The present data suggest that there is a considerable overlap between the behavioral syndrome caused by innate immune cytokines and DSM-IV idiopathic major depression in otherwise healthy individuals. This overlap was apparent in most prominent dimensions of depression, including depressive symptoms, anxiety symptoms and impaired activity. However, in comparison to medically healthy depressed patients and IFN-alpha-treated non-depressed subjects, patients with IFN-alpha-induced depression exhibited significantly greater symptoms of psychomotor retardation and reported weight loss, suggesting that these symptoms may be preferentially expressed in the cytokine-induced depressive syndrome. In contrast, patients with IFN-alpha-induced depression expressed significantly less severe feelings of guilt.
The greater prominence of psychomotor retardation in IFN-alpha-treated patients is consistent with two studies documenting motor slowing during IFN-alpha therapy using computerized neuropsychological testing. In addition, treatment of rhesus monkeys with IFN-alpha was associated with reduced locomotor activity in subordinate animals (Capuron et al., 2001
; Felger et al., 2007
; Majer et al., 2008
). IFN-alpha-induced motor slowing has in turn been associated with the development of depression and fatigue in patients with cancer and infectious disease (hepatitis C) (Capuron et al., 2001
; Majer et al., 2008
). Given the role of the basal ganglia in regulating motor activity, these data are compatible with altered glucose metabolism in basal ganglia nuclei (putamen, globus pallidus and nucleus accumbens) of IFN-alpha-treated subjects as measured by positron emission tomography (Capuron et al., 2007
; Juengling et al., 2000
). Of note, administration of typhoid vaccination has also been shown to lead to psychomotor slowing associated with altered activation patterns in the basal ganglia (substantia nigra) as assessed by functional magnetic resonance imaging (Brydon et al., 2008
). Taken together, these data suggest that immune activation and innate immune cytokines such as IFN-alpha may target the basal ganglia, leading to alterations in psychomotor speed.
Patients with IFN-alpha-induced depression also reported higher levels of weight loss, likely due to the anorectic effects of this and other cytokines (Plata-Salaman, 1996
; Plata-Salaman, 1998
). This possibility is supported in part by the lack of difference in scores of reported weight loss between patients with IFN-alpha-induced depression and IFN-alpha-treated non-depressed subjects, indicating an impact on reported weight across IFN-alpha treatment irrespective of the development of depression. Moreover, GI symptoms (which largely refer to appetite) were slightly, although not significantly, higher in IFN-alpha-treated subjects.
Interestingly, general somatic symptoms (which largely refer to muscle aches and fatigue) were increased to a comparable degree in all groups. Somatic symptoms are not surprising in IFN-alpha-treated patients. Nevertheless, the presence of physical symptoms in medically healthy individuals is consistent with previous studies on co-morbid physical complaints in ostensibly medically healthy depressed patients (Bair et al., 2003
; Kroenke et al., 1997
; Simon et al., 1999
The absence of symptoms of excessive guilt in IFN-alpha-treated patients is noteworthy and similar to what has been recently reported in patients who developed depression following bereavement (Kendler et al., 2008
). The absence of guilt under these circumstances of depression may reflect, in part, the sense of IFN-alpha-treated (and bereaved individuals) that the source of emotional distress is outside their locus of control (Kendler et al., 2008
). In addition, it is possible that the relatively delimited exposure to IFN-alpha-induced depression may obviate the psychological consequences of long-term depression exposure, which may impinge upon more endearing aspects of self-appraisal including affective/cognitive distortions such as low-self esteem and high self-criticism. Of relevance in this regard is the possibility that the expression of depressive symptoms in the later stages of IFN-alpha therapy (i.e. after 12 weeks) may differ from that early in treatment. Because IFN-alpha-treated patients were not examined after 12 weeks, it remains possible that chronic exposure to cytokine therapy may eventually influence aspects of psychological function including self esteem and guilt.
Limitations of the study include the relatively small sample of subjects with IFN-alpha-induced depression. Given the sample size of the study, power calculations revealed a 99% power to detect a 1 point difference between groups in individual items on the HAM-D, an 83% power for the detection of a 0.5 point difference and 30% power to detect a 0.25 point difference (Cohen, 1988
). Nevertheless, the clinical relevance of small differences (below 0.5 points) in symptom severity is unclear. Moreover, the differences that were detected represent large effect sizes between groups which likely reflect true differences in the expression of relevant symptoms.
In sum, findings from the present study indicate a high degree of overlap between idiopathic major depression in healthy subjects and IFN-alpha-induced depression. These data are consistent with the capacity of innate immune cytokines to interact with multiple pathophysiologic pathways known to be involved in depression. Moreover, given the prominence of psychomotor retardation in the context of IFN-alpha (and other immune stimuli), consideration should be given to the notion that cytokines may preferentially target basal ganglia circuitry with related implications for other neurovegetative functions including anhedonia and fatigue as well as dopamine metabolism. Finally, increased feelings of guilt in idiopathic major depression, suggest that such cognitive-affective symptoms may be a consequence of chronic depressive illness or may represent a psychological (or characterologic) vulnerability factor for the disease.