Table 1.
Summary of case-control studies investigating cytokines in internalizing disorders.
| Study | Country | Participants | Age range | Diagnostic method | Internalizing disorder/co-morbidity | Cytokines investigated | Summary of findings |
|---|---|---|---|---|---|---|---|
| Brambilla et al., 2004* | Italy | Clinical (outpatient) | 6-14y | K-SADS (DSM-IV) | MDD, DYS Co-morbidity: Axis I co-morbidities were excluded. |
TNF-α, IL-1β |
↑ IL-1β & TNF-α in MDD vs HC (NS). ↑ IL-1β in DYS vs HC (NS). ↓ TNF-α in DYS vs HC. No difference between MDD vs DYS. Negative correlation between depression severity and TNF-α in MDD patients. Positive correlation between depression and anxiety severity and IL-1β in MDD patients. Quality Rating: Moderate |
| Pervanidou et al., 2007* | Greece | Clinical (hospitalization) | 7-18y | K-SADS-PL (DSM-IV) | PTSD-MVA Co-morbidity: Other mental disorders or pre-existing psychopathology were excluded. |
IL-6 | ↑ morning IL-6 in PTSD > non-PTSD > HC at baseline, but not 1 month or 6 month follow up. Morning IL-6 positively correlated with PTSD severity at 6 month follow up. IL-6 levels correlated with salivary cortisol. Quality Rating: Moderate |
| Gabbay et al., 2009a* | USA | Clinical (inpatient/outpatient) | 12-19y | K-SADS-PL (DSM-IV) | MDD Co-morbidity: n = 16 (53%) ADHD, Anxiety, ODD |
IFN-γ, TNF-α, IL-6, IL-4, IL-1β |
↑ IFN-γ in MDD vs HC. ↑ IFN-γ/IL-4 ratio in MDD vs HC. No correlations found for MDD features and the investigated cytokines. Quality Rating: High |
| Study | Country | Participants | Age range | Diagnostic method | Internalizing disorder/co-morbidity | Cytokines investigated | Summary of findings |
| Gabbay et al. (2009b) | USA | Clinical (inpatient/outpatient) | 12-19y | K-SADS-PL (DSM-IV) | MDD Co-morbidity: n = 14 (78%) ADHD, Anxiety, ODD |
IFN-γ, TNF-α, IL-6, IL-4, IL-1β |
↓ TNF-α in suicidal MDD vs non-suicidal MDD. ↑ IFN-γ in suicidal MDD vs HC. ↑ IFN-γ in non-suicidal MDD vs HC. ↑ IFN-γ/IL-4 ratio in non-suicidal MDD vs HC. Quality Rating: Moderate |
| Henje-Blom et al., 2012* | Sweden | Clinical (outpatient) | 14-18y | DAWBA (DSM-IV) | GAD, SoP, SP, PD, SAD, PTSD and/or MDD Comorbidity: permitted, but details not reported |
IFN-γ, TNF-α, IL-2, IL-6, IL-1β, IL-10 |
↑ IL-2, IL-1β, IL-10 in clinical sample vs HC. ↑ IL-2 in medicated clinical sample vs HC. ↑ IL-6 in unmedicated clinical sample vs HC. ↑ IFN-γ, IL-6 associated with self-assessment of more severe depression and anxiety symptoms. Quality Rating: Moderate |
| Byrne et al. (2013) | Australia | Community (high school) | 12-18y | K-SADS (DSM-IV) | MDD, DNOS Co-morbidity: Not specified |
IL-2, IL-4, IL-6, IL-8, IL-1α, IL-10, IL-12, IL-13 IL-17, TNF-α, IFN-α2, IFN-γ |
No difference in the investigated cytokines between depressed and healthy adolescents. Quality Rating: Moderate |
| Gariup et al., 2015* | Spain | Clinical (inpatient) | 8-17y | K-SADS-PL (DSM-IV-TR) | Anxiety, Depression Co-morbidity: Not specified |
IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IFN-γ, TNF-α, GM-CSF |
↑ IL-1β in anxiety and depression vs HC. ↑ IL-8 in anxiety and depression vs HC. ↑ IL-6 and IL-10 in depression. Quality Rating: Moderate |
| Study | Country | Participants | Age range | Diagnostic method | Internalizing disorder/co-morbidity | Cytokines investigated | Summary of findings |
| Pallavi et al., 2015* | India | Clinical (outpatient) | 13-18y | SCID-I/NP (DSM-IV) | Depression Co-morbidity: Not specified |
IL-1β, IL-2, IL-6, TGF-β1 IFN-γ, IL-17, TNF-α, IL-10 |
↑ IL-2 and IL-6 in depression vs HC. ↑ IL-2 in male depression vs male HC. ↑ IL-6 in female depression vs female HC. ↑ TGF-β1 in medicated vs non-medicated depression. Negative correlation between depression, state anxiety, trait anxiety scores and TGF-β1 levels. In depressed females, TNF-α positively correlated with depression scores. Quality Rating: Moderate |
| Ayaydin et al., 2016* | Turkey | Clinical (outpatient) | 13-18y | K-SADS-PL (DSM-IV) | PTSD Co-morbidity: MDD (61%) |
IFN-γ, TNF-α | ↓ IFN-γ in PTSD vs HC. Quality Rating: Moderate |
| Miklowitz et al., 2016* | USA | clinical (outpatient) | 12-18y | K-SADS-PL (DSM-IV-TR) | MDD Co-morbidity: ADHD (30.8%) Anxiety (38.5%) |
IL-1β, IL-6, IL-8, IL-10, TNF-α |
No difference in tested cytokines between MDD vs HC. No correlations with the tested cytokines and medication status or mood symptoms. Quality Rating: Moderate |
| Şimşek et al., 2016* | Turkey | clinical (hospitalization) | 7-17y | K-SADS-PL (DSM-V) | OCD Co-morbidity: Tic Disorder (11.8%) |
IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ IL-17a |
↑ IL-17a, TNF-α, and IL-2 in OCD vs HC. Negative correlation between TNF-α levels and OCD symptoms. Quality Rating: Moderate |
| Study | Country | Participants | Age range | Diagnostic method | Internalizing disorder/co-morbidity | Cytokines investigated | Summary of findings |
| Belem da Silva et al., 2017* | Brazil | Community (schools) | 10-17y | K-SADS-PL (DSM-IV-TR) | MDD, GAD, SAD, SoP, PD Co-morbidity: Not specified |
IL-6, IL-10 | ↑ IL-6 in internalizing disorders compared to those without internalizing disorders. Quality Rating: Moderate |
| Rodríguez et al., 2017* | Spain | Clinical (outpatient) | 8-19y | K-SADS-PL (DSM-IV) | OCD Co-morbidity: Anxiety or mood disorder (45.1%) ADHD or tic disorder (21.6%) |
IL-1β, IL-6, IL-8, TNF-α, GM-CSF |
No difference in tested cytokines between OCD vs HC during basal conditions. Higher cytokine levels in OCD observed: LPS > DEX + LPS > basal conditions. After treatment with LPS, ↑ IL-1β, IL-6, IL-8, TNF-α, GM-CSF in OCD vs HC. After treatment with LPS + DEX, ↑ IL-1β, IL-6, and IL-8 in OCD vs HC. Quality Rating: Moderate |
| Colak-Sivri et al., 2018* | Turkey | Clinical (outpatient) | 8-18y | K-SADS-PL (DSM-V) | OCD Co-morbidity: GAD (29.5%) SoP (27.3%) SAD (9.1%) |
TNF-α, IL-17 TGF-β, IL-12, |
↑ TNF-α in OCD vs HC. ↓ IL-12 in OCD vs HC. No association between OCD symptoms and any of the tested cytokines. Quality Rating: Moderate |
| Pérez-Sánchez et al., 2018* | Mexico | Clinical (outpatient) | 14-19y | MINI v.5 (DSM-IV-TR) | MDD Co-morbidity: Not specified |
IL-2, IL-12p70, IFN-γ, IL-1β, TNF-α, IL-6, IL-15, IL-4, IL-5, IL-13, IL-1Ra, IL-10 |
↑ IL-2, IFN-γ, TNF-α, IL-1β, IL-6, IL-12p70, and IL-15 in MDD vs HC. ↑ IL-2 in MDD after 8 weeks of treatment with anti-depressant, fluoxetine. ↓ IFN-γ, TNF-α, IL-1β, IL-6, IL-12p70, and IL-15 in MDD after 4 weeks of treatment with anti-depressant, fluoxetine, however levels restored after 8 weeks. Quality Rating: Moderate |
| Study | Country | Participants | Age range | Diagnostic Method | Internalizing Disorder/Co-morbidity |
Cytokines investigated | Summary of findings |
| Petrov et al., 2018* | USA | Clinical (outpatient) | 6-13y | K-SADS-PL (DSM-V) | MDD Co-morbidity: Not specified |
IL-6 | Significant positive association between BMI and IL-6 for both non-mood and mood disorders. No significant difference in IL-6 levels between MDD vs HC and MDD vs BD contrasts. Quality Rating: Moderate |
| Becerril-Villanueva et al. (2019) | Mexico | Clinical (outpatient) | 14-19y | MINI v.5 (DSM-IV-TR) | MDD Co-morbidity: Not specified |
IL-7, IL-9, IL-17a, VEGF, FGF, G-CSF, GM-CSF |
↑ IL-7, IL-9, IL-17a and VEGF in MDD vs HC. ↑ FGF, G-CSF and GM-CSF in MDD vs HC. ↓ FGF, G-CSF and GM-CSF in MDD after 4 weeks of treatment with anti-depressant, fluoxetine, however levels restored after 8 weeks. No correlation between depression severity and tested cytokines. Quality Rating: Moderate |
| Calarge et al., 2019* | USA | Clinical (outpatient) | 12-17y | MINI v.6 (DSM-V) | MDD Comorbidity: permitted, but details not reported |
IL-6, IL-1β, TNF-α |
No significant difference between MDD vs HC for all cytokines tested. Depression severity was positively correlated with TNF-α. Neuro-vegetative symptom severity was positively correlated with IL-1β. Quality Rating: Moderate |
| Study | Country | Participants | Age range | Diagnostic method | Internalizing disorder/co-morbidity | Cytokines investigated | Summary of findings |
| De Baumont et al., 2019* | Brazil | Community (schools) | 8-18y | K-SADS-PL (DSM-IV) | GAD, SoP, SP, SAD, PD Co-morbidity: Not specified |
IL-6, IL-10, IL-1β, TNF-α |
↑ IL-6 for anxiety diagnosis vs HC at 5 years follow up, but not baseline. ↑ HDL-cholesterol partially mediated the relationship between anxiety diagnosis and IL-6. Quality Rating: Moderate |
| Freed et al. (2019) | USA | Community (not specified) | 12-20y | K-SADS-PL (DSM-IV) | MDD, Anxiety Co-morbidity: Not specified |
EGF, MCP-3, Eotaxin, FGF-2. Flt3-L, VEGF Fractalkine, G-CSF, GM-CSF, GRO, IFN-α2, IL-2 IFN-γ, IL-1α, IL-1β, IL-1ra, IL-3, TGF-α, IL-5, PDGF, IL-9, IL-10, MDC IL-12p40, IL-7, IL-12p70, IL-8, IL-13, IL-15, IP-10, MCP-1, IL-6 IL-17a, IL-4 MIP-1α, MIP-1β, TNF-α, TNF- β, sCD40L, RANTES |
No difference in tested cytokines between adolescents with psychiatric disorders vs HC after LPS administration. Anhedonia score positively correlated with FGF-2, Flt3-L, Fractalkine, G-CSF, IL-1α, IL-2, IL-3, IL-4, IL-7, IL-9, IL-10, IL-12p40, IL-12p70, IL-15, IL-17α, TNF-β, VEGF in the psychiatric sample. Quality Rating: High |
| Study | Country | Participants | Age range | Diagnostic method | Internalizing disorder/co-morbidity | Cytokines investigated | Summary of findings |
| Peters et al., 2019* | USA | Clinical (outpatient) and Community | 12-17y | K-SADS-PL (DSM-IV) | Depression Co-morbidity: PD (10.0%) SP (2.5%) SoP (27.5%) AG (2.5%) GAD (42.5%) PTSD (12.5%) ADHD (15.0%) ODD (5.0%) |
IL-1β, IL-6, TNF-α |
↑ IL-6 in depression w/and w/o trauma vs HC. ↑ TNF-α in depression vs HC. TNF-α and inhibitory accuracy were inversely correlated in the depression w/trauma sample. IL-6 and IL-1β were not associated with executive function. BMI was positively correlated with IL-6. Quality Rating: High |
| Lee et al., 2020* | Korea | Clinical (outpatient) | 13-18y | K-SADS-PL (DSM-IV) | First-episode MDD Co-morbidity: ADHD (16.0%) OCD (4.0%) Anxiety (4.0%) SoP (4.0%) |
IL-1β, IL-6, TNF-α, IL-2, IL-4, IL-10, IFN-γ |
↓ IL-2, IFN-γ, TNF-α, and IL-10 in MDD vs HC. ↑ IL-2, IFN-γ, IL-10 in MDD after 12 weeks of SSRI/TCA treatment. Negative correlation of depression scores with IFN-γ and IL-10. Quality Rating: Moderate |
| Öztürk et al., 2020* | Turkey | Clinical (outpatient) | 13-18y | K-SADS-PL (DSM-V) | MDD Co-morbidity: Anxiety (58.3%) ADHD (4.2%) |
IL-6, IL-1β, IFN-γ, CRP |
No significant difference between MDD vs HC for all cytokines tested. Significant negative correlation between IL-6 and DSM-V level 2 depression and irritability. Significant negative correlation between IFN-γ and Kyn/TRP levels. Quality Rating: High |
| Study | Country | Participants | Age range | Primary Diagnostic method |
Internalizing disorder/co-morbidity | Cytokines investigated | Summary of findings |
| Perry et al., 2020* | England | Community (birth cohort) | 7-18y | CIS-R (ICD-10) | Depression Co-morbidity: Not specified |
CRP | No significant difference between depressed and non-depressed for CRP levels at age 18. No significant correlation between CRP and depression severity at age 18. BMI associated with current depression after adjusting for raised CRP longitudinally at age 9 and 18. Quality Rating: Moderate |
| Reddy et al., 2020* | USA | Clinical (outpatient) and Community | 15-18y | MINI v.6 (DSM-V) | MDD Co-morbidity: Not specified |
IL-6, TNF-α, IL-8 IL-10 |
↑ TNF-α in MDD vs HC. Positive correlation between sleep quality and hyperactivity scores and TNF-α.TNF-α indirect link between MDD and sleep disturbance in adolescents. Quality Rating: Moderate |
| Chen et al., 2021* | Taiwan | Clinical (outpatient) | 12-19y | MINI (DSM-V) | First episode MDD Co-morbidity: Not specified |
CRP, IL-6, TNF-α, IL-2 | No significant difference between MDD vs HC for CRP, IL-6, TNF-α. ↓ IL-2 in MDD vs HC. Quality Rating: Moderate |
| Gomes et al. (2021) | Brazil | Community (birth cohort) | 7-18y | MINI (DSM-V) | MDD, GAD Co-morbidity: Not specified |
CRP, IL-6 | Diet quality at 18 was associated with lower levels of CRP. No association between CRP or IL-6 and MDD or GAD diagnosis at 18. Quality Rating: Moderate |
| Study | Country | Participants | Age range | Primary Diagnostic method |
Internalizing disorder/co-morbidity | Cytokines investigated | Summary of findings |
| Liu et al., 2021* | USA | Clinical (outpatient) and Community | 12-20y | K-SADS-PL (DSM-IV) | MDD, Anxiety Co-morbidity: Dysthymia (7.9%) DNOS (3.9%) Other mood (4.7%) ODD (9.5%) ADHD (23.6%) OCD (1.6%) Other (2.4%) |
CRP | Significant positive correlation between CRP levels and BMI in psychiatric group. No difference in CRP levels between psychiatric group and HC. No correlation between CRP and anxiety, suicidality, or anhedonia symptom measures. Quality Rating: Moderate |
| Martins et al., 2021* | USA | Clinical (outpatient) | 15-20y | DISC-IV (DSM-IV) | MDD Co-morbidity: Not specified |
IL-6, IL-8, MCP-1, TNF-α, IL-1β |
No difference in tested cytokines between MDD vs HC at baseline or 8-month follow up. Positive correlation between depression scores and MCP-1 at 8-month follow up only. Quality Rating: Moderate |
| Peters et al., 2021* | USA | Clinical (outpatient) and Community | 12-17y | K-SADS (DSM-IV) | Depression Co-morbidity: PD (5.9%) SoP (20.6%) AG (2.9%) GAD (47.1%) PTSD (11.8%) ADHD (14.7%) ODD (5.9%) |
IL-1β, IL-6, TNF-α | ↑ IL-6 in depression vs HC. IL-6 inversely associated with accuracy and discrimination of angry and neutral faces. Quality Rating: High |
| Study | Country | Participants | Age range | Primary Diagnostic method |
Internalizing disorder/co-morbidity | Cytokines investigated | Summary of findings |
| Rengasamy et al., 2021b* | USA | Clinical (outpatient) and Community | 12-18y | K-SADS-PL f(DSM-IV) | MDD Co-morbidity: Not specified |
IL-6, TNF-α | No difference in IL-6 and TNF-α levels in MDD vs HC or medicated vs unmedicated MDD. ↑ TNF-α associated with greater childhood trauma and emotional abuse even after correction for depression severity. Quality Rating: High |
| Ho et al. (2022)* | USA | Community | 13-18y | K-SADS-PL (DSM-IV) | MDD Co-morbidity: Not specified |
IL-6, TNF-α | No association between IL-6 and BMI. ↑ IL-6 and TNF-α in MDD vs HC. Quality Rating: High |
| Li et al., 2022* | China | Clinical (outpatient) | 12-20y | K-SADS-PL (DSM-IV) | First-episode MDD Co-morbidity: Not specified |
IL-6, TNF-α | ↑ IL-6 and TNF-α in first-episode MDD vs HC. Positive correlation between IL-6 and TNF-α in all participants. IL-6 positively correlated with emotional abuse, physical neglect and total trauma. TNF-α positively correlated with total trauma. Quality Rating: Moderate |
Note: * = study was included in meta-analysis, y = years, MDD = Major Depressive Disorder, DNOS = Depression Not Otherwise Specified, IL = interleukin, NS = Not Significant, TNF = Tumor Necrosis Factor, IFN = interferon, γ = gamma, α = alpha, HC = Healthy Controls, GAD = Generalized Anxiety Disorder, PD = Panic Disorder, SoP = Social Phobia, SAD = Separation Anxiety Disorder, PTSD = Post-Traumatic Stress Disorder, MVA = Motor Vehicle Accident, SP = Specific Phobia, DYS = Dysthymia, AG = Agoraphobia, GM-CSF = Granulocyte-Macrophage Colony-Stimulating Factor, BD = Bipolar Disorder, OCD = Obsessive Compulsive Disorder, LPS = LipoPolySaccharides, DEX = Dexamethasone, VEGF = Vascular Endothelial Growth Factor, G-CSF = Granulocyte Colony-Stimulating Factor, FGF = Fibroblast Growth Factor, Flt3-L = Fms-like tyrosine kinase 3 ligand, MCP, Other = Other Disorders, ADHD = Attention Deficit Hyperactivity Disorder, SSRI = Selective Serotonin Reuptake Inhibitors, TCA = Tricyclic Antidepressant, K-SADS(-PL) = Kiddie Schedule for Affective Disorders and Schizophrenia(-Present & Lifetime), ICD-10 = International Classification of Diseases (10th revision), DSM = Diagnostic and Statistical Manual of Mental Disorders, ODD = Oppositional Defiant Disorder, SCID-I/NP = Structured Clinical Interview for DSM (non-patient edition), DAWBA = Development and Well-being Assessment, MINI = Mini International Neuropsychiatric Interview, CRP = C-Reactive Protein, Kyn = Kynurenine, TRP = Tryptophan, BMI = Body Mass Index, CIS-R = Clinical Interview Scheduled-Revised.