Of the many studies that have addressed the issue of whether IFNα induces depression, the vast majority suggest that treatment with IFNα represents a significant risk factor for the development of both depressive symptoms and a syndrome that meets criteria for major depression as defined by the DSM-IV.
(Although by strict DSM-IV criteria, IFNα-induced depression should be diagnosed as a “Substance-induced mood disorder”, it should be noted that the symptoms for the latter are the same as those for major depression, with the exception that there is a clearly identified pharmacologic aetiological factor.) Indeed, depression and symptoms frequently comorbid with depression, such as anxiety and fatigue, have been cited as a primary reason for treatment discontinuation, highlighting both their ubiquity mid potential morbidity [1,2]
However, despite strong evidence that IFNα causes depression, reliably determining prevalence rates of mood disturbance during treatment has proven problematic for several reasons. As discussed more extensively below (see section 1.3.3), rates of IFNα-induced depression appear sensitive to dosage and duration of treatment, as well as to premorbid patient-related risk factors.[1,2]
In addition, depression during IFNα treatment appears to follow the old biblical adage “Seek and ye shall find”, given that rates of depression are consistently higher in studies that specifically examine IFNα-induced mood disorders using prospective designs and depression-specific assessment instruments when compared with studies that only identify depression retrospectively and/or as part of a generalised adverse effects screening process.
Finally, the very construct of depression in the context of IFNα treatment has been given widely divergent interpretations, with definitions across studies ranging from the single symptom of depressed mood through conditions defined by elevated scores on screening instruments to the full categorical syndrome of major depression. In general, rates of depression are higher when the condition is identified symptomatically rather than categorically, because many patients receiving IFNα develop constellations of depression-related symptoms that, while clinically meaningful do not meet full criteria for major depression.
Given abundant evidence that such depressive symptoms, even when subsyndromal, can significantly impair outcome across a variety of medical conditions,
it is important to recognise that studies utilising major depression as the definition of IFNα-induced depressive morbidity probably under-report clinically significant mood disturbances during treatment.
When these factors are taken into consideration, a clear pattern emerges. Early studies (i.e. those published prior to the mid-1990s) tended to define depression as a single symptom based on patient self-report during general screening for IFNα-related adverse effects. Not surprisingly, rates of depression tended to be low in these studies. For example, in one of the few trials comparing IFNα-treated patients with HCV-positive controls, Davis and colleagues
found that only 9% of patients receiving 3 million units of IFNα per week and 14% of patients receiving 9 million units per week reported depressed mood during 24 weeks of treatment. These rates were not significantly greater than the 8% rate reported by control subjects. Similarly, only 23 of 987 patients (2%) evinced significant depressive symptoms during 22 weeks of treatment in a large Japanese study of patients receiving IFNα monotherapy (i.e. without concomitant ribavirin) for 24 weeks.
Furthermore, a meta-analysis of randomised controlled trials of various doses of IFNα for HCV published prior to 1996 found that, in the 21 studies for which adverse effect information was available, 7% of patients reported significant depressed mood during treatment.
In a more recent study of 912 patients with HCV in which depression was assessed by self-report, McHutchison et al.
reported that 11% of patients receiving IFNα monotherapy and 16% of patients receiving combined IFNα/ribavirin developed depressed mood during treatment.
In contrast, studies that have evaluated depression as a syndrome of related symptoms (including fatigue and other neurovegetative symptoms, such as changes in sleep and appetite) and/or those that have used depression-specific screening assessments have routinely reported far higher rates of IFNα-induced depression. For example, an early study that specifically screened for depression during treatment found a significant increase in depressive symptoms in hepatitis B virus (HBV)-positive patients receiving IFNα compared with controls, although it should be noted that the effect of IFNα was most striking in patients who were comorbid for HIV.
In a large trial that did not utilise depression-specific assessment instruments, Lindsay and colleagues
nonetheless observed a 57% rate of ‘CNS’ adverse effects that included irritability, depression, impaired concentration and insomnia. Consistent with this, in a large French trial that observed a mere 9% depression rate during IFNα treatment, rates of neurasthenia reached 50%.
It should be noted that the construct of neurasthenia contains many neurovegetative symptoms that contribute to increased scores on depression-specific rating scales and that are included in the diagnosis of major depression. Interestingly, even when evaluated as a single symptom during a generalised screening process, rates of depression seem to be increasing in more recent, clinical trials compared with older trials, probably reflecting increased awareness on the part of study clinicians of the significant risk for depression during IFNα treatment. [40–42]
Over the last several years, a number of studies specifically designed to assess the prevalence of mood disturbance during IFNα treatment have been conducted. Whether assessed as DSM-IV-diagnosed major depression or as elevated scores on standardised depression rating scales, depression has emerged as a significant concomitant of treatment in virtually all these studies, with prevalence rates varying between 16% and 58%.[4,5,43–54]
Three of these studies included control groups and in each case IFNα therapy was associated with significant increases in depression-related symptoms.[47,51,53]
The majority of these studies have evaluated patients receiving IFNα with or without ribavirin for HCV. However, one study of patients receiving significantly higher doses of IFNα for the treatment of malignant melanoma reported that 50% of patients not pretreated with an antidepressant met diagnostic criteria for major depression at some point during 3 months of treatment.
Rates of depressive symptoms in this study were even higher, with 60% of patients endorsing depressed mood and 80% of patients endorsing significant fatigue during treatment.
In the last several years, treatment with pegylated forms of IFNα-2b (PEG Intron®
and IFNα-2a (Pegasys®
) in combination with the antiviral agent ribavirin has become the standard of care for patients with HCV. Pegylation involves the addition of a polyetheleneglycol molecule to IFNα, a process that increases the half-life of IFNα, allows once-a-week administration and improves antiviral efficacy. However, despite being the current standard of care, little is known about the relative proclivity of either pegylated IFNα-2b or pegylated IFNα-2a to cause depression compared with treatment with older, thrice weekly preparations of IFNα. In large registration trials, the rate of depression during 52 weeks of treatment with pegylated IFNα-2b was 31%%
and the rate with pegylated IFNα-2a over 48 weeks was 22%.
However, it should be noted that in these trials, depression was defined as a single symptom and was assessed by self-report as part of a generalised adverse effect screening process. Rates of other depress ion-related symptoms for pegylated IFNα-2b were fatigue (64%). insomnia (40%), irritability (35%) and weight loss (29%). The rates for pegylated IFNα-2a were fatigue (54%), insomnia (37%). irritability (24%) and reduced appetite (21%). The only study that has directly compared rates of major depression between pegylated and non-pegylated forms of IFNα found no differences between the two agents.
However, these results must be considered tentative, given the small sample size (36 patients receiving pegylated IFNα-2a) and the fact that the study reported uniformly low rates of major depression (12%), probably as a result of the fact that the study was designed primarily to evaluate the efficacy of antidepressant treatment rather than to comprehensively determine the prevalence of IFNα-induced depression.
1.3.2 Clinical Presentation: Neurovegetative and Depression-Specific Sub-Syndromes
As conceived in current psychiatric nosology, depression is not the single symptom of depressed mood, but rather a syndrome comprised of emotional, cognitive and neurovegetative abnormalities that can present in different combinations, but that tend to co-occur often enough to be recognised as forming a single spectrum of disease activity.
It should be noted that DSM-IV criteria include a number of symptoms, including fatigue, psychomotor slowing and changes in sleep and appetite that are also common in the context of immune system activation, such as occurs during medical illness or cytokine therapy.
While properly conceived of as contributing to major depression during IFNα treatment, recent data from patients receiving high-dose therapy for malignant melanoma suggest that these neurovegetative symptoms represent a sub-syndrome that is distinct from the more depression-specific symptoms (i.e. symptoms not as commonly observed in the context of illness) of depressed mood, anhedonia, anxiety and subjective cognitive disturbance. In a dimensional analysis, Capuron and colleagues
observed that neurovegetative symptoms of fatigue, psychomotor slowing and anorexia (loss of appetite) occurred early in treatment and persisted, whereas depression-specific symptoms co-developed significantly later in treatment. Depression-specific symptoms were exquisitely responsive to treatment with the selective serotonin reuptake inhibitor (SSRI) paroxetine, whereas neurovegetative symptoms were minimally responsive. These findings confirm clinical impressions that fatigue and related physical symptoms, while counting toward a diagnosis of depression, frequently occur in isolation from more depression-specific complaints.
That is, many patients receiving IFNα complain of chronic exhaustion, malaise, loss of appetite and insomnia, without also reporting significant sadness, hopelessness, guilt or loss of pleasure in life. These observations have clear treatment implications that are discussed below.
1.3.3 Risk Factors for IFNα-lnduced Depression
The high rate of depression during IFNα therapy has led many clinicians to routinely pretreat patients with antidepressants before initiation of therapy, a practice supported by data indicating that antidepressant pretreatment protects against the development of major depression in patients receiving high-dose IFNα for malignant melanoma.
However, even when administered in high doses, IFNα does not induce symptoms severe enough to qualify for major depression in at least 50% of patients, suggesting that routine antidepressant pretreatment may expose a significant number of patients to an additional unnecessary medication burden. Although generally benign, antidepressants are not without their own risks and adverse effects, especially in the medically ill who are often especially susceptible to medication adverse effects. Thus, determining risk factors for the development of IFNα-induced depression might help identify patients who would be especially likely to benefit from close psychiatric follow-up and/or antidepressant pretreatment, while decreasing the burden of providing such intensive follow-up to all patients receiving IFNα.
Risk factors for the development of depression can be divided into those that are inherent to IFNα treatment itself and premorbid factors that reflect each patient’s past history and pretreatment physical and psychiatric condition. Risk factors inherent to treatment include dosage and duration, as well as mode of IFNα delivery, with adverse effects generally worsening as dosage increases and treatment duration extends.[1,57]
All neuropsychiatric adverse effects appear to be more common and more severe in patients receiving ICV and IV IFNα (who typically also receive high doses) than in patients receiving IFNα subcutaneously (as occurs in the treatment of HCV). Hence, patients receiving high-dose therapy administered either ICV or IV may especially benefit from close psychiatric follow-up and/or antidepressant pretreatment. Although preliminary, some data suggest that ribavirin, an antiviral agent typically used in combination with IFNα for HCV, may synergistically increase the proclivity of IFNα to induce depression.
If confirmed in prospective trials, this finding may take on increasing importance in light of evidence that higher dosages of ribavirin increase rates of viral clearance.
A number of premorbid patient-related risk factors for the development of IFNα-induced depression have been reported. The most replicated risk factor appears to be the presence of psychiatric disturbance just prior to commencing IFNα treatment. The majority of studies that have looked at this issue find that baseline depression and/or anxiety, even when subclinical, predicts the development of psychiatric morbidity during treatment.[5,45,53,54,57,58]
Consistent with this, patients receiving psychiatric treatment at the time of IFNα initiation appear to be at increased risk of developing depression.[53,54]
On the other hand, although one study reported that a history of past psychiatric disturbance significantly increased the risk of depression during IFNα therapy,
other studies do not find that a past history of depression significantly increases the risk of neuropsychiatric disturbance or is associated with higher rates of treatment discontinuation.[5,7,43,51]
Indeed, one study found that even patients with severe psychiatric disorders, such as schizophrenia, can be successfully treated with IFNα if they are psychiatrically stable prior to treatment.
Similarly, a past history of drug or alcohol abuse does not appear to increase the risk of IFNα-induced depression, provided patients remain abstinent during treatment.[5,46,54]
Although women are typically more vulnerable than men to mood and anxiety disorders, studies with IFNα are split between those that do[48,52,54]
and those that do not find gender to be a risk factor.[44–46]
Likewise, although one study found that very elderly patients may experience increased IFNα-induced depression,
age has not emerged as a consistent risk factor.[45,46]
Finally, an early study of patients receiving IFNα for HBV infection reported that lack of social support significantly increased the risk of developing depressive symptoms during treatment,
a finding in line with a voluminous literature documenting the detrimental health effects of social isolation.[60,61]
Several physiological factors appear to increase the risk of developing depression during IFNα treatment. An obvious factor shared by all patients undergoing treatment is that physical illness itself is a significant risk factor for the development of depression.
Indeed, many studies have documented elevated rates of depression in patients with a wide range of medical disorders, including cancers and viral infections, the conditions against which IFNα is most typically directed. Traditionally, the causes for this increased prevalence of depression have been ascribed to the multiple psychological stressors that typically accompany illness. However, accumulating data indicate that physiological processes inherent to most illnesses, and especially activation of the proinflammatory cytokine network, may directly predispose towards the pathophysiology of depression via effects on the CNS.
In humans and animals, the administration of proinflammatory cytokines, or of substances that induce cytokines, such as lipopolysaccharide, reliably induces a behavioural syndrome that has been termed sickness behaviour and that includes symptoms also commonly seen in depression, including fatigue, anhedonia, social isolation, psychomotor slowing, decreased food and water intake, decreased libido, hyperalgesia, altered sleep patterns and cognitive impairment.
These symptoms can be ameliorated or prevented by blocking cytokine activity in the CNS.
IFNα has been shown to be a potent inducer of proinflammatory cytokine production and thus may be especially likely to induce depression-related physical and emotional symptoms in patients already experiencing illness-related increases in proinflammatory cytokine activity.
Consistent with this, premorbid fatigue in patients with HCV has been reported to be a powerful predictor of the development of disabling fatigue during IFNα therapy.
In addition to the general vulnerability to depression posed by immune system activation in the context of medical illness, recent studies point to more specific physiological risk factors for the development of depression during IFNα treatment. For example, patients who responded to a first dose of IFNα with hyperactivity of corticotropin-releasing hormone (CRH)-mediated stress pathways, as assessed by increased production of corticotropin and cortisol, were significantly more likely to develop major depression during treatment than were patients with more modest stress system responses to the initial injection, even though none of the patients demonstrated major depression at baseline prior to treatment.
CRH activates both the hypothalamic-pituitary-adrenal axis and sympathetic nervous system and is widely recognised as the principal orchestrator of the mammalian stress response.
Significant data indicate that CRH hyperactivity is a central abnormality in major depression and is apparent in persons exposed to early life stress and/or who meet criteria for posttraumatic stress disorder.
Thus, the finding that CRH hyperactivity in response to an initial dose of IFNα predicts the later development of depression may point to a potential pathway by which psychological stress predisposes towards the development of mood disorders in the context of medical illness.
A second mechanism implicated in the development of depression during IFNα therapy involves CNS serotonergic neurotransmission. By activating the proinflammatory cytokine network, IFNα induces the enzyme indoleamine 2,3-dioxegenase (IDO). which shunts the metabolism of tryptophan away from serotonin and toward kynurenine.
Because tryptophan is an essential amino acid not produced by the body, IDO-induced tryptophan depletion results in reduced serotonergic availability, a condition that has been demonstrated to rapidly induce significant dysphoria in many patients vulnerable to mood disorders.
Several studies report a correlation between reduced tryptophan levels and depression in patients receiving IFNα.[22,70–72]
For example, Capuron et al,
recently observed that patients who developed major depression during IFNα treatment had significantly reduced plasma concentrations of tryptophan and increased concentrations of kynurenine compared with patients who did not develop depression, implicating increased IFNα-induced IDO activity as a risk factor for the development of depression during treatment. Interestingly, dimensional analyses indicated that evidence of both CRH and IDO hyperactivity correlated with depression-specific symptoms (depressed mood, anxiety and subjective memory and attentional difficulties), but not with neurovegetative (fatigue, anorexia and pain) symptoms,[65,70]
providing further evidence that depression in the context of IFNα therapy may represent two separable syndromes. The first of these is a depression-specific syndrome characterised by symptoms more common in the context of major depression than sickness. These symptoms include depressed mood and anxiety, which are associated with activity in CRH and serotonin pathways and respond to antidepressant treatment consistent with the well known effects of antidepressants on these pathways. The second syndrome is a neurovegetative condition characterised by symptoms such as fatigue and anorexia that are also common in the context of sickness, develop early in treatment and are minimally responsive to treatment with serotonergic antidepressants.
In addition to CRH and serotonin pathways, other neurotransmitter and neuroendocrine systems may contribute to psychiatric symptoms during IFNα treatment. Animal studies demonstrate that IFNα alters CNS opioid, dopamine and noradrenaline (norepinephrine) activity.
Like other inflammatory stimuli. IFNα also appears to increase free radical and glutamate production, which, in turn, promote neuronal damage.
Finally, recent data from humans suggest that carriers of the epsilon 4 allele of the apolipoprotein E gene may be at increased risk of developing many neuropsychiatric symptoms during IFNα treatment, including irritability, anxiety and depressive symptoms.