Sertraline
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2008-07-12T11:14:55Z
Paul gene
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/* Other indications */ added a ref to binge-eating disorder
{{redirect|Lustral|the electronic music band|Lustral (band)}}
{{drugbox
| IUPAC_name = (1''S'')-''cis''-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-<BR>''N''-methyl-1-naphthalenamine
| image = Sertraline structure.svg
| image2 = Sertraline-A-3D-balls.png
| width = 200
| CAS_number = 79617-96-2
| ATC_prefix = N06
| ATC_suffix = AB06
| PubChem = 68617
| DrugBank = APRD00175
| C=17|H=17|Cl=2|N=1
| molecular_weight = 306.229 g/mol
| smiles = CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc12
| bioavailability = 44%
| metabolism = N-[[demethylation]] ([[liver]])
| elimination_half-life = Approximately 26 hours
| excretion = Renal
| pregnancy_AU =
| pregnancy_US =
| pregnancy_category = C
| legal_status = Rx-only
| routes_of_administration = Oral
}}
'''Sertraline hydrochloride''' (trade names '''Zoloft''', '''Lustral''') is an [[antidepressant]] of the [[selective serotonin reuptake inhibitor]] (SSRI) class. It was introduced to the market by [[Pfizer]] in 1991. Sertraline is primarily used to treat [[clinical depression]] in adult [[Patient#Outpatient vs inpatient|outpatients]] as well as [[obsessive-compulsive disorder|obsessive-compulsive]], [[panic disorder|panic]] and [[social phobia|social anxiety]] disorders in both adults and children. In 2007 it was the most prescribed antidepressant on the US retail market, with 29,652,000 prescriptions.<ref>The sertraline prescriptions were calculated as a total of prescriptions for Zoloft and generic Sertraline using data from the charts for generic and brand name drugs, see: {{cite web | url = http://www.drugtopics.com/drugtopics/article/articleDetail.jsp?id=491181 | title = Top 200 Generic Drugs by Units in 2007| accessdate = 2008-03-30 | author = Verispan|date = 2008-02-18| format = PDF| publisher = Drug Topics}} and {{cite web | url = http://www.drugtopics.com/drugtopics/article/articleDetail.jsp?id=491207 | title = Top 200 Brand Drugs by Units in 2007| accessdate = 2008-03-30 | author = Verispan|date = 2008-02-18| format = PDF | publisher = Drug Topics}}</ref>
The efficacy of sertraline for depression is similar to that of older [[tricyclic antidepressant]]s, but its [[adverse drug reaction|side effects]] are much less pronounced. Differences with newer antidepressants are subtler and also mostly confined to side effects. Evidence suggests that sertraline may work better than [[fluoxetine]] (Prozac) for some subtypes of depression.<ref name="pmid10529069"/> Sertraline is highly effective for the treatment of panic disorder, but [[cognitive behavioral therapy]] is a better treatment for obsessive-compulsive disorder, whether by itself or in combination with sertraline. Although approved for social phobia and [[posttraumatic stress disorder]], sertraline leads to only modest improvement in these conditions. Sertraline also alleviates the symptoms of [[premenstrual dysphoric disorder]] and can be used in sub-therapeutic doses or intermittently for its treatment.
Sertraline shares the common side effects and [[contraindication]]s of other SSRIs, with high rates of nausea, diarrhea, insomnia, and sexual side effects; however, it does not cause [[weight gain]], and its effects on cognition are mild. In pregnant women taking sertraline, the drug was present in significant concentrations in fetal blood, and was also associated with a higher rate of various [[congenital disorder#Congenital malformations (birth defects)|birth defect]]s. Similarly to other antidepressants, the use of sertraline for depression may be associated with a higher rate of suicidality. Due to the rarity of this side effect, [[statistical significance|statistically significant]] data are difficult to obtain, and suicidality continues to be a subject of controversy.
==History==
[[Image:Chlorprotixene and tametraline.png|thumb|right|[[Skeletal formula]]e of chlorprothixene and tametraline, from which sertraline was derived]]
The history of sertraline dates back to the early 1970s, when [[Pfizer]] chemist Reinhard Sarges invented a novel series of psychoactive compounds based on the structures of neuroleptics [[chlorprothixene]] and [[thiothixene]].<ref name=Welch/><ref>{{cite journal |author= Sarges R, Tretter JR, Tenen SS, Weissman A |title=5,8-Disubstituted 1-Aminotetralins. A Class of Compounds with a Novel Profile of Central Nervous System Activity |journal=Journal of Medicinal Chemistry |volume=16 |issue=9|pages=1003–1011 |year=1973 |doi=10.1021/jm00267a010}}</ref> Further work on these compounds led to tametraline, a [[norepinephrine reuptake inhibitor|norepinephrine]] and weaker [[dopamine reuptake inhibitor]]. Development of tametraline was soon stopped because of undesired [[stimulant]] effects observed in animals. A few years later, in 1977, pharmacologist Kenneth Koe, after comparing the structural features of a variety of reuptake inhibitors, became interested in the tametraline series. He asked another Pfizer chemist, Willard Welch, to synthesize some previously unexplored tametraline derivatives. Welch generated a number of potent norepinephrine and [[serotonin-noradrenaline-dopamine reuptake inhibitor|triple reuptake]] inhibitors, but to the surprise of the scientists, one representative of the generally inactive [[cis-trans isomerism|cis-analogs]] was a serotonin reuptake inhibitor. Welch then prepared [[stereoisomerism|stereoisomers]] of this compound, which were tested ''[[in vivo]]'' by animal behavioral scientist Albert Weissman. The most potent and selective (+)-isomer was taken into further development and eventually named sertraline. Weissman and Koe recalled that the group did not set up to produce an antidepressant of the SSRI type—in that sense their inquiry was not "very goal driven", and the discovery of the sertraline molecule was [[serendipity#Pharmacology|serendipitous]]. According to Welch, they worked outside the mainstream at Pfizer, and even "did not have a formal project team". The group had to overcome initial bureaucratic reluctance to pursue sertraline development, as Pfizer was considering licensing an antidepressant candidate from another company.<ref name=Welch>The most complete account of sertraline discovery, targeted at chemists, see: {{cite journal |author=Welch WM |title=Discovery and Development of Sertraline |journal=Advances in Medicinal Chemistry |volume=3 |pages=113–148 |year=1995 |doi=10.1016/S1067-5698(06)80005-2}}</ref><ref>See also: {{cite journal |author=Mullin R |title=ACS Award for Team Innovation |journal=Chemical & Engineering News |volume=84 |issue=5 |pages=45–52 |year=2006}}</ref><ref>A short blurb on the history of sertraline, see: {{cite journal |author=Couzin J |title=The brains behind blockbusters |journal=[[Science (journal)|Science]] |volume=309 |issue=5735 |pages=728 |year=2005 |pmid=16051786 |doi=10.1126/science.309.5735.728}}</ref>
Sertraline was approved by the U.S. [[Food and Drug Administration]] (FDA) in 1991 based on the recommendation of the Psychopharmacological Drugs Advisory Committee; it had already become available in the United Kingdom the previous year.<ref name=He168>{{cite book |title=The Antidepressant Era |last=Healy |first=David |authorlink=David Healy (psychiatrist)|year=1999 |publisher=Harvard University Press |location=Cambridge, Massachusetts |isbn=0-674-03958-0 |pages=p. 168}}</ref> The FDA committee achieved a consensus that sertraline was safe and effective for the treatment of [[Clinical depression|depression]]. During the discussion, Paul Leber, Director of the FDA Division of Neuropharmacological Drug Products, noted that granting approval was a "tough decision", since the treatment effect on [[Patient#Outpatient vs inpatient|outpatients]] with depression had been "modest to minimal". Other experts emphasized that the drug's effect on inpatients had not differed from [[placebo]] and criticized poor design of the trials by Pfizer.<ref name=pdac>{{cite web |url = http://www.healyprozac.com/PDAC/PDAC-Zoloft%20Nov%2090.pdf |title= Minutes of the 33rd Meeting of Psychopharmacological Drugs Advisory Committee on November 19, 1990 |accessdate=2008-07-11 |publisher=FDA |date=1990 |format=PDF }}</ref> For example, 40% of participants dropped out of the trials, significantly decreasing their [[validity]].<ref name="pmid8573661">See also:{{cite journal |author=Fabre LF, Abuzzahab FS, Amin M, Claghorn JL, Mendels J, Petrie WM, Dubé S, Small JG |title=Sertraline safety and efficacy in major depression: a double-blind fixed-dose comparison with placebo |journal=Biol. Psychiatry |volume=38 |issue=9 |pages=592–602 |year=1995 |pmid=8573661 |doi=10.1016/0006-3223(95)00178-8}}</ref>
Sertraline entered the [[Australia]]n market in 1994 and became the most often prescribed antidepressant in 1996 (2004 data).<ref name="pmid15462638">{{cite journal |author=Mant A, Rendle VA, Hall WD, ''et al'' |title=Making new choices about antidepressants in Australia: the long view 1975-2002 |journal=Med. J. Aust. |volume=181 |issue=7 Suppl |pages=S21–4 |year=2004 |month=October |pmid=15462638 |doi= |url=http://www.mja.com.au/public/issues/181_07%20Suppl_041004/man10822_fm.html}}</ref> It was measured as among the top ten drugs ranked by cost to the Australian government in 1998 and 2000–01, having cost $45 million and $87 million in subsidies respectively.<ref>{{cite journal |year=1999 |title=Top 10 drugs - 1998 |journal=Australian Prescriber |volume=22|pages=119|url=http://www.australianprescriber.com/magazine/22/5/artid/328/ |accessdate=2008-04-30}}</ref><ref>{{cite journal |year=2001 |title=Top 10 drugs - 2000-01 |journal=Australian Prescriber |volume=24|pages=136|url=http://www.australianprescriber.com/magazine/24/6/artid/549/ |accessdate=2008-04-30}}</ref> Sertraline is less popular in the UK (2003 data) and Canada (2006 data)—in both countries it was fifth, based on the number of prescriptions.<ref name="url">{{cite web |url=http://www.mhra.gov.uk/home/groups/pl-p/documents/websiteresources/con019473.pdf |title=Prescribing trends for SSRIs and related antidepressants|date=2004 |format=PDF |publisher=UK MHRA |accessdate=2008-04-30}}</ref><ref>{{cite web |url=http://www.fraserinstitute.org/COMMERCE.WEB/publication_details.aspx?pubID=4542 |title=Canada's Drug Price Paradox 2007 |author=Skinner BJ, Rovere M |date=2007-07-31 |format=PDF |publisher=The Fraser Institute |pages=21-29 |accessdate=2008-07-11}}</ref>
Until 2003, sertraline was only approved for use in adults ages 18 and over; that year, it was approved by the FDA for use in treating children aged 6 or older with severe [[obsessive-compulsive disorder]] (OCD). In 2003, the UK [[Medicines and Healthcare products Regulatory Agency]] issued a guidance that, apart from [[fluoxetine]] (trade name{{ref label|TradeName|A|A}} Prozac), [[selective serotonin reuptake inhibitor|SSRIs]] are not suitable for the treatment of depression in patients under 18.<ref>{{cite web |url=http://www.mhra.gov.uk/NewsCentre/Pressreleases/CON002045|title=Safety review of antidepressants used by children completed |accessdate=2008-07-11 |publisher=[[Medicines and Healthcare products Regulatory Agency|MHRA]] |date=2003-12-10 }}</ref><ref>{{cite news | url = http://www.guardian.co.uk/uk_news/story/0,3604,1103563,00.html | title = Drugs for depressed children banned | last = Boseley | first = Sarah | date = 2003-12-10 | accessdate = 2007-04-19 | work = [[The Guardian]]}}</ref> However, sertraline can still be used in the UK for the treatment of OCD in children and adolescents.<ref>{{cite web |url=http://www.mhra.gov.uk/Safetyinformation/Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/CON019494 |title=Overview of regulatory status and CSM advice relating to major depressive disorder (MDD) in children and adolescents |accessdate=2008-04-17 |publisher=MHRA }}</ref> In 2005, the FDA added a [[black box warning]] concerning pediatric suicidality to all [[antidepressant]]s, including sertraline. In 2007, labeling was again changed to add a warning regarding suicidality in young adults ages 18 to 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 |accessdate=2008-07-11 |author=Food and Drug Administration |date=2007-05-02}}</ref>
The U.S. patent for Zoloft expired in 2006,<ref>{{cite web | url = http://money.cnn.com/2006/07/17/news/companies/pfizer/index.htm | accessdate = 2007-01-27 | title = Pfizer needs more drugs | last = Smith | first = Aaron | date = 2006-07-17 | publisher = [[CNN.com|CNNMoney.com]]}}</ref> and sertraline is now available in [[generic drug|generic]] form.
==Indications==
Sertraline has been approved for the following indications: [[Clinical depression|depression]], [[obsessive-compulsive disorder]] (OCD), [[posttraumatic stress disorder]] (PTSD), [[premenstrual dysphoric disorder]] (PMDD), [[panic disorder]] and [[social phobia]] (social anxiety disorder).
===Depression===
The original pre-marketing clinical trials demonstrated only weak-to-moderate efficacy of sertraline for depression.<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=}}</ref> Nevertheless, a considerable body of later research established it as one of the drugs of choice for the treatment of depression in [[Patient#Outpatient vs inpatient|outpatients]]. Despite the negative results of early trials, sertraline is often used to treat depressed inpatients as well.<ref name="pmid17475736">For example, in this study two-thirds of depressed inpatients were treated with sertraline and only one-third with the TCA amitriptyline. {{cite journal |author=Schramm E, van Calker D, Dykierek P, Lieb K, Kech S, Zobel I, Leonhart R, Berger M |title=An intensive treatment program of interpersonal psychotherapy plus pharmacotherapy for depressed inpatients: acute and long-term results |journal=Am J Psychiatry |volume=164 |issue=5 |pages=768–77 |year=2007 |pmid=17475736 |doi=10.1176/appi.ajp.164.5.768}}</ref> Sertraline is effective for both severe depression<ref name="pmid10993128">{{cite journal |author=Lépine JP, Goger J, Blashko C, Probst C, Moles MF, Kosolowski J, Scharfetter B, Lane RM |title=A double-blind study of the efficacy and safety of sertraline and clomipramine in outpatients with severe major depression |journal=International Clinical Psychopharmacology |volume=15 |issue=5 |pages=263–71 |year=2000 |pmid=10993128 |doi=}}</ref> and [[dysthymia]], a milder and more chronic variety of depression. In several [[Blind experiment#Double-blind trials|double-blind]] studies, sertraline was consistently more effective than [[placebo]] for dysthymia<ref name="pmid11105734">{{cite journal |author=Ravindran AV, Guelfi JD, Lane RM, Cassano GB |title=Treatment of dysthymia with sertraline: a double-blind, placebo-controlled trial in dysthymic patients without major depression |journal=The Journal of Clinical Psychiatry |volume=61 |issue=11 |pages=821–7 |year=2000 |pmid=11105734 |doi=}}</ref><ref name="pmid8792754">{{cite journal |author=Thase ME, Fava M, Halbreich U, Kocsis JH, Koran L, Davidson J, Rosenbaum J, Harrison W |title=A placebo-controlled, randomized clinical trial comparing sertraline and imipramine for the treatment of dysthymia |journal=Arch. Gen. Psychiatry |volume=53 |issue=9 |pages=777–84 |year=1996 |pmid=8792754 |doi=}}</ref><ref name="pmid10518174">{{cite journal |author=Ravindran AV, Anisman H, Merali Z, Charbonneau Y, Telner J, Bialik RJ, Wiens A, Ellis J, Griffiths J |title=Treatment of primary dysthymia with group cognitive therapy and pharmacotherapy: clinical symptoms and functional impairments |journal=Am J Psychiatry |volume=156 |issue=10 |pages=1608–17 |year=1999 |pmid=10518174 |doi=}}</ref><ref name="pmid16263177">{{cite journal |author=Markowitz JC, Kocsis JH, Bleiberg KL, Christos PJ, Sacks M |title=A comparative trial of psychotherapy and pharmacotherapy for "pure" dysthymic patients |journal=J Affect Disord |volume=89 |issue=1–3 |pages=167–75 |year=2005 |pmid=16263177 |doi=10.1016/j.jad.2005.10.001}}</ref> and comparable to [[imipramine]] (Tofranil) in that respect.<ref name="pmid8792754"/> Sertraline also improved the depression of dysthymic patients to a greater degree than group [[cognitive behavioral therapy]] or [[interpersonal psychotherapy]], and adding psychotherapy to sertraline did not seem to enhance the outcome.<ref name="pmid10518174"/><ref name="pmid16263177"/> These results also held up in a two-year follow-up of sertraline-treated and interpersonal-therapy-treated groups.<ref name="pmid12063159">{{cite journal |author=Browne G, Steiner M, Roberts J, Gafni A, Byrne C, Dunn E, Bell B, Mills M, Chalklin L, Wallik D, Kraemer J |title=Sertraline and/or interpersonal psychotherapy for patients with dysthymic disorder in primary care: 6-month comparison with longitudinal 2-year follow-up of effectiveness and costs |journal=J Affect Disord |volume=68 |issue=2-3 |pages=317–30 |year=2002 |pmid=12063159|doi=10.1016/S0165-0327(01)00343-3}}</ref> In the treatment of depression accompanied by [[obsessive-compulsive disorder|OCD]], sertraline performed [[statistical significance|significantly]] better than [[desipramine]] (Norpramine) on the measures of both OCD and depression.<ref name="pmid10632236">{{cite journal |author=Hoehn-Saric R, Ninan P, Black DW, Stahl S, Greist JH, Lydiard B, McElroy S, Zajecka J, Chapman D, Clary C, Harrison W |title=Multicenter double-blind comparison of sertraline and desipramine for concurrent obsessive-compulsive and major depressive disorders |journal=Arch. Gen. Psychiatry |volume=57 |issue=1 |pages=76–82 |year=2000 |pmid=10632236|doi=10.1001/archpsyc.57.1.76}}</ref> Sertraline was equivalent to imipramine for the treatment of depression with co-morbid [[panic disorder]], but it was better tolerated.<ref name="pmid12823079">{{cite journal |author=Lepola U, Arató M, Zhu Y, Austin C |title=Sertraline versus imipramine treatment of comorbid panic disorder and major depressive disorder |journal=J Clin Psychiatry |volume=64 |issue=6 |pages=654–62 |year=2003 |pmid=12823079 |doi=}}</ref> Sertraline treatment of depressed patients with co-morbid [[personality disorder]]s improved their personality traits, and this improvement was almost independent from the improvement of their depression.<ref name="pmid9817625">{{cite journal |author=Ekselius L, von Knorring L |title=Personality disorder comorbidity with major depression and response to treatment with sertraline or citalopram |journal=Int Clin Psychopharmacol |volume=13 |issue=5 |pages=205–11 |year=1998 |pmid=9817625|doi=10.1097/00004850-199809000-00003}}</ref>
====Comparison with tricyclic antidepressants====
The effect of sertraline on the core symptoms of depression is similar to that of [[tricyclic antidepressant]]s (TCAs); however, it is better tolerated and results in a better [[quality of life]]. Similar improvement of depression scores was seen in studies comparing sertraline with [[clomipramine]] (Anafranil)<ref name="pmid10993128"/> and [[amitriptyline]] (Elavil).<ref name="pmid2258378">{{cite journal |author=Reimherr FW, Chouinard G, Cohn CK, Cole JO, Itil TM, LaPierre YD, Masco HL, Mendels J |title=Antidepressant efficacy of sertraline: a double-blind, placebo- and amitriptyline-controlled, multicenter comparison study in outpatients with major depression |journal=J Clin Psychiatry |volume=51 Suppl B |issue= |pages=18–27 |year=1990 |pmid=2258378 |doi=}}</ref><ref name="pmid9413414">{{cite journal |author=Lydiard RB, Stahl SM, Hertzman M, Harrison WM |title=A double-blind, placebo-controlled study comparing the effects of sertraline versus amitriptyline in the treatment of major depression |journal=The Journal of Clinical Psychiatry |volume=58 |issue=11 |pages=484–91 |year=1997 |pmid=9413414 |doi=}}</ref> At the same time, sertraline resulted in a much lower rate of side effects than amitriptyline (49%, vs. 72% for amitriptyline and 32% for [[placebo]]), particularly dry mouth, somnolence, constipation and increased appetite.<ref name="pmid9413414"/> However, there were more cases of nausea and sexual dysfunction in the sertraline group.<ref name="pmid2258378"/><ref name="pmid9413414"/> Participants taking sertraline showed a greater improvement of the subjective quality of life on such measures as work satisfaction, subjective feeling, perceptions of health and cognitive function.<ref name="pmid9413414"/>
A large and thorough [[Blind experiment#Double-blind trials|double-blind]] study compared sertraline—prescribed for chronic (longer than two years) depression or depression with [[dysthymia]]—to the "gold standard" of depression treatment, the TCA [[imipramine]] (Tofranil). Sertraline was equivalent to imipramine for both of these indications during the first 12 weeks of the study<ref name="pmid9862605">{{cite journal |author=Rush AJ, Koran LM, Keller MB, Markowitz JC, Harrison WM, Miceli RJ, Fawcett JA, Gelenberg AJ, Hirschfeld RM, Klein DN, Kocsis JH, McCullough JP, Schatzberg AF, Thase ME |title=The treatment of chronic depression, part 1: study design and rationale for evaluating the comparative efficacy of sertraline and imipramine as acute, crossover, continuation, and maintenance phase therapies |journal=J Clin Psychiatry |volume=59 |issue=11 |pages=589–97 |year=1998 |pmid=9862605 |doi=}}</ref><ref name="pmid9862606">{{cite journal |author=Keller MB, Gelenberg AJ, Hirschfeld RM, Rush AJ, Thase ME, Kocsis JH, Markowitz JC, Fawcett JA, Koran LM, Klein DN, Russell JM, Kornstein SG, McCullough JP, Davis SM, Harrison WM |title=The treatment of chronic depression, part 2: a double-blind, randomized trial of sertraline and imipramine |journal=The Journal of Clinical Psychiatry |volume=59 |issue=11 |pages=598–607 |year=1998 |pmid=9862606 |doi=}}</ref><ref name="pmid9862607">{{cite journal |author=Miller IW, Keitner GI, Schatzberg AF, Klein DN, Thase ME, Rush AJ, Markowitz JC, Schlager DS, Kornstein SG, Davis SM, Harrison WM, Keller MB |title=The treatment of chronic depression, part 3: psychosocial functioning before and after treatment with sertraline or imipramine |journal=The Journal of Clinical Psychiatry |volume=59 |issue=11 |pages=608–19 |year=1998 |pmid=9862607 |doi=}}</ref> and the 16-week continuation phase.<ref name="pmid11426506">{{cite journal |author=Koran LM, Gelenberg AJ, Kornstein SG, Howland RH, Friedman RA, DeBattista C, Klein D, Kocsis JH, Schatzberg AF, Thase ME, Rush AJ, Hirschfeld RM, LaVange LM, Keller MB |title=Sertraline versus imipramine to prevent relapse in chronic depression |journal=Journal of Affective Disorders |volume=65 |issue=1 |pages=27–36 |year=2001 |pmid=11426506|doi=10.1016/S0165-0327(00)00272-X}}</ref> Only 11% of patients on sertraline suffered from severe side effects vs. 24% on imipramine. Constipation, dizziness, tremor, dry mouth, [[micturition]] disorder and sweating were observed more often with imipramine, and diarrhea and insomnia with sertraline.<ref name="pmid9862606"/> Patients on sertraline also reported significantly better social and physical functioning. The 30% of the patients treated with sertraline or imipramine who achieved a remission during the trial did not differ from the healthy population on the measures of marital, parental, physical and work functioning and were close to normal on [[social interaction|social adjustment]] and other measures of [[interpersonal relationship|interpersonal functioning]].<ref name="pmid9862607"/>
TCAs as a group are considered to work better than [[selective serotonin reuptake inhibitor]]s for [[melancholic depression]]<ref name="pmid11247097">{{cite journal |author=Parker G, Roy K, Wilhelm K, Mitchell P |title=Assessing the comparative effectiveness of antidepressant therapies: a prospective clinical practice study |journal=J Clin Psychiatry |volume=62 |issue=2 |pages=117–25 |year=2001 |pmid=11247097 |doi=}}</ref> and in inpatients,<ref name="pmid9597346">{{cite journal |author=Anderson IM |title=SSRIS versus tricyclic antidepressants in depressed inpatients: a meta-analysis of efficacy and tolerability |journal=Depress Anxiety |volume=7 Suppl 1 |issue= |pages=11–7 |year=1998 |pmid=9597346 |doi=}}</ref> but not necessarily for simply more severe depression.<ref name="pmid10362442">{{cite journal |author=Hirschfeld RM |title=Efficacy of SSRIs and newer antidepressants in severe depression: comparison with TCAs |journal=J Clin Psychiatry |volume=60 |issue=5 |pages=326–35 |year=1999 |pmid=10362442 |doi=}}</ref> In line with this generalization, sertraline was no better than placebo in inpatients (see [[Sertraline#History|History]]) and as effective as the TCA clomipramine for severe depression.<ref name="pmid10993128"/> The comparative efficacy of sertraline and TCAs for melancholic depression has not been studied. A 1998 review suggested that, due to its pharmacology, sertraline may be more efficacious than other SSRIs and equal to TCAs for the treatment of melancholic depression.<ref name="pmid9808081">{{cite journal |author=Amsterdam JD |title=Selective serotonin reuptake inhibitor efficacy in severe and melancholic depression |journal=J. Psychopharmacol. (Oxford) |volume=12 |issue=3 Suppl B |pages=S99–111 |year=1998 |pmid=9808081 |doi=}}</ref> A later [[Open-label trial|open-label]] study of general practice patients, funded by [[Pfizer]], found that sertraline had equal efficacy in melancholic vs. non-melancholic patients, as well as in previous TCA non-responders vs. all other patients.<ref name="pmid15014677">{{cite journal |author=Lydiard RB, Perera P, Batzar E, Clary CM |title=From the Bench to the Trench: A Comparison of Sertraline Treatment of Major Depression in Clinical and Research Patient Samples |journal=Prim Care Companion J Clin Psychiatry |volume=1 |issue=5 |pages=154–162 |year=1999 |pmid=15014677 |doi=}}</ref>
====Comparison with other antidepressants====
Comparative clinical trials demonstrated that sertraline's efficacy in depression is similar to that of [[moclobemide]] (Aurorix),<ref name="pmid17168253">{{cite journal |author=Papakostas GI, Fava M |title=A metaanalysis of clinical trials comparing moclobemide with selective serotonin reuptake inhibitors for the treatment of major depressive disorder |journal=Canadian Journal of Psychiatry. Revue Canadienne de Psychiatrie |volume=51 |issue=12 |pages=783–90 |year=2006 |pmid=17168253 |doi=}}</ref> [[nefazodone]] (Serzone),<ref name="pmid8626364">{{cite journal |author=Feiger A, Kiev A, Shrivastava RK, Wisselink PG, Wilcox CS |title=Nefazodone versus sertraline in outpatients with major depression: focus on efficacy, tolerability, and effects on sexual function and satisfaction |journal=The Journal of Clinical Psychiatry |volume=57 Suppl 2 |issue= |pages=53–62 |year=1996 |pmid=8626364 |doi=}}</ref> [[escitalopram]] (Lexapro),<ref name="pmid17288677">{{cite journal |author=Ventura D, Armstrong EP, Skrepnek GH, Haim Erder M |title=Escitalopram versus sertraline in the treatment of major depressive disorder: a randomized clinical trial |journal=Current Medical Research and Opinion |volume=23 |issue=2 |pages=245–50 |year=2007 |pmid=17288677 |doi=10.1185/030079906X167273}}</ref> [[bupropion]] (Wellbutrin),<ref name="pmid9448656">{{cite journal |author=Kavoussi RJ, Segraves RT, Hughes AR, Ascher JA, Johnston JA |title=Double-blind comparison of bupropion sustained release and sertraline in depressed outpatients |journal=The Journal of Clinical Psychiatry |volume=58 |issue=12 |pages=532–7 |year=1997 |pmid=9448656 |doi=}}</ref> [[citalopram]] (Celexa), [[fluvoxamine]] (Luvox), [[paroxetine]] (Paxil) and [[mirtazapine]] (Remeron).<ref name="pmid16172440">For the review, see:{{cite journal |author=Hansen RA, Gartlehner G, Lohr KN, Gaynes BN, Carey TS |title=Efficacy and safety of second-generation antidepressants in the treatment of major depressive disorder |journal=Ann. Intern. Med. |volume=143 |issue=6 |pages=415–26 |year=2005 |pmid=16172440 |doi=}}</ref> Compared to patients on bupropion, those taking sertraline had much higher rates of sexual dysfunction (61% vs. 10% for men and 41% vs. 7% for women), nausea, diarrhea, somnolence and sweating, as well as a higher rate of discontinuation due to side effects (13% vs. 3%).<ref name="pmid9448656"/> [[Meta-analysis]] by the independent [[Cochrane Collaboration]] indicated that sertraline is more effective for the treatment of depression than [[fluoxetine]] (Prozac), with a 1.4 times higher probability of response, and is possibly better tolerated.<ref name="pmid16235353">{{cite journal |author=Cipriani A, Brambilla P, Furukawa T, Geddes J, Gregis M, Hotopf M, Malvini L, Barbui C |title=Fluoxetine versus other types of pharmacotherapy for depression |journal=Cochrane Database of Systematic Reviews (Online) |volume= |issue=4 |pages=CD004185 |year=2005 |pmid=16235353 |doi=10.1002/14651858.CD004185.pub2}}</ref> The greatest advantage of sertraline over fluoxetine was seen among severely depressed and [[melancholic depression|melancholic]] patients with low anxiety.<ref name="pmid10529069">{{cite journal |author=Flament MF, Lane RM, Zhu R, Ying Z |title=Predictors of an acute antidepressant response to fluoxetine and sertraline |journal=Int Clin Psychopharmacol |volume=14 |issue=5 |pages=259–75 |year=1999 |pmid=10529069 |doi=}}</ref> Comparative studies of sertraline and [[venlafaxine]] (Effexor) found marginal differences in favor of venlafaxine<ref name="pmid10732656">{{cite journal |author=Mehtonen OP, Søgaard J, Roponen P, Behnke K |title=Randomized, double-blind comparison of venlafaxine and sertraline in outpatients with major depressive disorder. Venlafaxine 631 Study Group |journal=The Journal of Clinical Psychiatry |volume=61 |issue=2 |pages=95–100 |year=2000 |pmid=10732656 |doi=}}</ref><ref name="pmid17196045">{{cite journal |author=Shelton RC, Haman KL, Rapaport MH, Kiev A, Smith WT, Hirschfeld RM, Lydiard RB, Zajecka JM, Dunner DL |title=A randomized, double-blind, active-control study of sertraline versus venlafaxine XR in major depressive disorder |journal=The Journal of Clinical Psychiatry |volume=67 |issue=11 |pages=1674–81 |year=2006 |pmid=17196045 |doi=}}</ref><ref name="pmid11105744">{{cite journal |author=Wise TN, Sheridan MJ |title=Venlafaxine versus sertraline for major depressive disorder |journal=The Journal of Clinical Psychiatry |volume=61 |issue=11 |pages=873–4 |year=2000 |pmid=11105744 |doi=}}</ref> or no differences.<ref name="pmid16259546">{{cite journal |author=Sir A, D'Souza RF, Uguz S, George T, Vahip S, Hopwood M, Martin AJ, Lam W, Burt T |title=Randomized trial of sertraline versus venlafaxine XR in major depression: efficacy and discontinuation symptoms |journal=The Journal of Clinical Psychiatry |volume=66 |issue=10 |pages=1312–20 |year=2005 |pmid=16259546 |doi=}}</ref>
====Depression in the elderly====
Sertraline used for the treatment of depression in elderly (older than 60) patients was superior to [[placebo]] and comparable to another SSRI fluoxetine, and TCAs amitriptyline, [[nortriptyline]] (Pamelor) and imipramine. Sertraline had much lower rates of adverse effects than these TCAs, with the exception of nausea, which occurred more frequently with sertraline. In addition, sertraline appeared to be more effective than fluoxetine or nortriptyline in the older-than-70 subgroup.<ref name="pmid12093324">{{cite journal |author=Muijsers RB, Plosker GL, Noble S |title=Sertraline: a review of its use in the management of major depressive disorder in elderly patients |journal=Drugs & Aging |volume=19 |issue=5 |pages=377–92 |year=2002 |pmid=12093324 |doi=}}</ref> A 2003 trial of sertraline vs. placebo in elderly patients showed a [[statistical significance|statistically significant]] (that is, unlikely to occur by chance), but clinically very modest improvement in depression and no improvement in [[quality of life]].<ref name="pmid12832242">{{cite journal |author=Schneider LS, Nelson JC, Clary CM, Newhouse P, Krishnan KR, Shiovitz T, Weihs K |title=An 8-week multicenter, parallel-group, double-blind, placebo-controlled study of sertraline in elderly outpatients with major depression |journal=Am J Psychiatry |volume=160 |issue=7 |pages=1277–85 |year=2003 |pmid=12832242|doi=10.1176/appi.ajp.160.7.1277}}</ref> The authors were sharply criticized by Bernard Carroll, a one-time chairman of the FDA Psychopharmacological Drugs Advisory Committee,<ref>{{cite web |url=http://www.mc.vanderbilt.edu/sc_diglib/archColl/233.html |archiveurl=http://web.archive.org/web/20060907224703/http://www.mc.vanderbilt.edu/sc_diglib/archColl/233.html |archivedate=2006-09-07 |title=Bernard J. Caroll|publisher = Vanderbilt University Medical Center|accessdate=2008-07-11 |format=html }}</ref> for presenting these results as positive: "The study has all the hallmarks of an 'experimercial,' a cost-is-no-object exercise driven by a corporate sponsor to create positive publicity for its product in a market niche. ... Thus does the corporate mandate to put lipstick on the pig prevail over the academic duty to communicate independent analyses of the data."<ref name="pmid15056533">{{cite journal |author=Carroll BJ |title=Sertraline and the Cheshire cat in geriatric depression |journal=Am J Psychiatry |volume=161 |issue=4 |pages=759; author reply 759–61 |year=2004 |pmid=15056533|doi=10.1176/appi.ajp.161.4.759}}</ref>
===Obsessive-compulsive disorder===
[[Placebo#Use in clinical trials|Placebo-controlled]] studies have demonstrated sertraline to be efficacious for the treatment of OCD in adults and children.<ref>{{cite journal | author=Kronig MH, Apter J, Asnis G, Bystritsky A, Curtis G, Ferguson J, Landbloom R, Munjack D, Riesenberg R, Robinson D, Roy-Byrne P, Phillips K, Du Pont IJ. | title=Placebo-controlled, multicenter study of sertraline treatment for obsessive-compulsive disorder | journal=Journal of Clinical Psychopharmacology | volume=19 | issue=2 | year=1999 | pages=172–176| pmid=10211919 | doi=10.1097/00004714-199904000-00013}}</ref><ref name="pmid2274626">{{cite journal |author=Chouinard G, Goodman W, Greist J, Jenike M, Rasmussen S, White K, Hackett E, Gaffney M, Bick PA |title=Results of a double-blind placebo controlled trial of a new serotonin uptake inhibitor, sertraline, in the treatment of obsessive-compulsive disorder |journal=Psychopharmacology Bulletin |volume=26 |issue=3 |pages=279–84 |year=1990 |pmid=2274626 |doi=}}</ref><ref name="pmid7702445">{{cite journal |author=Greist J, Chouinard G, DuBoff E, Halaris A, Kim SW, Koran L, Liebowitz M, Lydiard RB, Rasmussen S, White K |title=Double-blind parallel comparison of three dosages of sertraline and placebo in outpatients with obsessive-compulsive disorder |journal=Arch. Gen. Psychiatry |volume=52 |issue=4 |pages=289–95 |year=1995 |pmid=7702445 |doi=}}</ref><ref name="pmid14594734">{{cite journal |author=Geller DA, Biederman J, Stewart SE, Mullin B, Martin A, Spencer T, Faraone SV |title=Which SSRI? A meta-analysis of pharmacotherapy trials in pediatric obsessive-compulsive disorder |journal=The American Journal of Psychiatry |volume=160 |issue=11 |pages=1919–28 |year=2003 |pmid=14594734|doi=10.1176/appi.ajp.160.11.1919}}</ref> It was better tolerated and, based on [[intention to treat analysis]], performed better than the gold standard of OCD treatment [[clomipramine]].<ref name="pmid9393392">{{cite journal |author=Flament MF, Bisserbe JC |title=Pharmacologic treatment of obsessive-compulsive disorder: comparative studies |journal=The Journal of Clinical Psychiatry |volume=58 Suppl 12 |issue= |pages=18–22 |year=1997 |pmid=9393392 |doi=}}</ref> Sertraline was also marginally more efficacious than [[fluoxetine]] (Prozac).<ref name="pmid11910259">{{cite journal |author=Bergeron R, Ravindran AV, Chaput Y, Goldner E, Swinson R, van Ameringen MA, Austin C, Hadrava V |title=Sertraline and fluoxetine treatment of obsessive-compulsive disorder: results of a double-blind, 6-month treatment study |journal=Journal of Clinical Psychopharmacology |volume=22 |issue=2 |pages=148–54 |year=2002 |pmid=11910259|doi=10.1097/00004714-200204000-00007}}</ref> If the patient did not respond to sertraline, increasing the dose to 250–400 mg, higher than the maximum recommended, did not bring any additional benefits.<ref name="pmid16426083">{{cite journal |author=Ninan PT, Koran LM, Kiev A, Davidson JR, Rasmussen SA, Zajecka JM, Robinson DG, Crits-Christoph P, Mandel FS, Austin C |title=High-dose sertraline strategy for nonresponders to acute treatment for obsessive-compulsive disorder: a multicenter double-blind trial |journal=The Journal of Clinical Psychiatry |volume=67 |issue=1 |pages=15–22 |year=2006 |pmid=16426083 |doi=}}</ref> The patients who responded to sertraline during a short-term trial sustained their improvement when the treatment continued for a year<ref name="pmid7673657">{{cite journal |author=Greist JH, Jefferson JW, Kobak KA, Chouinard G, DuBoff E, Halaris A, Kim SW, Koran L, Liebowitz MR, Lydiard B |title=A 1 year double-blind placebo-controlled fixed dose study of sertraline in the treatment of obsessive-compulsive disorder |journal=International Clinical Psychopharmacology |volume=10 |issue=2 |pages=57–65 |year=1995 |pmid=7673657|doi=10.1097/00004850-199506000-00001}}</ref> and longer.<ref name="pmid9547132">{{cite journal |author=Rasmussen S, Hackett E, DuBoff E, Greist J, Halaris A, Koran LM, Liebowitz M, Lydiard RB, McElroy S, Mendels J, O'Connor K |title=A 2-year study of sertraline in the treatment of obsessive-compulsive disorder |journal=International Clinical Psychopharmacology |volume=12 |issue=6 |pages=309–16 |year=1997 |pmid=9547132 |doi=}}</ref> At the same time, the prolonged treatment may not be necessary for everyone. In a [[Randomized controlled trial#Types of trial|double-blind study]], half of the subjects who had been successfully treated for a year were discontinued from sertraline. More of the subjects who stopped taking sertraline, than of those who continued, subsequently dropped out of the study, mostly, due to worsening of the OCD symptoms and side effects, possibly [[Sertraline#Discontinuation syndrome|withdrawal syndrome]]. Only 48% of the patients in the discontinuation group were able to complete the study; however, these completers fared as well as the subjects who continued taking sertraline.<ref name="pmid11772695">{{cite journal |author=Koran LM, Hackett E, Rubin A, Wolkow R, Robinson D |title=Efficacy of sertraline in the long-term treatment of obsessive-compulsive disorder |journal=The American Journal of Psychiatry |volume=159 |issue=1 |pages=88–95 |year=2002 |pmid=11772695|doi=10.1176/appi.ajp.159.1.88}}</ref> [[Cognitive behavioral therapy|CBT]] alone was superior to sertraline in both adults and children; however, the best results were achieved using a combination of these treatments.<ref name="pmid15507582">{{cite journal |author= |title=Cognitive-behavior therapy, sertraline, and their combination for children and adolescents with obsessive-compulsive disorder: the Pediatric OCD Treatment Study (POTS) randomized controlled trial |journal=JAMA |volume=292 |issue=16 |pages=1969–76 |year=2004 |pmid=15507582 |doi=10.1001/jama.292.16.1969}}</ref><ref name="pmid16889458">{{cite journal |author=Sousa MB, Isolan LR, Oliveira RR, Manfro GG, Cordioli AV |title=A randomized clinical trial of cognitive-behavioral group therapy and sertraline in the treatment of obsessive-compulsive disorder |journal=The Journal of Clinical Psychiatry |volume=67 |issue=7 |pages=1133–9 |year=2006 |pmid=16889458 |doi=}}</ref> A review mentions that sertraline can be used for the treatment of OCD co-morbid with [[Tourette syndrome]];<ref name="pmid11772131">{{cite journal |author=Jiménez-Jiménez FJ, García-Ruiz PJ |title=Pharmacological options for the treatment of Tourette's disorder |journal=Drugs |volume=61 |issue=15 |pages=2207–20 |year=2001 |pmid=11772131 |doi= |url=}}</ref> however, sertraline may cause exacerbation of tics in Tourette syndrome.<ref name="pmid8552129">{{cite journal |author=Hauser RA, Zesiewicz TA |title=Sertraline-induced exacerbation of tics in Tourette's syndrome |journal=Mov. Disord. |volume=10 |issue=5 |pages=682–4 |year=1995 |month=September |pmid=8552129 |doi=10.1002/mds.870100529 |url=}}</ref>
===Panic disorder===
In four large [[Randomized controlled trial#Types of trial|double-blind]] studies sertraline was shown to be superior to [[placebo]] for the treatment of panic disorder. The response rate was independent of the dose (50–200 mg). In addition to decreasing the frequency of panic attacks by about 80% (vs. 45% for placebo) and decreasing general anxiety, sertraline resulted in improvement of quality of life on most parameters. The patients rated as "improved" on sertraline reported better quality of life than the ones who "improved" on placebo. The authors of the study argued that the improvement achieved with sertraline is different and of a better quality than the improvement achieved with placebo.<ref name="pmid10945134">Review: {{cite journal |author=Hirschfeld RM |title=Sertraline in the treatment of anxiety disorders |journal=Depress Anxiety |volume=11 |issue=4 |pages=139–57 |year=2000 |pmid=10945134 |doi=10.1002/1520-6394(2000)11:4<139::AID-DA1>3.0.CO;2-C}}</ref><ref name="pmid16292466">Meta-analysis: {{cite journal |author=Clayton AH, Stewart RS, Fayyad R, Clary CM |title=Sex differences in clinical presentation and response in panic disorder: pooled data from sertraline treatment studies |journal=Arch Womens Ment Health |volume=9 |issue=3 |pages=151–7 |year=2006 |pmid=16292466 |doi=10.1007/s00737-005-0111-y}}</ref> Sertraline was equally effective for men and women<ref name="pmid16292466"/> and for patients with or without [[agoraphobia]].<ref name="pmid11206597">{{cite journal |author=Pollack MH, Rapaport MH, Clary CM, Mardekian J, Wolkow R |title=Sertraline treatment of panic disorder: response in patients at risk for poor outcome |journal=J Clin Psychiatry |volume=61 |issue=12 |pages=922–7 |year=2000 |pmid=11206597 |doi=}}</ref> Previous unsuccessful treatment with [[benzodiazepine]]s did not diminish its efficacy.<ref name="pmid11199932">{{cite journal |author=Rapaport MH, Pollack MH, Clary CM, Mardekian J, Wolkow R |title=Panic disorder and response to sertraline: the effect of previous treatment with benzodiazepines |journal=J Clin Psychopharmacol |volume=21 |issue=1 |pages=104–7 |year=2001 |pmid=11199932|doi=10.1097/00004714-200102000-00019}}</ref> However, the response rate was lower for the patients with more severe panic.<ref name="pmid11206597"/> Double-blind comparative studies found sertraline to have the same effect on panic disorder as [[paroxetine]] (Paxil)<ref name="pmid15096081">{{cite journal |author=Bandelow B, Behnke K, Lenoir S, Hendriks GJ, Alkin T, Goebel C, Clary CM |title=Sertraline versus paroxetine in the treatment of panic disorder: an acute, double-blind noninferiority comparison |journal=J Clin Psychiatry |volume=65 |issue=3 |pages=405–13 |year=2004 |pmid=15096081 |doi=}}</ref> or the gold standard of panic disorder treatment [[alprazolam]] (Xanax).<ref name="pmid16053461">{{cite journal |author=Fiseković S, Loga-Zec S |title=Sertraline and alprazolam in the treatment of panic desorder{{sic}} |journal=Bosn J Basic Med Sci |volume=5 |issue=2 |pages=78–81 |year=2005 |pmid=16053461 |doi=}}</ref> While imprecise, comparison of the results of trials of sertraline with separate trials of other anti-panic agents ([[clomipramine]] (Anafranil), [[imipramine]] (Tofranil), [[clonazepam]] (Klonopin), alprazolam, [[fluvoxamine]] (Luvox) and paroxetine) indicates approximate equivalence of these medications.<ref name="pmid10945134"/> Although panic disorder is considered to be a chronic condition, continuous treatment may not be necessary for everyone. In a double-blind discontinuation trial, abruptly stopping sertraline after one year of successful treatment resulted in relapse of the disorder in 33% of the patients vs. 13% of those who continued taking sertraline over the following 28 weeks. The patients experienced distinct [[Sertraline#Discontinuation syndrome|withdrawal syndrome]], expressed primarily as insomnia and dizziness, and the authors noted that a significant part of the relapse rate among the discontinued patients could possibly be accounted for by the withdrawal syndrome.<ref name="pmid11722304">{{cite journal |author=Rapaport MH, Wolkow R, Rubin A, Hackett E, Pollack M, Ota KY |title=Sertraline treatment of panic disorder: results of a long-term study |journal=Acta Psychiatr Scand |volume=104 |issue=4 |pages=289–98 |year=2001 |pmid=11722304 |doi=10.1034/j.1600-0447.2001.00263.x}}</ref> Confirming these hypotheses, in another study, gradual discontinuation of sertraline after 12 weeks of treatment did not lead to the return of panic symptoms. In the same study, discontinuation of paroxetine caused exacerbation of panic in about a fifth of the previously responding patients. The authors attributed this difference to the more severe withdrawal syndrome with paroxetine, which even discontinuation over three weeks could not remedy.<ref name="pmid15096081"/>
===Social phobia===
Sertraline has been successfully used for the treatment of social phobia.<ref name="pmid17092192">Review: {{cite journal |author=Davidson JR |title=Pharmacotherapy of social anxiety disorder: what does the evidence tell us? |journal=J Clin Psychiatry |volume=67 Suppl 12 |issue= |pages=20–6 |year=2006 |pmid=17092192 |doi=}}</ref> In a flexible dosing study, it appeared that a higher dose range was needed for adequate response. Furthermore, improvement was achieved slowly, separating from the placebo response only by week six, and continuing to increase until week 12.<ref name="pmid12934979">{{cite journal |author=Liebowitz MR, DeMartinis NA, Weihs K, Londborg PD, Smith WT, Chung H, Fayyad R, Clary CM |title=Efficacy of sertraline in severe generalized social anxiety disorder: results of a double-blind, placebo-controlled study |journal=J Clin Psychiatry |volume=64 |issue=7 |pages=785–92 |year=2003 |pmid=12934979 |doi=}}</ref> The response was higher among the patients with later onset, especially adult onset, of the disorder.<ref name="pmid14709946">{{cite journal |author=Van Ameringen M, Oakman J, Mancini C, Pipe B, Chung H |title=Predictors of response in generalized social phobia: effect of age of onset |journal=J Clin Psychopharmacol |volume=24 |issue=1 |pages=42–8 |year=2004 |pmid=14709946 |doi=10.1097/01.jcp.0000104909.75206.6f}}</ref> Among the different rating scales, the clinician-rated global improvement demonstrated the highest difference vs. placebo, while the patient self-rated quality of life differed from placebo only modestly. The greatest improvement of quality of life was observed among the most impaired patients.<ref name="pmid12934979"/> In addition to psychological components of social phobia, such as fear and avoidance, sertraline also ameliorated some physiological components, such as blushing and palpitations but not sweating and trembling.<ref name="pmid16216019">{{cite journal |author=Connor KM, Davidson JR, Chung H, Yang R, Clary CM |title=Multidimensional effects of sertraline in social anxiety disorder |journal=Depress Anxiety |volume=23 |issue=1 |pages=6–10 |year=2006 |pmid=16216019 |doi=10.1002/da.20086}}</ref> In a four-way placebo-controlled comparison trial of sertraline and exposure therapy, sertraline performed significantly better than placebo, while the exposure therapy resulted in only marginal improvement. The combination of sertraline and exposure therapy was not significantly better than sertraline alone; however, it appeared that the response was achieved faster with the combined treatment.<ref name="pmid11435264">{{cite journal |author=Blomhoff S, Haug TT, Hellström K, Holme I, Humble M, Madsbu HP, Wold JE |title=Randomised controlled general practice trial of sertraline, exposure therapy and combined treatment in generalised social phobia |journal=Br J Psychiatry |volume=179 |issue= |pages=23–30 |year=2001 |pmid=11435264|doi=10.1192/bjp.179.1.23}}</ref>
===Premenstrual dysphoric disorder===
According to several double-blind studies, sertraline is effective in alleviating the symptoms of [[premenstrual dysphoric disorder|PMDD]], a severe form of [[premenstrual syndrome]]. Significant improvement was observed in 50–60% of cases treated with sertraline vs. 20–30% of cases on placebo. The improvement began during the first week of treatment, and in addition to mood, irritability, and anxiety, improvement was reflected in better family functioning, social activity and general quality of life. Work functioning and physical symptoms, such as swelling, bloating and breast tenderness, were less responsive to sertraline.<ref>{{cite journal | author=Yonkers KA, Halbreich U, Freeman E, Brown C, Endicott J, Frank E, Parry B, Pearlstein T, Severino S, Stout A, Stone A, Harrison W. | title= Symptomatic improvement of premenstrual dysphoric disorder with sertraline treatment. A randomized controlled trial. Sertraline Premenstrual Dysphoric Collaborative Study Group| journal=The Journal of the American Medical Association | volume=278 | issue=12 | year=1997 | pages=983–988| pmid=9307345 | doi=10.1001/jama.278.12.983}}</ref><ref name="pmid12215058">Review: {{cite journal |author=Pearlstein T |title=Selective serotonin reuptake inhibitors for premenstrual dysphoric disorder: the emerging gold standard? |journal=Drugs |volume=62 |issue=13 |pages=1869–85 |year=2002 |pmid=12215058|doi=10.2165/00003495-200262130-00004}}</ref><ref name="pmid11972726">Review: {{cite journal |author=Ackermann RT, Williams JW |title=Rational treatment choices for non-major depressions in primary care: an evidence-based review |journal=J Gen Intern Med |volume=17 |issue=4 |pages=293–301 |year=2002 |pmid=11972726|doi=10.1046/j.1525-1497.2002.10350.x}}</ref> Despite the well-known sexual side effects of sertraline, significantly higher improvement of sexual functioning was achieved by the sertraline group as compared to the placebo group.<ref name="pmid14754784">{{cite journal |author=Freeman EW, Rickels K, Sondheimer SJ, Polansky M, Xiao S |title=Continuous or intermittent dosing with sertraline for patients with severe premenstrual syndrome or premenstrual dysphoric disorder |journal=Am J Psychiatry |volume=161 |issue=2 |pages=343–51 |year=2004 |pmid=14754784 |doi=10.1176/appi.ajp.161.2.343}}</ref> A three-way comparison of sertraline, [[norepinephrine reuptake inhibitor]] [[tricyclic antidepressant]] [[desipramine]], and placebo demonstrated the superiority of sertraline, while desipramine fared no better than placebo.<ref name="pmid10530636">{{cite journal |author=Freeman EW, Rickels K, Sondheimer SJ, Polansky M |title=Differential response to antidepressants in women with premenstrual syndrome/premenstrual dysphoric disorder: a randomized controlled trial |journal=Arch. Gen. Psychiatry |volume=56 |issue=10 |pages=932–9 |year=1999 |pmid=10530636|doi=10.1001/archpsyc.56.10.932}}</ref> Taking sertraline only during the [[luteal phase]], that is, the 12–14 days before menses, was shown to work as well as continuous treatment.<ref name="pmid10418540">{{cite journal |author=Jermain DM, Preece CK, Sykes RL, Kuehl TJ, Sulak PJ |title=Luteal phase sertraline treatment for premenstrual dysphoric disorder. Results of a double-blind, placebo-controlled, crossover study |journal=Arch Fam Med |volume=8 |issue=4 |pages=328–32 |year=1999 |pmid=10418540|doi=10.1001/archfami.8.4.328}}</ref><ref name="pmid12468166">{{cite journal |author=Halbreich U, Bergeron R, Yonkers KA, Freeman E, Stout AL, Cohen L |title=Efficacy of intermittent, luteal phase sertraline treatment of premenstrual dysphoric disorder |journal=Obstet Gynecol |volume=100 |issue=6 |pages=1219–29 |year=2002 |pmid=12468166|doi=10.1016/S0029-7844(02)02326-8}}</ref><ref name="pmid14754784">{{cite journal |author=Freeman EW, Rickels K, Sondheimer SJ, Polansky M, Xiao S |title=Continuous or intermittent dosing with sertraline for patients with severe premenstrual syndrome or premenstrual dysphoric disorder |journal=Am J Psychiatry |volume=161 |issue=2 |pages=343–51 |year=2004 |pmid=14754784 |doi=10.1176/appi.ajp.161.2.343}}</ref> Although the luteal-phase treatment may be more acceptable to patients, there have been indications that by the end of a three-month period it is less well-tolerated than the continuous treatment. The study authors suggested that the continuous treatment may allow the tolerance to side effects of sertraline to develop faster.<ref name="pmid14754784"/> The most recent (2006) trial findings indicate that continuous treatment with sub-therapeutic doses of sertraline (25 mg vs. usual 50–100 mg) may both afford the highest effectiveness and minimize the side effects.<ref name="pmid17107257">{{cite journal |author=Kornstein SG, Pearlstein TB, Fayyad R, Farfel GM, Gillespie JA |title=Low-dose sertraline in the treatment of moderate-to-severe premenstrual syndrome: efficacy of 3 dosing strategies |journal=J Clin Psychiatry |volume=67 |issue=10 |pages=1624–32 |year=2006 |pmid=17107257 |doi=}}</ref>
===Posttraumatic stress disorder===
Two double-blind placebo-controlled studies confirmed the efficacy of sertraline for severe chronic PTSD in civilians, with the mean duration of the illness more than ten years. Physical or sexual assault was the traumatic event for more than 60% of the subjects, and 75% of them were women. Over the 12-week period, 53–60% of the patients treated with sertraline were much or very much improved vs. 32–38% for placebo.<ref name="pmid10770145">{{cite journal |author=Brady K, Pearlstein T, Asnis GM, Baker D, Rothbaum B, Sikes CR, Farfel GM |title=Efficacy and safety of sertraline treatment of posttraumatic stress disorder: a randomized controlled trial |journal=JAMA |volume=283 |issue=14 |pages=1837–44 |year=2000 |pmid=10770145|doi=10.1001/jama.283.14.1837}}</ref><ref name="pmid11343529">{{cite journal |author=Davidson JR, Rothbaum BO, van der Kolk BA, Sikes CR, Farfel GM |title=Multicenter, double-blind comparison of sertraline and placebo in the treatment of posttraumatic stress disorder |journal=Arch. Gen. Psychiatry |volume=58 |issue=5 |pages=485–92 |year=2001 |pmid=11343529|doi=10.1001/archpsyc.58.5.485}}</ref> The treatment was continued for another year with some participants from both trials. The condition of the responders further improved; some of the patients who did not respond to the initial 12-week trial slowly improved as well, so that about half of them were classified as responders by the end of the following 24 weeks. The authors noted that the medication worked more slowly for those with more severe symptoms.<ref name="pmid11411812">{{cite journal |author=Londborg PD, Hegel MT, Goldstein S, Goldstein D, Himmelhoch JM, Maddock R, Patterson WM, Rausch J, Farfel GM |title=Sertraline treatment of posttraumatic stress disorder: results of 24 weeks of open-label continuation treatment |journal=The Journal of Clinical Psychiatry |volume=62 |issue=5 |pages=325–31 |year=2001 |pmid=11411812 |doi=}}</ref><ref name="pmid16734498">{{cite journal |author=Davis LL, Frazier EC, Williford RB, Newell JM |title=Long-term pharmacotherapy for post-traumatic stress disorder |journal=CNS Drugs |volume=20 |issue=6 |pages=465–76 |year=2006 |pmid=16734498|doi=10.2165/00023210-200620060-00003}}</ref> Discontinuation of the successful treatment after six months resulted in the return of the PTSD symptoms in 52% of the patients vs. 16% in those who continued taking sertraline.<ref name="pmid11729012">{{cite journal |author=Davidson J, Pearlstein T, Londborg P, Brady KT, Rothbaum B, Bell J, Maddock R, Hegel MT, Farfel G |title=Efficacy of sertraline in preventing relapse of posttraumatic stress disorder: results of a 28-week double-blind, placebo-controlled study |journal=The American Journal of Psychiatry |volume=158 |issue=12 |pages=1974–81 |year=2001 |pmid=11729012|doi=10.1176/appi.ajp.158.12.1974}}</ref> Longer-term treatment has been advocated in such cases.<ref name="pmid16734498"/>
Three-way (placebo–sertraline–third antidepressant) comparison trials of sertraline for PTSD found it to be better than placebo and equivalent to [[venlafaxine]] (Effexor)<ref name="pmid16702890">{{cite journal |author=Davidson J, Rothbaum BO, Tucker P, Asnis G, Benattia I, Musgnung JJ |title=Venlafaxine extended release in posttraumatic stress disorder: a sertraline- and placebo-controlled study |journal=Journal of Clinical Psychopharmacology |volume=26 |issue=3 |pages=259–67 |year=2006 |pmid=16702890 |doi=10.1097/01.jcp.0000222514.71390.c1}}</ref> or [[citalopram]] (Celexa),<ref name="pmid14608246">{{cite journal |author=Tucker P, Potter-Kimball R, Wyatt DB, Parker DE, Burgin C, Jones DE, Masters BK |title=Can physiologic assessment and side effects tease out differences in PTSD trials? A double-blind comparison of citalopram, sertraline, and placebo |journal=Psychopharmacology Bulletin |volume=37 |issue=3 |pages=135–49 |year=2003 |pmid=14608246 |doi=}}</ref> and in a two-way comparison it had the same efficacy as [[nefazodone]] (Serzone).<ref name="pmid15129422">{{cite journal |author=McRae AL, Brady KT, Mellman TA, Sonne SC, Killeen TK, Timmerman MA, Bayles-Dazet W |title=Comparison of nefazodone and sertraline for the treatment of posttraumatic stress disorder |journal=Depression and Anxiety |volume=19 |issue=3 |pages=190–6 |year=2004 |pmid=15129422 |doi=10.1002/da.20008}}</ref> Sertraline was not effective for veterans with combat-related PTSD.<ref name="pmid11910265">{{cite journal |author=Zohar J, Amital D, Miodownik C, Kotler M, Bleich A, Lane RM, Austin C |title=Double-blind placebo-controlled pilot study of sertraline in military veterans with posttraumatic stress disorder |journal=Journal of Clinical Psychopharmacology |volume=22 |issue=2 |pages=190–5 |year=2002 |pmid=11910265|doi=10.1097/00004714-200204000-00013}}</ref><ref name="pmid17503980">{{cite journal |author=Friedman MJ, Marmar CR, Baker DG, Sikes CR, Farfel GM |title=Randomized, double-blind comparison of sertraline and placebo for posttraumatic stress disorder in a Department of Veterans Affairs setting |journal=The Journal of Clinical Psychiatry |volume=68 |issue=5 |pages=711–20 |year=2007 |pmid=17503980 |doi=}}</ref>
===Other indications===
Two large placebo-controlled clinical trials of sertraline for [[generalized anxiety disorder]] have been conducted. While one trial demonstrated highly significant improvements on all measures used, including anxiety, depression and quality of life,<ref>{{cite journal | author=Allgulander C, Dahl AA, Austin C, Morris PL, Sogaard JA, Fayyad R, Kutcher SP, Clary CM. | title= Efficacy of sertraline in a 12-week trial for generalized anxiety disorder| journal=The American Journal of Psychiatry | volume=161 | year=2004 | pages=1642–1649| pmid=15337655 | doi=10.1176/appi.ajp.161.9.1642}}</ref> the other showed only marginal improvement of anxiety, and insignificant improvement of quality of life.<ref name="pmid16848646">{{cite journal |author=Brawman-Mintzer O, Knapp RG, Rynn M, Carter RE, Rickels K |title=Sertraline treatment for generalized anxiety disorder: a randomized, double-blind, placebo-controlled study |journal=J Clin Psychiatry |volume=67 |issue=6 |pages=874–81 |year=2006 |pmid=16848646 |doi=}}</ref> Small double-blind studies of sertraline for eating disorders, such as [[binge eating disorder]],<ref>{{cite journal | author=McElroy SL, Casuto LS, Nelson EB, Lake KA, Soutullo CA, Keck PE Jr, Hudson JI. | title= Placebo-controlled trial of sertraline in the treatment of binge eating disorder| journal=The American Journal of Psychiatry | volume=157 | issue=6| year=2000|pages=1004–1006| pmid=10831483 | doi=10.1176/appi.ajp.157.6.1004}}</ref><ref name="pmid18598735">{{cite journal |author=Leombruni P, Pierò A, Lavagnino L, Brustolin A, Campisi S, Fassino S |title=A randomized, double-blind trial comparing sertraline and fluoxetine 6-month treatment in obese patients with Binge Eating Disorder |journal=Prog. Neuropsychopharmacol. Biol. Psychiatry |volume= |issue= |pages= |year=2008 |month=June |pmid=18598735 |doi=10.1016/j.pnpbp.2008.06.005 |url=}}</ref> [[night eating syndrome]]<ref name="pmid16648332">{{cite journal |author=O'Reardon JP, Allison KC, Martino NS, Lundgren JD, Heo M, Stunkard AJ |title=A randomized, placebo-controlled trial of sertraline in the treatment of night eating syndrome |journal=Am J Psychiatry |volume=163 |issue=5 |pages=893–8 |year=2006 |pmid=16648332 |doi=10.1176/appi.ajp.163.5.893}}</ref> and [[bulimia nervosa]]<ref name="pmid15605617">{{cite journal |author=Milano W, Petrella C, Sabatino C, Capasso A |title=Treatment of bulimia nervosa with sertraline: a randomized controlled trial |journal=Adv Ther |volume=21 |issue=4 |pages=232–7 |year=2004 |pmid=15605617|doi=10.1007/BF02850155}}</ref> indicated its effectiveness.
Although sertraline can be used for the treatment of [[premature ejaculation]]<ref>{{cite journal | author=McMahon CG. | title= Treatment of premature ejaculation with sertraline hydrochloride: a single-blind placebo controlled crossover study| journal=The Journal of Urology | volume=159 | issue=6| year=1998 | pages=1935–1938| pmid=9598491 | doi=10.1016/S0022-5347(01)63201-4}}</ref> a comparative study found it to be inferior to another SSRI, [[paroxetine]].<ref name="pmid9690692">{{cite journal |author=Waldinger MD, Hengeveld MW, Zwinderman AH, Olivier B |title=Effect of SSRI antidepressants on ejaculation: a double-blind, randomized, placebo-controlled study with fluoxetine, fluvoxamine, paroxetine, and sertraline |journal=J Clin Psychopharmacol |volume=18 |issue=4 |pages=274–81 |year=1998 |pmid=9690692|doi=10.1097/00004714-199808000-00004}}</ref> 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"/>
A small study suggested that sertraline may help some children and adolescents with refractory [[vasovagal syncope|syncope]].<ref>{{cite journal | author=Grubb BP, Samoil D, Kosinski D, Kip K, Brewster P. | title= Use of sertraline hydrochloride in the treatment of refractory neurocardiogenic syncope in children and adolescents| journal=Journal of the American College of Cardiology | volume=24 | issue=2 | year=1994 | pages=490–494| pmid=8034887}}</ref> Subsequent case reports indicated that sertraline may itself cause syncope in adolescents<ref name="pmid9433163">{{cite journal |author=Lenk MK, Alehan D, Ozme S, Celiker A, Ozer S |title=Vasovagal syncope: asystole provoked by head-up tilt testing under sertraline therapy |journal=Turk. J. Pediatr. |volume=39 |issue=4 |pages=573–7 |year=1997 |pmid=9433163 |doi=}}</ref> and that sertraline treatment of syncope may make it more frequent.<ref name="pmid9365060">{{cite journal |author=Lenk M, Alehan D, Ozme S, Celiker A, Ozer S |title=The role of serotonin re-uptake inhibitors in preventing recurrent unexplained childhood syncope -- a preliminary report |journal=Eur. J. Pediatr. |volume=156 |issue=10 |pages=747–50 |year=1997 |pmid=9365060|doi=10.1007/s004310050704}}</ref><ref name="pmid9113018">{{cite journal |author=Tandan T, Giuffre M, Sheldon R |title=Exacerbations of neurally mediated syncope associated with sertraline |journal=Lancet |volume=349 |issue=9059 |pages=1145–6 |year=1997 |pmid=9113018 |doi=10.1016/S0140-6736(05)63021-8}}</ref>
==Adverse effects==
[[Image:Zoloft bottles.jpg|thumb|right|Bottles of Zoloft as sold in the United States, with blue (50 mg) and green (25 mg) tablets]]
According to Pfizer, sertraline is [[contraindicated]] in individuals taking [[monoamine oxidase inhibitor]]s or the [[antipsychotic]] [[pimozide]] (Orap). Sertraline concentrate contains alcohol, and is therefore contraindicated with [[disulfiram]] (Antabuse). The prescribing information recommends that treatment of the elderly and patients with liver impairment "must be approached with caution". Due to the slower elimination of sertraline in these groups, their exposure to sertraline may be as high as three times the average exposure for the same dose.<ref name="zoloftpi">{{cite web |url=http://www.zoloft.com |title=Zoloft Prescribing Information for the U.S.|format= PDF|publisher=Pfizer |accessdate=2008-04-26}}</ref>
Among the common [[adverse drug reaction|adverse effects]] associated with sertraline and listed in the prescribing information, those with the greatest difference from [[placebo]] are [[nausea]] (25% vs. 11% for placebo), [[ejaculation]] failure (14% vs. 1% for placebo), [[insomnia]] (21% vs. 11% for placebo), [[diarrhea]] (20% vs. 10% for placebo), [[dry mouth]] (14% vs. 8% for placebo), [[somnolence]] (13% vs. 7% for placebo), [[dizziness]] (12% vs. 7% for placebo), [[tremor]] (8% vs. 2% for placebo) and decreased [[libido]] (6% vs. 1% for placebo).<ref name=zoloftpi/> Those that most often resulted in interruption of the treatment were nausea (3%), diarrhea (2%) and insomnia (2%).<ref name=zoloftpi/> Sertraline appears to be associated with [[microscopic colitis]], a rare condition of unknown [[etiology]].<ref name="pmid17100977">{{cite journal |author=Fernández-Bañares F, Esteve M, Espinós JC, Rosinach M, Forné M, Salas A, Viver JM |title=Drug consumption and the risk of microscopic colitis |journal=Am. J. Gastroenterol. |volume=102 |issue=2 |pages=324–30 |year=2007 |pmid=17100977 |doi=10.1111/j.1572-0241.2006.00902.x}}</ref>
[[Akathisia]]—that is, "inner tension, restlessness, and the inability to stay still"—caused by sertraline was observed in 16% of patients in a [[case series]].<ref name="pmid9018398">{{cite journal |author=Olivera AO |title=Sertraline and akathisia: spontaneous resolution |journal=Biol. Psychiatry |volume=41 |issue=2 |pages=241–2 |year=1997 |pmid=9018398|doi=10.1016/S0006-3223(96)00384-8}}</ref> This and other reports<ref name="pmid8909330">Review:{{cite journal |author=Leo RJ |title=Movement disorders associated with the serotonin selective reuptake inhibitors |journal=The Journal of Clinical Psychiatry |volume=57 |issue=10 |pages=449–54 |year=1996 |pmid=8909330 |doi=}}</ref><ref name="pmid9378692">{{cite journal |author=Lauterbach EC, Meyer JM, Simpson GM |title=Clinical manifestations of dystonia and dyskinesia after SSRI administration |journal=The Journal of Clinical Psychiatry |volume=58 |issue=9 |pages=403–4 |year=1997 |pmid=9378692 |doi=}}</ref><ref name="pmid12407283">{{cite journal |author=Walker L |title=Sertraline-induced akathisia and dystonia misinterpreted as a panic attack |journal=Psychiatric Services (Washington, D.C.) |volume=53 |issue=11 |pages=1477–8 |year=2002 |pmid=12407283 |doi=}}</ref> note that akathisia begins soon after the initiation of treatment or a dose increase; often, several hours after taking the medication. Akathisia usually disappears within several days after sertraline is stopped or its dose is decreased. In some cases, clinicians confused akathisia with [[anxiety]] and increased the dose of sertraline, causing further worsening of the patients' symptoms.<ref name="pmid12407283">{{cite journal |author=Walker L |title=Sertraline-induced akathisia and dystonia misinterpreted as a panic attack |journal=Psychiatric Services (Washington, D.C.) |volume=53 |issue=11 |pages=1477–8 |year=2002 |pmid=12407283 |doi=}}</ref> Experts note that because of the possible link of akathisia with suicide and the distress it causes to the patient, "it is of vital importance to increase awareness amongst staff and patients of the symptoms of this relatively common condition".<ref name="pmid12404546">{{cite journal |author=Hansen L |title=A critical review of akathisia, and its possible association with suicidal behaviour |journal=Hum Psychopharmacol |volume=16 |issue=7 |pages=495–505 |year=2001 |month=October |pmid=12404546 |doi=10.1002/hup.325 |url=}}</ref><ref name="pmid16449715">{{cite journal |author=Hansen L, Kingdom D |title=Akathisia as a risk factor for suicide |journal=The [[British Journal of Psychiatry]] : the journal of mental science |volume=188 |issue= |pages=192 |year=2006 |pmid=16449715 |doi=10.1192/bjp.188.2.192}}</ref>
Over more than six months of sertraline therapy for depression, patients showed an insignificant weight increase of 0.1%.<ref name="pmid11105740">{{cite journal |author=Fava M, Judge R, Hoog SL, Nilsson ME, Koke SC |title=Fluoxetine versus sertraline and paroxetine in major depressive disorder: changes in weight with long-term treatment |journal=The Journal of Clinical Psychiatry |volume=61 |issue=11 |pages=863–7 |year=2000 |pmid=11105740 |doi=}}</ref> Similarly, a 30-month-long treatment with sertraline for [[obsessive compulsive disorder|OCD]] resulted in a mean weight gain of 1.5% (1 kg).<ref name="pmid15491240">{{cite journal |author=Maina G, Albert U, Salvi V, Bogetto F |title=Weight gain during long-term treatment of obsessive-compulsive disorder: a prospective comparison between serotonin reuptake inhibitors |journal=The Journal of Clinical Psychiatry |volume=65 |issue=10 |pages=1365–71 |year=2004 |pmid=15491240 |doi=}}</ref> Although the difference did not reach [[statistical significance]], the weight gain was lower for [[fluoxetine]] (Prozac) (1%) but higher for [[citalopram]] (Celexa), [[fluvoxamine]] (Luvox) and [[paroxetine]] (Paxil) (2.5%). Only 4.5% of the sertraline group gained a large amount of weight (defined as more than 7% gain). This result compares favorably with placebo, where, according to the literature, 3–6% of patients gained more than 7% of their initial weight. The large weight gain was observed only among female members of the sertraline group; the significance of this finding is unclear because of the small size of the group.<ref name="pmid15491240"/>
Over a two-week treatment of healthy volunteers, sertraline slightly improved verbal [[fluency]] but did not affect word learning, [[short-term memory]], [[alertness|vigilance]], [[flicker fusion threshold|flicker fusion time]], choice [[reaction time]], [[memory span]], or [[motor coordination|psychomotor coordination]].<ref name="pmid11565624">{{cite journal |author=Schmitt JA, Kruizinga MJ, Riedel WJ |title=Non-serotonergic pharmacological profiles and associated cognitive effects of serotonin reuptake inhibitors |journal=J. Psychopharmacol. (Oxford) |volume=15 |issue=3 |pages=173–9 |year=2001 |pmid=11565624 |doi=}}</ref><ref name="pmid12692706">{{cite journal |author=Siepmann M, Grossmann J, Mück-Weymann M, Kirch W |title=Effects of sertraline on autonomic and cognitive functions in healthy volunteers |journal=Psychopharmacology (Berl.) |volume=168 |issue=3 |pages=293–8 |year=2003 |pmid=12692706 |doi=10.1007/s00213-003-1448-4}}</ref> In spite of lower subjective rating, that is, feeling that they performed worse, no clinically relevant differences were observed in the objective cognitive performance in a group of people treated for depression with sertraline for 1.5 year as compared to healthy controls.<ref name="pmid16485140">{{cite journal |author=Gorenstein C, de Carvalho SC, Artes R, Moreno RA, Marcourakis T |title=Cognitive performance in depressed patients after chronic use of antidepressants |journal=Psychopharmacology (Berl.) |volume=185 |issue=1 |pages=84–92 |year=2006 |pmid=16485140 |doi=10.1007/s00213-005-0274-2}}</ref> In children and adolescents taking sertraline for six weeks for anxiety disorders, 18 out of 20 measures of memory, attention and alertness stayed unchanged. [[Attention#Clinical model of attention|Divided attention]] was improved and verbal memory under [[Interference theory#Proactive interference|interference conditions]] decreased marginally. Because of the large number of measures taken, it is possible that these changes were still due to chance.<ref name="pmid16190792">{{cite journal |author=Günther T, Holtkamp K, Jolles J, Herpertz-Dahlmann B, Konrad K |title=The influence of sertraline on attention and verbal memory in children and adolescents with anxiety disorders |journal=J Child Adolesc Psychopharmacol |volume=15 |issue=4 |pages=608–18 |year=2005 |pmid=16190792 |doi=10.1089/cap.2005.15.608}}</ref>
===Birth defects and effects on breast-fed infants===
The studies comparing the levels of sertraline and its principal [[metabolite]], desmethylsertraline, in mother's blood to their concentration in [[umbilical cord]] blood at the time of delivery indicated that fetal exposure to sertraline and its metabolite is approximately a third of the maternal exposure.<ref name="pmid11082480">{{cite journal |author=Hostetter A, Ritchie JC, Stowe ZN |title=Amniotic fluid and umbilical cord blood concentrations of antidepressants in three women |journal=Biol. Psychiatry |volume=48 |issue=10 |pages=1032–4 |year=2000 |pmid=11082480|doi=10.1016/S0006-3223(00)00958-6}}</ref><ref name="pmid12727706">{{cite journal |author=Hendrick V, Stowe ZN, Altshuler LL, Hwang S, Lee E, Haynes D |title=Placental passage of antidepressant medications |journal=The American Journal of Psychiatry |volume=160 |issue=5 |pages=993–6 |year=2003 |pmid=12727706|doi=10.1176/appi.ajp.160.5.993}}</ref> The use of sertraline during the first trimester of pregnancy was associated with increased odds of the following [[congenital disorder|birth defects]]: [[omphalocele]] (six-fold), [[anal atresia]] and limb reduction defects (four-fold), and [[septal defect]]s (two-fold).<ref name="pmid17596601">{{cite journal |author=Louik C, Lin AE, Werler MM, Hernández-Díaz S, Mitchell AA |title=First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects |journal=N. Engl. J. Med. |volume=356 |issue=26 |pages=2675–83 |year=2007 |pmid=17596601 |doi=10.1056/NEJMoa067407}}</ref> Concentration of sertraline and desmethylsertraline in [[breast milk]] is highly variable and, on average, is of the same order of magnitude as their concentration in the [[blood plasma]] of the mother. As a result, more than half of breast-fed babies receive less than 2 mg/day of sertraline and desmethylsertraline combined, and in most cases these substances are undetectable in their blood.<ref name="pmid12590627">{{cite journal |author=Stowe ZN, Hostetter AL, Owens MJ, Ritchie JC, Sternberg K, Cohen LS, Nemeroff CB |title=The pharmacokinetics of sertraline excretion into human breast milk: determinants of infant serum concentrations |journal=The Journal of Clinical Psychiatry |volume=64 |issue=1 |pages=73–80 |year=2003 |pmid=12590627 |doi=}}</ref> No changes in [[serotonin]] uptake by the [[platelets]] of breast-fed infants were found, as measured by their blood serotonin levels before and after their mothers began sertraline treatment.<ref name="pmid11578995">{{cite journal |author=Epperson N, Czarkowski KA, Ward-O'Brien D, Weiss E, Gueorguieva R, Jatlow P, Anderson GM |title=Maternal sertraline treatment and serotonin transport in breast-feeding mother-infant pairs |journal=The American Journal of Psychiatry |volume=158 |issue=10 |pages=1631–7 |year=2001 |pmid=11578995|doi=10.1176/appi.ajp.158.10.1631}}</ref>
===Sexual side effects===
Like other SSRIs, sertraline is associated with sexual side effects, including arousal disorder and difficulty achieving orgasm. The observed frequency of sexual side effects depends greatly on whether they are reported by patients spontaneously, as in the manufacturer's trials, or actively solicited by the physicians. There have been several [[blind experiment|double-blind studies]] of sexual side effects comparing sertraline with placebo or other antidepressants.<ref name="pmid11229450">{{cite journal |author=Ferguson JM |title=The effects of antidepressants on sexual functioning in depressed patients: a review |journal=The Journal of Clinical Psychiatry |volume=62 Suppl 3 |issue= |pages=22–34 |year=2001 |pmid=11229450 |doi=}}</ref> While [[nefazodone]] (Serzone) and [[bupropion]] did not have negative effects on sexual functioning, 67% of men on sertraline experienced ejaculation difficulties vs. 18% before the treatment<ref name="pmid11229450"/> (or 61% vs. 0% according to another paper<ref name="pmid9448656"/>). Similarly, in a group of women who initially did not have difficulties achieving orgasm, 41% acquired this problem during treatment with sertraline.<ref name="pmid9448656"/> A 40% rate of [[anorgasmia|orgasm dysfunction]] (vs. 9% for placebo) on sertraline was observed in a mixed group in another study.<ref name="pmid10363731">{{cite journal |author=Croft H, Settle E, Houser T, Batey SR, Donahue RM, Ascher JA |title=A placebo-controlled comparison of the antidepressant efficacy and effects on sexual functioning of sustained-release bupropion and sertraline |journal=Clinical Therapeutics |volume=21 |issue=4 |pages=643–58 |year=1999 |pmid=10363731 |doi=10.1016/S0149-2918(00)88317-4}}</ref> [[Sexual arousal]] disorder, defined as "inadequate lubrication and swelling for women and erectile difficulties for men", occurred in 12% of patients on sertraline as compared with 1% of patients on placebo. The mood improvement resulting from the treatment with sertraline counteracted these side effects, so that [[sexual desire]] and overall satisfaction with sex stayed the same as before the sertraline treatment. However, under the action of placebo the desire and satisfaction slightly improved.<ref name="pmid10363731"/>
===Suicidality===
The FDA requires all antidepressants, including sertraline, to carry a [[black box warning]] stating that antidepressants may increase the risk of suicide in persons younger than 25. This warning is based on statistical analyses conducted by two independent groups of FDA experts that found a 2-fold increase of suicidal ideation and behavior in children and adolescents, and a 1.5-fold increase of suicidality in the 18–24 age group.<ref name=FDA>{{cite web | author = Levenson M, Holland C| title =Antidepressants and Suicidality in Adults: Statistical Evaluation. (Presentation at Psychopharmacologic Drugs Advisory Committee; December 13, 2006)|publisher = FDA|accessdate = 2008-07-11 | url = http://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4272s1-04-FDA.ppt}}</ref><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 = 2008-07-11 | 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 = 2008-07-11 | 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>
[[Suicidal ideation]] and behavior in clinical trials are rare. For the above analysis, the FDA combined the results of 295 trials of 11 antidepressants for psychiatric indications in order to obtain [[statistically significant]] results. Considered separately, sertraline use in adults decreased the odds of suicidality with a marginal statistical significance by 37%<ref name =FDA3/> or 50%<ref name =FDA2/> depending on the statistical technique used. The authors of the FDA analysis note that "given the large number of comparisons made in this review, chance is a very plausible explanation for this difference".<ref name =FDA2/> The more complete data submitted later by the sertraline manufacturer Pfizer indicated increased suicidality.<ref>{{cite web |url=http://www.fda.gov/ohrms/dockets/dockets/06n0414/06N-0414-EC32-Attach-1.pdf |title=Memorandum from Pfizer Global Pharmaceuticals Re: DOCKET: 2006N-0414 –"Suicidality data from adult antidepressant trials" Background package for December 13 Advisory Committee|accessdate=2008-07-11 |author=Pfizer Inc. |date= 2006-11-30|format=PDF |work=FDA DOCKET 2006N-0414 |publisher=FDA }}</ref> Similarly, the analysis conducted by the UK [[Medicines and Healthcare products Regulatory Agency|MHRA]] found a 50% increase of odds of suicide-related events, not reaching statistical significance, in the patients on sertraline as compared to the ones on placebo.<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=2008-07-11 |date=2004-12 |format=PDF |publisher=MHRA }}</ref><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|accessdate=2007-09-25}}</ref>
===Discontinuation syndrome===
{{main|SSRI discontinuation syndrome}}
Abrupt interruption of sertraline treatment may result in [[withdrawal]] or discontinuation syndrome. This syndrome occurred in 60% of the remitted depressed patients taking sertraline in a blind discontinuation study, as compared to 14% of patients on fluoxetine and 66% of patients on paroxetine.<ref name="pmid9646889">{{cite journal |author=Rosenbaum JF, Fava M, Hoog SL, Ascroft RC, Krebs WB |title=Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial |journal=Biol. Psychiatry |volume=44 |issue=2 |pages=77–87 |year=1998 |pmid=9646889|doi=10.1016/S0006-3223(98)00126-7}}</ref> During the 5–8-day period when sertraline was temporarily replaced by placebo, the most frequent symptoms (reported by more than a quarter of patients) were irritability, agitation, dizziness, headache, nervousness, crying, emotional lability, bad dreams and anger. Around a third experienced mood worsening to the level generally associated with a major depressive episode.<ref name="pmid9646889"/> In a double-blind study of remitted panic disorder patients, abrupt discontinuation of sertraline treatment resulted in insomnia and dizziness (both 16–17% vs. 4% for continuing treatment), although headache, depression and malaise did not increase significantly.<ref name="pmid11722304">{{cite journal |author=Rapaport MH, Wolkow R, Rubin A, Hackett E, Pollack M, Ota KY |title=Sertraline treatment of panic disorder: results of a long-term study |journal=Acta Psychiatr Scand |volume=104 |issue=4 |pages=289–98 |year=2001 |pmid=11722304 |doi=10.1034/j.1600-0447.2001.00263.x}}</ref> In another double-blind study of recovered panic disorder patients, the withdrawal syndrome was completely avoided when sertraline was gradually discontinued over three weeks, while patients stopping paroxetine treatment still suffered from it.<ref name="pmid15096081"/>
==Mechanism of action==
Sertraline is primarily a [[serotonin reuptake inhibitor]] (SRI). Therapeutic doses of sertraline (50–200 mg/day) taken by patients for four weeks resulted in 80–90% inhibition of [[serotonin transporter]] (SERT) in [[striatum]] as measured by [[positron emission tomography]]. A daily 9 mg dose was sufficient to inhibit 50% of SERT.<ref name="pmid15121647">{{cite journal |author=Meyer JH, Wilson AA, Sagrati S, Hussey D, Carella A, Potter WZ, Ginovart N, Spencer EP, Cheok A, Houle S |title=Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [<sup>11</sup>C]DASB positron emission tomography study |journal=The American Journal of Psychiatry |volume=161 |issue=5 |pages=826–35 |year=2004 |pmid=15121647 |doi=}}</ref> Sertraline is also a [[dopamine reuptake inhibitor]], with 1% of its SRI potency,<ref name="pmid11543737">{{cite journal |author=Owens MJ, Knight DL, Nemeroff CB |title=Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine |journal=Biol. Psychiatry |volume=50 |issue=5 |pages=345–50 |year=2001 |pmid=11543737|doi=10.1016/S0006-3223(01)01145-3}}</ref> and a [[sigma-1 receptor]] agonist with 5% of its SRI potency.<ref name="pmid8831113">{{cite journal |author=Narita N, Hashimoto K, Tomitaka S, Minabe Y |title=Interactions of selective serotonin reuptake inhibitors with subtypes of sigma receptors in rat brain |journal=Eur. J. Pharmacol. |volume=307 |issue=1 |pages=117–9 |year=1996 |pmid=8831113|doi=10.1016/0014-2999(96)00254-3}}</ref> Sertraline weakly blocks [[alpha blocker|α1-adrenoreceptors]] with 1–10% of its SRI potency.<ref name="pmid11543737"/><ref name="pmid9400006">{{cite journal |author=Owens MJ, Morgan WN, Plott SJ, Nemeroff CB |title=Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites |journal=J. Pharmacol. Exp. Ther. |volume=283 |issue=3 |pages=1305–22 |year=1997 |pmid=9400006 |doi=}}</ref>
==Pharmacokinetics==
Sertraline is absorbed slowly when taken by mouth, achieving its maximal concentration in the plasma 4–6 hours after ingestion. In the blood, it is 98.5% [[plasma protein binding|bound to plasma proteins]]. Its half-life in the body is 13–45 hours and, on average, is about 1.5 times longer in women (32 hours) than in men (22 hours), leading to a 1.5-times-higher exposure in women.<ref name="pmid12452737">{{cite journal |author=DeVane CL, Liston HL, Markowitz JS |title=Clinical pharmacokinetics of sertraline |journal=Clinical Pharmacokinetics |volume=41 |issue=15 |pages=1247–66 |year=2002 |pmid=12452737|doi=10.2165/00003088-200241150-00002}}</ref> According to ''[[in vitro]]'' studies, sertraline is metabolized by multiple [[cytochrome 450]] [[isoenzyme|isoforms]]: [[CYP2D6]], [[CYP2C9]], [[CYP2B6]], [[CYP2C19]] and [[CYP3A4]]. It appeared unlikely that inhibition of any single isoform could cause clinically significant changes in sertraline pharmacokinetics.<ref name="pmid10383917">{{cite journal |author=Kobayashi K, Ishizuka T, Shimada N, Yoshimura Y, Kamijima K, Chiba K |title=Sertraline N-demethylation is catalyzed by multiple isoforms of human cytochrome P-450 in vitro |journal=Drug Metab. Dispos. |volume=27 |issue=7 |pages=763–6 |year=1999 |pmid=10383917 |doi=}}</ref><ref name="pmid15547048">{{cite journal |author=Obach RS, Cox LM, Tremaine LM |title=Sertraline is metabolized by multiple cytochrome P450 enzymes, monoamine oxidases, and glucuronyl transferases in human: an in vitro study |journal=Drug Metab. Dispos. |volume=33 |issue=2 |pages=262–70 |year=2005 |pmid=15547048 |doi=10.1124/dmd.104.002428}}</ref> No differences in sertraline pharmacokinetics were observed between people with high and low activity of CYP2D6;<ref name="pmid8941024">{{cite journal |author=Hamelin BA, Turgeon J, Vallée F, Bélanger PM, Paquet F, LeBel M |title=The disposition of fluoxetine but not sertraline is altered in poor metabolizers of debrisoquin |journal=Clin. Pharmacol. Ther. |volume=60 |issue=5 |pages=512–21 |year=1996 |pmid=8941024 |doi=10.1016/S0009-9236(96)90147-2}}</ref> however, [[poor metabolizer|poor CYP2C19 metabolizers]] had a 1.5-times-higher level of sertraline than normal metabolizers.<ref name="pmid11452243">{{cite journal |author=Wang JH, Liu ZQ, Wang W, Chen XP, Shu Y, He N, Zhou HH |title=Pharmacokinetics of sertraline in relation to genetic polymorphism of CYP2C19 |journal=Clin. Pharmacol. Ther. |volume=70 |issue=1 |pages=42–7 |year=2001 |pmid=11452243 |doi=10.1067/mcp.2001.116513}}</ref> ''In vitro'' data also indicate that the inhibition of CYP2B6 should have even greater effect than the inhibition of CYP2C19, while the contribution of CYP2C9 and CYP3A4 to the metabolism of sertraline would be minor. These conclusions have not been verified in human studies.<ref name="pmid15547048">{{cite journal |author=Obach RS, Cox LM, Tremaine LM |title=Sertraline is metabolized by multiple cytochrome P450 enzymes, monoamine oxidases, and glucuronyl transferases in human: an in vitro study |journal=Drug Metab. Dispos. |volume=33 |issue=2 |pages=262–70 |year=2005 |pmid=15547048 |doi=10.1124/dmd.104.002428}}</ref> Sertraline can be [[deamination|deaminated]] ''in vitro'' by [[monoamine oxidase]]s; however, this metabolic pathway has never been studied ''in vivo''.<ref name="pmid15547048"/> The major metabolite of sertraline, desmethylsertraline, is about 50 times weaker as a serotonin transporter inhibitor than sertraline and its clinical effect is negligible.<ref name="pmid9400006">{{cite journal |author=Owens MJ, Morgan WN, Plott SJ, Nemeroff CB |title=Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites |journal=J. Pharmacol. Exp. Ther. |volume=283 |issue=3 |pages=1305–22 |year=1997 |pmid=9400006 |doi=}}</ref>
==Interactions==
Sertraline is a moderate [[enzyme inhibitor|inhibitor]] of [[CYP2D6]] and [[CYP2B6]] ''in vitro''.<ref name="pmid16192315">{{cite journal |author=Obach RS, Walsky RL, Venkatakrishnan K, Gaman EA, Houston JB, Tremaine LM |title=The utility of in vitro cytochrome P450 inhibition data in the prediction of drug-drug interactions |journal=J. Pharmacol. Exp. Ther. |volume=316 |issue=1 |pages=336–48 |year=2006 |pmid=16192315 |doi=10.1124/jpet.105.093229}}</ref> Accordingly, in human trials it caused increased blood levels of CYP2D6 [[substrate (biochemistry)|substrates]] such as [[metoprolol]] (Lopressor, Toprol XL), [[dextromethorphan]] (Robitussin cough suppressant), [[desipramine]] (Norpramin), [[imipramine]] (Tofranil) and [[nortriptyline]] (Pamelor), as well as the [[CYP3A4]]/[[CYP2D6]] substrate [[haloperidol]] (Haldol).<ref name="pmid9472843">{{cite journal |author=Ozdemir V, Naranjo CA, Herrmann N, Shulman RW, Sellers EM, Reed K, Kalow W |title=The extent and determinants of changes in CYP2D6 and CYP1A2 activities with therapeutic doses of sertraline |journal=Journal of Clinical Psychopharmacology |volume=18 |issue=1 |pages=55–61 |year=1998 |pmid=9472843 |doi=}}</ref><ref name="pmid10211917">{{cite journal |author=Alfaro CL, Lam YW, Simpson J, Ereshefsky L |title=CYP2D6 status of extensive metabolizers after multiple-dose fluoxetine, fluvoxamine, paroxetine, or sertraline |journal=Journal of Clinical Psychopharmacology |volume=19 |issue=2 |pages=155–63 |year=1999 |pmid=10211917|doi=10.1097/00004714-199904000-00011}}</ref><ref name="pmid10631623">{{cite journal |author=Alfaro CL, Lam YW, Simpson J, Ereshefsky L |title=CYP2D6 inhibition by fluoxetine, paroxetine, sertraline, and venlafaxine in a crossover study: intraindividual variability and plasma concentration correlations |journal=Journal of Clinical Pharmacology |volume=40 |issue=1 |pages=58–66 |year=2000 |pmid=10631623 |doi=}}</ref> This effect is dose-dependent; for example, co-administration with 50 mg of sertraline resulted in 20% greater exposure to desipramine, while 150 mg of sertraline led to a 70% increase.<ref name="pmid12452737"/><ref name="pmid17224709">{{cite journal |author=Preskorn SH, Greenblatt DJ, Flockhart D, Luo Y, Perloff ES, Harmatz JS, Baker B, Klick-Davis A, Desta Z, Burt T |title=Comparison of duloxetine, escitalopram, and sertraline effects on cytochrome P450 2D6 function in healthy volunteers |journal=Journal of Clinical Psychopharmacology |volume=27 |issue=1 |pages=28–34 |year=2007 |pmid=17224709|doi=10.1097/00004714-200702000-00005}}</ref> In a placebo-controlled study, the concomitant administration of sertraline and [[methadone]] caused a 40% increase in blood levels of the latter, which is primarily metabolized by CYP2B6.<ref name="pmid10914294">{{cite journal |author=Hamilton SP, Nunes EV, Janal M, Weber L |title=The effect of sertraline on methadone plasma levels in methadone-maintenance patients |journal=The American Journal on Addictions / American Academy of Psychiatrists in Alcoholism and Addictions |volume=9 |issue=1 |pages=63–9 |year=2000 |pmid=10914294 |doi=}}</ref> Sertraline had a slight inhibitory effect on the metabolism of [[diazepam]] (Valium), [[tolbutamide]] (Orinase) and [[warfarin]] (Coumadin), which are [[CYP2C9]] or [[CYP2C19]] substrates; this effect was not considered to be clinically relevant.<ref name="pmid12452737"/> As expected from ''in vitro'' data, sertraline did not alter the human metabolism of the [[CYP3A4]] substrates [[erythromycin]], [[alprazolam]] (Xanax), [[carbamazepine]] (Tegretol), [[clonazepam]] (Klonopin), and [[terfenadine]] (Seldane); neither did it affect metabolism of the [[CYP1A2]] substrate [[clozapine]] (Clozaril). Sertraline had no effect on the actions of [[digoxin]] (Lanoxin) and [[atenolol]] (Tenormin), which are not metabolized in the liver.<ref name="pmid12452737"/><ref name="pmid16192315"/><ref name=zoloftpi/><ref name="pmid14709940">{{cite journal |author=DeVane CL, Donovan JL, Liston HL, Markowitz JS, Cheng KT, Risch SC, Willard L |title=Comparative CYP3A4 inhibitory effects of venlafaxine, fluoxetine, sertraline, and nefazodone in healthy volunteers |journal=Journal of Clinical Psychopharmacology |volume=24 |issue=1 |pages=4–10 |year=2004 |pmid=14709940 |doi=10.1097/01.jcp.0000104908.75206.26}}</ref> [[Case report]]s suggest that taking sertraline with [[phenytoin]] (Dilantin) or [[zolpidem]] (Ambien) may induce sertraline metabolism and decrease its efficacy, and taking sertraline with [[lamotrigine]] (Lamictal) may increase the blood level of lamotrigine via an unknown mechanism. Clinical reports indicate that interaction between sertraline and the [[Monoamine oxidase inhibitor|MAOIs]] [[isocarboxazid]] (Marplan) and [[tranylcypromine]] (Parnate) may cause [[serotonin syndrome]]. In a placebo-controlled study in which sertraline was co-administered with [[lithium pharmacology|lithium]], 35% of the subjects experienced [[tremor]]s, while none of those taking placebo did.<ref name="pmid12452737"/>
==Controversy==
The brand-name form of sertraline, Zoloft, was [[direct-to-consumer advertising|advertised to consumers]] by Pfizer using the following wording: "While the cause is unknown, depression may be related to an imbalance of natural chemicals between nerve cells in the brain. Prescription Zoloft works to correct this imbalance. You just shouldn't have to feel this way anymore." An essay published in the journal ''[[PLoS Medicine]]'' noted that there is no scientific support for the "serotonin imbalance" theory of depression, and criticized Pfizer and manufacturers of other SSRIs for using it. When asked to comment on this apparent breach of federal regulations, the FDA answered that such "reductionist statements" are acceptable to explain the neurochemistry of depression "to the fraction of the public that functions at no higher than a 6th grade reading level".<ref name="PLoS">{{cite journal |author=Lacasse J, Leo J |title=Serotonin and depression: a disconnect between the advertisements and the scientific literature |journal=[[PLoS Medicine|PLoS Med]] |volume=2 |issue=12 |pages=e392 |year=2005 |pmid=16268734 |doi=10.1371/journal.pmed.0020392.g001}} [http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0020392 Free full text, open-access source]</ref> However, the FDA reacted promptly with a warning letter when a Zoloft advertisement omitted information about the risk of suicidality.<ref>{{cite web |url=http://www.fda.gov/cder/warn/2005/zoloft_letter.pdf |title=Food and Drug Administration Division of Drug Marketing Advertising and Communications. (2005) Zoloft warning letter. |accessdate=2008-07-11 |publisher= FDA }}</ref>
In the case of ''Regina vs Hawkins'', an Australian criminal case from the state of [[New South Wales]], Zoloft was described as an important factor in David Hawkins's killing in 1999 (through strangling) of his wife. Hawkins had been depressed, was prescribed 50 mg of Zoloft a day and on his first day of treatment took 250 mg. He claimed that on the night of the murder he could not sleep and was agitated, and that he had hallucinations during the attack on his wife. Several experts agreed that "Zoloft can cause agitation and a certain amount of disinhibition so that some individuals engage in aggressive or dangerous behaviours without due regard for the consequences and in a manner that is out of character for them" and that the prisoner's behavior was consistent with agitated depression further exacerbated by akathisia and toxic delirium that developed as a result of Zoloft overdose. The court concluded that "it can be seen that the medical evidence strongly supports a conclusion that, but for the effects of the 250 milligrams of Zoloft he had taken, it is wholly unlikely that the prisoner would have committed the crime to which he has pleaded guilty. Furthermore, it is common ground that his having done such an act is quite foreign to his former life history, his personality and psychological make up. It was also wholly inconsistent with his love for his marriage partner of nearly fifty years."<ref>{{cite web | url = http://www.lawlink.nsw.gov.au/scjudgments/2001nswsc.nsf/27602436db586906ca256983001e137a/bd5c743050325110ca256a54007de04f?opendocument | accessdate = 2008-07-11 | title = Regina v Hawkins <nowiki>[2001]</nowiki> NSWSC 420| date = 2001-05-24 | publisher = New South Wales Supreme Court}}</ref>
In 2004, a [[Los Angeles, California|Los Angeles]] nurse sued Pfizer as a [[private attorney general]] "on behalf of all California residents who have been misled about Zoloft", claiming the company covered up side effects.<ref>{{cite press release | url =http://findarticles.com/p/articles/mi_m0EIN/is_2004_July_23/ai_n6122283 | title = Suit Claims Pfizer Conceals Evidence and Misleads Doctors and Patients About Safety and Effectiveness of Zoloft | date = 2004-07-23 | accessdate = 2008-07-11 | publisher = Business Wire/Findarticles.com}}</ref> In 2005, the Los Angeles Superior Court dismissed the case and ordered the plaintiff to pay Pfizer's cost of the suit.<ref name=lasc>Enter the case number "BC 318871" into the form to see the summary of the case stating that the suit was dismissed. The images of the case documents are available for a nominal price. {{cite web |url = http://www.lasuperiorcourt.org/civilCaseSummary/index.asp?CaseType=Civil |title= Los Angeles Superior Court — Civil Case Summary|accessdate=2007-11-04 |date=2005-05-31 |publisher= Los Angeles Superior Court |quote=It is thereby ordered, adjudged and decreed that this action is dismissed and that Defendant Pfizer Inc is awarded its costs of suit incurred therein.}}</ref>
==Notes==
<div class="references-small">
:{{note label|TradeName|A|A}} Medication trade names may differ between countries. In general, this article uses North American trade names.
</div>
==References==
{{Reflist|2}}
==External links==
{{commonscat|Sertraline}}
*[http://www.merck.com/mmpe/lexicomp/sertraline.html List of international brand names for sertraline]
*Prescribing information from [http://www.zoloft.com/ Zoloft] manufacturer
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{{Antidepressants}}
{{featured article}}
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