C-reactive protein level in late-onset depression: A case-control study.

BACKGROUND: Late-onset depression (LOD) is less responsive to standard antidepressant medication compared to early-onset depressive disorder. A group of early-onset depressive episode is less responsive to antidepressant medication, and immune dysregulation is critically involved in it. LOD has been associated with increased vascular risk factor and atherosclerosis and immune dysregulation is critically involved in vascular disease. We hypothesized that increased inflammatory activity may be associated with late-onset depressive disorders. AIM: The aim of this study is to study the C-reactive protein (CRP) levels in LOD compared with age-matched controls and association between CRP levels and severity of depressive episode. SETTINGS AND
DESIGN: This was a case-control study at tertiary care psychiatry department.
MATERIALS AND METHODS: Depressed patients (as per International Classification of Disease 10 Diagnostic and Research Criteria) of age >55 years were recruited and age-matched control participant were recruited after informed consent. A complete clinical assessment, assessment of vascular risk factors, blood sample for the evaluation of serum CRP was obtained, and baseline depression severity was measured on Hamilton Depression Rating Scale (HDRS). STATISTICAL ANALYSIS: The quantitative and qualitative variables were described as means, standard deviation, and P value. The student's t-test for parametric data and the mann-whitney test for nonparametric data spearman correlation coefficient method were used.
RESULTS: The mean age of cases (n = 25) was 64.7 ± 5.8 years, and mean age of controls (n = 25) was 64.2 ± 3.7 years. Patients with current depressive disorders had 40% times higher levels of CRP than control. Baseline HDRS of cases was 18 ± 3. CRP level and depression severity shows strong positive (r = 0.935, P = <0.001) correlation between CRP level and depression severity.
CONCLUSION: LOD was associated with higher level of CRP compared to age-matched nondepressed patients. Raised CRP was associated with severity of depressive episode of LOD.

INTRODUCTION

More than 120 million people are suffering from depressive disorder in the world. A recent WHO epidemiological survey reports more than 16% lifetime prevalence of depressive disorder in general population.[1] Late-onset depression (LOD) constitutes about 2% of depressive disorders.[2] LOD is a major health issue in elderly population that increases the risk of morbidity, suicide, physical, cognitive, and psychosocial impairment. These are associated with increased mortality.[34]

Pathophysiology and phenomenology

LOD has been associated with lower rate of family history of depression and associated with more cognitive decline compared to early-onset depression especially in executive function, memory, attention, and processing speed.[56] In addition, several studies have demonstrated that initially cognitive impairment in LOD is independent of dementia, and on the other hand, LOD increases risk of mild cognitive impairment and dementia,[7] even accelerates cognitive decline in dementia.[8] Early-onset depression has been largely correlated to stress factors and genes, while LOD has been correlated principally to vascular dysfunction.[9]

Currently available antidepressant medications largely target monoamine pathways; however, treatment of depression is only effective (up to remissions) in about one-third to a half of the patients.[10] It shows that a different pathophysiological mechanism also works beside monoaminergic mechanism. Patients with a history of nonresponsiveness to antidepressants have been found to demonstrate increased plasma concentrations of interleukin (IL-6) and acute phase reactants when compared with treatment-responsive patients.[11] Recent studies show that inflammatory mediators mainly C-reactive protein (CRP), IL-6 is raised in depressive disorder more in male patients compared to female patients and correlates with severity and duration of depressive disorder.[12] Immune dysregulation is critically involved in vascular disease[13] and inflammation is associated with atherosclerotic changes.[14] Atherosclerotic changes disrupt the frontal-subcortical circuits and precipitate depression.

We conceptualize that in LOD, CRP has a significant role in disease pathogenesis and important mediator for vascular event and immune dysregulation. Hence, this study was undertaken to study the CRP level among the elderly and association between CRP levels and severity of depressive episode to enrich the knowledge regarding LOD.

MATERIALS AND METHODS

Data for this study were collected from outpatient psychiatry clinics of Medical College. A research protocol was framed and Institutional Ethics committees approved the study. Psychiatrists experienced in diagnosing and treating depressive disorder supervised data collection.

Study design sample

This was a case–control study. Treatment-seeking patients aged ≥55 years with an International Classification of Disease 10 Diagnostic and Research Criteria diagnosis of the first depressive episode were purposively recruited, from outpatient services, for this study. Age-matched healthy control participant was recruited after taking informed consent to participate in the study. Assessments were carried out by face-to-face interviews and patients were excluded if they had a history of psychosis or bipolar disorder, severe medical illnesses (who are incapable for interview, need intensive care, and in delirium), or of autoimmune disease, renal insufficiency and pregnancy, tuberculosis, and dementia or organic brain syndrome. Serum CRP was measured, patients who had high levels of high-sensitivity-CRP (hs-CRP) (≥10 mg/L) were excluded from the study because high levels of hs-CRP (>10 mg/L) may represent nonspecific inflammation and lack positive predictive value.[15] Patients with depressive episode occurring as part of a general medical or neurological disorder, and medication or substance-induced symptoms were also excluded.

Tools

Data were collected on a specifically designed proforma to record sociodemographic and clinical details such as comorbid diagnoses, age at onset of illness, duration of illness, and family history. Sample size calculated with right size software assuming the prevalence of depression 14% with 5% margin of errors. A detailed psychiatric assessment was performed, and symptom severity was assessed using the17-item Hamilton depression rating scale of depression (HAM-D). HAM-D is a 17-item questionnaire used to provide an indication of depression. Max Hamilton originally published the scale in 1960, increasing scores correlate well with severity of depressive episode.[16] Atherosclerosis process increases with age and also increases stroke risk. To compare the stroke risk in case and control subjects, Framingham Stroke Risk was used, calculations were based on the following predictors: age, systolic blood pressure, diabetes mellitus, cigarette smoking, prior cardiovascular disease, atrial fibrillation, left ventricular hypertrophy by electrocardiography, and use of antihypertensive medication.[17] To measure serum CRP, blood samples were drawn from the antecubital vein from controls and cases during diagnosis of depressive episode in the outpatient department. No participants were given anti-inflammatory drugs for ≥3 days before the study because these drugs may be associated with improved endothelial function and might affect the results. Phlebotomy tubes contained no anticoagulants. Blood was centrifuged at 3000 ×g for 10 min and stored at −20°C until analysis. Serum hs-CRP was measured by latex-enhanced immunoturbidimetry using monoclonal anti-CRP antibodies (Infinite Turbilatex CRP, Accurex Biochemical Private Limited, Mumbai - 401 506, Maharashtra, India) (hs-CRP reference level, ≤5 mg/L).

Statistical analysis

Statistical analysis was performed using the IBM SPSS Statistics for Windows, Version 21.0. (IBM Corp, Armonk, NY). The quantitative and qualitative variables were described as means, standard deviation, and P value. The Student's t-test for parametric data and the mann-whitney test for nonparametric data were employed. Spearman's correlation statistical method was used to obtained correlation between CRP level and severity of depressive severity score. All statistical tests were two-sided, and the level for statistical significance was 0.05.

RESULTS

The baseline characteristics of the patients who had depressive episode (case subjects) and those who remained free of depressive episode (controls) are shown in Table 1.

Table 1

Sociodemographic characteristics of the sample

Sociodemographic profile

As shown in Table 1, on comparison of sociodemographic profiles between cases and controls, mean age of participants (64.7 ± 5.8 vs. 62.6 ± 3.8) was higher in cases and mean years of education was higher in controls (4.4 ± 5.2 vs. 11.6 ± 5). Cases had higher rural residence and lived in extended family than control subjects.

Comparison of clinical characteristics [Table 2] reveals that the mean age of onset of illness ( First depressive episode) was 63.7 ± 5.9 years, while duration of illness (mean 9 ± 7.8 month) range was 0.5–24 months. Illness severity, assessed on HAM-D was (18 ± 3 vs. 4 ± 2), which comes under moderate depression level. Nearly 62% patients had comorbid medical illness in which one-third were currently taking treatment for hypertension and diabetes mellitus. There was no significant difference in Framingham study score, body mass index (BMI), Mini-Mental State Exam (MMSE).

Table 2

Clinical characteristics of the sample

Higher CRP levels were found in persons with a current depressive episode compared with controls (5.6 ± 1.8 vs. 3.9 ± 1.5 mg/dl, P = 0.001) and shows significant difference (P = <0.05). Correlation (r = 0.935, P ≤ 0.001) between CRP level and depression severity rating scale shows strong positive and significant correlation.

DISCUSSION

The present study examined the CRP level in a cohort of elderly depressed persons and controls. After considering a large set of possibly confounding factors into account, it was found that patients with current depressive disorders had 40% times higher levels of CRP. Average severity of depressive episode was moderate in study participants.

Results of this study confirm previous findings of immune dysregulation in depressed persons.[1018] Vogelzangs et al. found that in men correlation of severity of depression and CRP was moderate; in our study, there is strong correlation between CRP and severity of depression in both sexes. This might be due to greater mean age of study sample in our study as age is independent marker of atherosclerosis, more the age more atherosclerosis present. This strong correlation in our study favors the possible role of inflammatory process in LOD. Subclinical vascular dysregulations, such as atherosclerosis, have been found to relate to LOD.[1920] These findings are in line with the vascular hypothesis of depression, which suggests that vascular damage in the brain predisposes to LOD.[21] As immune dysregulation is critically involved in vascular disease,[13] this vascular damage could also be the result of increased inflammation. Our results confirm previous findings of the presence of immune dysregulation in elderly depressed persons.

This study shows positive correlation between severities of depression with CRP level in LOD cases and this is in line with results from another large and relatively young cohort study in which severity of depression was associated with CRP levels in men, but not women.[22] Hormonal changes throughout female life due to phase of menstrual cycle, use of hormonal contraceptives, menopause, and use of estrogens greatly impact on inflammation levels,[232425] which could confound a clear association between depression and inflammation. However, in our study, all the women were postmenopausal and not taking any hormonal therapy.

The inclusion of patients with late onset of a depressive episode, exclusively, is an important advantage; clinical diagnosis is established on diagnostic criteria by not using depressive scales. Further, the study participants were systematically recruited. Based on these data, our sample seems to be representative for an Indian population of patients in psychiatric hospital care diagnosed with late-onset depressive episode. Depressive severity was rated on HAM D17 scale. Inflammatory marker CRP is used, a major advantage of CRP lies in its easy availability. CRP can be obtained from a nonfasting peripheral blood sample, and high-sensitivity assays are routine in most medical laboratories, Further, we used Framingham vascular risk factor scale to adjust vascular confounding factor in case and control group. To adjust age-related dementia change, we used MMSE score. Role of inflammatory mediators is much greater extend in LOD as thought previous studies and invariably present in both sexes. Role of inflammatory mediators not only limited up to etiopathogenesis of LOD but also correlate with severity of the current depressive episode. Role of inflammatory marker and poor response to monoaminergic antidepressant medication in LOD need to evaluate the role of anti-inflammatory medication in LOD, future research needed to established the clinical utility of anti-inflammatory medications in LOD.

Limitations of the study

Study sample size may be an important limitation of study; the interviewers were not blinded. Stress, childhood adversities, social support, or positive life events, which might also be associated with age-of-onset, were not evaluated. The absence of other medical disorders in subjects was based on history given by the subjects and not by any clinical workup of participants. Finally, and probably most importantly, we investigated a sample of patients to psychiatric tertiary hospital care, and consequently, our findings cannot be generalized to patients with milder depressions treated in primary care.

CONCLUSION

This study included LOD which is a major health issue in geriatric population and explored the role of immune dysregulation along with vascular basis of LOD. In conclusion, our study suggests that immune dysregulation has an important role in the LOD.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.