Selective serotonin reuptake inhibitors (SSRIs)

Selective serotonin reuptake inhibitors (SSRIs) are a class of antidepressants for treating depression, anxiety disorders and some personality disorders. These drugs are designed to allow the available neurotransmitter serotonin to be utilized more effeciently. A low level or utilization of serotonin is currently seen as one among several neurochemical symptoms of depression. Low levels of serotonin in turn can be caused by an anxiety disorder, because serotonin is needed to metabolize stress hormones.

These medications evolve their effects at the serotonin transporter. They increase the extracellular level of the neurotransmitter serotonin by inhibiting its reuptake into the presynaptic cell. They have no or only weak effects at other monoamine transporters, thus having little direct influence on the level of other neurotransmitters. That distinguishes them from the older tricyclic antidepressants (TCAs), thus they are named selective. SSRIs are considered to be considerably safer than TCAs, since the toxic dose is much higher and they are said to have fewer and weaker side effects and drug interactions.

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,Esertia)
 * fluoxetine (Prozac, Fontex, Seromex, Seronil, Sarafem, Fluctin (EUR))
 * fluvoxamine maleate (Luvox, Faverin)
 * paroxetine (Paxil, Seroxat, Aropax, Deroxat)
 * sertraline (Zoloft, Lustral, Serlain)

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, 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.

Basic understanding
In the brain, messages are 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 fully.

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

Usually, several weeks of continuous SSRI use are necessary for the antidepressant effects to become fully manifested. Pharmacologically, this delay is due to a side-effect of the initially high levels of serotonin within the synaptic gap: high serotonin levels will not only activate the postsynaptic receptors, but also flood the autoreceptors of the presynaptic cell, triggering 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.

Consequently, during SSRI therapy, the body must first adapt to the high levels of serotonin within the synaptic gap by downregulating the sensitivity of the autoreceptors, which can take up to 3 weeks. To expedite the onset of the antidepressant effect, bifunctional SSRIs are currently under development, which will additionally occupy the autoreceptors, and thus deactivate the serotonin production throttling mechanism.

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.

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 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. Pharmaceutical grade L-tryptophan is currently available by prescription in the U.S. However the supplement 5-htp can be bought over the counter and is a direct precursor to serotonin.

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

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.

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.

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 has been shown to be mitigated by several different drugs. These include bupropion, buspirone, methylphendiate, 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. 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."

Apathy
SSRI's have been noted for their tendency to induce a so called "frontal lobe syndrome". Features of the syndrome include reduced activity, inability to plan ahead, lack of drive, lack of concern, emotional blunting, apathy and indifference. These symptoms are similar to those in the category of negative schizophrenia.

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'." Many physicians do not get informed consent at the time of initial prescription that covers the difficulties of later withdrawal from the drug, so this syndrome can be an unexpected barrier to patients, especially those who tried the drug in response to a specific crisis, who expected an easy withdrawal once their emotional situation stabilized. In addition, warnings to patients not to stop taking the drug without doctor's approval, while indicated, may lead to a reluctance to discontinue SSRI therapy.

Drug interaction
SSRI's are contraindicated with concomittant use of MAOI's (monoamine oxidase inhibitors), this can lead to increase serotonin levels which could lead to Serotonin Syndrome.

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. Other studies have shown no increase in rates of suicide but a small increase of non-fatal self-harm (Gunnell 2005) and even of reduced incidence of suicide (Fazel 2006). 

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 compounds (for instance MDMA and Fenfluramine) as well as from depression itself.

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.

Many depressed patients describe complex social situations as the root cause of their depression. Critics point out that it is an unproven assumption that such cases of depression result from "hardware" errors in the brain, when their very nature: jobs, love, money, family frustrations, are clearly in the realm of "social software". Changing the "hardware" chemistry is seen as unproven, and on a different level from the one where the adjustments may need to be made.

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.

A comprehensive theory of how and why a slower fading of signals on the serotonin pathway will affect depression and not impair other brain functions simply does not exist. Most patients do not realize the extent that the SSRI phenomenon is based on experiental observations rather than deep biochemical understanding.

Decreased social responsibility
Partners and social contacts of persons taking SSRI medications sometimes report a frustration in getting SSRI consumers to take important matters seriously. Sober feedback about behavioral excesses, irresponsibility, or similar failures to respect social conventions or boundaries of others dissipates without corrective action in a feeling of personal well being attributed to the SSRI drug.

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.

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.