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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.

They are chemically similar to methylenedioxymethamphetamine and other reuptake inhibiting drugs. They act similar by allowing chemicals to stay in synapses longer.

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 the primary action of St. John's wort is as an MAOI.

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.

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 atypical 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 or somnolence
• headache
• dizziness
• changes in appetite
• weight loss/gain
• changes in sexual behaviour (see the next section)
• increased feelings of depression and anxiety
• tremors
• autonomic dysfunction including orthostatic hypotension, increased or reduced sweating
• akathisia
• liver or renal impairment
• thoughts of suicide

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 and Aggression

Over the years there have been many accusations by patients and their families of SSRIs causing suicidal ideation and aggressive behavior. Previously there wass little scientific support for this claim, but judicial evidence is piling up that patients committed suicide or engadged in aggressive acts using SSRIs. Manufactures of SSRIs historically have vehemently denied any such link and have always blamed the disease rather than the treatment, but now important papers and documents previously unreleased are being found.

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

On Dec 13, 2006, a U.S. Food and Drug Administration advisory panel recommended Wednesday that "black-box" warnings on SSRIs be raised from 18 to 25 years old. The FDA is not obligated to follow the recommendations of its advisory committees but usually does.

Fluoxetine (Prozac) and Suicide

The signs of violence and suicidality were there since the first SSRI antidepressant, Prozac (fluoxetine) was tested in premarketing trials.

In May 1984, Germany’s regulatory agency (GBA) rejected Prozac as “totally unsuitable for treating depression.” In July 1985, Eli Lilly’s own data analysis—from a pool of 1,427 patients—showed high incidence of adverse drug effects and evidence of drug-induced violence in some patients. In May 1985, FDA’s (then) chief safety investigator, Dr. Richard Kapit, wrote: “Unlike traditional tricyclic antidepressants fluoxetine’s profile of adverse side effects more closely resembles that of a stimulant drug than one that causes sedation.” He warned “It is fluoxetine’s particular profile of adverse side-effects which may perhaps, in the future give rise to the greatest clinical liabilities in the use of this medication to treat depression.”

Dr. Kapit’s safety review described the clinical trial data from 46 trials with a total of 1,427 patients. He noted under the section, “Catastrophic and Serious Events,” 52 cases of “egregiously abnormal laboratory reports which were the reason for early termination,” and “additional adverse event reports not reported by the company were revealed on microfiche.” Dr. Kapit reported: “In most cases, these adverse events involved the onset of an unreported psychotic episode.” There were 10 reports of psychotic episodes; 2 reports of completed suicides; 13 attempted suicides; 4 seizures—including a healthy volunteer; and 4 reports of movement disorders.

“Nervousness,” Dr. Kapit wrote, “was the most common adverse symptom cited by long-term fluoxetine patients who eventually discontinued the drug.” He pointed out that “depressed patients often suffer from insomnia, nervousness, anorexia and weight loss” the drug’s propensity to induce these same symptoms “may possibly exacerbate” their illness. Germany’s regulatory agency, BGA, did not approve Prozac until 1989, when Lilly agreed to add a warning in the drug’s label in Germany. In 1985 Dr. Kapit recommended “labeling warning the physician that such signs and symptoms of depression may be exacerbated by this drug". No such warning was issued until 2004.

Sertraline (Zoloft) and Aggression

Pfizer’s data from the pediatric Zoloft (sertraline) trials shows that “aggression was the joint commonest cause for discontinuation from the two sertraline placebo-controlled trials in depressed children. In these trials, eight of 189 patients randomised to sertraline discontinued for aggression, agitation, or hyperkinesis, (otherwise known as akathisia) compared with no dropouts for these reasons in 184 patients on placebo. There were 15 discontinuations on Zoloft compared with two on placebo in any treatment induced manifestation of activation (i.e., suicidal ideation or attempts, aggression, agitation, hyperkinesis, or aggravated depression)". The published report failed to include this data in the analysis.

Failure to report these data in published reports is prima facie evidence of journal failure as scientific gatekeepers: peer review as currently practiced results in biased reports and concealment of negative data. Governor and former New York State Attorney General, Elliot Spitzer, correctly termed this practice, fraud.

Paroxetine (Paxil) and Aggression

In the trials posted on the GlaxoSmithKline (GSK) website, the authors note, “hostile events are found to excess in both adults and children on paroxetine compared with placebo, and are found across indications, and both on therapy and during withdrawal".

The authors suggest that, perhaps the most significant evidence for drug-induced violence probably comes from healthy volunteer studies: hostile events occurred in three of 271 (1.1%) volunteers taking paroxetine, compared with zero in 138 taking placebo. By 2003, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) received 121 cases of aggression on paroxetine, and by January 2006 that number had risen to 211. Note, that estimates for such physician adverse drug effect reporting systems range between 1% and 10% of actual adverse effects on treatment.

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.

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. Discontinuation symptoms can last from weeks to months and can be quite distressing for the patient.

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-harmCite error: A <ref> tag is missing the closing </ref> (see the help page).

Much of 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.

One early and 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.

Lawsuits

In many cases SSRI drug manufacturers have with held information from the FDA and the public to play down the risks and adverse effects associated with SSRIs. This had led to litigation against many of the pharmaceutical manufacturers of SSRI anti-depressants in cases covering suicidality, SSRI withdrawal and birth defects in neonates from nursing mothers on SSRIs.

In one of the only three cases to ever go to trial for SSRI indication of suicide, Eli Lilly was caught corrupting the judicial process by making a deal with the plaintiff's attorney to throw the case, in part by not disclosing damaging evidence to the jury.

The case involved a Kentucky man on Prozac, who went to his workplace and opened fire with an assault rifle killing 8 people, and injuring 12 others before turning the gun on himself. The jury returned a 9-to-3 verdict in favor of Lilly. The judge, in the end, took the matter to the Kentucky Supreme Court, which found that "there was a serious lack of candor with the trial court and there may have been deception, bad faith conduct, abuse of judicial process and, perhaps even fraud." The judge later revoked the verdict and instead, recorded the case as settled. The value of the secret settlement deal has been reported to be over $20 million.

On Dec 22, 2006, a US court decided in Hoorman, et al. v. SmithKline Beecham Corp. that individuals who purchased Paxil(R) or Paxil CR(TM) (paroxetine) for a minor child may be eligible for benefits under a $63.8 million Proposed Settlement. The lawsuit won the claim that pharmaceutical maker GlaxoSmithKline (GSK) promoted Paxil(R) or Paxil CR(TM) for prescription to children and adolescents while withholding and concealing material information about the medication's safety and effectiveness for minors.

The lawsuit stemmed from a consumer advocate protest against Paroxetine manufacturer GSK. Since the FDA approved paroxetine in 1992, approximately 5,000 U.S. citizens – and thousands more worldwide – have sued GSK. Most of these people feel they were not sufficiently warned in advance of the drug's side effects and addictive properties. However, GSK certainly must have known of the drug's potential dangers since, in clinical trials, up to 50 percent of patients taking paroxetine experienced adverse withdrawals from the drug.

According to the Paxil Protest website, http://www.paxilprotest.com, hundreds more lawsuits have been filed against GSK. The Paxil Protest website was launched August 8, 2005 to offer both information about the protest and information on Paxil previously unavailable to the public. Just three weeks after its launch, the site received more than a quarter of a million hits.

References and Notes

1. Malberg JE et al. (2000): "Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus" J. Neurosci. 20 (24), 9104-10
2. Anderson IM (2000): "Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability", J. Affect. Disord. 58(1), 19-3
3. Overview SSRI antidepressants. Paxil
4. Eli Lilly internal analysis submitted to the Joachim Wernicke (July 2, 1985), PZ 2441 2000. Document uncovered during Fentress litigation.
5. Kapit R. FDA Safety Review NDA 18-963, March 23, 1985.
6. Wagner KD, Ambrosini P, Rynn M, Wohlberg C, Yang R, et al. (2003) Effi cacy of sertraline in the treatment of children and adolescents with major depressive disorder: Two randomized controlled trials. JAMA 290: 1033–1041.
7. www.paxil.com
8. Medicines and Healthcare Products Regulatory Agency (2006) Adverse drug reactions online information tracking: Drug analysis print
9. Landen M, Hogberg P, Thase ME (2005). "Incidence of sexual side effects in refractory depression during treatment with citalopram or paroxetine". J Clin Psychiatry. 66: 100–6. PMID 15669895.{{cite journal}}: CS1 maint: multiple names: authors list (link)
10. Hu XH; et al. (2004). "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. 65: 959–65. PMID 15291685. {{cite journal}}: Explicit use of et al. in: |author= (help)
11. ^ Isbister G, Bowe S, Dawson A, Whyte I (2004). "Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose". J Toxicol Clin Toxicol. 42 (3): 277–85. PMID 15362595.{{cite journal}}: CS1 maint: multiple names: authors list (link)
12. Borys D, Setzer S, Ling L, Reisdorf J, Day L, Krenzelok E (1992). "Acute fluoxetine overdose: a report of 234 cases". Am J Emerg Med. 10 (2): 115–20. PMID 1586402.{{cite journal}}: CS1 maint: multiple names: authors list (link)
13. Oström M, Eriksson A, Thorson J, Spigset O (1996). "Fatal overdose with citalopram". Lancet. 348 (9023): 339–40. PMID 8709713.{{cite journal}}: CS1 maint: multiple names: authors list (link)
14. Sporer K (1995). "The serotonin syndrome. Implicated drugs, pathophysiology and management". Drug Saf. 13 (2): 94–104. PMID 7576268.
15. Moncrieff J, Cohen D. Do Antidepressants Cure or Create Abnormal Brain States? PLoS Medicine 2006;3:e240.
16. Damsa C, Bumb A, Bianchi-Demicheli F, Vidailhet P, Sterck R, Andreoli A, Beyenburg S. "Dopamine-dependent" side effects of selective serotonin reuptake inhibitors: a clinical review. J Clin Psychiatry. 2004;65:1064-8. PMID 15323590.
17. http://www.newstarget.com/011470.html

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)
• PROZAC Product/Prescribing Information
• Professor David Healy's Site 'healyprozac'
• SSRI Stories
• Woody Matters

• SSRI Side Effects web site
• Yahoo Support Group for those suffering from PSSD
• phpBB Support Group for PSSD sufferers
• SSRI Withdrawal Support Groups
• UK: SSRI Withdrawal Support & Info Group
• Danmark: SSRI Withdrawal Support Group
• Sverige: SSRI Withdrawal Support Group
• Norvege: SSRI Withdrawal Support Group

• Selective serotonin reuptake inhibitors