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Ventral prefrontal serotonin 1A receptor binding: a neural marker of vulnerability for mood disorder and suicidal behavior?


Mood disorders and suicidal behavior have moderate heritability and are associated with altered corticolimbic serotonin 1A receptor (5-HT1A) brain binding. However, it is unclear whether this reflects genetic effects or epigenetic effects of childhood adversity, compensatory mechanisms, or illness stress-related changes. We sought to separate such effects on 5-HT1A binding by examining high familial risk individuals (HR) who have passed through the age of greatest risk for psychopathology onset with and without developing mood disorder or suicidal behavior. PET imaging quantified 5-HT1A binding potential BPND using [11C]CUMI-101 in healthy volunteers (HV, N = 23) and three groups with one or more relatives manifesting early-onset mood disorder and suicide attempt: 1. unaffected HR (N = 23); 2. HR with lifetime mood disorder and no suicide attempt (HR-MOOD, N = 26); and 3. HR-MOOD with previous suicide attempt (HR-MOOD + SA, N = 20). Findings were tested in an independent cohort not selected for family history (HV, MOOD, and MOOD + SA, total N = 185). We tested for regional BPND differences and whether brain-wide patterns distinguished between groups. Low ventral prefrontal 5-HT1A BPND was associated with lifetime mood disorder diagnosis and suicide attempt, but only in subjects with a family history of mood disorder and suicide attempt. Brain-wide 5-HT1A BPND patterns including low ventral prefrontal and mesiotemporal cortical binding distinguished HR-MOOD + SA from HV. A biological endophenotype associated with resilience was not observed. Low ventral prefrontal 5-HT1A BPND may reflect familial mood disorder and suicide-related pathology. Further studies are needed to determine if higher ventral prefrontal 5-HT1A BPND confers resilience, reducing risk of suicidal behavior in the context of familial risk, and thereby offer a potential prevention target.

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Fig. 1: Individuals with both lifetime and family history of mood disorder and suicide attempt have lower 5-HT1A binding in ventromedial prefrontal and orbitofrontal cortex with respect to healthy volunteers and patients without family history for these traits.
Fig. 2: Voxel-wise PET binding distinguishes healthy volunteers from depressed suicide attempters.

Data availability

The derived, de-identified data that support the findings of this study are available upon reasonable request from the corresponding authors. The raw data are not publicly available as participants of this study did not agree for their data to be shared publicly.


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This study was supported by National Institute of Mental Health MH108039 (NMM) MH056390, 5P50MH090964 and 5R01MH040695 (JJM) and American Foundation for Suicide Prevention (AFSP) SRG-0-102-16 (SPP). The funding sources did not participate in the design and conduct of the study; in the collection, management, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

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The authors confirm contribution to the paper as follows. Study conception and design: NMM, DAB, JJM; data collection: NMM, DAB, AB, JMM, JJM; analysis, analysis conception, and interpretation of results: SPP, FZ, EAB, ML, JJM; original draft manuscript preparation: SPP; manuscript review and editing: SPP, NMM, DAB, FZ, EAB, ML, JMM, JJM. All authors reviewed the results and approved the final version of the manuscript.

Corresponding authors

Correspondence to Spiro P. Pantazatos or J. John Mann.

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Competing interests

Authors SPP, NMM, FZ, ML, EAB, JMM have no conflicts of interest to report. JJM and AB receive royalties for commercial use of the C-SSRS from the Research Foundation for Mental Hygiene. DAB receives research support from NIMH, AFSP, the Once Upon a Time Foundation, and the Beckwith Foundation, receives royalties from Guilford Press, from the electronic self-rated version of the C-SSRS from eRT, Inc., and from performing duties as an UptoDate Psychiatry Section Editor, receives consulting fees from Healthwise, receives Honoraria from the Klingenstein Third Generation Foundation for scientific board membership and grant reviews, and is a scientific board member for AFSP. Intellectual Property, currently with no financial interest: Funding from the National Institute of Mental Health supported the development of intellectual property for BRITE, the As Safe As Possible intervention, the Computerized Adaptive Screen for Suicidal Youth (CASSY) measure, a suicide risk machine learning algorithm, and the Screening Wizard screening tool.

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Pantazatos, S.P., Melhem, N.M., Brent, D.A. et al. Ventral prefrontal serotonin 1A receptor binding: a neural marker of vulnerability for mood disorder and suicidal behavior?. Mol Psychiatry (2022).

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