Metabolomic signatures associated with weight gain and psychosis spectrum diagnoses: A pilot study

Jiwon Lee; Kenya Costa-Dookhan; Kristoffer Panganiban; Nicole MacKenzie; Quinn Casuccio Treen; Araba Chintoh; Gary Remington; Daniel J Müller; Sanjeev Sockalingam; Philip Gerretsen; Marcos Sanches; Alla Karnovsky; Kathleen A Stringer; Vicki L Ellingrod; Ivy F Tso; Stephan F Taylor; Sri Mahavir Agarwal; Margaret K Hahn; Kristen M Ward

doi:10.3389/fpsyt.2023.1169787

Metabolomic signatures associated with weight gain and psychosis spectrum diagnoses: A pilot study

Front Psychiatry. 2023 Apr 24:14:1169787. doi: 10.3389/fpsyt.2023.1169787. eCollection 2023.

Authors

Jiwon Lee^{1

2}, Kenya Costa-Dookhan^{1

2}, Kristoffer Panganiban^{1

2}, Nicole MacKenzie¹, Quinn Casuccio Treen¹, Araba Chintoh^{1

2

3}, Gary Remington^{1

2

3}, Daniel J Müller^{2

3

4

5}, Sanjeev Sockalingam^{2

3

6}, Philip Gerretsen^{2

3

7}, Marcos Sanches⁸, Alla Karnovsky⁹, Kathleen A Stringer¹⁰, Vicki L Ellingrod^{10

11}, Ivy F Tso^{11

12}, Stephan F Taylor¹¹, Sri Mahavir Agarwal^{1

2

3

13}, Margaret K Hahn^{1

2

3

13}, Kristen M Ward⁹

Affiliations

¹ Schizophrenia Division, Centre for Addiction and Mental Health, Toronto, ON, Canada.
² Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
³ Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
⁴ Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
⁵ Pharmacogenetics Research Clinic, Centre for Addiction and Mental Health, Toronto, ON, Canada.
⁶ Education, Centre for Addiction and Mental Health, Toronto, ON, Canada.
⁷ Geriatric Mental Health Services, Centre for Addiction and Mental Health, Toronto, ON, Canada.
⁸ Biostatistics, Centre for Addiction and Mental Health, Toronto, ON, Canada.
⁹ Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, United States.
¹⁰ Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI, United States.
¹¹ Department of Psychiatry, University of Michigan Medical School, Ann Arbor, MI, United States.
¹² Department of Psychiatry & Behavioral Health, Ohio State University, Columbus, OH, United States.
¹³ Banting and Best Diabetes Centre, University of Toronto, Toronto, ON, Canada.

Abstract

Psychosis spectrum disorders (PSDs), as well as other severe mental illnesses where psychotic features may be present, like bipolar disorder, are associated with intrinsic metabolic abnormalities. Antipsychotics (APs), the cornerstone of treatment for PSDs, incur additional metabolic adversities including weight gain. Currently, major gaps exist in understanding psychosis illness biomarkers, as well as risk factors and mechanisms for AP-induced weight gain. Metabolomic profiles may identify biomarkers and provide insight into the mechanistic underpinnings of PSDs and antipsychotic-induced weight gain. In this 12-week prospective naturalistic study, we compared serum metabolomic profiles of 25 cases within approximately 1 week of starting an AP to 6 healthy controls at baseline to examine biomarkers of intrinsic metabolic dysfunction in PSDs. In 17 of the case participants with baseline and week 12 samples, we then examined changes in metabolomic profiles over 12 weeks of AP treatment to identify metabolites that may associate with AP-induced weight gain. In the cohort with pre-post data (n = 17), we also compared baseline metabolomes of participants who gained ≥5% baseline body weight to those who gained <5% to identify potential biomarkers of antipsychotic-induced weight gain. Minimally AP-exposed cases were distinguished from controls by six fatty acids when compared at baseline, namely reduced levels of palmitoleic acid, lauric acid, and heneicosylic acid, as well as elevated levels of behenic acid, arachidonic acid, and myristoleic acid (FDR < 0.05). Baseline levels of the fatty acid adrenic acid was increased in 11 individuals who experienced a clinically significant body weight gain (≥5%) following 12 weeks of AP exposure as compared to those who did not (FDR = 0.0408). Fatty acids may represent illness biomarkers of PSDs and early predictors of AP-induced weight gain. The findings may hold important clinical implications for early identification of individuals who could benefit from prevention strategies to reduce future cardiometabolic risk, and may lead to novel, targeted treatments to counteract metabolic dysfunction in PSDs.

Keywords: antipsychotics; fatty acids; metabolomics; psychosis; schizophrenia; weight gain.

Grants and funding

Funding for this work was supported in part by grants from the following centers (no funding agencies were involved in study design, collection, analysis and interpretation of data, writing of the manuscript, or decision to submit for publication): the University of Michigan's Regional Comprehensive Metabolomics Resource Core (grant DK097153). KW was supported by the National Institute of Health (NIH), National Center for Advancing Translational Sciences (NCATS), Award Nos. 2UL1TR000433 and KL2TR002241. KS effort was supported in part by an NIH award from the National Institute of General Medical Sciences (NIGMS; R35GM136312). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. JL is supported by the Hilda and William Courtney Clayton Pediatric Research Fund and LG Rao/Industrial Partners Graduate Student Award from the University of Toronto, and Meighen Family Chair in Psychosis Prevention. MH holds the Meighen Family Chair in Psychosis Prevention, the Cardy Schizophrenia Research Chair, a Danish Diabetes Academy Professorship, a Steno Diabetes Center Fellowship, and a U of T Academic Scholar Award, and is funded by operating grants from the Canadian Institutes of Health Research (CIHR), the Banting and Best Diabetes Center, and the PSI Foundation. IT was supported by National Institute of Mental Health (R01MH122491). GR has received research support from the Canadian Institutes of Health Research (CIHR), University of Toronto, and HLS Therapeutics, Inc. ST has received contracted research funding from Boehringer-Ingelheim, not relevant to the content of this report.