International Journal of Clinical Practice
Prevention of Interferon-Alpha-Associated Depression With Antidepressant Medications in Patients With Hepatitis C Virus
A Systematic Review and Meta-analysis
M. Ehret, D. M. Sobieraj
Int J Clin Pract. 2014;68(2):255-261.
Abstract and Discussion Only
Abstract
Objective: To conduct a systematic review and meta-analysis evaluating the efficacy and safety of antidepressant medications for the prevention of interferon-alpha (INF-α)-associated depression in patients with chronic hepatitis C virus (HCV).
Data sources: Medline, Cochrane Central and PsycInfo from inception to September 2012, without limitations using terms describing hepatitis C and the individual drug names.
Study selection: We reviewed 132 citations for inclusion using the following criteria: randomised controlled trials in patients with chronic HCV initiating INF-α comparing prophylactic use of an antidepressant vs. placebo and reporting at least one outcome of interest [depression, completion of antiviral therapy, sustained virologic response (SVR), and serious adverse events and bleeding].
Data extraction: Trial characteristics, assessment of risk of bias and data needed for analyses were extracted by two independent investigators using a standard extraction form. Disagreements were reviewed by a third investigator.
Results: A DerSimonian and Laird random-effects model was used for analysis. Heterogeneity and publication bias were evaluated where applicable. Of the seven included trials, the risk of bias was low in four and unclear in the remaining three. All trials evaluated selective serotonin reuptake inhibitors (SSRIs). Prophylactic use of a SSRI significantly reduced the risk of depression by 41% compared with placebo [RR, relative risk 0.59 (0.37–0.93)]. The impact of SSRIs on completion of antiviral therapy, SVR and serious adverse events was not found to be significant.
Conclusions: SSRIs prevent depression in patients with HCV treated with INF-α therapy. The impact of SSRIs on completion of antiviral therapy or on the development of adverse events is less clear.
Discussion Only
To our knowledge, this is the first systematic review and meta-analysis analysing the use of SSRIs for the prevention of INF-α-associated depression in patients with chronic HCV. The trials which have previously evaluated this clinical practice have had differing results. The trials were all very similar in terms of interventions, outcomes assessment and follow up. Although the sample sizes varied and most were small, two of the smallest trials concluded SSRIs were not effective as did two of the larger trials. By using methods of systematic review and meta-analysis, we were able to pool the results of these trials to discern an overall effect of SSRIs in this population. In our analysis, the prophylactic use of a SSRI during INF-α-based therapy in patients with HCV reduced the risk of depression during antiviral treatment. However, the severity of depressive symptoms as measured by the MADRS score did not differ. SSRI therapy was initiated at least 2 weeks prior to antiviral therapy and was continued throughout the duration of antiviral therapy. Although SSRI therapy was successful in reducing depression risk, this did not translate into differences in completion rates of antiviral therapy or achievement of SVR. Safety outcomes were not frequently reported and therefore the overall safety of this practice is unclear.
Selective serotonin reuptake inhibitors work by inhibiting 5-HT reuptake and thus increasing serotoninergic transmission. This is opposite to the proposed mechanism by which INF-α is thought to cause depression (decreasing tryptophan and 5-HT levels, increasing 5-HT reuptake and thus decreasing synaptic availability of 5-HT and 5-HT transmission). [21,22] SSRIs have high rates of success in treating IFN-α-induced depression, beyond that typically observed in RCTs in major depression. [23] Although SSRIs have considerably less adverse effects compared with other antidepressant classes, several major concerns should be considered prior to use, including an increased risk of bleeding and development of manic episodes. [24–26] Other mild and transient adverse effects include sexual dysfunction, gastrointestinal distress, anxiety, sweating, and headache. [27] Despite these limitations, SSRIs should be considered the first choice for the prevention of IFN-α-induced depression because of their excellent efficacy, favourable adverse effect profile, minimal hepatic toxicity and few drug–drug interactions. [23]
Although the use of SSRIs did decrease the risk of depression by 41%, there was no significant difference in the change of MADRS scores from baseline to follow up in those treated with SSRIs vs. placebo. It would be expected that a reduction in the diagnosis of depression would equate to a decrease in the change score for those treated with SSRIs. There was a higher level of statistical heterogeneity seen between the studies in this analysis, with disagreement in both magnitude and direction of effect, which may be related to the small number of participants in the studies and type II error. Additionally, the MADRS was developed to measure the overall severity of depressive symptoms in patients with a diagnosis of major depressive disorder. [28] It does not focus on the somatic symptoms of depression, which are included in the DSM-IV criteria used to diagnose depression in six of the seven included studies. The neurovegetative and somatic symptoms of depression, such as anorexia, fatigue and altered sleep and pain, typically develop with the first few weeks of treatment with IFN-α and are less responsive to antidepressants. While, depressed mood, anxiety and cognitive dysfunction typically develop later (i.e. 12 weeks) during IFN-α treatment and are more responsive to antidepressants. [29]
There are several limitations to the analysis and literature base that are worth noting. The patient population evaluated in the included trials represented four HCV genotypes (1–4) although slightly more than half of the population had genotype 1. In 2011, two protease inhibitors were approved in the United States for the treatment of HCV, genotype 1, in combination with pegylated INF-α and ribavirin: boceprevir (Victrelis®) and telaprevir (Incivek®). Most recent guidelines from the American Association for the Study of Liver Disease recommend this triple therapy for patients with genotype 1. [30] Although our current analysis does not reflect the use of triple therapy to treat HCV, we do not anticipate a difference in SSRI treatment effect since the protease inhibitors are not known to cause depression as a side effect. [31,32] However, it is noteworthy that the package insert for both protease inhibitors does warn of a potential drug interaction with escitalopram and that 'SSRIs such as escitalopram have a wide therapeutic index, but doses may need to be adjusted when combined'. [31,32] The populations of the included trials may in fact have been diverse. Although the studies excluded patients with a current depressive episode, previous depressive episodes were not used as an exclusion criterion which could have diversified the population of subjects. Previous studies have demonstrated rates of neuropsychiatric symptoms of 12–41% in those that excluded patients with psychiatric histories while those studies without this exclusion criteria report an incidence of 17–58%. [33] This diverse population could account for different rates of changes in MADRS scores and the heterogeneity seen within the studies. Additional research should focus on each population, those with and those without psychiatric histories, separately in determining the use of antidepressants in preventing depressive symptoms. Although we sought to identify trials evaluating other antidepressant, none was found in the peer reviewed literature. Therefore, little is known about whether or not other types of antidepressants, which have varying types of adverse effects, such as the serotonin norepinephrine reuptake inhibitors, mirtazapine, or bupropion, may decrease the development of depression in this population. There is also a lack of reported information on adverse effects from the use of the SSRIs in this population. Bleeding is a potential issue with the use of SSRIs because of the ability to decrease intraplatelet 5-HT content and inhibit platelet function. [24] This is a significant concern in those with liver dysfunction who are at an increased risk of gastrointestinal bleeding. Included trials did not routinely report liver function tests or markers of liver function to know the severity of liver dysfunction. Although the true risk vs. benefit is unclear, a retrospective analysis recently found an overall rate of 0.3% of bleeding in those with hepatitis C treated with SSRIs, suggesting a low risk. [34]
Patients receiving SSRIs had a lower risk of developing depression vs. placebo in those with HCV treated with INF-α-plus ribavirin. Future research should focus on the evaluation of other antidepressants and the safety of antidepressant use in this patient population.
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