**3. Depression and hepatitis C virus**

Depression has long been recognized and associated with many chronic medical conditions. The occurrence of depression is higher in patients with chronic liver disease than that in the general population. The depression is a very common psychiatric comorbidity in HCV patients. The link between HCV and depression has been the focus of many investigations. Several studies have reported variability in the prevalence of depression among the HCV population. The prevalence of depression in HCV patients has been estimated to be 1.5–4 times higher than in general population. Moreover, the prevalence rate seems to be unrelated to liver disease severity and interferon treatment. However, psychiatric comorbidities are usually underdiagnosed or overlooked when patients seek primary care, even though depression affects overall disease progression in the HCV-infected population [36–40].

Understanding the depressive disorder comorbid with HCV may be critical for developing effective intervention strategies. Most patients with depression will suffer noticeable changes in social and physical activities, a loss of interest in work or leisure activities, or poor academic performance. Another important issue is that HCV infection is often associated with behaviors that are condemned by society (e.g., drug use, alcoholism, and high-risk sexual behaviors), promoting prejudice, discrimination, and abuse against patients. Also, these maladaptive behaviors could further exacerbate the depression.

The high prevalence of psychiatric comorbidities in HCV-infected patients has been typically associated with direct effects of the virus on the central nervous system or adverse effects of hepatitis C treatment. The high prevalence of psychiatric comorbidities in HCV-infected patients has been typically associated with direct effects of the virus on the central nervous system or adverse effects of hepatitis C treatment.

The comorbid depression in HCV patients could be:


Both biological and psychosocial factors are important considerations for the effective clinical management of HCV and the prevention of HCV disease progression.

#### **3.1. Psychosocial factors involved in development of depression**

It is very important to distinguish between psychological reactions to the knowledge that one has been infected with HCV and the direct effects of the virus itself. Learning that one has contracted HCV infection represents a significant life stressor and will produce emotional stress in most patients, and psychiatric disorder in many. The psychological reasons for the development of depression are illustrated in **Table 4**. The psychosocial factors involved in the development of depression are illustrated in **Table 4**.

Stigma negatively affects the HRQOL, mental health, and social life of the patients, and leads to difficulties with receiving or accepting treatment. Poor social and work adjustment, lower acceptance of the illness, and higher subjective complaints are other problems associated with stigmatization. Researches showed that women generally are prone to experience more stigmatization. The social stigma may cause some HCV individuals to refuse to disclose their HCV diagnosis. Furthermore, HCV-related stigma is an important stressor that leads to poor treatment adherence. In some cases, HCV-infected individuals tend to isolate themselves to prevent stigma-related negative attitudes. Low income is also a socio-demographic factor significantly associated with the appearance of depressive symptoms [41–46].

The most commonly used coping styles by HCV patients are:



There is evidence that cognitive dysfunctions in HCV patients have some impact in the reduction of health-related quality of life, chronic fatigue, and impaired functionality. The literature demonstrates evidence of neurocognitive impairment in patients with chronic HCV infection. However, until now, it is not clear that these dysfunctions can be linked, wholly or in part, to the virus itself. The longitudinal evaluation of the cognitive functioning could provide valuable information regarding the persistence of symptoms after the clearance of

Depression has long been recognized and associated with many chronic medical conditions. The occurrence of depression is higher in patients with chronic liver disease than that in the general population. The depression is a very common psychiatric comorbidity in HCV patients. The link between HCV and depression has been the focus of many investigations. Several studies have reported variability in the prevalence of depression among the HCV population. The prevalence of depression in HCV patients has been estimated to be 1.5–4 times higher than in general population. Moreover, the prevalence rate seems to be unrelated to liver disease severity and interferon treatment. However, psychiatric comorbidities are usually underdiagnosed or overlooked when patients seek primary care, even though depression affects overall disease progression in the HCV-infected population [36–40].

Understanding the depressive disorder comorbid with HCV may be critical for developing effective intervention strategies. Most patients with depression will suffer noticeable changes in social and physical activities, a loss of interest in work or leisure activities, or poor academic performance. Another important issue is that HCV infection is often associated with behaviors that are condemned by society (e.g., drug use, alcoholism, and high-risk sexual behaviors), promoting prejudice, discrimination, and abuse against patients. Also, these mal-

The high prevalence of psychiatric comorbidities in HCV-infected patients has been typically associated with direct effects of the virus on the central nervous system or adverse effects of hepatitis C treatment. The high prevalence of psychiatric comorbidities in HCV-infected patients has been typically associated with direct effects of the virus on the central nervous

Both biological and psychosocial factors are important considerations for the effective clinical

management of HCV and the prevention of HCV disease progression.

virus in the periphery.

208 Liver Research and Clinical Management

**3. Depression and hepatitis C virus**

adaptive behaviors could further exacerbate the depression.

system or adverse effects of hepatitis C treatment.

**b.** a reactive depression to the diagnosis of HCV,

**a.** depression that may be pre-existent,

**c.** a biological effect of HCV infection, or **d.** an α-interferon-induced depression.

The comorbid depression in HCV patients could be:

Risk of cirrhosis/cancer and other health-related worries Fear of transmitting the disease Concerns about the complications of disease/treatment Functional disability Impaired quality of life Fatigue severity Personality disorders Low income Social stigma Coping styles

Social support

**Table 4.** Psychosocial factors associated with the development of depression in HCV patients.

Several studies have reported using inappropriate coping strategies in patients with HCV, which may negatively affect several aspects of their management.

The predictors of development of depression during antiviral treatment are:

Standard treatment for CHC was for a period a combination of pegylated interferon (pegIFN) and ribavirin (RBV), which was known to exacerbate fatigue and depressive symptoms. Interferon-based regimens are related to complicated dosing schedules, weekly administration of subcutaneous injections, and many side effects. Interferon alpha combined with ribavirin has been shown to be more effective than interferon alone on obtaining sustained virologic response. Moreover, it seems that SVR achieved with PEG-IFN-α and RBV combina-

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Until now, we do not have sufficient data whether or not the cognitive impairments are irreversible in patients who have eliminated HCV after successful treatment. A study performed by Byrnes et al. concluded that HCV eradication was associated with an improvement in memory (visual and spatial) and verbal learning [52]. Another survey of 168 HCV patients receiving antiviral therapy with interferon and ribavirin evaluated 12 months after the termination of antiviral treatment concluded that in patients with a sustained viral response a significant improvement was observed in three out five cognitive domains (working memory,

Approval of direct-acting antivirals (DAA) against the hepatitis C virus has dramatically changed the management of HCV infection due to high cure rates and a favorable safety profile. It was reported that DAA in certain combinations are curing HCV infection in almost 100% of cases [55]. DAA are taken once-daily in oral combinations. Treatment duration has also been shortened considerably in comparison with interferon therapies, making treatment regimens more tolerable. Patient-reported outcomes (PROs) provide the patient's perspective on the physical, functional, and psychological consequences of treatment and the degree and impact of disease symptoms. Recent regimens are interferon-free, and in many cases, RBV-free, and involve a combination of DAA agents. Many studies showed a consistent improvement in the quality of life, fatigue, and work productivity during treatment in patients receiving IFN and RBV-free strategy. Newly approved oral anti-HCV drugs are very safe and effective, but unfortunately, they are very costly. DAAs do not seem to increase the neuropsychiatric risks to patients undergoing HCV triple therapy [56–60].

**1.** history of depressive disorder,

**4.** low educational level, and

**3.** female gender,

**2.** sub-threshold depressive symptoms,

tion therapy is durable over time [51].

vigilance, and shared attention) [53, 54].

**3.3. Direct-acting antivirals**

**5.** high baseline serum interleukin 6 (IL6) concentrations.

Specific risk factors for IFN-induced suicide are still unknown.

Psychosocial interventions that include cognitive, behavioral and lifestyle strategies may influence the negative impact of HCV symptoms and treatment side effects on HRQOL.

#### **3.2. Biological factors**

Biological factors appear to play a significant role as well. Major depressive disorder is associated with the increased production of pro-inflammatory cytokines, such as interleukin-1 (IL-1), IL-6, and interferon gamma (IFN-γ). Chronic HCV infection is also known to increase inflammatory cytokines like IL-1, IL-6, and tumor necrosis factor alpha (TNF-α). The inflammatory model of depression provides a possible link between the HCV infection and major depressive disorder. An increased macrophage migration inhibitory factor was also demonstrated in patients with major depression. Elevated pro-inflammatory cytokines have been found in patients with anxiety and depression symptoms and pharmacological agents who specifically inhibit inflammatory mediators seem to determine a reduction in depression and anxiety symptoms. The rise in cytokine levels is associated with fatigue, malaise, lethargy, and depression. Another effect of pro-inflammatory cytokines is the activation of the hypothalamic–pituitary–adrenal (HPA) axis, which represents the regulator of the stress response.

Many studies suggest that the activation of HPA pathways can modify monoamine expression in the CNS, and as a consequence, leading to symptoms of depression. It was demonstrated that the neurochemical imbalance of serotonin (5-HT), norepinephrine (NE), and dopamine (DA) is linked to the development of depression. Studies in HCV-infected patients demonstrate impaired levels of dopamine and serotonin among distinct brain regions.

Many studies suggest that the activation of HPA pathways can modify monoamine expression in the CNS, and as consequence, leading to symptoms of depression. It was demonstrated that the neurochemical imbalance of serotonin (5-HT), norepinephrine (NE), and dopamine (DA) is linked to the development of depression. Studies in HCV-infected patients demonstrate impaired levels of dopamine and serotonin among distinct brain regions [47–50].

IFN-α-induced depression may increase suicidality, impair quality of life, increase, and lead to noncompliance or even treatment withdrawal among patients with chronic HCV infection. Following IFN treatment of patients with HCV, up to 70% may develop depression. Several mechanisms have been proposed:


The predictors of development of depression during antiviral treatment are:


Several studies have reported using inappropriate coping strategies in patients with HCV,

Psychosocial interventions that include cognitive, behavioral and lifestyle strategies may influence the negative impact of HCV symptoms and treatment side effects on HRQOL.

Biological factors appear to play a significant role as well. Major depressive disorder is associated with the increased production of pro-inflammatory cytokines, such as interleukin-1 (IL-1), IL-6, and interferon gamma (IFN-γ). Chronic HCV infection is also known to increase inflammatory cytokines like IL-1, IL-6, and tumor necrosis factor alpha (TNF-α). The inflammatory model of depression provides a possible link between the HCV infection and major depressive disorder. An increased macrophage migration inhibitory factor was also demonstrated in patients with major depression. Elevated pro-inflammatory cytokines have been found in patients with anxiety and depression symptoms and pharmacological agents who specifically inhibit inflammatory mediators seem to determine a reduction in depression and anxiety symptoms. The rise in cytokine levels is associated with fatigue, malaise, lethargy, and depression. Another effect of pro-inflammatory cytokines is the activation of the hypothalamic–pituitary–adrenal (HPA) axis, which represents the regulator

Many studies suggest that the activation of HPA pathways can modify monoamine expression in the CNS, and as a consequence, leading to symptoms of depression. It was demonstrated that the neurochemical imbalance of serotonin (5-HT), norepinephrine (NE), and dopamine (DA) is linked to the development of depression. Studies in HCV-infected patients demon-

Many studies suggest that the activation of HPA pathways can modify monoamine expression in the CNS, and as consequence, leading to symptoms of depression. It was demonstrated that the neurochemical imbalance of serotonin (5-HT), norepinephrine (NE), and dopamine (DA) is linked to the development of depression. Studies in HCV-infected patients demonstrate impaired levels of dopamine and serotonin among distinct brain

IFN-α-induced depression may increase suicidality, impair quality of life, increase, and lead to noncompliance or even treatment withdrawal among patients with chronic HCV infection. Following IFN treatment of patients with HCV, up to 70% may develop depression. Several

strate impaired levels of dopamine and serotonin among distinct brain regions.

which may negatively affect several aspects of their management.

**3.2. Biological factors**

210 Liver Research and Clinical Management

of the stress response.

regions [47–50].

mechanisms have been proposed:

**a.** altered monoamine metabolism,

**c.** increased rate of apoptosis, and

**b.** altered hypothalamus–pituitary–adrenal axis function,

**d.** brain-derived neurotrophic factor (BDNF) reduction.


Specific risk factors for IFN-induced suicide are still unknown.

Standard treatment for CHC was for a period a combination of pegylated interferon (pegIFN) and ribavirin (RBV), which was known to exacerbate fatigue and depressive symptoms. Interferon-based regimens are related to complicated dosing schedules, weekly administration of subcutaneous injections, and many side effects. Interferon alpha combined with ribavirin has been shown to be more effective than interferon alone on obtaining sustained virologic response. Moreover, it seems that SVR achieved with PEG-IFN-α and RBV combination therapy is durable over time [51].

Until now, we do not have sufficient data whether or not the cognitive impairments are irreversible in patients who have eliminated HCV after successful treatment. A study performed by Byrnes et al. concluded that HCV eradication was associated with an improvement in memory (visual and spatial) and verbal learning [52]. Another survey of 168 HCV patients receiving antiviral therapy with interferon and ribavirin evaluated 12 months after the termination of antiviral treatment concluded that in patients with a sustained viral response a significant improvement was observed in three out five cognitive domains (working memory, vigilance, and shared attention) [53, 54].

#### **3.3. Direct-acting antivirals**

Approval of direct-acting antivirals (DAA) against the hepatitis C virus has dramatically changed the management of HCV infection due to high cure rates and a favorable safety profile. It was reported that DAA in certain combinations are curing HCV infection in almost 100% of cases [55]. DAA are taken once-daily in oral combinations. Treatment duration has also been shortened considerably in comparison with interferon therapies, making treatment regimens more tolerable. Patient-reported outcomes (PROs) provide the patient's perspective on the physical, functional, and psychological consequences of treatment and the degree and impact of disease symptoms. Recent regimens are interferon-free, and in many cases, RBV-free, and involve a combination of DAA agents. Many studies showed a consistent improvement in the quality of life, fatigue, and work productivity during treatment in patients receiving IFN and RBV-free strategy. Newly approved oral anti-HCV drugs are very safe and effective, but unfortunately, they are very costly. DAAs do not seem to increase the neuropsychiatric risks to patients undergoing HCV triple therapy [56–60]. In the absence of the neurocognitive side effects of interferon, it should be expected a significant improvement in neurocognitive functioning if, as suggested, the impairments are directly attributable to HCV action on CNS.

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#### **3.4. Treatment of depression**

Several studies have specifically investigated the treatment of depression in HCV patients. The literature suggests that depression, anxiety symptoms, and cognitive complaints are responsive to selective serotonin reuptake inhibitors (SSRIs) antidepressants. However, the neurovegetative symptoms seem to be less sensitive to SSRIs. Some evidence suggests that dual antidepressants neurovegetative symptoms can be better influenced with serotonin-norepinephrine reuptake inhibitors (SNRIs). Although the data are not strong, it does appear that SSRIs might be the first choice for the treatment of interferon-induced MDD and citalopram is recommended as first-line treatment for IFN-induced depression. Antidepressant medication should be continued for at least 12 weeks following the end of IFN treatment. Antidepressant therapy is also indicated for those patients with baseline depressive symptoms and those with a history of IFN-induced depression. Data showed that antidepressant pre-treatment with SSRIs lowers the incidence and severity of IFN-associated depression in patients with chronic hepatitis C infection. But we need to keep in mind that antidepressants are not recommended for all HCV patients, and the indication should be tailored to each patient [54, 61–65].
