be higher than 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.

SSRIs versus 5-HT-Prodrugs

Why not give serotonin directly? First, serotonin ingested orally will not cross the blood-brain barrier, and therefore won't have an effect on brain functions. Second, serotonin would turn on 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 FDA 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. As the production error responsible for the contamination would have been easily correctable, some critics have suggested that this appears to have been done to make money for the manufacturers of SSRIs. This bureaucratic action neglecting the most important fact established regarding the biochemistry of tryptophan: that it is an essential amino acid that humans cannot live without eating, led to renewed questioning as to whether the FDA was a science based or political agency. Pharmaceutical grade L-tryptophan is currently available over the counter in the U.S.

Adverse effects

General side effects

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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, a phenomenon known as "SSRI discontinuation syndrome" (Tamam & Ozpoyraz, 2002). Compared to the withdrawal symptoms of such drugs as opiates, alcohol, or cocaine, these reactions are quite different and frequently less significant, although the prescribing labels acknowledge the possibility of "intolerable" discontinuation reactions and some patients are never able to completely withdraw from SSRI drugs. In Europe, SSRI manufacturers are not permitted to promote their products as "non-habit forming", in the U.S., this statement is used to promote SSRIs. SSRIs meet the World Health Organization definition of 'addictive'.

Drug interaction

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Criticism of SSRIs

SSRIs have been the focus of much controversy. Some feel that SSRIs are prescribed by overzealous doctors or psychiatrists in cases where their use is only marginally indicated. According to this argument, societal pressures have created a precedent for the pursuit of "normal" mental or emotional functioning by chemical means versus a more holistic approach (diet, exercise, sleep, stress reduction, etc). Furthermore, 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.

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 (Lacasse & Leo, 2005). Much of the criticism stems from questions about the validity of claims that such drugs work by 'correcting' chemical imbalances.

Neurotoxicity

Some studies have suggested the possibility that SSRIs may be neurotoxic. Neurotoxicity has been observed in cell lines. There have also been anecdotal reports of "mental fog" arising from SSRI use.

Other studies have suggested that SSRIs may increase the growth of new brain cells and that this may be responsible for their effects in depression. Also, SSRIs may protect against neurotoxicity caused by other compunds (for instance MDMA and Fenfluramine) as well as from depression itself.

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% (Landen et al 2005) and 83% of patients (Hu et al 2004). This dysfunction occasionally disappears spontaneously without stopping the SSRI, and in most cases resolves after discontinuance.

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. The panel concluded "that there is sufficient evidence in humans that fluoxetine can produce reproductive toxicity in men and women as manifested by reversible, impaired sexual function, specifically orgasm."

Effect not well understood

Some say that the supposed biological causes of depression, which SSRIs were designed for, have never in fact been proven scientifically. They claim that there is no scientific evidence for the existence of the disorders that SSRIs are designed to treat, or that they are based on a chemical imbalance of the brain, or that SSRIs effectively handle this chemical imbalance.

The mode of action of these antidepressant drugs on their direct target, the serotonin transport protein, and possible regulatory mechanisms with respect to long-term alleviation of depression, although having been investigated both neurobiologically and clinically over the last years, are not yet understood.

Other medications to treat depression

The majority of medications most recently approved to treat depression work on multiple neurotransmitters. Venlafaxine and duloxetine 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)

References

• Hu XH, Bull SA, Hunkeler EM, Ming E, Lee JY, Fireman B, Markson LE. Incidence and duration of side effects and those rated as bothersome with selective serotonin reuptake inhibitor treatment for depression: patient report versus physician estimate. J Clin Psychiatry 2004;65:959-65. PMID 15291685.
• Lacasse JR, Leo J. Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature, PLoS Medicine 2005;2(12):e392.
• Landen M, Hogberg P, Thase ME. Incidence of sexual side effects in refractory depression during treatment with citalopram or paroxetine. J Clin Psychiatry 2005;66:100-6. PMID 15669895.
• Tamam L, Ozpoyraz N. Selective serotonin reuptake inhibitor discontinuation syndrome: a review. Adv Ther 2002;19:17-26. PMID 12008858.