We performed this meta-analysis of randomized double-blind placebo-controlled clinical trials to evaluate the efficacy and safety of prophylactic antidepressants to prevent PEG-IFN-α/RBV-associated depression in patients with CHC. The results reveal that preemptive and concomitant therapy with SSRIs can significantly reduce the incidence of PEG-IFN-α/RBV-associated depression in patients with CHC. SSRI interventions were safe, did not negatively decrease SVR, and did not influence the rate of drug discontinuation or withdrawal.
Interferon-α/RBV-associated depression is characteristic of a serotonergic deficiency and changes in the serotonin signaling pathway, which requires the prophylactic administration of SSRIs 
, because these drugs increase serotonin and have been widely used over the past decade, with a good safety profile 
The pooled rate of depression in the placebo group was 31.0%, which fell within the 20–40% incidence of depression in patients treated with IFN-α/RBV 
. Compared with placebo, prophylactic antidepressants can significantly reduce the incidence of PEG-IFN-α/RBV-associated depression, by up to 18.7% in CHC patients without a history of severe mental disease. Although standard INF-α was used in some CHC patients in two studies 
, the results from the other four trials showed that antidepressants markedly decreased the incidence of depression to 17.2% during PEG-IFN-α-based antiviral therapy. Furthermore, both current types of PEG-IFN-α, that is, PEG-IFN-α2a and 2b, were administrated in all six trials, so the type of IFN-α may be ignored when prophylactic SSRIs are used in patients with CHC. Escitalopram and paroxetine share the same mechanism of action to treat depression, although the former is superior to the latter for prophylactic intervention according to the present study. Escitalopram was developed after citalopram and is considered safer and more effective for treating major depression. However, a previous meta-analysis showed that escitalopram was not superior to citalopram in short-to-medium term treatment of major depressive disorder 
. The rate of depression was 10.5% when citalopram was used 
, which was lower than 17.9%—the pooled rate of depression in three trials when escitalopram was used 
. However, the sample size in the trial on citalopram was only 39 patients, which was 10% of the pooled sample in the three trials of escitalopram. Clinically, clinicians should pay more attention to the results of meta-analyses.
With respect to the effect of SSRIs on the SVR, the results varied among the trials, although the trials were of similar design 
. The pooled SVR rate in the setting of prophylactic SSRIs did not differ significantly compared with that in the placebo group. Subgroup analysis also reached a similar conclusion. Consequently, prophylactic SSRIs have little effect on the SVR in patients with CHC when they are treated with antiviral therapy. However, we suggest that escitalopram should be used because of the higher SVR rate and its increased use for intervention in depression.
IFN-α/RBV-associated depression was an important reason for discontinuing antiviral therapy 
. Consequently, successful treatment of CHC needs prevention of depression. The pooled rate of drug discontinuation differed significantly between the SSRI and placebo groups after subgroup analyses, which was consistent with the results from each trial individually. These results suggest that prophylactic SSRIs have little effect on drug discontinuation during treatment of CHC with the currently available antiviral therapy.
The lower rates of rescue therapy, muscle and joint pain and respiratory problems in the SSRI group indicated the better safety and tolerability of SSRIs. These results suggest that prophylactic SSRIs reduce the occurrence of these two adverse events associated with PEG-IFN-α/RBV combination therapy in patients with CHC. However, the pooled rate of dizziness was higher in the SSRI group than the placebo group, which was consistent with the results of each separate trial. This reminds clinicians to pay more attention to the occurrence of this adverse event when prophylactic SSRIs are administrated to patients with CHC. Therefore, prophylactic SSRIs did not worsen most adverse events apart from dizziness. Moreover, adverse events (e.g. diarrhea, headache, and sleep disturbance) were not increased as a result of concurrent administration of antiviral therapy and SSRIs. Although it was reported that citalopram could be safely used during IFN treatment in patients with CHC 
, there were risks of using SSRIs during IFN treatment, because CHC may alter the pharmacokinetics of SSRIs. Therefore, SSRI dose may require adjustment to optimize the treatment 
We need to emphasize that according to our clinical experience and inclusion criteria, the optimal candidates for SSRI prophylaxis are CHC patients with concurrent subsyndromal depression symptoms (such as insomnia and anxiety) or a history of past major depressive disorders and eligibility for PEG-IFN-α/RBV treatment.
There were several limitations to our study. First, only six eligible RCTs were included, and we were limited by data availability. Second, sample sizes in most of the trials were small and included <50 subjects. Third, the possibility of omission of unpublished or ongoing studies still exist, although publication bias was not found according to the funnel plots and the Begg–Mazumdar test. Fourth, possible variation in the definition of depression and severity of depression were present in the studies included in our analysis, although the criteria for diagnosis and severity of depression were similar in all studies. These defects may weaken our results. Further analysis of increased numbers of multicenter RCTs with larger sample sizes are warranted to evaluate comprehensively the true value of prophylactic SSRIs to prevent PEG-IFN-α/RBV-associated depression during antiviral therapy in patients with CHC.
Despite these limitations, our meta-analysis of double-blind, placebo-controlled RCTs shows that prophylactic SSRIs can significantly reduce the incidence of PEG-IFN-α/RBV-associated depression in patients with CHC, with good safety and tolerability and without reduction of SVR.