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International Journal of Bipolar Disorders logoLink to International Journal of Bipolar Disorders
. 2026 Apr 3;14:20. doi: 10.1186/s40345-026-00419-9

Thyroid peroxidase antibodies in bipolar disorder: implications for clinical sub-phenotypes and lithium response

Bishnu D Pathak 1, Mete Ercis 1, Melissa Solares-Bravo 1, Nik Ghafouri 1,2, Balwinder Singh 1, Aysegul Ozerdem 1, Jin Hong Park 1, Deniz Ceylan 1,3, Brandon J Coombes 4, Francisco Romo-Nava 5,6, Marin Veldic 1, Alfredo Cuellar-Barboza 1,7, Manuel Gardea-Resendez 1,7, Matthew L Baum 8, Katherine E Burdick 9, Marius N Stan 10, Susan L McElroy 5,6, Joanna M Biernacka 1,4, Mark A Frye 1,✉
PMCID: PMC13172239  PMID: 41931247

Abstract

Background

Bipolar disorder (BD) is a heterogeneous psychiatric disorder that is increasingly recognized as having immune-inflammatory pathogenesis. Previous studies have shown thyroid autoimmunity, in particular, thyroid peroxidase antibody (TPO-Ab), is associated with rapid cycling and antidepressant-induced mania in BD. We examined the relationship between TPO-Ab seropositivity and BD clinical sub-phenotypes and lithium response.

Methods

In this cross-sectional study, adult patients with BD enrolled in the Mayo Clinic BD Biobank were stratified into TPO-Ab positive versus negative groups using all available information (research data and electronic health records). Multivariable logistic regression analyses were conducted to assess associations between TPO-Ab status and clinical sub-phenotypes, including early age at onset, history of psychosis, rapid cycling, suicide attempt, and antidepressant-induced mania. Linear regression was used to examine associations with lithium treatment response (Alda A score). All models were adjusted for age, sex, BMI, and laboratory data source for TPO-Ab values.

Results

Among 339 individuals (mean age = 43.8 ± 15.2 years, 61.1% female), 23.9% were TPO-Ab positive. In adjusted models, TPO-Ab positivity was associated with reduced odds of history of psychosis (OR = 0.49, 95% CI 0.27–0.87, p = 0.017) and poorer treatment response to lithium (β = -0.92, 95% CI -1.74 – -0.11, p = 0.026). In exploratory analyses, no significant interactions of TPO-Ab status with age and sex were observed across different sub-phenotypes.

Conclusions

Our findings suggest that thyroid autoimmunity is associated with a distinct BD phenotype characterized by less psychosis and a poor response to lithium treatment. Future prospective longitudinal studies should validate these findings in larger cohorts and investigate underlying biological mechanisms by incorporating thyroid function status, thyroid antibody dynamics, and broader autoantibody proteome.

Supplementary Information

The online version contains supplementary material available at 10.1186/s40345-026-00419-9.

Keywords: Bipolar disorder, Thyroid, Autoantibodies, Lithium, Psychosis

Background

Bipolar disorder (BD) is a complex, multifactorial disorder which is increasingly found to be associated with immune-inflammatory changes, as evidenced by higher rates of chronic autoimmune and inflammatory comorbidities (Barbosa et al. 2014; Chen et al. 2021; Cremaschi et al. 2017; Frye 2011; Hsu et al. 2014; Joseph et al. 2021; Rosenblat and McIntyre 2017; Sidhom et al. 2012). The role of immune dysfunction in psychiatric disorders has gained increasing attention over the past few decades, with autoimmune disturbance being particularly reported in mood disorders and schizophrenia (Gibney and Drexhage 2013; Kupka et al. 2000). Studies have also shown that BD might be related to organ-specific autoimmunity; especially of the thyroid gland (Jucevičiūtė et al. 2019; Merrill and Mu 2015; Padmos et al. 2004). Autoimmune thyroiditis is one of the major causes of thyroid dysfunction (Chakrabarti 2011; Kupka et al. 2002; Rapoport and McLachlan 1996), with an estimated prevalence of approximately 5% in the United States (Antonelli et al. 2015; Dillon et al. 2025). While the influence of thyroid hormones on mood is well-established, emerging research suggests that thyroid autoantibodies may exert effects on brain functions and behaviors independent of thyroid functional status, representing a distinct potential mechanism in psychiatric morbidity (Kupka and Regeer 2007; Leyhe and Müssig 2014; Müssig et al. 2012).

The prevalence of thyroid autoantibodies, especially thyroid peroxidase antibody (TPO-Ab), in the general population is estimated to be approximately 10–15%, with higher titers observed in females and in older individuals (Amouzegar et al. 2017; Fröhlich and Wahl 2017; Vanderpump 2011). Among individuals with BD, this prevalence has been found to be notably higher, ranging from 28% to 45% as reported in different studies (Barbero et al. 2014; Kraszewska et al. 2015; Kupka et al. 2002). Consistent with these findings, a systematic review by Barbuti et al. (2017) demonstrated an increased prevalence of thyroid autoantibodies in patients with BD compared to healthy controls, especially during depressive and mixed episodes. However, the results are largely inconsistent across the literature; not all studies document similar associations (Kuman Tunçel et al. 2017; Snijders et al. 2020) which may partly be explained by differences in sample size, study design, and laboratory assays. Nevertheless, the accumulating evidence points towards the potential involvement of thyroid autoimmunity in at least a subset of BD patients. Moreover, outside of bipolar status and autoimmunity, there has been increasing interest in delineating sub-phenotypes of the illness and associated thyroid antibody status. In this context, Gan et al. (2019) reported a positive association of TPO-Abs with rapid cycling, while Koc et al. (2022) found an association with antidepressant-induced mania (AIM). These findings suggest that an in-depth investigation is warranted to clarify the role of thyroid autoimmunity in the clinical heterogeneity of BD.

The objective of this study was to examine the relationship between TPO-Ab positivity and important clinical sub-phenotypes of BD, namely early age at onset (AAO), history of psychosis, rapid cycling, AIM, suicide attempt, and lithium treatment response.

Methods

Study design, participants, and eligibility criteria

This cross-sectional study utilized data from the Mayo Clinic Bipolar Disorder Biobank (MCBDB, IRB #08-008794). Only participants recruited from Mayo Clinic sites were included in the present analysis, and all provided written informed consent at the time of their enrollment. Participants were adults (≥ 18 years) with BD confirmed by Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (SCID-IV) and were enrolled from 2009 to 2018 (Frye et al. 2015). The present analysis was limited to participants with an available TPO-Ab measurement, obtained either from previous research data or their electronic health records (EHR).

Data collection

Clinical data

Data on demographics, comorbidities, medications, and relevant clinical characteristics of BD were collected as a part of the MCBDB assessment through clinician- and patient-applied questionnaires (Frye et al. 2015).

TPO-Ab measurement

TPO-Ab status for each participant was determined either from research laboratory testing of serum collected at the time of their MCBDB enrollment or from historical clinical tests documented in the EHR (Fig. 1). All assays were conducted using certified and validated clinical immunoassays, and seropositivity (TPO-Ab positive versus TPO-Ab negative) was defined according to the reference ranges established by the respective laboratories.

Fig. 1.

Fig. 1

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Selection of cases with known TPO-Ab status from Mayo Clinic Bipolar Disorder Biobank. EHR: Electronic Health Record, TPO-Ab: Thyroid Peroxidase Antibody

Outcomes of interest

The clinical outcomes of interest were defined as specific BD sub-phenotypes (five dichotomous and one continuous variable), including:

  1. early AAO (having the first episode of mania or depression at ≤ 19 years of age).

  2. psychosis (lifetime history of hallucinations or delusions, specified in mania, depression or both or outside of episodes).

  3. rapid cycling (presence of ≥ 4 distinct mood episodes in the last year).

  4. AIM (manic/hypomanic episode occurring within 60 days of starting or increasing an antidepressant dose).

  5. suicide attempt.

  6. lithium treatment response (continuous variable).

The A-subscale of the Alda Scale (Retrospective Assessment of the Lithium Response Phenotype Scale) was used to assess lithium treatment response (Nunes et al. 2020; Scott et al. 2020). The lithium response was further categorized into poor (score ≤ 3), moderate (score 4–6), or good (score ≥ 7) responders in accordance with prior studies (Joseph et al. 2023).

Statistical analysis

The patients were grouped based on TPO-Ab status, i.e., positive or negative. The univariate analysis was performed to compare demographic and clinical characteristics between TPO-Ab positive and TPO-Ab negative patients. The association between TPO-Ab status and the clinical sub-phenotypes was assessed using multivariable regression analyses, adjusting for age, sex, BMI, and laboratory data source for TPO-Ab values (research versus EHR). Additionally, a post-hoc analysis using 2 × 2 pair-wise Fisher’s exact test (Holm-adjusted) was performed to compare lithium response distribution across the groups. While the sample size was limited, an exploratory test of interaction of TPO-Ab status with age, sex, and BD subtype was also tested for each clinical sub-phenotype. Furthermore, associations were re-examined using log-transformed standardized TPO-Ab titer as a predictor, which was calculated as the ratio of actual TPO-Ab titer to its respective laboratory-specific upper normal limit (cut-off value). The standardization of TPO-Ab titer was performed to address differences in lab cut-offs reported across few participants.

For each statistical analysis, only participants with complete data available for the variables of interest were included. All data analyses were performed by using BlueSky Statistics (version 10.3.4), and R (version 4.5.0), and p-values < 0.05 were considered statistically significant.

Results

A total of 339 patients with BD were included in this study, out of which 81 (23.9%) patients were TPO-Ab positive. The demographic and clinical characteristics of the study participants are presented in Table 1. There was a trend towards a higher proportion of females (p = 0.088) and a higher mean BMI (p = 0.059) in the TPO-Ab positive group.

Table 1.

Demographic and clinical characteristics of participants by thyroid peroxidase antibody (TPO-Ab) status

Variables TPO-Ab positive cases
(N = 81)		 TPO-Ab negative cases
(N = 258)		 All cases
(N = 339)		 P value
Age (years) 43.8 (13.7) 43.8 (15.7) 43.8 (15.2) 0.974

Sex

   • Female

   • Male

56 (69.1)

25 (30.9)

151 (58.5)

107 (41.5)

207 (61.1)

132 (38.9)

 0.088

Race (n = 334)

   • White

   • Black

   • Asian

   • Multiracial

   • Other

74 (92.5)

2 (2.5)

0 (0.0)

3 (3.8)

1 (1.2)

236 (92.9)

1 (0.4)

3 (1.2)

12 (4.7)

2 (0.8)

310 (92.8)

3 (0.9)

3 (0.9)

15 (4.5)

3 (0.9)

 0.376
BMI (kg/m2) (n = 322) 31.7 (7.9) 29.9 (7.0) 30.3 (7.3) 0.059

Marital status (n = 338)

   • No

   • Yes

32 (39.5)

49 (60.5)

119 (46.3)

138 (53.7)

151 (44.7)

187 (55.3)

 0.283

Education (n = 325)

   • HS or below

   • Above HS

12 (15.4)

66 (84.6)

33 (13.4)

214 (86.6)

45 (13.8)

280 (86.2)

 0.652

Employment status (n = 321)

   • Unemployed

   • Employed (full-time)

   • Employed (part-time)

39 (50.6)

20 (26.0)

18 (23.4)

129 (52.9)

67 (27.5)

48 (19.7)

168 (52.3)

87 (27.1)

66 (20.6)

 0.781

History of tobacco use (n = 325)

   • No

   • Yes

40 (51.3)

38 (48.7)

122 (49.4)

125 (50.6)

162 (49.8)

163 (50.2)

 0.771

Diagnosis

   • Bipolar I

   • Bipolar II

49 (60.5)

32 (39.5)

176 (68.2)

82 (31.8)

225 (66.4)

114 (33.6)

 0.199

Age at BD diagnosis (n = 303)

   • ≤ 19 years

   • > 19 years

27 (39.1)

42 (60.9)

77 (32.9)

157 (67.1)

104 (34.3)

199 (65.7)

 0.339

Comorbidities:

   • ADHD (n = 332)

   • Anxiety disorders (n = 334)

   • Eating disorders (n = 332)

   • ≥ 1 autoimmune disorders

(n = 121)

12 (15.6)

50 (64.1)

9 (11.5)

8 (17.8)

54 (21.2)

150 (58.6)

34 (13.4)

12 (15.8)

66 (19.9)

200 (59.9)

43 (13.0)

20 (16.5)

0.281

0.385

0.671

0.776

History of psychosis (mania, depression, or euthymia)

(n = 336)

 21 (25.9) 102 (40.0) 123 (36.6) 0.022

History of rapid cycling

(n = 272)

 25 (48.1) 112 (50.9) 137 (50.4) 0.713

History of ≥ 1 suicide attempt

(n = 338)

 30 (37.0) 68 (26.5) 98 (29.0) 0.067

History of lithium treatment

(n = 296)

 48 (72.7) 165 (71.7) 213 (72.0) 0.875

Current mood stabilizers

   • Lithium (n = 253)

   • Valproate (n = 216)

   • Lamotrigine (n = 238)

35 (60.3)

9 (15.3)

26 (42.6)

141 (72.3)

37 (23.6)

75 (42.4)

176 (69.6)

46 (21.3)

101 (42.4)

0.082

0.184

0.973
Lithium treatment response (n = 160)
   • Lithium Alda-A score 5.8 (2.7) 6.7 (2.0) 6.5 (2.2) 0.067
   • Lithium Alda response
      ✓ Good (score ≥ 7) 19 (48.7) 67 (55.4) 86 (53.8) 0.016
      ✓ Moderate (score 4–6) 12 (30.8) 48 (39.7) 60 (37.5)
      ✓ Poor (score ≤ 3) 8 (20.5) 6 (5.0) 14 (8.8)
History of AIM (n = 248) 8 (11.9) 38 (21.0) 46 (18.5)  0.103
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TPO-Ab: Thyroid Peroxidase Antibody, BMI: Body Mass Index, HS: Higher Secondary, ADHD: Attention-Deficit/Hyperactivity Disorder, AIM: Antidepressant-Induced Mania

Continuous variables are reported as mean (Standard Deviation) and categorical variables are reported as n (%)

On univariate analysis, TPO-Ab positive patients showed a significantly lower lifetime prevalence of psychosis compared to TPO-Ab negative group. Likewise, there was a trend towards a higher rate of suicide attempts in the TPO-Ab positive group (37.0% vs. 26.5%, p = 0.067). Furthermore, the lithium response distribution differed significantly across TPO-Ab positive and negative groups (overall Fisher’s exact test, p = 0.016) (Table 1).

After adjusting for age, sex, BMI, and laboratory data source in multivariable logistic regression models, TPO-Ab positivity was significantly associated with reduced odds of lifetime psychosis (OR = 0.49, 95% CI 0.27–0.87, p = 0.017) (Fig. 2). Furthermore, in an adjusted linear regression model, TPO-Ab positivity was significantly associated with a poorer lithium response score (β = -0.92, 95% CI -1.74 to -0.11, p = 0.026). A post-hoc analysis of lithium response distribution confirmed this difference was primarily driven by higher TPO-Ab positivity in the poor responders’ category in comparison to the other categories (p = 0.019) (Fig. 3). No significant associations were observed for other clinical sub-phenotypes, including early AAO, rapid cycling, AIM, or suicide attempts in the multivariable models.

Fig. 2.

Fig. 2

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Multivariable regression analyses assessing TPO-Ab positivity and clinical sub-phenotypes in bipolar disorder. (Each variable is adjusted for age, sex, BMI, and laboratory data source for TPO-Ab values CI: confidence interval, AAO: age at onset; OR: odds ratio, AIM: antidepressant-induced mania)

Fig. 3.

Fig. 3

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Lithium response distribution by TPO-Ab status. TPO = Thyroid peroxidase, ns = not significant

In the sensitivity analysis restricted to the research-collected cohort (n = 193), the association with the history of psychosis remained consistent with the primary analysis, demonstrating reduced odds of psychosis among TPO-Ab positive individuals (p = 0.0053). However, the association with lithium Alda-A score did not reach statistical significance although the effect estimate continued to suggest a negative association with TPO-Ab status (Supplementary Table 1).

Exploratory interaction analyses showed no significant effects of age and sex on TPO-Ab status for any of the clinical sub-phenotypes. However, one interaction between TPO-Ab status and BD subtype was observed for history of rapid cycling (p = 0.036) due to TPO-Ab being positively associated with rapid cycling in BD-I and the reverse in BD-II (Supplementary Tables 2–4). Nevertheless, this interaction did not survive multiple testing correction.

Furthermore, taking the log-transformed standardized TPO-Ab titer as a continuous measurement did not yield significant associations with any of the clinical sub-phenotypes. (Supplementary Table 5)

Discussion

In this study, we examined the relationship between thyroid autoimmunity (evidenced by TPO-Ab) and several clinical sub-phenotypes of BD. Notably, after adjustment for age, sex, BMI, and laboratory data source, TPO-Ab positivity was significantly associated with lower odds of history of psychosis as well as poorer response to lithium treatment.

BD is recognized as a biologically heterogeneous condition, with multiple potential pathophysiological pathways contributing to its onset and progress. Large-scale genomic studies have shown that Bipolar I Disorder, driven by psychosis, genetically aligns more with schizophrenia, indicating a distinct mechanistic pathway for psychosis vulnerability, whereas Bipolar II is more strongly correlated with Major Depressive Disorder (Markota et al. 2018; Singh et al. 2025; Stahl et al. 2019). These findings suggest that distinct biological pathways may be associated with different BD sub-phenotypes. This is conceptually relevant to our thyroid autoimmune subgroup where the negative association of thyroid antibodies with psychosis may have important clinical implications. Rather than implying a protective effect per se, thyroid autoimmunity may reflect a unique subset characterized by immune-endocrine mechanisms contributing to mood dysregulation with lower psychosis vulnerability. In this context, our finding of lower rate of psychosis in TPO-Ab positive cases possibly indicates that thyroid autoimmunity might be associated with BD phenotype characterized by lesser degree of psychotic symptoms. Although direct evidence remains limited, the study by Barbero et al. (2020) offers indirect support for our results, showing that thyroid autoimmunity was less correlated with positive symptoms but significantly associated with negative and depressive symptom scores in individuals with early psychosis. To our knowledge, this is a noble finding in BD which has not been previously described. Further mechanistic and longitudinal studies are needed to clarify whether this association represents a clinically meaningful phenotype. On the contrary, there is a notable body of evidence from a rare clinical entity called ‘Hashimoto encephalopathy’ or ‘Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT)’ that describes prevalence of neuropsychiatric symptoms (including psychosis) in individuals with autoimmune thyroiditis. While the etiopathogenesis of psychotic symptoms in this condition is largely unknown, it is hypothesized that these symptoms might emerge as a complex interplay of immunological and hormonal disturbances (Laurent et al. 2016; Runge et al. 2023; Wells et al. 2025). This discrepancy underscores the need to delineate the possible divergent outcomes of thyroid autoimmunity in individuals with or without BD, especially concerning the clinical presentation of psychosis.

Likewise, we found a poorer lithium treatment response in TPO-Ab positive patients. On the 0–10 Alda A scale, the observed β of − 0.92 corresponds to nearly a one-point reduction in lithium response. Given a standard deviation of 2.23 for Alda-A score in our sample, this corresponds to a Cohen’s d of approximately − 0.41, consistent with a small-to-moderate effect size. A plausible mechanism for this association could be the mediating role of hypothyroidism. It is well-established that long-term lithium treatment can cause hypothyroidism, a risk significantly increased by concomitant presence of thyroid antibodies (Bocchetta and Loviselli 2006; Cobo et al. 2015; Krishna et al. 2013; Kupka et al. 2002; Norman et al. 2024). Lithium interferes with thyroid function via multiple mechanisms, including inhibition of iodine uptake and iodotyrosine coupling, alteration of thyroglobulin structure, and blockade of thyroid hormone release, the latter being the most predominant effect (Bocchetta and Loviselli 2006; Lazarus 2009). Not only this, but also lithium has been reported to exacerbate the pre-existing thyroid autoimmune process which can further reinforce the hypothyroid state (Kibirige et al. 2013). Furthermore, thyroid dysfunction is associated with refractory mood symptoms (Chakrabarti 2011) and slower response to psychotherapeutic drugs in patients with mood disorders (Fagiolini et al. 2006). Therefore, it would be important to test whether this particular subset of patients might potentially benefit from adjunctive thyroid and/or immunomodulatory treatments. When we performed sensitivity analysis restricted to research-collected cohort, the association between TPO-Ab positivity and lithium Alda-A score was no longer statistically significant although the direction of effect remained consistently negative. The exact reason for this attenuation is uncertain; however, it may be attributable to reduced statistical power following restriction of the sample to research-collected cohort. Future prospective studies are needed to rigorously test this hypothesis, explore the treatment response to other mood stabilizers, and ultimately disentangle whether the observed association for poorer lithium response is secondary to thyroid dysfunction or reflects a more direct effect of autoimmunity.

In our analysis, we did not find a significant association between TPO-Ab positivity and a history of rapid cycling. This result is consistent with earlier reports by Kupka et al. (2002) and Bartalena et al. (1990), who also failed to detect a significant link between thyroid autoimmunity and rapid cycling in their respective cohorts. Our finding, however, contrasts with a more recent study by Gan et al. (2019), which reported a strong association (OR = 5.13, 95% CI = 2.06–12.75, p < 0.001). This discrepancy may be attributable to differences in sample characteristics; Gan et al. (2019) included relatively younger patients (mean age = 27.5 vs. 43.8 years) of Asian descent. Future studies, therefore, should explore the association of rapid cycling with demographic factors like age and race.

Similarly, we found no association between TPO-Abs and AIM. This differs from a study by Koc et al. (2022) in pediatric mood disorders, which identified TPO-Abs as a significant risk factor for AIM (OR = 3.67, 95% CI = 1.2–11.1, p = 0.022). This discrepancy may be explained by key methodological differences, as Koc et al. (2022) was conducted exclusively in a smaller cohort of pediatric patients (aged 12–18 years) while our study included a larger sample of adult participants. Given that clinical presentation and underlying immunobiology of BD may evolve across the lifespan, these differences in the study populations could lead to disparate findings. Therefore, large-scale prospective studies are needed to clarify the role of TPO autoimmunity in these clinical sub-phenotypes across different age groups.

Data from previous studies show sex-based differences in autoimmunity and clinical characteristics of BD. Most autoimmune disorders, including autoimmune thyroid diseases, are more common in females (Arnold 2003; Bauer et al. 2014; Merrill and Mu 2015; Ngo et al. 2014; Ortona et al. 2016). Likewise, females with BD are found to experience higher rate of depressive and mixed episodes, rapid cycling, and antidepressant induced mood switches (Arnold 2003; Bauer et al. 2014). In our study, while females exhibited a greater trend toward TPO-Ab seropositivity than males, sex had no interactive effect on TPO-Ab positivity across all BD sub-phenotypes. Given the limited power for interaction testing and failure to survive multiple testing correction, the observed interaction effect for rapid cycling should be considered exploratory and require replication in larger cohort.

Interestingly, our analysis using TPO-Ab titer as a continuous measure did not yield any significant associations, a finding consistent with Snijders et al. (2020). This might suggest a complex, non-linear relationship between thyroid autoimmunity and clinical presentation of BD. In other words, the effect of thyroid autoimmunity on the clinical presentation of BD may operate on a threshold basis, rather than an exact dose-response relationship. However, this hypothesis needs further investigations in longitudinal studies with larger sample size and uniform standardized laboratory assays.

Clinical implications and recommendations

In clinical practice, TPO-Ab status could serve as a candidate biomarker for a particular sub-phenotype of BD, helping clinicians to appropriately adjust the treatment strategies. Moreover, it might be used to decide whether or not to start certain mood stabilizers like lithium in at least a subset of patients with BD (e.g., if there is otherwise equipoise between choosing lithium and another mood stabilizer in a particular case).

There is an increasing interest in the potential for immunomodulation as a novel treatment approach in psychiatry including BD (Bai et al. 2020; Chandra et al. 2023; De Picker 2021; Khandaker et al. 2017; Lee et al. 2020; Lombardo et al. 2019; Miller and Raison 2015; Wittenberg et al. 2020). As such, it may be fruitful to investigate whether TPO-Ab might serve as a useful biomarker to enrich future clinical trials with BD subgroups more likely to have immune dysregulation.

Although different thyroid autoantibodies, namely TPO-Ab, thyroglobulin antibody (TG-Ab), and thyrotropin receptor antibody, are commonly described together, their individual pathophysiological contributions to BD sub-phenotypes may differ and remain to be fully elucidated (Fröhlich and Wahl 2017). In this regard, Barbero et al. (2014) found that TG-Ab positive patients (initially admitted for manic or mixed episodes) had a significantly lower readmission rate after one year of follow up while no such result was found for TPO-Ab positive cases. This highlights the fact that not all types of thyroid autoantibodies are the same, and there is a need to study their differential roles and clinical implications in BD. Not only this, but also future studies should confirm the causal link between thyroid autoimmunity and BD sub-phenotypes, and additionally, they should focus on other systemic and organ-specific antibodies (if possible, broader antibody proteome) to ascertain their differential biological roles in BD.

Limitations

Our study has various strengths. We used a well-characterized cohort of BD patients from the MCBDB. All of them were diagnosed by Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria and were representative of the real-world clinical population of patients with BD. Likewise, we used Alda-A score to assess treatment response to lithium therapy in a considerable number of cases in our sample.

However, our study has several limitations to be considered while interpreting its results. First, it is a retrospective, cross-sectional study with a moderate sample size, and without any non-psychiatric controls for comparison. Second, our study sample consisted predominantly of United States-based individuals, which limits the generalizability of the findings to more diverse populations across the globe. Third, we were unable to examine thyroid function due to unavailability of the data (Thyroid Stimulating Hormone, T3, T4), especially at the time of study enrollment when blood samples were drawn for autoantibody assays, precluding evaluation of thyroid status and autoimmunity. Likewise, we have not investigated the concomitant presence of other autoantibodies or autoimmune diseases which might have possibly contributed to differential mood features or lithium treatment response. The cross-sectional design and a single measurement of TPO-Ab status restricted our ability to assess the temporal changes in autoantibody levels over the course of illness which significantly limits the causal inference. Additionally, we could not delineate thyroid autoimmunity status as a trait or state marker of bipolar illness. Future studies should incorporate detailed thyroid function assessments, thyroid medication use, concomitant autoantibody proteome, and longitudinal changes in autoantibody titers. In addition, our TPO-Ab measurement in EHR samples (i.e., TPO-Ab results taken from EHR) might have been biased as this particular group of patients are more likely to have performed their antibody testing as a part of their clinical care. However, we have tried to address this limitation by adjusting for laboratory data source as one of the co-variates in our multivariable regression analyses.

Conclusions

Our study suggests that, in patients with BD, thyroid autoimmunity is associated with a distinct clinical profile characterized by a lower likelihood of psychosis and a poorer response to lithium. TPO-Ab status could serve as a useful biomarker to help identify these sub-phenotypes and guide personalized treatment strategies. To build on these findings, future prospective, longitudinal studies should aim to validate these associations as clinically meaningful phenotypes and explore the underlying biological mechanisms. Expanding this research to the broader autoantibody proteome may further enhance our ability to stratify patients for both illness staging and treatment selection.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary Material 1 (20.9KB, docx)

Acknowledgements

We acknowledge the research team and the patients who generously participated in the Mayo Clinic Bipolar Disorder Biobank.

Abbreviations

AAO

Age at Onset

ADHD

Attention-Deficit/Hyperactivity Disorder

AIM

Antidepressant-Induced Mania

BD

Bipolar Disorder

BMI

Body Mass Index

CI

Confidence Interval

DSM-IV

Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition

EHR

Electronic Health Record

HS

High School

IRB

Institutional Review Board

OR

Odds Ratio

SD

Standard Deviation

SREAT

Steroid-Responsive Encephalopathy associated with Autoimmune Thyroiditis

TG

Thyroglobulin

TPO-Ab

Thyroid Peroxidase Antibody

Author contributions

All authors made substantial contributions to the respective areas as follows: Study conceptualization and design: BDP, MSB, ME, NG, MAF; Funding acquisition: JLB, MAF; Supervision, Visualization and Validation: ME, JLB, MAF; Data curation: MSB, BDP, ME, BJC; Data analysis and interpretation: BDP, ME, BJC, JMB; Writing original draft: BDP; Review and editing: All authors. All the authors confirm they have read and approved the final submitted version of the manuscript.

Funding

This study was supported by a generous gift from ‘The J. Willard and Alice S. Marriott Foundation’ and from ‘The Thomas and Elizabeth Grainger Family Charitable Fund at The Chicago Community Foundation.’ The foundation had no role in the study design, collection, analysis or interpretation of the data, in the writing of the report, or in the decision to submit the manuscript for publication.

Data availability

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

Declarations

Ethical approval and consent to participate

All the participants provided written informed consent prior to enrollment in Mayo Clinic Bipolar Disorder Biobank. Ethical approval was obtained from Mayo Clinic Institutional Review Board (IRB# 08-008794).

Consent for publication

Not applicable.

Competing interests

B.S. has received research grant support from Mayo Clinic, the National Network of Depression Centers, Breakthrough Discoveries for Thriving with Bipolar Disorder and NIH. He is a KL2 Mentored Career Development Program scholar, supported by CTSA Grant Number KL2TR002379 from the NCATS. He has received honoraria (to Mayo Clinic) from Elsevier for editing a Clinical Overview on Treatment-Resistant Depression.A.O. receives funding from Mayo Clinic, through a grant Thomas and Elizabeth Grainger Family Charitable Fund at The Chicago Community Foundation and CME travel and honoraria from Carnot Laboratories.F.R.N. is supported in part by NIMH grants K23MH120503 and 1R61MH133770-01A1; is the inventor on a U.S. Patent and Trademark Office patent # 10857356.M.L.B. has received grant support from Breakthrough Discoveries for Thriving with Bipolar Disorder (BD2), Brigham and Women’s Hospital, Harvard Medical School, and receives royalties from Oxford University Press for the sale of his book “The Neuroethics of Biomarkers.” KEB receives honorarium from Breakthrough Discoveries for thriving with Bipolar Disorder (BD2) and as a consultant for Alto Neuroscience and Suven Life Sciences.S.L.M. has received consultation fees and grant support from Axsome Therapeutics.M.A.F. has received grant support from Assurex Health, Baszucki Group, Breakthrough Discoveries for Thriving with Bipolar Disorder (BD2), and Mayo Foundation. He is a consultant for Carnot Laboratories and the American Physician Institute, from which he has received CME/travel supports and honoraria. He also has a financial interest in Chymia LLC through stock ownership and royalties.

Footnotes

The original online version of this article was revised: In Table 1, the rows labeled “Lithium Alda-A score” and “Lithium Alda response,” the values provided in the ‘TPO-positive,’ ‘TPO-negative,’ and ‘all cases’ columns appear to be shifted upward by one row. The table has been updated.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Change history

5/23/2026

The original online version of this article was revised: In Table 1, the rows labeled “Lithium Alda-A score” and “Lithium Alda response,” the values provided in the ‘TPO-positive,’ ‘TPO-negative,’ and ‘all cases’ columns appear to be shifted upward by one row. The table has been updated.

Change history

6/12/2026

A Correction to this paper has been published: 10.1186/s40345-026-00430-0

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Associated Data

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Supplementary Materials

Supplementary Material 1 (20.9KB, docx)

Data Availability Statement

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

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