Selective serotonin reuptake inhibitor

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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.

Contents 1 List of SSRIs 2 Other types of antidepressants 3 Medical indications 4 Contraindications / drug interaction 5 Mode of action 5.1 Basic understanding 5.2 Pharmacodynamics 5.3 Pharmacogenetics 5.4 Interaction with carbohydrate metabolism 5.5 Neuroprotection 5.6 SSRIs versus TCAs 5.7 SSRIs versus 5-HT-Prodrugs 6 Adverse effects 6.1 General side effects 6.2 Rare Side Effects 6.3 Sexual side effects 6.4 Cardiovascular Side Effects 6.5 Discontinuation syndrome 6.6 SSRIs and Pregnancy 7 Suicidality and Aggression 7.1 Fluoxetine and Suicide 7.2 Sertraline and Aggression 7.3 Paroxetine and Aggression 8 Overdose 9 Criticism 10 Lawsuits 11 See also 12 References and notes 13 External links

[edit] List of SSRIs

Drugs in this class include:
(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 the left-handed s-enantiomer of the racemic citalopram. It was introduced to the market two and a half years before the patent protection for citalopram expired.

[edit] Other types of antidepressants

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).

[edit] 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. All SSRIs are approved in conjunction with psychiatric disorders as outlined in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV).

Different SSRIs have different approval uses in different countries dependent on 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. Most other countries make their approval decisions based on FDA decisions, but not always.

[edit] 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.

[edit] Mode of action

[edit] Basic understanding

Further information: Chemical synapse

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.

[edit] Pharmacodynamics

Further information: 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.

[edit] Pharmacogenetics

Large bodies of research are devoted to using genetic markers to predict whether patients will respond to SSRI's or have side effects which will cause their discontinuation, although these tests are not yet ready for widespread clinical use^[1]. In a double blind randomized controlled clinical trial, single nucleotide polymorphisms of the 5-HT(2A) gene were found to correlate with increased paroxetine discontinuation, but not mirtazapine (a non-SSRI antidepressant) discontinuation ^[2]

[edit] 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.

[edit] Neuroprotection

Studies have suggested that SSRIs may promote the growth of new neural pathways.^[3] Also, SSRIs may protect against neurotoxicity caused by other compounds (for instance MDMA and Fenfluramine) as well as from depression itself.

[edit] 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.^[4] 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.

[edit] SSRIs versus 5-HT-Prodrugs

Further information: 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.

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.

[edit] Adverse effects

[edit] General side effects

General side effects are mostly present during the first 1-4 weeks while the body adapts to the drug. In fact, it often takes 6-8 weeks for the drug to begin reaching its full potential. Almost all SSRIs are known to cause either one or more of these symptoms:

• nausea
• drowsiness or somnolence
• headache
• clenching of teeth
• extremely vivid and strange dreams
• dizziness
• changes in appetite
• weight loss/gain
• 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
• thoughts of suicide
• depersonalization (derealization)

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

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.

[edit] Rare Side Effects

Rare side effects of SSRIs include the following:

Mania or hypomania is a very rare but very possible side-effect. Users with some type of bipolar disorder are at a much higher risk for this to happen. Often it is a trigger for a bipolar diagnosis.

• Body as a Whole:

Acute abdominal syndrome, hypothermia, intentional injury, neuroleptic malignant syndrome, photosensitivity reaction.

• Cardiovascular System:

Atrial fibrillation, bradycardia, cerebral embolism, cerebral ischemia, cerebrovascular accident, extrasystoles, heart arrest, heart block, pallor, peripheral vascular disorder, phlebitis, shock, thrombophlebitis, thrombosis, vasospasm, ventricular arrhythmia, ventricular extrasystoles, ventricular fibrillation.

• Digestive System:

Biliary pain, bloody diarrhea, cholecystitis, duodenal ulcer, enteritis, esophageal ulcer, fecal incontinence, gastrointestinal hemorrhage, hematemesis, hemorrhage of colon, hepatitis, intestinal obstruction, liver fatty deposit, pancreatitis, peptic ulcer, rectal hemorrhage, salivary gland enlargement, stomach ulcer hemorrhage, tongue edema.

• Endocrine System:

Diabetic acidosis, diabetes mellitus.

• Hemic and Lymphatic System:

Blood dyscrasia, hypochromic anemia, leukopenia, lymphedema, lymphocytosis, petechia, purpura, thrombocythemia, thrombocytopenia.

• Metabolic and Nutritional:

Alcohol intolerance, alkaline phosphatase increased, BUN increased, creatine phosphokinase increased, hyperkalemia, hyperuricemia, hypocalcemia, iron deficiency anemia, SGPT increased.

• Musculoskeletal System:

Arthrosis, chondrodystrophy, myasthenia, myopathy, myositis, osteomyelitis, osteoporosis, rheumatoid arthritis.

• Nervous System:

Abnormal electroencephalogram, antisocial reaction, circumoral paresthesia, coma, delusions, dysarthria, dystonia, extrapyramidal syndrome, foot drop, hyperesthesia, neuritis, paralysis, reflexes decreased, reflexes increased, stupor.

• Respiratory System:

Apnea, atelectasis, cough decreased, emphysema, hemoptysis, hypoventilation, hypoxia, larynx edema, lung edema, pneumothorax, stridor.

• Skin and Appendages:

Furunculosis, herpes zoster, hirsutism, petechial rash, psoriasis, purpuric rash, pustular rash, seborrhea.

• Special Senses:

Blepharitis, deafness, diplopia, exophthalmos, eye hemorrhage, glaucoma, hyperacusis, iritis, parosmia, scleritis, strabismus, taste loss, visual field defect.

• Urogenital System:

Breast engorgement, glycosuria, hypomenorrhea, kidney pain, oliguria, priapism, uterine hemorrhage, uterine fibroids enlarged.

[edit] 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 41%^[5] and 83% of patients.^[6] 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 SSRIs 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.

[edit] Cardiovascular Side Effects

SSRIs inhibit cardiac and vascular Na(+), Ca(2+) and K(+) channels and prolong QT intervals. These results suggest that SSRIs have clinically important cardiac as well as vascular effects. Clinicians should be more vigilant about these potential adverse reactions and ECG control may be suggested during therapy, especially in patients with cardiovascular disorders.^{[7] [8]}

Vascular resistance is modulated in a complex fashion by serotonin receptors. In healthy people, serotonin causes vasodilation. For example, in the cerebral arteries, the 5-HT1 receptor causes vasoconstriction, which is why sumatriptan succinate (a 5-HT1 agonist) can be used in the treatment of migraine headaches. Serotonin also plays an important role in angina. While serotonin has a vasodilatory effect on normal coronary arteries (an effect that is blocked by the 5-HT2 receptor antagonist ketanserin), serotonin produces direct unopposed vasoconstriction in damaged endothelium. In patients with damaged endothelium (such as those with significant coronary artery disease), it has been speculated that there may be an increase in myocardial ischemia secondary to an increase in vasoconstrictive serotonin in the environment caused by treatment with SSRIs.^[9]

In the first 2.5 million patients exposed to fluoxetine, there were reports of 34 cases of atrial arrhythmias, 60 cases of bradycardia, 26 cases of varying degrees of heart block, 54 cases of significant ventricular arrhythmias, 24 cases of congestive heart failure, and 42 cases of other arrhythmias ^[10]

Cardiovascular events associated with SSRI use include cardiac arrhythmias, orthostatic hypotension, atrial fibrillation, atrial flutter and supraventricular tachycardia. In overdose, fluoxetine has been reported to cause sinus tachycardia, myocardial Infarction, junctional rhythms and trigeminy. However, the total incidence of adverse cardiac effects has been indicated to be less than 0.0003 percent.^[11]

Although rare, cardiovascular side effects do occur in the presence of SSRIs. It is suggested physicians should be extremely careful employing SSRI use in patients with a history of heart disease and in the elderly.

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

[edit] SSRIs and Pregnancy

The FDA issued a warning on July 19, 2006 to 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. Although SSRIs have not been associated with congenital malformations, some evidence suggests that they are associated with neonatal complications such as neonatal abstinence syndrome (NAS) and persistent pulmonary hypertension (PPH).

A study suggests there may be additional, though rare, risks of SSRI medications during pregnancy. This study focused on newborn babies with persistent pulmonary hypertension (PPHN), which is a serious and life-threatening lung condition that occurs soon after birth of the 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. In this study PPHN was six times more common in babies whose mothers took an SSRI antidepressant after the 20th week of the pregnancy compared to babies whose mothers did not take an antidepressant.^[12]

SSRI withdrawal syndromes also have been documented in neonates. Investigators found that 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.^[13]

An article by the Wall Street Journal, revealed that psychiatrists from Harvard, UCLA and Emory, whose report published in the Journal of the American Medical Association (JAMA) urging pregnant women to continue taking antidepressants - challenging the common assumption that hormonal changes during pregnancy protected expectant mothers against depression - had financial interests in making those recommendations. Dr. Catherine DeAngelis admitted that JAMA published the report without disclosing authors' ties to the manufacturers of the drugs they recommended for pregnant women.^[14]

An October 2006 study revealed SSRIs may decrease youth suicide overall.^[15] A more recent study [9] released in November 2006, however concluded only "The aggregate nature of these observational data precludes a direct causal interpretation of the results. More SSRI prescriptions... may reflect antidepressant efficacy".

Inevitably statistics such as these (and the conclusions drawn from them) are considered controversial by commentators in the UK,^[16] and the USA.^[17]

Any claimed causal linkage is actually negated by the facts. In October 2004, the American Psychiatric Association wrote: "In 2003, U.S. physicians wrote 15 million antidepressant prescriptions for patients under age 18, according to FDA data. In the first six months of 2004, antidepressant prescriptions for children increased by almost 8 percent, despite the new drug labeling."^[18]

According to these facts, antidepressant prescriptions for children increased by almost 8% in the first six months of 2004, if this is the case, it is difficult to link an increased suicide rate the same year to reduced use of antidepressants.

So despite the suggestions of a connection between the drop in SSRI prescriptions (even this fact is a matter of debate) and the spike in child and teen suicides, much more research will be needed before a conclusive link can be drawn.

In fact the only SSRI that is licensed for use in children in the the UK and USA is Prozac. All other SSRIs have been banned from paediatric use as their safety and efficacy have not been proven. Even of its own paediatric trials of Seroxat, Glaxo said[10] “The best which could have been achieved was a statement that although safety data was reassuring, efficacy had not been demonstrated.”

[edit] Suicidality and Aggression

Over the years there have been many accusations by patients and their families of SSRIs causing suicidal ideation and aggressive behavior. There was little scientific support for this claim, but alternative medicine sites often claim that patients committed suicide or engaged in aggressive acts using SSRIs. ^[19] Manufacturers of SSRIs historically have vehemently denied any such link and have always blamed the disease rather than the treatment.

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 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.

[edit] Fluoxetine 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.^[20] 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.”^[21]

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 [which] 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.

In 1985 Dr. Kapit recommended “labeling warning [for] the physician that such signs and symptoms of depression may be exacerbated by this drug". No such warning was issued until 2004.

[edit] Sertraline 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.^[22]

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 Eliot Spitzer termed this practice "fraud".

[edit] Paroxetine 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".^[23]

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.^[24] Note, that estimates for such physician adverse drug effect reporting systems range between 1% and 10% of actual adverse effects on treatment.

[edit] Overdose

Main article: Serotonin syndrome

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.^[25] However, case reports of SSRI poisoning have indicated that severe toxicity can occur^[26] and deaths have been reported following massive single ingestions,^[27] although this is exceedingly uncommon when compared to the tricyclic antidepressants.^[25]

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.^[28] Other reported significant effects include coma, seizures, and cardiac toxicity.^[25]

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.

[edit] Criticism

See also: Biopsychiatry controversy and Biological psychiatry

SSRIs have been the focus of controversy. Several studies have been published demonstrating that SSRIs do not significantly outperform placebos at reducing depressive symptoms.^[29] These articles claim that depressive symptoms respond strongly to placebo, and that methodological errors have inflated what small difference in effects there may be.

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.^[30]

Some 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.^[31]

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.^[32]

One possible mechanism is by inhibition of dopaminergic neurotransmission.^[33]

Most 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 ^[34]). 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. ^[35]

Critics suggest mainstream psychiatry theory is influenced by pharmaceutical companies' sales and marketing departments. Richard Smith (former editor of the British Medical Journal) wrote about how the drug industry can subtly influence what is published in the scholarly literature. He said, "I must confess that it took me almost a quarter of a century editing for the BMJ to wake up to what was happening." ^[36]

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.

In many cases SSRI drug manufacturers have withheld information from the FDA and the public to play down the risks and adverse effects associated with SSRIs, including information regarding withdrawals and discontinuation events. This had led to litigation with many of the pharmaceutical manufacturers of SSRIs.

[edit] Lawsuits

In many cases SSRI drug manufacturers have withheld 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 in 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, known as the Fentress Case involved a Kentucky man, Joseph Wesbecker, on Prozac, who went to his workplace and opened fire with an assault rifle killing 8 people (including Fentress), 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 never been disclosed, but was reportedly "tremendous".^[37]

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.^[38]

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.

According to the Paxil Protest website, http://www.paxilprotest.com, hundreds more lawsuits have been filed against GSK.^[39] 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.

The original Paxil Protest website is no longer available. It is understood that the action to remove the site from the internet was undertaken as part of a confidentiality agreement or 'gagging order' which the owner of the site entered into as part of a settlement of his action against GlaxoSmithKline. (However, in March 2007, the website Seroxat Secrets [11]discovered that an archive of Paxil Protest site [12]was still available on the internet via Archive.org) Gagging orders are common in such cases and can extend to documents that defendants wish to remain hidden from the public. However in some cases, such documents can become public at a later date, such as those made public by Peter Breggin in February of 2006. A press release from Dr. Breggin can be seen here: [13]

In January 2007, according to the Seroxat Secrets website, [14], the national group litigation in the United Kingdom, on behalf of several hundred people who allege withdrawal reactions through their use of the drug Seroxat, against GlaxoSmithKline plc, moved a step closer to the High Court in London, with the confirmation that Public Funding had been reinstated following a decision by the Public Interest Appeal Panel. The issue at the heart of this particular action claims Seroxat is a defective drug in that it has a propensity to cause a withdrawal reaction. Hugh James Solicitors confirm this news on their website [15]

On January 29 2007, the BBC in the UK aired a fourth documentary in its 'Panorama' [16] series about the controversial drug Seroxat. This programme, entitled Secrets of the Drug Trials, focuses on on three GSK paediatric clinical trials on depressed children and adolescents. The documentary claims Seroxat could not be proven to work for teenagers, and that one clinical trial indicated they were six times more likely to become suicidal after taking it.^{[citation needed]}

[edit] See also

• Neuropsychopharmacology
• Neuropharmacology
• Neurotoxicology
• Neuropsychotoxicology
• Pharmacology
• Psychoactive drug

[edit] References and notes

[edit] 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
• Dr. David Healy explores threats to safety & academic freedom surrounding SSRIs
• Dr. Yolande Lucire: SSRIs and their Complications
• SSRI Stories - News stories involving people on SSRI's
• Woody Matters - Timeline of SSRI controversy

v • d • e Antidepressants (ATC N06A)
Monoamine oxidase inhibitors (MAOI)	Harmaline, Iproniazid, Isocarboxazid, Nialamide, Pargyline, Phenelzine, Selegiline, Toloxatone, Tranylcypromine RIMAs: Brofaromine, Moclobemide
Dopamine reuptake inhibitor (DARI)	Amineptine, Phenmetrazine, Vanoxerine
Norepinephrine-dopamine reuptake inhibitors (NDRI)	Bupropion
Norepinephrine reuptake inhibitor (NRI) or (NARI)	Atomoxetine, Maprotiline, Reboxetine, Viloxazine
Serotonin-norepinephrine reuptake inhibitor (SNRI)	Duloxetine, Milnacipran, Nefazodone , Venlafaxine
Selective serotonin reuptake inhibitor (SSRI)	Alaproclate, Citalopram, Escitalopram, Etoperidone, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Zimelidine
Selective serotonin reuptake enhancer (SSRE)	Tianeptine
Noradrenergic and specific serotonergic antidepressant (NaSSA)	Mirtazapine
Tricyclic antidepressants (TCA)	Amitriptyline, Amoxapine, Butriptyline, Clomipramine, Desipramine, Dibenzepin, Dothiepin, Doxepin, Imipramine, Iprindole, Lofepramine, Melitracen, Nortriptyline, Opipramol, Protriptyline, Trimipramine
Tetracyclic antidepressants	Maprotiline, Mianserin, Nefazodone, Trazodone