Interaction Between Atypical Antipsychotics and the Gut Microbiome in a Bipolar Disease Cohort
Open accessAbstract
Objectives: The atypical antipsychotic (AAP) class is often associated with metabolic disease, but the mechanistic underpinnings of this risk are not understood. Due to reports linking gut bacteria function to metabolic disease, we hypothesize that AAP treatment in adults results in gut dysbiosis potentiating metabolic criteria. This report describes recent findings linking AAP treatment with differences in gut microbiota communities in a human cohort with bipolar disorder (BD). Methods: In a cross‐sectional design, we obtained 16S ribosomal sequences from 117 BD patients (49 AAP treated, 68 non‐AAP treated). Analysis of molecular variance (AMOVA) was used to detect significant clustering of microbial communities between groups, and the inverse Simpson Diversity Index was used to calculate alpha diversity. Detection of differentially abundant operational taxonomic units (OTU s) between groups was performed using linear discriminant analysis effect size. Results: The AAP‐treated cohort was significantly younger and had an increased body mass index compared with non‐AAP‐treated patients. Groups did not differ in other psychotropic medication use with the exception of higher use of benzodiazepines in the AAP cohort. We detected significant separation between microbiota communities of AAP‐treated and nontreated patients (AMOVA; p=0.04). AAP‐treated females showed significant decreased species diversity when compared with non‐AAP‐treated females (p=0.015). Males showed no significant diversity between treatment groups (p=0.8). Differentially abundant OTU s between treatment groups were OTU 1, OTU 25, and OTU 32 that classified to Lachnospiraceae, Akkermansia, and Sutterella, respectively. Conclusions: These data suggest that AAP treatment is associated with specific representation of gut bacterial families in AAP‐treated patients. In addition, AAP treatment is associated with decreased species richness in female AAP‐treated patients.
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Atypical antipsychotics induced a decrease in microbial diversity in patients with bipolar disease, with the effect present in females but not males.
“Another recent study of patients with bipolar disease found that atypical antipsychotics induced a decrease in microbial diversity, with the effect being present in females but not in males (Flowers et al., 2017).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Flowers et al., 2017
The Results (Participant Demographics; page not provided) report lower microbial diversity in AAP-treated females than in non-AAP-treated females, but no significant difference among males. The Methods (Abstract; page not provided) describe a cross-sectional comparison, so the study supports an association, not the claim that antipsychotics induced the decrease. (LLM, conf=0.90)
Experimental — accuracy not yet measuredIn bipolar cohort, atypical antipsychotics treated individuals had significant increase in Lachnospiraceae and significant decrease in Akkermansia.
“At the microbiota genus level, individuals in this bipolar cohort treated with atypical antipsychotics exhibited a significant increase in Lachnospiraceae abundance and a significant decrease in Akkermansia.”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Flowers et al., 2017
The Participant Demographics results report that the Lachnospiraceae-classified OTU was more abundant in AAP-treated patients, while the Akkermansia-classified OTU was more abundant in untreated patients; both differences remained significant after adjustment. The claim's genus-level description is imprecise: the paper reports differences in classified OTUs, and Lachnospiraceae is a family, not a genus. Page numbers are unavailable in our copy. (LLM, conf=0.88)
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“43 Interestingly, our previous investigation in an independent bipolar cohort also showed Alistipes to drive AAP-associated separation in gut microbial communities.(33) A recent screening of more than 1000 marketed drugs was conducted against the top-40 representative gut bacterial strains, and it was observed that 24…”
BackgroundSelf-citationThe Novel Perspectives of Adipokines on Brain Health
Lee, T. H.-Y., Cheng, K. K. Y., Hoo, R. L. C., Siu, P. M., & Yau, S. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20225638 · Cited by 100 · see citing works
Interactions of commensal and pathogenic microorganisms with the mucus layer in the colon
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The Burden of Antipsychotic-Induced Weight Gain and Metabolic Syndrome in Children
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“males treated with an AP (263), suggesting that sex differences must also be considered.”
BackgroundEltokhi, A., Janmaat, I. E., Genedi, M., Haarman, B. C. M., & Sommer, I. E. (2020) · Journal of Neuroscience Research · doi:10.1002/jnr.24616 · Cited by 100 · see citing works
The effects of antipsychotic medications on microbiome and weight gain in children and adolescents
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“Interestingly, female participants receiving treatment showed a more significant reduction in diversity than male participants; a result that correlates with earlier findings of gender-dependent SGA-induced weight gain [97].”
ResultInflammatory Markers in Anorexia Nervosa: An Exploratory Study
Dalton, B., Campbell, I. C., Chung, R., Breen, G. D., Schmidt, U. H., & Himmerich, H. (2018) · Nutrients · doi:10.3390/nu10111573 · Cited by 95 · see citing works
Systematically investigating the impact of medication on the gut microbiome
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Gut Microbiome Signatures Are Biomarkers for Cognitive Impairment in Patients With Ischemic Stroke
Ling, Y., Gong, T., Zhang, J., Gu, Q., Gao, X., Weng, X., Liu, J., & Sun, J. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.511562 · Cited by 92 · see citing works
Aspirin in the Prevention of Colorectal Neoplasia
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McGovern, A. S., Hamlin, A. S., & Winter, G. (2019) · Australian & New Zealand Journal of Psychiatry · doi:10.1177/0004867419877954 · Cited by 89 · see citing works
“, 2016), nonsteroidal anti-inflammatory drugs (NSAIDs; Rogers and Aronoff, 2016) and atypical antipsychotics (AAPs; Flowers et al., 2017).”
BackgroundGut microbiota, kynurenine pathway and mental disorders – Review
Więdłocha, M., Marcinowicz, P., Janoska-Jaździk, M., & Szulc, A. (2020) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.110145 · Cited by 87 · see citing works
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Sex Differences in the Gut-Brain Axis: Implications for Mental Health
Holingue, C., Budavari, A. C., Rodriguez, K. M., Zisman, C. R., Windheim, G., & Fallin, M. D. (2020) · Current Psychiatry Reports · doi:10.1007/s11920-020-01202-y · Cited by 85 · see citing works
An investigation into physical frailty as a link between the gut microbiome and cognitive health
Verdi, S., Jackson, M. A., Beaumont, M., Bowyer, R. C. E., Bell, J. T., Spector, T. D., & Steves, C. J. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00398 · Cited by 82 · see citing works
Gut Microbiota and Bipolar Disorder: An Overview on a Novel Biomarker for Diagnosis and Treatment
Lucidi, L., Pettorruso, M., Vellante, F., Carlo, F. D., Ceci, F., Santovito, M. C., Muzio, I. D., Fornaro, M., Ventriglio, A., Tomasetti, C., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073723 · Cited by 82 · see citing works
“Furthermore, in a cohort of patients with BD, the AAPs treatment resulted in a reduction of Alistipes muciniphila when compared to BD patients not treated with AAPs [79,80].”
BackgroundResultInfluentialPredicting drug-microbiome interactions with machine learning
McCoubrey, L. E., Gaisford, S., Orlu, M., & Basit, A. W. (2021) · Biotechnology Advances · doi:10.1016/j.biotechadv.2021.107797 · Cited by 80 · see citing works
Gut Microbiota in Bipolar Depression and Its Relationship to Brain Function: An Advanced Exploration
Lu, Q., Lai, J., Lu, H., Ng, C. H., Huang, T., Zhang, H., Ding, K., Wang, Z., Jiang, J., Hu, J., et al. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00784 · Cited by 80 · see citing works
“However, this is not significant in male patients (19).”
BackgroundInfluentialGiordan, Q., Salleron, J., Vallance, C., Moriana, C., & Clément-Duchêne, C. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.716317 · Cited by 81 · see citing works
“muciniphila in the microbiota of non-obese patients (37), as well as non-steroidal anti-inflammatory drugs, which are thought to modulate interindividual diversity in the gut microbiome (16, 38).”
BackgroundMalan‐Müller, S., Valles‐Colomer, M., Foxx, C. L., Vieira‐Silva, S., van den Heuvel, L. L., Raes, J., Seedat, S., Lowry, C. A., & Hemmings, S. M. J. (2021) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2021.11.009 · Cited by 81 · see citing works
Antibacterial activity of nonantibiotics is orthogonal to standard antibiotics
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Gut microbiome in serious mental illnesses: A systematic review and critical evaluation
Nguyen, T. T., Hathaway, H., Kościółek, T., Knight, R. D., & Jeste, D. V. (2019) · Schizophrenia Research · doi:10.1016/j.schres.2019.08.026 · Cited by 78 · see citing works
“Only three articles (Evans et al., 2017; Flowers et al., 2017; Schwarz et al., 2018) overlappedwith our original review (Nguyen et al.”
BackgroundGut Microbiome: Profound Implications for Diet and Disease
Hills, R. D., Pontefract, B., Mishcon, H. R., Black, C. A., Sutton, S. C., & Theberge, C. R. (2022) · Kompass Nutrition & Dietetics · doi:10.1159/000523712 · Cited by 79 · see citing works
“In human and rodent studies, one species of the Verrucomicrobia phylum inversely correlates with obesity and T2D, Akkermansia muciniphila, a mucus colonizer that can use mucin as its sole carbon and nitrogen source in times of caloric restriction.”
BackgroundInfluentialWarren, A., Nyavor, Y., Beguelin, A., & Frame, L. A. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1365871 · Cited by 75 · see citing works
“In a study involving atypical antipsychotics in females with bipolar disorder, the treatment group demonstrated decreases in the family Lachnospiraceae and in the genuses Akkermansia and Sutterella compared to treatment-naïve controls (58).”
ResultSkott, E., Yang, L. L., Stiernborg, M., Söderström, Å., Rüegg, J., Schalling, M., Forsell, Y., Giacobini, M., & Lavebratt, C. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.05.056 · Cited by 76 · see citing works
“…all, less than 3 months, 3–6 months, > 6 months, don’t know), body mass index (BMI) and pharmacological treatment (Table 1) where melatonin, and some antipsychotic and antidepressant medication have been reported to influence the gut microbiota (Flowers, 2017; Zhu, 2018; Serrano-Contreras, 2016).”
The neurobiology of adaptation to seasons: Relevance and correlations in bipolar disorders
Maruani, J., Anderson, G., Étain, B., Lejoyeux, M., Bellivier, F., & Geoffroy, P. A. (2018) · Chronobiology International · doi:10.1080/07420528.2018.1487975 · Cited by 71 · see citing works
“It is of note that the effects of atypical antipsychotics in BD are associated with alterations in the gut microbiome (Flowers et al. 2017), suggesting that the gut has been an inadvertent target for classical BD treatments.”
BackgroundGut Microbiota and Salivary Diagnostics: The Mouth Is Salivating to Tell Us Something
Kodukula, K., Faller, D. V., Harpp, D. N., Kanara, I., Pernokas, J., Pernokas, M., Powers, W. R., Soukos, N. S., Steliou, K., & Moos, W. H. (2017) · BioResearch open access · doi:10.1089/biores.2017.0020 · Cited by 69 · see citing works
Bipolar disorder and the gut microbiome: A systematic review
Sublette, M. E., Cheung, S. G., Lieberman, E. E., Hu, S., Mann, J. J., Uhlemann, A., & Miller, J. M. (2021) · Bipolar Disorders · doi:10.1111/bdi.13049 · Cited by 68 · see citing works
Targeting the Microbiota in Pharmacology of Psychiatric Disorders
Pascale, A., Marchesi, N., Govoni, S., & Barbieri, A. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.104856 · Cited by 67 · see citing works
Approach to the diagnosis and management of dysbiosis
Alagiakrishnan, K., Morgadinho, J., & Halverson, T. (2024) · Frontiers in Nutrition · doi:10.3389/fnut.2024.1330903 · Cited by 74 · see citing works
“…also found that female patients treated with atypical antipsychotics had decreased species diversity with Lachnospiraceae, Akkermansia , and Sutterella , compared to those treated with non-atypical antipsychotics; interestingly male patients did not show a significant diversity difference (139).”
ResultVerhaegen, A. A., & Gaal, L. F. V. (2017) · Journal of Endocrinological Investigation · doi:10.1007/s40618-017-0719-6 · Cited by 68 · see citing works
Cohort Profile: The Heinz C. Prechter Longitudinal Study of Bipolar Disorder
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Self-citationEpigenetics of the molecular clock and bacterial diversity in bipolar disorder
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The Gut Microbiome in Schizophrenia and the Potential Benefits of Prebiotic and Probiotic Treatment
Liu, J. C. W., Gorbovskaya, I., Hahn, M., & Müller, D. J. (2021) · Nutrients · doi:10.3390/nu13041152 · Cited by 65 · see citing works
“A study examining the effects of APs on the GMB in patients with bipolar disorder found a significant decrease in species diversity in females [64].”
BackgroundAffective Immunology: The Crosstalk Between Microglia and Astrocytes Plays Key Role?
Yang, L., Zhou, Y., Jia, H., Qi, Y., Tu, S., & Shao, A. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01818 · Cited by 64 · see citing works
“Likewise, an abundance of Lachnospira was reported in the gut of BD patients (44).”
BackgroundPełka-Wysiecka, J., Kaczmarczyk, M., Bąba-Kubiś, A., Liśkiewicz, P., Wroński, M., Skonieczna-Żydecka, K., Marlicz, W., Misiak, B., Starzyńska, T., Kucharska-Mazur, J., et al. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8101605 · Cited by 59 · see citing works
“[32] revealed that clusters of gut microbiota were associated with pharmacological treatment in patients with bipolar disorder.”
BackgroundExploring the microbiota-gut-brain axis: impact on brain structure and function
Yassin, L. K., Nakhal, M. M., Alderei, A., Almehairbi, A., Mydeen, A. B., Akour, A. A., & Hamad, M. I. K. (2025) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2025.1504065 · Cited by 60 · see citing works
“Nevertheless, atypical antipsychotics have been shown to significantly increase Lachnospiraceae levels in bipolar cohorts’ microbiomes (Flowers et al., 2017).”
Gut microbiome: An intermediary to neurotoxicity
Dempsey, J. L., Little, M., & Cui, J. Y. (2019) · NeuroToxicology · doi:10.1016/j.neuro.2019.08.005 · Cited by 62 · see citing works
“abundance and better self-reported outcomes (Flowers et al., 2017).”
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The Role of the Microbiome in Drug Response
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Pharmacologic and Nonpharmacologic Therapies for the Gut Microbiota in Type 2 Diabetes
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Psycho-Pharmacomicrobiomics: A Systematic Review and Meta-Analysis
Minichino, A., Preston, T., Fanshawe, J. B., Fusar‐Poli, P., McGuire, P. K., Burnet, P. W. J., & Lennox, B. (2023) · Biological Psychiatry · doi:10.1016/j.biopsych.2023.07.019 · Cited by 58 · see citing works
“Across these three studies, 263 only one study included obese participants in their study population (35), one was conducted 264 in children and adolescents (27), all used polypharmacy, and all included participants in 265 “chronic” treatment with antipsychotics.”
BackgroundInfluentialAltered gut bacterial–fungal interkingdom networks in patients with current depressive episode
Jiang, H., Pan, L., Zhang, X., Zhang, Z., Zhou, Y., & Ruan, B. (2020) · Brain and Behavior · doi:10.1002/brb3.1677 · Cited by 55 · see citing works
Systematic review of probiotics as an adjuvant treatment for psychiatric disorders
Forth, E., Buehner, B. J., Storer, A., Sgarbossa, C., Milev, R. V., & Meyyappan, A. C. (2023) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2023.1111349 · Cited by 54 · see citing works
“study have been found to be associated with significant changes in the gut microbiome and a decrease in species diversity in females (Flowers et al., 2017).”
BackgroundLong-term effects of antimicrobial drugs on the composition of the human gut microbiota
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Castellani, L. N., Costa-Dookhan, K. A., McIntyre, W. B., Wright, D. C., Flowers, S. A., Hahn, M., & Ward, K. M. (2019) · Journal of Psychiatry and Brain Science · doi:10.20900/jpbs.20190013 · Cited by 53 · see citing works
“Flowers SA, Evans SJ, Ward KM, et al. Interaction Between Atypical Antipsychotics and the Gut Microbiome in a Bipolar Disease Cohort.”
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“Recent reports on the intestinal microbiota of human psychiatric disorders including depression (23, 24) and bipolar disorder (25, 26) report a similar pattern of reduced diversity.”
BackgroundThe gut microbiome in psychiatry: A primer for clinicians
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The Gut Microbiome in Bipolar Disorder and Pharmacotherapy Management
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Dysregulation of the gut–brain axis in schizophrenia and bipolar disorder
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Moody microbiome: Challenges and chances
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- Authors
- Flowers, S. A., Evans, S. J., Ward, K. M., McInnis, M. G., & Ellingrod, V. L.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Ellingrod, Vicki L.
- Venue
- Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy
- Publisher
- Wiley
- Published
- 2017-02-20
- Volume
- 37
- Issue
- 3
- Pages
- 261-267
- ISSN
- 0277-0008 (ISSN-L)
- 1875-9114
- OpenAlex
- W2562779988
- Cited by
- 235
- References
- 36
- Citations by year
- 2026: 10 · 2025: 17 · 2024: 20 · 2023: 28 · 2022: 30 · 2021: 30 · 2020: 36 · 2019: 35 · 2018: 24 · 2017: 5
- FWCI
- 11.09
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Locations
- Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy (publishedVersion)
- PubMed (publishedVersion)
- Deep Blue (University of Michigan) (submittedVersion)
- Funders
- Heinz C. Prechter Bipolar Research Fund
- Richard Tam Foundation
- University of Michigan Depression Center
- National Institute for Mental Health (R01MH082784)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- atypical antipsychotics, gut microbiota, bipolar disorder, gut dysbiosis, metabolic side effects, microbial diversity, sex differences, Akkermansia, Lachnospiraceae, Sutterella, benzodiazepines, body mass index
- MeSH terms
- Gastrointestinal Microbiome, Adult, Age Factors, Aged, Bipolar Disorder, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, RNA, Ribosomal, 16S, Sex Factors, Antipsychotic Agents, Body Mass Index, Discriminant Analysis
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