Reduced kynurenine pathway metabolism and cytokine expression in the prefrontal cortex of depressed individuals

Sarah M. Clark; Ana Pocivavsek; James D. Nicholson; Francesca M. Notarangelo; Patricia Langenberg; Robert P. McMahon; Joel E. Kleinman; Thomas M. Hyde; John Stiller; Teodor T. Postolache; Robert Schwarcz; Leonardo H. Tonelli

doi:10.1503/jpn.150226

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Fig. 1
Subgroup comparisons of nontransformed values for the kynurenine:tryptophan (TRP) ratio (kynurenine formation) in the ventrolateral pre-frontal cortex (VLPFC). (A) Scatter plots with median of controls and depressed individuals; (B) depressed individuals who died by suicide versus other causes; (C) depressed individuals who died by overdose versus no overdose; (D) depressed individuals positive for alcohol versus negative for alcohol (ETOH) at the time of death; (E) depressed individuals who died from cardiovascular disease (CVD)–related events versus other causes; (F) and nonpsychiatric controls who died from CVD-related events versus accidents and homicide. *Wilcoxon test, z₁ = 2.44, p = 0.015.

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Table 1

Demographic and tissue status characteristics of postmortem brain tissue donors

	Group; no. of tissue sample donors^*

Characteristic	Control (n = 36)	Depressed (n = 45)
Age, mean ± SD, yr	42.1 ± 14.3	43.3 ± 13.6
Sex, F:M	9:27	15:30
pH, mean ± SD	6.6 ± 0.3	6.6 ± 0.2
PMI, mean ± SD, h	29.9 ± 13.6	33.95 ± 17.5
Race
White	20	26
Black	12	13
Other	4	6
Cause of death
Natural	25	7
Accident	3	10
Homicide	8	3
Suicide	0	25
Cardiovascular event	24	7
Accidental overdose	0	15
Smoker^†	14	11
Ethanol at death^‡	0	13

F = female; M = male; PMI = postmortem interval; SD = standard deviation.
↵* Unless indicated otherwise.
↵† Data on smoking status missing for 16 depressed individuals.
↵‡ Data on ethanol status missing for 11 depressed individuals.

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Table 2

Geometric means with 95% confidence intervals for kynurenine pathway metabolites and gene expression of associated enzymes in the VLPFC of controls and depressed individuals

Metabolite/enzyme	Control		Depressed		ANCOVA^*

	n	Mean (95% CI)	n	Mean (95% CI)	Statistic	p value^†	Adjusted p value^‡
TRP	35	914.8 (764.18–1095.1)	45	1050.67 (900.77–1225.53)	t₇₄ = 1.22	0.23	0.45
Kynurenine	35	40.91 (33.47–50.0)	45	39.7 (33.44–47.14)	t₇₄ = 0.24	0.81	0.89
Kynurenine:TRP	35	0.045 (0.04–0.05)	45	0.038 (0.034–0.042)	t₇₄ = 2.41	0.019	0.044
KYNA	36	1.73 (1.28–2.34)	45	1.45 (1.12–1.89)	t₇₅ = 0.9	0.37	0.50
3-HK	36	1.88 (1.45–2.44)	45	1.61 (1.28–2.02)	t₇₅ = 0.95	0.35	0.50
QUIN	35	1.59 (1.26–2.0)	45	1.11 (0.91–1.35)	t₇₄ = 2.46	0.016	0.044
IDO1	32	0.96 (0.7–1.32)	43	0.4 (0.31–0.52)	t₆₈ = 4.39	0.001	0.001
IDO2	30	0.84 (0.56–1.24)	26	0.4 (0.28–0.56)	t₅₉ = 2.95	0.005	0.018
TDO2	32	0.92 (0.66–1.30)	43	0.37 (0.28–0.49)	t₆₈ = 4.39	0.001	0.001
KAT II	32	0.95 (0.77–1.18)	42	0.85 (0.71–1.02)	t₆₇ = 0.84	0.41	0.50
KMO	32	0.97 (0.77–1.22)	43	0.86 (0.72–1.04)	t₆₈ = 0.82	0.41	0.50

3-HK = 3-hydroxykynurenine; ANCOVA = analysis of covariance; CI = confidence interval; IDO = indoleamine 2,3-dioxygenase; KAT II = kynurenine aminotransderase II; KMO = kynurenine 3-monooxygenase; KP = kynurenine pathway; KYNA = kynurenic acid; QUIN = quinolinic acid; TDO = tryptophan-2,3-dioxygenase; TRP = tryptophan; VLPFC = ventrolateral prefrontal cortex.
↵* Adjusted means were estimated by ANCOVA on log-transformed KP metabolites to test control v. depressed differences, adjusting for age, sex and postmortem interval.
↵† Significant levels for unadjusted values for multiple comparisons.
↵‡ Significant levesl for adjusted values for multiple comparisons using the Benjamini–Hochberg modification of the Bonferroni method.

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Table 3

Geometric means with 95% confidence intervals for cytokine gene expression in the VLPFC of control and depressed individuals

	Control		Depressed		ANCOVA^*

Cytokine	n	Mean (95% CI)	n	Mean (95% CI)	Statistic	p value^†	Adjusted p value^‡
IL1-β	30	1.09 (0.78–1.52)	39	0.94 (0.72–1.24)	t₆₂ = 0.68	0.50	0.55
IL2	30	0.66 (0.34–1.29)	39	0.27 (0.16–0.47)	t₆₁ = 2.15	0.036	0.07
IL4	30	1.02 (0.74–1.41)	38	0.85 (0.65–1.11)	t₆₂ = 0.93	0.36	0.43
IL5	30	0.90 (0.65–1.25)	39	1.25 (0.96–1.62)	t₄₈ = −1.64	0.11	0.15
IL6	30	1.11 (0.72–1.69)	39	0.72 (0.51–1.02)	t₆₂ = 1.63	0.11	0.15
IL13	24	0.92 (0.7–1.2)	31	0.64 (0.51–0.79)	t₆₂ = 2.23	0.029	0.06
IL33	25	1.00 (0.74–1.36)	31	0.52 (0.41–0.67)	t₄₉ = 3.57	0.001	0.009
IFN-γ	30	0.96 (0.66–1.39)	39	0.50 (0.37–0.68)	t₆₂ = 2.85	0.006	0.022
TNF-α	30	1.04 (0.79–1.38)	39	0.64 (0.51–0.8)	t₆₂ = 2.86	0.006	0.022
CCL2	30	1.29 (0.89–1.68)	39	0.76 (0.56–1.02)	t₆₂ = 2.37	0.021	0.06
COX2	25	0.80 (0.56–1.13)	31	0.89 (0.67–1.17)	t₄₉ = −0.51	0.61	0.61

ANCOVA = analysis of covariance; CCL2 = chemokine ligand 2; CI = confidence interval; COX2 = cyclooxygenase-2; IFN = interferon; IL = interleukin; TNF = tumour necrosis factor; VLPFC = ventrolateral prefrontal cortex.
↵* Adjusted means were estimated by ANCOVA on log-transformed KP metabolites to test control v. depressed differences, adjusting for age, sex and postmortem interval.
↵† Significant levels for unadjusted values for multiple comparisons.
↵‡ Significant levels for adjusted values for multiple comparisons using the Benjamini–Hochberg modification of the Bonferroni method.

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Table 4

Pearson correlations of log-transformed data on kynurenine pathway metabolites and enzymes with cytokines

Cytokine^*	Kynurenine	Kynurenine/TRP	KYNA	QUIN	IDO1	IDO2	TDO2	KAT II	KMO
IL6 (n = 70)
r	0.325	0.428	0.304	0.230	0.347	0.366	0.279	0.054	0.224
p^†	0.006	< 0.001	0.011	0.06	0.004	0.003	0.021	0.67	0.06
adj p^‡	0.015	0.001	0.024	0.09	0.009	0.007	0.039	0.70	0.10
IL13 (n = 69)
r	0.241	0.278	0.121	0.162	0.484	0.507	0.501	0.150	0.360
p^†	0.046	0.021	0.32	0.19	< 0.001	< 0.001	< 0.001	0.22	0.002
adj p^‡	0.08	0.039	0.38	0.23	0.001	0.001	0.001	0.27	0.007
IL33 (n = 56)
r	−0.067	0.413	0.119	0.166	0.415	0.467	0.540	0.381	0.341
p^†	0.63	0.002	0.38	0.22	0.002	< 0.001	< 0.001	0.004	0.010
adj p^‡	0.68	0.005	0.44	0.27	0.005	0.002	< 0.001	0.010	0.023
IFN-γ (n = 69)
r	0.087	0.262	0.035	0.190	0.689	0.755	0.533	0.167	0.381
p^†	0.48	0.030	0.78	0.12	< 0.001	< 0.001	< 0.001	0.18	0.001
adj p^‡	0.53	0.05	0.79	0.17	< 0.001	< 0.001	< 0.001	0.23	0.005
TNF-α (n = 69)
r	0.162	0.302	0.169	0.236	0.495	0.437	0.450	0.024	0.360
p^†	0.18	0.012	0.17	0.05	< 0.001	< 0.001	< 0.001	0.85	0.002
adj p^‡	0.23	0.024	0.22	0.09	< 0.001	0.001	< 0.001	0.85	0.007
CCL2 (n = 69)
r	0.170	0.449	0.362	0.297	0.210	0.230	−1.02	0.047	0.170
p^†	0.16	< 0.001	0.002	0.013	0.08	0.07	0.41	0.70	0.16
adj p^‡	0.22	0.001	0.007	0.027	0.13	0.10	0.46	0.73	0.22

adj = adjusted; CCL2 = chemokine ligand 2; IDO = indoleamine 2,3-dioxygenase; IFN = interferon; IL = interleukin; KAT II = kynurenine aminotransferase II; KMO = kynurenine 3-monooxygenase; KYNA = kynurenic acid; QUIN = quinolinic acid; TDO = tryptophan-2,3-dioxygenase; TNF = tumour necrosis factor; TRP = tryptophan.
↵* The n value includes both controls and depressed individuals.
↵† Significance level for unadjusted values for multiple comparisons.
↵‡ Adjusted for multiple comparisons using the Benjamini–Hochberg modification of the Bonferroni method.