The goal for this work is preventative treatments that can be targeted towards specifically mitigating those mechanisms underlying vulnerability. Poor sleep quality prior to IFN-α treatment may be one such risk factor.121,122
Patients with scores greater than 10 on the Pittsburgh Sleep Quality Index, a validated self-report assessment of sleep quality,123
were ten times more like to subsequently develop IFN-MDD than patients sleeping better than this.122
This large effect size was evident even when controlling for other depression symptoms. It is also consistent with large epidemiological studies wherein insomnia predicted the subsequent development of MDD over follow-up intervals of 1 to 35 years.124-127
As many treatments for sleep exist, this may be a potentially modifiable risk factor for preventing IFN-MDD. This has previously been suggested for MDD,128
but may now be readily testable in patients about to be treated with IFN-α.
There is also evidence that increased age may be another risk factor for IFN-MDD,129
although this is certainly not a consistent finding.130,131
Despite the fact that age itself is not modifiable, this could indicate the presence of agerelated modifiable risk factors. Related to this, elevated levels of inflammatory cytokines, such as interleukin-6 (IL-6), prior to IFN-a therapy have been associated with subsequent IFN-MDD.132,133
Additionally, a polymorphism in IL-6 that has been associated with increased IL-6 levels is predictive of IFN-MDD.134
In the subset of people with increased IL-6 during IFN-α administration, the IL6 levels temporally predicted next month's depression symptoms.133
This is consistent with cross-sectional studies in which elevated IL-6 levels are associated with MDD.54,132,135-140
Thus, increased IL-6 may be another plausibly modifiable target for preventive intervention in depressed individuals. Interestingly, IL-6 increases with age but can be modified by diet141
Potential premorbid risk factors for IFN-MDD that may be modifiable through psychosocial interventions could include social isolation144
However, when controlling for other premorbid risk factors, the effect size for these is fairly small.146
Another risk factor may be a hyperactive stress response in the hypothalamic-pituitaryadrenal (HPA) axis.147
Given the common association between abnormalities in the HPA axis and MDD,148-150
this may also be a potentially useful predictive marker. Interestingly, HPA axis responsiveness can be therapeutically modifiable by antidepressants.154
It is therefore plausible that patients with overactive HPA responses may be the subjects who benefit most from antidepressant prophylaxis. Consistent with this, stress-reactivity did correlate with depressive symptoms prior to IFN-α therapy147
- and thus elevated stress-reactivity may be a potential predictor of the need for ”indicated“ SSRI prevention.
Genetic polymorphisms within the serotonergic system have also been associated with vulnerability to IFN-MDD.134,146,155
Two studies have replicated the finding that a short allele in the serotonin transporter robustly increases risk for IFN-MDD.134,146
Vulnerability to tryptophan depletion has also been associated with polymorphisms in the 5-HT reuptake transporter.59
Because IFN-MDD has been associated with lowered tryptophan levels during treatment,57,91,93
this suggests that differences in serotonergic tone may leave some people vulnerable to IFN-MDD. It is also plausible that these are the same subjects who may benefit from SSRI prophylaxis, a possibility that requires testing.
Interestingly, gender has not been a consistent predictor of IFN-MDD,37,157,158
which suggests that IFN-MDD maybe partially distinct from some forms of MDD that are unique to females. Also, as long as patients remain abstinent, a past history- of drug and alcohol abuse is not predictive of increased risk.15,37,131
This suggests that risks for drug and alcohol abuse are distinct from risk for IFN-MDD. One critical implication is that a past history of drug use, in remission, is not a contraindication to prescribing IFN-α. Nonetheless, several leads are now suggested by these various predictive risk factors, several of which may be amenable to modification. The IFN-MDD paradigm has now been used in several studies to examine whether SSRIs can prevent depression. It may now be useful to determine whether other preventive treatments are effective.