one approach for delineating modifiable risk factors is to examine homogeneous groups of people who are definitively known to soon be exposed to a specific mdd - evoking situation . towards this end
mdd during ifn- treatment ( ifn - mdd ) typically develops within the first 2 or 3 months of administration , and occurs in about 15% to 40% of patients .
thus , prospectively assessing ifn - mdd onset is feasible - and consequently it may be possible to determine predictive modifiable vulnerabilities in the 15% to 40% who subsequently develop ifn - mdd . of course , it is conceivable that ifn - mdd is unique , and that other forms of mdd are completely distinct from it .
however , several lines of evidence indicate that ifn - mdd may successfully inform us about mdd in general .
first , a variety of studies have found a robust relationship between ifn- and mde , including those demonstrating a dose - response relationship , studies with control groups , and prospective documentations of worsening depression during ifn - a treatment with a return to baseline mood after discontinuation .
that is , ifn - mdd is not simply fatigue and malaise but - similarly to mdd - involves anhedonia , depressed mood , irritability , anxiety , social withdrawal , poor concentration , altered sleep , personality- changes , and suicidal ideation ( table i ) .
third , mdd and ifn - mdd may share similar pathophysiologic mechanisms , as indicated by various independent lines of investigation : many inflammatory cytokines are elevated during mdd . 
  psychosocial stress can increase the levels of inflammatory cytokines . 
 
peripheral cytokines and ifn- have access to the cns through a variety of routes in addition to being synthesized in the brain . 
   endogenous ifn- mrna can be induced in the cortex , hippocampus , and hypothalamus , with correlated changes in behavior in animal models of depression . 
 
systemic administration of ifn- and other cytokines can affect amotivation and anhedonia behaviors in rodent models of depression . 
 
once ifn - mdd is diagnosed , it responds to treatments that are effective for idiopathic mdd , ranging from selective serotonin reuptake inhibitors ( ssris ) and tricyclic antidepressants to electroconvulsive therapy , with about 79% to 85% of patients responding to antidepressants . 
 
ifn- administration can influence frontal lobe and anterior cingulate function , dopaminergic activity , and serotonergic function , - all of which may contribute to the development of depression in a manner homologous to other types of mdd .
of further public health significance , the use of ifn - a is not rare .
ifn - a is the only fda - approved treatment for hcv , whereas about 170 million people worldwide have been infected with hcv .
supporting ifn- 's widespread use , untreated chronic hcv can lead to cirrhosis , hepatocellular cancer , and liver failure , resulting in about 10 000 deaths per year in the us , a rate which exceeds that from acquired immunodeficiency syndrome .
unfortunately , ifn - mdd can potentially result in suicide , dose reduction with risk for viral relapse , discontinuation of treatment , and lower quality of life
. therefore , the two rationales for preventing ifn - mdd are that ( i ) this is a common and disabling syndrome ; and ( ii ) it may be and ideal strategy for informing us about ways to prevent mdd in general .
these prevention studies initiated ssris in patients who were not currently experiencing any mde prior to beginning the ifn - a therapy ( table ii ) .
the first randomized placebo - controlled trial ( rct ) was done in patients with metastatic melanoma , using very high doses of intravenous ifn - a .
this initial study found strong evidence for prevention of ifn - mdd , with only 2/18 par oxe tinetreated patients ( 11% ) developing ifn - mdd , as compared with 45% of the placebo - treated group .
similarly , in three open - label trials of prophylactic ssris given to nondepressed hcv patients , only 3/32 patients ( 9% ) developed ifn - mdd , despite all 32 patients having a prior history of affective disorder .
these open - label studies are thus consistent with this rct study , supporting the conclusion that preventative treatment with ssris may be useful .
however , two small rct studies have now been completed in patients with hcv ( table ii ) .
prophylactic ssris may therefore not be universally effective . despite these two negative findings , one of these studies did report that 24/29 patients in the placebo group developed elevated depression symptoms compared with 10/23 in the paroxetine group . additionally , further exploratory analyses indicated that prevention may have been most successful for those subjects who already had high pretreatment baseline levels of depressive symptoms .
it has been well - replicated that higher levels of pretreatment depression symptoms are associated with the development of ifn - mdd , and these subthreshold symptoms may be an appropriate target for using preventive ssris .
another open possibility is that prophylactic ssris specifically prevented ifn - mdd in those with past histories of mdd in remission .
this type of prevention would be consistent with the use of antidepressants to prevent recurrence of remitted mdd . 
  to explore this latter possibility
, we prospectively followed 31 patients who were not depressed at the onset of ifn- therapy ( as determined using a structured clinical interview of dsm - iv axis i diagnoses ) .
all of these patients had no mdes within 6 months prior to starting ifn- , but they did have a history of past mdd .
only 20% ( 2/10 ) of the patients on ssris developed ifn - mdd , while 47.6% ( 10/21 ) not on antidepressants did .
this very limited analysis suggests a more targeted use of ssris to prevent recurrence , limiting prophylactic ssri to those patients who are known to have past mdd histories .
however , all of these studies have been very limited in size , and therefore power .
assessing all of the six published prevention studies and our open - label data combined - in a very exploratory type of meta - analysis - 15/97 ( 15% ) patients receiving ssris prior to starting ifn- developed ifn - mdd , compared with 36/99 ( 36% ) .
however , limiting the meta - analysis to the three rcts , 10/55 ( 18% ) subjects randomized to pretreatment paroxetine developed ifn - mdd while 21/68 ( 31% ) randomized to placebo did .
the trend is numerically similar to the larger meta - analysis , but does not have the power to be significant in a chi - square test ( =1.98 ) . at this point ,
only tentative conclusions are possible : ( i ) prophylactic ssris may plausibly cut in half the incidence of ifn - mdd . to conclusively determine this , however , will require a larger - size trial than those performed to date ; ( ii ) ssris may specifically benefit subjects with either pre - existing depressive symptoms ( ie , subthreshold depression ) and/or a history of prior mdd . this is consistent either with studies of  indicated prevention  in which patients with subthreshold depression are prevented from worsening to full categorical mdd by about 30% , or with studies preventing recurrence of mdd
. a more targeted prevention rct would be valuable to examine these two possibilities ; ( iii ) even if ssris are found to be effective prophylactics for some people , about 15% to 20% of patients still developed ifn - mdd even when prescribed ssris , there fore antidepressants may not be universally effective .
other targets and approaches for prevention are needed ; ( iv ) most importantly , about half of the patients with a history of mdd remain resilient even during ifn- treatment . identifying the source of this resilience for potential replication in other patients would be beneficial .
the goal for this work is preventative treatments that can be targeted towards specifically mitigating those mechanisms underlying vulnerability .
patients with scores greater than 10 on the pittsburgh sleep quality index , a validated self - report assessment of sleep quality , were ten times more like to subsequently develop ifn - mdd than patients sleeping better than this .
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 .
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 , but may now be readily testable in patients about to be treated with ifn-. there is also evidence that increased age may be another risk factor for ifn - mdd , although this is certainly not a consistent finding . 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 .
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- administration , the il6 levels temporally predicted next month 's depression symptoms .
this is consistent with cross - sectional studies in which elevated il-6 levels are associated with mdd .
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 diet and/or exercise . 
 
potential premorbid risk factors for ifn - mdd that may be modifiable through psychosocial interventions could include social isolation and neuroticism .
however , when controlling for other premorbid risk factors , the effect size for these is fairly small .
another risk factor may be a hyperactive stress response in the hypothalamic - pituitaryadrenal ( hpa ) axis . given the common association between abnormalities in the hpa axis and mdd , this may also be a potentially useful predictive marker .
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- therapy - 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 .
two studies have replicated the finding that a short allele in the serotonin transporter robustly increases risk for ifn-mdd.vulnerability to tryptophan depletion has also been associated with polymorphisms in the 5-ht reuptake transporter .
because ifn - mdd has been associated with lowered tryptophan levels during treatment,- 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 , 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 .
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-. 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 .
in summary , encouraging results indicate that : ( i ) specific patients may be at elevated risk for ifn - mdd ; ( ii ) this vulnerability may be identifiable prior to ifn- treatment ; ( iii ) some sources of this vulnerability ( such as poor sleep ) may be modifiable ; and ( iv ) therefore personalized prevention is testable and could become a reality . because of the high incidence of ifn - mdd in the first few months of treatment , and the ability to recruit nondepressed patients prior to ifn- treatment , examining these possibilities appears to be practical and feasible in this population . several studies with prophylactic ssris
furthermore , because of the homologies between ifn - mdd and mdd in general , any lessons learned from ifn - mdd may be translatable to other types of mdd . as examples
, mdd occurs at higher rates in populations with multiple chronic illnesses , during bereavement , in caregivers of demented patients , in stroke survivors , in postpartum mothers , and there is preliminary evidence that mdd incidence could potentially be reduced in these settings .
similar to ifn - mdd , most people in these settings are resilient to developing mdd , with only a subset who are vulnerable . 

it remains an intriguing possibility that modifiable risk factors identified for ifn - mdd may also be modifiable risk factors in these other settings .
thus , targeting the appropriate prevention to the appropriate patient may be possible , and this may soon lead to the personalized prevention of mdd .
 major depressive disorder ( mdd ) during interferons ( ifn- ) treatment can occur within a few months of therapy , and shares many homologies with other forms of mdd , most patients are resilient to the side effect ofinterferon - induced depression ( ifn - mdd ) , but 15% to 40% are vulnerable . 
 several studies have employed antidepressants to prevent the incidence of an ifn - mdd episode , and the results suggest that prophylactic antidepressants may be specifically useful in those with pre - existing subthreshold depressive symptoms andlor a history of prior mdd episodes . 
 several other potential markers of vulnerability for ifn - mdd have been implicated in assessments of nondepressed patients before they start ifn- these include poor sleep quality , premorbid elevations in inflammatory cytokines , genetic polymorphisms in the serotonin system , personality , and social support . 
 the interplay of these factors strongly predicts who is at risk for ifn - mdd , and indicates several potentially modifiable targets for the personalized prevention of ifn - mdd , 
MDD during IFN- therapy
Prevention studies of IFN-MDD
Modifiable risk factors for IFN-MDD
Other populations at selective risk for MDD
Conclusion