The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: a systematic review and meta-analysis of cerebrospinal fluid studies

Inam, Mehmet Enes; Fernandes, Brisa S.; Salagre, Estela; Grande, Iria; Vieta, Eduard; Quevedo, João; Zhao, Zhongming

doi:10.47626/1516-4446-2022-2973

person Mehmet Enes Inam

schoolCenter for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA * These authors have contributed equally to this manuscript.

0000-0002-6779-9377

person Brisa S. Fernandes

schoolCenter for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA * These authors have contributed equally to this manuscript.

0000-0002-3797-7582

person Estela Salagre

schoolDepartment of Affective Disorders, Aarhus University Hospital, Aarhus, DenmarkschoolDepartment of Clinical Medicine, Aarhus University, Aarhus, Denmark

person Iria Grande

schoolBipolar and Depressive Disorders Unit, Hospital Clinic, Institute of Neurosciences, University of Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Salud Mental, Barcelona, Catalonia, Spain

0000-0002-0137-0666

person Eduard Vieta

schoolBipolar and Depressive Disorders Unit, Hospital Clinic, Institute of Neurosciences, University of Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Salud Mental, Barcelona, Catalonia, Spain

0000-0002-0548-0053

person João Quevedo

schoolFaillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, UTHealth, Houston, TX, USA

0000-0003-3114-6611

person Zhongming Zhao

schoolCenter for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USAschoolFaillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, UTHealth, Houston, TX, USAschoolHuman Genetics Center, School of Public Health, UTHealth, Houston, TX, USA

0000-0002-3477-0914

Correspondence: Zhongming Zhao, The University of Texas Health Science Center at Houston, School of Biomedical Informatics, 7000 Fannin Street, Houston, TX 77030, USA. E-mail:
zhongming.zhao@uth.tmc.edu

*

These authors have contributed equally to this manuscript.

Disclosure IG has received grants and served as consultant, advisor, or continuing medical education (CME) speaker for the following entities: ADAMED, Angelini, Casen Recordati, Ferrer, Janssen Cilag, Lundbeck, Lundbeck-Otsuka, Luye, and SEI Healthcare, all outside the submitted work. EV has received grants and served as consultant, advisor, or CME speaker for the following entities (unrelated to the present work): AB-Biotics, Abbott, Aimentia, Allergan, Angelini, Celon, Dainippon Sumitomo Pharma, Ferrer, Gedeon Richter, GH Research, Janssen, Lundbeck, Otsuka, Sage, Sanofi-Aventis, and Takeda. JQ has received support from LivaNova, Janssen, Myriad Neuroscience, AbbVie, Instituto de Neurociências Dr. João Quevedo, Artmed Editora, Artmed Panamericana, and Elsevier/Academic Press. The other authors report no conflicts of interest.

How to cite this article: Inam ME, Fernandes BS, Salagre E, Grande I, Vieta E, Quevedo J, et al. The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: a systematic review and meta-analysis of cerebrospinal fluid studies. Braz J Psychiatry. 2023;00:000-000. http://doi.org/10.47626/1516-4446-2022-2973

Study, country	Subjects	Sample size(P/HC)	Gender(M/F)	Skin color, % white	BMI, mean(P/HC)	Age, mean(P/HC)	Diagnostic method	Current psychiatric medications(Y/N [%], details)	TRP	KYN	3-HK	QA	KA	Key findings
SZ: total number of studies (max n=8)									5	4	1	1	6
Erhardt,²⁵ Sweden	Acute†	28/17	45/0	NA	NA	27/27	DSM-III-R	Y (11), not specified					‡	KA levels increased in SZ patients vs. controls (p = 0.038).
Holtze,²⁷ Sweden	Stable	17/33	38/12	NA	NA	33/28	NA	Y (82), multiple types					‡	No major difference in KA levels in SZ patients vs. controls; however, a KMO SNP is identified and linked to elevated levels of KA in both SZ patients and controls (SNP: rs1053230) (p = 0.023).
Issa,²⁸ United States	Acute	24/12	23/13	25§	NA	30/31	DSM-III, DSM-III-R	N	‡	‡	‡			This study controlled for freezer time. It is the only study in SZ to show increased levels of TRP in SZ patients (p < 0.01). This is also the only study with a large non-white population for SZ. There are no significant differences in KYN and 3-HK levels in SZ patients vs. controls.
Kegel,²⁹ Sweden	Stable	21/26	30/17	100	25/24	38/25	DSM-IV, BPRS, GAF	Y (100), olanzapine	‡	‡		‡	‡	Nonsignificant trend for decreased levels of TRP in SZ patients, while KYN and KA levels are significantly increased (p < 0.01 and p = 0.012, respectively). Trend toward increased QA levels, but the QA/KA ratio is lower in SZ patients than in controls (p = 0.027).
Linderholm,¹³ Sweden	Stable	16/29	45/0	NA	NA	37/25	DSM-IV, BPRS, GAF	Y (100), olanzapine	‡	‡			‡	Nonsignificant decrease in TRP levels in SZ patients, while KYN and KA levels are significantly increased (p < 0.01).
Nilsson,³⁰ Sweden	Acute	90/49	139/0	NA	NA	30/27	DSM-III-R	Y (38), not specified					‡	KA levels in SZ patients are significantly increased (p = 0.031) in drug-naive (n=37), first-episode, or those on antipsychotics (n=34), but not in those with previous history of antipsychotic use who were drug-free at the time (n=19).
Schwieler,³¹ Sweden	Stable	23/37	38/22	NA	26/23	35/23	DSM-IV, BPRS, GAF	Y (100), olanzapine, zopiclone, and lithium	‡	‡			‡	Nonsignificant trend toward decreased TRP levels and KYN:KA ratio. Significant decrease in TRP:KYN and TRP:KA ratios (p < 0.01), and significant increase in KYN and KA levels in SZ patients (p < 0.05).
Gerner,²⁶ United States	Stable	20/38\|\|	34/24	NA	NA	25/31	NA	N	‡					No significant difference in TRP levels in SZ patients vs. controls.
BD: total number of studies (max n=8)									7	1	0	1	2
Bech,³³ Denmark	Depressed	9/22	22/9	NA	NA	37/34(from MED)	Beck’s Self-Rating Scale (1961)	N	‡					No difference in TRP levels between patients and controls. Positive correlation between TRP and age (p < 0.01).
Bech,³³ Denmark	Manic	15/22	27/10	NA	NA	47/34(from MED)	Biegel’s Manic-State Rating Scale (1971)	N	‡					No difference in TRP levels between patients and controls. Positive correlation between TRP and age (p < 0.01).
Trepci,³⁶ Sweden	Euthymic	101/80	79/102	NA	25/23 (MED)	43/33 (MED)	DSM-IV	Y (NA), multiple types	‡	‡		‡	‡	Antidepressants significantly increased CSF levels of KYN, KA, and KYN:TRP ratio (p ≤ 0.02). Lamotrigine is also associated with increased levels of KYN (p = 0.03). Suicidal ideation is also associated with increased TRP levels and KYN:TRP ratio (p = 0.03 and p = 0.04, respectively). In general, KA levels are increased in bipolar patients compared to controls (p = 0.007).
Ashcroft,³² Scotland	Depressed	6/26	NA	NA	NA	-/45	PSE, Hargreaves Rating Scale	Y (NA), phenothiazine or butyrophenone groups	‡					No significant difference in TRP levels in BD patients vs. controls.
Ashcroft,³² Scotland	Manic	7/26	NA	NA	NA	-/45	PSE, Hargreaves Rating Scale	Y (NA), ECT or phenothiazine or butyrophenone groups	‡					No significant difference in TRP levels in BD patients vs. controls.
Coppen,³⁴ England	Manic	3/14	8/9	NA	NA	46/52	NA	NA; (100) lithium indicated, but not specified	‡					Plasma levels of TRP are normal, but CSF concentrations of TRP are decreased in BD patients.
Sellgren,³⁵ Sweden	Euthymic	94/113	90/117	NA	-/23	36/35	DSM-IV, MADRS, YMRS, ADE, MINI, D-KEFS	Y (73) lithium, divalproex, olanzapine, quetiapine, lamotrigine					‡	Selective increase in CSF levels of KA in BD patients with history of psychotic symptoms (p = 0.029). No significant difference in KA levels for BD patients in general compared to controls.
Gerner,²⁶ United States	Manic	15/38\|\|	28/25	NA	NA	34/31	RDC	N	‡					No significant difference in TRP levels in BD patients vs. controls.

MDD: total number of studies (max n=11)									9	4	1	2	2
Bech,³³ Denmark	Depressed	9/22	22/9	NA	NA	56/34(from MED)	Beck’s Self-Rating Scale (1961)	N	‡					No difference in TRP levels between patients and controls. Positive correlation between TRP and age (p < 0.01).
Paul,⁴² Sweden	Depressed	36/33	22/47	NA	25/24 (MED)	31/26 (MED)	MINI, ICD-10, DSM-V	Y (44), not specified		‡	‡	‡	‡	No significant differences in KYN, 3-HK, KA, or QA levels in depressed patients vs. controls.
Curzon,³⁸ England	Depressed	14/10	NA	NA	NA	51/51	Bridges & Bartlett (1977)	Y (NA), diazepam, nitrazepam	‡					No significant difference in TRP levels in depressed patients vs. controls.
Kaddurah-Daouk,⁴¹ United States	Depressed	15/18	16/17	NA	27/29	38/40	MDRS, HAM-D, HAM-A	N	‡	‡				No significant difference in TRP levels in depressed patients vs. controls.
Kaddurah-Daouk,⁴¹ United States	Remission	14/18	15/17	NA	29/29	45/40	MDRS, HAM-D, HAM-A	N	‡	‡				No significant difference in TRP and KYN levels in MDD patients in remission vs. controls. There is likely a shift toward the KIM pathway in MDD patients in remission, based on decreased 5HIAA:TRP and 5HIAA:KYN ratios (p < 0.01).
Erhardt,³⁹ Sweden	NA	64/36	59/37	NA	24/24	37/30	DSM-III-R, SCID I & II, MADRS, SIS	N				‡	‡	While there is no difference in KA levels of depressed patients with suicidal ideation vs. controls, QA levels are increased (p < 0.01).
Banki,³⁷ Hungary	Depressed	33/32	NA	NA	NA	NA	Taylor-Feighner System	N	‡					No significant difference in TRP levels in depressed patients vs. controls.
Ashcroft,³² Scotland	Depressed	9/26	NA	NA	NA	-/45	PSE, Hargreaves Rating Scale	Y (NA), ECT or phenothiazine or butyrophenone groups	‡					No significant difference in TRP levels in depressed patients vs. controls.
Hestad,⁴⁰ Norway	Depressed	44/31	30/45	NA	NA	45/44	ICD-10, F32-34 Spectra, DSM-IV, MADRS, 0	Y (51), not specified	‡	‡				No significant differences in TRP and KYN levels nor in KYN:TRP ratio in depressed patients vs. controls.
Coppen,³⁴ England	Depressed	10/14	9/15	NA	NA	52/52	NA	NA	‡					Plasma levels of TRP were normal but CSF concentrations of TRP were decreased in depressed patients (p < 0.01).
Coppen,³⁴ England	Remission	3/14	8/9	NA	NA	52/48	NA	NA	‡					No significant difference in TRP levels in MDD patients in remission vs. controls.

[TFN01t01] Acute refers to inpatient.

[TFN02t01] 3-HK = 3-hydroxykynurenine; ADE = Affective Disorder Evaluation; BD = bipolar disorder; BDI-II = Beck Depression Inventory - Second Version; BMI = body mass index; D-KEFS = Delis-Kaplan Executive Function System; ECT = electroconvulsive therapy; F = female; HAM-A = Hamilton Anxiety Rating Scale; HAM-D = Hamilton Depression Rating Scale; HC = healthy controls; KA = kynurenic acid; KIM = kynurenine; KMO = kynurenine 3-monooxygenase; M = male; MINI = Mini International Neuropsychiatric Interview; MADRS = Montgomery-Asberg Depression Rating Scale; MDD = major depressive disorder; MDRS = Male Depression Risk Scale; MED = median (or “from MED”, calculated from median); N = no; NA = not available; P = patients; PSE = Present State Examination; QA = quinolinic acid; RDC = Research Diagnostic Criteria; SCID I & II = Structured Clinical Interview for DSM; SIS = Suicide Intent Scale; SNP = single-nucleotide polymorphism; SZ = schizophrenia; TRP = tryptophan; Y = yes; YMRS = Young Mania Rating Scale.

[TFN03t01] ^†
89% first-episode.

[TFN04t01] ^‡
Measurements for the metabolite were reported.

[TFN05t01] ^§
75% African Americans reported.

[TFN06t01] ^||
Measurements reported for only 19 SZ and 37 HC individuals.

The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: a systematic review and meta-analysis of cerebrospinal fluid studies

Abstract