The role of cytokines and hot flashes in perimenopausal depression

Throughout most of their lives, women are at greater risk of becoming depressed than men. The perimenopause and early postmenopausal period has been considered as 'window of vulnerability', during which emerging physical and emotional discomforts and hormonal changes can lead to the appearance of depression [1‐3]. The mechanisms responsible for the development of depression in perimenopausal women remain unclear.

Major depression, in general, is associated with inflammatory processes and neural-immune interactions [4‐9]. Proinflammatory cytokines, such as interleukin 6 (IL-6) and tumor necrosis factor α (TNFα) have been considered as key neuromodulators of behavioral, neuroendocrine and neurochemical features of depressive disorders [10]. This view is supported by the frequent appearance of depressive features in cytokine-mediated chronic inflammatory responses, such as rheumatoid arthritis, and in cytokine-treated patients with cancer and chronic hepatitis C [11]. Administration of proinflammatory cytokines in animals induces 'sickness behavior', similar to the behavioral symptoms of depression in humans [8].

Postmenopausal women seem to have higher serum levels of IL-6 and TNFα compared to women of reproductive age [12]. The extent by which the cytokine milieu is altered in women with perimenopausal depression is the focus of ongoing investigation. A single study has reported an association between depression and elevated plasma IL-6 and soluble IL-6 receptor (sIL-6R) [13]. The same study failed to find an association between the levels of these cytokines and the appearance of hot flashes. However, another study showed that serum IL-8 concentrations in premenopausal, perimenopausal and postmenopausal women and bilateral oophorectomized women with severe hot flashes were significantly higher than those in women without hot flashes [14].

Selective serotonin reuptake inhibitors (SSRIs) are a first-line treatment for perimenopausal depression, but hormone therapy could be considered for women experiencing menopausal symptoms unless there are contraindications [15].

The aims of this study were to simultaneously measure the levels of the proinflammatory cytokines IL-6 and TNFα and the anti-inflammatory cytokine IL-10 in women with or without perimenopausal depression, and to assess whether cytokine levels are associated with hot flashes or with the use of selective serotonin reuptake inhibitors. We also examined whether the presence and severity of hot flashes contribute to the presence of perimenopausal depression.

The major characteristics of the perimenopausal women with or without depression are summarized in Table 1. The two groups did not differ in terms of age, years of education, months of amenorrhea, smoking habits or marital status. As was expected, depressed women scored higher on the HAM-D 17 than women without depression (Table 1). In many women, the cytokine levels were below the limits of detection [19]. Table 2 shows the number of cases below sensitivity in the clinical sample and in the control sample, respectively.

The main finding of this study in Caucasian patients is that the proinflammatory cytokines IL-6 and TNFα are not significantly increased and the anti-inflammatory cytokine IL-10 is not decreased in perimenopausal women with depression. This finding does not add strength to the cytokine hypothesis of depression, which supports the view that depression in general is characterized by increased levels of proinflammatory cytokines, such as IL-6 and TNFα, and decreased levels of anti-inflammatory cytokines, such as IL-10. According to this hypothesis specific alterations of the cytokine environment are induced by external and internal stressors and by an increased translocation of lipopolysaccharide (LPS) from Gram-negative bacteria (leaky gut) [20, 21]. The study of Ushiroyama et al. [13] measured IL-6 in a large sample of non-Caucasian patients. He found increased plasma levels of IL-6 in the subgroup of women with depression and hot flashes when compared to women with hot flashes without depression and to control subjects. However, it has to be mentioned that in our study there was a trend in increasing levels for TNFα and a trend in decreasing levels for IL-6 in perimenopausal women with depression when compared to perimenopausal women without depression. This is in line with the data existing in the literature on the topic as far as TNFα, while it is in contrast to what has been shown for IL-6; it is reported that both cytokines increase significantly in depressed patients when compared to normal subjects [9, 22‐24].

Our findings are not unexpected as perimenopause is associated with spontaneous increases of proinflammatory cytokines, especially IL-6 and TNFα, attributed to decreased levels of estrogens. This release seems to affect perimenopausal women without distinction among those with or without depression. The mechanism by which estrogens alter cytokine expression is elusive and may include interactions of the estrogen receptors with other transcription factors, modulation of nitric oxide activity, antioxidative effects, plasma membrane actions and changes in immune cell function [25]. According to our findings these cytokine levels are not statistically different among those with or without depression. Circulating cytokine levels may not reflect the local production of cytokines in women with depression and a better understanding of local cytokine levels would be more informative. Cerebrospinal fluid levels of cytokines have been measured in other infectious and non-infectious diseases, including psychiatric disorders such as schizophrenia, as an indicator of central nervous system (CNS) cytokine levels. It is well known that cytokines are synthesized mainly by monocytes, but they can also be secreted by other immune and non-immune cells, such as microglia and astrocytes in the CNS [26].

The design of the present study did not allow for invasive procedures, such as collection of cerebrospinal fluid (CSF) and measurements of cytokine levels in such biological material.

It also needs to be noted that variations in standards and pairs of antibodies used by different companies may affect the validity and the performance of the ELISA kits used for the measurement. Thus, differences in the sensitivity and specificity of these kits have been reported [27].

We found a significant association between hot flashes and perimenopausal depression. Such an association adds support to the 'domino theory' of the pathophysiology of perimenopausal depression. This theory asserts that experience of the somatic symptoms, caused by diminishing estrogen, is the direct cause of the onset of depression during perimenopause. Mental and physical discomforts such as hot flashes, inability to concentrate, insomnia, and vasomotor symptoms, which characterize the menopausal transition, may easily disrupt a woman's emotional life. In particular, when combined with a lack of understanding of or control over their source, these symptoms may lead a woman into a downward spiral towards depression [3, 28‐33]. The association of hot flashes with perimenopausal depression is not a consistent finding, as Ozturk et al. were unable to report it [34].

When we analyzed our data in relation to the administration or not of SSRIs, we found that despite their presumed immunomodulatory properties (in favor of decreased IL-6) [35, 36], SSRIs are not linked to any specific cytokine. Suppression of proinflammatory cytokines does not occur in patients who fail to respond to SSRIs (treatment-resistant depression) [37] and our report demonstrates that this is also the case in perimenopausal depression. A plausible explanation for this would be that SSRIs cannot relieve women from severe vasomotor and other symptoms associated with decreased estrogen, which cause the perimenopausal depression; consequently, perimenopausal depression becomes refractory to treatment with antidepressants and proinflammatory cytokines are not suppressed in depressed perimenopausal women who take SSRIs.

Cytokines such as IL-6 and TNFα appear to be increased in menopause and to be potent vasodilators [38, 39]. This raises the question as to whether they would be further increased in the subgroup that experienced hot flashes. It appears that in our enrolled perimenopausal women neither IL-6 and TNFα or IL-10 were associated with the presence or the severity of hot flashes.

The present study has several limitations. First of all circulating cytokine levels do not necessarily reflect the local production of cytokines in women with depression. Moreover, this study is a preliminary report and its data should be confirmed by studies that include larger samples of patients and controls.

It seems that hot flashes play a crucial role in the presence of perimenopausal depression. The inflammatory theory of depression is not suitable for perimenopausal depression, since serum concentrations of the proinflammatory cytokines TNFα and IL-6 are not raised. Perimenopausal depression has unique characteristics that must be taken into account during its treatment, with an emphasis on hormone replacement therapy that will alleviate the hot flashes and improve the perimenopausal depression prognosis.