A serotonin transporter gene promoter polymorphism (5-HTTLPR) and prefrontal cortical binding in major depression and suicide
Abstract
BACKGROUND: Major depression and suicide are associated with fewer serotonin transporter (5-HTT) sites. The 5'-flanking promoter region of the 5-HTT gene has a biallelic insertion/deletion (5-HTTLPR). We assayed prefrontal cortical (PFC) 5-HTT binding in major depression and suicide and examine the relationship to the 5-HTTLPR allele. METHODS: Postmortem brain samples from 220 individuals were genotyped for the 5-HTTLPR polymorphism. Binding of 5-HTT was assayed by quantitative autoradiography in the PFC of a subset of subjects (n = 159). Clinical information, including DSM-III-R Axis I diagnoses, was obtained by psychological autopsy and medical chart review. RESULTS: Binding to 5-HTT was lower in the ventral PFC of suicides compared with nonsuicides and was lower throughout the PFC of subjects with a history of major depression. The 5-HTTLPR genotype was associated with major depression but not with suicide or 5-HTT binding. CONCLUSIONS: A diffuse reduction of 5-HTT binding in the PFC of individuals with major depression may reflect a widespread impairment of serotonergic function consistent with the range of psychopathologic features in major depression. The localized reduction in 5-HTT binding in the ventral PFC of suicides may reflect reduced serotonin input to that brain region, underlying the predisposition to act on suicidal thoughts. The 5-HTTLPR genotype was not related to the level of 5-HTT binding and does not explain why 5-HTT binding is lower in major depression or suicide. Arch Gen Psychiatry. 2000;57:729-738
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Postmortem and imaging findings show decreased serotonin transporter (SERT) binding in the ventral prefrontal cortex of suicide victims, suggesting region-specific serotonergic deficits linked to behavioral dyscontrol.
“Postmortem and imaging findings show decreased serotonin transporter (SERT) binding in the ventral PFC of suicide victims, suggesting region-specific serotonergic deficits linked to behavioral dyscontrol (25).”
From Exploring the neurobiological markers of suicidal behaviors in pediatric population: a narrative review (2026) · cites this paper as [25]
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LUMBAR CSF 5- HYDROXYINDOLEACETIC ACID AND HOMOVANILLIC ACID IN AFFECTIVE SYNDROMES
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Relevance of serotonergic postmortem studies to suicidal behavior
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Methodological Strategies in Suicidea
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Serotonin and Major Depression
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Self-citationPost, R. M., & Goodwin, F. K. (2010) · Psychotherapy and Psychosomatics · doi:10.1159/000286638 · Cited by 13 · see citing works
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The interpersonal theory of suicide.
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A Systematic Review Assessing Bidirectionality between Sleep Disturbances, Anxiety, and Depression
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Neurobiology of suicidal behaviour
Mann, J. J. (2003) · Nature Reviews Neuroscience · doi:10.1038/nrn1220 · Cited by 1,260 · see citing works
Self-citationInflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications
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Stress, serotonin, and hippocampal neurogenesis in relation to depression and antidepressant effects
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Self-citationThe suicidal mind and brain: A review of neuropsychological and neuroimaging studies
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Poor replication of candidate genes for major depressive disorder using genome-wide association data
Bosker, F. J., Hartman, C. A., Nolte, I. M., Prins, B. P., Terpstra, P., Posthuma, D., van Veen, T., Willemsen, G., DeRijk, R. H., de Geus, E. J., et al. (2011) · Molecular Psychiatry · doi:10.1038/mp.2010.38 · Cited by 309 · see citing works
Toward a Biosignature for Suicide
Oquendo, M. A., Sullivan, G. M., Sudol, K., Baca-Garcia, E., Stanley, B. H., Sublette, M. E., & Mann, J. J. (2014) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2014.14020194 · Cited by 299 · see citing works
Self-citationNeumeister, A., Nugent, A. C., Waldeck, T., Geraci, M., Schwarz, M., Bonne, O., Bain, E. E., Luckenbaugh, D. A., Herscovitch, P., Charney, D. S., et al. (2004) · Archives of General Psychiatry · doi:10.1001/archpsyc.61.8.765 · Cited by 273 · see citing works
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Self-citationDysfunctional Attitudes and 5-HT<sub>2</sub> Receptors During Depression and Self-Harm
Meyer, J. H., McMain, S., Kennedy, S. H., Korman, L., Brown, G. M., DaSilva, J. N., Wilson, A. A., Blak, T., Eynan-Harvey, R., Goulding, V. S., et al. (2003) · American Journal of Psychiatry · doi:10.1176/appi.ajp.160.1.90 · Cited by 264 · see citing works
Orbitofrontal cortex response to angry faces in men with histories of suicide attempts
Jollant, F., Lawrence, N. S., Giampietro, V., Brammer, M. J., Fullana, M. A., Drapier, D., Courtet, P., & Phillips, M. L. (2008) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2008.07081239 · Cited by 262 · see citing works
Genetics of the serotonergic system in suicidal behavior
Arango, V., Huang, Y.-Y., Underwood, M. D., & Mann, J. J. (2003) · Journal of Psychiatric Research · doi:10.1016/s0022-3956(03)00048-7 · Cited by 239 · see citing works
Self-citationMeta-analysis of molecular imaging of serotonin transporters in major depression
Gryglewski, G., Lanzenberger, R., Kranz, G. S., & Cumming, P. (2014) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2014.82 · Cited by 227 · see citing works
Microglia of Prefrontal White Matter in Suicide
Schnieder, T. P., Trencevska, I., Rosoklija, G., Stankov, A., Mann, J. J., Smiley, J., & Dwork, A. J. (2014) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0000000000000107 · Cited by 202 · see citing works
Self-citationCannon, D. M., Ichise, M., Fromm, S. J., Nugent, A. C., Rollis, D., Gandhi, S. K., Klaver, J. M., Charney, D. S., Manji, H. K., & Drevets, W. C. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.05.005 · Cited by 197 · see citing works
Serotonin-1A autoreceptor binding in the dorsal raphe nucleus of depressed suicides
Boldrini, M., Underwood, M. D., Mann, J. J., & Arango, V. (2008) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2007.05.004 · Cited by 190 · see citing works
Self-citationDepression like characteristics of 5HTTLPR polymorphism and temperament in excessive internet users
Lee, Y. S., Han, D. H., Yang, K. C., Daniels, M. A., Na, C., Kee, B. S., & Renshaw, P. F. (2008) · Journal of Affective Disorders · doi:10.1016/j.jad.2007.10.020 · Cited by 188 · see citing works
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More tryptophan hydroxylase in the brainstem dorsal raphe nucleus in depressed suicides
Boldrini, M., Underwood, M. D., Mann, J. J., & Arango, V. (2005) · Brain Research · doi:10.1016/j.brainres.2005.01.083 · Cited by 174 · see citing works
Self-citationBach-Mizrachi, H., Underwood, M. D., Tin, A., Ellis, S. P., Mann, J. J., & Arango, V (2008) · Molecular Psychiatry · doi:10.1038/sj.mp.4002143 · Cited by 153 · see citing works
Self-citationDougherty, D. D., Rauch, S. L., Deckersbach, T., Marci, C., Loh, R., Shin, L. M., Alpert, N. M., Fischman, A. J., & Fava, M. (2004) · Archives of General Psychiatry · doi:10.1001/archpsyc.61.8.795 · Cited by 161 · see citing works
Neumeister, A., Hu, X.-Z., Luckenbaugh, D. A., Schwarz, M., Nugent, A. C., Bonne, O., Herscovitch, P., Goldman, D., Drevets, W. C., & Charney, D. S. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.9.978 · Cited by 161 · see citing works
Cadoret, R. J., Langbehn, D., Caspers, K., Troughton, E. P., Yucuis, R., Sandhu, H. K., & Philibert, R. (2003) · Comprehensive Psychiatry · doi:10.1053/comp.2003.50018 · Cited by 152 · see citing works
Stress, Genes and the Biology of Suicidal Behavior
Currier, D., & Mann, J. J. (2008) · Psychiatric Clinics of North America · doi:10.1016/j.psc.2008.01.005 · Cited by 142 · see citing works
Self-citationUnderwood, M. D., Kassir, S. A., Bakalian, M. J., Galfalvy, H., Dwork, A. J., Mann, J. J., & Arango, V. (2018) · Translational Psychiatry · doi:10.1038/s41398-018-0309-1 · Cited by 128 · see citing works
Self-citationOlié, E., Ding, Y., Le Bars, E., de Champfleur, N. M., Mura, T., Bonafé, A., Courtet, P., & Jollant, F. (2015) · Psychiatry Research: Neuroimaging · doi:10.1016/j.pscychresns.2015.09.020 · Cited by 123 · see citing works
Personality influences limbic-cortical interactions during sad mood induction
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Impulsive Choice and Psychological Pain in Acutely Suicidal Depressed Patients
Cáceda, R., Durand, D., Cortes, E., Prendes-Alvarez, S., Moskovciak, T., Harvey, P. D., & Nemeroff, C. B. (2014) · Psychosomatic Medicine · doi:10.1097/psy.0000000000000075 · Cited by 113 · see citing works
Neuron density and serotonin receptor binding in prefrontal cortex in suicide
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Iowa gambling task performance in currently depressed suicide attempters
Gorlyn, M., Keilp, J. G., Oquendo, M. A., Burke, A. K., & John Mann, J. (2013) · Psychiatry Research · doi:10.1016/j.psychres.2013.01.030 · Cited by 94 · see citing works
Cellular abnormalities in depression: evidence from postmortem brain tissue
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Serotonin transporter polymorphisms (5-HTTLPR) in emotion processing
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Depression and antisocial personality disorder: two contrasting disorders of 5HT function
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Neural substrates of suicide and suicidal behaviour: From a neuroimaging perspective
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Salehi, M., Saeidi, M., Amanat, M., Barias, T., Anyeji, U., Alzein, O., & Gunturu, S. (2026) · Frontiers in Pediatrics · doi:10.3389/fped.2026.1738009
- Authors
- Mann, J. J., Huang, Y.-Y., Underwood, M. D., Kassir, S. A., Oppenheim, S., Kelly, T. M., Dwork, A. J., & Arango, V.
- Affiliations
- New York State Psychiatric Institute (US)
- Venue
- Archives of General Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2000-08-01
- Volume
- 57
- Issue
- 8
- Pages
- 729
- ISSN
- 0003-990X (ISSN-L)
- OpenAlex
- W2107995274
- Cited by
- 613
- References
- 123
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 10 · 2023: 8 · 2022: 4 · 2021: 14 · 2020: 9 · 2019: 8 · 2018: 16 · 2017: 13 · 2016: 24 · 2015: 23 · 2014: 30 · 2013: 26 · 2012: 27
- FWCI
- 15.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Archives of General Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (R01MH040695, MH46745, MH-40210, R01MH040210, MH 40695)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- serotonin transporter, 5-HTTLPR, promoter polymorphism, major depressive disorder, suicide, prefrontal cortex, serotonin transporter binding, ventral prefrontal cortex, serotonergic function, postmortem brain
- MeSH terms
- Adult, Autoradiography, Mental Disorders, Carrier Proteins, Depressive Disorder, Female, Genotype, Humans, Male, Membrane Glycoproteins, Middle Aged, Nerve Tissue Proteins, Polymorphism, Genetic, Promoter Regions, Genetic, Serotonin, Sex Factors, Suicide, Gene Expression, Prefrontal Cortex, Membrane Transport Proteins, Serotonin Plasma Membrane Transport Proteins
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