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Psychiatry and Clinical Neurosciences 2014; 68: 96–109 doi:10.1111/pcn.12097 Review Article HIV infection and depression Stylianos Arseniou, MD,* Aikaterini Arvaniti, MD, PhD and Maria Samakouri, MD, PhD Department of Psychiatry, School of Medicine, Democritus University of Thrace, Alexandroupolis, Greece Major depression is highly prevalent among HIVpositive patients (HIVpp). The prevalence of depression ranges between 18% and 81%, depending on the population studied and the methodology of the study. The etiology of depression in HIVpp is likely determined by: (i) biological factors (alterations in the white matter structure, hypothalamic–pituitary– thyroid dysfunction, Tat-protein-induced depressive behavior); (ii) psychosocial factors (HIV stigma, occupational disability, body image changes, isolation and debilitation); (iii) history or comorbidity of psychiatric illness; and (iv) the perinatal period in HIVpp women. Symptomatology of depression differs between HIVpp and HIV-negative patients (HIVnp). Depression may also alter the function of lymphocytes in HIVpp and decrease natural killer cell activity, contributing to the increased mortality in these patients. Selective serotonin re-uptake inhibitors are considered the first-line treatment. Treatment of depression can improve quality of life and lead to a better prognosis of HIV infection. T IS KNOWN that Human Immunodeficiency Virus (HIV) causes a progressive failure of the immune system, which can lead to subsequent increased vulnerability to infections and other immunological disorders, and increased risk for different types of cancer (e.g. Kaposi’s sarcoma).1 HIV infection progresses in four stages: primary infection; clinically asymptomatic stage; symptomatic HIV infection; and progression from HIV to AIDS, and is associated with a progressive decrease of the CD4 T-cell count. Each of its stages has a different duration and severity of symptoms.2 Major depression (MD) is highly prevalent in HIVinfected patients and presents significant diagnostic challenges because of the biological, psychological, and social components associated with the infection. The differential diagnosis between (i) depression that occurs as a complication of the disease; and (ii) depression that occurs due to HIV infection itself (secondary) can be very difficult to identify. Psychiatric disorders increase mortality and have a negative (HIVnp) impact on quality of life and health of the HIV-positive patients (HIVpp), whereas MD can alter immune function and may affect HIV disease progression. Depression can be unrecognized and untreated in HIVpp.3,4 The aim of this paper was to review the recent research related to depression in HIV-infected patients and discuss both methodological limitations and future directions of research on this topic, as well as to formulate useful recommendations concerning diagnosis and management of MD in these patients. I *Correspondence: Stylianos Arseniou, MD, Aghialou 21A, 69100 Komotini, Greece. Email: [email protected] Received 18 November 2012; revised 15 July 2013; accepted 28 July 2013. 96 Key words: anti-retroviral therapy, clinical manifestations, depression, HIV, risk factors. METHODS A systematic electronic search of Pubmed (Medline) was conducted in order to identify all relevant scientific articles published after the introduction of ‘highly active anti-retroviral therapy’ (HAART) in 1996. The key words used for this search were: ‘HIV and depression’, ‘mortality’, ‘risk factors’, ‘etiology’, ‘clinical manifestations’, and ‘antiretroviral therapy’. From the 447 articles published after the HAART introduction we have cited 105, according the date of © 2013 The Authors Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology Psychiatry and Clinical Neurosciences 2014; 68: 96–109 publication: we have opted not to use prior studies with similar methodology and outcomes. We have, also, cited 23 articles published in the pre-HAART period when necessary. EPIDEMIOLOGY Major depression is the most common psychiatric manifestation associated with HIV infection.5 The estimation of depression prevalence is particularly difficult because it is necessary to take into account (i) demographic data (gender, age); (ii) whether the depressive disorder is caused by the infection itself or is a complication (primary or secondary); and (iii) whether there is an overlap between HIV symptoms and depression. Compared with the general population, HIVpp are 2–7-fold more likely to meet the diagnostic criteria for MD in accordance with international classification systems (DSM-IV or ICD-10),6 while MD prevalence rates range from 18% to 81%, depending on the subjects.7–22 Most studies, however, have not used strict diagnostic criteria, according to DSM-IV or ICD10, but have relied on physician reporting or structured screening surveys.23 Prevalence rates based on DSM-IV diagnostic criteria may be lower than those based on screening instruments. The variation in MD prevalence rate may be due to differences in methodology and subject characteristics.6,8 Risk factors Gender Most studies have focused on HIV-positive men, although it has been estimated that women today represent 50% of the new HIV-positive cases.24 It is known, however, that the prevalence of depression in the general population is greater in female subjects.25 Additionally, Reis et al., in a cross-sectional quantitative study, compared the presence of depressive symptoms between the genders and reported statistically significant differences between HIVpp men and women, given that the women presented symptoms of a more severe intensity of depression than the men.26 According to the literature, it is estimated that (i) HIV-positive women are more likely to experience depressive symptoms compared with seronegative women of the same age (19.4% vs. 4.8%);27 (ii) 1.9– 35.0% of seropositive hospitalized women present depression symptoms;5 and (iii) 30–60% of seroposi- HIV infection and depression 97 tive women not hospitalized, suffer from depression.28 Ickovics et al. reported chronic depressive symptoms in 42% and intermittent depressive symptoms in 35% of a sample of 765 HIV-positive women.29 Depression is also highly prevalent in HIVpp men, with estimated ranges that vary accordingly to the racial group or country in which the study was conducted: for example, 65% in a cross-sectional study of HIVpp Hispanic men,30 31.4% in a cross-sectional study in Botswana,15 29% in India.31 Lopes et al. reported that when compared with their HIVnegative counterparts, HIVpp men were more likely to have MD (odds ratio, 3.77).32 In a meta-analysis, Ciesla and Roberts concluded that the degree to which HIV is associated with a greater risk for MD disorder appears to be the same for homosexual and bisexual men as it is for the general HIV-positive population.33 Age The combination of old age and HIV infection increases the risk of neuropsychiatric symptoms, among the depressive ones. Hinkin et al., in a study of 131 HIVpp, of whom 25% were over the age of 50, found that there was a higher rate of current depressive disorder in the older patients (20%) compared with the younger ones (12%).6 Grov et al. studied 914 HIVpp men and women over the age of 50 and noted that 39.1% of participants exhibited symptoms of MD.34 HIVpp teenagers have an up to fourfold greater risk of developing depression than their peers in the general population; this risk is higher than other groups with chronic diseases such as diabetes or cancer. Pao et al., in a study of 34 HIVpp adolescents, reported that 44% of HIVpp adolescents suffered from depression, and from these, 40% developed drug and alcohol abuse.35 Pre-infection history of MD Patients with MD secondary to HIV infection do not necessarily have a prior history of mood disorders; the MD may be a primary consequence of the involvement of HIV in the central nervous system (CNS). The stigmatization and emotional consequences of the diagnosis can trigger a new depressive episode or relapse of pre-existing depression in individuals with recent infection.3 © 2013 The Authors Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology 98 S. Arseniou et al. Psychiatry and Clinical Neurosciences 2014; 68: 96–109 Few studies have been conducted on the prevalence of depression before and after the appearance of infection. Jin et al. studied the lifetime prevalence rates of MD in 28 HIVpp. Almost 79% (n = 22) reported lifetime MD and, of these 22, only one experienced onset before learning of their HIV status.36 Disease stage Starace et al. and Atkinson et al. reported that MD rates are low in patients whose disease has not evolved to AIDS or who have received HAART compared with those who did not receive it.37,38 Antakly de Mello and Malgebier studied 60 HIVpp women with AIDS symptoms and 60 HIVpp without AIDS symptoms. The prevalence of MD was higher in the symptomatic group (38.3%) than in the asymptomatic group (13. 3%), in comparison to the asymptomatic ones.39 ETIOLOGY Biological factors It is well recognized that lesions in specific neuroanatomic structures due to disease or insult, such as those resulting from a stroke or brain tumor, may contribute to the development of secondary depression (Table 1).40 Neurocognitive deficits in HIV disease is a strong indicator of CNS infection by the virus. To investigate whether depression appears due to the infection of CNS by the virus, studies have generally sought to correlate depression severity with HIV-associated cognitive deficits.41 In HIVnp with MD, morphological alterations have been identified in cortical and subcortical regions, including basal ganglia, the parahippocampal cortex, amygdala, orbitofrontal cortex and anterior cingulate gyrus.42,43 Furthermore, alterations have been reported in functional neural networks, including areas in the bilateral frontal cortex, parietal cortex, caudate head, and thalamus.44,45 Given that many of these structures comprise putative neural networks that are vulnerable to HIV infection, it may be that HIV infection is involved in the etiology of secondary depression. But, it is still to be ascertained whether the involvement of HIV in the CNS is entirely responsible for the vulnerability of HIVpp to depression; cross-sectional and short-term prospective studies have not detected remarkably higher rates of depressive disorder in those having HIV-associated neurocognitive impairment.46,47 Longer-term studies are needed for more reliable conclusions. Until today, few studies have used structural neuroimaging in order to investigate the relationship between HIV-associated brain structural alterations and depression.48,49 Although basal ganglia atrophy has been associated both with HIV infection and also with MD, as well, in HIVnp, Davidson et al. did not find a correlation between basal ganglia atrophy and MD in HIVpp.48 In a more recent study, however, apathy – a discrete component of depression – was associated with decreased volume of the nucleus accumbens, in HIVpp.49 Previous studies have reported that MD is associated with alterations in the structure of white matter, as evidenced by the reductions in fractional anisotropy (FA) within the dorsolateral prefrontal cortex, anterior cingulate, left lateral occipitotemporal region, parietal lobe and parahippocampal gyrus.50,51 These decreases in FA observed in MD reflect the Table 1. Etiology Etiology Findings Biological factors Alterations of: brain morphology, functional neural networks, white matter structure; abnormal HPT axis feedback, Tat protein, somatostatin dysregulation, tryptophan degradation History of depression or two or more psychiatric disorders History of psychiatric illness and comorbidity Psychosocial factors Perinatal period Stigma, occupational disability, body image changes, isolation, and debilitation Maternal guilt, fear of infecting the fetus, stigma, insufficient social network, stress, poverty, and interpersonal issues HPT, hypothalamus–pituitary–thyroid; Tat, trans-activator of transcription. © 2013 The Authors Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology Psychiatry and Clinical Neurosciences 2014; 68: 96–109 degradation of the microstructural white matter integrity.52 Smith et al. in a cross-sectional study compared the normal-appearing white matter (NAWM: white matter with hidden, but magnetic resonance imagingvisible damage) FA of 15 HIVpp with depressive symptoms and 15 HIVpp without depressive symptoms.53 They reported regional alterations in the architecture of the white matter in the depressive HIVpp. Furthermore this group had an increased NAWM FA in the left thalamus, the temporal and frontal area, and the right cingulate, which are regions associated with mood regulation. The regional increase of the FA in HIVpp probably reflects a reduction in the complexity of white matter-crossing fibers and, thus, justifies the appearance of secondary depression. In contrast, Atkinson et al. reported that abnormal neuroimaging was not associated with an interval episode of MD in HIVpp, and failed to predict MD during follow up.38 Hypothalamus–pituitary–thyroid (HPT) dysfunction in the absence of HIV infection commonly causes mood disorders, depression and even dementia. Langford et al. reported that HIV infection of the CNS may contribute to changes in the hypothalamus– thyroid hormone signaling, thereby resulting in abnormal HPT axis feedback, and concluded that HIV may play a role in the pathogenesis of depression in HIVpp through this mechanism.54 Dantzer et al. concluded that increasing proinflammatory cytokines that act on the brain can cause depressive-like behavior.55 Lawson et al. investigated the role of the HIV trans-activator of transcription (Tat protein) in activation of brain cytokine signaling and subsequent induction of depressionlike behavior in a murine model; they found that a single exposure to Tat protein in brain tissue is sufficient to induce brain cytokine signaling that culminates in depression. These results indicate a possible role of Tat protein in the development of depression in HIVpp.56 Everall et al. found reduced somatostatin gene expression in depressed HIVpp. The authors reported that somatostatin dysregulation may be part of the molecular pathological process of MD in HIVpp.57 Schroecksnadel et al. observed significant associations between tryptophan degradation and immune activation. Degradation of the tryptophan, a serotonin precursor, is well documented in HIVpp, and its depletion by an activated immune system could also affect the synthesis of serotonin, a neurotransmitter implicated in MD.58 HIV infection and depression 99 Atkinson et al., in a 2-year prospective study, concluded that the symptomatic HIV disease, but not HIV infection itself, increases the risk of MD. HIV disease staging was established according to 1993 Centers for Disease Control criteria.38 Laboratory assessments were calculated for white blood cell count (WBC), CD4+ lymphocyte count, HIV viral burden in plasma (HIV-RNA, copies/mL), and, in volunteers, WBC and HIV-RNA in cerebrospinal fluid. Lima et al. found that patients with greater frequency and severity of symptoms, as assessed by these biomarkers, also had increased risk of MD.59 History of psychiatric illness and comorbidity Lifetime multiple psychiatric comorbidity (i.e. the presence of two or more lifetime psychiatric disorders) and past history of MD increase the risk of an MD episode on follow up almost fivefold and fourfold, respectively.38 It is well known that individuals at high risk for HIV, such as i.v. drug users, also have a higher risk of developing depression.60 Psychosocial factors Studies so far relate increased depression symptoms to stressful life events and diminished social support within the context of HIV infection.61,62 Various factors, such as HIV stigma, occupational disability, body image changes, isolation, and debilitation heighten depression in HIVpp.63 The aforementioned stress factors burden elderly patients to a greater degree; they must also cope with aging and its related problems.34 Nevertheless, Braden et al. reported that even HIVpp with poor physical functioning may find it important to live if a high sense of quality of life is achieved (e.g. a sense of achievement, strong interpersonal relationships, and increased positive self-expression).64 In contrast to the findings of the prospective study of Atkinson et al., which identified objective health indicators of disease progression (i.e. CD4 count, AIDS diagnosis) as predictors of MD,38 Grov et al. highlighted the importance of looking beyond physical health indicators.34 Given that neither HIV stigma nor loneliness were associated with health indicators, the aforementioned psychosocial factors are considered as primary factors contributing to depression, rather than physical symptoms of disease severity.34 Additional risk factors for MD in HIVpp include the © 2013 The Authors Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology 100 S. Arseniou et al. care of children or other minor dependants, which may serve as an additional stressor,65 and low socioeconomic and education level.66 Perinatal period The antenatal and postnatal periods for women have been identified as additional risk factors for MD, which is called perinatal depression (PND). Ross et al., in a cross-sectional study, reported that 74.1% of HIVpp postpartum women in a sample of 85 participants in Thailand had depressive symptoms, while infant health status, education and self-esteem were negatively associated with depressive symptoms.67 Chibanda et al. studied 210 postpartum women (31 HIV positive, 148 HIV negative, 31 unknown status) in Zimbabwe and found that 54% of HIVpp women met DSM-IV criteria for MD.68 HIV-infected pregnant women have to deal with specific psychosocial issues related to pregnancy or to the child, such as maternal guilt, fear of infecting the fetus, stigma, insufficient social network, stress, poverty, and interpersonal issues emerging around diagnostic disclosure. Kapetanovic et al. showed that a history of psychiatric illness, substance use during pregnancy, social stress during pregnancy and CD4 nadir during pregnancy (≤200 cells/mm3), were independent risk factors for PND.69 The lack of association between PND and race or ethnicity suggests that PND in HIV-infected women might indeed be primarily caused by a biological mechanism that significantly outweighs pertinent cultural factors. CLINICAL MANIFESTATIONS AND DIAGNOSIS Depressive symptoms in HIVpp have generally the same clinical characteristics as those in HIVnp with depression: low mood; anhedonia; insomnia; anorexia/polyphagia and subsequent changes in bodyweight; irritability; difficulty concentrating; memory impairment; and psychomotor changes.70 Comparing depressive symptomatology, the HIVpp have significantly more problems in making decisions, more frequent sleep and appetite disorders, and more cognitive impairment.71 According to Wolff et al., the principal difference lays in the greater frequency and intensity of the symptoms in HIVpp, especially in women.66 Millikin et al. studied the relationship between fatigue and depression in HIVpp men and concluded that fatigue severity was related to Psychiatry and Clinical Neurosciences 2014; 68: 96–109 depressive symptoms but not to AIDS diagnosis or medication status. The authors suggest that adults with fatigue and HIV-infection (with or without AIDS) should be screened for depression.72 Akena et al. compared the clinical features of MD between HIVpp and HIVnp and concluded that, compared to HIVnp, HIVpp were more likely to be widowed, less likely to have a family member with a mental illness; a later onset of depression (>30 years) and were more likely to already have an organic disease for which he/she received medication before the onset of depression.71 Based on the DSM-IV criteria, depression resulting from the direct physiological effects of HIV infection is defined as ‘mood disorder due to disease from infection with HIV – code 293.83,’73 while according to ICD-10 criteria it is defined as ‘organic affective disorder – F06.3; category: other mental disorders due to brain damage and dysfunction and to physical disease – F06’.74 Patterson et al. suggested the Profile of Mood States Depression–Dejection Scale (POMS) as a screening instrument for MD in HIVpp.75 Lipps et al. proposed the Beck Depression Inventory II as a reliable and valid measure for assessing depression in HIVpp.76 The diagnosis of depression in this patient group is complicated by the fact that some physical symptoms, such as sleep disorder, loss of appetite, fatigue, and difficulty concentrating, are also common symptoms of HIV infection.77 Furthermore, symptoms of comorbid disorders, such as psychoactive substance abuse or dependence, may be misinterpreted as depressive symptoms.78 Because HIV-related symptoms can mimic the neurovegetative symptoms of depression, the diagnostic value of classic depression indicators (changes in sleep, appetite, and energy) vary with the stage of HIV illness; neurovegetative symptoms are of less consistent value during later stages of the disease.72 It is important to note that in both the early and late period of HIV infection, several of these depressive symptoms are indicative of depression, as well as several neurodegenerative processes, such as dementia of AIDS (HIV-associated dementia, HAD) and HIV-associated mild neurocognitive disorder (MND).3,79 Depression can be an early manifestation of HAD and can negatively be related to the cognitive decline of the patient.80 It is of great significance to discriminate MD from AIDS-related mild cognitive impairment. Babiloni et al. studied the neurophysiological abnormalities using electroencephalography © 2013 The Authors Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology Psychiatry and Clinical Neurosciences 2014; 68: 96–109 (EEG) in HIVpp, and found: (i) central and parietal delta sources that showed increased amplitude; and (ii) topographically widespread cortical sources of resting-state low-and high-frequency alpha rhythms that showed lower amplitude in HIVpp than in control subjects.81 The authors stated that these findings can provide useful information for an early detection of cognitive impairment in HIVpp. Furthermore, several event-related brain potential (ERP) reports have also evaluated the HIV-associated cognitive impairment, using the P300 ERP component because it reflects operations requiring attention and immediate memory processes and it is sensitive to dementia.82–87 Polich et al. studied the effects of HIV infection in CNS with EEG and ERP.87 They found: (i) increased frontal and decreased central parietal delta EEG spectral power in HIVpp that may be related to increased fatigue and decreased arousal in these patients; and (ii) smaller and slower P300 component in HIVpp, compared to the control subjects. Depression in HIVpp is often underdiagnosed and not adequately treated. The main reason is the lack of assessment of psychiatric symptoms by clinicians. There is a misconception that depression is a normal reaction in patients diagnosed with HIV infection, that it does not necessarily require immediate medical intervention, and that after a period of adjustment, normothymia will return. In contrast, many HIVpp are reluctant to seek psychiatric intervention because of the stigma caused by the infection.66 SUICIDALITY Before the introduction of HAART, studies recorded higher rates of suicide in HIVpp than in the general population. Given that HAART was not available and the survival time was shorter, lack of hope for effective treatment made patients more vulnerable to suicide.88,89 Studies in China and South Africa by Jin et al. and by Schlebusch and Vawda, respectively, reported an increased risk of suicidality in HIVpp than in the general population.36,90 In a review article, Catalan et al. reported elevated rates of suicidal behavior (i.e. completed suicide, suicidal ideation and thoughts, deliberate self-harm) among HIVpp.91 The authors emphasized that most studies were conducted in the USA and Europe, while only 25% were done in Africa and Asia, although the HIV prevalence in those areas is higher. There was, however, wide diversity in the assessment of suicidality between HIV infection and depression 101 the studies; different scales were used and the study samples were heterogeneous, making it difficult to compare the results and the assessment of the influence that HAART had on suicidality. In the literature, there is no consensus on the stage of disease with the highest rate of suicidal behavior. Cooperman and Simoni found a higher rate of suicidality during the period immediately after the diagnosis of HIV infection,92 while other studies, surprisingly, underline the low prevalence of suicidal ideation in AIDS, compared with previous stages of HIV infection.93,94 It is speculated that during the course of infection, patients adapt and make use of new and more efficient survival strategies to cope with difficulties, rather than behaviors that lead to suicide. Nevertheless, some studies found no difference in the incidence of suicidal ideation in the various stages of HIV infection,94,95 and, according to them, it seems that suicidal ideation is associated more with psychosocial variables, such as social isolation and lack of social support, than with the stage or the severity of HIV infection.92,96 RELATIONSHIP BETWEEN DEPRESSION AND OUTCOME IN HIV INFECTION Depression is likely to negatively affect the course of HIV infection and may also affect the immune response of the organism against the infection.4 The cells that play a key role in the response of the organism against HIV infection, but which can also be influenced by depressive symptoms, are the CD4 T lymphocytes, CD8 T lymphocytes and natural killer cells (NK). These three types of cells destroy body cells infected by the virus (cytotoxicity), while CD4 T cells and CD8 T lymphocytes also secrete cytokines that inhibit virus replication.97 Two major classification systems are currently in use for HIV disease staging: the US Centers for Disease Control and Prevention (CDC) classification system and the World Health Organization (WHO) Clinical Staging and Disease Classification System. The CDC disease staging system (most recently revised in 1993) assesses the severity of HIV disease by CD4 cell count and by the presence of specific HIV-related conditions. The definition of AIDS includes all HIVpp with CD4 count <200 cells/μL (or CD4 percentage <14%) as well as those with certain HIV-related conditions and symptoms, such as opportunistic infections and cancer.98 © 2013 The Authors Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology 102 S. Arseniou et al. Psychiatry and Clinical Neurosciences 2014; 68: 96–109 During the first weeks after the infection, CD4 count decreases sharply due to the infection, while the number of CD8 cells, which inhibit the replication of the virus in the early stages of HIV infection, increases, so that the total number of T lymphocytes remain constant (blind homeostasis).99 It is likely that early in the course of HIV infection, an efficient CD8 cell response can control HIV replication, whereas in long-term HIV infection, a high level of CD8 cell activation is instead associated with increased viral load, a lower CD4 number, progression in AIDS and increased mortality.100–103 Before the availability of HAART, there was no consensus in findings on whether MD affected HIV disease progression. Some studies showed more rapid progression to the AIDS stage or death in depressed HIVpp,104–106 and faster decline in CD4 and CD8 T lymphocytes,107,108 whereas others found no effect of MD on these outcomes.109–111 After the availability of HAART, more studies confirmed the negative impact of MD in HIV disease progression (Table 2). Evans et al., in a longitudinal study of 93 women (63 HIVpp and 30 HIVnp), con- Table 2. Effect of MD in HIV disease progression in the HAART era Studies Evans et al., 2002112 Ironson et al., 200562 Ickovics et al., 200129 Alciati et al., 2007113 Cruess et al., 2005114 Cook et al., 2004115 Leserman, 2008116 Schuster et al, 2012117 Grossman and Potter, 1999118 Effect of MD in HIV disease progression: HAART era ↓NK, ↑ viral load, ↑ activated CD8 ↓CD4, ↑ viral load ↓CD4 ↓NK, failure of NK to be restored ↑NK with improvement of MD AIDS-related deaths in women ↓CD4, ↑ viral load, greater risk of mortality (i) Faster progression to AIDS through elevating cortisol secretion mechanisms; (ii) ↓CD4, ↑ viral load, medication-resistant strains of HIV through poor medication adherence HIV replication through increasing of norepinephrine HAART, highly active anti-retroviral therapy; MD, major depression; NK, natural killer. cluded that depression and anxiety are related to reduction of NK cell level, decreased NK cell activity, and lead to an increase in activated CD8 T lymphocytes and viral load, having a negative effect on HIV disease progression.112 Ironson et al. also reported that depression was associated with faster decline in CD4 count and increased viral load,62 while Ickovics et al., in a study of 765 HIVpp women, found that chronic depression was associated with greater decline in CD4 count.29 Nearly half of the participants received HAART during the study period. In contrast, Alciati et al. found no relationship between MD and CD4/CD8 count and the CD4/CD8 ratio, while they observed lower NK concentration in depressed than in non-depressed patients.113 The same authors also reported that although the NK cells typically are restored after 12 weeks on HAART, in depressed HIVpp the NK decline cannot be restored, despite HAART treatment. Cruess et al., in contrast, reported increased NK activity with improvement of depressive symptomatology.114 The majority of studies have shown that MD leads to worse clinical outcome. According to Cook et al., AIDS-related death was more likely among women with chronic depressive symptoms.115 Ickovics et al. observed that HIVpp women with depressive symptoms were nearly twice as likely to die as those without depressive symptoms.29 In contrast, Kilbourne et al. did not find an association between MD and worsening in clinical outcome.119 That study was, however, conducted early in the HAART era, with only 54% of patients receiving HAART, a fact that potentially explains the discrepancy with newer studies. Considering the aforementioned, it is interesting to investigate whether depression is a predictor or a result of disease progression. It seems that depression may be more likely to lead to clinical worsening of disease than vice versa; it has been observed that depressive symptoms become more severe in the year preceding AIDS-associated death.115,116,119 Leserman concluded that (i) CD4 cell count and the onset of clinical symptoms of AIDS did not predict MD;4 (ii) chronic depression may negatively affect HIV disease progression, in terms of decrease in CD4 T-cells, increase of viral load, and greater risk of mortality;116 and (iii) depressive symptoms did predict faster progression to AIDS and increased risk of CD4 count decline.61 It is now known that in depression there is overactivity of the hypothalamic–pituitary–adrenal © 2013 The Authors Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology Psychiatry and Clinical Neurosciences 2014; 68: 96–109 axis, which leads to increased secretion of cortisol.120 It is hypothesized that elevated cortisol level might hasten HIV disease progression by altering T lymphocyte production of cytokines (i.e. shift from Th1 to Th2 cytokines), triggering the destruction of CD4 lymphocytes and stimulating HIV replication. Leserman et al. reported that HIVpp with increased stress, less social support, and elevated cortisol level were at higher risk for rapid progression to AIDS.121 Schuster et al. confirmed that intermediated factors, such as substance use, poor social support and hopelessness, which are associated with both depression and immunosuppression among HIVpp, can lead to a compromised immune response through the mechanism of enhanced cortisol secretion. In turn, elevated cortisol may compromise the immune response; increase the risk of secondary disease and lead to faster progression to AIDS.117 The plasma level of catecholamines (especially norepinephrine) increases in response to psychological stress and depression.118 Norepinephrine, in turn, may increase HIV replication.122 Furthermore, there are behavioral factors, such as medication non-adherence and sexual risk-taking, that link depression with compromised immune status. Depression is associated with poor medication adherence, which can result in medication-resistant strains of HIV, declining CD4 count and increased viral load. In addition, depression can increase risky sex behaviors, which in turn increases the probability of contracting additional diseases that compromise the immune system.117 THERAPEUTIC APPROACHES The treatment of depressive symptomatology in HIVpp is likely to reduce the incidence of medical complications and improve prognosis and quality of life. It is necessary, however, to take into account possible interactions between antiretroviral drugs, such as protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), and antidepressant drugs. The PI and NNRTI are primarily metabolized through the hepatic enzymatic system, P450 3A, and secondarily through P450 2D6, interacting with drugs that are also metabolized by this system, such as antidepressants.123 The selective serotonin re-uptake inhibitors (SSRIs) are considered first-line drugs for the treatment of MD in HIVpp due to their more favorable side-effect profile in comparison to tricyclic antidepressants. HIV infection and depression 103 Sertraline, escitalopram and citalopram are considered first-choice SSRI.66 Treatment with antidepressants is best started at lower doses and with slower titration in HIVpp in order to avoid complications, especially in those with advanced illness or complex medication regimens. It is also important to monitor closely the HIVpp for possible side-effects.68 Tricyclic antidepressants are not recommended because of their many side-effects, such as orthostatic hypotension, urinary retention, exacerbation of conduction delays, and neurocognitive impairment, to which HIVpp appear particularly sensitive.68 If it is necessary to use a tricyclic antidepressant, those with fewer anticholinergic and hypotensive side-effects are suggested, such as nortriptiline and desipramine.124 Serotonin and norepinephrine re-uptake inhibitors such as venlafaxine and duloxetine constitute an alternative treatment when SSRI are not well tolerated. Antidepressant treatment, in combination with psychotherapeutic interventions, is thought to be effective in the treatment of MD. Despite its efficacy, pharmacologic treatment of MD would likely be complicated by HIV illness, adverse drug effects and drug interactions. Thus, psychotherapeutic interventions may offer an advantage. Wiles et al. underlined the effectiveness of cognitive behavioral therapy in depressed patients even in those with treatment resistance MD.125 Sherr et al. reviewed 90 studies concerning therapeutic interventions (psychological, psychotropic, psychosocial, physical, HIV-specific health psychology interventions and HIV treatment-related interventions) on depression in HIVpp.126 They concluded that psychotherapeutic interventions appear to be effective, especially those that incorporated a cognitive behavioral component. Cognitive behavioral stress management therapy appears to be particularly effective in decreasing the depressive symptoms. In contrast, coping effectiveness interventions, without the cognitive behavioral component were not effective. Electroconvulsive therapy (ECT) is an alternative method for severely depressed patients who do not respond to medication. There are few case reports in the literature that confirm its efficacy and usefulness in HIVpp,127,128 and we did not find any studies that thoroughly investigated the effects of ECT in this target group of patients, except the aforementioned case reports. The successful management of depression in HIVpp can lead to better prognosis and can have multiple positive outcomes: improved quality of life, © 2013 The Authors Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology 104 S. Arseniou et al. improved adherence to medication, reduction of high-risk behaviors and suicidality.66 Treatment of depression could potentially increase HAART adherence, which would in turn affect illness progression.63 Walkup et al. compared the HAART adherence in depressed HIVpp before and after treatment with antidepressant drugs.129 While the HAART adherence rate was low among patients without antidepressant therapy, the prior month’s addition of antidepressant drug increased the odds of adherence up to 30%. Yun et al. evaluated HAART adherence in depressed HIVpp before and after initiation of antidepressant treatment. The proportion of depressed patients adherent to HAART was significantly lower among those not receiving antidepressant treatment compared with those who were (35% vs 65%, respectively). In addition, the proportion of HIVpp adherent to HAART was significantly higher among patients adherent to antidepressant treatment compared with those non-adherent (69% vs 31%, respectively).130 DISCUSSION In this article we have reviewed the epidemiology, the possible mechanisms that lead to depression in HIVpp, the symptomatology and assessment of MD in this patient group, the possible interactions between MD and HIV infection progression and the therapeutic approaches in this target group. There are some limitations, however, that must be taken into consideration. Concerning the biological mechanisms, the identified brain regional alterations could be a direct result of HIV infection or could be attributable to other comorbid factors that have been associated with increased risk for HIV-related disease, such as hepatitis C virus co-infection, or past/current alcohol/drug abuse. Furthermore, the identified brain alterations may be associated with alterations before the onset of the infection.53 As Smith et al. state, these results need to be replicated in samples that include all possible covariates (hepatitis C virus status, frequency/ duration/quantity of illicit drug use).53 More evidence is needed to understand the complex biological relationships between depression and HIV infection. The best way to detect more accurately the biological mediators on disorders that are heterogeneous, complex and multifactorial, is to increase the research sample size (numbers in thousands) and to Psychiatry and Clinical Neurosciences 2014; 68: 96–109 make clear the research hypothesis and run it with appropriate models.131 Among psychiatric conditions that influence the progression to AIDS is post-traumatic stress disorder or severe life stress, factors that are by no means thoroughly studied. Whether these factors influence the relationship between depression and HIV progression, and any of the intermediary variables, remains unknown at this point. Furthermore, the lack of assessment of stress that has been demonstrated to be related to reduction in immune cells count, independently from depressive symptoms, must be taken into account.113 Future longitudinal research should also investigate issues such as how fluctuating depression level affects social support status, substance use, and progression to AIDS in HIVpp and how in turn these factors influence depression.117 It will be also interesting to investigate whether HIV infection is an additional risk factor for depression in i.v. drug users, considering that these individuals have a higher risk of developing MD. It is important to consider if MD has a negative impact on the outcome of HIV disease, or if adverse HIV progression is associated with an increased risk of MD appearance. The available data suggest that depression has a negative impact on HIV progression, predicts faster progression to AIDS, and increases mortality risk, even in an era of decreasing prevalence of opportunistic infections. Considering the high prevalence of MD in HIVpp and the adverse progression of the HIV disease in untreated patients with MD, it is important for the clinicians attending HIVpp to be able to evaluate possible signs of depression and refer symptomatic patients for psychiatric assessment whenever necessary. The most important psychiatric and psychosocial factors for the disruption and discontinuation of HAART are depression, lack of social support networks and substance abuse. In contrast, poor treatment of depression can lead to increased rates of high-risk behaviors, such as substance abuse and high-risk sexual behaviors, increasing the risk of acquiring other sexual diseases, and transmitting HIV infection.115,132 Inadequate treatment of depression in HIVpp can also be explained by the reluctance of some clinicians to prescribe antidepressant therapy in patients with certain characteristics such as low educational level or in patients of minority ethnic groups.133 © 2013 The Authors Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology Psychiatry and Clinical Neurosciences 2014; 68: 96–109 Identification and management of depression are integral components of comprehensive HIV care. Early diagnosis and treatment of depression improve quality of life and contribute positively to HIV disease progression. Consequently, easy access should be organized for psychiatric services. Towards this direction, some have argued that mental health services should be housed in the same building where patients are monitored periodically for HIV infection. Conclusion MD is highly prevalent among HIVpp. Clinicians attending HIVpp should be able to evaluate possible signs of depression and refer symptomatic patients for psychiatric assessment whenever necessary. Given the adverse progression of untreated depression in HIV illness, identification and management of depression are integral components of comprehensive HIV care. Early diagnosis and treatment of depression improve quality of life and contribute positively to HIV disease progression. ACKNOWLEDGMENT The authors declare that they have no conflicts of interest. REFERENCES 1. Ioachim HL. Immunopathogenesis of human immunodeficiency virus infection. Cancer Res. 1990; 50: 5612S– 5617S. 2. WHO. Interim WHO Clinical Staging of HIV/AIDS and HIV/AIDS case definitions for surveillance. African region. 2005. 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