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Prediction of lithium treatment response in bipolar depression using 5-HTT and 5-HT1A PET

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Abstract

Background

Lithium, one of the few effective treatments for bipolar depression (BPD), has been hypothesized to work by enhancing serotonergic transmission. Despite preclinical evidence, it is unknown whether lithium acts via the serotonergic system. Here we examined the potential of serotonin transporter (5-HTT) or serotonin 1A receptor (5-HT1A) pre-treatment binding to predict lithium treatment response and remission. We hypothesized that lower pre-treatment 5-HTT and higher pre-treatment 5-HT1A binding would predict better clinical response. Additional analyses investigated group differences between BPD and healthy controls and the relationship between change in binding pre- to post-treatment and clinical response. Twenty-seven medication-free patients with BPD currently in a depressive episode received positron emission tomography (PET) scans using 5-HTT tracer [11C]DASB, a subset also received a PET scan using 5-HT1A tracer [11C]-CUMI-101 before and after 8 weeks of lithium monotherapy. Metabolite-corrected arterial input functions were used to estimate binding potential, proportional to receptor availability. Fourteen patients with BPD with both [11C]DASB and [11C]-CUMI-101 pre-treatment scans and 8 weeks of post-treatment clinical scores were included in the prediction analysis examining the potential of either pre-treatment 5-HTT or 5-HT1A or the combination of both to predict post-treatment clinical scores.

Results

We found lower pre-treatment 5-HTT binding (p = 0.003) and lower 5-HT1A binding (p = 0.035) were both significantly associated with improved clinical response. Pre-treatment 5-HTT predicted remission with 71% accuracy (77% specificity, 60% sensitivity), while 5-HT1A binding was able to predict remission with 85% accuracy (87% sensitivity, 80% specificity). The combined prediction analysis using both 5-HTT and 5-HT1A was able to predict remission with 84.6% accuracy (87.5% specificity, 60% sensitivity). Additional analyses BPD and controls pre- or post-treatment, and the change in binding were not significant and unrelated to treatment response (p > 0.05).

Conclusions

Our findings suggest that while lithium may not act directly via 5-HTT or 5-HT1A to ameliorate depressive symptoms, pre-treatment binding may be a potential biomarker for successful treatment of BPD with lithium.

Clinical trial registration

PET and MRI Brain Imaging of Bipolar Disorder Identifier: NCT01880957; URL: https://clinicaltrials.gov/ct2/show/NCT01880957

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Abbreviations

BPD:

bipolar depression

PET:

positron emission tomography

MRI:

magnetic resonance imaging

5-HTT:

serotonin transporter

5-HT1A :

serotonin-1A receptor

HV:

healthy volunteer

SSRI:

selective serotonin reuptake inhibitor

CUMC:

Columbia University Medical Center

BNL:

Brookhaven National Laboratory

Yale:

Yale University Medical Center

SBU:

Stony Brook University

DSM-IV:

Diagnostic and Statistical Manual of Mental Disorders – version IV

HDRS-24:

Hamilton Depression Rating Scale – 24 Item

LEGA:

likelihood estimation in graphical analysis

V T :

distribution volume

f P :

free fraction in plasma

BPF :

binding potential

SCID:

Structured Clinical Interview for DSM-IV

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Acknowledgments

We would like to thank the study coordinators Kristin Kolb, Sunia Choudhury, Kalynn Gruenfelder, Robert Lopez, Meghan Leonhardt, and study nurse practitioners Sally South and Colleen Oliva. We would also like to thank the Yale PET Center for radiotracer synthesis, PET scanning, and blood analysis. Finally, we thank the Center for Understanding Biology using Imaging Technology (CUBIT) image analysts at SBU for their work in data importing, analysis, and quality control.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Funding

The National Institute of Mental Health provided funding for this study (R01MH090276, PI: Ramin Parsey, MD, PhD).

Author information

Authors and Affiliations

  1. Neurobiology & Behavior, Stony Brook University, Stony Brook, NY, 11794, USA

    Mala Ananth

  2. Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA

    Elizabeth A. Bartlett, Christine DeLorenzo & Ramin V. Parsey

  3. Psychiatry, Stony Brook University, Stony Brook, NY, USA

    Christine DeLorenzo, Laura Kunkel, Greg Perlman, Michala Godstrey, Ramin V. Parsey & Chuan Huang

  4. Biostatistics, Columbia University, New York, NY, USA

    Xuejing Lin & R. Todd Ogden

  5. Psychiatry and Molecular Medicine, Hofstra Northwell School of Medicine, Great Neck, NY, USA

    Nehal P. Vadhan

  6. College of Health Professions, South University, Savannah, GA, USA

    Daniel Holzmacher

  7. Radiology, Stony Brook University, Stony Brook, NY, USA

    Ramin V. Parsey & Chuan Huang

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  1. Mala Ananth
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  2. Elizabeth A. Bartlett
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Contributions

MA and EB have contributed to the acquisition, analysis, and interpretation of the data, the draft, revision and finalization of the manuscript. CD contributed to the design of the work, the acquisition and interpretation of the data, and the revision and finalization of the manuscript. XL and RTO contributed to the analysis and interpretation of the data, and the revision and finalization of the manuscript. LK, NV, GP, MG, and DH contributed to the design of the work, the acquisition and analysis of the data, and the revision and finalization of the manuscript. CH contributed to the interpretation and revision and finalization of the manuscript. RVP contributed to the conception and design of work, the acquisition and interpretation of the data, and the revision and finalization of the manuscript.

Corresponding author

Correspondence to Mala Ananth.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the Institutional Review Boards of Columbia University Medical Center (CUMC), Brookhaven National Laboratory (BNL), Yale University Medical Center (Yale), and Stony Brook University (SBU). All participants provided written, informed consent. Recruitment occurred from March 2008 through June 2017.

Competing interests

The authors declare that they have no competing interests.

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This article is part of the Topical Collection on Neurology

Mala R. Ananth and Elizabeth Bartlett are co-first author

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Ananth, M., Bartlett, E., DeLorenzo, C. et al. Prediction of lithium treatment response in bipolar depression using 5-HTT and 5-HT1A PET. Eur J Nucl Med Mol Imaging 47, 2417–2428 (2020). https://doi.org/10.1007/s00259-020-04681-6

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