Сертралин

Источники

1. Регуляторное

   Viatris Specialty LLC. ZOLOFT (sertraline hydrochloride) tablets, for oral use; ZOLOFT (sertraline hydrochloride) oral solution: full prescribing information US Food and Drug Administration-approved labelling, published in DailyMed (National Library of Medicine); structured product label version 7, published 24 July 2025, label text revised 8/2023; initial US approval 1991, 2025.

   https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fda754f6-d0f3-4dce-a17a-927d64f912f7

   Финансирование и результат

   Финансирование

   not stated. The document is prescribing information approved by the US Food and Drug Administration and published by the labeller, Viatris Specialty LLC.

   Результат

   Indicated for major depressive disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, social anxiety disorder and premenstrual dysphoric disorder; starting dose 50 mg per day for major depressive disorder, maximum 200 mg per day. Sertraline potentiates serotonergic activity in the central nervous system through inhibition of neuronal reuptake of serotonin; at clinically relevant doses it blocks the uptake of serotonin into human platelets; in vitro studies in animals suggest potent and selective inhibition of neuronal serotonin reuptake with only very weak effects on norepinephrine and dopamine reuptake; no significant affinity for adrenergic, cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2) or benzodiazepine receptors; does not inhibit monoamine oxidase. Peak plasma concentrations 4.5 to 8.4 hours after dosing; average terminal elimination half-life about 26 hours; steady state after one week of once-daily dosing; 98% bound to serum proteins. Extensive first-pass metabolism; the principal initial pathway is N-demethylation; N-desmethylsertraline is substantially less active and has a terminal half-life of 62 to 104 hours. Drugs that interfere with serotonin reuptake, including sertraline, increase the risk of bleeding events, and aspirin, NSAIDs, other antiplatelet drugs, warfarin and other anticoagulants may add to this risk. Hyponatraemia may occur with SSRIs and SNRIs; in many cases it appears to result from the syndrome of inappropriate antidiuretic hormone secretion; elderly patients, patients taking diuretics and volume-depleted patients may be at greater risk. Adverse reactions after discontinuation, particularly abrupt discontinuation, include nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances such as electric shock sensations, tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus and seizures; gradual dose reduction rather than abrupt cessation is recommended whenever possible, and patients are advised not to stop abruptly and to discuss any tapering regimen with their healthcare provider. In pooled randomised placebo-controlled trials in 3066 adults exposed to sertraline for 8 to 12 weeks across six indications: nausea 26% against 12% on placebo (n=2293), diarrhoea or loose stools 20% against 10%, ejaculation failure 8% against 1% of men; 368 of 3066 (12%) discontinued for an adverse reaction against 93 of 2293 (4%) on placebo.

2. Регуляторное

   Viatris Specialty LLC. ZOLOFT (sertraline hydrochloride) tablets, for oral use; ZOLOFT (sertraline hydrochloride) oral solution: full prescribing information US Food and Drug Administration-approved labelling, published in DailyMed (National Library of Medicine); structured product label version 7, published 24 July 2025, effective 8 August 2023; boxed warning and sections 5, 6, 8, 10, 12.2 and 14, 2025.

   https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fda754f6-d0f3-4dce-a17a-927d64f912f7

   Финансирование и результат

   Финансирование

   not stated. The document is prescribing information approved by the US Food and Drug Administration and published by the labeller, Viatris Specialty LLC.

   Результат

   Boxed warning: antidepressants increased the risk of suicidal thoughts and behaviours in paediatric and young adult patients in short-term studies. In pooled placebo-controlled trials of antidepressants in about 77,000 adults and over 4,400 paediatric patients, drug-placebo differences in patients with suicidal thoughts or behaviours per 1000 treated were 14 more under 18 years, 5 more at 18 to 24, 1 fewer at 25 to 64 and 6 fewer at 65 or older; no suicides occurred in paediatric studies; whether the risk extends beyond four months is unknown. Warnings: serotonin syndrome, potentially life-threatening, also when SSRIs are used alone; increased risk of bleeding events from ecchymosis to life-threatening haemorrhage, to which aspirin, NSAIDs, antiplatelet drugs and anticoagulants may add, and a less than 2-fold increase in postpartum haemorrhage with exposure in the month before delivery; mania or hypomania in 0.4% of sertraline-treated patients in trials that generally excluded bipolar disorder; discontinuation reactions including dizziness, electric shock sensations, anxiety, confusion, hypomania and seizures; seizures (patients with seizure history excluded from trials); angle-closure attack from pupillary dilation in people with untreated narrow angles; hyponatraemia, with serum sodium below 110 mmol/L reported and severe cases with seizure, coma, respiratory arrest and death, often through SIADH, with elderly, diuretic-treated and volume-depleted patients possibly at greater risk; QTc prolongation and torsade de pointes reported after marketing, and in a thorough QTc study in 54 healthy adults at twice the maximum dose (about 3-fold steady-state exposure) the largest mean placebo-corrected QTc increase was 10 ms (upper 90% bound 12 ms); sexual dysfunction (ejaculatory delay or failure, decreased libido, erectile dysfunction, delayed or absent orgasm), which may not be spontaneously reported. In pooled 8- to 12-week trials (3066 sertraline, 2293 placebo): insomnia 20% against 13%, somnolence 11% against 6%, decreased appetite 7% against 2%, tremor 9% against 2%, hyperhidrosis 7% against 3%; in men (1316 against 973) ejaculation failure 8% against 1%, decreased libido 7% against 2%, erectile dysfunction 4% against 1%; in women (1750 against 1320) decreased libido 4% against 2%; the label states that these estimates may underestimate the actual incidence of sexual adverse experiences. Paediatric MDD trials (n=373, 10 weeks): about 1 kg weight difference, weight loss above 7% in about 7% of sertraline-treated children against 0% on placebo. Galactorrhoea is listed among premarketing adverse reactions with an incidence below 2%. Postmarketing reports include hyperprolactinaemia, gynaecomastia, SIADH, severe liver events including fatal liver failure, pancreatitis, agranulocytosis, aplastic anaemia, thrombocytopenia, Stevens-Johnson syndrome and toxic epidermal necrolysis, reversible cerebral vasoconstriction syndrome, pulmonary hypertension and rhabdomyolysis. Third-trimester exposure: neonatal complications requiring prolonged hospitalisation, respiratory support and tube feeding, and persistent pulmonary hypertension of the newborn (background 1 to 2 per 1000 live births). Overdose: seizures, coma, QRS and QTc prolongation, serotonin syndrome. Efficacy in MDD rests on two short-term trials (6 and 8 weeks) and one randomised withdrawal trial in which 295 responders to 8 weeks of open sertraline continued sertraline or switched to placebo for 44 weeks: relapse 11 (8%) against 31 (39%). In two further PTSD trials sertraline did not differ significantly from placebo; post hoc analyses showed essentially no effect in men.

3. Независимое

   Coupland C, Dhiman P, Morriss R, Arthur A, Barton G, Hippisley-Cox J. Antidepressant use and risk of adverse outcomes in older people: population based cohort study BMJ, 2011.

   doi:10.1136/bmj.d4551PubMed 21810886

   Финансирование и результат

   Участники

   60 746

   Наблюдение

   new depression diagnoses from 1996 to 2007, followed to 31 December 2008; absolute risks estimated at 1 year

   Финансирование

   This project was funded by the NIHR Health Technology Assessment Programme (project number 06/42/01).

   Результат

   Adjusted hazard ratios for SSRIs against no antidepressant use: upper gastrointestinal bleeding 1.22 (95% CI 1.07 to 1.40), hyponatraemia 1.52 (1.33 to 1.75). Adjusted absolute risks over 1 year: upper gastrointestinal bleeding 0.42% without antidepressants, 0.51% with SSRIs, 0.44% with sertraline; hyponatraemia 0.29% without antidepressants, 0.44% with SSRIs, 0.29% with sertraline. Citalopram, escitalopram and fluoxetine were associated with significantly increased risks of hyponatraemia, paroxetine and sertraline were not. Observational design susceptible to confounding by indication, channelling bias and residual confounding.

4. Независимое

   Renoux C, Vahey S, Dell'Aniello S, Boivin JF. Association of Selective Serotonin Reuptake Inhibitors With the Risk for Spontaneous Intracranial Hemorrhage JAMA Neurology, 2017.

   doi:10.1001/jamaneurol.2016.4529PubMed 27918771

   Финансирование и результат

   Участники

   1 363 990

   Наблюдение

   mean 5.8 years, 1995 to 2014

   Финансирование

   This study was supported by operating grant MOP-133553 from the Canadian Institutes of Health Research and a Chercheur-Boursier Award from the Fonds de la Recherche en Santé du Québec. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

   Результат

   Overall incidence of intracranial haemorrhage 3.8 per 10,000 person-years. Current SSRI use against tricyclic use: RR 1.17 (95% CI 1.02 to 1.35), an absolute excess of 6.7 (0.2 to 13.2) per 100,000 person-years; first 30 days RR 1.44 (1.04 to 1.99). Strong against weak serotonin reuptake inhibitors RR 1.25 (1.01 to 1.54), excess 9.5 per 100,000 person-years; among users of oral anticoagulants RR 3.08 (0.89 to 10.63) with sampled controls and 1.73 (0.89 to 3.39) with all controls, neither statistically significant. Against non-use, SSRIs RR 1.35 (1.22 to 1.50).

5. Регуляторное

   Medicines and Healthcare products Regulatory Agency. SSRI/SNRI antidepressant medicines: small increased risk of postpartum haemorrhage when used in the month before delivery Drug Safety Update volume 14, issue 6, January 2021: 5, 2021.

   https://www.gov.uk/drug-safety-update/ssri-slash-snri-antidepressant-medicines-small-increased-risk-of-postpartum-haemorrhage-when-used-in-the-month-before-delivery

   Финансирование и результат

   Финансирование

   not stated; a safety communication of the UK medicines regulator

   Результат

   Published 7 January 2021. SSRIs and SNRIs increase bleeding risk, thought to be through a serotonergic effect impairing platelet aggregation. After an EU review (PRAC, September to October 2020) of observational studies, use in the month before delivery was estimated to increase the risk of postpartum haemorrhage by less than two-fold; background rates in Europe in one study were 12.7% for blood loss over 500 mL and 2.8% over 1000 mL; severity was not reported, and no fatalities were flagged in the European dataset. The review found sufficient evidence to update the product information for citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, desvenlafaxine, milnacipran, venlafaxine and vortioxetine, and the MHRA stated that warnings were being added. The update restates the association with persistent pulmonary hypertension of the newborn and neonatal withdrawal and toxicity reactions.

6. Независимое

   Coupland C, Dhiman P, Morriss R, Arthur A, Barton G, Hippisley-Cox J. Antidepressant use and risk of adverse outcomes in older people: population based cohort study BMJ, 2011.

   doi:10.1136/bmj.d4551PubMed 21810886

   Финансирование и результат

   Участники

   60 746

   Наблюдение

   new depression diagnoses from 1996 to 2007, followed to 31 December 2008; absolute risks estimated at 1 year

   Финансирование

   This project was funded by the NIHR Health Technology Assessment Programme (project number 06/42/01).

   Результат

   Adjusted hazard ratios for SSRIs against no antidepressant use: falls 1.66 (95% CI 1.58 to 1.73; 3575 events), fracture 1.58 (1.48 to 1.68), all-cause mortality 1.54 (1.48 to 1.59), attempted suicide or self-harm 2.16 (1.71 to 2.71), stroke or TIA 1.17 (1.10 to 1.26), epilepsy or seizures 1.83 (1.49 to 2.26). Adjusted absolute risks over 1 year without antidepressants against sertraline: falls 3.46% against 5.57%, fracture 1.76% against 2.80%, all-cause mortality 7.04% against 10.20%, seizures 0.21% against 0.55%, stroke or TIA 2.23% against 2.70%, adverse drug reactions 0.26% against 0.42%. For most outcomes, risks were highest in the first 28 days of use and the first 28 days after stopping; the authors suggest that the rise after stopping may reflect illness or admission to hospital or a residential home that prompted stopping. Observational design susceptible to confounding by indication, channelling bias and residual confounding.

7. Регуляторное

   European Medicines Agency, Pharmacovigilance Risk Assessment Committee. PRAC recommendations on signals adopted at the 13-16 May 2019 PRAC meeting European Medicines Agency, EMA/PRAC/265212/2019, 2019.

   https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-13-16-may-2019-prac-meeting_en.pdf

   Финансирование и результат

   Финансирование

   not stated; a recommendation of the EU medicines regulator's pharmacovigilance committee

   Результат

   Signal 1.3 (EPITT 19277), adopted 16 May 2019: having considered EudraVigilance, literature, social media and cumulative reviews from marketing authorisation holders, PRAC required holders of products containing citalopram, escitalopram, fluvoxamine, fluoxetine, paroxetine and sertraline, and the SNRIs duloxetine, venlafaxine, desvenlafaxine and milnacipran, to add to SmPC section 4.4: 'SSRIs/SNRIs may cause symptoms of sexual dysfunction. There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs/SNRI', and to the package leaflet that in some cases these symptoms have continued after stopping treatment. Signal 1.4 (EPITT 19341): maculopathy added to the sertraline SmPC section 4.8 with frequency not known, and partial loss of vision to the leaflet.

8. Независимое

   Grigoriadis S, Vonderporten EH, Mamisashvili L, Tomlinson G, Dennis CL, Koren G, et al. Prenatal exposure to antidepressants and persistent pulmonary hypertension of the newborn: systematic review and meta-analysis BMJ, 2014.

   doi:10.1136/bmj.f6932PubMed 24429387

   Финансирование и результат

   Финансирование

   This study was funded by a research syntheses grant from the Canadian Institutes of Health Research (KRS-83127) and the Ontario Ministry of Health and Long-Term Care through the Drug Innovation Fund (grant No 2008-005). The funding sources had no role in the study design; collection, analysis, or interpretation of results; writing of the manuscript; or submission of the manuscript for publication.

   Результат

   SSRI exposure in early pregnancy was not associated with persistent pulmonary hypertension of the newborn (OR 1.23, 95% CI 0.58 to 2.60); exposure in late pregnancy was (OR 2.50, 1.32 to 4.73). Absolute risk difference 2.9 to 3.5 per 1000 infants; 286 to 351 women treated with an SSRI in late pregnancy for one additional case.

9. Независимое

   Henssler J, Schmidt Y, Schmidt U, Schwarzer G, Bschor T, Baethge C. Incidence of antidepressant discontinuation symptoms: a systematic review and meta-analysis Lancet Psychiatry, 2024.

   doi:10.1016/S2215-0366(24)00133-0PubMed 38851198

   Финансирование и результат

   Участники

   21 002

   Наблюдение

   observation after discontinuation 1.5 to 196 days; prior antidepressant use 1 to 156 weeks

   Финансирование

   There was no funding source for this study.

   Результат

   Incidence of at least one discontinuation symptom 0.31 (95% CI 0.27 to 0.35) in 62 antidepressant groups and 0.17 (0.14 to 0.21) in 22 placebo groups; risk difference in 20 randomised trials 0.079 (0.039 to 0.119). Studies using a structured instrument gave 0.40 against 0.27 without one. Severe symptoms 0.028 (0.014 to 0.057) after antidepressants and 0.006 (0.002 to 0.013) after placebo. Sertraline 0.18 (0.08 to 0.35) in 5 studies. Tapering 0.30 against abrupt stopping 0.29. 45 of the analysed studies were funded by pharmaceutical companies. The authors estimated that about 15% of people stopping have pharmacologically caused symptoms.

10. Независимое

    Sharma T, Guski LS, Freund N, Gøtzsche PC. Suicidality and aggression during antidepressant treatment: systematic review and meta-analyses based on clinical study reports BMJ, 2016.

    doi:10.1136/bmj.i65PubMed 26819231

    Финансирование и результат

    Участники

    18 526

    Финансирование

    This study is part of a PhD (TS) thesis, funded by the Laura and John Arnold Foundation. The funding source had no role in the design and conduct of the study; data collection, management, analysis, and interpretation; preparation, review, and approval of the manuscript; or the decision to submit the paper for publication.

    Результат

    Children and adolescents: suicidality OR 2.39 (95% CI 1.31 to 4.33), aggression 2.79 (1.62 to 4.81). Adults: suicidality 0.81 (0.51 to 1.28), aggression 1.09 (0.55 to 2.14), akathisia 2.00 (0.79 to 5.04). Individual patient listings were available for only 32 trials and case report forms for none. 27 suicide attempts and 32 ideation events were coded as emotional lability or worsening depression; in three sertraline trials with verbatim terms, akathisia was coded as hyperkinesia, and 16 sertraline trials used the WHO Adverse Drug Reaction Terminology, which does not allow coding of akathisia or suicidal ideation. Eli Lilly's summary trial reports omitted all suicidal ideation events.

11. Независимое

    FOCUS Trial Collaboration. Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial Lancet, 2019.

    doi:10.1016/S0140-6736(18)32823-XPubMed 30528472

    Финансирование и результат

    Регистрация

    ISRCTN83290762

    Участники

    3 127

    Наблюдение

    6 and 12 months

    Финансирование

    UK Stroke Association and NIHR Health Technology Assessment Programme. None of the funding organisations had any role in study design, data collection, data analysis, data interpretation, or writing of this report, or the decision to publish.

    Результат

    At 6 months, bone fractures in 45 of 1564 (2.88%) on fluoxetine against 23 of 1563 (1.47%) on placebo, difference 1.41 percentage points (95% CI 0.38 to 2.43), about 1 extra fracture per 71 treated; new depression 13.43% against 17.21%; functional outcome did not differ (common OR 0.951, 0.839 to 1.079). Epileptic seizures 3.71% against 2.56% and hyponatraemia below 125 mmol/L 1.41% against 0.90% were not significantly different.

12. Независимое

    Huybrechts KF, Bateman BT, Palmsten K, Desai RJ, Patorno E, Gopalakrishnan C, et al. Antidepressant use late in pregnancy and risk of persistent pulmonary hypertension of the newborn JAMA, 2015.

    doi:10.1001/jama.2015.5605PubMed 26034955

    Финансирование и результат

    Участники

    3 789 330

    Наблюдение

    first 30 days after delivery

    Финансирование

    This study was supported by grant R01 HS018533 from the Agency for Healthcare Research and Quality; individual career and training grants from NIMH and NICHD. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Результат

    Persistent pulmonary hypertension of the newborn in 20.8 per 10,000 births without antidepressant exposure and 31.5 per 10,000 after late-pregnancy SSRI exposure (322 infants). Odds ratio 1.51 (95% CI 1.35 to 1.69) unadjusted and 1.10 (0.94 to 1.29) when restricted to women with depression with high-dimensional propensity score adjustment; for primary PPHN, adjusted OR 1.28 (1.01 to 1.64).

13. Справочное издание

    National Institute of Diabetes and Digestive and Kidney Diseases. Sertraline LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-, entry updated 8 April 2020, 2020.

    PubMed 31643831

    Финансирование и результат

    Финансирование

    National Institute of Diabetes and Digestive and Kidney Diseases (publisher of LiverTox).

    Результат

    Read as the PubMed abstract of the entry; the Bookshelf page returned a browser check. Sertraline therapy can be associated with transient asymptomatic elevations in serum aminotransferase levels and has been linked to rare instances of clinically apparent acute liver injury.

14. Справочное издание

    UniProt Consortium. UniProt: the Universal Protein Knowledgebase in 2025 Nucleic Acids Research, 2025.

    doi:10.1093/nar/gkae1010PubMed 39552041

    Финансирование и результат

    Финансирование

    National Human Genome Research Institute (NHGRI) [HG002273]; Office of the Director, NIH OD [U24HG007822]; NIAID; NIA; NIGMS [R35GM141873]; NIDDK; NEI; NCI; NHLBI; BBSRC [BB/T015608/1]; National Science Foundation's Directorate for Biological Sciences [BB/X002179/1]; Open Targets; Horizon 2020 [825575]; State Secretariat for Education, Research and Innovation (SERI); EMBL Australia. Funding for open access charge: National Institutes of Health.

    Результат

    Reviewed human UniProtKB entries, release 2026_03, read through rest.uniprot.org. TPH1 (P17752): oxidises L-tryptophan to 5-hydroxy-L-tryptophan in the rate-determining step of serotonin biosynthesis. SLC6A4 (P31645): modulates mucosal serotonin in the gastrointestinal tract through uptake and clearance in enterocytes, is required for enteric neurogenesis and gastrointestinal reflexes (by similarity), and regulates blood serotonin through rapid high-affinity uptake from plasma into platelets for storage in dense granules. HTR3A (P46098): serotonin-gated cation channel; detected in cortex, amygdala, hippocampus, small and large intestine, spleen and tonsil monocytes, uterus, prostate, ovary and placenta. HTR4 (Q13639): Gs-coupled receptor activating adenylate cyclase; expressed in ileum, brain and cardiac atria. HTR2B (P41595): Gq-coupled, detected in liver, kidney, heart, pulmonary artery and intestine; required for cardiac development, osteoblast function and bone density, and proliferation of intestinal interstitial cells of Cajal (by similarity). HTR2A (P28223): Gq-coupled; detected in brain cortex and blood platelets; role in intestinal smooth muscle contraction and possibly arterial vasoconstriction (by similarity). HTR1A (P08908): Gi/Go-coupled; detected in lymph nodes, thymus, spleen and activated T cells. AANAT (Q16613): N-acetylates serotonin to N-acetylserotonin, controlling the night-day rhythm of melatonin production in the pineal gland; ASMT (P46597): methylates N-acetylserotonin to melatonin.

15. Справочное издание

    UniProt Consortium. UniProt: the Universal Protein Knowledgebase in 2025 Nucleic Acids Research, 2025.

    doi:10.1093/nar/gkae1010PubMed 39552041

    Финансирование и результат

    Финансирование

    National Human Genome Research Institute (NHGRI) [HG002273]; Office of the Director, NIH OD [U24HG007822]; National Institute of Allergy and Infectious Diseases (NIAID); National Institute on Aging (NIA); National Institute of General Medical Sciences (NIGMS) [R35GM141873]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Eye Institute (NEI); National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI); Biotechnology and Biological Sciences Research Council (BBSRC) [BB/T015608/1]; National Science Foundation's Directorate for Biological Sciences [BB/X002179/1]; Open Targets; Horizon 2020 - Research and Innovation Framework Programme [825575]; State Secretariat for Education, Research and Innovation (SERI); European Molecular Biology Laboratory (EMBL) Australia. Funding for open access charge: National Institutes of Health.

    Результат

    Reviewed human UniProtKB entries, release 2026_03, read through rest.uniprot.org. TPH2 (Q8IWU9): neuron-specific enzyme that converts L-tryptophan into 5-hydroxy-L-tryptophan, the rate-limiting step in serotonin production, with Fe2+ as cofactor and O2 and tetrahydrobiopterin as cosubstrates; brain specific. DDC (P20711): decarboxylates L-5-hydroxytryptophan to serotonin and CO2; pyridoxal 5'-phosphate cofactor. SLC18A2 (Q05940), VMAT2: electrogenic antiporter that exchanges one cationic monoamine, including serotonin, for two intravesicular protons, using the proton gradient of the V-type ATPase to accumulate monoamines in vesicles before release by exocytosis; strongly inhibited by reserpine and tetrabenazine. SLC6A4 (P31645), serotonin transporter: cotransports serotonin with one Na+ in exchange for one K+ and possibly one proton, from the extracellular compartment to the cytosol; mediates uptake from the synaptic cleft back into the presynaptic terminal, terminating synaptic signalling; ensures rapid high-affinity uptake of serotonin from plasma into platelets, which store it in dense granules and release it on stimulation; expressed in platelets. MAOA (P21397): FAD enzyme of the mitochondrial outer membrane that catalyses oxidative deamination of neurotransmitters and preferentially oxidises serotonin: serotonin + O2 + H2O = (5-hydroxyindol-3-yl)acetaldehyde + H2O2 + NH4+. ALDH9A1 (P49189): (5-hydroxyindol-3-yl)acetaldehyde + NAD+ + H2O = (5-hydroxyindol-3-yl)acetate + NADH + 2 H+, with experimental evidence.

16. Независимое

    Ortuño MJ, Robinson ST, Subramanyam P, Paone R, Huang YY, Guo XE, et al. Serotonin-reuptake inhibitors act centrally to cause bone loss in mice by counteracting a local anti-resorptive effect Nature Medicine, 2016.

    doi:10.1038/nm.4166PubMed 27595322

    Финансирование и результат

    Финансирование

    The National Institute of Health grant AG032959 (PD) supported this work.

    Результат

    In mice, 3 weeks of fluoxetine raised bone volume through a direct, serotonin reuptake-independent inhibition of osteoclast differentiation (Ca2+-calmodulin-NFATc1), whereas 6 weeks caused net bone loss with lower bone formation, through a brain serotonin-dependent rise in sympathetic output; co-treatment with propranolol prevented the bone loss. Animal data.

17. Независимое

    Gafoor R, Booth HP, Gulliford MC. Antidepressant utilisation and incidence of weight gain during 10 years' follow-up: population based cohort study BMJ, 2018.

    doi:10.1136/bmj.k1951PubMed 29793997

    Финансирование и результат

    Участники

    294 719

    Наблюдение

    1,836,452 person-years over up to 10 years

    Финансирование

    MCG was supported by the NIHR Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London. The funders were not involved in the design, conduct, or reporting of this study.

    Результат

    Incidence of a new 5% or greater weight gain: 8.1 per 100 person-years without and 11.2 per 100 person-years with antidepressants (adjusted rate ratio 1.21, 95% CI 1.19 to 1.22), raised for at least six years; in the second year, 27 people treated for one year for one additional episode. Transition from normal weight to overweight or obesity rate ratio 1.29 (1.25 to 1.34). Sertraline accounted for 9.0% of antidepressant use; individual-drug estimates were reported in figures. Associations may not be causal.

18. Независимое

    Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA. The serotonin theory of depression: a systematic umbrella review of the evidence Molecular Psychiatry, 2023.

    doi:10.1038/s41380-022-01661-0PubMed 35854107

    Финансирование и результат

    Регистрация

    PROSPERO CRD42020207203

    Финансирование

    There was no specific funding for this review. MAH is supported by a Clinical Research Fellowship from North East London NHS Foundation Trust (NELFT). This funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

    Результат

    Two meta-analyses of 5-HIAA (largest n=1002) showed no association with depression; a meta-analysis of cohort studies of plasma serotonin (n=1869) showed no relationship with depression; 5-HT1A receptor and SERT binding studies gave weak and inconsistent evidence; tryptophan depletion had no effect in most healthy volunteers, with weak evidence of an effect in those with a family history of depression (n=75); the largest SERT gene studies (n=115,257 and n=43,165) found no association with depression and no gene-stress interaction. The authors concluded that the main areas of serotonin research provide no consistent evidence of an association between serotonin and depression.

19. Независимое

    Jauhar S, Arnone D, Baldwin DS, Bloomfield M, Browning M, Cleare AJ, et al. A leaky umbrella has little value: evidence clearly indicates the serotonin system is implicated in depression Molecular Psychiatry, 2023.

    doi:10.1038/s41380-023-02095-yPubMed 37322065

    Финансирование и результат

    Финансирование

    Several authors acknowledge part funding by the NIHR Maudsley and Oxford Health Biomedical Research Centres, the Medical Research Council, the Wellcome Trust, the Maudsley Charity, the Rosetrees Trust, NIMH, NICHD and SAMHSA.

    Результат

    The authors argue that the umbrella review overstated its conclusion through methodological weaknesses, selective reporting and misinterpretation; for example, in the tryptophan depletion meta-analysis it cited, the mood effect in depressed people not taking antidepressants was large (Hedges g -1.9, 95% CI -3.02 to -0.78; -1.06 after removing a potential outlier; 8 samples, several from one group), and they interpret tryptophan depletion as implicating serotonin in people vulnerable to depression and in those remitted on SSRIs.

20. Финансирование не установлено

    Erritzoe D, Godlewska BR, Rizzo G, Searle GE, Agnorelli C, Lewis Y, et al. Brain serotonin release is reduced in patients with depression: a [11C]Cimbi-36 positron emission tomography study with a d-amphetamine challenge Biological Psychiatry, 2023.

    doi:10.1016/j.biopsych.2022.10.012PubMed 36635177

    Финансирование и результат

    Участники

    37

    Финансирование

    Funding statement not read: the publisher's full text requires payment, the archived journal page shows only the abstract, and repository copies returned HTTP 403 or 503 to automated access. Publisher-deposited Crossref metadata list Innovationsfonden, the Medical Research Council, the Michael J. Fox Foundation for Parkinson's Research, the University of Exeter, Eli Lilly and Company, King's College London, the CHDI Foundation and the European Commission as funders. Six of the 19 authors list Invicro, London, as an affiliation.

    Результат

    [11C]Cimbi-36 PET before and 3 hours after oral d-amphetamine 0.5 mg/kg. Frontal 5-HT2A receptor non-displaceable binding potential fell from 1.04 to 0.87 in controls (p<0.001) and from 0.97 to 0.92 in patients (not significant); the reduction was 15% against 6.5% (p=0.041), which the authors interpret as reduced serotonin release capacity in depression. Results read from the abstract.

21. Независимое

    Bråten LS, Haslemo T, Jukic MM, Ingelman-Sundberg M, Molden E, Kringen MK. Impact of CYP2C19 genotype on sertraline exposure in 1200 Scandinavian patients Neuropsychopharmacology, 2020.

    doi:10.1038/s41386-019-0554-xPubMed 31649299

    Финансирование и результат

    Участники

    1 202

    Финансирование

    The project was partly funded by the South-Eastern Norway Regional Health Authority.

    Результат

    In vitro studies suggest that CYP2C19, CYP2B6, CYP2C9, CYP2D6 and CYP3A4 are all involved in sertraline metabolism, but CYP2C19 and CYP2B6 are regarded as the most relevant enzymes. Against CYP2C19 normal metabolisers, dose-harmonised serum sertraline was 2.68-fold (95% CI 2.16 to 3.31) higher in poor metabolisers (n=35) and 1.38-fold (1.26 to 1.50) higher in intermediate metabolisers; about 10% lower in ultrarapid metabolisers. Odds ratio for a concentration above the 250 nM target range 8.69 (3.88 to 19.19) in poor metabolisers.

22. Независимое

    Bråten LS, Ingelman-Sundberg M, Jukic MM, Molden E, Kringen MK. Impact of the novel CYP2C:TG haplotype and CYP2B6 variants on sertraline exposure in a large patient population Clinical and Translational Science, 2022.

    doi:10.1111/cts.13347PubMed 35668575

    Финансирование и результат

    Участники

    840

    Финансирование

    The project was partly funded by the South-Eastern Norway Regional Health Authority, the European Union's Horizon 2020 research and innovation program U-PGx (grant agreement 668353) and the Swedish Research Council (grant 2021-02732). Open access funding enabled and organized by ProjektDEAL.

    Результат

    Against CYP2B6*1/*1 (n=454), serum sertraline was 25% higher in patients homozygous for CYP2B6*6 or *9 (n=40) and 15% higher in heterozygous carriers (n=261), and 17.4% lower in carriers of CYP2B6*4 (n=37). CYP2C19 poor metabolisers (n=29) had 2.3-fold higher concentrations than CYP2C19*1/*1. Predicted concentration with combined CYP2C19 and CYP2B6 poor metaboliser phenotypes was 2.89-fold (95% CI 2.02 to 4.15) that of combined normal metabolisers, from 2 patients.

23. Консенсус

    Bousman CA, Stevenson JM, Ramsey LB, Sangkuhl K, Hicks JK, Strawn JR, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A genotypes and serotonin reuptake inhibitor antidepressants Clinical Pharmacology and Therapeutics, 2023.

    doi:10.1002/cpt.2903PubMed 37032427

    Финансирование и результат

    Финансирование

    National Institutes of Health funding for CPIC (R24GM115264 and U24HG010135), PharmGKB (U24HG010615) and PharmVar (R24GM123930); individual authors received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD099775, R01HD098757), the Yung Family Foundation, the National Center for Advancing Translational Sciences (UL1TR001425) and the Patient-Centered Outcomes Research Institute.

    Результат

    Sertraline is metabolised by CYP2D6, CYP2C19, CYP2B6 and other CYP enzymes, with CYP2C19 the major pathway. CYP2C19 poor or likely poor metabolisers: consider a lower starting dose, slower titration and 50% reduction of the standard maintenance dose, or an alternative antidepressant not predominantly metabolised by CYP2C19 (moderate). CYP2C19 intermediate metabolisers: standard starting dose, consider slower titration and lower maintenance dose (moderate). CYP2B6 poor metabolisers: consider a lower starting dose, slower titration and 25% reduction of the standard maintenance dose, or an alternative not predominantly metabolised by CYP2B6 (optional). Combined CYP2C19 and CYP2B6 poor metabolisers: select an alternative antidepressant not primarily metabolised by CYP2C19 or CYP2B6 (optional). No recommendations from SLC6A4 or HTR2A genotype, because the evidence is mixed or insufficient to support clinical validity and utility.

24. Независимое

    Stone MB, Yaseen ZS, Miller BJ, Richardville K, Kalaria SN, Kirsch I. Response to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration: individual participant data analysis BMJ, 2022.

    doi:10.1136/bmj-2021-067606PubMed 35918097

    Финансирование и результат

    Участники

    73 388

    Наблюдение

    acute treatment, 3 weeks or longer

    Финансирование

    Funding: None. The authors declared no support from any organisation for the submitted work. Three authors are FDA staff.

    Результат

    Mean improvement 9.8 points on the HAMD17 with drug and 8.0 with placebo, difference 1.75 (95% CI 1.63 to 1.86; SMD 0.23 to 0.25). The difference rose by 0.09 points per point of baseline severity, from 1.1 points at a baseline of 16 to 2.5 at 29.6. Response distributions fitted three groups: a large response (mean 16 points) in 24.5% on drug against 9.6% on placebo, number needed to treat 6.7 (5.7 to 7.7); a minimal response in 12.2% against 21.5%; a non-specific response in 63.3% against 68.9%. The authors estimated that about 15% of participants have a substantial drug effect beyond placebo.

25. Независимое

    Jakobsen JC, Katakam KK, Schou A, Hellmuth SG, Stallknecht SE, Leth-Møller K, et al. Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential Analysis BMC Psychiatry, 2017.

    doi:10.1186/s12888-016-1173-2PubMed 28178949

    Финансирование и результат

    Регистрация

    PROSPERO CRD42013004420

    Участники

    27 422

    Финансирование

    The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen, Denmark, provided economic support for JCJ, KKK, JL and CG. Otherwise, we have received no funding.

    Результат

    All trials were at high risk of bias. Hamilton score fell by 1.94 points more than placebo (95% CI -2.50 to -1.37; 49 trials), below the authors' 3-point threshold for clinical significance; risk of no remission RR 0.88 (0.84 to 0.91; 34 trials). Serious adverse events (death, life threat, disability, hospital admission) in 239 of 8242 (2.7%) on SSRIs against 106 of 4956 (2.1%) on placebo, OR 1.37 (1.08 to 1.75; 44 trials), 31 against 22 per 1000, number needed to harm 138. Almost no data on suicidal behaviour, quality of life or long-term effects.

26. Независимое

    Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis Lancet, 2018.

    doi:10.1016/S0140-6736(17)32802-7PubMed 29477251

    Финансирование и результат

    Регистрация

    PROSPERO CRD42012002291

    Участники

    116 477

    Наблюдение

    acute treatment, outcomes recorded as close to 8 weeks as possible (range 4 to 12 weeks)

    Финансирование

    National Institute for Health Research (NIHR) Oxford Health Biomedical Research Centre (BRC-1215-20005) and the Japan Society for the Promotion of Science (17K19808). The funder had no role in study design, data collection, data analysis, data interpretation, writing of the report, or the decision to submit for publication.

    Результат

    522 trials with 116,477 participants; 409 of 522 trials (78%) were funded by pharmaceutical companies. Response was a reduction of at least 50% in an observer-rated depression score. All 21 antidepressants were more efficacious than placebo, with odds ratios from 2.13 (95% CrI 1.89 to 2.41) for amitriptyline to 1.37 (1.16 to 1.63) for reboxetine; sertraline against placebo: response OR 1.67 (95% CrI 1.49 to 1.87), all-cause dropout OR 0.96 (0.85 to 1.08). Summary effect sizes were mostly modest; the random-effects summary SMD for all antidepressants was 0.30 (95% CrI 0.26 to 0.34). The certainty of evidence was moderate to very low.

27. Независимое

    Lewis G, Duffy L, Ades A, Amos R, Araya R, Brabyn S, et al. The clinical effectiveness of sertraline in primary care and the role of depression severity and duration (PANDA): a pragmatic, double-blind, placebo-controlled randomised trial Lancet Psychiatry, 2019.

    doi:10.1016/S2215-0366(19)30366-9PubMed 31543474

    Финансирование и результат

    Регистрация

    ISRCTN84544741

    Участники

    655

    Наблюдение

    12 weeks; primary outcome at 6 weeks

    Финансирование

    Independent research commissioned by the National Institute for Health Research (NIHR) Programme Grant for Applied Research (RP-PG-0610-10048). The funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

    Результат

    Sertraline 50 mg daily for 1 week, then 100 mg for up to 11 weeks (n=326), or placebo (n=329). PHQ-9 at 6 weeks 7.98 against 8.76, adjusted proportional difference 0.95 (95% CI 0.85 to 1.07; p=0.41); at 12 weeks 0.87 (0.79 to 0.97). GAD-7 at 6 weeks 0.79 (0.70 to 0.89). Feeling better at 6 weeks in 157 of 267 (59%) against 132 of 285 (46%), adjusted OR 1.90 (1.24 to 2.91). Standardised mean difference for PHQ-9 at 6 weeks -0.09 (-0.23 to 0.05) and at 12 weeks -0.18 (-0.33 to -0.03), against -0.27 (-0.34 to -0.21) for sertraline against placebo in the network meta-analysis by Cipriani and colleagues. Described by the authors as the largest placebo-controlled trial of an antidepressant not funded by the pharmaceutical industry.

28. Независимое

    Blumenthal JA, Babyak MA, Doraiswamy PM, Watkins L, Hoffman BM, Barbour KA, et al. Exercise and pharmacotherapy in the treatment of major depressive disorder Psychosomatic Medicine, 2007.

    doi:10.1097/PSY.0b013e318148c19aPubMed 17846259

    Финансирование и результат

    Участники

    202

    Наблюдение

    16 weeks

    Финансирование

    This research was supported by Grant MH 49679 from the National Institutes of Health and NIH Grant MO1-RR-30 from the National Center for Research Resources. Medication and matched placebo pills were provided by a grant from Pfizer Pharmaceuticals; Pfizer had no other role in the study design, data acquisition, data analysis, or preparation of this manuscript.

    Поддержка в натуральной форме

    Sertraline and matching placebo provided by Pfizer.

    Результат

    Remission (no MDD diagnosis and HAM-D below 8) at 16 weeks: supervised exercise 45%, home exercise 40%, sertraline 47%, placebo 31% (p=0.057); HAM-D scores of active groups did not differ significantly from placebo (p=0.23). No treatment by severity interaction; with baseline HAM-D of 18 or more, remission 44%, 30%, 39% and 27%.

29. Независимое

    Amick HR, Gartlehner G, Gaynes BN, Forneris C, Asher GN, Morgan LC, et al. Comparative benefits and harms of second generation antidepressants and cognitive behavioral therapies in initial treatment of major depressive disorder: systematic review and meta-analysis BMJ, 2015.

    doi:10.1136/bmj.h6019PubMed 26645251

    Финансирование и результат

    Финансирование

    This project was funded under contract 290-2012-00008i from the Agency for Healthcare Research and Quality by the RTI-UNC Evidence-based Practice Center.

    Результат

    Antidepressants against CBT: response RR 0.91 (95% CI 0.77 to 1.07), remission 0.98 (0.73 to 1.32), Hamilton score difference -0.38 (-2.87 to 2.10); withdrawal for adverse events RR 3.29 (0.42 to 25.72) with antidepressants. Strength of evidence low for most outcomes; small numbers may preclude detection of small differences.

30. Регуляторное

    Melander H, Ahlqvist-Rastad J, Meijer G, Beermann B. Evidence b(i)ased medicine—selective reporting from studies sponsored by pharmaceutical industry: review of studies in new drug applications BMJ, 2003.

    doi:10.1136/bmj.326.7400.1171PubMed 12775615

    Финансирование и результат

    Финансирование

    Funding: None. All authors were staff of the Swedish Medical Products Agency.

    Результат

    21 trials contributed to at least two publications each and three to five publications; trials with significant drug effects were published as stand-alone papers more often than trials with non-significant results; many publications reported only the more favourable per-protocol analyses and ignored the intention-to-treat results. The authors concluded that recommending a specific SSRI from publicly available data alone is likely to rest on biased evidence.

31. Независимое

    Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration PLoS Medicine, 2008.

    doi:10.1371/journal.pmed.0050045PubMed 18303940

    Финансирование и результат

    Участники

    5 133

    Финансирование

    The authors received no specific funding for this study.

    Результат

    Weighted mean improvement 9.60 points on the Hamilton scale with drug and 7.80 with placebo, a difference of 1.80, below the 3-point NICE criterion; the difference reached that criterion only at mean baseline scores of about 28. For sertraline, four trials with 486 participants, 38% of patients in sertraline trials, were reported by the FDA as not achieving a significant drug effect without mean scores. Three sertraline trials allowed replacement of patients not improving after 2 weeks, and trials excluded patients who improved by 20% or more during a 1- to 2-week placebo washout.

32. Консенсус

    Gelenberg AJ, Freeman MP, Markowitz JC, Rosenbaum JF, Thase ME, Trivedi MH, et al. Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition American Psychiatric Association; approved May 2010, published October 2010, 2010.

    https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf

    Финансирование и результат

    Финансирование

    not stated in the guideline; developed under the direction of the APA Steering Committee on Practice Guidelines.

    Результат

    An antidepressant medication is recommended as an initial treatment choice for mild to moderate major depressive disorder [I] and definitely should be provided for severe disorder unless ECT is planned [I]; for most patients an SSRI, SNRI, mirtazapine or bupropion is optimal [I]; depression-focused psychotherapy alone is also recommended as an initial choice for mild to moderate disorder [I]. SSRIs generally should be tapered over several weeks; discontinuation-emergent symptoms are more likely with paroxetine than sertraline and typically resolve without treatment over 1 to 2 weeks, although some patients have more protracted syndromes.

33. Консенсус

    National Institute for Health and Care Excellence. Depression in adults: treatment and management NICE guideline NG222, published 29 June 2022; recommendations 1.5 and 1.6, tables 1 and 2, 2022.

    https://www.nice.org.uk/guidance/ng222/chapter/Recommendations

    Финансирование и результат

    Финансирование

    not stated in the guideline text.

    Результат

    Treatment options for a new episode of less severe depression (PHQ-9 below 16), in order of the committee's interpretation of clinical and cost effectiveness and implementation: guided self-help, group CBT, group behavioural activation, individual CBT, individual behavioural activation, group exercise (moderate-intensity aerobic exercise, usually more than one session a week for 10 weeks), group mindfulness and meditation, interpersonal psychotherapy, SSRIs, counselling, short-term psychodynamic psychotherapy; antidepressants are not routinely offered first-line for less severe depression unless that is the person's informed preference. For more severe depression, all options in table 2 can be first-line, in the order: individual CBT combined with an antidepressant, individual CBT, individual behavioural activation, antidepressant medication, individual problem-solving, counselling, short-term psychodynamic psychotherapy, interpersonal psychotherapy, guided self-help, group exercise. For SSRIs, a review is advised usually within 2 weeks, and after 1 week for people aged 18 to 25 or with particular concern about suicide risk.

34. Независимое

    Lewis G, Marston L, Duffy L, Freemantle N, Gilbody S, Hunter R, et al. Maintenance or discontinuation of antidepressants in primary care New England Journal of Medicine, 2021.

    doi:10.1056/NEJMoa2106356PubMed 34587384

    Финансирование и результат

    Регистрация

    ISRCTN15969819

    Участники

    478

    Наблюдение

    52 weeks

    Финансирование

    Supported by the National Institute for Health Research (HTA Program 13/115/48). The trial was sponsored by University College London and funded by the National Institute for Health Research, with no commercial involvement.

    Результат

    Double-blind; 238 assigned to maintenance and 240 to discontinuation, of whom 41 and 37 took sertraline. In the discontinuation group, citalopram, sertraline or mirtazapine was given at half dose for 1 month, then half dose on alternate days with placebo for 1 month, then placebo; fluoxetine 20 mg on alternate days for 1 month, then placebo. Relapse by 52 weeks in 92 of 238 (39%) with maintenance and 135 of 240 (56%) with discontinuation (hazard ratio 2.06, 95% CI 1.56 to 2.70). At 12 weeks, new or worsened withdrawal symptoms on the modified DESS 1.3 against 3.1 (difference 1.9, 95% CI 1.5 to 2.3). Serious adverse events 9 (4%) against 8 (3%); no deaths or suicide attempts.

35. Независимое

    Van Leeuwen E, van Driel ML, Horowitz MA, Kendrick T, Donald M, De Sutter AIM, et al. Approaches for discontinuation versus continuation of long-term antidepressant use for depressive and anxiety disorders in adults Cochrane Database of Systematic Reviews, 2021.

    doi:10.1002/14651858.CD013495.pub2PubMed 33886130

    Финансирование и результат

    Участники

    4 995

    Финансирование

    Internal sources: Ghent University, Belgium. External sources: National Institute for Health Research (NIHR), UK; LR work on this review is supported by NIHR Cochrane Infrastructure funding to the Common Mental Disorders Cochrane Review Group.

    Результат

    All trials were at high risk of bias in at least one domain, most often reporting bias and then attrition bias; the authors name confounding of relapse by withdrawal symptoms as the main limitation of the review; most tapers lasted 4 weeks or less, and withdrawal symptoms were generally not assessed. Against continuation, abrupt stopping: relapse HR 2.09 (95% CI 1.59 to 2.74; 1373 participants, 10 studies), very low certainty; tapered stopping: HR 2.97 (2.24 to 3.93; 1546 participants, 13 studies), very low certainty. Tapering with preventive cognitive therapy or MBCT: 40% to 75% discontinued, relapse HR 0.89 (0.66 to 1.19; 690 participants, 3 studies), low certainty, withdrawal symptoms not measured. No trial used tapering over several months, liquid formulations or tapering strips.

36. Независимое

    Moncrieff J, Hobday H, Sørensen A, Read J, Plöderl M, Hengartner M, et al. Evidence on antidepressant withdrawal: an appraisal and reanalysis of a recent systematic review Psychological Medicine, 2025.

    doi:10.1017/S0033291725100652PubMed 40692314

    Финансирование и результат

    Участники

    601

    Финансирование

    This study received no specific funding.

    Результат

    46 of the 62 cohorts (74%) had definite or probable pharmaceutical company funding and held 96.2% (12,119 of 12,603) of participants. In 52 of 62 cohorts withdrawal figures came from adverse events, open questions, clinician judgement or an unspecified method, mostly spontaneous reports; only 5 studies (601 participants, 4.8%) measured withdrawal systematically. In 11 of 19 studies, severe withdrawal was proxied by leaving the study or by serious adverse events. Pooled incidence in the 5 studies was 0.55 (N=601; the results section gives a 95% CI of 0.36 to 0.72, the abstract 31% to 81%), 0.25 to 0.39 after deducting a 30% placebo rate; prior use was 12 weeks or less in 4 of the 5.

37. Независимое

    Hengartner MP, Plöderl M. Prophylactic effects or withdrawal reactions? An analysis of time-to-event data from antidepressant relapse prevention trials submitted to the FDA Therapeutic Advances in Psychopharmacology, 2021.

    doi:10.1177/20451253211032051PubMed 34394912

    Финансирование и результат

    Финансирование

    The authors received no financial support for the research, authorship, and/or publication of this article.

    Результат

    20.6% (95% CI 10.9% to 30.3%) of the total drug-placebo difference in relapse had accrued by week 3, 50.3% by week 6 and 69.0% by week 12, with no further separation from week 24 (101.0%); around week 6 the separation was about three times larger than expected for a constant prophylactic effect. The authors interpret the early excess of relapses in placebo arms as possibly due to withdrawal reactions after abrupt or rapid discontinuation, in which case long-term prophylactic effects are overestimated. They also report that the FDA's own censoring of relapses in the first 4 weeks reduced the absolute risk difference from 19% to 12%.