Abstract
This study investigates whether insulin resistance was positively associated with the presence, severity, or chronicity of major depression.
Insulin resistance (IR) is a physiological state characterized by the attenuated response of peripheral receptors to insulin.1 It is a known risk factor for somatic and brain-based disorders, including cardiovascular disease, Alzheimer disease, and major depressive disorder (MDD).1,2 Several plausible mechanisms tie IR to MDD.3 Insulin resistance leads to diminished insulin-mediated glucose disposal, compensatory hyperinsulinemia, and type 2 diabetes.1,2 However, there is little evaluation of how IR is associated with specific features of major depression. Characterization of these associations represents a critical step at better phenotyping, a prelude to longitudinal studies, and a more targeted approach to the treatment of MDD. We investigated whether IR was positively associated with the presence of major depression, the severity of major depression, and the chronicity of major depression using the Netherlands Study of Depression and Anxiety (NESDA).
Methods
The NESDA is a longitudinal Dutch study of adults that describes the course and consequences of depressive and anxiety disorders.4 We studied 1269 participants with proteomic data in 3 diagnostic groups: current MDD, remitted MDD, and those with no history of the disorder (control individuals). Non-Dutch speakers and those with a history of other psychiatric disorders were excluded. The NESDA protocol was approved by the Vrije University Medical Center ethical committee, and all participants provided written informed consent.
We used 2 well-validated surrogate biomarkers of IR, the quantitative insulin sensitivity check index (QUICKI) and the triglyceride to high-density lipoprotein (HDL) ratio, with the aim of understanding whether using different surrogate IR measures has consistent associations with MDD. Those in the bottom QUICKI quartile were categorized as insulin resistant and all others as insulin sensitive, as is standard in studies of IR.5 The triglyceride-HDL ratio is an index based on fasting blood sample measurements and used a sex-specific cutpoint for IR.
Trained research staff assessed depression diagnostic status via the Composite International Diagnostic Interview, version 2.1.6 The Inventory of Depressive Symptomatology assessed depression severity. Depression chronicity over the preceding 4 years was measured using the life chart interview.
The association between depression group and IR status was evaluated using multivariable-adjusted multinomial logistic regression. We used adjusted linear regression to investigate the association between IR and depression characteristics among current and remitted cases. A supplementary analysis adjusted models of MDD characteristics for antidepressant use. All models were adjusted for age, sex, education, partner status, smoking, and alcohol use.
Results
The IR participants (defined by QUICKI) were older, less educated, and had higher body mass index than those who were insulin sensitive (Table 1). Insulin resistance was associated with current MDD compared with control individuals (odds ratio [OR], 1.51; 95% CI, 1.08-2.12), but not with remitted MDD (OR, 1.14; 95% CI, 0.79-1.64).
Table 1. Demographic and Clinical Characteristics by Depression Group and Insulin Resistance Status by QUICKIa.
| Characteristic | No. (%) | |||||
|---|---|---|---|---|---|---|
| Control participantsa (n = 339) | Participants with MDD | |||||
| Remitted (n = 394) | Current (n = 536) | |||||
| Insulin resistant (n = 69 [20.4%]) | Insulin sensitive (n = 270 [79.6%]) | Insulin resistant (n = 93 [24.7%]) | Insulin sensitive (n = 301 [75.9%]) | Insulin resistant (n = 156 [29.1%]) | Insulin sensitive (n = 380 [70.9%]) | |
| Age, mean (SD), y | 40.6 (15.8) | 38.1 (14.8) | 46.3 (13.2) | 42.7 (12.9) | 43.1 (12.6) | 39.7 (12.5) |
| Female | 39 (56.5) | 164 (60.7) | 58 (62.4) | 205 (71.7) | 93 (59.6) | 265 (69.7) |
| Northern European ancestry vs other | 68 (98.6) | 263 (97.4) | 92 (98.9) | 279 (97.6) | 144 (92.3) | 362 (95.3) |
| Education, mean (SD), y | 11.8 (3.1) | 12.6 (3.1) | 11.6 (3.3) | 12.2 (3.2) | 10.7 (3.0) | 11.8 (3.1) |
| Smoking status | ||||||
| Current | 19 (27.5) | 78 (28.9) | 36 (38.7) | 112 (39.2) | 59 (37.8) | 159 (41.8) |
| Past | 21 (30.4) | 97 (35.9) | 42 (45.1) | 89 (31.1) | 53 (34.0) | 115 (30.3) |
| Use | ||||||
| Alcohol, mean (SD), units/wk | 6.0 (8.8) | 8.9 (10.7) | 7.2 (10.4) | 7.4 (9.7) | 6.9 (10.4) | 6.3 (10.9) |
| SSRIs | 0 | 3 (1.1) | 19 (20.4) | 46 (15.3) | 50 (32.1) | 108 (28.4) |
| Tricyclic antidepressants | 0 | 0 | 3 (3.2) | 8 (2.7) | 8 (5.1) | 18 (4.7) |
| Other antidepressants | 0 | 0 | 1 (1.1) | 10 (3.3) | 24 (15.4) | 37 (9.7) |
| BMI, mean (SD) | 29.1 (5.2) | 24.5 (4.3) | 30.9 (5.9) | 25.3 (3.7) | 31.0 (6.5) | 25.0 (4.8) |
| Fasting plasma level, mean (SD) | ||||||
| Glucose, mg/dLa | 97.7 (18.5) | 88.5 (12.2) | 103.8 (21.9) | 90.5 (11.2) | 106.5 (30.3) | 88.8 (11.8) |
| Insulin, mmol/L | 2.1 (0.9) | 0.6 (0.3) | 2.3 (1.4) | 0.6 (0.3) | 2.6 (2.0) | 0.6 (0.3) |
| HDL, mean (SD), mg/dLa | 52.9 (13.5) | 61.4 (15.5) | 53.7 (14.7) | 64.0 (15.1) | 53.3 (15.1) | 63.3 (16.2) |
| Triglycerides, mean (SD), mg/dLa | 147.9 (72.2) | 111.6 (76.6) | 175.0 (108.1) | 111.4 (72.9) | 172.3 (131.5) | 109.5 (60.2) |
| Triglyceride to HDL ratio, IR status | 41 (60.3) | 67 (25.5) | 55 (59.8) | 66 (22.4) | 93 (60.0) | 101 (26.7) |
| Depression severity (IDS-SR), mean (SD), score | 8.0 (6.8) | 8.6 (7.4) | 19.2 (10.6) | 17.8 (10.6) | 35.2 (12.6) | 30.9 (11.9) |
| Depression chronicity, mean, (SD), % | NA | NA | 12.2 (18.5) | 13.7 (22.2) | 39.9 (31.3) | 33.4 (27.6) |
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); HDL, high-density lipoprotein; IDS-SR, Inventory of Depressive Symptomatology, Clinician Rating, and Self-Report; IR, insulin resistance; MDD, major depressive disorder; NA, not applicable; QUICKI, quantitative insulin sensitivity check index; SSRIs, selective serotonin reuptake inhibitors.
SI conversion factors: To convert glucose to millimoles per liter, multiply by 0.0555; high-density lipoprotein cholesterol to millimoles per liter, multiply by 0.0259; triglycerides to millimoles per liter, multiply by 0.0113.
Adjusted for medication use. Participants in the QUICKI bottom quartile were categorized as insulin resistant, and those in the top 3 quartiles were categorized as insulin sensitive.
Controls were participants with no history of depression or anxiety.
Among participants with current MDD, both measures of IR were positively associated with depression severity (Table 2). Depression chronicity was associated with triglyceride-HDL ratio but not the QUICKI (Table 2). Among participants with remitted MDD, neither depression severity nor chronicity was associated with IR (not shown). There were no substantial changes in model outcomes after adjustment for antidepressant use.
Table 2. Linear Regression Models of the Association Between Depression Characteristics and Measures of Insulin Resistance: Depression Severity and Depression Chronicity Among Participants With Current MDDa.
| Linear regression | No. | QUICKI category (reference group: IS participants), β (95% CI) | No. | Triglyceride-HDL ratio (reference group: IS participants), β (95% CI) |
|---|---|---|---|---|
| Depression severity score | ||||
| Model 1 | 528 | 3.30 (1.01 to 5.59) | 526 | 2.98 (1.20 to 3.87) |
| Model 2 | 516 | 3.42 (1.11 to 5.73) | 514 | 2.41 (1.06 to 3.77) |
| Depression chronicity, % | ||||
| Model 1 | 536 | 4.27 (−1.10 to 9.64) | 534 | 3.31 (0.77 to 5.86) |
| Model 2 | 524 | 4.97 (−0.43 to 7.92) | 522 | 3.20 (0.65 to 5.75) |
Abbreviations: HDL, high-density lipoprotein; IS, insulin sensitivity; MDD, major depressive disorder; QUICKI, quantitative insulin sensitivity check index.
Participants in the QUICKI bottom quartile were categorized as insulin resistant, and those in the top 3 quartiles were categorized as insulin sensitive. Triglyceride-HDL ratio was measured using sex-specific cut points (female ratio: insulin resistance greater than 1.9; male ratio: insulin resistance greater than 2.8). Model 1 was adjusted for age, sex, education, and partner status. Model 2 added adjustment for smoking status and weekly units of alcohol.
Discussion
We report an association between IR and current MDD but not with remitted MDD, suggesting that IR is a state, rather than trait, biomarker of depression. Among specific biomarkers of IR, triglyceride-HDL ratio was positively associated with depression severity and chronicity (again, among participants with current MDD only), whereas IR measured by QUICKI was associated with depression severity. Taken together, these biomarkers of metabolic dysfunction represent simple, clinically accessible methods of identification of IR among currently depressed patients. One limitation of this analysis was the cross-sectional design. Longitudinal analyses need to extend these findings and examine temporality and are the subject of our current investigations.
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