Hair cortisol as a biomarker for mood in bipolar disorder: a pilot study

doi:10.21203/rs.3.rs-2484487/v1

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Hair cortisol as a biomarker for mood in bipolar disorder: a pilot study

https://doi.org/10.21203/rs.3.rs-2484487/v1

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Background

Bipolar disorder (BD) is characterized by episodes of manic, depressive and mixed mood states which have profound effects on the patient's quality of life. BD is diagnosed and followed up clinically using psychiatric assessment, with currently no biomarkers in clinical use for diagnosis or follow-up of the disorder. One potential biomarker is the stress hormone cortisol, but this has not been tested by comparing mood and cortisol within a cohort of people with BD. Here we asked whether hair cortisol might serve as a biomarker for mood in BD, with its advantage of averaging cortisol over months, bypassing concerns of circadian rhythm and acute stresses.

Methods

We measured cortisol in 2cm hair segments proximal to the scalp, which correspond to two months of hair growth. At the time hair was harvested, participants with BD were scored for depression and anxiety using the Hamilton Depression Rating Scale (HDRS), Beck Depression Inventory (BDI) and Hamilton Anxiety Rating Scale (HAM-A). We calculated partial Pearson correlations between mood scales and hair cortisol levels, accounting for participant’s age, gender, family status, education and medication.

Results

Hair cortisol correlated positively with mood scores in all three scales (r = 0.45–0.55, n = 38, p < = 0.01).

Conclusions

We conclude that hair cortisol may be a useful candidate biomarker for mood of BD patients over recent months.

Hair cortisol

bipolar disorder

HDRS

BDI

HAM-A

Bipolar disorder (BD) is a chronic and recurrent disorder with an estimated lifetime prevalence of 2.4% (1). It is characterized by mood swings between mania or hypomania and depression (2). The biological mechanisms underlying BD are heterogeneous and complex (3–6). Diagnosis and follow up of patients is based on psychiatric assessment, including patient self-report of mood and symptoms over the previous weeks. Although several classes of biomarkers have been studied (7), including metabolic, endocrine, immune, neurotrophic and neuroimaging markers, no objective biological measure is available to support clinical decision-making in the management of bipolar disorder. Developing such biomarkers could complement clinical interviews and help evaluate the effectiveness of treatment (8, 9).

One physiological system implicated in BD is the cortisol stress-hormone pathway, the HPA axis (10, 11). Cortisol is produced by the adrenal gland, under control of the pituitary, which in turn is regulated by hypothalamic corticotropin releasing hormone (CRH) secretion in response to stress inputs. Average cortisol levels are higher in BD patients than in control populations as documented by a meta-analysis of 41 studies (12) as well as additional studies (13–16). BD patients also show dysregulation of the HPA axis as is evident in an enhanced cortisol response to the dexamethasone suppression test (17–20) and altered pituitary size (21–23).

High cortisol levels not only correlate with BD, they can also cause BD-like symptoms. Treatment with glucocorticoid steroids, which are cortisol analogues, sets off mania or depression symptoms in a fraction of the treated population, about 4% and 2–11%, respectively (24–26). Similar findings occur in Cushing's syndrome, a condition in which cortisol levels are elevated (27–29). Cushing’s patients show mania in 30% of cases and depression in over 50% (29–31). This indicates that certain individuals are sensitive to chronically high cortisol levels in terms of triggering BD-like symptoms. Furthermore, early BD episodes are often triggered by stressful life events (32, 33).

Several additional lines of evidence suggest that the HPA axis plays a role in the pathophysiology of BD. Drugs targeting the HPA axis improved BD symptoms in the short term (34–36). Unaffected relatives of patients with BD display abnormal HPA axis activity (37, 38), although this is not an endophenotype of BD, but seems related to environmental risk factors, such as childhood trauma (12). Childhood traumatic experiences were reported to associate with epigenetic modifications of the glucocorticoid receptor (GR) gene (39, 40). Since childhood maltreatment is a known risk factor for BD (41–43), HPA axis dysfunction might act as a mediator.

In this study we hypothesize that hair cortisol levels might serve as a biomarker for mood over the past two months in BD patients. Unlike most previous studies that compared mean cortisol between BD and control populations, we measured cortisol levels within a population of people with BD and tested whether they correlate positively with depression and anxiety scales. To measure cortisol we use hair, because it offers advantages over other assays, namely blood, saliva and urine measurements (44–47). Cortisol accumulates passively in the hair, and protocols exist to measure hair cortisol. A 2cm hair sample represents about 2 months of growth, offering a window into the mean cortisol over the last two months (44, 48). For example, hair cortisol reports accurately on cortisol dynamics over months in patients with Cushing's syndrome (49). Averaging cortisol over 2 months bypasses the sensitivity of blood or saliva cortisol tests to circadian rhythm, the menstrual cycle and acute stresses at the time of the test. Hair is also easy to collect and store.

Participants

Participants diagnosed with BD were recruited from Merchavim mental health hospital and via ads approved by the Weizmann Institute IRB (study code 1312-1). Inclusion criteria were diagnosis of BD (DSM III-V), age 18–65, stable medical treatment in the last 2 months or without medical treatment, with at least 12 centimeters of natural hair with no cosmetic treatment such as dying or perming (50). The reason for requiring 12cm of hair is that the present study is part of a larger study that aimed at measuring cortisol over one year of hair growth. This requirement resulted in a larger number of females than males in the study. Here we used data only from the first 2cm segment. Since cortisol does not diffuse in hair, each 2cm segment corresponds to 2 months (51). Results for the 12cm cortisol assays will be reported separately. Exclusion criteria: substance use disorder, diagnosis of post-traumatic stress disorder (PTSD) (due to reports of lower resting levels of circulating cortisol, and from consistent evidence of heightened HPA axis response to challenge tests in chronic PTSD (52, 53)) or schizophrenia, steroid treatment in the 6 months prior to participation, surgery or brain stimulation in the 6 months prior to participation and pregnancy in the year before participating. Oral contraceptives were allowed as long as there was no change in prescription during the year prior to participation. The study was anonymous; each hair sample received a serial number, and the case report form was coded with initials and a serial number.

Hair Cortisol Measurements

We used the method of Maimon et. al. (54) to measure hair cortisol. A lock of hair (a pencil-width group of about 100 hair strands) from the vertex posterior area (47, 50) of the head was tied with a thread and cut with fine scissors as close to the scalp as possible. Samples were kept in the laboratory at room temperature. We adapted a protocol by Schonblum et al. (55) for the extraction and measurement of hair cortisol. The first 12 centimeters of each hair sample, starting from the proximal end, were segmented to six 2 cm segments. The segments were placed in vials (Fisherbrand, 21x70 mm) and washed twice with 5 ml isopropanol while mixing on an orbital rotator for 3 minutes. Isopropanol was then decanted and the open vials were left in a chemical hood to dry overnight. Then, 2 ml of methanol was added to each vial, which was sonicated for 60 min and incubated overnight (approximately 20 hours) at 50°C while shaking. The following day, methanol was transferred to 2 ml Eppendorf tubes and centrifuged for 10 minutes at 4°C. Methanol (1.5 ml) from each tube was transferred to a glass vial (Falcon, 12x75 mm) and evaporated under a stream of nitrogen at 45°C. Samples were reconstituted in 10% methanol and 90% assay buffer provided by the kit manufacturer and cortisol was quantified using competitive Enzyme-Linked Immunosorbent Assays (ELISA; Salimetrics Europe, Newmarket, cat.no1-3002-5 for cortisol, UK). Reported antibody cross-reactivity was 19.2% with dexamethasone, and less than 1% with 15 other tested steroids. Linearity was observed between 30–70 mg of hair, hence we used 30–70 mg of hair to measure cortisol. The assay detection threshold was 112 pg as specified by the manufacturer. To control for inter-assay variation, we generated a standard curve for each plate, consisting of 6 known concentrations of cortisol supplied by the kit manufacturer. To estimate inter-batch variation, we assayed multiple standard hair samples. Each standard sample was taken from a large, well-mixed, sample of hair collected from a single individual. The coefficient of variation (CV = STD/mean) of 13 standard samples measured on 2 different days was 14%.

Psychological Measurements

Interviews were conducted by a graduate student with training and supervision of a psychiatrist. Each participant was interviewed to collect medical history, medication treatment and mood evaluation. The interview included a clinical interview and supervised taking of the Hamilton Depression Rating Scale (HDRS) (56), together with a self-report using the Beck Depression Inventory (BDI) (57). Mania was rated using the Young Mania Rating Scale (YMRS) (58). Anxiety was measured using the Hamilton Anxiety Rating Scale (HAM-A) (59), general functioning was assessed using the Clinical Global Impressions inventory (CGI) (60) and the Global Assessment of Functioning scale (GAF) (61). Interviews were conducted with training and supervision of a psychiatrist.

Analysis

We excluded from the analysis one male participant with average cortisol exceeding 240 pg/ml that was higher by more than three std than the population mean. A total of 25 participants were analyzed. 13 participants returned for a second measurement. They were thus tested twice at intervals longer than 2 months, to provide a total of 38 hair samples with 38 corresponding sets of psychological scores. Sample size meets the requirements for detecting correlation of 0.45 with power = 0.8 and alpha = 0.05. We used log cortisol to adjust for the large variation in cortisol between individuals (54). We calculated partial Pearson correlations in order to adjust for participant’s age, gender, family status, education and medication. The null hypothesis was that cortisol does not correlate positively with scale scores. Hence we used a one tailed statistical test to evaluate significance. Statistical analysis was conducted using Python Scipy and pingouin packages.

Hair cortisol of participants with BD correlated with depression and anxiety scores

Participants diagnosed with BD (n = 25, 21 females, see Table 1) contributed a hair sample and were evaluated using mania, depression and anxiety scales. 13 participants returned for a second measurement. They were thus tested twice at intervals longer than 2 months, to provide a total of 38 hair samples with 38 corresponding sets of psychological scores.

Table 1

Demographic and clinical characteristics of sample
Total group	n = 25
Socio-demographics
Male	4 (16%)
Age (year); median (IQR)	32 (13)
Family status
single	18 (72%)
divorced	4 (16%)
married	3 (12%)
Years of education
less than 9	0 (0%)
9 to 12	4 (16%)
more than 12	21 (84%)
Medicated
medicated	14 (56%)
irregular	2 (8%)
unmedicated	9 (36%)
Medications	N = 16
mood stabilizer	15 (94%)
antipsychotics	10 (62.5%)
antidepressants	10 (62.5%)

The YMRS mania scale showed low scores for all participants (mean score = 2, std = 3.3), indicating that none of the participants had mania symptoms during the study. YMRS scores did not correlate with log cortisol (\(r=0.23, p=0.26\)).

The depression and anxiety scales showed a higher range of scores between individuals indicating a range of depression and anxiety syndromes in the participant group. The two depression scales BDI and HDRS correlated positively and well with log hair cortisol (adjusted partial Pearson correlation \(r=0.47\), \(p=0.007\) BDI, \(r=0.55\), \(p=0.001\) HDRS). The anxiety scale HAM-A also correlated positively and well with log cortisol (adjusted partial Pearson correlation \(r=0.45\), \(p=0.01\)) (Fig. 1A-C).

We repeated the analysis excluding the 13 repeat measurements. The HDRS correlation remained significant: \(r=0.53, p=0.025\). The other two scales show non-significant positive correlation trends: BDI \(r=0.38, p=0.09\) and HAM-A \(r=0.3, p=0.15\).

The BDI, HAM-A and HDRS scale scores also correlated well with each other (\(r=0.88\), \(p=6\cdot 1{0}^{-13}\) BDI vs. HDRS, \(r=0.72\), \(p=5\cdot 1{0}^{-7}\) BDI vs. HAM-A, \(r=0.66\), \(p=7\cdot 1{0}^{-6}\) HDRS vs. HAM-A) (Fig. 1D-F) indicating satisfactory reliability of the questionnaires.

We studied the association of hair cortisol from participants with BD and mood scales. Scores on depression and anxiety scales positively correlated with log transformed cortisol in the proximal 2cm hair segment that represents about 2 months of growth. These findings indicate that hair cortisol is a candidate biological marker for depression in BD over the previous two months.

Hair cortisol is easy to measure, minimally invasive, and is insensitive to circadian effects or acute stress, because it averages over one month per cm of hair. This averaging lends robustness to the test. There is no other method that can test, in a single measurement, the ‘tone’ of the HPA axis averaged over months.

These properties of hair cortisol may explain why a previous study that used saliva cortisol in BD participants (62) found no statistically significant associations between cortisol awakening response (CAR) and patient-evaluated Cohen’s perceived stress scale (PSS), the Hamilton depression rating scale (HDRS) and the Young mania rating scale (YMRS). Salivary cortisol measures cortisol over recent hours whereas hair cortisol from a 2cm sample gives a retrospective measure of average cortisol during the last two months.

The positive correlation of hair cortisol and mood scales within a BD population adds to the long-appreciated association of the HPA axis and mood disorders. It indicates that BD depression ‘intensity’ may be, in a sense, dose-dependent on cortisol levels averaged over months. Mechanistically, this makes sense given the widespread expression of glucocorticoid receptors in the brain, including the hippocampus and prefrontal cortex, and the effects of chronically high cortisol on neuron function, synaptic connections and neurogenesis (5–7, 29).

Hair cortisol may be a mood biomarker in conditions other than BD. A recent study on participants with Generalized Anxiety Disorder (GAD) (63) found good correlations between hair cortisol and an anxiety scale, HAM-A, and a patient health questionnaire, PHQ-4. The authors suggested that a hair cortisol test can be a simple and objective diagnostic aid in detecting GAD. Here we find correlation between cortisol and anxiety in BD, as well as between depression and anxiety scales, despite the fact that anxiety is not a core symptom in BD.

Cortisol was found to be a predictive marker for onset/relapse/recurrence in unipolar depression, namely major depression disorder (MDD), in a recent meta-analysis (64), but the results were influenced by disease state. In this meta-analysis, all other tested biomarkers did not reach significance, including neuroimaging, immune and endocrine markers. The 19 cortisol studies in the meta-analysis included blood and saliva cortisol tests, and did not include hair cortisol. Two studies on hair cortisol in MDD differ from the meta-analysis conclusions: one study found a negative correlation between hair cortisol and HAMD-17 scores (65), and another study found no significant correlation (66). It is possible that the heterogeneity of MDD may require larger samples in order to test whether hair cortisol could be a biomarker for unipolar depression.

The limitations of this study include use of a small sample of BD participants of which the majority are female. The female enrichment is due to the requirement for 12cm of hair due to a larger study; the 2cm of hair required here can apply also to many males. We note that a meta-analysis found no significant effect of the fraction of female participants on the difference in cortisol levels between BD patients and controls (12).

Future work can enlarge sample size and sample additional populations, which is important given the temporal component of BD and the large variability in cortisol in the population as well as the diverse manifestation of BD symptoms and treatment. The study excluded those with drug use disorder, a limitation given that substance use is highly comorbid with BD.

This study had no participants with high scores on the mania scale, and thus it did not probe whether hair cortisol is a useful biomarker in mania contexts. Future work can extend this study to mania and mixed states. Use of other methods to measure cortisol, such as mass spectrometry of hair samples, or blood, urine and saliva cortisol assays, can test the validity of the results. Use of multiple 2cm hair samples from the same individual over time can test whether mood correlates with cortisol longitudinally. Inclusion criteria were based on BD diagnosis based on DSM III-V, future studies can adopt a single criterion such as DSM-V.

Cortisol from a 2cm proximal hair segment (log transformed) correlated positively with depression scores for participants with BD in a pilot study. The potential use of this biomarker in psychiatry, if further validated, may be analogous to the use of the Hemoglobin A1C blood test in the field of diabetes: the test measures the average blood glucose over approximately 100 days, and is a biomarker that can track patient progress for diabetes control. We hope that this prompts further research into the feasibility of using hair cortisol as a biomarker to assist with clinical follow-up and evaluation of treatment efficacy in bipolar disorder over time.

BD - Bipolar disorder

BDI - Beck Depression Inventory

CAR - cortisol awakening response

CGI - Clinical Global Impressions inventory

CRH - corticotropin releasing hormone

GAD - Generalized Anxiety Disorder

GAF - Global Assessment of Functioning scale

GR - glucocorticoid receptor

HAM-A - Hamilton Anxiety Rating Scale

HDRS - Hamilton Depression Rating Scale

MDD - major depression disorder

PSS - patient-evaluated Cohen’s perceived stress scale

PTSD - post-traumatic stress disorder

YMRS - Young Mania Rating Scale

Ethics approval and consent to participate

The study protocol was approved by the ethics committee of Merchavim mental health hospital (study code 613) and by the Review Board of the Weizmann Institute of Science (study code 1312-1). Written informed consent was obtained from all participants. All procedures were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration.

Consent for publication

Not Applicable

Availability of data and materials

Further information and requests for resources should be directed to and will be fulfilled by the Lead Contact, Uri Alon ([email protected]). This study did not generate new unique reagents.

Competing interests

All co-authors declare that they have no conflict of interest

Funding

Not Applicable

Authors' contributions

L.M., T.M., and U.A. designed the study. L.M., B.C. and G.C.R recruited participants. L.M. conducted the interviews under the supervision of B.C and G.C.R. L.M., T.D. and A.B. performed the experiments. T.M., A.M., D.H. and L.M. analyzed the data. L.M., T.M., G.C.R and U.A. wrote the paper.

Acknowledgements

Not Applicable

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Hair cortisol as a biomarker for mood in bipolar disorder: a pilot study

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Abstract

Background

Methods

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Background

Methods

Participants

Hair Cortisol Measurements

Psychological Measurements

Analysis

Results

Hair cortisol of participants with BD correlated with depression and anxiety scores

Discussion

Conclusions

Abbreviations

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Competing interests

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Acknowledgements

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