Depression and infectious diseases are linked in multiple ways. Depression contributes to initial infection in several diseases; for example depression predisposes to both hepatitis C (HCV) and HIV acquisition. Conversely, depression may result from the stress of living with a serious infectious disease, or may stem from the effect of an infectious disease on the immune and central nervous systems (CNS). In addition, the medications used to treat infectious diseases may cause depression. The interrelationship is further complicated by the fact that depression may be more prevalent among groups at greater risk of infection, such as individuals with substance-related conditions or individuals who are homeless or living in poverty.

Early identification and treatment of depression leads to improved quality of life and may improve medical outcomes by facilitating engagement in and adherence to the medical regimen. Given shared underlying pathophysiologic mechanisms, effective treatment of depression may in some instances even influence the course of disease. This chapter will address the salient features of depression found among those infectious diseases most commonly associated with mood disturbances.

EPIDEMIOLOGY (FIG. 11-1)

PREVALENCE AND INCIDENCE OF DEPRESSIVE DISORDERS

Patients with HCV are disproportionately affected by depression, the most common mental health concern among HCV-infected individuals.^1–4 Compared to the general population, depression is three to four times more prevalent in individuals with HCV.^5–7 Current prevalence rates for depressive disorders among individuals with HCV range from 28% to 35%,^3,7–9 and lifetime rates are reported to be between 34% and 44%.^3,7 The prevalence of particular depressive disorders varies widely depending on the study; the prevalence of major depressive disorder (MDD) is variously reported between 8% and 25%.^3,7,10 The most common depressive diagnosis is adjustment disorder with depressed mood, reported in 40% of cases, while the least prevalent is dysthymia or depressive disorder NOS (3%).³

One alarming result of MDD is suicidal ideation and suicide attempts. HCV patients are twice as likely to have attempted suicide as matched controls.¹¹ The suicide risk is greater for males and those under 45 years of age.¹²

RISK FACTORS AND CORRELATES OF DEPRESSION

Increasing age is associated with greater risk for depression and severity of depression in those with HCV (Box 11-1).^3,13 As in the general population, the prevalence is higher in women (44%) with HCV than in men (22%).³

One explanation of the increased prevalence of depression in HCV may be the increased rate of substance use in this population, since intravenous drug use is the leading cause of HCV infections in the United States.¹⁴ Individuals who are depressed may be more likely to engage in intravenous or intranasal drug use, putting them at greater risk of HCV.⁷ Another possible reason for the heightened depressive comorbidity is the pathophysiology of the disease itself,^3,15,16 in that depressive disorder may be the direct result of the infectious process itself.¹⁷ Finally, the stress of living with a stigmatized, serious illness may also increase the vulnerability to developing depression.^7,18 Indeed, increasing depressive symptom severity has been linked to poor acceptance of HCV and HCV-related stigma.³

PATHOPHYSIOLOGY

Depressive symptoms may result from changes in immunological functioning, in particular, interleukin-1 and tumor necrosis factor¹⁹ and/or from changes in platelet 5-HT functioning (Box 11-2).^3,15,16,20

CLINICAL PRESENTATION

Depression in HCV patients is often characterized by fatigue and malaise (Box 11-3).^21,22 However, the neurovegetative and somatic symptoms of depression are often caused by the hepatitis infection itself.²³ The Beck Depression Inventory-II has been used to distinguish depressive symptoms from HCV symptoms using a somatic factor and a cognitive-affective factor. Patients with current MDD score significantly higher on both factors than those without MDD, but the cognitive-affective factor may become a more valid measure of depression as liver disease progresses.²³

Patients with chronic HCV experience an impaired quality of life (QoL).²¹ This is not associated with age, gender, mode of acquiring the virus, alanine aminotransferase (ALT) levels, substance use or social support,^24,25 but instead is related to depressive symptoms and fatigue.^22,23 One source of this diminished QoL is the emotional distress and uncertainty that accompany HCV.^18,26,27 Illness uncertainty has been related to depressive symptoms in a cross-sectional study of HCV patients. Ambiguity about the disease is the primary component of illness uncertainty associated with depressive symptoms, diminished quality of life, and fatigue.²²

Eighty-five percent of HCV-infected Veterans have one or more past or current psychiatric disorders.¹¹ The most prevalent psychiatric comorbidities with HCV, in addition to depressive disorders, are alcohol use disorder, substance use disorder, and anxiety disorders (Box 11-4). Lifetime prevalence rates of alcohol use disorder range from 81% to 86%^8,9 and point prevalence of substance use disorders ranging from 30% to 60%.^1,8,9,11 Approximately 71% of HCV patients have a past or current anxiety disorder,¹¹ and 62% have PTSD (Box 11-5).⁸

COURSE AND NATURAL HISTORY

DEPRESSION AND ANTIVIRAL MEDICATION

There is some evidence that quality of life with HCV improves after antiviral therapy or liver transplantation.²¹ Antiviral therapy (AVT), consisting of interferon and ribavirin, was the standard treatment for HCV, but the antiviral treatment landscape is now changing rapidly. The recent addition of more effective and less toxic antiviral agents has improved treatment success rates for the most prevalent HCV genotypes.¹⁴ The side effect profile of interferon-free HCV therapies is markedly improved, with a drastic reduction in psychiatric side effects.

Between 50% and 60% of HCV patients treated with interferon experience clinically significant depressive symptoms,^28–31 with 25% developing a major depressive episode.³² Interestingly, interferon therapy in patients with HCV is associated with depression more frequently than when used in other patient populations (e.g., multiple sclerosis).³³ See Box 11-6.

DEPRESSION AND ADHERENCE TO ANTIVIRAL MEDICATION AND DISEASE OUTCOME

Untreated depression negatively affects the course of HCV. It jeopardizes the receipt of HCV treatment and engagement in care.³ During antiviral therapy, depression can lead to nonadherence, and alcohol and/or substance relapse.³⁴ Although two studies have found that an increase in depression during AVT was associated with lower rates of virologic response to treatment,^35,36 other studies showed that patients whose depression began during AVT had significantly higher rates of treatment completion.^34,37 In addition, the development of a depressive disorder during AVT did not negatively impact virologic response rates.^34,37,38 One possible explanation is that HCV patients who experience more depressive and neuropsychiatric side effects during AVT may also be expe riencing a more robust immunological activation response, resulting in viral suppression.^34,39

IMPACT OF COMORBID DEPRESSION ON THE COURSE OF HCV, HCV SEVERITY, AND CHRONICITY

Depression may have adverse effects on the amplification of physical symptoms, treatment engagement and adherence, and functioning and quality of life.^3,7 Several studies have found that severity of the HCV infection does not differ significantly in those with and without current depression.⁷ However, depression appears to have more of an impact on fatigue and functional impairment than does HCV disease severity.⁷

ASSESSMENT AND DIFFERENTIAL DIAGNOSIS

All HCV patients should be systematically assessed for psychiatric disorders, particularly depression, as recommended by treatment and practice guidelines and consensus reports (Box 11-7).^40,41 As discussed above, assessing depressive symptoms among HCV patients is made more difficult by the overlap between the somatic symptoms of depression and those of HCV and AVT side effects. However, due to the persistent under-detection of depressive disorders among individuals with HCV,^3,8 assessing and monitoring all depressive symptoms is recommended.⁴² Several self-report and clinician administered depression scales are recommended for use in this population: Self-report scales include the Patient Health Questionnaire-9 (PHQ-9), Center for Epidemiologic Studies-Depression Scale (CES-D), and the Beck Depression Inventory (BDI-II).⁴³ The HAM-7 is a clinician administered scale whose accuracy in detecting depression among HCV patients is comparable to that of the PHQ-9.⁴³

TREATMENT OF DEPRESSION IN HCV

PHARMACOTHERAPY

Serotonin reuptake inhibitors (SSRIs) are considered first-line treatment in this setting. General principles for treatment of depression in HCV still apply. Side effect profile and pharmacokinetic considerations should guide choice of agents. For example, SSRI treatment may be limited for some patients due to the associated risk of GI bleeding or hepatic insufficiency. ECT has also been reported to be effective.⁴⁴

Much of the empirical evidence for the pharmacotherapy of depression in HCV comes from trials of antiviral therapy with interferon.^45–49 In light of the recent development of interferon-free HCV therapies, these data may be of limited relevance. In the largest randomized controlled trial of interferon-based therapy, escitalopram outperformed placebo in both preventing incident depression and in treating depressive symptoms.⁵⁰

PSYCHOSOCIAL INTERVENTIONS

Guidelines for assessing and monitoring depression before and during HCV treatment were developed prior to the introduction of interferon-free HCV therapies. The relevance of these recommendations in the absence of interferon is limited. For patients receiving interferon-based therapy, regular monitoring of depressive symptoms during the course of antiviral therapy is recommended (approximately every 4 weeks), even among those patients not exhibiting depression before starting the treatment. Those with moderate to severe depression should be followed closely (i.e., at least 2 weeks) by a mental health professional, and also considered for antidepressants.³⁸ In this setting, the depression accompanying HCV is characterized by pronounced somatic and neurovegetative symptoms, as opposed to cognitive-affective symptoms, which may require modification of the standard psychotherapies for depression. Cognitive and behavioral interventions may therefore target the somatic side effects first.⁵¹ There is currently insufficient data to recommend similar guidelines for patients undergoing HCV treatment with novel antiviral agents.

Studies evaluating psychological interventions for depression are lacking. It has been recommended that CBT be initiated before interferon-based antiviral therapy is begun in patients with premorbid mood symptoms in order to build coping skills.⁵¹ One RCT of CBT for depression prophylaxis in patients undergoing interferon-based antiviral therapy for HCV reported a trend favoring the CBT arm although overall the results were inconclusive.⁵² The therapy consisted of mood monitoring, pleasant activity scheduling, constructive thinking, and social skills and assertiveness training.⁵²

Several empirically supported psychological treatment approaches can be adapted for treating comorbid depression in HCV. These include the Cognitive–Behavioral Treatment for Depression and Adherence (CBT-AD) model that combines CBT with problem-solving skills targeting medication adherence and motivational interviewing.⁵³ Another model is the Cognitive–Behavioral Stress Management (CBSM) intervention, a group-based intervention focused on stress management and relaxation skills, assertiveness and communication training, and anger management.^53,54 Finally, an acceptance-based behavioral therapy, such as Acceptance and Commitment Therapy, has potential to treat depression in the HCV population.⁵²

SUMMARY

Individuals living with HCV are at substantially increased risk for depression and experience more neurovegetative and somatic depressive features due to the overlap with HCV symptoms themselves. In line with national practice guidelines, we recommend assessing all HCV patients for depression and providing information to HCV patients about treatment options. A sound evidence base exists for pharmacological treatment, structured skills-based psychotherapies, and for the integrated behavioral healthcare delivery of both.

The herpes viruses, including herpes simplex viruses (HSV) 1 and 2, varicella zoster virus, Epstein–Barr virus, and cytomegalovirus, are some of the most widespread worldwide, and there is some evidence that immune responses to all of them are associated with depression and anxiety.⁵⁵

EPIDEMIOLOGY (FIG. 11-1)

Epstein–Barr virus infection is ubiquitous in human populations throughout the world, often acquired in early childhood with subclinical primary infection or in adolescence with an infectious mononucleosis syndrome (glandular fever).⁵⁶ There is some evidence to suggest that active EBV infection or reactivation of the virus is associated with depressive disease. One study evaluated depressive symptoms after “glandular fever” and found that MDD was the most common new diagnosis in patients with EBV (28% of subjects) and non-EBV glandular fever (14% of subjects), and was significantly more common in those populations than in patients with recent upper respiratory infection (URI). The relative risk of a new MDD with EBV was 2.5 that with an ordinary URI. Interestingly, all depressive disorders occurring after glandular fever resolved fairly quickly, at a median of 3 weeks.⁵⁷ The association with depression appears strongest for highly symptomatic EBV primary infection—mononucleosis syndrome.

PATHOPHYSIOLOGY, CLINICAL PRESENTATION, COURSE, AND NATURAL HISTORY

An association has been reported between severity of depressive symptoms and seropositivity for EBV antibodies in patients with seasonal affective disorder (SAD).⁵⁸ The fact that this relationship was still present in the summer months, when SAD sufferers were unaffected by depressive symptoms, and that chronic fatigue syndrome (CFS) sufferers showed a similar relationship between severity of symptoms and seropositivity for EBV antibodies, led the authors to suggest that EBV seropositivity could indicate susceptibility to fatiguing illness.⁵⁸ However, the relationship between EBV antibodies and CFS remains controversial. Many infectious disease specialists consider this association unproven since the same antibody patterns are found in nonfatigued controls.

Pregnant depressed women are more likely to have EBV reactivation than nondepressed pregnant women (48% vs. 30%) after controlling for confounders.⁵⁹ This suggests that depression and stress lead to EBV reactivation rather than EBV reactivation itself leading to depression. However, there has been no work thus far to definitively disentangle cause and effect.

Several case reports indicate that delusional depression can be associated with elevated titers to Epstein–Barr virus.⁶⁰ The psychiatric consequences of Epstein–Barr infection may not be limited to depressive disorders however; evaluation of the relationship between early-life exposure to EBV and psychotic experiences in early adolescence found that EBV exposure increased the risk of psychotic experiences five-fold.^61,62

ASSESSMENT AND DIFFERENTIAL DIAGNOSIS

Although the assessment of depression in the patient with Epstein–Barr infection has not been studied, one diagnostic consideration is worth mentioning. CFS, the much-debated entity theorized to be associated with certain viral infections and potentially other immunologic triggers, may present with many of the same symptoms (fatigue, low mood, somatic symptoms) as depression and is an important differential diagnostic consideration.

TREATMENT

To the extent that antibodies may be associated with depressive symptoms after Epstein–Barr infection, immune-modulatory therapies may be a treatment consideration in addition to the usual array of antidepressants. One small open label study suggested that in a subgroup of patients with depressive symptoms and elevated EBV antibodies and CFS, antiviral therapy may reduce CNS symptoms by suppressing viral activity.⁶³

SUMMARY

Although evidence suggests that primary infection and reactivation of Epstein–Barr virus may be associated with both depressive disorders and other psychiatric symptoms as well, not enough data exist to clarify the pathophysiology of depressive disorders in this context or to comment on the unique considerations for treatment in these populations.

EPIDEMIOLOGY

HSV infection is common, with prevalence estimates of infection with either HSV-1, HSV-2, or both around 90% in the general population.⁶⁴ Labial or peri-oral lesions are caused by HSV-1 whereas anogenital herpes usually results from infection with HSV-2. In both types symptoms are typically mild. While treatment can speed healing and reduce risk of active lesions, the infection establishes chronic latency and is not cleared. Among seropositive patients, there is wide variation in the frequency of symptomatic reactivation.⁶⁵

In contrast, herpes simplex virus encephalitis (HSVE) is a rare but serious necrotizing brain infection with a high mortality rate and high rate of permanent neuropsychiatric sequelae among those who survive. It is the most common sporadic encephalitis in the West, with incidence between 1 in 250,000 and 1 in 1,000,000 persons per year.⁶⁶ Over 90% of HSVE cases are attributable to HSV-1, with the remainder caused by HSV-2.⁶⁶ HSVE occurs sporadically, without preceding systemic illness or localized case clustering or epidemics.⁶⁶

In cross-sectional studies, HSV infection is associated with depressive symptoms. In patients with acute coronary syndrome, chronic latent HSV infection was found in 100% of patients with the worst depressive symptoms, significantly more than the 43% infection rate in the lowest symptom group.⁶⁷ A greater overall pathogen burden, as measured by antibodies to HSV, cytomegalovirus, and Epstein–Barr virus, was also significantly associated with more severe depressive symptoms.⁶⁷

In the one longitudinal study of HSV and depression, more than 95% of patients were seropositive for HSV-1 at inception, and no relationship was found between this infection and incident depression.⁶⁵ Although there is limited support in the literature, individuals with HSV-2—anogenital herpes—may be at increased risk for depression due to feelings of stigma, shame, or anxiety related to having a chronic, incurable, sexually transmitted infection. This could be relevant even when latent, as the virus still could be transmitted to others.

The prevalence of depression following HSVE is a different phenomenon. Neurologic deficits are common in patients after this severe infection. One study of (HSVE) survivors found that 45% had changes in behavior and personality, with 17% of them experiencing depression despite a negative prior psychiatric history.⁶⁸ Other studies have found somewhat lower numbers: Among 13 HSVE survivors, two had severe behavioral disturbance and two others had depression.⁶⁹ Psychiatric symptoms including depression may precede the diagnosis of HSVE, and may also emerge sometime after the acute illness has been treated.⁶⁴

PATHOPHYSIOLOGY

The effects of HSVE on neurotransmitter levels in animal models uggest several possible mechanisms for the neuropsychiatric features of the disease (Box 11-2). Rabbits with HSVE have substantially decreased levels of serotonin and a serotonin metabolite in their raphe nuclei, as well as decreased hemispheric serotonin.⁷⁰ Dopamine level alterations have also been implicated: rabbits with HSVE have decreased dopamine receptor (D2) density in the substantia nigra and ventral tegmental area on the side contralateral to inoculation, with associated movement disturbances.⁷¹ There may be involvement of acetylcholine as well. The expression of certain viral genes appears to be associated with diminished acetylcholinesterase activity, at least in vitro.⁷²

Behavioral changes have been associated with left prefrontal hypoperfusion and left amygdala damage. Patients with HSVE have reduced amygdala and hippocampal volumes, and prefrontal hypoperfusion. The latter may result from diminished inputs from damaged amygdalar efferents to the frontal lobes.⁶⁹ It was thought that the psychiatric disturbances common after HSVE may be related to the dysfunction of the amygdalar-prefrontal circuits.

At the genetic level, HSV-1 binds to a number of proteins and modifies the expression of multiple genes, producing a host/ pathogen “interactome” involving well over 1000 host genes, including genes thought to increase susceptibility to depression and other neuropsychiatric disorders.⁷³

CLINICAL PRESENTATION

As noted above, HSVE is an acute illness—patients are usually febrile, confused, and agitated. Psychiatric disturbance may also occur and typically includes depression as well as aggression, anxiety, apathy, irritability, mania, and panic. As mentioned previously, these symptoms can precede the onset of neurological symptoms and occur well after encephalitis has been treated and the patient discharged from the hospital.⁶⁴ Persistent problems with social and occupational functioning are most closely tied to behavioral changes rather than to the memory deficits that are also common in HSVE survivors.⁶⁹ This is an important consideration is the rehabilitation of postencephalitis patients.

The psychiatric presentations, if any, associated with latent HSV infection are less clear. The psychological impact of anogenital herpes and associated shame and stigma of living with an incurable sexually transmitted disease are discussed above.

COURSE AND NATURAL HISTORY

Psychiatric symptoms associated with HSVE have been reported to occur prior to, during, and after the acute illness.⁶⁴ Acute and subacute changes in psychiatric status initially thought to be due to functional disorders can in fact be early manifestations of HSVE and respond to acyclovir treatment.⁷⁴ Acute encephalitis should be considered in the differential diagnosis of any patient with acute changes in mental status until laboratory or imaging investigations suggest otherwise.

Although many patients with HSVE demonstrate psychiatric symptoms early in the course of their illness, a delayed presentation is possible. The onset of behavioral and emotional disturbance (including insomnia, hostility, and agitation) has been reported as long as 6 months after resolution of HSVE.⁷⁵ In this case, there were no EEG abnormalities or other medical findings to explain the presentation, but encephalomalacia and gliosis were noted in temporal and frontal lobes, suggesting a possible etiology of the delayed presentation.⁷⁵ On the other hand, there is also evidence that many patients continue to improve after the acute injury and that depression is not a major cause of ongoing morbidity in most HSVE survivors.⁷⁶

ASSESSMENT AND DIFFERENTIAL DIAGNOSIS

Little is known about the assessment of depression specifically in HSV infection or HSVE. Differential diagnostic considerations should include the possibility of relapse; in one study a significant minority of patients with HSVE experienced a relapse.⁶⁸ Thus, acute worsening in mental status, even in patients treated successfully with acyclovir, should raise concern for HSVE recurrence rather than simply secondary psychiatric manifestations.

TREATMENT

There are no large-scale studies of depression treatment after HSVE. Research to evaluate whether some agents are more beneficial than others will be extremely valuable. In the absence of such evidence, treatment of depression and other accompanying disorders should proceed with attention to medication side effects and comorbidities that may inform treatment. For example, patients with a history of HSVE are at high risk for seizures, which may preclude bupropion as a therapeutic choice even in patients with prominent amotivational symptoms. Conversely, treatment of comorbid seizure disorder should take into account psychiatric symptoms that may be aggravated by selection of seizure medication. A few case reports suggest that carbamazepine may provide some benefit in management of residual psychiatric disturbance after HSVE.^75,77 Ropinorole has also been suggested to have some benefit.⁷⁸

SUMMARY

Chronic HSV infection, which is common in the general population, has not been clearly demonstrated to be associated with an increased risk for depression, though some studies are suggestive. HSVE, however, is associated with serious psychiatric presentations and sequelae, including depression. Treatment of the infection with acyclovir is an important step in resolution of all manifestations of the disease, but depressive and other debilitating psychiatric symptoms may persist as a result of damage to medial temporal and frontal brain regions and may require independent treatment.

EPIDEMIOLOGY

PREVALENCE AND INCIDENCE OF DEPRESSIVE DISORDERS

Recent CDC surveillance data estimate that there are 1,148,200 people living with HIV in the United States, 18.1% of whom are unaware they are infected.^79,80 Despite widespread knowledge about effective prevention methods, the HIV incidence rate has remained constant over the past decade with roughly 50,000 new infections annually.⁸¹

In numerous studies, the prevalence of lifetime and current depressive disorders exceeded expected rates both in those at risk for HIV as well as in HIV seropositive individuals. Data from the HIV Cost and Services Utilization Study of HIV-infected individuals estimated a 12 month prevalence of MDD of 36%, nearly five times higher than 7.6% found in the National Household Survey on Drug Abuse (NHSDA).⁸² 26.5% of the sample screened positive for dysthymia (not assessed by the NHSDA) and 21% screened positive for both major depression and dysthymia.⁸² More recent nationally representative data of HIV-infected individuals receiving medical care in the United States in 2009 found a prevalence of current major depression of 12.4%, or 3.1 times that found in the general population.⁸³ In early studies, suicide rates among individuals with HIV/AIDS were as high as 36 times that of the general population.^84,85 More recent studies have found lower rates corresponding to the introduction of antiretroviral therapies in the mid-1990s.⁸⁶

See Table 11-1: Comparison of Epidemiologic Studies of Depression in HIV.^{82,87,88–90}