Therapeutics

Citalopram

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Overview

Name: Citalopram
Synonyms: escitalopram, Celexa, Lexapro , Cipralex
Chemical Name: (RS)-1-[3-(Dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease, Preclinical Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3), Preclinical Alzheimer's Disease (Inactive)
Approved for: Depression, generalized anxiety disorder

Background

Citalopram is a selective serotonin reuptake inhibitor used to treat depression and anxiety. It is a chiral molecule that exists as two enantiomers. Citalopram consists of a 1:1 mixture of (R)- and (S)-stereoisomers. A purified (S)-isomer formulation, marketed as Escitalopram, is approved to treat depression and generalized anxiety disorder. Both are available as generics. Both work by increasing serotonin activity in the brain. Escitalopram is considered superior at treating depression, with faster onset at lower doses than citalopram (Lepola et al., 2004; Gartlehner et al., 2011). Side effects in older adults include abnormal heart rhythm, loss of coordination, and bleeding.

Many people with Alzheimer’s disease have noncognitive symptoms, which add to their and caregivers’ burdens. Agitation, including disruptive or aggressive behaviors, may stem from degeneration of serotonin systems. No treatments are approved for agitation in people with Alzheimer’s disease, but based on existing clinical evidence, citalopram and escitalopram are sometimes used (Aga 2019; Kales et al., 2019).

Some research has suggested anti-amyloid actions for SSRIs. Activation of certain serotonin receptors reduces Aβ production by increasing non-amyloidogenic α-secretase processing of APP (Nitsch et al., 1996; Fisher et al., 2016). Citalopram was reported to lower Aβ production and amyloid plaque load in mice and people (Cirrito et al., 2011; Sheline et al., 2014; Zhang et al., 2018). However, in one study, escitalopram did not reduce brain Aβ in mice (von Linstow et al., 2017). More recently, escitalopram was found to increase hippocampal α-secretase activity by 50 percent, and reduce brain interstitial Aβ42 in mice (Cirrito et al., 2020). The same study showed chronic escitalopram halted plaque growth, but did not remove established plaques. In cognitively normal older people, two or eight weeks of treatment with escitalopram led to a 6 percent reduction in CSF Aβ42 concentrations, compared to a slight increase in placebo-treated volunteers (Sheline et al., 2020).

In ADNI participants with a history of depression, long-term use of SSRIs was linked to a three-year delay in progression to dementia (Bartels et al., 2018). Another study linked SSRI use in people with depression and MCI or AD to slowed cognitive decline, reduced progression of gray-matter atrophy, and a trend toward slower amyloid deposition (Brendel et al., 2018). A retrospective review of medical records of 14,269 people with MCI in New York found that use of citalopram or escitalopram was associated with a significant slowing of progression to dementia (Xu et al., 2023).

Findings

In the first placebo-controlled trial of citalopram for behavioral disturbances in people with AD, four weeks of citalopram led to decreased confusion, anxiety, and irritability (Nyth and Gottfries, 1990). A second randomized trial, in dementia patients hospitalized for agitation or psychosis symptoms, found citalopram taken for 17 days lessened agitation and aggression (Pollock et al., 2002). Citalopram or escitalopram improved agitation and psychosis as effectively as the typical antipsychotic risperidone, but with fewer side effects (Pollock et al., 2007; Barak et al., 2011).

In July 2009, a group of academic investigators started a randomized study of citalopram. Called CitAD, it enrolled 186 participants with probable AD and agitation, and compared a nine-week course of psychosocial intervention plus 30 mg/day citalopram to psychosocial intervention plus placebo. Citalopram reduced agitation and caregiver distress compared with placebo, but caused cardiac side effects and cognitive worsening (Feb 2014 news; Dec 2014 conference news; Porsteinsson et al., 2014). Subsequent to this trial, the FDA established a safe limit for citalopram of 20 mg/day for people over 60 (Marcum et al., 2012).

An analysis of the blood concentrations of citalopram isomers associated cognitive worsening with the (R) isomer and clinical improvements with the (S) form (Ho et al., 2016). In January 2018, the same investigators began an NIA-funded Phase 3 trial of escitalopram, called S-CitAD (Ehrhardt et al., 2019). In the run-in phase, participants with AD and agitation received a psychosocial intervention for three weeks. Those who did not improve were randomized to receive up to 15 mg/day escitalopram or placebo for three months, with continuing psychosocial intervention. The planned primary outcome in this pragmatic trial was the proportion of patients showing marked improvement on a modified form of the ADCS-Clinical Global Impression of Change scale after 12 weeks. The trial spanned the COVID-19 pandemic, and was completed in November 2023. According to results presented at the August 2024 AAIC in Philadelphia, the trial failed to meet its primary endpoint. It intended to enroll 392 patients, but just 205 started the psychosocial intervention, and 173 went on to randomization. Adverse events included falls, anxiety, constipation and diarrhea, and cardiac rhythm changes. Compared to citalopram, fewer patients showed marked or moderate improvement in agitation, but escitalopram did not cause cognitive worsening.

A trial in South Korea evaluated 20 mg/day escitalopram for one year on AD progression in 74 people with probable AD, and found no difference in hippocampal or whole-brain volumes, and no benefit on cognitive, neuropsychiatric, or depression scores, compared with placebo (Choe et al., 2015). Another trial in South Korea, of a 12-week course of 15 mg/d escitalopram or placebo in 84 participants with a clinical diagnosis of AD, reported no differences outcomes of depression and cognition (An et al., 2017).

Starting in July 2017, a Phase 1 study at NYU began comparing 5 mg/d of escitalopram with 37.5 mg/d of venlafaxine, a different antidepressant medication, and with placebo, in 31 people with subjective memory concerns. The study was to evaluate the drugs' ability to slow down progression to mild cognitive impairment or Alzheimer's disease, using EEG and metabolic imaging in the hippocampal formation as primary outcome measures. This trial was terminated in September 2019 due to insufficient enrollment.

In February 2022, a trial began to assess the effects of eight weeks of escitalopram on Aβ dynamics in adults with major depression. Participants must be at least 60 years old and have normal cognitive function. They will take 10 or 20 mg escitalopram daily as tolerated, or placebo. The primary endpoints are change in CSF Aβ40, Aβ42, and vascular dysfunction biomarkers, plus depressive symptoms. Other outcomes include plasma Aβ and CSF total tau and phosphorylated tau. The study, at two sites in New York, will run until early 2026.

For details on citalopram and escitalopram trials in Alzheimer's disease, see clinicaltrials.gov.

Last Updated: 15 Aug 2024

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References

News Citations

  1. Citalopram Calms Agitation in Alzheimer’s, but Carries Risks
  2. New Treatments for Alzheimer’s Behavioral Symptoms on Horizon

Paper Citations

  1. Nyth AL, Gottfries CG. The clinical efficacy of citalopram in treatment of emotional disturbances in dementia disorders. A Nordic multicentre study. Br J Psychiatry. 1990 Dec;157:894-901. PubMed.
  2. Pollock BG, Mulsant BH, Rosen J, Sweet RA, Mazumdar S, Bharucha A, Marin R, Jacob NJ, Huber KA, Kastango KB, Chew ML. Comparison of citalopram, perphenazine, and placebo for the acute treatment of psychosis and behavioral disturbances in hospitalized, demented patients. Am J Psychiatry. 2002 Mar;159(3):460-5. PubMed.
  3. Pollock BG, Mulsant BH, Rosen J, Mazumdar S, Blakesley RE, Houck PR, Huber KA. A double-blind comparison of citalopram and risperidone for the treatment of behavioral and psychotic symptoms associated with dementia. Am J Geriatr Psychiatry. 2007 Nov;15(11):942-52. Epub 2007 Sep 10 PubMed.
  4. Barak Y, Plopski I, Tadger S, Paleacu D. Escitalopram versus risperidone for the treatment of behavioral and psychotic symptoms associated with Alzheimer's disease: a randomized double-blind pilot study. Int Psychogeriatr. 2011 Apr 15;:1-5. PubMed.
  5. Porsteinsson AP, Drye LT, Pollock BG, Devanand DP, Frangakis C, Ismail Z, Marano C, Meinert CL, Mintzer JE, Munro CA, Pelton G, Rabins PV, Rosenberg PB, Schneider LS, Shade DM, Weintraub D, Yesavage J, Lyketsos CG, CitAD Research Group. Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA. 2014 Feb 19;311(7):682-91. PubMed.
  6. Marcum ZA, Vande Griend JP, Linnebur SA. FDA drug safety communications: a narrative review and clinical considerations for older adults. Am J Geriatr Pharmacother. 2012 Aug;10(4):264-71. Epub 2012 Jun 8 PubMed.
  7. Ho T, Pollock BG, Mulsant BH, Schantz O, Devanand DP, Mintzer JE, Porsteinsson AP, Schneider LS, Weintraub D, Yesavage J, Drye LT, Munro CA, Shade DM, Lyketsos C, Bies R. R- and S-citalopram concentrations have differential effects on neuropsychiatric scores in elders with dementia and agitation. Br J Clin Pharmacol. 2016 Sep;82(3):784-92. Epub 2016 Jun 20 PubMed.
  8. Ehrhardt S, Porsteinsson AP, Munro CA, Rosenberg PB, Pollock BG, Devanand DP, Mintzer J, Rajji TK, Ismail Z, Schneider LS, Baksh SN, Drye LT, Avramopoulos D, Shade DM, Lyketsos CG, S-CitAD Research Group. Escitalopram for agitation in Alzheimer's disease (S-CitAD): Methods and design of an investigator-initiated, randomized, controlled, multicenter clinical trial. Alzheimers Dement. 2019 Nov;15(11):1427-1436. Epub 2019 Oct 3 PubMed.
  9. Choe YM, Kim KW, Jhoo JH, Ryu SH, Seo EH, Sohn BK, Byun MS, Bak JH, Lee JM, Yun HJ, Han MI, Woo JI, Lee DY. Multicenter, randomized, placebo-controlled, double-blind clinical trial of escitalopram on the progression-delaying effects in Alzheimer's disease. Int J Geriatr Psychiatry. 2015 Nov 9; PubMed.
  10. An H, Choi B, Park KW, Kim DH, Yang DW, Hong CH, Kim SY, Han SH. The Effect of Escitalopram on Mood and Cognition in Depressive Alzheimer's Disease Subjects. J Alzheimers Dis. 2017;55(2):727-735. PubMed.
  11. Lepola U, Wade A, Andersen HF. Do equivalent doses of escitalopram and citalopram have similar efficacy? A pooled analysis of two positive placebo-controlled studies in major depressive disorder. Int Clin Psychopharmacol. 2004 May;19(3):149-55. PubMed.
  12. Gartlehner G, Hansen RA, Morgan LC, Thaler K, Lux LJ, Van Noord M, Mager U, Strobelberger M, Gaynes BN, Thieda P, Lloyd S, Reichenpfader U, Lohr KN. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 Dec. Report No.: 12-EHC012-EF. AHRQ Comparative Effectiveness Reviews.
  13. Aga VM. When and How to Treat Agitation in Alzheimer's Disease Dementia With Citalopram and Escitalopram. Am J Geriatr Psychiatry. 2019 Oct;27(10):1099-1107. Epub 2019 May 10 PubMed.
  14. Kales HC, Lyketsos CG, Miller EM, Ballard C. Management of behavioral and psychological symptoms in people with Alzheimer's disease: an international Delphi consensus. Int Psychogeriatr. 2019 Jan;31(1):83-90. Epub 2018 Aug 2 PubMed.
  15. Nitsch RM, Deng M, Growdon JH, Wurtman RJ. Serotonin 5-HT2a and 5-HT2c receptors stimulate amyloid precursor protein ectodomain secretion. J Biol Chem. 1996 Feb 23;271(8):4188-94. PubMed.
  16. Fisher JR, Wallace CE, Tripoli DL, Sheline YI, Cirrito JR. Redundant Gs-coupled serotonin receptors regulate amyloid-β metabolism in vivo. Mol Neurodegener. 2016 Jun 18;11(1):45. PubMed.
  17. Cirrito JR, Disabato BM, Restivo JL, Verges DK, Goebel WD, Sathyan A, Hayreh D, D'Angelo G, Benzinger T, Yoon H, Kim J, Morris JC, Mintun MA, Sheline YI. Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans. Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14968-73. PubMed.
  18. Sheline YI, West T, Yarasheski K, Swarm R, Jasielec MS, Fisher JR, Ficker WD, Yan P, Xiong C, Frederiksen C, Grzelak MV, Chott R, Bateman RJ, Morris JC, Mintun MA, Lee JM, Cirrito JR. An antidepressant decreases CSF Aβ production in healthy individuals and in transgenic AD mice. Sci Transl Med. 2014 May 14;6(236):236re4. PubMed.
  19. Zhang Q, Yang C, Liu T, Liu L, Li F, Cai Y, Lv K, Li X, Gao J, Sun D, Xu H, Yang Q, Fan X. Citalopram restores short-term memory deficit and non-cognitive behaviors in APP/PS1 mice while halting the advance of Alzheimer's disease-like pathology. Neuropharmacology. 2018 Mar 15;131:475-486. Epub 2017 Dec 11 PubMed.
  20. von Linstow CU, Waider J, Grebing M, Metaxas A, Lesch KP, Finsen B. Serotonin augmentation therapy by escitalopram has minimal effects on amyloid-β levels in early-stage Alzheimer's-like disease in mice. Alzheimers Res Ther. 2017 Sep 12;9(1):74. PubMed.
  21. Cirrito JR, Wallace CE, Yan P, Davis TA, Gardiner WD, Doherty BM, King D, Yuede CM, Lee JM, Sheline YI. Effect of escitalopram on Aβ levels and plaque load in an Alzheimer mouse model. Neurology. 2020 Nov 10;95(19):e2666-e2674. Epub 2020 Sep 10 PubMed.
  22. Sheline YI, Snider BJ, Beer JC, Seok D, Fagan AM, Suckow RF, Lee JM, Waligorska T, Korecka M, Aselcioglu I, Morris JC, Shaw LM, Cirrito JR. Effect of escitalopram dose and treatment duration on CSF Aβ levels in healthy older adults: A controlled clinical trial. Neurology. 2020 Nov 10;95(19):e2658-e2665. Epub 2020 Sep 10 PubMed.
  23. Bartels C, Wagner M, Wolfsgruber S, Ehrenreich H, Schneider A, Alzheimer’s Disease Neuroimaging Initiative. Impact of SSRI Therapy on Risk of Conversion From Mild Cognitive Impairment to Alzheimer's Dementia in Individuals With Previous Depression. Am J Psychiatry. 2018 Mar 1;175(3):232-241. Epub 2017 Nov 28 PubMed.
  24. Brendel M, Sauerbeck J, Greven S, Kotz S, Scheiwein F, Blautzik J, Delker A, Pogarell O, Ishii K, Bartenstein P, Rominger A, Alzheimer’s Disease Neuroimaging Initiative. Serotonin Selective Reuptake Inhibitor Treatment Improves Cognition and Grey Matter Atrophy but not Amyloid Burden During Two-Year Follow-Up in Mild Cognitive Impairment and Alzheimer's Disease Patients with Depressive Symptoms. J Alzheimers Dis. 2018;65(3):793-806. PubMed.
  25. Xu J, Wang F, Zang C, Zhang H, Niotis K, Liberman AL, Stonnington CM, Ishii M, Adekkanattu P, Luo Y, Mao C, Rasmussen LV, Xu Z, Brandt P, Pacheco JA, Peng Y, Jiang G, Isaacson R, Pathak J. Comparing the effects of four common drug classes on the progression of mild cognitive impairment to dementia using electronic health records. Sci Rep. 2023 May 19;13(1):8102. PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. Yesavage JA, Taylor JL, Friedman L, Rosenberg PB, Lazzeroni LC, Leoutsakos JS, Kinoshita LM, Perlow MJ, Munro CA, Devanand DP, Drye LT, Mintzer JE, Pollock BG, Porsteinsson AP, Schneider LS, Shade DM, Weintraub D, Lyketsos CG, Noda A, CitAD Research Group. Principal components analysis of agitation outcomes in Alzheimer's disease. J Psychiatr Res. 2016 Aug;79:4-7. Epub 2016 Apr 16 PubMed.
  2. Charu V, Rosenberg PB, Schneider LS, Drye LT, Rein L, Shade D, Lyketsos CG, Frangakis CE. Characterizing Highly Benefited Patients in Randomized Clinical Trials. Int J Biostat. 2017 May 20;13(1) PubMed.
  3. Schneider LS, Frangakis C, Drye LT, Devanand DP, Marano CM, Mintzer J, Mulsant BH, Munro CA, Newell JA, Pawluczyk S, Pelton G, Pollock BG, Porsteinsson AP, Rabins PV, Rein L, Rosenberg PB, Shade D, Weintraub D, Yesavage J, Lyketsos CG, CitAD Research Group. Heterogeneity of Treatment Response to Citalopram for Patients With Alzheimer's Disease With Aggression or Agitation: The CitAD Randomized Clinical Trial. Am J Psychiatry. 2016 May 1;173(5):465-72. Epub 2016 Jan 15 PubMed.
  4. Newell J, Yesavage JA, Taylor JL, Kraemer HC, Munro CA, Friedman L, Rosenberg PB, Madore M, Chao SZ, Devanand DP, Drye LT, Mintzer JE, Pollock BG, Porsteinsson AP, Schneider LS, Shade DM, Weintraub D, Lyketsos CG, Noda A, CitAD Research Group. Sedation mediates part of Citalopram's effect on agitation in Alzheimer's disease. J Psychiatr Res. 2016 Mar;74:17-21. Epub 2015 Dec 12 PubMed.
  5. Leonpacher AK, Peters ME, Drye LT, Makino KM, Newell JA, Devanand DP, Frangakis C, Munro CA, Mintzer JE, Pollock BG, Rosenberg PB, Schneider LS, Shade DM, Weintraub D, Yesavage J, Lyketsos CG, Porsteinsson AP, CitAD Research Group. Effects of Citalopram on Neuropsychiatric Symptoms in Alzheimer's Dementia: Evidence From the CitAD Study. Am J Psychiatry. 2016 May 1;173(5):473-80. Epub 2016 Apr 1 PubMed.
  6. Newell J, Yesavage JA, Taylor JL, Kraemer HC, Munro CA, Friedman L, Rosenberg PB, Madore M, Chao SZ, Devanand DP, Drye LT, Mintzer JE, Pollock BG, Porsteinsson AP, Schneider LS, Shade DM, Weintraub D, Lyketsos CG, Noda A, CitAD Research Group. Sedation mediates part of Citalopram's effect on agitation in Alzheimer's disease. J Psychiatr Res. 2016 Mar;74:17-21. Epub 2015 Dec 12 PubMed.
  7. Peters ME, Vaidya V, Drye LT, Devanand DP, Mintzer JE, Pollock BG, Porsteinsson AP, Rosenberg PB, Schneider LS, Shade DM, Weintraub D, Yesavage J, Lyketsos CG, Avramopoulos D, CitAD Research Group. Citalopram for the Treatment of Agitation in Alzheimer Dementia: Genetic Influences. J Geriatr Psychiatry Neurol. 2016 Mar;29(2):59-64. Epub 2015 Aug 23 PubMed.
  8. Drye LT, Spragg D, Devanand DP, Frangakis C, Marano C, Meinert CL, Mintzer JE, Munro CA, Pelton G, Pollock BG, Porsteinsson AP, Rabins PV, Rosenberg PB, Schneider LS, Shade DM, Weintraub D, Yesavage J, Lyketsos CG, CitAD Research Group. Changes in QTc interval in the citalopram for agitation in Alzheimer's disease (CitAD) randomized trial. PLoS One. 2014;9(6):e98426. Epub 2014 Jun 10 PubMed.
  9. Weintraub D, Drye LT, Porsteinsson AP, Rosenberg PB, Pollock BG, Devanand DP, Frangakis C, Ismail Z, Marano C, Meinert CL, Mintzer JE, Munro CA, Pelton G, Rabins PV, Schneider LS, Shade DM, Yesavage J, Lyketsos CG, CitAD Research Group. Time to Response to Citalopram Treatment for Agitation in Alzheimer Disease. Am J Geriatr Psychiatry. 2015 Nov;23(11):1127-33. Epub 2015 May 19 PubMed.
  10. Jones HE, Joshi A, Shenkin S, Mead GE. The effect of treatment with selective serotonin reuptake inhibitors in comparison to placebo in the progression of dementia: a systematic review and meta-analysis. Age Ageing. 2016 Jul;45(4):448-56. Epub 2016 Apr 7 PubMed.
  11. Herrmann N, Black SE, Chow T, Cappell J, Tang-Wai DF, Lanctôt KL. Serotonergic Function and Treatment of Behavioral and Psychological Symptoms of Frontotemporal Dementia. Am J Geriatr Psychiatry. 2011 Nov 4; PubMed.