The correlation between longitudinal changes in hypothalamic–pituitary–adrenal (HPA)-axis activity and changes in neurocognitive function in mixed-state bipolar II disorder

Figures & data

Table 1 Comparison of baseline characteristics of the BD-II patients and healthy controls

	BD-II	Healthy controls	T	P-value
Number, n	32	30
Gender, n (male/female)	12/22	8/22
Age, years (mean ± SD)	37.9±10.8	30.4±5.8	3.5	0.001
Years of education, years (mean ± SD)	13.9±2.2	16.4±1.3	5.2	<0.001
Age at onset, years (mean ± SD)	13.8±4
HDRS score (mean ± SD)	15.5±3.6
YMRS score (mean ± SD)	11.7±3.1
Cortisol, μg/dL (mean ± SD)	10.3±3.5	7.4±2.3	3.7	0.001
BACA (composite T score) (mean ± SD)	35.9±11.4	50.1±12.0	4.4	<0.001
Past hospitalization, n (yes/no)	(2/30)
Number of hospitalization for those ever hospitalized	1
Lifetime history of psychotic symptoms (yes/no)	(0/32)
Family history of affective disorders, n (yes/no)	(0/32)
Axis I comorbidity, n
Panic disorder (yes/no)	11/21
GAD (yes/no)	15/17
Other anxiety disorders (phobia, PTSD; yes/no)	9/23
Mood state at baseline (depressive/hypomanic/mixed)	(5/2/25)
Medication, n
Use of fluoxetine (yes/no)	28/4
Use of valproate	32/0
Use of risperdal	10
Borderline features	7

Abbreviations: HDRS, Hamilton Depression Rating Scale; YMRS, Young Mania Rating Scale; BACA, Brief Assessment of Cognition in Affective Disorders; GAD, generalized anxiety disorder; PTSD, post-traumatic stress disorder; BD-II, bipolar-II disorder.

Figure 1 Study flow chart.

Abbreviation: BD-II, bipolar-II disorder.

Table 2 Characteristics, cortisol level, and performance of cognitive test in the BD-IIpatients at baseline and each follow-up

	Baseline	Week 8	Week 16	Week 24	P-value	Effect size (Cohen’s d)
Number, n	32	20	13	10
Gender, n (male/female)	12/22	5/15	3/10	2/8
Age, years (mean ± SD)	37.9±10.8	36.5±9.9	34.2±10.1	34.8±10.6
Years of education, years (mean ± SD)	13.9±2.2	13.4±2.2	13.6±2.4	14.0±2.5
Age at onset, years (mean ± SD)	13.8±4	13.6±4.2	14.0±4.8	14.0±5.0
HDRS score (mean ± SD)	15.5±3.6	9.7±3.2	9.0±2.7	9.9±1.5	<0.001**	1.43
YMRS score (mean ± SD)	11.7±3.1	9.4±2.1	8.9±2.7	8.4±2.0	<0.001**	1.06
Mood state at baseline, n (depressive/hypomanic/mixed)	(5/2/25)			(3/0/7)
Cortisol, μg/dL (mean ± SD)	10.3±3.5	11.1±4.9	10.5±3.7	9.4±4.5	0.67	0.12
BACA (mean ± SD)
Verbal Memory (T score)	43.7±10.0			44.4±10.5	0.42	0.15
Token Motor (T score)	45.9±8.7			46.4±5.9	0.34	0.18
Digit Sequencing (T score)	44.2±8.1			46.0±4.0	0.43	0.15
Verbal Fluency (T score)	39.9±10.8			41.8±11.0	0.008**	0.51
Symbol Coding (T score)	38.3±10.6			36.0±13.1	0.69	0.08
Tower of London (T score)	47.2±12.2			48.6±12.7	0.48	0.14
BACA composite scores	31.9±19.0			33.9±20.7	0.07	0.35
Affective interference test (mean ± SD)
Total affective scores	44.1±6.7			42.5±9.1	0.38	0.17
Total non-affective scores	47.1±10.1			39.9±5.8	<0.001**	0.72
Cued affective words	45.5±6.4			43.6±5.9	0.29	0.23
Cued non-affective words	51.8±6.5			43.1±7.0	0.001**	0.67
Affective interference test: delayed (mean ± SD)
Correct affective words	54.2±4.2			51.0±7.7	0.21	0.24
Non-affective correct words	52.1±4.7			47.0±9.3	0.06	0.36
Affective false alarms	46.4±10.4			47.1±8.5	0.75	0.06
Non-affective false alarms	46.3±7.7			46.6±7.9	0.87	0.03
Emotion inhibition test (mean ± SD)
Color naming score	40.7±7.7			41.2±5.0	0.97	0.01
Neutral color word score	39.4±8.0			38.6±7.3	0.45	0.15
Affective color word score	38.5±9.2			38.9±7.4	0.015	0.47
Neutral word score	38.6±10.1			41.6±7.0	0.36	0.18
Affective composite T score	39.1±9.3			34.9±8.4	0.13	0.29
BACA (composite T score)	35.9±11.4			33.1±11.4	0.53	0.12

Notes: We adopted the GEE method to evaluate the change of clinical characteristics over the 24-week follow-up period by setting each BACA subscore as an independent variable and the treatment duration as an independent variable as well, which was interpreted as the effect of change over time.

** P<0.05.

Abbreviations: HDRS, Hamilton Depression Rating Scale; YMRS, Young Mania Rating Scale; BACA, Brief Assessment of Cognition in Affective Disorders; GEE, generalized estimating equation; BD-II, bipolar-II disorder.

Figure 2 Changes in cortisol level at baseline and endpoint.

Abbreviation: BD-II, bipolar-II disorder.

Figure 3 Changes of BACA and all subscores of BACA at baseline and endpoint (week 24).

Notes: (A) Mean BACA total (composite T score); (B) Mean Verbal Memory (T score); (C) Mean Token Motor (T score); (D) Mean Digit Sequencing (T score); (E) Mean Verbal Fluency (T score); (F) Mean Symbol Coding (T score); (G) Mean Tower of London (T score); (H) Mean affective composite (T score).
Abbreviations: BACA, Brief Assessment of Cognition in Affective Disorders; BD-II, bipolar-II disorder.

Table 3 Correlation between levels of cortisol and cognitive testing (BACA) over 24 weeks of follow-up

	Cortisol			Cortisol
	Model A			Model B
	B	Wald χ2	P-value	B	Wald χ2	P-value
BACA total (composite T score)	0.38	0.2	0.65	−0.78	0.19	0.66
Verbal Memory (T score)	−3.9	15.7	<0.001*	1.28	11.85	0.001*
Token Motor (T score)	1.4	8.6	0.003*	1.36	8.60	0.003*
Digit Sequencing (T score)	0.26	0.85	0.36	0.20	0.27	0.60
Verbal Fluency (T score)	−2.2	88.1	<0.001*	−2.24	89.86	<0.001*
Symbol Coding (T score)	0.02	<0.001	0.98	0.15	0.16	0.69
Tower of London (T score)	0.93	0.24	0.62	2.16	9.49	0.002*
Affective composite (T score)	0.57	1.29	0.26	0.36	1.35	0.25

Notes: Controlling for age, gender, years of education, and scores of HDRS and YMRS. We adopted the GEE method to evaluate the correlations between change of cortisol levels and changes in performance of BACA by setting each outcome (BACA with each subscore) as a dependent variable. Model A: controlled for treatment duration, years of education, and HDRS and YMRS scores. Model B: controlled for treatment duration, years of education, HDRS and YMRS scores, type of drug treatment (fluoxetine yes/no; risperidone yes/no), type of mood episode (depressive, hypomanic, mixed), presence of borderline PD features, past hospitalization, lifetime of psychotic symptoms, family history of affective disorder, and axis I comorbidity.

* P<0.05/8=0.00625 as significance.

Abbreviations: BACA, Brief Assessment of Cognition in Affective Disorders; HDRS, Hamilton Depression Rating Scale; PD, personality disorder; YMRS, Young Mania Rating Scale; GEE, generalized estimating equation.

Table S1 Correlations between cortisol and all BACA scales at baseline

Test and subtests	BD-II		Controls
	r	P-value	r	P-value
BACA (composite T score)	−0.11	0.65	−0.14	0.48
Verbal Memory (T score)	0.17	0.48	−0.20	0.32
Digit Sequencing (T score)	−0.08	0.74	0.04	0.86
Token Motor (T score)	−0.28	0.26	−0.13	0.53
Verbal Fluency (T score)	−0.20	0.42	−0.001	0.99
Symbol Coding (T score)	−0.25	0.30	−0.08	0.70
Tower of London (T score)	0.13	0.61	−0.14	0.47
Affective composite (T score)	−0.09	0.71	−0.10	0.63

Notes: Pearson correlation was used to evaluate the correlation between cortisol level and BACA performances in all the BD-II patients at baseline.

Abbreviation: BACA, Brief Assessment of Cognition in Affective Disorders; BD-II, bipolar II disorder.

Table S2 Correlation between levels of cortisol and cognitive testing (BACA) in mixed-state BD-II patients over 24 weeks of follow-up

	Cortisol			Cortisol
	Model A			Model B
	B	Wald χ^2	P-value	B	Wald χ^2	P-value
BACA total (composite T score)	−0.61	0.15	0.70	−0.61	0.75	0.70
Verbal Memory (T score)	−0.2	0.5	0.58	1.1	5.2	0.024
Token Motor (T score)	−0.02	0.005	0.94	−0.02	0.002	0.97
Digit Sequencing (T score)	0.1	0.06	0.81	0.43	2.80	0.10
Verbal Fluency (T score)	−2.3	1,662	<0.001*	−2.26	1,656	<0.001*
Symbol Coding (T score)	0.28	0.07	0.79	0.23	0.32	0.57
Tower of London (T score)	−0.32	0.06	0.81	2.99	11.67	0.001*
Affective composite (T score)	0.12	0.06	0.81	1.00	9.8	0.002*

Notes: Controlling for age, gender, and years of education, and scores of HDRS and YMRS.

* P<0.05/8=0.00625 as significance. We adopted the GEE method to evaluate the correlations between change of cortisol levels and changes in performance of BACA by setting each outcome (BACA with each subset) as a dependent variable. Model A: controlled for treatment duration, years of education, and HDRS and YMRS scores. Model B: controlled for treatment duration, years of education, HDRS and YMRS scores, type of drug treatment (fluoxetine yes/no; risperidone yes/no), type of mood episode (depressive, hypomanic, mixed), presence of borderline PD features, past hospitalization, lifetime of psychotic symptoms, family history of affective disorder, and axis I comorbidity.

Abbreviations: BACA, Brief Assessment of Cognition in Affective Disorders; BD-II, bipolar II disorder; HDRS, Hamilton Depression Rating Scale; PD, personality disorder; YMRS, Young Mania Rating Scale; GEE, generalized estimating equation.