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Serotonin transporter availability in physically aggressive personality disordered patients: associations with trait and state aggression, and response to fluoxetine

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Abstract

Rationale

Characterizing the neuroanatomical basis of serotonergic abnormalities in severe, chronic, impulsive aggression will allow for rational treatment selection, development of novel therapeutics, and biomarkers to identify at-risk individuals.

Objectives

The aim of this study is to identify associations between regional serotonin transporter (5-HTT) availability and trait and state aggression, as well as response to the anti-aggressive effects of fluoxetine.

Methods

We examined 5-HTT availability using positron emission tomography (PET) imaging with [11C]DASB in personality disordered patients with current physical intermittent explosive disorder (IED; n = 18), and healthy comparison participants (HC; n = 11), in the anterior cingulate cortex (ACC), amygdala (AMY), ventral striatum (VST), and midbrain (MID). After PET imaging, IED patients were treated with fluoxetine 20 mg daily (n = 9) or placebo (n = 6) for 12 weeks. Trait and state aggression, trait callousness, and childhood trauma were assessed.

Results

In IED patients, trait aggression was positively associated with [11C]DASB binding in the ACC and VST; covarying for trait callousness and childhood trauma enhanced these correlations. Baseline state aggression was positively correlated with ACC [11C]DASB in IED patients. Greater baseline VST [11C]DASB binding predicted greater decreases in state aggression with fluoxetine treatment.

Conclusions

Consistent with prior reports, ACC 5-HTT is related to trait aggression, and adjusting for factors related to proactive (callousness) and reactive (childhood trauma) aggression subtypes further resolves this relationship. Novel findings of the study include a better understanding of the association between regional 5-HTT availability and state aggression, and the involvement of VST 5-HTT with trait aggression, and with the anti-aggressive effects of fluoxetine.

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Abbreviations

5-HT:

5-Hydroxytryptamine or serotonin

5-HTT:

Serotonin transporter

ACC:

Anterior cingulate cortex

AMY:

Amygdala

ASPD:

Antisocial personality disorder

AvPD:

Avoidant personality disorder

BPAQ:

Buss-Perry aggression questionnaire

BPD:

Borderline personality disorder

CTQ:

Childhood trauma questionnaire

CU:

Callous-unemotional

DAPP:

Dimensional assessment of pathological personality

HC:

Healthy comparison

IED:

Intermittent explosive disorder

MAO-A:

Monoamine oxidase-A

MRI:

Magnetic resonance imaging

MID:

Midbrain

NPD:

Narcissistic personality disorder

OAS-M:

Overt aggression scale-modified

OCPD:

Obsessive-compulsive personality disorder

PDNOS:

Personality disorder not otherwise specified

PET:

Positron emission tomography

PPD:

Paranoid personality disorder

ROI:

Region of interest

SPD:

Schizotypal personality disorder

SSRI:

Serotonin specific reuptake inhibitor

Verb/Phys:

Verbal and physical

VST:

Ventral striatum

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Acknowledgements

The authors declare no financial conflict of interest. This research was supported by Grant RO1MH063875 from the National Institute of Mental Health to Larry J. Siever and subsequently to Harold W. Koenigsberg. This publication was made possible by Grant Number MO1-RR-00071 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH).

The authors would like to thank Lauren Brickman, Cameryn Cooley, Samuel Fels, Hayley Galitzer, Nabila Hoque, Maria Martin Lopez, Jacqueline Trumbull, and Lauren Zaluda for their technical assistance on this project.

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Authors and Affiliations

  1. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Daniel R. Rosell, M. Mercedes Perez-Rodriguez, Margaret M. McClure, Erin A. Hazlett, Antonia S. New, Larry S. Siever & Harold W. Koenigsberg

  2. Department of Psychiatry, Stony Brook University, Stony Brook, NY, 11794, USA

    Mark Slifstein & Anissa Abi-Dargham

  3. Department of Psychiatry, University of Rochester Medical Center, Rochester, NY, 14642, USA

    Judy Thompson

  4. Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, 10032, USA

    Xiaoyan Xu

  5. Department of Psychology, Fairfield University, Fairfield, CT, 06824, USA

    Margaret M. McClure

  6. Mental Illness Research, Education, and Clinical Center (VISN 2), James J. Peters Veterans Affairs Medical Center, Bronx, NY, 10468, USA

    Erin A. Hazlett & Larry S. Siever

  7. Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, 06520, USA

    Nabeel Nabulsi, Yiyun Huang & Richard E. Carson

  8. Outpatient Psychiatry, James J. Peters Veterans Affairs Medical Center, Bronx, NY, 10468, USA

    Larry S. Siever & Harold W. Koenigsberg

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  1. Daniel R. Rosell
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  2. Mark Slifstein
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  3. Judy Thompson
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  4. Xiaoyan Xu
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  5. M. Mercedes Perez-Rodriguez
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  12. Larry S. Siever
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Correspondence to Harold W. Koenigsberg.

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Conflict of interest

Research reported in this publication was supported by the National Institute of Mental Health of the National Institutes of Health under Award Number R01 MH063875. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors declare no financial conflict of interest. Dr Rosell receives a royalty from UpToDate. Dr Slifstein has consulted for Curasen Therapeutics and Neurocrine Inc., and has stock options in Storm Bioscience. Dr. Thompson has received research support from diaMentis for a project unrelated to this work. Dr. Perez-Rodriguez has received research grant funding from Neurocrine Biosciences (Inc.), Millennium Pharmaceuticals, Takeda, Merck, and AI Cure for projects unrelated to this work. She is an Advisory Board member for Neurocrine Biosciences, Inc., and a consultant on an American Foundation for Suicide Prevention (AFSP) grant (LSRG-1–005-16, PI: Baca-Garcia). She is part of the research networks “CIBERSAM” (https://www.cibersam.es/en), “WORECA” (World Research Consortium forSuicide), MEMind Working Group, and the Borderline Personality Disorder International Genetics Consortium. Dr. Hazlett is supported by a VA CSR&D Research Career Scientist Award (1 IK6 CX001738). Dr. Abi-Dargham received consulting fees and/or honoraria from Sunovion, Otsuka, Merck, Neurocrine and Intracellular Therapies. She holds stock options in Systems 1 Bio and in Terran Biosciences. Dr. Koenigsberg has received research grant funding from NIMH grants R01 MH 109730, R61 MH125130 and R01 MH123069. He receives salary support from James J Peters Veterans Affairs Medical Center.

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Rosell, D.R., Slifstein, M., Thompson, J. et al. Serotonin transporter availability in physically aggressive personality disordered patients: associations with trait and state aggression, and response to fluoxetine. Psychopharmacology 240, 361–371 (2023). https://doi.org/10.1007/s00213-022-06306-2

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