Zoloft mechanism of action

Zoloft mechanism of action DEFAULT

General Information

Zoloft (sertraline HCl) is a selective serotonin reuptake inhibitor.

Zoloft has been approved for:

  • major depressive disorder
  • obsessive-compulsive disorder
  • panic disorder
  • Premenstrual dysphoric disorder
  • Post-traumatic stress disorder (PTSD)
  • Social anxiety disorder (SAD)

Clinical Results

In clinical trials with adult patients, Zoloft demonstrated significant reduction in frequency of panic attacks without regard to age, gender or race. Patients suffering from panic disorder experience recurrent, unexpected panic attacks. The more common symptoms include heart palpitations, sensations of shortness of breath, dizziness and fear of losing control or going crazy. Panic attacks, or the fear of them, can also result in worry, concern or even dramatic behavioral and lifestyle changes.

The approval of Zoloft for the treatment of PMDD is supported by two placebo-controlled trials involving 532 women diagnosed with the disorder. Zoloft was significantly more effective in improving emotional and behavioral symptoms of PMDD than placebo, regardless if the drug was taken continously or only during the premenstrual phase of the menstrual cycle. These symptoms included feelings of being depressed, hopeless or overwhelmed, and being angry or irritable and having conflicts with others. Those who were admistered Zoloft every day also noted improvement in physical symptoms including breast tenderness, bloating and headache.

Side Effects

Adverse events associated with the use of Zoloft may include (but are not limited to) the following:

  • Upset stomach
  • Trouble sleeping
  • Diarrhea
  • Abdominal pain
  • Dry mouth
  • Sexual dysfunction

Mechanism of Action

Zoloft (sertraline HCl) is a selective serotonin reuptake inhibitor. Zoloft helps correct the chemical imbalance of serotonin in the brain. The effectiveness of Zoloft is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin (5HT). Serotonin is a naturally occurring chemical in the brain that is involved in the transmission of messages between nerve cells.

Sours: https://www.centerwatch.com/directories/1067-fda-approved-drugs/listing/4524-zoloft-sertraline-hcl

Sertraline

Continuing Education Activity

Sertraline is a medication used to manage and treat major depressive disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder, and social anxiety disorder. It is in the SSRI class of medications. This activity outlines the indications, action, and contraindications for sertraline as a valuable agent in the treatment of major depressive disorder and other disorders. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, monitoring, relevant interactions) pertinent for members of the interprofessional healthcare team in treating patients with major depressive disorder and related conditions.

Objectives:

  • Identify the mechanism of action of sertraline.

  • Describe the adverse effects of sertraline.

  • Review the appropriate monitoring for sertraline.

  • Summarize interprofessional team strategies for improving care coordination and communication to advance sertraline and improve outcomes.

Access free multiple choice questions on this topic.

Indications

Sertraline is an antidepressant used as a first-line treatment of major depressive disorder. The Food and Drug Administration (FDA) has also approved other indications for sertraline, including the treatment of obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder, and social anxiety disorder.

There are many off-label, non-FDA-approved uses for sertraline. Sertraline has been used to treat many psychiatric conditions, including binge eating disorder, body dysmorphic disorder, bulimia nervosa, generalized anxiety disorder, and premature ejaculation.[1][2][3]

Mechanism of Action

Sertraline is an antidepressant medication within the selective serotonin reuptake inhibitors (SSRIs) class. Sertraline is an antidepressant with primarily inhibitory effects on presynaptic serotonin reuptake. This inhibition of serotonin reuptake results in an accumulation of serotonin. Serotonin in the central nervous system plays a role in regulating mood, personality, and wakefulness, which is why blocking serotonin reuptake is thought to be beneficial in disorders such as major depression. Sertraline also has minimal effects on norepinephrine and dopamine uptake, and research has shown that it has more dopaminergic activity than other medications in the same SSRI class. Sertraline's mechanism of action makes it highly efficacious when used in the treatment of various psychiatric conditions.[4][5][2]

Administration

Sertraline is orally administered once daily in the morning or evening. If the patient experiences somnolence with sertraline, administer it in the evening. Available dosages in the oral tablet form are 25 mg, 50 mg, 100 mg, and solution form 20mg/ml. The absorption of sertraline may be improved when taken with food.[6]

Per FDA recommendation, the starting dose for major depressive disorder is 50 mg/day, but for PTSD, PD and ASD are 25mg/day. The sertraline dose increase in 50 mg/day increments at weekly intervals up to a maximum of 200 mg/day. Sertraline dosing is generally once daily, and administration may be at any time of the day.[7]

Adverse Effects

SSRIs, considered a newer class of antidepressants, are better tolerated than tricyclic antidepressants or monoamine oxidase inhibitors. The primary side effects of sertraline include syncope, lightheadedness, diarrhea, nausea, sweating, dizziness, xerostomia, confusion, hallucinations, tremor, somnolence, impotence, a disorder of ejaculation, fatigue, rhinitis, and female sexual disorder.

There is a bleeding risk associated with sertraline, as it may inhibit platelet aggregation. 

Sertraline can prolong the QT interval; however, the prolongation is dose-dependent and is very modest. Furthermore, this risk is higher in citalopram rather than sertraline or other SSRIs.

Sertraline may rarely produce symptoms of serotonin syndrome, though this generally happens when combining it with another serotonergic medication. These symptoms include myoclonus, muscle rigidity, diaphoresis, tremor, hyperreflexia, agitated delirium, and hyperthermia.

Sertraline, like other antidepressants, may increase the risk of suicidal ideation and behavior in children, adolescents, and young adults with major depression.

Sertraline use requires caution in patients 65 years and older. It is identified in the Beers Criteria as a high-risk medication in geriatric patients, as it may induce a syndrome of inappropriate antidiuretic hormone or hyponatremia.[5][8][9][10]

Sertraline use in the first trimester of pregnancy increased the risk of cardiovascular-related malformations such as atrial and/or ventricular septal defects in infants.[11]

Contraindications

Sertraline is contraindicated in patients with documented hypersensitivity to the drug or its components. The coadministration of sertraline with thioridazine, pimozide, or monoamine oxidase inhibitors, including linezolid or methylene blue, is also contraindicated. Patients who are taking other serotonergic medications should receive education regarding the risks of coadministration with sertraline. Sertraline is contraindicated with disulfiram only in solution form as it contains 12% alcohol, and it may cause an alcohol-disulfiram reaction.

Sertraline therapy should not start within two weeks of discontinuing any monoamine oxidase inhibitor to prevent toxicity with serotonin syndrome.

There is a US black box warning for use in pediatric patients and young adults. Use with caution in patients who are ages 18 to 24 years old due to the risk of an increase in suicidal ideation.[12]

Monitoring

It is essential to monitor patients for unusual changes in behavior, anxiety, suicidality, or any other clinical signs of worsening illness. Regularly evaluate for depression and suicidality, especially when changing the dose of sertraline. Sertraline may also precipitate mania in patients who are at risk for bipolar disorder. Monitor for symptoms of mania in patients who are started on sertraline, especially if they have a family history of mania or bipolar disorder.

Monitor for abnormal bleeding, adverse effects of medication use, or withdrawal symptoms from abrupt discontinuation in patients taking sertraline. The abnormal bleeding may primarily occur if used concurrently with aspirin, NSAIDs, warfarin, or other anticoagulants, as sertraline may impair platelet aggregation and cause bruising, epistaxis, or hemorrhage.

For geriatric patients, monitor for changes in mental status, and check their sodium concentration regularly due to the risk of SIADH or hyponatremia.

Sertraline is considered safe in patients with a history of myocardial infarction, heart failure, and other cardiac conditions. However, due to the minor effect of QT prolongation, it may benefit the provider to monitor the QT interval with electrocardiograms. 

Sertraline is also considered safe in pregnancy and with breastfeeding. Although not mandatory, therapeutic drug monitoring may be a consideration to ensure the safety of pregnant patients and infants who may have exposure to the medication.[13][14][15][16][17]

Toxicity

The overdose of sertraline is generally well-tolerated. Sertraline toxicity may result in serotonin syndrome, resulting in myoclonus, muscle rigidity, diaphoresis, tremor, hyperreflexia, agitated delirium, and hyperthermia. Treatment of serotonin syndrome requires discontinuing the medication and supportive care. Consider antiemetics (non-serotonergic), benzodiazepines, and standard cooling measures for symptom relief. The patient can also receive serotonin antagonists such as cyproheptadine. If there is severe toxicity and the patient develops muscular rigidity and hyperthermia with body temperatures higher than 41 degrees C, consider sedation, endotracheal intubation, external cooling, and neuromuscular paralysis. It is important to note that antipyretics are likely not beneficial to patients experiencing hyperthermia due to serotonin syndrome.[18]

Enhancing Healthcare Team Outcomes

Healthcare providers who often prescribe sertraline include primary care physicians, psychiatrists, nurse practitioners, and others, functioning as an interprofessional team. All healthcare team members must follow the patient regularly to monitor for the reduction of symptoms or any adverse effects. All providers should know the medication's contraindications, adverse effects, and interactions with other drugs. It is also essential to educate all patients who are prescribed sertraline on the possible adverse effects and the prevention and recognition of toxicity due to sertraline (in combination with other serotonergic drugs). Patient education regarding medication use and compliance will improve outcomes and ensure patient safety.

Patient safety can also be improved when dosing adjustments are considered by health care professionals who are a part of a patient's care team. Elderly patients may need dosing adjustments, as they may tolerate lower doses better. Patients with medical conditions affecting their liver may also need decreased doses for better tolerability. 

Clinicians require vigilance regarding the toxic effects of serotonergic medications and ensure not to prescribe multiple medications that can cause serotonin syndrome, which is possible by preventing polypharmacy and minimizing unnecessary use of these drugs; this is one of the areas where the pharmacist can provide valuable input to the team as they monitor and verify the patient's medication regimen as well as monitor dosing of sertraline and other drugs. Furthermore, should a patient need to be switched to a different serotonergic medication, physicians and other healthcare team members must ensure that no new medication starts until at least two weeks after the discontinuation of sertraline.[18] Nursing can play a significant role in this type of monitoring, ensuring patient compliance, providing counsel, assessing therapeutic effectiveness, being aware of potential adverse drug reactions, and alerting the team of any concerns. Only with this type of cohesive interprofessional team coordination can sertraline therapy provide an optimal therapeutic benefit while minimizing adverse events. [Level 5]

References

1.

Fenske JN, Schwenk TL. Obsessive compulsive disorder: diagnosis and management. Am Fam Physician. 2009 Aug 01;80(3):239-45. [PubMed: 19621834]

2.

Cipriani A, La Ferla T, Furukawa TA, Signoretti A, Nakagawa A, Churchill R, McGuire H, Barbui C. Sertraline versus other antidepressive agents for depression. Cochrane Database Syst Rev. 2010 Apr 14;(4):CD006117. [PMC free article: PMC4163971] [PubMed: 20393946]

3.

Aigner M, Treasure J, Kaye W, Kasper S., WFSBP Task Force On Eating Disorders. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of eating disorders. World J Biol Psychiatry. 2011 Sep;12(6):400-43. [PubMed: 21961502]

4.

Kitaichi Y, Inoue T, Nakagawa S, Boku S, Kakuta A, Izumi T, Koyama T. Sertraline increases extracellular levels not only of serotonin, but also of dopamine in the nucleus accumbens and striatum of rats. Eur J Pharmacol. 2010 Nov 25;647(1-3):90-6. [PubMed: 20816814]

5.

Sanchez C, Reines EH, Montgomery SA. A comparative review of escitalopram, paroxetine, and sertraline: Are they all alike? Int Clin Psychopharmacol. 2014 Jul;29(4):185-96. [PMC free article: PMC4047306] [PubMed: 24424469]

6.

Hicks JK, Bishop JR, Sangkuhl K, Müller DJ, Ji Y, Leckband SG, Leeder JS, Graham RL, Chiulli DL, LLerena A, Skaar TC, Scott SA, Stingl JC, Klein TE, Caudle KE, Gaedigk A., Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clin Pharmacol Ther. 2015 Aug;98(2):127-34. [PMC free article: PMC4512908] [PubMed: 25974703]

7.

Preskorn SH, Lane RM. Sertraline 50 mg daily: the optimal dose in the treatment of depression. Int Clin Psychopharmacol. 1995 Sep;10(3):129-41. [PubMed: 8675965]

8.

Beach SR, Kostis WJ, Celano CM, Januzzi JL, Ruskin JN, Noseworthy PA, Huffman JC. Meta-analysis of selective serotonin reuptake inhibitor-associated QTc prolongation. J Clin Psychiatry. 2014 May;75(5):e441-9. [PubMed: 24922496]

9.

By the 2019 American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatrics Society 2019 Updated AGS Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2019 Apr;67(4):674-694. [PubMed: 30693946]

10.

Varela Piñón M, Adán-Manes J. Selective Serotonin Reuptake Inhibitor-Induced Hyponatremia: Clinical Implications and Therapeutic Alternatives. Clin Neuropharmacol. 2017 Jul/Aug;40(4):177-179. [PubMed: 28622213]

11.

Shen ZQ, Gao SY, Li SX, Zhang TN, Liu CX, Lv HC, Zhang Y, Gong TT, Xu X, Ji C, Wu QJ, Li D. Sertraline use in the first trimester and risk of congenital anomalies: a systemic review and meta-analysis of cohort studies. Br J Clin Pharmacol. 2017 Apr;83(4):909-922. [PMC free article: PMC5346877] [PubMed: 27770542]

12.

DeVane CL, Liston HL, Markowitz JS. Clinical pharmacokinetics of sertraline. Clin Pharmacokinet. 2002;41(15):1247-66. [PubMed: 12452737]

13.

Glassman AH, O'Connor CM, Califf RM, Swedberg K, Schwartz P, Bigger JT, Krishnan KR, van Zyl LT, Swenson JR, Finkel MS, Landau C, Shapiro PA, Pepine CJ, Mardekian J, Harrison WM, Barton D, Mclvor M., Sertraline Antidepressant Heart Attack Randomized Trial (SADHEART) Group. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA. 2002 Aug 14;288(6):701-9. [PubMed: 12169073]

14.

O'Connor CM, Jiang W, Kuchibhatla M, Silva SG, Cuffe MS, Callwood DD, Zakhary B, Stough WG, Arias RM, Rivelli SK, Krishnan R., SADHART-CHF Investigators. Safety and efficacy of sertraline for depression in patients with heart failure: results of the SADHART-CHF (Sertraline Against Depression and Heart Disease in Chronic Heart Failure) trial. J Am Coll Cardiol. 2010 Aug 24;56(9):692-9. [PMC free article: PMC3663330] [PubMed: 20723799]

15.

Paulzen M, Goecke TW, Stickeler E, Gründer G, Schoretsanitis G. Sertraline in pregnancy - Therapeutic drug monitoring in maternal blood, amniotic fluid and cord blood. J Affect Disord. 2017 Apr 01;212:1-6. [PubMed: 28129551]

16.

Pinheiro E, Bogen DL, Hoxha D, Ciolino JD, Wisner KL. Sertraline and breastfeeding: review and meta-analysis. Arch Womens Ment Health. 2015 Apr;18(2):139-146. [PMC free article: PMC4366287] [PubMed: 25589155]

17.

Leverich GS, Altshuler LL, Frye MA, Suppes T, McElroy SL, Keck PE, Kupka RW, Denicoff KD, Nolen WA, Grunze H, Martinez MI, Post RM. Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. Am J Psychiatry. 2006 Feb;163(2):232-9. [PubMed: 16449476]

18.

Wang RZ, Vashistha V, Kaur S, Houchens NW. Serotonin syndrome: Preventing, recognizing, and treating it. Cleve Clin J Med. 2016 Nov;83(11):810-817. [PubMed: 27824534]

Sours: https://www.ncbi.nlm.nih.gov/books/NBK547689/
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Sertraline

Antidepressant medication

"Lustral" redirects here. For other uses, see Lustral (disambiguation).

Sertraline.svg
Sertraline-A-3D-balls.png
Pronunciation
Trade namesAmy, Lustral, others[1]
AHFS/Drugs.comMonograph
MedlinePlusa697048
License data
Pregnancy
category
Addiction
liability
None[3]
Routes of
administration
By mouth
Drug classSelective serotonin reuptake inhibitor (SSRI) but also rarely used as SDRI
ATC code
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Bioavailability44%
Protein binding98.5%
MetabolismLiver (N-demethylation mainly by CYP2B6)[9]
Metabolitesnorsertraline
Elimination half-life~23–26 h (66 h [less-active[4] metabolite, norsertraline])[5][6][7][8]
ExcretionKidney

IUPAC name

  • (1S,4S)-4-(3,4-Dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine

CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
FormulaC17H17Cl2N
Molar mass306.23 g·mol−1
3D model (JSmol)

SMILES

InChI

  • InChI=1S/C17H17Cl2N/c1-20-17-9-7-12(13-4-2-3-5-14(13)17)11-6-8-15(18)16(19)10-11/h2-6,8,10,12,17,20H,7,9H2,1H3/t12-,17-/m0/s1 checkY
  • Key:VGKDLMBJGBXTGI-SJCJKPOMSA-N checkY
  (verify)

Sertraline, sold under the brand name Zoloft among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class.[10] The efficacy of sertraline for depression is similar to that of other antidepressants, and the differences are mostly confined to side effects. Sertraline is better tolerated than the older tricyclic antidepressants, and it may work better than fluoxetine for some subtypes of depression. Sertraline is effective for panic disorder, social anxiety disorder, generalized anxiety disorder, and obsessive–compulsive disorder (OCD). However, for OCD, cognitive behavioral therapy, particularly in combination with sertraline, is a better treatment. Although approved for post-traumatic stress disorder, sertraline leads to only modest improvement in this condition.[11][12] Sertraline also alleviates the symptoms of premenstrual dysphoric disorder and can be used in sub-therapeutic doses or intermittently for its treatment.[13]

Sertraline shares the common side effects and contraindications of other SSRIs, with high rates of nausea, diarrhea, insomnia, and sexual side effects, but it appears not to lead to much weight gain, and its effects on cognitive performance are mild. Similar to other antidepressants, the use of sertraline for depression may be associated with a higher rate of suicidal thoughts and behavior in people under the age of 25. It should not be used together with MAO inhibitor medication: this combination causes serotonin syndrome. Sertraline taken during pregnancy is associated with a significant increase in congenital heart defects in newborns.[14][15]

Sertraline was invented and developed by scientists at Pfizer and approved for medical use in the United States in 1991. It is on the World Health Organization's List of Essential Medicines.[16] It is available as a generic medication.[10] In 2016, sertraline was the most commonly prescribed psychiatric medication in the United States[17] and in 2018, it was the fourteenth most commonly prescribed medication in the United States, with over 38 million prescriptions.[18][19]

Medical uses[edit]

Sertraline has been approved for major depressive disorder (MDD), obsessive–compulsive disorder (OCD), posttraumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), panic disorder, and social anxiety disorder (SAD). Sertraline is not approved for use in children except for those with OCD.[20]

Depression[edit]

Multiple controlled clinical trials established efficacy of sertraline for the treatment of depression. Sertraline is also an effective antidepressant in the routine clinical practice. Continued treatment with sertraline prevents both a relapse of the current depressive episode and future episodes (recurrence of depression).[21]

In several double-blind studies, sertraline was consistently more effective than placebo for dysthymia, a more chronic variety of depression, and comparable to imipramine in that respect. Sertraline also improves the depression of dysthymic patients to a greater degree than psychotherapy.[21]

Sertraline provides no benefit to children and adolescents with depression.[22]

Comparison with other antidepressants[edit]

In general, sertraline efficacy is similar to that of other antidepressants.[23] For example, a meta-analysis of 12 new-generation antidepressants showed that sertraline and escitalopram are the best in terms of efficacy and acceptability in the acute-phase treatment of adults with depression.[24] Comparative clinical trials demonstrated that sertraline is similar in efficacy against depression to moclobemide,[25]nefazodone,[26]escitalopram, bupropion,[27]citalopram, fluvoxamine, paroxetine,[24] venlafaxine[28] and mirtazapine.[29] Sertraline may be more efficacious for the treatment of depression in the acute phase (first 4 weeks) than fluoxetine.[30]

There are differences between sertraline and some other antidepressants in their efficacy in the treatment of different subtypes of depression and in their adverse effects. For severe depression, sertraline is as good as clomipramine but is better tolerated.[28] Sertraline appears to work better in melancholic depression than fluoxetine, paroxetine, and mianserin and is similar to the tricyclic antidepressants such as amitriptyline and clomipramine.[23] In the treatment of depression accompanied by OCD, sertraline performs significantly better than desipramine on the measures of both OCD and depression.[21][31] Sertraline is equivalent to imipramine for the treatment of depression with co-morbid panic disorder, but it is better tolerated.[32] Compared with amitriptyline, sertraline offered a greater overall improvement in quality of life of depressed patients.[23]

Depression in elderly[edit]

Sertraline used for the treatment of depression in elderly (older than 60) patients is superior to placebo and comparable to another SSRI fluoxetine, and tricyclic antidepressants (TCAs) amitriptyline, nortriptyline and imipramine. Sertraline has much lower rates of adverse effects than these TCAs, with the exception of nausea, which occurs more frequently with sertraline. In addition, sertraline appears to be more effective than fluoxetine or nortriptyline in the older-than-70 subgroup.[33] Accordingly, a meta-analysis of antidepressants in older adults found that sertraline, paroxetine and duloxetine were better than placebo.[34] On the other hand, in a 2003 trial the effect size was modest, and there was no improvement in quality of life as compared to placebo.[35] With depression in dementia, there is no benefit of sertraline treatment compared to either placebo or mirtazapine.[36]

Obsessive–compulsive disorder[edit]

Sertraline is effective for the treatment of OCD in adults and children.[20][37] It was better tolerated and, based on intention-to-treat analysis, performed better than the gold standard of OCD treatment clomipramine.[38] Continuing sertraline treatment helps prevent relapses of OCD with long-term data supporting its use for up to 24 months.[39] It is generally accepted that the sertraline dosages necessary for the effective treatment of OCD are higher than the usual dosage for depression.[40] The onset of action is also slower for OCD than for depression. The treatment recommendation is to start treatment with a half of maximal recommended dose for at least two months. After that, the dose can be raised to the maximal recommended in the cases of unsatisfactory response.[41]

Cognitive behavioral therapy alone was superior to sertraline in both adults and children; however, the best results were achieved using a combination of these treatments.[42][43]

Panic disorder[edit]

Sertraline is superior to placebo for the treatment of panic disorder.[20] The response rate was independent of the dose. 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.[44][45] Sertraline is equally effective for men and women,[45] and for patients with or without agoraphobia.[46] Previous unsuccessful treatment with benzodiazepines does not diminish its efficacy.[47] However, the response rate was lower for the patients with more severe panic.[46] Starting treatment simultaneously with sertraline and clonazepam, with subsequent gradual discontinuation of clonazepam, may accelerate the response.[48]

Double-blind comparative studies found sertraline to have the same effect on panic disorder as paroxetine or imipramine.[49] While imprecise, comparison of the results of trials of sertraline with separate trials of other anti-panic agents (clomipramine, imipramine, clonazepam, alprazolam, and fluvoxamine) indicates approximate equivalence of these medications.[44]

Other anxiety disorders[edit]

Sertraline has been successfully used for the treatment of social anxiety disorder.[50][51] All three major domains of the disorder (fear, avoidance, and physiological symptoms) respond to sertraline.[21] Maintenance treatment, after the response is achieved, prevents the return of the symptoms.[52] The improvement is greater among the patients with later, adult onset of the disorder.[53] In a comparison trial, sertraline was superior to exposure therapy, but patients treated with the psychological intervention continued to improve during a year-long follow-up, while those treated with sertraline deteriorated after treatment termination.[54] The combination of sertraline and cognitive behavioral therapy appears to be more effective in children and young people than either treatment alone.[55]

Sertraline has not been approved for the treatment of generalized anxiety disorder; however, several guidelines recommend it as a first-line medication referring to good quality controlled clinical trials.[56][32][39]

Premenstrual dysphoric disorder[edit]

Sertraline is effective in alleviating the symptoms of premenstrual dysphoric disorder (PMDD), a severe form of premenstrual syndrome.[57] 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.[58][59] Taking sertraline only during the luteal phase, that is, the 12–14 days before menses, was shown to work as well as continuous treatment.[57] Continuous treatment with sub-therapeutic doses of sertraline (25 mg vs. usual 50–100 mg) is also effective.[60]

Other indications[edit]

Sertraline is approved for the treatment of post-traumatic stress disorder (PTSD).[20]National Institute of Clinical Excellence recommends it for patients who prefer drug treatment to a psychological one.[61] Other guidelines also suggest sertraline as a first-line option for pharmacological therapy.[62][32] When necessary, long-term pharmacotherapy can be beneficial.[62] There are both negative and positive clinical trial results for sertraline, which may be explained by the types of psychological traumas, symptoms, and comorbidities included in the various studies.[39] Positive results were obtained in trials that included predominantly women (75%) with a majority (60%) having physical or sexual assault as the traumatic event.[62] Contrary to the above suggestions, a meta-analysis of sertraline clinical trials for PTSD found it to be not significantly better than placebo.[11] Another meta-analysis relegated sertraline to the second line, proposing trauma focused psychotherapy as a first-line intervention. The authors noted that Pfizer had declined to submit the results of a negative trial for the inclusion into the meta-analysis making the results unreliable.[12]

Sertraline when taken daily can be useful for the treatment of premature ejaculation.[63] A disadvantage of sertraline is that it requires continuous daily treatment to delay ejaculation significantly.[64]

A 2019 systematic review suggested that sertraline may be a good way to control anger, irritability and hostility in depressed patients and patients with other comorbidities.[65]

Contraindications[edit]

Sertraline is contraindicated in individuals taking monoamine oxidase inhibitors or the antipsychotic pimozide. Sertraline concentrate contains alcohol and is therefore contraindicated with disulfiram. 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.[20]

[edit]

See also: List of adverse effects of sertraline

Nausea, ejaculation failure, insomnia, diarrhea, dry mouth, somnolence, dizziness, tremor, and decreased libido are the common adverse effects associated with sertraline with the greatest difference from placebo. Those that most often resulted in interruption of the treatment are nausea, diarrhea and insomnia.[20] The incidence of diarrhea is higher with sertraline—especially when prescribed at higher doses—in comparison with other SSRIs.[66]

Over more than six months of sertraline therapy for depression, people showed a nonsignificant weight increase of 0.1%.[67] Similarly, a 30-month-long treatment with sertraline for OCD resulted in a mean weight gain of 1.5% (1 kg).[68] Although the difference did not reach statistical significance, the average weight gain was lower for fluoxetine (1%) but higher for citalopram, fluvoxamine and paroxetine (2.5%). Of the sertraline group, 4.5% 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.[68]

Over a two-week treatment of healthy volunteers, sertraline slightly improved verbal fluency but did not affect word learning, short-term memory, vigilance, flicker fusion time, choice reaction time, memory span, or psychomotor coordination.[69][70] 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 years as compared to healthy controls.[71] In children and adolescents taking sertraline for six weeks for anxiety disorders, 18 out of 20 measures of memory, attention and alertness stayed unchanged. Divided attention was improved and verbal memory under interference conditions decreased marginally. Because of the large number of measures taken, it is possible that these changes were still due to chance.[72] The unique effect of sertraline on dopaminergicneurotransmission may be related to these effects on cognition and vigilance.[73][74]

Sertraline has a low level of exposure of an infant through the breast milk and is recommended as the preferred option for the antidepressant therapy of breast-feeding mothers.[75][76] There is 29-42% increase in congenital heart defects among children whose mothers were prescribed sertraline during pregnancy,[14][15] with sertraline use in the first trimester associated with 2.7-fold increase in septal heart defects.[14]

Abrupt interruption of sertraline treatment may result in withdrawal or discontinuation syndrome. Dizziness, insomnia, anxiety, agitation, and irritability are its common symptoms.[77] It typically occurs within a few days from drug discontinuation and lasts a few weeks.[78] The withdrawal symptoms for sertraline are less severe and frequent than for paroxetine, and more frequent than for fluoxetine.[77][78] In most cases symptoms are mild, short-lived, and resolve without treatment. More severe cases are often successfully treated by temporary reintroduction of the drug with a slower tapering off rate.[79]

Sertraline and SSRI antidepressants in general may be associated with bruxism and other movement disorders.[80][81] Sertraline appears to be associated with microscopic colitis, a rare condition of unknown etiology.[82]

Sexual[edit]

Like other SSRIs, sertraline is associated with sexual side effects, including sexual arousal disorder, erectile dysfunction and difficulty achieving orgasm. While nefazodone and bupropion do not have negative effects on sexual functioning, 67% of men on sertraline experienced ejaculation difficulties versus 18% before the treatment.[83]Sexual arousal disorder, defined as "inadequate lubrication and swelling for women and erectile difficulties for men", occurred in 12% of people on sertraline as compared with 1% of patients on placebo. The mood improvement resulting from the treatment with sertraline sometimes 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.[84] Some people continue experiencing sexual side effects after they stop taking SSRIs.[85]

Suicide[edit]

The FDA requires all antidepressants, including sertraline, to carry a boxed warning stating that antidepressants increase the risk of suicide in persons younger than 25 years. This warning is based on statistical analyses conducted by two independent groups of FDA experts that found a 100% increase of suicidal thoughts and behavior in children and adolescents, and a 50% increase - in the 18 – 24 age group.[86][87][88]

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 suicidal behavior with a marginal statistical significance by 37%[88] or 50%[87] 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".[87] The more complete data submitted later by the sertraline manufacturer Pfizer indicated increased suicidal behavior.[89] Similarly, the analysis conducted by the UK 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.[90][91]

Overdose[edit]

Acute overdosage is often manifested by emesis, lethargy, ataxia, tachycardia and seizures. Plasma, serum or blood concentrations of sertraline and norsertraline, its major active metabolite, may be measured to confirm a diagnosis of poisoning in hospitalized patients or to aid in the medicolegal investigation of fatalities.[92] As with most other SSRIs its toxicity in overdose is considered relatively low.[93][94]

Interactions[edit]

Sertraline is a moderate inhibitor of CYP2D6 and CYP2B6in vitro.[6] Accordingly, in human trials it caused increased blood levels of CYP2D6 substrates such as metoprolol, dextromethorphan, desipramine, imipramine and nortriptyline, as well as the CYP3A4/CYP2D6 substrate haloperidol.[95][96][97] 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.[7][98] 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.[99]

Sertraline had a slight inhibitory effect on the metabolism of diazepam, tolbutamide and warfarin, which are CYP2C9 or CYP2C19 substrates; the clinical relevance of this effect was unclear.[7] As expected from in vitro data, sertraline did not alter the human metabolism of the CYP3A4 substrates erythromycin, alprazolam, carbamazepine, clonazepam, and terfenadine; neither did it affect metabolism of the CYP1A2 substrate clozapine.[7][20][8][6]

Sertraline had no effect on the actions of digoxin and atenolol, which are not metabolized in the liver.[4]Case reports suggest that taking sertraline with phenytoin or zolpidem may induce sertraline metabolism and decrease its efficacy,[100][101] and that taking sertraline with lamotrigine may increase the blood level of lamotrigine, possibly by inhibition of glucuronidation.[102]

CYP2C19 inhibitor esomeprazole increased sertraline concentrations in blood plasma by approximately 40%.[103]

Clinical reports indicate that interaction between sertraline and the MAOIsisocarboxazid and tranylcypromine may cause serotonin syndrome. In a placebo-controlled study in which sertraline was co-administered with lithium, 35% of the subjects experienced tremors, while none of those taking placebo did.[7]

Sertraline may interact with grapefruit juice - see Grapefruit–drug interactions.

Pharmacology[edit]

Pharmacodynamics[edit]

SiteKi (nM)SpeciesReferences
SERT0.15-3.3Human[105][106][107]
NET420-925Human[105][106][107]
DAT22-315Human[105][106][107]
5-HT1A>35,000Human[108]
5-HT2A2,207Rat[107]
5-HT2C2,298Pig[107]
α1A1900Human[109]
α1B3500Human[109]
α1D2500Human[109]
α2477–4,100Human[106][108]
D210,700Human[108]
H124,000Human[108]
mACh427–2,100Human[107][108][110]
σ132–57Rat[111][112]
σ25,297Rat[112]
Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to or inhibits the site.

Sertraline is a selective serotonin reuptake inhibitor (SSRI). By binding serotonin transporter (SERT) it inhibits neuronal reuptake of serotonin and potentiates serotonergic activity in the central nervous system.[20] It does not significantly affect norepinephrine transporter (NET), serotonin, dopamine, adrenergic, histamine, acetylcholine, GABA or benzodiazepine receptors.[20]

Sertraline also shows relatively high activity as an inhibitor of the dopamine transporter (DAT)[105][113][114] and antagonist of the sigmaσ1 receptor (but not the σ2 receptor).[111][112][115] However, sertraline affinity for its main target (SERT) is much greater than its affinity for σ1 receptor and DAT.[104][105][112][111] Although there could be a role for the σ1 receptor in the pharmacology of sertraline, the significance of this receptor in its actions is unclear.[23] Similarly, the clinical relevance of sertraline's blockade of the dopamine transporter is uncertain.[105]

Pharmacokinetics[edit]

Desmethylsertraline—sertraline's major metabolite

Sertraline is absorbed slowly when taken orally, achieving its maximal concentration in the plasma 4 to 6 hours after ingestion. In the blood, it is 98.5% 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.[7] According to in vitro studies, sertraline is metabolized by multiple cytochrome 450isoforms;[9][116] however, it appears that in the human body CYP2C19 plays the most important role, followed by CYP2B6.[117] Poor CYP2C19 metabolizers have 2.7-fold higher levels of sertraline,[118] and intermediate metabolizers - 1.4-fold higher levels,[119] than normal (extensive) metabolizers. In contrast, poor CYP2B6 metabolizers have 1.6-fold higher levels of sertraline and intermediate metabolizers - 1.2-fold higher levels.[117]

The major metabolite of sertraline, desmethylsertraline, is about 50 times weaker as a serotonin transporter inhibitor than sertraline and its clinical effect is negligible.[106] Sertraline can be deaminatedin vitro by monoamine oxidases; however, this metabolic pathway has never been studied in vivo.[9]

History[edit]

Skeletal formulaeof thiothixene, lometraline and tametraline, from which sertraline was derived. Commonalities to the structure of sertraline are highlighted in green.

The history of sertraline dates back to the early 1970s, when Pfizer chemist Reinhard Sarges invented a novel series of psychoactive compounds, including lometraline, based on the structures of the neuroleptics thiothixene and pinoxepin.[120][121] Further work on these compounds led to tametraline, a 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 triple reuptake inhibitors, but to the surprise of the scientists, one representative of the generally inactive cis-analogs was a serotonin reuptake inhibitor. Welch then prepared 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 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.[120][122][123]

Sertraline was approved by the US 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.[124] The FDA committee achieved a consensus that sertraline was safe and effective for the treatment of major depression. During the discussion, Paul Leber, the director of the FDA Division of Neuropharmacological Drug Products, noted that granting approval was a "tough decision", since the treatment effect on 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 clinical trials by Pfizer.[125] For example, 40% of participants dropped out of the trials, significantly decreasing their validity.[126]

Until 2002, 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 OCD. In 2003, the UK Medicines and Healthcare products Regulatory Agency issued a guidance that, apart from fluoxetine (Prozac), SSRIs are not suitable for the treatment of depression in patients under 18.[127][128] However, sertraline can still be used in the UK for the treatment of OCD in children and adolescents.[129] In 2005, the FDA added a boxed warning concerning pediatric suicidal behavior to all antidepressants, including sertraline. In 2007, labeling was again changed to add a warning regarding suicidal behavior in young adults ages 18 to 24.[130]

Society and culture[edit]

Generic availability[edit]

The US patent for Zoloft expired in 2006,[131] and sertraline is available in generic form and is marketed under many brand names worldwide.[1]

In May 2020, the FDA placed Zoloft on the list of drugs currently facing a shortage.[132]

See also[edit]

References[edit]

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Sours: https://en.wikipedia.org/wiki/Sertraline
Pharmacology - ANTIDEPRESSANTS - SSRIs, SNRIs, TCAs, MAOIs, Lithium ( MADE EASY)

Svetlana knew how to speak convincingly, combining affection and firmness. And if she decided something, then I still had no choice, and it will be exactly as she wants. - Forgive madam. I apologized, glancing briefly at my adamant queen. - Henceforth, so that I no longer see such a sour face, of course.

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This time it was equipped with a flash. - Stand up straight and freeze - she ordered, taking the camera at the ready. Click.

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In what mode did you turn on the wash. I blushed even more and said that the machine was broken. After a short pause, Lena narrowed her eyes, smiled bitterly and asked: - did you wash everything with your hands. - Yes.

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She probably didn't shave her vagina. She quietly said that she needed to go, she removed her fingers from my vagina. I sat down on the floor, I was very pleased when I raised my eyes, they looked directly under the skirt. Of this woman. She also had silk lace white panties.



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