Childhood Trauma May Drive Poor Outcomes in Anxious Depression

Liam Davenport

October 11, 2018

BARCELONA, Spain — Childhood trauma, particularly sexual abuse, is more common in those with anxious depression and causes permanent biological changes that may explain poorer responses to standard treatment in this patient population, new research suggests.

A study of almost 150 patients with major depressive disorder (MDD) showed that those with anxious depression were almost twice as likely to have suffered sexual abuse in childhood and were 1.3 times more likely to have experienced emotional neglect than those with depression that was not accompanied by anxiety.

In addition, patients with anxious depression showed increases in FK506-binding protein 5 (FKBP5), which modulates glucocorticoid receptor (GR) sensitivity and regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Sexual abuse was also linked to enhanced immune responses.

"Childhood trauma is clearly overrepresented in patients with anxious depression, especially sexual abuse. In addition, we showed that patients with anxious depression have a heightened sensitivity to stress hormones, such as glucocorticoids, whereas major depression is more or less associated with a reduced sensitivity to stress hormones," lead investigator Andreas Menke, MD, said in a release.

"In addition, we observed that patients who have experienced childhood sexual abuse have more reactive immune cells. This is a surprising finding, because this is not found in anxious depressive patients in the absence of childhood abuse or trauma. We suspect that this is because the type of trauma these patient have experienced in early life has conditioned their immune system to react differently," Menke he added.

The findings were presented here at the 31st European College of Neuropsychopharmacology (ECNP) Congress and were published in the December 2018 issue of Psychoneuroendocrinology.

Greater Severity, Increased Suicidality

Previous research suggests that approximately 50% of patients with MDD have anxious depression, which is associated with greater severity, poorer outcomes, and increased suicidality.

Although it has been shown that individuals with MDD often are found to have alterations in the HPA axis, particularly with respect to GR function, and that childhood trauma influences both the HPA axis and risk for depression, the association with anxious depression is unclear.

The current study included 144 inpatients with depression. Of these, 49% were women. The presence of childhood trauma was determined by using the Childhood Trauma Questionnaire (CTQ).

The investigators took blood samples at 6:00 PM the night before and 3 hours after participants were administered a 1.5-mg dose of dexamethasone to determine changes in levels of FKBP5 mRNA, cortisol, and adrenocorticotropic hormone. Blood counts were also measured.

Anxious depression, which was defined as a Hamilton Depression Rating Scale (HAMD) anxiety/somatization factor score of 7 or greater, was identified in 51.3% of the participants.

The researchers found the anxious depression was associated with greater depression severity compared to the depressed patients who did not have anxiety (HAMD score, 29.9 vs 21.5; P < .001), thereby confirming that the sample of patients with anxious depression was representative.

Those with anxious depression also had more previous depressive episodes than nonanxious patients (average, 9.5 vs 4.5, respectively; P = .023) and more previous suicide attempts (39.7 vs 22.5; P = .05). They were also more likely to have a family history of depression (79.5% vs 57.5%; P = .016).

Moreover, anxious depression was associated with a slower response to antidepressant treatment in comparison with nonanxious depression (P < .001), as well as a reduced rate of response after 4 weeks (52% vs 75%, P = .022).

Trauma Screening a Must

The investigators found that childhood trauma was overrepresented among the group with anxious depression; the total score on the CTQ was 45.96 for patients with anxious depression vs 40.51 for nonanxious patients (P = .043).

On CTQ subscales, only scores for sexual abuse and emotional neglect were significantly different between the anxious depression and nonanxious depression groups, at average scores of 23 vs 10 (P = .042) and 58 vs 37 (P = .02), respectively.

The prevalence of childhood sexual abuse was 30% vs 16%, respectively; the prevalence of emotional neglect was 76% vs 58%.

Results also showed that for the patients with anxious depression, GR-induced FKBP5 mRNA expression was increased in comparison with nonanxious patients (P = .03), and cortisol levels were reduced, after adjusting for the FKBP5 rs1360780 risk allele, which was partially dependent on a history of sexual abuse (P = .006).

In both the anxious depression and nonanxious depression groups, a history of sexual abuse was associated with an enhanced GR-induced leukocyte response (P = .008).

HPA axis function was not associated with a history of emotional neglect.

Menke told Medscape Medical News that although the findings imply that there is a specific target for intervention, "it is important to note that there could be other mechanisms than those in major depression involved which could explain the worse outcomes."

He also noted that because there are "no specific interventions right now," there is a need for further investigation. FKBP5 antagonists are currently being studied in this patient population by other researchers.

Menke believes that the presence of anxious depression and childhood trauma is a flag for clinicians to consider psychotherapy in addition to treatment with antidepressants, "because when you have childhood trauma, psychotherapy is essential.

"Normally, you do not check every patient for childhood trauma, [although] you should. But when you have an anxious depressed patient, then you absolutely must check for childhood trauma and deliver psychotherapy," he said.

Practice Changing?

Commenting on the findings in a release, Brenda W. J. H. Penninx, PhD, professor of psychiatric epidemiology at the VU University Medical Center in Amsterdam, the Netherlands, said the findings suggest that "anxious depression and/or childhood trauma may identify a specific depressed patient group where glucocorticoid receptor function is dysregulated.

"However, whether this truly explains worse outcomes to standard treatment — as now indicated by the study authors — needs to be formally tested in a larger study before we can think about it affecting clinical practice," she added.

31st European College of Neuropsychopharmacology (ECNP) Congress. Abstract P.555, presented October 8, 2018.

Psychoneuroendocrinology. 2018;98:22-29. Abstract

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