All data were loaded into the R statistical environment v. The descriptive characteristics of the sample were compared between cancer patients, caregivers, and healthy controls. The cytokine concentration data were transformed into log 2 -space, and infinite values were removed by imposing a ceiling of 14 as the maximum of all finite cytokine levels.
Levels of the 15 cytokines and five ratios were visualized in the R statistical environment using the lattice v0. Since age and sex may contribute to the differing cytokine levels in these groups, 23 multiple logistic regression analysis was performed to adjust for these variables in group-wise comparisons, with FDR correction applied to the resulting p -values.
Ham-Dep and Ham-Som were used to study the relationships between cytokine levels and depressive symptom domains in cancer patients and caregivers. Multiple linear regression was performed to determine the coefficients, standard errors, and p -values that related each cytokine level or ratio to the Ham-D subfactor.
This analysis was performed with the Ham-D subfactors as continuous variables.
The caregiver results were adjusted for the effects of age and sex. The adjusted coefficients were visualized using dotmaps for cancer patients vs caregivers using lattice v0. Demographic and biobehavioral variables across the samples are summarized in Table 1.
Cytokines and depression in cancer patients and caregivers
Aside from medical comorbidity and exercise habits, there were no significant differences between the three groups. GRID Ham-D depression severity scores for cancer patients, caregivers, and healthy controls are summarized in Table 2. Mean psychological symptom scores Ham-Dep scores were not significantly different between cancer patients and caregivers 3.
Among cancer patients, there were higher levels in both Ham-Som and Ham-Dep subfactor scores 3. Among subjects with major depression, cancer patients scored highest on the Ham-Som subfactor score 3. Figure 1 Cytokine associations in cancer patients and caregivers with depression subfactors. Notes: A Dotmap of cytokine associations with Ham-Som scores.
B Dotmap of cytokine associations with Ham-Dep scores. Coefficient strength is represented by the size of the circle blue, negative: orange, positive , with the p -value represented in gray scale. Table 3 describes the impact of adjustments in the psychological symptom Ham-Dep analyses in cancer patients and caregivers, where the strongest and most statistically significant cytokine associations were identified.
Cancer pain and depression: management of the dual-diagnosed patient
The cytokine associations with depressive symptom scores did not always coincide with increased or decreased cytokine levels relative to healthy controls. Pro-inflammatory cytokines IL-2 negatively associated with somatic symptoms in caregivers and ILp70 negatively associated with psychological symptoms in cancer patients were increased in both caregivers OR: 2. Table 4 Cytokine levels and ratios in cancer patients and caregivers compared with healthy controls Notes: Fold differences between groups are given, with FDR-corrected p -values. The strongest and most statistically significant associations identified were the negative associations with psychological symptoms for anti-inflammatory cytokine IL-4 in cancer patients and pro-inflammatory cytokine IL in caregivers.
IL-4 was significantly increased in cancer patients OR: 1. In this study of cytokines and depressive symptoms in cancer patients and their caregivers, we found that cancer patients reported more somatic symptoms of depression. The higher somatic symptom scores in cancer patients with major depression could be explained by overlap with the symptoms of cancer and its treatment, but is also consistent with the known somatic symptom amplification of depression that has been shown to occur with depression.
A larger sample of depressed caregivers will be required to substantiate this possibility. We identified a negative association between IL-4 and psychological symptoms of depression in cancer patients. Interestingly, a negative association with IL-4 was also the only significant cytokine association found for SCID-based categorically defined major depression in this patient sample, 15 suggesting that it may be the biological markers of the psychological symptoms that distinguish cancer patients with and without major depression.
Evaluation of the impact of statistical control for biobehavioral variables on this association indicated that cancer stage and type overwhelm any effects of age, sex, BMI, or active treatment, which is an important consideration for future study designs. In caregivers, psychological symptoms of depression were negatively associated with IL, and in this noncancer population, age was found to have a significant impact on the association. We speculate that the difference in cytokine associations with psychological symptoms of depression between cancer patients and caregivers may be related to cytokine network alterations related to cancer and cancer treatment, obscuring alterations evoked purely by psychological stress, as represented in the caregiver population.
IL is the primary cytokine produced by Th17 cells, a highly pro-inflammatory effector T cell type that functions in autoimmunity. IL-6 has previously been reported in association with depression in cancer, particularly the somatic symptom domain. The differences between our results and those of other studies may be due to differences in the clinical population, the careful attention to biobehavioral confounds which sometimes lacking in other studies, or differences in the construct validity of the somatic symptom measures used. Cytokines are known to have pleiotropic functions and operate in interactive networks, reciprocally influencing the expression of each other.
These findings support our hypothesis that the biobehavioral mechanisms and cytokine profiles associated with depression would be distinct between the two groups. What might account for the apparent divergence in symptom domains associated with these cytokines and ratios between cancer patients and caregivers is unclear, highlighting it as an area of interest for future study in a larger, networked analysis. Anti-inflammatory approaches for the treatment of depression are now being explored. However, antidepressant effects of anti-inflammatory agents must be explored with an understanding of the underlying biobehavioral mechanisms in individual patients.
Limitations of the current study include the correlational nature of the reported associations, which do not permit causal interpretations, and the low number of caregivers with major depression recruited. Recruitment of sufficient numbers of cancer patients with major depression is often a significant barrier in biomarker studies, and recruitment of depressed caregivers may be an even greater challenge.
Cancer pain and depression: management of the dual-diagnosed patient | SpringerLink
In addition, BMI data were extracted from the electronic medical record and were therefore not available to include in statistical adjustments for caregivers or healthy controls. This study found distinct cytokine associations with Ham-D-defined somatic and psychological symptom domains of depression in cancer patients and caregivers, suggesting that there may be distinct therapeutic targets for these symptom domains in these populations.
This also suggests that there are different pathways to depressive symptoms in cancer patients and caregivers, which may be differentially precipitated by biological and psychological stressors. The clinical implication of such findings is that depressive symptoms in cancer patients can be precipitated by biological stressors, an important message to help de-stigmatize the emergence of depression in cancer patients. Effect of antidepressant switching vs augmentation on remission among patients with major depressive disorder unresponsive to antidepressant treatment: the VAST-D randomized clinical trial.
Systematic review and meta-analysis of collaborative care interventions for depression in patients with cancer. Inflammatory biomarkers in depression. An opportunity for novel therapeutic interventions. Curr Psychiatry Rep. Depressive symptoms in patients with cancer. Does cortisol keep cytokines from singing the blues? Psychosom Med. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. Translational approaches to treatment-induced symptoms in cancer patients.
Nat Rev Clin Oncol. Association of the physiological stress response with depressive symptoms in patients with breast cancer. Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer. J Clin Oncol. Cuthbert BN. World Psychiatry. Increased soluble interleukin-2 receptor levels are related to somatic but not to cognitive-affective features in major depression. Brain Behav Immun. Differential association of somatic and cognitive symptoms of depression and anxiety with inflammation: findings from the Netherlands Study of Depression and Anxiety NESDA.
The predictive value of somatic and cognitive depressive symptoms for cytokine changes in patients with major depression. Neuropsychiatr DisTreat. Hidden morbidity in cancer: spouse caregivers. Biologic cost of caring for a cancer patient: dysregulation of pro- and anti-inflammatory signaling pathways. Pro- and anti-inflammatory cytokine associations with major depression in cancer patients. Epub Nov doi J Clin Psychiatry.
The new GRID Hamilton Rating Scale for Depression demonstrates excellent inter-rater reliability for inexperienced and experienced raters before and after training. Psychiatry Res. Int Clin Psychopharmacol. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. Shafer AB.
J Clin Psychol. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. To assess, to control, to exclude: effects of biobehavioral factors on circulating inflammatory markers.
Emerging tendency towards autoimmune process in major depressive patients: a novel insight from Th17 cells. A meta-analysis of cytokines in major depression. J Affect Disord.
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The relationship between depression and physical symptom burden in advanced cancer. An important point the study does raise is that physical health and mental health are connected at a fundamental level. Poor mental health can affect you physically and vice versa.
If you or someone you know is suffering mental distress, talk to your GP. The study was carried out by researchers from University College London, Edinburgh University and the University of Sydney and had no specific funding. The Mail Online, The Sun and The Independent produced broadly accurate coverage of the study, although the reporting tended to overstate the findings, suggesting that anxiety and depression were big risk factors for cancer.
The Daily Telegraph misunderstood the study entirely, saying that "the people who were most distressed by their diagnosis were 32 per cent more likely to die from their cancer" and "staying positive could be the best way to fight the disease".
Related Depression and Cancer (World Psychiatric Association)
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