Selective serotonin reuptake inhibitor

Selective serotonin reuptake inhibitors (SSRIs) are a class of antidepressants used in the treatment of depression, anxiety disorders, and some personality disorders. They are also typically effective and used in treating premature ejaculation problems as well as some cases of insomnia.

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.

The first class of psychotropic drugs to be rationally designed, SSRIs are the most widely prescribed antidepressants in many countries. [(Chapter) ] 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.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 ]

RIs 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 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 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 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 Lancet study concluded that doctors should avoid or cautiously manage the prescribing of these drugs to pregnant women with psychiatric disorders. [ [http://www.medicalnewstoday.com/medicalnews.php?newsid=19631] Medical News Today - Lancet Press Release. Feb 05 2005]

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.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] 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] 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.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] Later it was found that neonatal citalopram and escitalopram makes persistent changes in the serotonergic transmission of the brain resulting in behavioral changes,cite journal |author=Popa D, Léna C, Alexandre C, Adrien J |title=Lasting syndrome of depression produced by reduction in serotonin uptake during postnatal development: evidence from sleep, stress, and behavior.|journal= J Neurosci. |volume=14 |issue=2 |pages=3546–3554 |year=2008 |pmid=18385313 |doi= |url=http://www.jneurosci.org/cgi/content/abstract/28/14/3546] 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=] which are reversed by treatment with antidepressants.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=] By treating normal and knockout mice lacking the serotonin transporter with fluoxetine scientists showed that normal emotional reactions in adulthood, like a short latency to escape foot shocks and inclination to explore new environments were dependent on unblocked serotonin transporters during the neonatal period. [ [http://www.sciencemag.org/cgi/content/full/sci;306/5697/792 NEUROSCIENCE: Prozac Treatment of Newborn Mice Raises Anxiety - Holden 306 (5697): 792 - Science ] ] [ [http://www.sciencemag.org/cgi/content/full/306/5697/879 Early-Life Blockade of the 5-HT Transporter Alters Emotional Behavior in Adult Mice - Ansorge et al. 306 (5697): 879 - Science ] ]

But when young mice were treated with the SNRI desimipramine they developed to normal adults, which suggests that serotonin and noradrenaline has different effects in the developing brain. [ [http://www.jneurosci.org/cgi/content/full/28/1/199 Inhibition of Serotonin But Not Norepinephrine Transport during Development Produces Delayed, Persistent Perturbations of Emotional Behaviors in Mice - Ansorge et al. 28 (1): ... ] ]

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. 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. 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. [ [http://www.fda.gov/CDER/DRUG/advisory/SSRI_PPHN200607.htm] FDA Public Health Advisory - Treatment Challenges of Depression in Pregnancy]

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

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.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] However, case reports of SSRI poisoning have indicated that severe toxicity can occurcite 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 ] and deaths have been reported following massive single ingestions,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 ] 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.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] 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

In late 2004 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 United States 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. At the same time, in adults SSRIs do not increase the risk of suicide.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]

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. [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.]

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. [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.]

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

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 [ [http://www.breggin.com/prbbooks.html Peter Breggin books including Toxic Psychiatry, Talking Back to Prozac, Brain-Disabling Treatments in Psychiatry ] ] ). 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. [cite book
last = Valenstein
first = Elliot
title = Blaming the Brain: The Truth about Drugs and Mental Health
publisher = The Free Press
year = 1998]

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.

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. [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= |month=February | year=2008 |format=htm |work= |publisher=PLoS Medicine |pages= |language= |archiveurl= |archivedate= |quote=] [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= February 27 2008 |accessdate=2008-03-01 ] [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 ] [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 ] [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= February 26, 2008 |accessdate=2008-03-01 ]

A study in the New England Journal of Medicine on a possible publication bias regarding the efficacy of SSRI medications in the treatment of depression suggests that their effectiveness and risk-benefit ratios may be greatly exaggerated. Of 74 studies registered with the United States FDA, 37 with positive results were published in academic journals, 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%.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/content/full/358/3/252 |accessdate=2008-05-29]

Lawsuits

Hundreds of lawsuits have been filed against drug manufacturers seeking compensation for harm attributed to the use of SSRIs. Suits based on product liability, for example, often allege failure to adequately warn users of potential side effects. Manufacturers have defended many suits on the merits and settled many others. In 2005, the U.S. Food and Drug Administration (FDA) asked manufacturers to include black box warnings on antidepressant drug packaging. [Center for Drug Evaluation and Research " [http://www.fda.gov/cder/drug/antidepressants Antidepressant Use in Children, Adolescents, and Adults] ". Retrieved September 30, 2008.]

See also

*Neuropsychopharmacology
*Neuropharmacology
*Neurotoxicology
*Neuropsychotoxicology
*Pharmacology
*Psychoactive drug
*Serotonin/Norepinephrine/Dopamine Reuptake Inhibitor

References and notes

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
*