Selective serotonin reuptake inhibitor
29581
225827005
2008-07-15T16:10:41Z
81.77.99.143
{{dablink|"SSRI" redirects here; for other uses, see [[SSRI (disambiguation)]].}}
[[Image:Serotonin (5-HT).svg|thumb|[[Serotonin]] ]]
'''Selective serotonergic reuptake inhibitors''' ('''SSRIs''') are a class of [[antidepressant]]s used in the treatment of [[Clinical depression|depression]], [[anxiety disorder]]s, and some [[personality disorder]]s. They are also typically effective and used in treating [[premature ejaculation]] problems.
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 transporter]]s, having little binding affinity for the [[noradrenaline]] and [[dopamine]] [[transporter]]s.
The first class of [[psychotropic drugs]] to be [[Drug design#Rational drug design|rationally designed]], SSRIs are the most widely prescribed antidepressants in many countries.<ref>(Chapter) {{citation | title = Selective serotonin reuptake inhibitor | pages = 242 | author = Sheldon H. Preskorn, Christina Y. Stanga, Ruth Ross}} in {{Citation | title = Antidepressants: Past, Present, and Future | publisher = Springer | year = 2004 | isbn = 3540430547 | author = Sheldon H. Preskorn, Christina Y. Stanga, John P. Feighner, Ruth Ross (Editors)}}</ref> Their effectiveness and safety have been questioned.
==List of SSRIs==
Drugs in this class include (trade names in parentheses):
* [[citalopram]] (''Celexa, Cipramil, Dalsan, Emocal, Sepram, Seropram'')
* [[dapoxetine]] (no trade name yet; not yet approved by the FDA)
* [[escitalopram]] (''Lexapro, Cipralex, Esertia'')
* [[fluoxetine]] (''Prozac, Fontex, Seromex, Seronil, Sarafem, Fluctin (EUR), Fluox (NZ), Depres (UZB)'')
* [[fluvoxamine]] (''Luvox, Fevarin, Dumyrox, Movox'')
* [[paroxetine]] (''Paxil, Seroxat, Sereupin, Aropax, Deroxat, Rexetin, Xetanor, Paroxat'')
* [[sertraline]] (''Zoloft, Lustral, Serlain'')
* [[zimelidine]] (''Zelmid, Normud'')
== Related antidepressants ==
SSRIs form a subclass of [[serotonin uptake inhibitor]]s, which includes other [[non-selective]] inhibitors as well. [[Serotonin-norepinephrine reuptake inhibitor]], [[serotonin-noradrenaline-dopamine reuptake inhibitor]]s and [[selective serotonin reuptake enhancer]]s are also [[serotonergic]] antidepressants.
==Medical indications==
The main indication for SSRIs is [[clinical depression]]. SSRIs are frequently prescribed for [[anxiety disorder]]s like [[social anxiety]], [[panic disorder]]s, [[obsessive-compulsive disorder]] (OCD), [[eating disorder]]s, and [[chronic pain]]. Though not specifically indicated by the manufacturers, they are sometimes prescribed to treat [[irritable bowel syndrome]] (IBS), [[Lichen simplex chronicus]], and [[premature ejaculation]].
A general disadvantage of SSRIs is that they require continuous daily treatment to delay ejaculation significantly.<ref name="pmid17983899">{{cite journal |author=Waldinger MD |title=Premature ejaculation: state of the art |journal=Urol. Clin. North Am. |volume=34 |issue=4 |pages=591–9, vii–viii |year=2007 |pmid=17983899 |doi=10.1016/j.ucl.2007.08.011}}</ref> For the occasional "on-demand", a few hours before coitus, treatment, [[clomipramine]] gave better results than paroxetine in one study,<ref name="pmid15363569">{{cite journal |author=Waldinger MD, Zwinderman AH, Olivier B |title=On-demand treatment of premature ejaculation with clomipramine and paroxetine: a randomized, double-blind fixed-dose study with stopwatch assessment |journal=Eur. Urol. |volume=46 |issue=4 |pages=510–5; discussion 516 |year=2004 |pmid=15363569 |doi=10.1016/j.eururo.2004.05.005}}</ref> while in another study both sertraline and clomipramine were indistinguishable from the pause–squeeze technique and inferior to paroxetine.<ref name="pmid11313839">{{cite journal |author=Abdel-Hamid IA, El Naggar EA, El Gilany AH |title=Assessment of as needed use of pharmacotherapy and the pause-squeeze technique in premature ejaculation |journal=Int. J. Impot. Res. |volume=13 |issue=1 |pages=41–5 |year=2001 |pmid=11313839 |doi=10.1038/sj.ijir.3900630}}</ref> The most recent research, conducted in 2007, suggests that on-demand treatment with [[sildenafil]] (Viagra) offers a dramatic improvement in ejaculation delay and sexual satisfaction as compared with daily paroxetine,<ref name="pmid17470165">{{cite journal |author=Wang WF, Wang Y, Minhas S, Ralph DJ |title=Can sildenafil treat primary premature ejaculation? A prospective clinical study |journal=Int. J. Urol. |volume=14 |issue=4 |pages=331–5 |year=2007 |pmid=17470165 |doi=10.1111/j.1442-2042.2007.01606.x}}</ref> with on-demand sertraline, paroxetine or clomipramine,<ref name="pmid11313839"/> and with the pause–squeeze technique.<ref name="pmid11313839"/><ref name="pmid17470165"/> All SSRIs are approved in the US for use with [[psychiatric]] disorders as outlined in the [[Diagnostic and Statistical Manual of Mental Disorders]] (DSM IV).
The uses for which SSRIs are approval vary by country and is determined by 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 company|pharmaceutical companies]]. In Europe, drugs can be approved either by the [[European Medicines Agency]] for human consumption throughout the [[European Union|EU]] or by the regulatory agencies of individual countries for use within those countries.{{Fact|date=April 2008}}. In Canada the drug approval process is carried out by [[Health Canada]].
==Contraindications and drug interaction==
One major contraindication of SSRIs is the concomitant use of MAOIs ([[monoamine oxidase inhibitor]]s). This is likely to cause severe [[serotonin syndrome]].
People taking SSRIs should also avoid taking [[pimozide]] (an [[antipsychotic]] diphenylbutylpiperidine derivative). The atypical [[Opioid|opioid analgesic]] [[tramadol]] hydrochloride (or Ultram, Ultracet) can, in rare cases, produce [[Seizure (medicine)|seizures]] when taken in conjunction with an SSRI or [[tricyclic antidepressant]]. [[Liver]] impairment is another contraindication for medications of this type.
SSRIs may increase blood levels and risk of toxicities of certain medications:
# highly protein-bound medications like [[warfarin]] (coumadin) and [[digoxin]]
# [[antiarrhythmic agent]]s like [[propafenone]] (Rythmol) or [[flecainide]] (Tambocor)
# [[beta blocker]]s like [[metoprolol]] (Toprol xl) or [[propranolol]] (Inderal)
# [[tricyclic antidepressant]]s like [[amitriptyline]] (Elavil) (may increase risk of serotonin syndrome)
# [[benzodiazepine]]s like [[alprazolam]] (Xanax) or [[diazepam]] (Valium)
# [[carbamazepine]] (Tegretol)
# [[cisapride]] (Propulsid)
# [[clozapine]] (Clozaril)
# [[ciclosporin]] (Neoral)
# [[haloperidol]] (Haldol)
# [[phenytoin]] (Dilantin)
# [[pimozide]] (Orap)
# [[theophylline]] (Theo-dur)
Certain drugs may increase toxicities of SSRIs:
# [[alcohol]] and other CNS depressants
# [[diuretic]]s (water pills)
# [[MAOIs]]
# [[sympathomimetic drug]]s like [[pseudoephedrine]] (Sudafed)
# [[lithium]]
# [[sibutramine]] (Meridia)
# [[MDMA]] (ecstasy)
# [[zolpidem]] (ambien)<ref>[http://www.emedicinehealth.com/ssris_and_depression/page4_em.htm SSRIs and Depression<!-- Bot generated title -->]</ref>
# [[Dextromethorphan]]
==Mode of action==
SSRIs acts by inhibiting the reuptake of [[serotonin]] after being released in synapses. How much an individual will respond to this, however, also depends on genetics. In addition, several other mechanisms are suggested for the desired effect, e.g. neuroprotection and anti-inflammatory and immunomodulatory factors. Taken together, SSRI has several advantages compared with [[tricyclic antidepressants]] (TCA)s and 5-HT-[[prodrugs]]. However, the latter might be required in addition to SSRIs in certain situations.
===Basic understanding===
{{see|Chemical synapse}}
In the [[brain]], messages are passed between two [[neuron|nerve cells]] via a [[synapse]], a small gap between the cells. The cell that sends the information releases [[neurotransmitter]]s (of which serotonin is one) into that gap. The neurotransmitters are then recognized by [[receptor (biochemistry)|receptor]]s 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 transporter]]s into the sending (''presynaptic'') cell (a process called ''reuptake'').
Some theories link [[Clinical depression|depression]] to a lack of stimulation of the recipient neuron at a synapse {{Fact|date=August 2007}}. 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 may be recognized again (and again) by the receptors of the recipient cell, stimulating it.
===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 [[autoreceptor]]s, that serve as a feedback sensor for the cell. Activation of the autoreceptors (by [[agonist]]s 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 ([[Downregulation|downregulating]]) the sensitivity of the autoreceptors {{Fact|date=March 2008}}.
Of greater importance is another adaptive process: the downregulation of postsynaptic [[5-HT2A receptor|serotonin 5-HT<sub>2A</sub> receptors]]. After the use of an SSRI, since there is more serotonin available, the response is to lower (to normal levels or less) the number of postsynaptic receptors over time, and in the long run, this modifies the serotonin/receptor ratio. Since a larger percentage of available receptors become activated by serotonin, transmission is enhanced or restored {{Fact|date=March 2008}}.
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 {{Fact|date=March 2008}}, and why increased anxiety is a common side effect in the first few days or weeks of use.
===Pharmacogenetics===
{{see | Pharmacogenetics}}
Large bodies of research are devoted to using [[genetic marker]]s to predict whether patients will respond to SSRIs or have side effects which will cause their [[discontinuation]], although these tests are not yet ready for widespread clinical use.<ref>PMID 17096399. Rasmussen-Torvik LJ, McAlpine DD. [[Genetic testing|Genetic screening]] for SSRI drug response among those with major depression: great promise and unseen perils. Depress Anxiety. 2006 Nov 9</ref> [[Single nucleotide polymorphisms]] of the [[5-HT|5-HT(2A)]] gene correlates with increased [[paroxetine]] discontinuation, but not [[mirtazapine]] (a non-SSRI antidepressant) discontinuation<ref>PMID 14514498. Murphy GM Jr, Kremer C, Rodrigues HE, Schatzberg AF. Pharmacogenetics of antidepressant medication intolerance. Am J Psychiatry. 2003 Oct;160(10):1830-5.</ref>
===Neuroprotection===
Studies have suggested that SSRIs may promote the growth of new [[neural pathway]]s or [[neurogenesis]] in rats.<ref>Malberg JE et al. (2000): "Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus" [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11124987&query_hl=14&itool=pubmed_docsum J. Neurosci. 20 (24), 9104-10]</ref> Also, SSRIs may protect against neurotoxicity caused by other compounds (for instance [[MDMA]] and [[Fenfluramine]]) as well as from depression itself.
===Anti-inflammatory and immunomodulation===
Recent studies show pro-inflammatory [[cytokine]] processes take place during [[Clinical depression|depression]], [[mania]] and [[Bipolar disorder|bipolar]] disorder, in addition to [[somatic]] disease (such as autoimmune [[hypersensitivity]]) and is possible that symptoms manifest in these psychiatric illnesses are being attenuated by pharmacological effect of antidepressants on the immune system.<ref>O'Brien SM, Scully P, Scott LV, Dinan TG. (2006). Cytokine profiles in bipolar affective disorder: focus on acutely ill patients. ''J Affect Disord.'', Feb, ''90''(2-3), 263-267.</ref><ref>Obuchowicz E, Marcinowska A, Herman ZS. (2005). Antidepressants and cytokines: clinical and experimental studies ''Psychiatr Pol.'', Sep-Oct, ''39''(5), 921-936.</ref><ref>Hong CJ, Yu YW, Chen TJ, Tsai SJ. Interleukin-6 genetic polymorphism and Chinese major depression. ''Neuropsychobiology'', ''52''(4), 202-205.</ref><ref>Elenkov IJ, Iezzoni DG, Daly A, Harris AG, Chrousos GP. (2005). Abstract cytokine dysregulation, inflammation and well-being. ''Neuroimmunomodulation'', ''12''(5), 255-269.</ref><ref>Kubera M, Maes M, Kenis G, Kim YK, Lason W. (2005). Effects of serotonin and serotonergic agonists and antagonists on the production of tumor necrosis factor alpha and interleukin-6. ''Psychiatry Res.'', Apr 30, ''134''(3), 251-258.</ref>
[[SSRI|SSRI's]] have been shown to be immunomodulatory and anti-inflammatory against pro-inflammatory [[cytokine]] processes, specifically on the regulation of [[Interferon-gamma]] (IFN-gamma) and [[Interleukin-10]] (IL-10), as well as [[TNF-alpha]] and [[Interleukin-6]] (IL-6). Antidepressants have also been shown to suppress [[T helper cell|TH1]] upregulation.<ref>Diamond M, Kelly JP, Connor TJ. (2006). Antidepressants suppress production of the Th1 cytokine interferon-gamma, independent of monoamine transporter blockade. ''Eur Neuropsychopharmacol.'', Oct, ''16''(7):481-490.</ref><ref>Kubera M, Lin AH, Kenis G, Bosmans E, van Bockstaele D, Maes M. (2001). Anti-inflammatory effects of antidepressants through suppression of the interferon-gamma/interleukin-10 production ratio. ''J Clin Psychopharmacol.'', Apr, ''21''(2):199-206.</ref><ref>Maes M. (2001). The immunoregulatory effects of antidepressants. ''Hum Psychopharmacol.'', Jan, ''16''(1):95-103.</ref><ref>Maes M, Kenis G, Kubera M, De Baets M, Steinbusch H, Bosmans E. (2005). The negative immunoregulatory effects of fluoxetine in relation to the cAMP-dependent PKA pathway. ''Int Immunopharmacol.'', Mar, ''5''(3):609-618.</ref>
Future serotonergic antidepressants may be made to specifically target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines.<ref>O'Brien SM, Scott LV, Dinan TG. (2004). Cytokines: abnormalities in major depression and implications for pharmacological treatment. ''Hum Psychopharmacol.'', Aug, ''19''(6), 397-403.</ref>
===SSRIs versus TCAs===
SSRIs are described as '[[drug selectivity|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 antidepressant]]s, which were the most commonly used class of antidepressants before the development of SSRIs.<ref>Anderson IM (2000): "Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a [[meta-analysis]] of efficacy and tolerability", [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10760555&dopt=Citation J. Affect. Disord. 58(1), 19-3]</ref> However, SSRIs have the important advantage that their [[drug overdose|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 [[Adverse drug reaction|side effects]]. Tricyclic antidepressant also have a higher risk of serious cardiovascular side effects which SSRIs lack.
===SSRIs versus 5-HT-Prodrugs===
{{see|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.
====SSRIs together with 5-HT-Prodrugs====
[[Biosynthesis|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.{{Fact|date=February 2008}} In 1989, the [[Food and Drug Administration]] made tryptophan available by [[Medical prescription|prescription]] only, in response to an outbreak of [[eosinophilia-myalgia syndrome]] caused by impure L-tryptophan supplements sold [[Over-the-counter drug|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. Combining 5-HTP with SSRIs may lead to [[serotonin syndrome]], as a result of too much serotonin activity in the brain. A doctor should be consulted before combining the two.
==Adverse effects==
===General side effects===
General side effects are mostly present during the first 1-4 weeks while the body adapts to the drug (with the exception of sexual side effects, which tend to occur later in treatment). In fact, it often takes 6-8 weeks for the drug to begin reaching its full potential (the slow onset is considered a downside to treatment with SSRIs). Almost all SSRIs are known to cause one or more of these symptoms:
*anhedonia
*nausea
*drowsiness or [[somnolence]]
*headache
*clenching of teeth
*extremely vivid and strange dreams
*dizziness
*changes in appetite
*weight loss/gain (measured by a change in bodyweight of 7 pounds)
*may result in a double risk of [[bone fracture]]s and injuries
*changes in [[Human sexual behavior|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 failure|renal impairment]]
*[[suicidal ideation]] (thoughts of [[suicide]])
* Photosensitivity (increased risk of sunburn) (Use protective clothing, such as long sleeves and hats, and sunscreen to decrease the risk of sunburn.)<ref>[http://www.emedicinehealth.com/ssris_and_depression/page5_em.htm SSRIs and Depression<!-- Bot generated title -->]</ref>
Common gastrointestinal side effects include [[nausea]], [[vomiting]], and [[diarrhea]], which are brought about by the actions of serotonin on the [[gastrointestinal tract]].
Most side effects usually disappear after the adaptation phase, when the antidepressive effects begin to show. However, despite being called general, the side effects and their durations are highly individual and drug-specific. 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 adjusted (eg. Prozac in the UK is begun at a 20mg dose, and then adjusted as necessary to 40mg or 60mg). Should the drug prove not to be effective, or the side effects intolerable to the patient, another common route is to switch treatment to either another SSRI, or an [[serotonin-norepinephrine reuptake inhibitor|SNRI]].<ref> A landmark study in the use of anti-depressants and their role in step-therapy can be found in the STAR*D trial.</ref>
[[Mania]] or [[hypomania]] is a possible side-effect. Users with some type of [[bipolar disorder]] are at a much higher risk, however SSRI-induced mania in patients previously diagnosed with unipolar depression can trigger a bipolar diagnosis.
===Sexual side effects===
{{see also|Post SSRI Sexual Dysfunction}}
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 17%<ref>{{cite journal | author = Hu XH et al | title = Incidence and duration of side effects and those rated as bothersome with selective serotonin reuptake inhibitor treatment for depression: patient report versus physician estimate | journal = J Clin Psychiatry | date = 2004 | volume = 65 | pages = 959–65 | pmid = 15291685}}</ref> and 41%<ref>{{cite journal | author = Landen M, Hogberg P, Thase ME | title = Incidence of sexual side effects in refractory depression during treatment with citalopram or paroxetine | journal = J Clin Psychiatry | date = 2005 | volume = 66 | pages = 100–6 | pmid = 15669895}}</ref> of patients. This dysfunction occasionally disappears spontaneously without stopping the SSRI, and in most cases resolves after discontinuation. In some cases, however, it does not; this is known as [[Post SSRI Sexual Dysfunction]] (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|Substantia Nigra]]. A number of drugs are not associated with sexual side-effects ([[bupropion]], [[mirtazapine]] (Remeron), [[maprotiline]] (Ludiomil), [[tianeptine]] (Stablon)<ref> For the review, see: {{cite journal | author = Clayton AH| title = Antidepressant-Associated Sexual Dysfunction: A Potentially Avoidable Therapeutic Challenge | journal = Primary Psychiatry| volume = 10| issue=1 |pages = 55–61 | year = 2003}}</ref><ref> For another review, see: {{cite journal | author = Kanaly KA, Berman JR| title = Sexual side effects of SSRI medications: potential treatment strategies for SSRI-induced female sexual dysfunction | journal = Curr Women's Health Rep| volume = 2| issue=6 |pages = 409–16 | year = 2002|pmid=12429073}}</ref> (some of these are also not associated with weight gain). As a result, sexual dysfunction caused by SSRIs can sometimes be mitigated by several different drugs. These include:
* [[bupropion]] ([[Norepinephrine reuptake inhibitor|norepinephrine]] and [[dopamine reuptake inhibitor]])
* [[buspirone]] ([[serotonin receptor agonist]])
* [[methylphenidate]] (stimulant)
* [[mirtazapine]] ([[noradrenergic and specific serotonergic antidepressant]] (NaSSA))
* [[amphetamine]] (stimulant)
* [[amantadine]] ([[antiviral]])
* [[pramipexole]] ([[dopamine agonist]]) and
* [[ropinirole]] ([[dopamine agonist]])
On the other hand, the effect of SSRIs to slow down sexual stimulation may be used as treatment; SSRIs have been proposed as a drug to treat [[premature ejaculation]].<ref>{{citation | title = Utility of selective serotonin reuptake inhibitors in premature ejaculation | journal = Curr Opin Investig Drugs |year = 2004 | date = July | volume = 5 | number = 7 | pages = 743–7 | pmid = 15298071 | author = Waldinger MD, Olivier B.}}</ref>
===Cardiovascular side effects===
Cardiovascular side effects are very rare with SSRI use, with a reported [[incidence (epidemiology)|incidence]] of less than 0.0003 percent.<ref>Grace Brooke Huffman. "Cardiac effects in patients using SSRI antidepressants - selective serotonin reuptake inhibitor - Tips from Other Journals". [[American Family Physician]], August, 1997.</ref> SSRIs inhibit cardiac and vascular [[Sodium channel|sodium]], [[calcium channel|calcium]] and [[potassium channel]]s and prolong [[QT interval]]s.<ref>Pacher P, Kecskemeti V."Cardiovascular side effects of new antidepressants and antipsychotics: new drugs, old concerns?". Curr Pharm Des. 2004;10(20):2463-2475. PMID 15320756</ref> However, a number of large studies of patients without known pre-existing heart disease have reported no [[electrocardiogram|EKG]] changes related to SSRI use.<ref name="afpssri">[http://archfami.ama-assn.org/cgi/content/full/7/1/78] Richard J. Goldberg, MD. Selective Serotonin Reuptake Inhibitors: Infrequent Medical Adverse Effects. Arch Fam Med. 1998;7:78-84.</ref> In overdose, fluoxetine has been reported to cause [[sinus tachycardia]], [[myocardial infarction]], [[junctional rhythm]]s and [[trigeminy]]. Some authors have suggested [[electrocardiogram|electrocardiographic]] monitoring in patients with severe pre-existing cardiovascular disease who are taking SSRI's.<ref>Pacher P, Ungvari Z, Nanasi PP, Furst S, Kecskemeti V."Speculations on difference between tricyclic and selective serotonin reuptake inhibitor antidepressants on their cardiac effects. Is there any?". Curr Med Chem. 1999 Jun;6(6):469-80. PMID 10213794</ref>
===Discontinuation syndrome===
{{main|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|withdrawal symptoms]]. Since [[Physical Dependence]] is a reality, discontinuation should be discussed with a medical practitioner before beginning treatment with this class of drugs.
===Suicidality and aggression===
Similarly to other antidepressants, SSRIs can cause suicidality in children.<ref name=FDA/><ref name=FDA2/><ref name=FDA3/> Analyses of the risks of SSRIs by governing bodies in the [[United States]] and [[United Kingdom]] have produced warnings about suicidality and aggression when the medications are used with children and adolescents.
A 2004 [[Food and Drug Administration]] (FDA) analysis of [[clinical trial]]s on children with [[major depressive disorder]] found statistically significant increases of the risks of "possible [[suicidal ideation]] and suicidal behavior" by about 80%, and of agitation and hostility by about 130%.<ref name =FDA>{{cite web | url = http://www.fda.gov/OHRMS/DOCKETS/ac/04/briefing/2004-4065b1-10-TAB08-Hammads-Review.pdf | title = Review and evaluation of clinical data. Relationship between psychiatric drugs and pediatric suicidality. | accessdate = 2008-05-29 | author = Hammad TA | date = 2004-08-116| format =PDF | publisher = FDA| pages = 42; 115}}</ref> An additional analysis by the FDA also indicated 1.5-fold increase of suicidality in the 18–24 age group.<ref name =FDA2>{{cite web | url = http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf | title =Clinical review: relationship between antidepressant drugs and suicidality in adults| accessdate = 2007-09-22 | author = Stone MB, Jones ML | date = 2006-11-17| format =PDF | work = Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC) | publisher = FDA| pages = 11–74}}</ref><ref name =FDA3>{{cite web | url = http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf | title = Statistical Evaluation of Suicidality in Adults Treated with Antidepressants | accessdate = 2007-09-22 | author = Levenson M, Holland C | date = 2006-11-17| format =PDF | work =Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC) | publisher = FDA| pages = 75–140}}</ref> This resulted in a [[black box warning]] on SSRI and other antidepressant medications regarding the increased risk of suicidality in patients younger than 24.<ref>{{cite web |url=http://www.fda.gov/bbs/topics/NEWS/2007/NEW01624.html |title=FDA Proposes New Warnings About Suicidal Thinking, Behavior in Young Adults Who Take Antidepressant Medications|date=2007-05-02 |format=htm |publisher=[[Food and Drug Administration|FDA]] |accessdate=2008-05-29}}</ref>
In 2004, the [[Medicines and Healthcare products Regulatory Agency]] (MHRA) in the [[United Kingdom]] judged [[fluoxetine]] (Prozac) to be the only antidepressant that offered a favorable [[Risk-benefit analysis|risk-benefit ratio]] in children with depression, though it was also associated with a slight increase in the risk of self-harm and suicidal ideation.<ref>{{cite web|url=http://www.mhra.gov.uk/home/groups/pl-p/documents/drugsafetymessage/con019472.pdf |title=Report of the CSM expert working group on the safety of selective serotonin reuptake inhibitor antidepressants|accessdate=2007-09-25 |date=2004-12-01 |format=PDF |publisher=[[Medicines and Healthcare products Regulatory Agency|MHRA]] }}</ref> Only two SSRIs are licensed for use with children in the UK, [[sertraline]] (Zoloft) and [[fluvoxamine]] (Luvox), and only for the treatment of [[obsessive-compulsive disorder]]. Fluoxetine, despite having a favorable risk-benefit ratio for use with depression in adolescents and children, is not licensed for this use.<ref name = MHRAoverview>{{cite web | url = http://www.mhra.gov.uk/Safetyinformation/Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/CON019494 |title=Selective Serotonin Reuptake Inhibitors (SSRIs): Overview of regulatory status and CSM advice relating to major depressive disorder (MDD) in children and adolescents including a summary of available safety and efficacy data |author=|authorlink= |coauthors= |date=2005-09-29 |format= ||publisher = [[Medicines and Healthcare products Regulatory Agency|MHRA]] | pages= |accessdate=2008-05-29}}</ref>
Other studies on SSRIs and suicide among adolescents are equivocal; rates of suicide attempts in high-risk populations appear to be unaffected by SSRI prescriptions in adults.<ref>{{cite journal |author=Olfson M, Marcus SC, Shaffer D |title=Antidepressant drug therapy and suicide in severely depressed children and adults: A case-control study |journal=Arch. Gen. Psychiatry |volume=63 |issue=8 |pages=865–72 |year=2006 |month=August |pmid=16894062 |doi=10.1001/archpsyc.63.8.865 |url=}}</ref> There is also evidence that higher rates of SSRI prescriptions are associated with lower rates of suicide in children, though since the evidence is [[correlation]]al, the true nature of the relationship is unclear.<ref name="pmid17074941">{{cite journal |author=Gibbons RD, Hur K, Bhaumik DK, Mann JJ |title=The relationship between antidepressant prescription rates and rate of early adolescent suicide |journal=Am J Psychiatry |volume=163 |issue=11 |pages=1898–904 |year=2006 |month=November |pmid=17074941 |doi=10.1176/appi.ajp.163.11.1898 | url = http://ajp.psychiatryonline.org/cgi/content/full/163/11/1898 | accessdate = 2008-05-29}}</ref> The introduction of a warning regarding the association between SSRIs and suicide led to a decrease in prescriptions for the medications in 2003 and 2004, and these decreases in prescriptions were associated with an increase in actual number of teenage suicide.<ref name="pmid17728420">{{cite journal |author=Gibbons RD, Brown CH, Hur K, ''et al'' |title=Early evidence on the effects of regulators' suicidality warnings on SSRI prescriptions and suicide in children and adolescents |journal=Am J Psychiatry |volume=164 |issue=9 |pages=1356–63 |year=2007 |month=September |pmid=17728420 |doi=10.1176/appi.ajp.2007.07030454 |url=http://ajp.psychiatryonline.org/cgi/content/full/164/9/1356 }}</ref>
===SSRIs and Pregnancy===
The [[FDA]] issued a warning on July 19, 2006 stating nursing mothers on SSRIs must discuss treatment with their physicians.
When taken by [[Pregnancy|pregnant women]], selective serotonin reuptake inhibitors (SSRIs) cross the placenta and have the potential to affect newborns. [[Sertraline]] and [[paroxetine]] have been associated with [[Congenital disorder|congenital malformations]]. Some evidence suggests that SSRIs are associated with neonatal complications such as [[neonatal abstinence syndrome]] (NAS) and persistent [[pulmonary hypertension]] (PPHN).
====Neonatal abstinence syndrome====
[[Neonatal abstinence syndrome]] is a [[withdrawal syndrome]] in [[Infant|newborn babies]]. It has been documented in SSRI treatment. 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 [[The Lancet|Lancet]] study concluded that doctors should avoid or cautiously manage the prescribing of these drugs to pregnant women with [[Mental illness|psychiatric disorders]].<ref>[http://www.medicalnewstoday.com/medicalnews.php?newsid=19631] [[Medical News Today]] - Lancet Press Release. Feb 05 2005</ref>
====Permanent neuropsychological changes====
Since the early 80's scientists have used a technique called neonatal clomipramine to produce animals used in depression research. If rats are given the tricyclic antidepressant [[clomipramine]] when they are 8-21 days old they will develop behavioural changes in adulthood which resembles depression in humans.<ref name="pmid2183099">{{cite journal |author=Vogel G, Neill D, Hagler M, Kors D |title=A new animal model of endogenous depression: a summary of present findings |journal=Neurosci Biobehav Rev |volume=14 |issue=1 |pages=85–91 |year=1990 |pmid=2183099 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0149-7634(05)80164-2}}</ref><ref name="pmid7902983">{{cite journal |author=Velazquez-Moctezuma J, Aguilar-Garcia A, Diaz-Ruiz O |title=Behavioral effects of neonatal treatment with clomipramine, scopolamine, and idazoxan in male rats |journal=Pharmacol. Biochem. Behav. |volume=46 |issue=1 |pages=215–7 |year=1993 |month=September |pmid=7902983 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/0091-3057(93)90343-R}}</ref> In 1997 Lundbeck found that treatment with the SSRI LU-10-134-C, which only differs from their product citalopram by two atoms could give similar results as clomipramine.<ref name="pmid9400008">{{cite journal |author=Hansen HH, Sánchez C, Meier E |title=Neonatal administration of the selective serotonin reuptake inhibitor Lu 10-134-C increases forced swimming-induced immobility in adult rats: a putative animal model of depression? |journal=J. Pharmacol. Exp. Ther. |volume=283 |issue=3 |pages=1333–41 |year=1997 |month=December |pmid=9400008 |doi= |url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9400008}}</ref> Later it was found that neonatal citalopram makes persistent changes in the serotonergic transmission of the brain resulting in behavioral changes,<ref name="pmid16012532">{{cite journal |author=Maciag D, Simpson KL, Coppinger D, ''et al'' |title=Neonatal antidepressant exposure has lasting effects on behavior and serotonin circuitry |journal=Neuropsychopharmacology |volume=31 |issue=1 |pages=47–57 |year=2006 |month=January |pmid=16012532 |doi=10.1038/sj.npp.1300823 |url=}}</ref> which are reversed by treatment with antidepressants.<ref name="pmid16483567">{{cite journal |author=Maciag D, Williams L, Coppinger D, Paul IA |title=Neonatal citalopram exposure produces lasting changes in behavior which are reversed by adult imipramine treatment |journal=Eur. J. Pharmacol. |volume=532 |issue=3 |pages=265–9 |year=2006 |month=February |pmid=16483567 |doi=10.1016/j.ejphar.2005.12.081 |url=}}</ref>
====Persistent pulmonary hypertension====
Persistent [[pulmonary hypertension]] (PPHN) is a serious and life-threatening, but rare, lung condition that occurs soon after birth of the newborn. [[Infant|newborn babies]] with PPHN have high pressure in their lung [[blood vessel]]s 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 [[Health care|medical care]]. One study has found that PPHN is six times more common in babies whose mothers take an SSRI antidepressant after the 20th week of the pregnancy compared to babies whose mothers do not take an antidepressant.<ref>[http://www.fda.gov/CDER/DRUG/advisory/SSRI_PPHN200607.htm] FDA Public Health Advisory - Treatment Challenges of Depression in Pregnancy</ref>
===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.
==Overdose==
{{main|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.<ref name="ClinTox2004-isbister">{{cite journal | author = Isbister G, Bowe S, Dawson A, Whyte I | title = Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose | journal = J Toxicol Clin Toxicol | volume = 42 | issue = 3 | pages = 277–85 | year = 2004 | pmid = 15362595 | doi = 10.1081/CLT-120037428}}</ref> However, case reports of SSRI poisoning have indicated that severe toxicity can occur<ref name="AmJEmergMed1992-Borys">{{cite journal | author = Borys D, Setzer S, Ling L, Reisdorf J, Day L, Krenzelok E | title = Acute fluoxetine overdose: a report of 234 cases | journal = Am J Emerg Med | volume = 10 | issue = 2 | pages = 115–20 | year = 1992 | pmid = 1586402 | doi = 10.1016/0735-6757(92)90041-U <!--Retrieved from CrossRef by DOI bot-->}}</ref> and deaths have been reported following massive single ingestions,<ref name="Lancet1996-Ostrom">{{cite journal | author = Oström M, Eriksson A, Thorson J, Spigset O | title = Fatal overdose with citalopram | journal = Lancet | volume = 348 | issue = 9023 | pages = 339–40 | year = 1996 | pmid = 8709713 | doi = 10.1016/S0140-6736(05)64513-8 <!--Retrieved from CrossRef by DOI bot-->}}</ref> although this is exceedingly uncommon when compared to the tricyclic antidepressants.<ref name="ClinTox2004-isbister"/>
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.<ref name="DrugSaf1995-Sporer">{{cite journal | author = Sporer K | title = The serotonin syndrome. Implicated drugs, pathophysiology and management | journal = Drug Saf | volume = 13 | issue = 2 | pages = 94–104 | year = 1995 | pmid = 7576268}}</ref> Other reported significant effects include [[coma]], [[seizures]], and [[Cardiotoxicity|cardiac toxicity]].<ref name="ClinTox2004-isbister"/>
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==
{{see also|Biopsychiatry controversy|Biological psychiatry}}
{{weasel|section}}
In late 2004 media attention was given to a proposed link between SSRI use and [[teenage suicide|juvenile suicide]]. For this reason, the use of SSRIs in pediatric cases of depression is now recognized by the United States FDA as warranting a cautionary statement to the parents of children who may be prescribed SSRIs by a [[General practitioner|family doctor]]. The FDA's currently required packaging insert for SSRIs includes a warning (known as a [[Black box warning|"black box warning"]]) that a pooled analysis of placebo [[randomized controlled trial|controlled trials]] of 9 antidepressant drugs (including multiple SSRIs) resulted in a risk of suicidality that was twice that of [[placebo]]. At the same time, in adults SSRIs do not increase the risk of suicide.<ref name="pmid15718537">{{cite journal |author=Gunnell D, Saperia J, Ashby D |title=Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults: meta-analysis of drug company data from placebo controlled, randomised controlled trials submitted to the MHRA's safety review |journal=BMJ |volume=330 |issue=7488 |pages=385 |year=2005 |pmid=15718537 |doi=10.1136/bmj.330.7488.385}}</ref>
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.<ref>Lacasse JR, Leo J. ''[http://medicine.plosjournals.org/archive/1549-1676/2/12/pdf/10.1371_journal.pmed.0020392-S.pdf Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature.]'' [[PLoS Medicine]] 2005;2:e392.</ref>
The criticism stems from questions about the validity of claims that SSRIs work by 'correcting' [[Chemical imbalance theory|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.<ref>Moncrieff J, Cohen D. ''[http://medicine.plosjournals.org/archive/1549-1676/3/7/pdf/10.1371_journal.pmed.0030240-p-S.pdf Do Antidepressants Cure or Create Abnormal Brain States?]'' PLoS Medicine 2006;3:e240.</ref>
One possible mechanism is by inhibition of [[dopamine]]rgic neurotransmission.<ref>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.</ref>
Biopsychiatrists believe that, among other factors, the balance of [[neurotransmitter]]s 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<ref>[http://www.breggin.com/prbbooks.html Peter Breggin books including Toxic Psychiatry, Talking Back to Prozac, Brain-Disabling Treatments in Psychiatry<!-- Bot generated title -->]</ref>). 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.<ref>{{cite book
| last = Valenstein
| first = Elliot
| title = Blaming the Brain: The Truth about Drugs and Mental Health
| publisher = The Free Press
| year = 1998
}}
</ref>
One controversial critic of antidepressants, [[Peter Breggin]], a physician who opposes the overuse of prescription medications to treat patients for mental health issues, predicted [[Iatrogenesis|iatrogenic]] issues that SSRIs incur on a significant percentage of patients. Another prominent SSRI critic is [[David Healy (psychiatrist)|David Healy]].
A widely-reported meta-analysis combined 35 clinical trials submitted to the [[FDA]] before licensing of four newer antidepressants (including the SSRIs [[paroxetine]] and [[fluoxetine]], and two non-SSRI antidepressants [[nefazodone]] and [[venlafaxine]]). The authors found that although the antidepressants were [[statistically]] superior to [[placebo]] they did not exceed the [[NICE]] criteria for a 'clinically significant' effect. In particular they found that the effect size was very small for moderate depression but increased with severity reaching 'clinical significance' for very severe depression. The relationship between severity and efficacy was attributed to a reduction of the placebo effect in severely depressed patients, rather than an increase in the effect of the medication.<ref>{{cite web |url=http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0050045 |title=Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration |accessdate=2008-02-26 |author=Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT |authorlink= |coauthors= |date=February 2008 |format=htm |work= |publisher=PLoS Medicine |pages= |language= |archiveurl= |archivedate= |quote=}}</ref>
<ref>{{cite news |first= |last= |authorlink=Darian Leader |coauthors= |title=The creation of the Prozac myth |url=http://www.guardian.co.uk/society/2008/feb/27/mentalhealth.health1 |work= |publisher=The Guardian |date= Wednesday February 27 2008 |accessdate=2008-03-01 }}</ref>
<ref>{{cite news |first=Michael |last=Day |authorlink=|coauthors= |title=Prozac does not work in majority of depressed patients |url=http://www.newscientist.com/article/dn13375-prozac-does-not-work-in-most-depressed-patients.html |work= |publisher=New Scientist |date=26 February 2008 |accessdate=2008-03-01 }}</ref>
<ref>{{cite news |first= |last= |authorlink= |coauthors= |title=Anti-depressants 'no better than placebo'|url=http://www.nursingtimes.net/clinicalnews/2008/02/antidepressants_such_as_prozac_not_clinically_effective.html |work= |publisher=Nursing Times |date=26 February 2008 |accessdate=2008-03-01 }}</ref>
<ref>{{cite news |first=Laura |last=Blue |authorlink= |coauthors= |title=Antidepressants Hardly Help |url=http://www.time.com/time/health/article/0,8599,1717306,00.html |work= |publisher= |date=Tuesday, Feb. 26, 2008 |accessdate=2008-03-01 }}</ref>
A study in the [[New England Journal of Medicine]] on a possible [[publication bias]] regarding the efficacy of SSRI medications suggests that their effectiveness and risk-benefit ratios may be greatly exaggerated. Of 74 studies registered with the United States [[Food and Drug Administration|FDA]], 37 with positive results were published in [[academic journal]]s, while 22 studies with negative results were not published and 11 with negative results were published in a way that conveyed a positive outcome (one positive study was not published and three negative studies were published with results that were portrayed as negative). Overall, 94% of studies actually published were positive outcomes; when published and unpublished studies were included for analysis, the percentage of positive outcomes was 51%.<ref name="pmid18199864">{{cite journal |author=Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R |title=Selective publication of antidepressant trials and its influence on apparent efficacy |journal=N. Engl. J. Med. |volume=358 |issue=3 |pages=252–60 |year=2008 |month=January |pmid=18199864 |doi=10.1056/NEJMsa065779 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=18199864&promo=ONFLNS19 |accessdate=2008-05-29}}</ref>
==Lawsuits==
In one of the only three cases to ever go to trial for SSRI indication in suicide, [[Eli Lilly]] was caught corrupting the [[Legal procedure|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 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".<ref>[http://www.judicialaccountability.org/articles/hideandseek.htm] from Richard Zitrin & Carol M. Langford. "Hide and Secrets in Louisville" from "The Moral Compass of the American Lawyer". [[Ballantine Books]], 1999</ref>
== See also ==
*[[Neuropsychopharmacology]]
*[[Neuropharmacology]]
*[[Neurotoxicology]]
*[[Neuropsychotoxicology]]
*[[Pharmacology]]
*[[Psychoactive drug]]
*[[Serotonin/Norepinephrine/Dopamine Reuptake Inhibitor]]
==References and notes==
{{reflist|2}}
==External links==
* [http://www.pendulum.org/articles/articles_misc_anhedonia.html] Notes on Anhedonia and SAD
* [http://www.nlm.nih.gov/medlineplus/druginformation.html MEDLINEplus drug information database] at [[NIH]]
* [http://www.ceri.com/trypto.htm The FDA Ban of L-Tryptophan] at ceri.com
* [http://www.fda.gov/cder/drug/antidepressants/PI_template.pdf "black box" warning for SSRIs] at [[FDA]]
* [http://www.fda.gov/cder/drug/antidepressants/antidepressantList.htm FDA list of SSRIs] receiving the [[black box warning]] at [[FDA]]
*[http://pi.lilly.com/us/prozac.pdf PROZAC Product/Prescribing Information] at [[Eli Lilly and Company]]
* Barry Yeoman [http://www.barryyeoman.com/articles/courtroom.html Putting Science in the Dock], The Nation at barryyeoman.com
* {{MeshName|Serotonin+uptake+inhibitors}}
{{Antidepressants}}
{{Receptor agonists and antagonists}}
[[Category:Selective serotonin reuptake inhibitors| Selective serotonin reuptake inhibitor]]
[[da:Lykkepille]]
[[de:Serotonin-Wiederaufnahmehemmer]]
[[es:Inhibidor selectivo de recaptación de Serotonina]]
[[fr:Inhibiteur sélectif de la recapture de la sérotonine]]
[[ko:선택적 세로토닌 재흡수 억제제]]
[[it:SSRI]]
[[he:SSRI]]
[[lt:SSRI]]
[[hu:Szelektív szerotoninvisszavétel-gátlók]]
[[nl:Selectieve serotonine-heropnameremmer]]
[[ja:選択的セロトニン再取り込み阻害薬]]
[[no:Selektiv serotoninreopptakshemmer]]
[[pl:Selektywne inhibitory zwrotnego wychwytu serotoniny]]
[[pt:Inibidor selectivo de recaptação de serotonina]]
[[fi:Selektiivinen serotoniinin takaisinoton estäjä]]
[[sv:Selektiva serotoninåterupptagshämmare]]
[[tr:Selektif serotonin gerialım inhibitörleri]]
[[zh:选择性血清再吸收抑制剂]]