Download HIV infection and depression

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
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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
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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
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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
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102 S. Arseniou et al.
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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
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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.
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