Dopaminergic impact of cART and anti-depressants on HIV neuropathogenesis in older adults

Abstract

The success of combination antiretroviral therapy (cART) has transformed HIV infection into a chronic condition, resulting in an increase in the number of older, cART-treated adults living with HIV. This has increased the incidence of age-related, non-AIDS comorbidities in this population. One of the most common comorbidities is depression, which is also associated with cognitive impairment and a number of neuropathologies. In older people living with HIV, treating these overlapping disorders is complex, often creating pill burden or adverse drug-drug interactions that can exacerbate these neurologic disorders. Depression, NeuroHIV and many of the neuropsychiatric therapeutics used to treat them impact the dopaminergic system, suggesting that dopaminergic dysfunction may be a common factor in the development of these disorders. Further, changes in dopamine can influence the development of inflammation and the regulation of immune function, which are also implicated in the progression of NeuroHIV and depression. Little is known about the optimal clinical management of drug-drug interactions between cART drugs and antidepressants, particularly in regard to dopamine in older people living with HIV. This review will discuss those interactions, first examining the etiology of NeuroHIV and depression in older adults, then discussing the interrelated effects of dopamine and inflammation on these disorders, and finally reviewing the activity and interactions of cART drugs and antidepressants on each of these factors. Developing better strategies to manage these comorbidities is critical to the health of the aging, HIV-infected population, as the older population may be particularly vulnerable to drug-drug interactions affecting dopamine.

1. Introduction

The use of combination antiretroviral therapy (cART) has greatly improved the lifespan and quality of life of HIV-infected individuals (Teeraananchai, 2017), transforming HIV infection into a chronic condition. However, the HIV-infected population is aging (Burgess et al., 2015; Negredo, 2017; Wing, 2016), increasing the disease burden as more infected individuals develop age-related impairments. The impact of chronic HIV infection and long-term cART on non-AIDS related comorbidities is not clear, but the increase in these comorbidities in older individuals living with HIV suggests a deleterious effect (Bhavan et al., 2008; Deeks, 2009; Simone and Appelbaum, 2008). Many of these comorbidities are neuropsychiatric disorders, among the most common of which is depression. The incidence of depression is between 20 and 70% of HIV-infected individuals (Campos et al., 2010; Savetsky, 2001), is the same in cART-naive and cART-treated populations (Bhatia and Munjal, 2014; Hobkirk, 2015; Pinheiro, 2016; Wang, 2018), and in both groups depression substantively worsens disease prognosis. Individuals over age 50 living with HIV show an increased risk for depression (Cahill and Valadéz, 2013; Milanini, 2017), and this disorder is commonly comorbid with cognitive impairment and neuropathology (Havlik et al., 2011; Arseniou et al., 2014). Treatment of these disorders is complex, often creating pill burden or deleterious drug-drug interactions, leading to problems with adherence and medication errors that can exacerbate disease symptoms and diminish quality of life.

Thus, developing better strategies to manage these comorbidities is critical to the health of the aging, HIV-infected population. Even with frequent co-administration of cART and antidepressants in older, HIV-infected patients, little information exists regarding the optimal clinical management of the interactions of these drugs within this population. Many of these drugs affect the dopaminergic system, and dopaminergic dysfunction is associated with the progression of both HIV and depression (Belujon and Grace, 2017; Nolan and Gaskill, 2018). Recent data suggest that dopamine may be an important regulator of inflammation (Nolan, 2018; Yan, 2015), which is also involved in the development of depression and HIV infection of the central nervous system (CNS), suggesting that dysregulated dopamine could exacerbate both of these diseases. Taken with the increase in dopamine-altering medications among older individuals, these data suggest that an older population may be particularly vulnerable to drug-drug interactions affecting CNS dopamine (see Fig. 1). To address this, we will first review the pathogenesis of NeuroHIV in the aging, HIV-infected population, focusing on the interaction with comorbid depression, and the issues surrounding its diagnosis and treatment. We will then discuss the overlapping impact of inflammation and dopamine on the etiology of depression and NeuroHIV, and how cART drugs and antidepressants alter these disorders. A more comprehensive understanding of the dopaminergic effects of cART-antidepressant crosstalk is important for the current HIV epidemic, as it could provide useful contraindication data, initiate drug repurposing, and spur the development of new therapeutic approaches for delaying or reducing HIV age-related comorbidities.

Fig. 1.

The Role of Dopamine in Mediating Antidepressant/cART Interactions in Older HIV-infected Individuals with Depression. This figure summarizes the interactions between dopamine and depression on aging, HIV-infected individuals with enhanced inflammation, demonstrating that cART drugs and antidepressants show significant influence on these factors. Synergistic effects of aging and HIV create a cycle of chronic inflammation that could result in significant age-related complications and decreased survival in HIV-infected older adults, relative to uninfected individuals. One of the most prevalent inflammation-mediated comorbidities in HIV-infected older adults is depression, which often necessitates complex treatment regimens of antidepressants in conjunction with cART drugs. This can cause pill burden, medication non-adherence or adverse drug-drug interactions that can exacerbate neuropathogenesis. Depression, NeuroHIV and many of the therapeutics used to treat them impact the dopaminergic system, suggesting that dopaminergic dysfunction may be a common factor in the development of these disorders. Further, changes in dopamine can influence the develop of inflammation and the regulation of immune function, which are also implicated in the development of NeuroHIV and depression.

2. Aging with HIV

Between 2015 and 2050, the proportion of people over 60 years old will nearly double from 12% to 22% (WHO, 2018). This trend is also prevalent in people living with HIV (Smit, 2015), as access to cART results in significantly longer life spans (High, 2012), transforming HIV from a terminal illness into a chronic disease. In HIV literature, individuals over the age of 50 are generally considered older adults (Blanco, 2012). Globally, more than 10% of the population living with HIV is aged 50 or older, and in higher income countries with better access to cART, this population makes up over 30% of infected individuals (UNAIDS, 2013.). Not only is the HIV-infected population aging, but older people represent an increasingly higher proportion of new HIV infections. In the US, around 18% of newly diagnosed patients are over the age of 50 years, and increasingly patients initially diagnosed at older ages are also diagnosed with a more advanced HIV infection (Tavoschi, 2017; Prevention, C.f.D.C.a., 2016). This may be due, in part, to a lack of awareness or education, as many older people consider HIV to be a “young person’s disease”, and there is less of a push for frequent disease screening in the 50+ population (Emlet, 2006; Sankar, 2011). However, immune function in older individuals is not as robust, and therefore the advanced disease presentation in this population may also be due to immunologic factors.

Older adults with HIV display more comorbidities and age-related conditions at a younger age than in the non-HIV population (Guaraldi, 2015; Vance, 2011), including many HIV-associated non-AIDS conditions that are becoming more frequent (Spano, 2016). Indeed, non-AIDS-related mortality is now more common than AIDS-related mortality as the major cause of death in the HIV-infected population (Alejos, 2014; Lifson, 2008). These conditions include diabetes (Abebe, 2016), hyperlipidemia (Lo, 2011), cardiovascular disease (Triant, 2013), and kidney disease (Maciel, 2018), but one of the largest problems associated with HIV infection in the aging population is neuropsychiatric diseases such as depression, anxiety and substance abuse (Watkins and Treisman, 2012).

Management of HIV in combination with these neuropsychiatric comorbidities is complicated by polypharmacy, drug–drug interactions and toxicity due to altered drug metabolism (Simone and Appelbaum, 2008; Greene, 2014). Older HIV-infected patients tend to use a higher number of medications at the same time (Marzolini, 2011), and one study found that 90% of patients over 50 had at least one concomitant medication and nearly 35% had three or more. Further, the same study found that age and duration of HIV infection were significantly associated with the number of concomitant medications (Serrao, 2019). Complex treatments with a high number of drugs leads to pill burden and is associated with a greater likelihood of medication errors and lack of adherence (Edelman, 2013). Polypharmacy is associated with an increase in inflammation and neuropsychiatric problems, such as depressive symptoms, in non-HIV-infected older adults (Ersoy and Engin, 2018), suggesting this association may also be present in the HlV-infected population. It has been estimated that nearly half of HIV-infected people aged 50 or older may be receiving concomitant drugs that are potentially prone to significant interactions with antiretroviral therapy, especially when the antiretroviral regimen includes boosted antiretroviral drugs (Marzolini, 2011). Historically, comparatively few HIV research studies specifically examined older adults, and these were often underrepresented, so relatively little information is available about optimal management for the older HIV population with neuropsychiatric conditions.

2.1. NeuroHIV in the aging population

The primary targets for HIV infection in the CNS are myeloid cells such as microglia and perivascular macrophages (Avalos, 2017.; Mallard and Williams, 2018; Rappaport and Volsky, 2015; Navia, 1986). Infection of the CNS occurs rapidly after initial infection in almost all individuals (Valcour, 2012; Davis, 1992), with HIV-infected monocytes crossing the blood brain barrier and differentiating into macrophages, which then disseminate virus throughout myeloid populations (Williams, 2014). Once infected, myeloid cells can produce new virus, act as viral reservoirs, and release neurotoxic factors that drive HIV neuropathology (Rappaport and Volsky, 2015; Williams and Hickey, 2002). Recent studies suggest that T-cells may also contribute to HIV infection of the CNS and act as reservoirs in this compartment, although this remains unclear (Honeycutt, 2018; Joseph, 2018; Spudich, 2019). Further, a number of studies suggest that astrocytes may be a target for HIV infection in the CNS (Churchill, 2009; Liu, 2004; Eugenin, 2011; Li, 2011; Reynolds, 2006; Carroll-Anzinger and Al-Harthi, 2006), but the importance of productive astrocyte infection in vivo, and how this influences the development of CNS infection, remains controversial (Russell, 2017; Ko, 2019; Al-Harthi and Nath, 2019). If infected, astrocytes could act as reservoirs, or amplify the spread neurotoxic signals (Eugenin and Berman, 2007; Eugenin and Berman, 2013; Carroll-Anzinger, 2007; Li et al., 2016), suggesting further examination of this cell type is needed to fully understand the development of CNS disease. However, for the purpose of this review, we will focus our discussion on myeloid cells as they are the most well characterized HIV targets in the CNS.

Prior to cART, this resulted in significant neuropathology, including microglial activation and the formation of multinucleated giant cells, reactive astrogliosis, inflammation, myelin loss, and regional atrophy, particularly in dopaminergic brain regions (Navia, 1986; Berger and Nath, 1997). While cART has greatly reduced and shifted these effects, more subtle forms of neuropathology are still seen in most infected individuals (Gelman, 2015). In the current era, cART-mediated suppression of viral replication has altered the severity, but not the prevalence, of HIV-associated neurocognitive disorders (HAND). Approximately 50% of all HIV-infected individuals still have some degree of neurological impairment, including, but not limited to, problems in attention, working memory, executive function, and processing speed, as well as behavioral changes and problems with motor coordination (Farhadian et al., 2017; Saylor, 2016). This constellation of symptoms, along with the underlying neuropathology, is known as NeuroHIV. The prevalence of these conditions in virally-suppressed individuals suggests that they are not caused directly by viral replication but are due to ancillary effects such as chronic neuroinflammation and subsequent disruptions in neurotransmission (Gannon et al., 2011; Tavazzi, 2014; Yuan, 2013; Yadav and Collman, 2009; Spudich, 2011; Anthony, 2005; Spudich, 2016). In older individuals, these effects could be compounded by age-associated inflammation, or “inflammaging,” which is a major risk factor for both morbidity and mortality in non-infected older adults (Franceschi and Campisi, 2014; Franceschi, 2007). Infection with HIV induces chronic immune activation similar to that seen healthy, aging adults, suggesting that aging and HIV synergistically enhance inflammation, particularly in the innate immune system (Zapata and Shaw, 2014; Martin, 2013). This could result in significant age-related complications and decreased survival in HIV-infected older adults, relative to uninfected individuals (Deeks, 2011; Grund, 2016).

The specific neuropathology present in older adults living with HIV is not well defined, but it is clear that these individuals are at greater risk for neurocognitive impairment, regardless of the duration of infection (Valcour, et al., 2004; Wendelken and Valcour, 2012). Advanced age increases susceptibility to more severe forms of impairment (Cañizares et al., 2014), and older HIV-infected individuals show an increased incidence of neuropathy (Watters, 2004) and dementia, with the risk for dementia being increased by more than three-fold for HIV-infected patients older than 50 years old compared to younger HIV-infected patients (Valcour, 2004). Older populations also show exacerbated extrapyramidal motor impairment, often associated with basal ganglia dysfunction and loss of dopamine, regardless of cART (Valcour, 2008; Tierney, 2019), and a greater neurocognitive impact in response to aging (Goodkin, 2017). Brain atrophy is increased with HIV, and older, cART-treated HIV-infected individuals show more rapid and progressive brain atrophy relative to healthy populations (Becker, 2011; Clifford, 2017).

Additionally, neuroimaging in HIV-infected individuals, particularly among older adults, shows elevations in abnormal white matter (Gongvatana, 2011), and metabolic abnormalities associated with a decline in neural efficiency (Ernst, 2009; Chang, 2013). These changes may be a reflection of the accelerated deterioration of dopaminergic circuits seen in HIV-infected individuals (Ipser, 2015; Anderson, 2016; Janssen, 2017; Ann, 2016), as well as in the specific sensitivity of dopaminergic neurons to HIV-associated neurotoxicity (Agrawal, 2010; Lopez, 1999; Hu, 2009). In addition, HIV itself may accelerate the aging process, as the increased rate of chronic comorbidities, along with persistent increased inflammatory markers, other senescent immune changes and frailty are present at younger ages compared to the non-HIV population (Deeks, 2009; Pathai, 2014). A recent study also showed that increased brain aging, predicted using neuroimaging, was related to cognitive deficits, despite effective viral suppression (Cole, 2017). However, the concept of accelerated aging in HIV-infected individuals is still controversial. While there is a higher occurrence of comorbidities in the HIV population for any given age, the rate of comorbidities does not increase with the amount of time a person is infected with HIV, suggesting that HIV does not appear to accelerate their occurrence over time (Rasmussen, 2015; Althoff, 2015). While these and other data suggest the cumulative effects of aging and HIV on brain function are substantial, the specific impact of these changes on the etiology of neuropsychiatric comorbidities is not clear.

2.2. NeuroHIV and comorbid depression in the aging population

Globally, major depressive disorder (MDD) is one of the most common neuropsychiatric disorders. This disorder is characterized by depressed mood, loss of interest in most activities, appetite and sleep disturbances, feelings of worthlessness and guilt, as well as suicidal thoughts and ideation (Richards, 2011). For HIV-infected individuals, depression is the most prevalent neuropsychiatric condition (Bhatia and Munjal, 2014; Rabkin, 2008), with 20–70% of people living with HIV showing depressive symptoms or MDD (Campos et al., 2010; Savetsky, 2001; Bing, 2001). Further, the severity of depression in people living with HIV is worse compared with the general population (Milanini, 2017; Do, 2014; Pence, 2018). The specific interaction between depression and aging with HIV is not well understood, but older HIV patients have an increased risk of depression compared with younger infected individuals (Hinkin, 2001; Grov, 2010), and the Research on Older Adults with HIV study found individuals with depression had a higher disease burden and an average of three other diseases (Havlik et al., 2011).

This same study also found significant correlations between Depression Scale scores and cognitive impairment in similar domains as non-infected individuals (Havlik et al., 2011), and other research shows around 33% of HIV-infected patients have deficits in subjective memory closely associated with depression and anxiety (Herrmann, 2019). Functional alterations of the medial prefrontal cortex and limbic structures such as the amygdala, hippocampus, parahippocampal cortex, and basal ganglia contribute to cognitive impairments in depression (Drevets, 2000; Sheline, 2000). These functional brain alterations overlap in part with the HIV-associated alterations in brain circuitry (Plessis, 2014), indicating HIV infection and depression could exacerbate each other, acting through common mechanisms to cause to behavioral and functional changes in these individuals.

However, the connection between depression and cognitive impairment in older people living with HIV is not clear and remains controversial in the cART era (Milanini, 2017). Studies in the Hawaii Aging with HIV cohort indicate that depression is significantly correlated with impaired neuropsychological performance in younger but not older individuals (Shimizu, 2011), and other research suggests that depression and cognitive impairment should be examined as independent processes (Cysique, 2007; Cole, 2007). For instance, although basal ganglia atrophy has been associated with both HIV infection and depression, no correlation was seen between basal ganglia atrophy and depression in HIV-infected individuals (Davison, 1997). Some studies have also noted gender- or ethnicity- specific impacts of depression in aging HIV populations (Brooks, 2012; Rubtsova, 2017). For example, unlike HIV-infected men, the depression scores of women with HIV increase yearly starting at age 40 (Aljassem, 2016). Another study found that with regards to the severity of depression, having a partner was protective for men as they aged, but not for women (Swendeman, 2018). Research into the links between NeuroHIV and depression in the aging population are relatively limited, and more data studying specific populations is urgently needed to fully understand these effects in this rapidly growing population.

Depression has been shown to be a predictor, cause and result of HIV disease progression. Depressed individuals living with HIV show increased plasma viral loads and rates of CD4+ T-cell loss, altered immune responses, and increased levels of inflammatory cytokines in both plasma and the CNS (Leserman, 2003; Rivera-Rivera, 2016). This leads to poorer viral suppression and cognitive impairment (Gonzalez, 2011), as well as more rapid HIV disease progression and higher mortality rates including higher rates of suicide (Ickovics, 2001; Dabaghzadeh, 2015). Depressive symptoms also reduce adherence to cART, and increase the risk of substance abuse, risky sexual behaviors and feelings of hopelessness (Hobkirk, 2015; Schuster et al., 2012). All of these effects significantly worsen individual clinical outcomes and promote the spread of HIV, which could be exacerbated in older individuals, making effective diagnosis and treatment of depression in this population a critical public health issue.

A major challenge in the current era is differentiating cognitive symptoms of depression from NeuroHIV, considering that in a high percentage of patients, the two disorders coexist. Depression may be an early manifestation of HIV-associated dementia (HAD), and depressive symptoms arising from HIV neurodegeneration may be associated with a risk of developing or worsening of cognitive impairment or HAD (Gibbie, 2006; Nanni, 2015; Castellon, 2006). Indeed, patients with cognitive decline and depression have significantly more functional impairment than those without depression (Fernandes Filho and de Melo, 2012), and there is a significant relationship between the extent of depression and the severity of loss of cognitive functioning in patients infected with HIV (Braganca and Palha, 2011). Further, the worsening of NeuroHIV could potentially increase risk for delayed diagnosis of other forms of dementia such as Alzheimer’s (Milanini and Valcour, 2017), although further studies are needed to assess this risk.

Compounding these issues, depressive symptoms are often overlooked, as almost 50% of HIV/AIDS patients suffering from depression are never diagnosed (Asch, 2003). In elderly patients with HIV, depression is often underdiagnosed and undertreated (Nyirenda, 2013; Zanjani et al., 2007), in part because older patients often present with a constellation of vague symptoms. These include somatic complaints such as headache and gastrointestinal disturbances, anger, and irritability instead of low mood (Krishnan, 2002), as well as poor sleep, appetite changes, lack of motivation, decreased concentration, fatigue, and weight loss, all of which can be caused by both depression and HIV. Further confusing the diagnostic process, the initial diagnosis of HIV often results in an “adjustment disorder”, which can present with depressive-like symptoms, and depressive-like symptoms can also be caused by substance intoxication, withdrawal and dementia (Angelino, 2002). Symptom confusion can be compounded by failure to use strict diagnostic criteria for MDD, such as the DSM-V or ICD-10, and instead defining depression based on physician reporting or structured screening surveys. Substitution of self-report or clinician rating is not an accurate substitute for neuropsychiatric testing (Justice, 2004; Underwood and Winston, 2016) and likely a major contributor to the large variation in depression prevalence seen in the literature. Because of these factors, it is difficult to delineate HIV symptoms from depression. This can contribute to delayed or inadequate diagnosis and treatment of this disorder in older HIV-infected adults (Malaspina, 2011; Cherner, 2004), exacerbating the development and spread of disease in this population.

2.3. Effects of cART in the aging population

Combination antiretroviral therapy (cART) – simultaneous treatment with several classes of antiretroviral drugs – was first developed in 1996 and rapidly became the primary treatment for HIV-infected individuals. Currently, the standard of care consists of three antiretroviral drugs from at least two different classes (Department of Health and Human Services, 2017), and many cART regimens are now available as a single tablet formulation (Astuti and Maggiolo, 2014). Some data show that older adults have a more robust viral suppression in response to cART (Silverberg, 2007; Orlando, 2006; Manfredi and Chiodo, 2000) although others do not see a difference between older and younger patients (Wellons, 2002; Greenbaum, 2008; Szadkowski, 2012). Some studies also show that despite effective cART, older adults have a blunted immune recovery relative to younger individuals, decreases in physical function, increased mortality, and faster disease progression (Khoury, 2017; Jourjy et al., 2015; Fatti, 2014). Notably, older patients have a number of distinct issues that can confound cART effectiveness. These are generally associated with medication compliance due to polypharmacy, as well as age-related cognitive and vision impairment, increased blood–brain barrier permeability, and diminished metabolism and kidney function (Burgess et al., 2015; Zeevi, 2010; Barclay, 2007; Winston and Underwood, 2015).

It is also likely that cART is less effective in older, HIV-infected individuals due to the additive effects of age-related conditions, including age-related inflammation (Deeks, 2011; Nasi, 2017). Treatment with cART generally reduces inflammation, decreasing T-cell activation and partially normalizing inflammation (Hileman and Funderburg, 2017; Jennes, 2004), especially early on in disease progression (de Paula, 2018; Allers, 2016). However, several studies show that cART has minimal effects on expression of several inflammatory markers, including IL-1β and IL-6 (Gay, 2011; Regidor, 2011; Osuji, 2018), and that there is no difference in inflammatory markers in patients regardless of time of initiation or duration of cART following infection (Ruggiero, 2015; Ruggiero, 2018; Amu, 2016). Further, two cohorts, the VACS-BC and APROCO-COPILOTE cohorts, showed elevated levels of inflammatory and immune activation markers in aging, long-term infected, cART-controlled HIV-infected patients (Bastard, 2015; Armah, 2012). This suggests that cART may have time and donor-dependent limits in its effectiveness in regard to immune recovery and control, and that these limits may be increased in older individuals with pre-existing inflammation and immune activation.

Several studies suggest that cART may specifically be less effective in controlling myeloid inflammatory activity. In a Thai cohort, early initiation of cART did not affect monocyte activation and levels of IL-6 and TNF-α remained elevated (Sereti, 2017), while in the MACS cohort, 1 year of cART normalized T-cell activity, but activation of monocytes and macrophages remained elevated (Wada, 2015). Persistent myeloid activation, measured by plasma sCD163, was shown in neurocognitively impaired, HIV-infected individuals on cART (Burdo, 2013), and a second group found that serum levels of sCD14, another myeloid activation marker, were elevated in adults over age 50 living with HIV on suppressive cART (Montoya, 2017). In the VACS-BC cohort, increased measures of monocyte activation (sCD14) and inflammation (IL-6) are correlated with increased mortality (So-Armah, 2016). In vitro, human monocyte-derived macrophages (MDM) from individuals on cART show elevated toll like receptor (TLR) responses and increased IL-6 and IL-1β production (Galvao-Lima, 2017; Merlini, 2016), and in THP-1 human macrophages, treatment with the cART drugs stavudine (d4T), zidovudine (AZT), nelfinavir (NFV) and lopinavir (LPV) increased production of IL-1β, TNF-α and ROS (Lagathu, 2007). Further the cART drug maraviroc (MVC), a CCR5 inhibitor, significantly increased activation of primary rat microglia exposed to gp120 (Lisi, 2012). These data suggest that myeloid cell-derived inflammation is not ameliorated by cART and suggest that this type of inflammation may be important to the development of age-related comorbidities in the aging, HIV-infected population (Lagathu, 2017).

3. Inflammation as a link between Depression, aging and NeuroHIV

There are a number of hypotheses regarding the etiology of depression, including nutritional deficiencies (Rao, 2008), abnormalities in circadian rhythm (Germain and Kupfer, 2008), impaired emotional processing (Carballedo, 2011), chronic inflammation (Hodes, 2015) and changes in monoamine levels, including serotonergic and adrenergic but also dopaminergic dysfunction of neural circuits (Belujon and Grace, 2017; Delgado, 2000; Dunlop and Nemeroff, 2007). While the precise etiology of depression is unclear, data indicate increased inflammation is a critical contributor to and target for treatment in this disease (Wohleb, 2016; Pfau et al., 2018; Miller and Raison, 2016; Kaufmann, 2017; Beydoun, 2019). Inflammation in both the CNS and peripheral regions are associated with depression, although each region’s role in initiating and sustaining depressive symptoms remains unclear. In older adults with HIV, emerging data indicate that the increased risk of neuropsychological comorbidities like depression is linked to the long-term use of cART, chronic inflammation, and persistent immune activation due to HIV infection (Schouten, 2014; Rivera-Rivera, 2014). Combined with age-associated increases in inflammation, these effects may also lead to higher rates of neuropsychiatric disorders in older HIV-infected individuals compared to healthy older adults (Rivera-Rivera, 2016; Effros, 2008; Leserman, 2008). Elevated levels of circulating inflammatory cytokines in HIV-infected individuals on cART (Regidor, 2011; Sereti, 2017; Funderburg, 2014; Gay, 2011; Shive, 2012), including IL-1β, TNF-α and IL-6, are associated with depressive symptoms in both rodents and humans (Hodes, 2015; Liu et al., 2012; Felger and Lotrich, 2013; Dowlati, 2010).

In many models, increased inflammation is associated with hyperactivity of the hypothalamic-pituitaryadrenal (HPA) axis and the release of glucocorticoids (Pariante and Lightman, 2008; Horowitz, 2013), which can be induced by both HIV infection and cART drugs (Collazos, 2003; Christeff, 1997). This suggests that HIV could disrupt the bidirectional immune interaction between the periphery and CNS (Wohleb, 2016; Raedler, 2011), triggering cascading inflammatory effects in both compartments. Inflammation resulting from depression has also been linked to activation of the indoleamine 2,3-dioxygenase (IDO) enzyme (Christmas et al., 2011; Dantzer, 2011), which initiates the metabolism of tryptophan into neurotoxic compound quinolinic acid. This could potentiate both depression and HIV neuropathogenesis, as IDO activity is increased in HIV-infected individuals and is only partially ameliorated by cART (Chen, 2014; Peltenburg, 2018; Jones, 2015). The Rhesus macaque model of NeuroAIDS shows myeloid lineage cells are the primary source of IDO in the brain, and that IDO expression is proportional to SIV viral load and IFN-γ (Burudi, 2002). Further, exposure to the HIV viral protein Tat in the brains of mice led to increased cytokine and IDO production along with development of depressive-like behaviors (Fu, 2011; Lawson et al., 2011).

A substantial amount of depression-associated inflammation is mediated by myeloid cell activation; microglia and perivascular macrophages in the CNS as well as different types of macrophages and monocytes in the periphery (Hodes, 2015; Wohleb, 2016; Yirmiya et al., 2015). Glucocorticoids increase the release of IL-1β, IL-6 and TNF-α from macrophages and monocytes (Busillo et al., 2011) and in social stress models of depression, extravasation of inflammatory monocytes and macrophages from the bone marrow is increased (Engler, 2004). Therapeutic administration of IFN-α, which increases macrophage inflammatory function (Raison et al., 2006), induces the development of depressive symptoms such as anhedonia, fatigue, and psychomotor retardation (Capuron, 2002; Raison, 2005). Further, the antidepressants fluoxetine and venlafaxine (Table 1) suppress immune activation and release of inflammatory factors such as IL-6 specifically by inhibiting macrophage function (Nazimek, 2017).

Table 1.

Compounds that Modulate the Dopaminergic System. A summary of compounds with varying mechanisms of action to increase or decrease dopaminergic activity. References in the table refer to the specific studies that demonstrate that these drugs change dopamine levels and/or dopamine turnover. As the aging HIV population uses a number of different drugs, many of which impact dopamine but are not always indicated to affect the dopaminergic system, caution should be used in taking them as they may affect the progression of NeuroHIV, depression, and other age-related comorbidities.

	Generic Name	Brand Names	Mechanism	Therapeutic Use	References
Dopamine Precursors	Levodopa	Atamet, Duopa, Larodopa, Parcopa, Prolopa, Rytary, Stalevo, Sinemet	Dopamine Precursor	Parkinsons’ Disease (PD)	(Yahr, 1969; Ng, 1970)
	L-phenylalanine	N/A	Dopamine Precursor	Dietary Supplement	(Milner et al., 1986; Fernstrom and Fernstrom, 2007; Kapatos and Zigmond, 1977)
	L-tyrosine	N/A	Dopamine Precursor	Dietary Supplement	(Fernstrom and Fernstrom, 2007; Kapatos and Zigmond, 1977; During et al., 1989)
Dopamine Receptor Agonists	Amantadine	Symmetrel	Dopamine Receptor Agonist/Dopamine Reuptake Inhibitor	PD, Antiviral	(Von Vigtlander and Moore, 1971; Mizoguchi, 1994)
	Apomorphine	Apokyn	Dopamine Receptor Agonist	PD	(Andén, 1967; de La Fuente-Fernandez, 2001)
	Aripiprazole	Abilify, Aripipex	Dopamine Receptor Agonist#	Schizophrenia, Bipolar Disorder, Major Depressive Disorder (MDD), Obsessive Compulsive Disorder (OCD), Autism	(Li, 2004)
	Bromocriptine	Cycloset, Parlodel, Brotin	Dopamine Receptor Agonist	PD, Pituitary tumors, Type 2 Diabetes, Hyperprolactinaemia, Neuroleptic malignant syndrome	(Brannan, 1993)
	Lisuride	Proclacam, Revanii, Dopergin	Dopamine Receptor Agonist	PD, Migraine	(Kehr, 1977)
	Memantine	Axura, Akatinol, Abixa, Memox, Ebixa, Namenda	Dopamine Receptor Agonist	Alzheimers’ Disease (AD)	(Spanagel et al., 1994)
	Pramexipole	Mirapex, Mirapexin, Sifrol	Dopamine Receptor Agonist	PD, Restless Leg Syndrome (RLS)	(Carter and Müller, 1991)
	Piribedil	Pronoran, Trivastal Retard, Trastal, Trivastan, Clarium	Dopamine Receptor Agonist	Parkinsons’ Disease, Elderly dizziness and cognitive deficit, retinal ischemic manifestations	(Gil-Loyzaga, 1994; Delbarre, 1995)
	Rotigotine	Neupro	Dopamine Receptor Agonist	MDD, PD, RLS, Willis-Ekborn Disease	(Kehr, 2007)
Dopamine Receptor Antagonists	Amisulpride	Solian	Dopamine Receptor Antagonist	Schizophrenia, Dysthymia	(Schoemaker, 1997)
	Chlorpromazine	Largactil, Thorazine	Dopamine Receptor Antagonist	ADHD, Bipolar Disorder, Nausea, Schizophrenia, Vomiting	(Starke, 1978; Stamford et al., 1986)
	Clozapine	Clozaril	Dopamine Receptor Antagonist	Treatment-resistant Schizophrenia	(Youngren, 1999; Meltzer, 1989; Drew, 1990)
	Domperidone	Motilium	Dopamine Receptor Antagonist	Nausea, vomiting, Gastroprokinetic, Galactagogue	(Champion, 1988)
	Fluphenazine	Prolixin	Dopamine Receptor Antagonist	Schizophrenia	(Bacopoulos et al., 1979; Goosey and Doggett, 1983)
	Haloperidol	Haldol	Dopamine Receptor Antagonist	Schizophrenia, Bipolar Disorder, Tourette Syndrome, Nausea, Vomiting, Delerium	(Drew, 1990; Gudelsky and Porter, 1980; Bunney and Grace, 1978)
	Loxapine	Loxitane	Dopamine Receptor Antagonist	Schizophrenia, Bipolar Disorder	(Li et al., 2003)
	Metoclopramide	Primperan, Reglan	Dopamine Receptor Antagonist	Nausea, Vomiting, Migraine	(Peringer, 1976)
	Molindone	Moban	Dopamine Receptor Antagonist	Schizophrenia	(McMillen and McDonald, 1983)
	Olanzapine	Zyprexa	Dopamine Receptor Antagonist	Schizophrenia, Bipolar Disorder	(Zhang, 2000; Li, 1998)
	Perphenazine	Trilafon	Dopamine Receptor Antagonist	Schizophrenia, Bipolar Disorder, Depression	(Mjörndal and Persson, 1990)
	Pimozide	Orap	Dopamine Receptor Antagonist	Schizophrenia, Tourette Syndrome	(Matsuo, 2010; Parsons et al., 1993)
	Prochlorperazine	Compro	Dopamine Receptor Antagonist	Schizophrenia, Nausea, Migraine, Anxiety	(Goosey and Doggett, 1983)
	Quetiapine	Seroquel	Dopamine Receptor Antagonist	Schizophrenia, Bipolar Disorder, Depression, Sleep Aid	(Pira et al., 2004; Silverstone et al., 2012)
	Risperidone	Risperdal	Dopamine Receptor Antagonist	Schizophrenia, Bipolar Disorder, Autism	(Hertel, 1996; Huang, 2006)
	Sulpiride*	Dogmatil	Dopamine Receptor Antagonist	Schizophrenia, Depression	(Andersen and Gazzara, 1996)
	Thiothixene	Navane	Dopamine Receptor Antagonist	Schizophrenia, Bipolar Disorder	(Bjerkenstedt, (1970), 1977)
	Trifluoperazine	Stelazine	Dopamine Receptor Antagonist	Schizophrenia, Generalized Anxiety Disorder (GAD)	(Goosey and Doggett, 1983)
	Ziprasidone	Geodon	Dopamine Receptor Antagonist	Schizophrenia, Bipolar Disorder	(Li et al., 2003)
Dopamine Reuptake Inhibitors	Armodafanil	Nuvigil, Acronite	Dopamine Reuptake Inhibitor	Sleep Disorders	(Loland, 2012)
	Benzatropin	Cogentin	Dopamine Reuptake Inhibitor	PD, Dystonia	(Goodale and Moore, 1975)
	Bupropion	Elontril, Wellbutrin, Zyban	Dopamine Reuptake Inhibitor	Depression, Smoking Cessation, ADHD	(Ascher, 1995; Nomikos, 1992)
	Dexmethylphenidate	Attenade, Focalin	Dopamine Reuptake Inhibitor	ADHD	(Volkow, 2001)
	Diphenylpyraline	Allergen, Arbid, Belfene, Diafen, Hispril, Histyn, Lergobine, Lyssipol, Mepiben, Neargal	Dopamine Reuptake Inhibitor	Allergies, PD	(Oleson, 2012)
	Esketamine	Ketanest, Spravato	Dopamine Reuptake Inhibitor	Anesthesia, Treatment-resistant depression	(Hashimoto, 2017)
	Methylphenidate	Methylin, Concerta, Medikinet, Ritalin, Equasym XL, Metadate, Quillivant XR	Dopamine Reuptake Inhibitor	ADHD	(Heal, 2008)
	Modafanil	Alertec, Modavigil, Modiodal, Provigil, Modalert	Dopamine Reuptake Inhibitor	Sleep Disorders	(Ferraro, 1996)
	Nefazdone	Serzone, Dutonin, Nefadar	Dopamine Reuptake Inhibitor	MDD	(Olausson, 1998; Dremencov, 2005)
	Nomifensine	Merital, Alival	Dopamine Reuptake Inhibitor	Depression, Anxiety Disorders	(Karoum, 1994)
	Sertraline	Zoloft	Weak Dopamine Reuptake Inhibitor	MDD, Anxiety Disorders, OCD	(Kitaichi, 2010)
	Tripelennamine	Pyrbenzamine	Weak Dopamine Reuptake Inhibitor	Allergies	(San-Martin-Clark, 1996; Oishi, 1994)
	Venlafaxine	Effexor, Lanvexin, Trevilor	Weak Dopamine Reuptake Inhibitor	MDD, Anxiety Disorders	(Czubak, 2010)
Monoamine Oxidase Inhibitors	Phenelzine	Nardil, Nardelzine	Non-Selective MAO-I	MDD, Anxiety Disorders	(Juorio et al., 1986)
	Rasagiline	Azilect	Selective MAO-B Inhibitor	PD	(Finberg, 1998)
	Selegiline	Anipryl, Emsam, Deprenyl, Eldepryl, Zelapar, Selgene	Selective MAO-B Inhibitor	PD, MDD, ADHD	(Kitaichi, 2013)
	Tranylcypromine	Parnate, Jatrosom	Non-Selective MAO-I	MDD, Mood Disorders, Anxiety Disorders	(Shioda, 2004; Ainsworth, 1998)
Vesicular Monoamine Transporter 2 (VMAT2) Inhibitors	Reserpine	Serpalan, Serpasil	VMAT2 Inhibitor	High Blood Pressure	(Elverfors and Nissbrandt, 1991; Okada, 1993)
	Tetrabenazine	Nitoman, Xenazine	VMAT2 Inhibitor	Huntington’s Disease, Tardive Dyskinesia, Tourette Syndrome, Hemiballismus	(Owesson-White, 2012)
Other Drugs with Dopaminergic Mechanisms	Agomelatine*	Melitor, Thymanax, Valdoxan	Dopamine Releasing Agent	Depression	(Millan, 2003)
	Buspirone	Buspar, Buspar Dividose, Vanspar	Dopamine Releasing Agent	Anxiety Disorders	(McMillen and McDonald, 1983; Silverstone et al, 2012; Sakaue, 2000)
	Clomipramine	Anafranil, Clofranil	Weak Dopamine Reuptake Inhibitor/Weak Dopamine Receptor Agonist	Depression, OCD, Anxiety Disorders, Other Psychiatric Disorders	(Ichikawa and Meltzer, 1995)
	Desipramine	Norpramin, Pertofrane	Dopamine Releasing Agent	Depression	(Dremencov, 2005)
	Disulfiram	Antabuse, Antabus	Prevents Dopamine Breakdown	Cocaine Dependence, Cancer, Alcoholism	(Devoto, 2012)
	Donepezil	Aricept	Dopamine Releasing Agent	AD	(Zhang et al., 2004)
	Entacapone	Comtan	Catechol-O-Methyl Transferase Inhibtor	PD	(Gerlach, 2004)
	Fluoxetine	Prozac, Sarafem	Dopamine Releasing Agent	MDD, OCD, Bulimia, Panic Disorder, Premenstrual Dysphoric Disorder	(Zhang, 2000; Sakaue, 2000; Ichikawa and Meltzer, 1995)
	Folate	N/A	Increases Dopamine Turnover	Dietary Supplement, Depression	(Miller, 2008)
	Galantamine	Nivalin, Razadyne, Razadyne ER, Reminyl, Lycoremine	Dopamine Releasing Agent	AD	(Schilstrom, 2007)
	Imipramine	Tofranil	Weak Dopamine Receptor Antagonist	Depression	(Ichikawa and Meltzer, 1995)
	L-methylfolate	N/A	Increases Dopamine Turnover	Dietary Supplement, Depression	(Miller, 2008)
	Lisdexamfetamine	Vyvanse	Dopamine Releasing Agent	ADHD, Binge eating disorder	(Rowley, 2012)
	Metirosine	Metyrosine	Tyrosine Hydroxylase Inhibitor	Hypertension, Headahce, Tachycardia, Constipation, Tremors	(Naruse, 2018)
	Mirtazapine	Remeron	Dopamine Releasing Agent	Depression	(Nakayama et al., 2004)
	Moclobemide*	Aurorix, Manerix	Selective MAO-A Inhibitor	Depression, Anxiety Disorders	(Da Prada, 1989)
	Paroxetine	Paxil, Seroxat	Dopamine Releasing Agent	Depression, OCD, PTSD, Panic Disorder, Generalized Anxiety Disorder, Premenstrual Dysphoric Disorder	(Nakayama, 2002)
	Pergolide*	Permax	Dopamine Receptor Agonist	PD	(Herdon and Nahorski, 1987; Fuller and Snoddy, 1981)
	Reboxetine	Edronax	Dopamine Releasing Agent	Depression	(Linner, 2001)
	S-adenosyl methionine	N/A	Increases Dopamine Turnover	Dietary Supplement, Depression	(Miller, 2008; Schalinske and Smazal, 2015)
	Tolcapone	Tasmar	Catechol-O-Methyl Transferase Inhibtor	PD	(Lapish, 2009; Tunbridge, 2004)
	Trimipramine	Surmontil, Rhotrimine, Stangyl	Weak Dopamine Reuptake	Depression	(Taylor, 1996)
Drugs of Abuse	Alcohol	N/A	Dopamine Releasing Agent	N/A	(Bosse and Mathews, 2011; Yan, 1999; Weiss, 1996)
	Alpha-Pyrrolidinopentiophenone (PVP)	N/A	Dopamine Reuptake Inhibitor	N/A	(Hataoka et al., 2017; Glennon and Young, 2016)
	Amphetamine	N/A	Dopamine Releasing Agent	N/A	(Moghaddam and Bunney, 1989; Tor-Agbidye et al., 2001)
	Cocaine	N/A	Dopamine Reuptake Inhibitor	N/A	(Wightman, 2007; Shou, 2006; Phillips, 2003)
	Heroin	N/A	Weak Dopamine Releasing Agent	N/A	(Hemby, 1995; Smith, 2006)
	Ketamine	Ketalar	Dopamine Reuptake Inhibitor	Depression	(Kokkinou et al., 2018)
	Lysergic Acid Diethylamide (LSD)	N/A	Dopamine Receptor Agonist	N/A	(Smith et al., 1975; Antkiewicz-Michaluk et al., 1997)
	Methylenedioxymethamphetamine (MDMA)	N/A	Dopamine Releasing Agent	N/A	(Baumann et al., 2008; Gudelsky et al., 1994)
	Methylenedioxypyrovalerone (MDPV)	N/A	Dopamine Reuptake Inhibitor	N/A	(Glennon and Young, 2016; Shekar, 2017)
	Methamphetamine	N/A	Dopamine Releasing Agent	N/A	(Wilson, 1996; Kita, 2000)
	Morphine	MorphaBond ER, Arymo ER, Astramorph-PF	Dopamine Releasing Agent	Pain Reliever	(Anagnostakis and Spyraki, 1994; Vander Weele, 2014)
	Nicotine	N/A	Weak Dopamine Releasing Agent	N/A	(Wing, 2015; Di Chiara, 2000)
	Oxycodone	Xtampza ER, Oxaydo, Roxicodone, and Oxycontin	Dopamine Releasing Agent	Pain Reliever	(Vander Weele, 2014; Zhang, 2009)
	Phencyclidine (PCP)	N/A	Dopamine Reuptake Inhibitor	N/A	(Hondo, 1994)
	Tetrahydrocannabinol (THC)	N/A	Dopamine Releasing Agent	N/A	(Chen, 1993; Pistis, 2002)

^*Not prescribed in the United States.

^#Acts as both a dopamine receptor agonist (presynaptic) and a dopamine receptor antagonist (postsynaptic).

In the CNS, rodent models of stress-induced depression show disturbances in microglial function (Tong, 2017; Kreisel, 2014) and neuroimaging studies in individuals with major depressive disorder show increased microglial density and inflammatory activity (Li et al., 2018; Li et al., 2018). Similar to what occurs in the non-HIV aged brain, immune cells such as microglia in HIV-infected persons may be “primed” to an activated phenotype in response to inflammatory stimuli in the periphery (Matt and Johnson, 2016; Tedaldi et al., 2015). This might occur through priming of the NLRP3 inflammasome, which is strongly correlated with the development of depression (Iwata et al., 2013; Wong, 2016) and increases depressive symptoms in stress-induced animal models (Alcocer-Gomez, 2016; Pan, 2014). The microglial inflammasome pathway is active during aging (Wang, 2018; Salminen, 2012), and is also activated by HIV infection (Chivero, 2017; Mamik, 2017; Walsh, 2014). Once primed by HIV and/or in response to aging, microglia may display an aberrant response to inflammatory stimuli, enhancing neuroinflammation by increasing the production of mediators such as IL-1β and IL-18, and contributing to the development or maintenance of depression. In line with this theory, the release of inflammatory mediators by activated myeloid cells in the CNS has been shown to be a better correlate of neuropathogenesis than the actual brain viral load (Kraft-Terry, 2010). Together these data suggest that depression, HIV and aging may act synergistically on a number of inflammatory pathways, many mediated by myeloid cells, to potentiate the development and maintenance of neurologic disease.

4. The role of dopamine in NeuroHIV and depression

Both depression and NeuroHIV are associated with changes in dopamine, an important CNS neurotransmitter associated with motor control, cognition, learning, reward and other processes (BrombergMartin et al., 2010). While both depression and NeuroHIV are also associated with other major neurotransmitter systems, such as serotonin, norepinephrine, glutamate, and GABA, the effects of these disorders on these systems have been discussed in greater detail elsewhere and refer the reader to a number of recent publications (Vázquez-Santiago, 2014; Sperner-Unterweger et al., 2014; Hammoud, 2010; Cody and Vance, 2016; Buzhdygan, 2016). Infection with HIV is strongly associated with dopaminergic dysfunction throughout disease progression. Studies show an increase in CNS dopamine in subcortical structures in early stage disease, and a reduction in CNS dopamine during more advanced infection. Increased dopamine is seen in the cerebrospinal fluid (CSF) of cART-naive, HIV-infected people in early stage disease (Scheller, 2010; Horn, 2013). while, individuals in later stages show decreases in CNS and CSF dopamine (Larsson, 1991; Berger, 1994; di Rocco, 2000; Koutsilieri et al., 2001; Kumar, 2011). In addition, HIV infection and neurodegenerative damage are particularly pronounced in dopaminergic areas, such as the caudate, putamen, globus pallidus, and substantia nigra (Navia, 1986; Becker, 2011; Kumar, 2009; Berger and Arendt, 2000; Aylward, 1995; Itoh et al., 2000; Gongvatana, 2013; Clifford, 2017).

Some studies also show CNS hypermetabolism in subcortical regions such as the basal ganglia in earlier stages of infection, and subcortical hypometabolism in later stage disease (Rottenberg, 1987; van Gorp, 1992; Rottenberg, 1996; Georgiou, 2008), changing CNS dopamine levels during these stages. These changes in dopaminergic tone may be due to the selective sensitivity of dopamine neurons to HIV-induced neurotoxicity (Schier, 2017; Nath, 2000; Aksenova, 2006). The death of dopaminergic neurons would decrease dopamine availability (Bennett et al., 1995; Cass, 2003; Maragos, 2002), and many HIV patients demonstrate parkinsonian symptoms associated with decreased dopamine, including bradykinesia and extrapyramidal symptoms (Koutsilieri, 2002). They are also sensitive to parkinsonism-inducing agents (Hriso, 1991; Edelstein and Knight, 1987), like antipsychotics that act as dopamine antagonists (Table 1), supporting the hypothesis that extensive dopaminergic degeneration takes place during HIV infection (Purohit et al., 2011). In addition, HIV proteins can bind to DAT and elevate dopamine levels by disrupting uptake (Zhu, 2011; Zhu, 2016; Zhu, 2009), further contributing to later stage HIV-induced neurological damage and neuropathogenesis.

In addition to mediating neurotoxicity, these changes in dopamine concentrations may also potentiate neuropathogenesis by modulating immune function (Matt and Gaskill, 2019; Gaskill, 2013; Pinoli et al., 2017). Data from our lab shows dopamine can significantly increase HIV infection (Gaskill, 2009; Gaskill, 2014), and promotes an inflammatory phenotype in primary human MDM, which occurs irrespective of cART treatment (Nolan and Gaskill, 2018; Nolan, 2018; Gaskill, 2012). Additionally, modulation of the dopaminergic system can alter production of inflammatory mediators such as nitric oxide, IL-6, and TNF-α in other myeloid cells and cell lines (Yamamoto, 2016; Huck, 2015; Bone, 2017). These data suggest changes in dopamine associated with HIV infection of the CNS may enhance infection and exacerbate neuroinflammation, playing an important role in the development of NeuroHIV in chronically infected individuals on cART.

These alterations in CNS dopamine could also substantially impact the development of comorbid depression in older people living with HIV. While the primary neurotransmitter circuits mediating depressive behaviors are often thought to be serotonergic and/or noradrenergic, changes in dopaminergic neurotransmission, and the interactions between these circuits are also important in depression (Belujon and Grace, 2017; Dunlop and Nemeroff, 2007; Tye, 2012). It has been postulated that the mesolimbic dopamine system is involved in the etiology of depression, with decreased activation of this system inducing anhedonia, reduced motivation, and decreased energy level in most depressed individuals (Dailly, 2004; Nestler and Carlezon, 2006). Depressed patients show decreases in jugular vein plasma dopamine and its metabolites (Lambert, 2000), and imaging studies show significantly lower dopamine transporter (DAT) binding compared with healthy subjects (Sarchiapone, 2006; Pizzagalli, 2019; Meyer, 2001), suggesting a compensatory downregulation to lower dopamine concentrations. Animal models of depression also show altered dopamine regulation is associated with depressive-like symptoms such as anhedonia, behavioral despair, and learned helplessness (Kram, 2002; Chaudhury, 2013; Di Chiara and Tanda, 1997; Perona, 2008; Chang and Grace, 2014).

Overall, these data suggest that changes in CNS dopamine could significantly impact the progression of both NeuroHIV and depression and indicate that further evaluation of the risks and benefits of dopamine-altering therapeutics is needed for proper treatment of the older, HIV-infected population. Further, other neurotransmitter systems such as serotonin, norepinephrine, GABA, and glutamate can impact the regulation of dopamine (Guiard, 2008; Nutt, 2008; Floresco, 2003; El Mansari, 2010). Further, these interactions change with aging (Mora et al., 2008), suggesting the use of antidepressants that impact more than one system provides an additional route by which dopamine could impact depressive symptoms. This also suggests that the neuroinflammation prominent in older HIV-infected individuals on cART could be exacerbated by the dopamine increases resulting from the use of many antidepressants, even those not primarily targeting dopamine (Table 1).

5. Dopamine-associated mechanisms by which antidepressants and cART potentiate disease in the aging population

Effective treatment of depressed, older adults living with HIV often requires a variety of different medications, including antidepressants, cART drugs and a number of other medications, as these individuals have a high disease burden (Havlik et al., 2011). Understanding the drug-drug interactions occurring in these therapeutic regimens is critical to effective treatment in this population, specifically the effects of cART on depression, and the effects of antidepressants on HIV disease. While many studies have examined cART interactions with other drugs, including antidepressants, very few studies have assessed the effects of cART on monoamine transmission, in particular dopamine. As dopamine is an inflammatory mediator in both the CNS and periphery (Matt and Gaskill, 2019) that is strongly connected to depression and HIV, a better understanding of the specific effects of dopamine-modulating therapeutics on the development and persistence of HIV and depression in older individuals is warranted.

5.1. Antidepressants and dopamine in the aging population

The specific antidepressant regimens for older adults are not different from those recommended for the general HIV-infected population, despite a higher prevalence of comorbidities and potential for drug-drug interactions. Although early antidepressants, such as tricyclic compounds, primarily targeted the dopaminergic system, in the current era, antidepressants that predominantly act as serotonin- and combined serotonin/noradrenaline-reuptake inhibitors (SSRIs and SNRIs) are drugs of choice in HIV-infected patients with depression (Caballero and Nahata, 2005). Notably, despite the focus on serotonin and/or norepinephrine, indirect effects of the dopaminergic system in the antidepressant-like activity of SSRIs have been demonstrated (Renard, 2001; Cervo et al., 1990), and many of these newer drugs also directly affect the dopaminergic system (Subbaiah, 2018) (Table 1).

A number of different types of antidepressants are efficacious in the HIV-infected population, although no single drug has been shown to be clearly superior (Yanofski and Croarkin, 2008). Many SSRIs and SNRIs such as fluoxetine, sertraline, reboxetine, and paroxetine have shown to be effective and well-tolerated in HIV-infected individuals in various stages of HIV progression (Carvalhal, 2003; Grassi, 1997; Ferrando et al., 1997). While several studies reported a potential benefit to tricyclic antidepressants (TCAs) and related compounds like mirtazipine (Rabkin, 1994; Elliott and Roy-Byrne, 2000), they are not recommended because of their many side-effects. In older populations, TCAs are contraindicated for precisely this reason, as older adults, particularly those with HIV, are sensitive to orthostatic hypotension, urinary retention, and neurocognitive impairment, as well as anticholinergic, hypertensive and sedating effects (Yanofski and Croarkin, 2008; American Geriatrics Society, 2012; McLennon et al., 2003). Evaluations of the effectiveness of antidepressants in older people living with HIV have not determined whether they improve cognition, although mixed results have been found for antidepressants improving cognitive symptoms in the general HIV population (Hinkin, 2001; Schifitto, 2007; Sacktor, 2018). However, treating depression in non-HIV individuals has generally been shown to improve cognition (Rosenblat et al., 2015), and further attempts to use antidepressants therapeutically should be evaluated for the aging HIV population in the future.

Notably, inflammatory symptoms related to reduced motivation and motor slowing, which are more common in older adults, are difficult to treat with standard antidepressants like SSRIs in patients with depression (Konsman et al., 2002; Goldsmith, 2016; Diniz, 2019). Dopaminemediated potentiation may be involved in these SSRI-resistant, inflammation-related symptoms in the HIV population, disrupting or counteracting the impact of these agents through immunomodulatory effects (Nolan and Gaskill, 2018), and age-related inflammation may exacerbate this even further. It may also be that there is only a small therapeutic window for these drugs to be effective because disrupted dopaminergic function is seen at all stages of HIV infection; high dopamine early on in infection and low during dopaminergic neuron loss in later stages of infection.

Given the changes in dopamine concentrations during HIV infection, augmentation strategies, such as the addition of an atypical antipsychotic to an SSRI treatment, are another way to optimize treatment in patients with treatment-resistant depression (Zhou, 2015). This type of depression is more common in the elderly population (Knöchel, 2015), and may benefit from a restoration of more optimal dopamine levels. Some SSRIs like fluoxetine or escitalopram induce a decrease in dopaminergic neuron firing in the ventral tegmental area (Dremencov et al., 2009; Di Mascio, 1998; Prisco and Esposito, 1995), and the combination of the antipsychotic aripiprazole with escitalopram reversed the inhibitory action of the antidepressant on firing (Chernoloz et al., 2009). The combination of fluoxetine with olanzapine, another atypical antipsychotic, also induced an increase in extracellular dopamine in the prefrontal cortex, which was higher than either drug alone (Zhang, 2000). Prior to cART, patients with AIDS showed improvements in delirium after treatment with dopamine receptor antagonists haloperidol and chlorpromazine (Breitbart, 1996), but effects of these antipsychotics on depressive symptoms in the cART-treated population has not been investigated. While these treatments may be more effective in HIV-infected individuals, careful evaluation is warranted in older adults, as this population is vulnerable to the adverse effects of these drugs (Gareri, 2014), and HIV patients in general have a higher susceptibility to neuroleptic-induced extrapyramidal symptoms (Hill and Lee, 2013; Dolder et al., 2004).

The reduced DAT and dopamine found in chronically infected HIV patients with more severe cognitive and motor deficits, who are now more likely to be older adults, also suggests that they may benefit from treatment with dopaminergic agents. One study showed that sustained-release bupropion, a dopamine/norepinephrine reuptake inhibitor, is effective and well-tolerated for the treatment of depression in HIV-infected patients, regardless of length of HIV progression (Currier et al., 2003). Phenelzine and tranylcypromine, both monoamine oxidase inhibitors (MAOIs), have been shown to be effective in subpopulations of HIV-infected patients with depression (Watkins et al., 2011). Triple reuptake inhibitors, such as venlafaxine, inhibit the reuptake of serotonin, norepinephrine, and dopamine (Marks et al., 2008), and have the potential to be more beneficial in HIV-infected individuals than current first line therapies such as SSRIs. However, a drug-interaction study found that venlafaxine decreased the plasma concentration of the protease inhibitor indinavir (Levin, 2001), suggesting it may interfere with the action of cART.

Studies have also found improvement on mood response rates and cognitive performance in HIV patients after treatment with methylphenidate (Hinkin, 2001), dextroamphetamine (Wagner and Rabkin, 2000) and selegiline (No author, 1998). The compounds folic acid, L-methylfolate, or S-adenosyl-methionine (Table 1), which boost tetra-hydrobiopterin (BH4) activity and facilitate the synthesis of dopamine (Miller, 2008), have all shown efficacy as antidepressants (Papakostas, 2010; Godfrey, 1990; Ginsberg et al., 2011; Galizia, 2016). Additionally, studies of modafinil in HIV patients over 6 months showed that those still taking modafinil had a decline in HIV RNA viral load, more energy and fewer depressive symptoms (Rabkin, 2010). However, a number of dopamine-altering antidepressants have also been shown to disrupt the immune system and alter the production of inflammatory modulators (Martino, 2012). In clinical trials in HIV-infected individuals, the MAOI selegiline showed no neurological benefit (Evans, 2007; Schifitto, 2009). A number of studies also indicate that selegiline and levodopa further exacerbate neurotoxicity and disease progression in a model of neuroAIDS (Czub, 2004; Czub, 2001). As these drugs increase dopamine levels, it is possible that increases in replication or inflammation (Nolan, 2018; Gaskill, 2009; Gaskill, 2014) could counteract any beneficial effects of this treatment. Overall, these studies suggest that the dopamine-mediated effects of antidepressants in older people living with HIV could substantially influence both depression and NeuroHIV, but that more research is needed to understand both the benefits and risks of using specific antidepressants in this population.

5.2. Impact of antidepressants on HIV pathogenesis

Few studies examine whether antidepressants directly affect the HIV replication process, but those that have been performed suggest that they may, although the specific effects and mechanisms remain unclear. Derivatives of paroxetine and femoxetine have been shown to directly inhibit HIV replication (Kristiansen and Hansen, 2000), and other studies report increased viral suppression and CD4⁺ T cells in HIV patients taking antidepressants (Pence, 2015). Citalopram decreases HIV infection in primary human macrophages and T-cell lines (Benton, 2010), possibly through a decrease in the expression of HIV receptor and coreceptor mRNA (Greeson, 2016). Serotonin itself has been shown to both increase and decrease HIV infection (Sidibe, 1996; Manéglier, 2008), elevated plasma serotonin is correlated with more effective viral suppression by cART (Miguez-Burbano, 2014), and prior to cART, the level of plasma serotonin in infected individuals is also inversely correlated with neuropsychiatric symptoms and disease severity (Launay, 1988; Launay, 1989).

As we and others have shown that dopamine can increase HIV replication, antidepressants that increase dopamine could also have a similar effect. In the cART era, and especially in the older, HIV-infected population, chronic inflammation is a central driver of disease, and antidepressants can also directly affect immune function. Reductions in cytokines such as IL-4, IL-6, IL-1β, TNF-α and IL-10 have been demonstrated after SSRI treatment (Wiedlocha, 2018; Kohler, 2018; Warner-Schmidt, 2011), although this does not always correlate with decreased depressive symptoms (Strawbridge, 2015; Hannestad et al., 2011). The TCAs clomipramine and imipramine as well as the SSRI fluoxetine may have anti-inflammatory and neuroprotective effects via modulation of glial activation (Hwang, 2008; Obuchowicz, 2014). Bupropion has been shown to suppress Th1 and Th17 immune responses (Ebbinghaus, 2012; Jha, 2017), and pramipexole, a dopamine agonist with evidence of efficacy in treatment-resistant depression (Fawcett, 2016), has been shown to inhibit the production of IL-17 (Lieberknecht, 2017). More research is needed to evaluate the specific effects of antidepressants on HIV replication and chronic inflammation, focused on both the impact on HIV pathogenesis and the effectiveness of antidepressants in the aging HIV population.

5.3. Neuropsychiatric effects of cART in the aging population

The primary function of cART drugs is viral suppression, but antiretroviral treatment can also ameliorate depressive symptoms and increase medication adherence in association with restored immune activity (Gutiérrez, 2014; Tsai, 2010). However, many other studies have found cART has no effect or adverse effects on depression. For example, initiation or changes in cART treatment can induce depression (Hill and Lee, 2013; Kaestner, 2012), and cART may also precipitate or worsen cognition, mood, and daily functioning (van der Lee, 2007; Ellis, 2010; Letendre, 2010). Depression can also inhibit the restoration of immune function, suggesting a reciprocal interaction between the effects of depression and cART on immune activation (Alciati, 2007; Hartzell et al., 2008). Further, as depression is associated with inflammation, the exacerbated myeloid inflammation associated with HIV, aging and cART may contribute to the development of this disease (Rivera-Rivera, 2016).

Neuropsychiatric symptoms from cART start anywhere within hours to months after initiation of cART, and can be transient or long-lasting, making the precise mechanisms underlying these side effects unclear (Kaestner, 2012; Gelmon, 1989). Several cART drugs in particular have been reported to induce neurological complications, although studies on the neuropsychiatric and inflammatory effects of specific cART drugs, are scarce, particularly in older adults. Specifically, efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor (NNRTI), causes neuropsychiatric adverse events (NPAEs) in a substantial number of patients, in particular increasing the risk for depression (Mollan, 2014; Silveira, 2012). In older adults, these effects may be partially mediated by slower metabolism of efavirenz, as this contributes to loss to care in an older population (Torgersen, 2019), and speed of efavirenz metabolism was positively correlated with better neuropsychological performance in older adults (Sandkovsky, 2017). In rats, efavirenz and efavirenz-containing regimens induce depressive-like behavior and lead to increases in IL-1β and TNF-α, and oxidative stress, suggesting an association with increased inflammatory activity (Akang, 2019; O’Mahony, 2005).

Two nucleotide reverse transcriptase inhibitors (NRTIs), including the first antiretroviral drug approved to treat HIV, zidovudine, are also associated NPAEs. Zidovudine has been shown to induce manic episodes following treatment, even in patients with no previous psychiatric history (Wright, 1989), while the NRTI abacavir (ABC) is associated with depression, fatigue, headache and psychotic symptoms (Colebunders, 2002; Foster et al., 2004). Recent studies show the second-generation integrase strand transfer inhibitor (INSTI) dolute-gravir (DTG), which is currently part of the recommended first line ART-regimen for adults, can also induce NPAEs. The effects of dolute-gravir include severe depression, as well as insomnia, anxiety and suicidality (Fettiplace, 2017; Scheper, 2018; Llibre, 2019), and one study observed 3-fold higher discontinuation rates for dolutegravir containing regimens in the older population because of NPAEs (Hoffmann, 2017). And while Truvada, a popular pre-exposure prophylaxis (PrEP) formulation has not been shown to cause depression (Defechereux, 2016), both of the drugs comprising this therapy, emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF), have shown depressive side effects (Arribas, 2008; Pozniak, 2006). Altogether, these studies underscore the need for more research on the role of cART drugs in the development of NPAEs, particularly depression in the older, HIV-infected population.

5.4. Dopaminergic effects of cART

As alterations in dopaminergic neurotransmission are strongly correlated with depression, it is likely that changes in this neurotransmitter are involved in the neuropsychiatric impact of cART. Very few studies have directly examined the effects of cART on the dopaminergic system, but those that have do show some cART drugs could have a substantial impact on dopamine. Efavirenz, which is strongly implicated in a number of neuropsychiatric complications in people living with HIV (Mollan, 2014; Silveira, 2012), has been shown to block presynaptic DAT (Gatch, 2013), inhibit MAO-A, and upregulate MAO-B (Akang, 2019; Dalwadi, 2016). Further, acute treatment with efavirenz can increase striatal levels of dopamine and decrease turnover rate which was associated with anxiety-like behaviors in rats, and subchronic efavirenz reduced the striatal levels of dopamine and increased the turnover rate which was associated with depressive-like effects (Cavalcante, 2017). In mice prenatally exposed to zidovudine, D1-like receptor signaling is hyporesponsive (Venerosi, 2005), while a number of protease inhibitors (PIs), particularly lopinavir, inhibit the activity of PMAT, a secondary monoamine uptake system (Duan, 2015). Further, CCR5 can be modulated by dopamine (Basova, 2018), and in a primate model of Parkinson’s, the entry inhibitor (EI) maraviroc actually protected from depletion of neurotransmitters and deterioration of the substantia nigra, improving locomotor function (Mondal, 2019). These different alterations in the dopaminergic system and subsequent behaviors suggest that the dopamine-modulating effects of cART may be involved in the emergence or disappearance of different types of neuropsychiatric adverse effects in HIV-infected patients. As some studies have shown that effective viral suppression correlates with less dopaminergic injury (Wang, 2004), future studies are warranted to evaluate HIV patients before and after antiretroviral treatment to better determine the effect of cART on dopaminergic circuits.

5.5. Interactions of cART, antidepressants and dopamine in the aging population

Combining neuropsychiatric treatment and cART can be of great benefit with respect to both HIV infection and depression. HIV-infected patients suffering from depression and treated with antidepressants are more likely to receive appropriate care for HIV than untreated subjects (Sambamoorthi, 2000), and adherence to cART has been shown to be higher in patients that are adherent to antidepressants (Walkup, 2008; Yun, 2005). Many studies show effectively treating depressive symptoms in the infected population reduces the incidence of medical complications and improves prognosis and quality of life (Watkins et al., 2011; Fulk, 2004). However, pharmacological interactions between cART and antidepressants have to be more carefully considered in order to successfully treat both HIV infection and depression. Additional consideration is needed in aging HIV individuals, where pharmacokinetic alterations with aging can result in changes to both body composition and function of drug-eliminating organs (Mangoni and Jackson, 2004; Shi and Klotz, 2011). The majority of clinical studies of antiretroviral therapy have not specifically evaluated patients over 50 years old, and therefore do not show adverse effect rates in older versus younger patients. The available studies of drug interactions often focus on healthy, younger patients without polypharmacy and with minimal or limited comorbid conditions or organ compromise, generating conclusions that may not be applicable to an older population. Currently, the best recommendations for treatment with antidepressants in older individuals are to start at low doses, and titrate slowly, especially in those with advanced illness or complex medication regimens (Burgess et al., 2015; Arseniou et al., 2014). Other treatment strategies such as cognitive behavioral therapy to reduce depressive symptoms may also be beneficial in the aging HIV population, in order to avoid drug interactions (Spies et al., 2013).

While there are many reported interactions between cART and antidepressants (Lefkowitz, 2007), most are in reference to interference with cytochrome p450 enzymes, particularly in respect to changes in drug exposure (Gleason et al., 2013; Thompson, 2006). This is particularly true with the use of pharmacokinetic boosters such as ritonavir (RTV), as this increases exposure times for a large number of antidepressants (Yanofski and Croarkin, 2008). Treatment with NNRTIs such as efavirenz and etravirine (ETV) can also lead to subtherapeutic concentrations of antidepressants. For example, taking trazodone in combination with ritonavir slowed clearance of trazodone and resulted in nausea, dizziness, and hypotension (Greenblatt, 2003), while in vitro studies indicate ritonavir, nelfinavir, and efavirenz all inhibited bupropion hydroxylation, suggesting the potential for increased levels of bupropion (Hesse, 2001).

The available literature on both HIV and cART altering the dopaminergic system, along with the clear dopamine-modulating properties of antidepressants (Table 1), warrants consideration of cART-antidepressant effects on the dopaminergic system. Increased or decreased exposure to these drugs through cytochrome p450 interactions could negatively impact treatment outcomes due to too much or too little production of dopamine. Timing and dosing of both types of drugs is also of major importance because dopamine can fluctuate throughout the course of infection, so poorly timed changes due to therapeutic use could render the drugs ineffective or potentiate the impact of dopamine disease progression. For example, during initial infection, enhanced dopamine availability in subcortical regions due to hypermetabolism may increase HIV replication and inflammatory cytokine production, an effect that could be potentiated by the use of therapeutics that enhance dopamine release. Or use of anti-depressants that stimulate dopamine release later in disease, during dopamine hypometabolism, may be ineffective between of the degradation of the dopaminergic system. Alternatively, a combination of cART and antidepressants reduces dopamine levels during a later stage of HIV infection could further precipitate neuropathology and create a Parkinson’s-like state in sensitive individuals. In addition, the negative effects of drugs that enhance dopamine may not be limited to the brain, as we and others have recently discussed the important role of dopamine in peripheral homeostasis (Matt and Gaskill, 2019; Rubí and Maechler, 2010; Zhang, 2017), and the effects of dopamine-modulating drugs in the periphery is very poorly understood. Increases in dopamine in peripheral regions such as the kidneys and lungs could increase viral replication and accelerate the development of HIV-related pathologies in these organs, as well as affect inflammatory pathways in peripheral organs that can signal to the CNS to cause additional damage leading to neuropsychiatric symptoms (Matt and Gaskill, 2019). Therefore, the drug combinations in the clinical management of HIV-infected patients has to be reconsidered in light of their effects on different dopaminergic circuits and the immunologic and inflammatory impact of those changes.

6. Additional considerations

The number of possible interactions between anti-depressants, cART drugs and dopamine in the aging, HIV-infected population is vast and very poorly studied, so a substantial amount of research is still needed in this area. However, there are a few considerations that are particularly important in this population. First, the nexus of these factors should be considered in the context of substance abuse, because unlike the general population where substance abuse rates decline in people over age 50, older HIV-positive patients maintain steady rates of substance abuse and dependence (Justice, 2004; Pappas and Halkitis, 2011). Chronic alcohol abuse and illicit drug use are also associated with a greater number of comorbid conditions in older HIV patients, including depression and cognitive disorders (Chiesi, 1996; Sullivan, 2011). Although described extensively elsewhere (Nolan and Gaskill, 2018; Gaskill, 2013), it is important to emphasize that exposure of HIV-infected patients to drugs of abuse also increases extracellular dopamine in the CNS (Table 1) to the levels needed to increase HIV entry and replication as well as production of cytokines, creating a synergistic negative impact on the CNS. These changes in dopamine may be associated with the higher prevalence and increased severity of cognitive dysfunction and depression also seen among drug abusers (Durvasula and Miller, 2014; Springer et al., 2009). Some research has also found enhanced sensitivity to antidepressants in active drug-abusing, HIV-infected individuals, potentially potentiating these effects. For example, an enhanced sensitivity to benzodiazepines in cocaine abusers (Volkow, 1998), SSRI-associated increases in cocaine-induced toxicity through monoaminergic mechanisms that include dopamine (O’Dell et al., 2000). Further, patients with depression and psychiatric comorbidities relating to illicit drug use are less likely to receive and respond to antidepressant treatment (DiPrete, 2019), compounding disease progression.

Second, the role of dopamine in HIV neuropathogenesis suggests that other dopamine-modulating therapeutics not prescribed for depression but often prescribed for other age-related comorbidities (Table 1) have the also have the potential for adverse interactions. For example, metoclopramide, a dopamine D2-like receptor antagonist used to treat nausea and migraines, can induce depressive and extrapyramidal symptoms in individuals with HIV (Hollander, 1985; Dahl and Diskin, 2014). New antidepressants should also be evaluated for their dopamine-associated properties and potential effects on this population. For example, ketamine, similar to esketamine, an active enantiomer of ketamine, which was recently approved by the FDA to treat depression, significantly increases dopamine and dopamine receptor levels across the rodent brain (Belujon and Grace, 2017; Kokkinou et al., 2018; Ma, 2015). Agomelatine, a potent melatonin receptor agonist and selective antagonist of the 5-HT2C receptors which is used to treat MDD (Taylor, 2014), can also increase dopamine and norepinephrine (Millan, 2003). Agomelatine increases the number and bursting of spontaneously active dopaminergic neurons (Chenu et al., 2013), with effects on neuronal plasticity in the prefrontal cortex, hippocampus, and amygdala (Dagyte, 2010; Ladurelle, 2012), which are important for modulating dopaminergic activity.

Third, to leverage multiple studies to support accurate, population level analyses, future studies need to emphasize comparability between experimental methodology. The inclusion of psychiatric disorders and standardized measures of peripheral inflammation, such as C-reactive protein or IL-6 will be tremendously useful, as will the use of rigorously validated measurements for a diagnosis. As the number of different drugs being used proliferates, especially in aging populations, a medication history listing prescribed and over the counter medications will also be invaluable, as this may lead to identification of unknown drug-drug or drug-disease interactions. And finally, to take better advantage of the data resulting from large meta-analyses, greater emphasis should be placed on expansion of in vitro mechanistic studies assessing drug-drug interactions in the context of HIV and depression, and proper validation of these studies in human populations. Human studies should take better advantage of collecting PBMCs, CSF, postmortem tissue, or plasma, and assess parallel measurements of inflammatory markers, dopamine, dopamine metabolites, or phenylalanine/tyrosine ratios, which are related to dopamine production and have been shown to be altered in HIV patients (Cassol, 2014; Zangerle, 2010; Nixon and Landay, 2010). This could allow for better understanding of patients regarding their potential responses to dopaminergic treatment regimens.

7. Conclusion

Although the prognosis of people living with HIV has improved dramatically over the past few decades, increased rates of comorbidities such as depression and neurocognitive dysfunction as this population ages poses challenges to effective treatment. In the era of polypharmacy, the increased risk of drug-related complications and exacerbation of comorbidities must be considered when choosing an appropriate cART or anti-depressant regimen. Better clinical management with careful monitoring and emphasis on personalized medicine is required, but this will require an expansion of current research, as the studies to support these requirements do not currently exist. A better understanding of dopamine-associated impact of cART, anti-depressants and other neuropsychiatric therapies is critical to understanding the association of depressive-like symptoms with particular inflammatory or neuropathogenic effects. Specific studies will be required to define the impact of therapeutic changes on dopamine in the context of the abnormal dopaminergic signaling and immune responses present older HIV-infected individuals with co-morbid depression. Further, the association of HIV and depression with inflammation and dysfunction of dopamine must be carefully considered to minimize side effects. Active consideration of all of these factors could help to reduce drug-drug interactions, ameliorate inflammation and potentially identify novel therapies for both depression and HIV-neuropathogenesis. Further, these types of studies will greatly advance our understanding of the complex interplay by which depression and NeuroHIV interact, paving the way toward the development of personalized multidisease treatment regimens.

HIGHLIGHTS.

• Depression, and its treatment, is a major factor in the progression of HIV.

• Depression, NeuroHIV, and their therapies impact the dopaminergic system.

• Dopamine associated inflammation may link the etiology of NeuroHIV and depression.

• Dopamine changes due to cART-antidepressant interaction can exacerbate NeuroHIV.

• Managing cART-antidepressant interactions is crucial to healthy aging with HIV.

Abbreviations

AD

Alzheimer’s disease

ADHD

attention deficit hyperactivity disorder

AZT

zidovudine

BBB

blood brain barrier

BH4

tetrahydrobiopterin

cART

combination antiretroviral therapy

CNS

central nervous system

CSF

cerebrospinal fluid

d4T

stavudine

DAT

dopamine transporter

DTG

dolutegravir

EFV

efavirenz

ETV

etravirine

FTC

emtricitabine

GAD

generalized anxiety disorder

HAD

HIV-associated dementia

HAND

HIV-associated neurocognitive disorder

HPA

hypothalamic-pituitary axis

HVA

homovanillic acid

IDO

indoleamine 2,3-dioxygenase

IL

interleukin

ISTI

integrase strand transfer inhibitor

LPV

lopinavir

MAO

monoamine oxidase

MDD

major depressive disorder

MDM

monocyte derived macrophages

NFV

nelfinavir

NLRP3

NLR family pyrin domain containing 3

NNRTI

non-nucleoside reverse transcriptase inhibitor

NO

nitric oxide

NPAE

neuropsychiatric adverse event

OCD

obsessive compulsive disorder

PBMC

peripheral blood mononuclear cells

PD

Parkinson’s disease

PMAT

plasma membrane monoamine transporter

RLS

Restless leg syndrome

ROS

reactive oxygen species

RTV

ritonavir

SIV

simian immunodeficiency virus

SNRI

serotonin/norepinephrine reuptake inhibitor

SSRI

selective serotonin reuptake inhibitor

TCA

tricyclic antidepressant

TDF

tenofovir disoproxil fumarate

TH

tyrosine hydroxylase

VMAT2

vesicular monoamine transporter 2