The Impact of Escitalopram on IL-2-Induced Neuroendocrine, Immune, and Behavioral Changes in Patients with Malignant Melanoma: Preliminary Findings

Abstract

Interleukin (IL)-2, a T-cell cytokine used to treat malignant melanoma, can induce profound depression. To determine whether pretreatment with the antidepressant escitalopram could reduce IL-2-induced neuroendocrine, immune, and neurobehavioral changes, 20 patients with Stage IV melanoma were randomized to either placebo or the serotonin reuptake inhibitor, escitalopram (ESC) 10-20 mg/day, 2 weeks before, and during IL-2 treatment (720 000 units/kg Q8 h  5 days (1 cycle) every 3 weeks  4 cycles). Generalized estimation equations were used to examine HPA axis activity (plasma ACTH and cortisol), immune activation (plasma IL-6), and depressive symptoms (Hamilton Depression Rating Scale (HDRS) score). Tolerance of IL-2 treatment (concomitant medications required) and adherence (number of IL-2 doses received) were also assessed. Both the groups (ESC (n ¼ 9), placebo (n ¼ 11)) exhibited significant IL-2-induced increases in plasma cortisol, IL-6, and depressive symptoms (po0.05), as well as a temporal trend for increases in plasma ACTH (p ¼ 0.054); the effects of age and treatment were not significant. Higher plasma ACTH concentrations were associated with higher depressive symptoms during cycles 1-3 of IL-2 therapy (po0.01). Although ESC had no significant effects on ACTH, cortisol, IL-6, tolerance of, or adherence to IL-2, ESC treatment was associated with lower depressive symptoms, ie, a maximal difference of B3 points on the HDRS, which, though not statistically significant (in part, due to small sample size), represents a clinically significant difference according to the National Institute for Health and Clinical Excellence guidelines. A larger sample size will establish whether antidepressant pretreatment can prevent IL-2-induced neurobehavioral changes.

Cognitive and Affective Symptoms Experienced by Cancer Patients Receiving High-Dose Intravenous Interleukin 2 Therapy

“…One study reported the reasons for attrition as: patient’s choice, major depression, brain metastases/disease progression or cardiac event. 26 Patients received re-evaluation scans after cycle 2 of high-dose IL-2 therapy, which might explain the high attrition rate after this cycle. Patients who had disease progression (development of brain metastases or development of additional lesions) were ineligible to receive additional cycles of IL-2.…”

“…1, 15, 17, 22, 24, 26 Of these six studies, two studies only enrolled RCC patients, 1, 22 two studies only enrolled melanoma patients, 15, 24 and two studies enrolled both melanoma and RCC patients. 17, 26 Table 4 shows the treatments that melanoma and RCC patients received prior to high-dose IL-2 therapy. Over 75% of patients diagnosed with RCC had a nephrectomy.…”

“…22 The symptom of depression has been reported; however, descriptions of other affective symptoms were only found on patient list-serves designed to allow patients and their family members to discuss their disease and treatments over the internet. 37 Musselman and colleagues measured depression with the Hamilton Depression Scale, 26 while Capuron and colleagues used the Montgomery-Asberg Depression Rating Scale to assess for depression. 23 The 21-item Hamilton Depression Scale rates scores 0–6 as “normal”, 7–17 as “mild” depression, 18–24 as “moderate” depression, and scores equal to or greater than 25 as “severe” depression.…”

“…Depression has been measured a month after the cessation of IL-2 therapy; 23 yet, longitudinal studies of symptoms following treatment are absent in published literature. Several studies have identified cognitive (fatigue, 15, 24, 25 confusion or disorientation, 15, 17 seizures, 1, 22 mental status changes 1 ), and affective (depression, 23, 26 hallucinations, 22 coma 1, 15, 17 ) symptoms. These studies grade the severity of these symptoms; however, absent from the literature are descriptions of when and how these symptoms present, and how they change over time.…”

Cognitive Dysfunction in Depression – Pathophysiology and Novel Targets

“…Treatment with IFN-γ may induce clinical depression in vulnerable individuals [103] and elevations in neopterin levels has been a consistent finding in MDD pointing to IFN-γ-mediated macrophage activation [104]. IL-2 may also induce depressive and anxiety symptoms in humans [105]. Depression is also associated with pathological microglial activation [106].…”