Neuroinflammatory responses likely play a central role in the neuropathology of HIV-associated depression ( Figure 2 ). The complex interplay between immune suppression and activation, elevated peripheral pro-inflammatory cytokines and other inflammatory markers, and cytokine involvement in neurophysiology suggests that inflammation is a key pathological mechanism underlying depression (73–76). Research has shown that low-grade inflammation and excessive cytokine secretion in peripheral blood are closely linked to HIV-associated depression (77). The “cytokine hypothesis of depression” proposes that inflammatory cytokines act as neuromodulators, influencing behavior, neuroendocrine function, and neurochemical characteristics associated with depression (78, 79). Clinical studies consistently report elevated levels of pro-inflammatory cytokines and other inflammatory markers, such as IL-1β, IL-6, CRP, and TNF-α, in individuals with depressive symptoms (80–82). Additionally, exogenous inflammation induction can lead to the development of core depressive features (83).

In HIV-infected individuals, the brain is a primary target for the virus, predominantly affecting perivascular macrophages, microglia, and astrocytes (84, 85). For instance, HIV-1 envelope glycoprotein 120 (gp120) activates microglial cells via the TLR2-NF-κB signaling pathway, triggering NLRP3 inflammasome activation and pro-inflammatory cytokine secretion (53, 55). Other viral proteins, such as HIV-Tat and Vpr, further activate microglial cells through multiple signaling pathways, exacerbating inflammatory responses and neurotoxicity, which leads to neuronal dysfunction and severe CNS damage (52, 54, 56). The synergistic effects of these viral proteins highlight the complexity of HIV-induced CNS damage, involving intricate inflammatory and neurotoxic pathways.

In an inflammatory state, microglia and astrocytes further amplify the secretion of pro-inflammatory cytokines such as IL-1β, IL-6, IL-18, and TNF-α (86). IL-1β and TNF-α regulate the expression of glutamate (Glu) receptors and enhance Glu release, causing excessive accumulation of Glu in the synaptic cleft. This not only promotes further cytokine release from glial cells but also amplifies inflammatory signaling within the CNS. Additionally, these cytokines trigger the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), directly damaging neurons and inducing oligodendrocyte apoptosis (87, 88). Chronic inflammation and TNF-α release by hyperactivated glial cells exacerbate neuroimmune activation by promoting oligodendrocyte apoptosis and demyelination, thereby contributing to progressive CNS damage (89, 90).

Metabolic dysregulation plays a critical role in HIV-associated depression. Depression itself is closely linked to impaired serotonin (5-HT) function, and HIV infection may exacerbate this through several pathways, including inflammation and stress. One such pathway is the metabolic shift from tryptophan (TRP) to kynurenine (KYN), which has been strongly associated with depression development (91, 92). As a precursor to 5-HT, the diversion of TRP towards the KYN pathway reduces 5-HT synthesis while promoting the overproduction of the neurotoxic metabolite quinolinic acid (QUIN), further amplifying neuroinflammation and neurotoxicity (93, 94). Inflammatory cytokines activate indoleamine 2,3-dioxygenase (IDO) via signaling pathways such as STAT1α, IRF-1, p38 MAPK, and NF-κB, driving this metabolic shift and contributing to neurotransmitter dysfunction linked to depression (95–97).

Although cART enables most PLWH to achieve viral suppression, some patients still exhibit residual neuronal dysfunction and abnormalities in neuroinflammatory biomarkers. In untreated HIV-1-infected individuals, CSF levels of sTREM2 not only increase with disease progression (as indicated by CD4⁺ T cell depletion) but are also closely associated with NfL levels (98). While PLWH who achieve viral suppression show an overall decrease in sTREM2 levels, neurodamage biomarkers, such as NfL, can still be detected, suggesting the presence of irreversible damage or low-level persistent inflammation (69–71). These changes are not only closely linked to the severity of depression but may also exacerbate HIV-related cognitive and emotional impairments.

HIV infection and inflammatory states also disrupt the balance of brain metabolites. Elevated levels of neurometabolites, such as myo-inositol (mI), have been linked to both the incidence and severity of depression (99). While cART partially mitigates HIV-induced neuroinflammation and metabolite changes (67, 100), neuronal dysfunction (evidenced by reduced N-acetylaspartate [NAA]) and neuroinflammation (indicated by increased mI and choline [Cho]) persist in chronically infected individuals, often accompanied by axonal damage (68, 100).

In summary, HIV disrupts the balance between neuroprotection and neurotoxicity within the CNS through neurotransmitter dysfunction, metabolic dysregulation, and the sustained elevation of pro-inflammatory cytokines. The excessive activation of microglia and astrocytes, driven by inflammation, amplifies these processes, ultimately contributing to the onset of depression.

Microglial activation linked to depression primarily occurs in the prefrontal cortex, insula, and anterior cingulate cortex, with neuronal and synaptic damage resulting from this activation serving as a key trigger for depressive-like behaviors. This activation is strongly associated with neuropsychiatric disorders, including depression and anxiety (101, 102). The process typically involves the secretion of pro-inflammatory cytokines, which initiate both peripheral and central inflammation. In HIV infection, glucose metabolism is significantly upregulated, as evidenced by increased glucose transport and metabolic flux (103, 104). This metabolic alteration is closely tied to heightened production of pro-inflammatory cytokines, such as CRP, TNF-α, and IL-6 (105, 106). These cytokines can cross the blood-brain barrier and affect key brain regions like the amygdala, hippocampus, hypothalamus, and cortex, influencing pathophysiological processes associated with depression, including neurotransmitter metabolism, neuroendocrine function, and neuroplasticity (107). These disruptions further impair mood and cognitive function, providing a critical pathological basis for depression.

Although the neurotoxicity of the latest generation of ART has been significantly reduced, treated individuals still exhibit metabolic abnormalities. These metabolic shifts may perpetuate inflammation and immune dysfunction, thereby increasing the risk of depression (108). Notably, while ART partially normalizes certain depression-related inflammatory cytokines in HIV-infected individuals, others, such as IL-6 and CRP, remain elevated (109, 110). Further research has highlighted significant changes in CNS metabolites in ART-treated PLWH through CSF metabolomics, including alterations in neurotransmitters (e.g., Glu and NAA), microglial activation markers (e.g., mI), and ketone bodies (e.g., β-hydroxybutyrate and 1,2-propanediol) (111). These alterations suggest ongoing inflammation, microglial activation, and glutamate-mediated neurotoxicity (111). Despite improvements in viral control and immune function, studies indicate that HIV-associated cognitive impairments and brain inflammatory changes persist in PLWH (67). These findings suggest that ART does not fully resolve CNS pathological changes induced by HIV infection, with underlying mechanisms likely related to persistent inflammation and metabolic dysregulation.

The hypothalamic-pituitary-adrenal (HPA) axis plays a critical role in regulating the stress response through the coordinated interaction of the hypothalamus, pituitary gland, and adrenal glands. Under stress, the hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary to secrete adrenocorticotropic hormone (ACTH), ultimately prompting the adrenal glands to release cortisol. Cortisol, in turn, modulates the secretion of CRH and ACTH through a negative feedback mechanism to maintain homeostasis. In PLWH, prolonged activation of the HPA axis can occur due to various stressors, such as emotional stress (e.g., death anxiety, stigma, and discrimination) and economic pressure. These factors exacerbate psychological burden and disrupt neuroendocrine function through abnormal cortisol levels (112). Research has shown that PLWH are particularly susceptible to HPA axis dysfunction and fatigue, heightening the risk of HIV-associated mood disorders (113, 114). For instance, the HIV-Tat protein, in response to stress, can induce neurodegeneration and impair HPA axis function, leading to excessive activation and elevated cortisol levels—key mechanisms driving HIV-related neuroendocrine dysfunction and mood symptoms (115, 116). However, studies on HPA axis alterations in PLWH remain scarce, warranting further investigation into the underlying mechanisms and their impacts.

Selective serotonin reuptake inhibitors (SSRIs) represent an important treatment strategy for managing HIV-associated depression by improving mood symptoms while also modulating neuroinflammation and neurodegeneration. SSRIs exert their therapeutic effects primarily by inhibiting the reuptake of 5-HT into presynaptic neurons, which results in increased 5-HT concentrations in the synaptic cleft. This boost in serotonin levels enhances binding to postsynaptic receptors such as 5-HT1A and 5-HT2A, thereby facilitating improved signal transmission (117, 118). With prolonged use, the enhanced 5-HT signaling helps regulate neural network function, leading to clinical improvements in mood disorders like depression and anxiety. In addition to their mood-regulating effects, SSRIs may also have anti-inflammatory and neuroprotective properties, making them a promising adjunctive therapy for depression in PLWH through their anti-inflammatory and neuroprotective effects (119). Studies have shown that SSRIs can reduce CNS inflammation and neuronal damage. For example, escitalopram has demonstrated the ability to repair HIV-1-mediated neuronal damage and improve neurological function (120). SSRIs may also downregulate the expression of CD4 receptors and chemokine receptors, reducing immune cell susceptibility to HIV infection, further supporting their potential as adjunctive therapies (121). However, despite the benefits, long-term SSRI use can lead to alterations in 5-HT receptor sensitivity, which may trigger side effects such as sexual dysfunction, mood fluctuations, weight changes, and even drug resistance (122). These potential adverse effects require careful monitoring and consideration in clinical practice.

Selective norepinephrine-serotonin reuptake inhibitors (SNRIs) enhance neurotransmitter concentrations in the synaptic cleft by inhibiting the reuptake of 5-HT and norepinephrine (NE), thus improving mood and alleviating depressive symptoms (123). Compared to SSRIs, SNRIs may offer superior efficacy in treating depression and anxiety, particularly in cases linked to NE deficiency. Mirtazapine, for example, due to its sedative and appetite-stimulating properties, coupled with relatively mild gastrointestinal side effects, may be preferred over SSRIs in certain patient populations (124). Additionally, SNRIs exert beneficial effects by reducing neuroinflammation through inhibition of pro-inflammatory cytokine release and modulation of inflammatory pathways, demonstrating significant efficacy in patients with major depressive disorder (125–127). However, prolonged SNRI use in HIV-associated depression treatment may lead to adverse reactions, such as drug interactions, liver toxicity, and withdrawal symptoms. Venlafaxine, for instance, has been associated with increased risk of sexual dysfunction, anorexia, nausea, and insomnia (128). Withdrawal reactions, including dizziness, anxiety, and emotional instability, have also been reported with SSRIs and SNRIs (e.g., venlafaxine and paroxetine) (129, 130), underscoring the importance of a gradual tapering process to prevent abrupt discontinuation. In conclusion, while SNRIs present distinct advantages in the treatment of depression, their potential adverse effects and drug interactions must be meticulously managed to ensure clinical safety and efficacy.

The concomitant use of SSRIs or SNRIs with ART drugs may lead to altered plasma concentrations and clinical adverse reactions. Most antidepressants are substrates of CYP2D6, CYP2B6, or CYP3A4, and interactions between certain ART drugs and antidepressants are primarily mediated through the CYP450 enzyme system. Protease inhibitors (PIs) and NNRTIs can significantly alter antidepressant concentrations by inhibiting or inducing these isoenzymes. Studies have shown that high-dose ritonavir can cause significant changes in the area under the curve (AUC) and maximum plasma concentration of desipramine and trazodone (131). Additionally, the combination of fosamprenavir-ritonavir may reduce the AUC of paroxetine by up to 55% (132). Furthermore, case reports suggest that co-administration of darunavir/ritonavir with duloxetine and aripiprazole may increase duloxetine exposure due to slowed metabolism and elevate the risk of aripiprazole toxicity (133). Therefore, for HIV-infected individuals with impaired liver function, the following measures are recommended: 1) avoid the concomitant use of potent CYP inhibitors (e.g., high-dose ritonavir combined with fluoxetine may trigger serotonin syndrome (134)); 2) regularly monitor liver function and drug concentrations; 3) closely monitor patients for drug-related adverse events when initiating antidepressant therapy and adjust the antiretroviral treatment regimen dosage based on individual responses.

Agomelatine (AGM) is an innovative antidepressant with a distinct mechanism of action, involving the activation of melatonin receptors (MT1/MT2) and inhibition of 5-hydroxytryptamine 2C receptors (5-HT2C). This dual action effectively regulates circadian rhythms while enhancing mood and sleep functions, making AGM particularly suitable for patients with depression accompanied by sleep disturbances or circadian rhythm disruptions (135). Additionally, AGM promotes neuroplasticity by activating melatonin receptors and upregulating brain-derived neurotrophic factor (BDNF) expression, demonstrating notable therapeutic effects in patients with depression linked to sleep disorders and neurofunctional impairments (136). Research indicates that AGM is generally well-tolerated, although it may lead to elevated liver enzyme levels; therefore, regular liver function monitoring is advised during the early stages of treatment (137). However, the use of AGM presents certain limitations (138): first, its efficacy depends on the extent of circadian rhythm disruption and the patient’s specific condition, with more pronounced effects seen in those with significant circadian disturbances; second, while its sleep-enhancing effects are rapid, antidepressant effects typically take several weeks to manifest, similar to other antidepressants.

Recent studies have highlighted that depression is not only a mental disorder linked to neurotransmitter imbalances but also closely associated with chronic low-grade inflammation. This insight suggests that anti-inflammatory agents could serve as potential adjunctive treatments for depression. Previous research has shown that various anti-inflammatory drugs, including non-steroidal anti-inflammatory drugs (NSAIDs), statins, cytokine inhibitors, glucocorticoids, and minocycline, demonstrate therapeutic potential in alleviating depression and its associated symptoms (139). As noted, depression is strongly connected to chronic inflammation, and NSAIDs, by inhibiting cyclooxygenase (COX) activity and reducing prostaglandin (PG) synthesis, indirectly regulate the NF-κB signaling pathway, thus decreasing the release of pro-inflammatory cytokines like interleukins and TNF-α, which may mitigate the inflammatory responses involved in depression (140). While earlier studies suggested that NSAIDs might have minimal effects on depressive symptoms (141), more recent research indicates that anti-inflammatory treatments, including NSAIDs, can improve depressive symptoms in patients with MDD (139, 142). However, further studies are needed to identify specific patient subgroups who may benefit most from these treatments. Bai et al. also emphasized that NSAIDs, alongside other anti-inflammatory agents such as Omega-3 fatty acids, statins, and minocycline, exhibit antidepressant effects in both monotherapy and adjunctive therapy for MDD, with favorable safety profiles (143). Furthermore, TNF antagonists have shown promise as adjunctive therapies to enhance antidepressant efficacy in treatment-resistant depression (144), and patients with MDD may also benefit from corticosteroids and NSAIDs (145). However, the long-term use of NSAIDs is associated with gastrointestinal side effects (such as ulcers and bleeding), an increased risk of cardiovascular events, and renal dysfunction. Consequently, NSAIDs are typically regarded as adjunctive treatments rather than primary therapeutic options for depression.

Statins may play a potential role in the adjunctive treatment of depression through several mechanisms, including anti-inflammatory effects, enhancement of cerebrovascular function, and neurovascular protection (146, 147). Recent studies further support their application in the prevention and management of depression. A cohort study utilizing the UK Biobank, which involved over 360,000 participants, found that regular statin use was associated with a reduced risk of depression (HR = 0.87, 95% CI: 0.81 – 0.94), with consistent results in sensitivity analysis (148). Similarly, a Swedish registry study encompassing more than 1.14 million individuals corroborated this finding, revealing that statin use was linked to a reduced risk of depressive disorders (HR = 0.91, 95% CI: 0.87 – 0.94), a result that remained robust even after adjusting for antidepressant use (HR = 0.91, 95% CI: 0.88 – 0.94) (149). Moreover, a comparison between fluoxetine monotherapy and combination therapy with high-dose atorvastatin (80 mg/day) demonstrated a reduction in pro-inflammatory cytokines and other pro-inflammatory cytokines and other inflammatory markers such as NLRP-3 and IL-6, as well as improved Hamilton Depression Rating Scale scores (150). These findings suggest that atorvastatin may be a promising adjunctive therapy for patients with MDD by modulating the AMPK/NLRP3 and IL-6/STAT-3 signaling pathways (150). Although these studies provide compelling evidence for the potential of statins in depression prevention and intervention, the pharmacokinetic properties and drug interaction risks of statins require careful consideration. Statins such as simvastatin, lovastatin, and atorvastatin are primarily metabolized via CYP3A4. When co-administered with strong CYP3A4 inhibitors (e.g., ritonavir, saquinavir), these statins may exhibit significantly increased blood concentrations, raising the risk of severe adverse effects such as rhabdomyolysis and liver damage (151). In contrast, statins with lower drug interaction risks, such as pravastatin and rosuvastatin, are cleared via non-hepatic enzymes and may be more suitable for special populations, including PLWH. Therefore, for patients requiring concomitant use of CYP3A4 inhibitors, pravastatin or rosuvastatin is preferred, with dose adjustments and close monitoring of muscle and liver function markers to minimize the risk of adverse effects.

As discussed in Section 3.4, PLWH who also suffer from depression often exhibit excessive activation of the HPA axis, leading to abnormally elevated cortisol levels. Consequently, interventions targeting the HPA axis are of considerable clinical and theoretical significance for treating depression, offering a scientific basis for optimizing antidepressant strategies and advancing personalized medicine. Cortisol, a central hormone in the stress response, when chronically elevated, can exert neurotoxic effects on brain regions such as the hippocampus and prefrontal cortex, which are essential for memory and emotional regulation. This prolonged exposure to elevated cortisol can lead to neuronal atrophy and functional impairment (152, 153). Mifepristone, a glucocorticoid receptor (GR) antagonist, exerts its therapeutic effects by blocking GR, thereby rectifying HPA axis overactivation, restoring negative feedback regulation, and lowering cortisol levels. This mechanism helps to reduce the stress-induced hyperactivity of the HPA axis, alleviate cortisol-induced neurotoxicity in the hippocampus and prefrontal cortex, and potentially provide neuroprotective effects in these regions (154, 155). In summary, mifepristone has shown potential efficacy in certain depression subtypes, such as treatment-resistant depression or cortisol-related depression. However, due to its antagonistic effects on progesterone receptors, its use in female patients, particularly those of reproductive age, warrants caution. While preliminary studies have shown promising results, its efficacy and safety must be confirmed through large-scale, long-term clinical trials to better define its practical application in depression treatment.

While pharmacological treatment remains the cornerstone of depression management in PLWH, concerns regarding its potential adverse effects—such as physical discomfort, sexual dysfunction, substance abuse, and overdose-related fatalities—along with the interactions between antidepressants and antiretroviral medications, and the risk of withdrawal and rebound phenomena, have prompted increasing interest in non-pharmacological treatments (131, 156). Non-pharmacological approaches, which include psychotherapy (e.g., cognitive-behavioral therapy) (157, 158), psychosocial support (e.g., meditation and yoga) (157–159), physical therapy (e.g., exercise) (160–162), and music therapy (163), have gained attention as complementary options. Clinical guidelines recommend psychotherapy and exercise therapy as first-line treatments, particularly for patients with mild to moderate depression (164). Studies indicate that exercise therapy offers significant benefits in addressing immune-mediated depression (IMD), particularly in patients with pronounced IMD features, and can serve as an alternative or adjunctive treatment to antidepressant medications (165). Moreover, a meta-analysis has demonstrated that resistance training provides clear antidepressant effects in patients without major physical comorbidities, highlighting its potential for clinical application in the comprehensive management of depression (166). These psychosocial intervention strategies are characterized by low technical requirements, high cost-effectiveness, and strong cultural adaptability, making them particularly suitable for implementation in resource-limited low- and middle-income countries. Overall, the increasing body of scientific evidence supports the integration of exercise therapy and psychotherapy as essential components of a comprehensive strategy for managing depression in PLWH.

Antiretroviral drugs used in the treatment of HIV infection include nucleoside reverse transcriptase inhibitors (NRTIs), NNRTIs, PIs, integrase strand transfer inhibitors (INSTIs), and fusion inhibitors. While these drugs effectively suppress HIV replication, lower viral load, enhance immune function, and significantly reduce the risk of drug resistance, certain medications, particularly NNRTIs, are associated with CNS toxicity, which may increase the risk of anxiety and depression (167, 168). These side effects can diminish treatment adherence, quality of life, and disease prognosis in PLWH, and may also lead to discontinuation of therapy. A prospective observational study involving 129 PLWH found that, on average, each participant experienced 2.4 neuropsychiatric disorders, with 89.9% of patients changing their treatment regimen due to symptoms such as sleep disturbances (75.2%), anxiety (65.1%), and depression (38.7%) induced by EFV (170). Another real-world study assessing discontinuation rates in patients on DTG-based regimens revealed that 13.7% of participants discontinued treatment due to intolerance, primarily due to neuropsychiatric symptoms such as sleep disturbances, anxiety, and depression (51).

Although CCR5 antagonists (e.g., Maraviroc), post-attachment inhibitors (e.g., Ibalizumab), and capsid inhibitors (e.g., Lenacapavir) hold significant therapeutic value in specific populations, their clinical use remains limited by targeted indication requirements and high treatment costs. Existing clinical trial data indicate that these three classes of drugs have not yet reported clinically significant neuropsychiatric side effects (169–171). However, their long-term neuropsychiatric safety in the real-world setting, particularly in individuals with comorbid mental health disorders, still requires further research for validation.

Maintaining good adherence to ART is a key factor in preventing viral rebound and associated neuroinflammation. It is important to note that depressive symptoms themselves may reduce medication adherence, highlighting the need for clinicians to closely monitor and intervene promptly when depressive symptoms occur in PLWH. For patients experiencing neuropsychiatric side effects, prompt adjustment of the treatment regimen is crucial to prevent further exacerbation of psychiatric symptoms. Studies have shown that compared to EFV(a NNRTI)-containing regimens, DTG (an INSTI)-based regimens, an integrase strand transfer inhibitor (INSTI), exhibit superior safety with a lower incidence of ADRs (172). According to the HIV Antiretroviral Therapy Guidelines for Adults and Adolescents, published by the U.S. Department of Health and Human Services (DHHS) on September 12, 2024, INSTIs such as DTG or bictegravir are recommended for ART due to their excellent virological suppression and favorable tolerability (173). Additionally, since the mechanism of action of NRTIs does not involve the CNS, they are particularly effective in minimizing neuropsychiatric symptoms. NRTIs are often combined with INSTIs, offering a lower risk of drug discontinuation due to toxicity and providing good overall treatment tolerability (174). In contrast, NNRTIs like EFV, which carry a higher risk of ADRs, should be used with caution in patients with existing neuropsychiatric symptoms. Overall, the combination of INSTIs and NRTIs is recommended to reduce the risk of psychiatric disorders, especially for patients with poor tolerance to other classes of drugs such as NNRTIs or PIs. It is particularly important to note that for PLWH presenting with unexplained cognitive impairment or neurological symptoms, even if plasma viral load is controlled, CSF HIV RNA quantification and drug resistance genotype testing should be considered to rule out the possibility of CSF viral escape (175).