Overview of the neuropsychiatric aspects of HIV infection and AIDS

INTRODUCTION — The high prevalence of neuropsychiatric disorders in individuals infected with HIV, is related to a wide variety of factors including direct effects of the virus, preexisting psychiatric conditions, personality vulnerabilities, affective disorders, addictions, and personal responses to the social isolation and disenfranchisement associated with the diagnosis of HIV. Furthermore, many HIV-infected persons experience difficulty with treatment adherence due to their behavior patterns as well as acquisition of specific neuropsychiatric disorders associated with HIV disease progression. Studies have shown that patients with neuropsychiatric conditions have poorer outcomes and less benefit from antiretroviral therapy; however, psychiatric treatment improves HIV-related outcomes [1].

Neuropsychiatric care in HIV disease ranges from supportive psychotherapy for grief and loss issues to treatment of specific HIV-associated neuropsychiatric conditions (eg, HIV-associated dementia, minor cognitive motor disorder [MCMD], acquired immunodeficiency syndrome [AIDS] mania), as well as management of unique clinical presentations of other psychiatric disorders such as depression and schizophrenia. The availability of effective psychiatric care to HIV-infected patients is critical for their treatment and also for controlling the HIV epidemic.

Mental disorders that are commonly comorbid with HIV disease include:

●Delirium

●MCMD

●HIV-associated dementia

●Major depression

●Bipolar disorder (including AIDS mania)

●Schizophrenia

●Substance abuse or dependence

●Posttraumatic stress disorder

An overview of the range of neuropsychiatric conditions associated with HIV infection will be presented here. More detailed reviews of these specific conditions are discussed separately. (See "HIV-associated neurocognitive disorders: Epidemiology, clinical manifestations, and diagnosis" and "Depression, mania, and schizophrenia in patients with HIV" and "Substance use disorder in patients with HIV".)

DELIRIUM — Delirium, a state of global derangement of cerebral function, occurs frequently in medically ill, brain-injured, or metabolically unstable patients. Delirium is characterized by inattention, disorganized thinking, confusion, emotional liability, and fluctuations in level of consciousness. Hallucinations and delusions are also common. The etiology of delirium is typically multifactorial, including elements of pharmacological toxicity, metabolic derangements, and sensory isolation due to illness and limited environmental stimulation. It is associated with high morbidity and mortality and should be diagnosed promptly and investigated thoroughly. In addition, delirium is associated with postdelirium psychiatric conditions such as posttraumatic stress disorder, suggesting a need for follow-up after an episode of delirium. (See "HIV-associated neurocognitive disorders: Epidemiology, clinical manifestations, and diagnosis" and "Diagnosis of delirium and confusional states".)

Due to the complexity and number of comorbid disorders, delirium is highly prevalent in HIV disease. Delirium is more common in older adults, those with brain injury (including dementia), posttransplant patients, hypoxic patients, and those with frequent intoxication. As an example, one study found that the incidence of delirium was modestly greater in aging patients with HIV than those without HIV [2]. The differential diagnosis of delirium in HIV-infected patients includes HIV-associated dementia, AIDS mania, minor cognitive motor disorder, major depression, bipolar disorder, panic disorder, and schizophrenia.

Delirium can usually be distinguished by its rapid onset, fluctuating level of consciousness, and link to a medical etiology. Common etiologies include:

●Toxic (eg, poisoning or medication toxicity, especially medications with potent anticholinergic activity)

●Metabolic

●Infectious, especially central nervous system (CNS) infection

●Endocrine (eg, thyroid and adrenal axes)

●CNS neoplasm

●Cardiovascular (eg, myocardial infarction or arrhythmia)

●Neurologic (eg, seizure or stroke)

●Pulmonary (eg, hypoxia or hypercapnia)

●Traumatic (eg, head injury or burns)

●Withdrawal from alcohol or medications

DEMENTIA — HIV infection is associated with multiple cognitive impairments. Early in the epidemic (1980s), a progressive subcortical dementing illness that was fatal was described and later termed AIDS-dementia. With the advent of effective antiviral therapy, rates of this condition diminished in developed settings, but some patients still develop cognitive impairment. The nosology was revised, such that the term HIV-associated neurocognitive disorder is used to describe the entire spectrum of HIV-associated neurocognitive impairment with subcategories of asymptomatic neurocognitive impairment, mild neurocognitive disorder, and HIV-associated dementia based on severity.

With the advent of antiretroviral therapy (ART), the pathogenesis of HIV-associated neurocognitive disorder is more often multifactorial and involves both cortical and subcortical changes in function [3]. Ongoing research suggests that plasma biomarkers (eg, exosomes) for HIV-associated neurocognitive disorders, which originate in the brain, may possibly serve as a marker of ongoing viral activity in the central nervous system and cognitive impairment [4].

HIV-associated dementia, the most severe form of HIV-associated neurocognitive disorder, must be distinguished from other causes of dementia including cytomegalovirus encephalitis, progressive multifocal leukoencephalopathy, cerebral toxoplasmosis, cryptococcal meningitis, and central nervous system lymphoma. (See "Approach to the patient with HIV and central nervous system lesions" and "Toxoplasmosis in patients with HIV" and "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV" and "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology".)

HIV-associated dementia usually occurs in patients with a CD4 count nadir <200 cells/microL. Risks factors for HIV-associated dementia include high serum or cerebrospinal fluid HIV viral load [5], low educational level, advanced age (see "HIV infection in older adults"), anemia, illicit drug use, and female sex. Since the introduction of potent ART, the incidence of HIV-associated dementia has declined, although not as much as some of the opportunistic infections. (See "HIV-associated neurocognitive disorders: Epidemiology, clinical manifestations, and diagnosis".)

MINOR COGNITIVE MOTOR IMPAIRMENT — Minor cognitive motor impairment (MCMD), cognitive impairment that approaches but does not meet diagnostic criteria for dementia [6], is less severe than HIV-associated dementia and emerges earlier in HIV disease. Symptoms of MCMD are subtle and often overlooked. It is not known whether MCMD predisposes to HIV-associated dementia. Some patients continue to have only minor problems while others progress to full dementia. (See "HIV-associated neurocognitive disorders: Epidemiology, clinical manifestations, and diagnosis".)

MAJOR DEPRESSION — Comorbid major depression (table 1) is common with HIV disease, both in those with HIV dementia and others, and depression hinders effective treatment of HIV-infected individuals, such that these patients are at significantly increased risk for HIV-disease progression and mortality [7-12]. Furthermore, depressive symptoms in patients with HIV worsen antiretroviral therapy adherence, while adherence to antidepressant therapy in HIV-positive individuals with depression reverses this trend [13,14]. HIV also increases the risk of developing depression through direct damage to subcortical brain areas, chronic stress, worsening social isolation and intense demoralization. Indeed, patients with symptomatic HIV disease are significantly more likely to undergo a major depressive episode than patients with asymptomatic HIV disease, or HIV-negative control study subjects [15]. Unfortunately, depression is underdiagnosed and undertreated in most medical clinics and has thus emerged as one of the most significant factors in the HIV/AIDS epidemic. (See "Depression, mania, and schizophrenia in patients with HIV".)

The differential diagnosis in HIV patients reporting depressive symptoms includes major depression, persistent depressive disorder (dysthymia), dementia, delirium, demoralization, intoxication, withdrawal, central nervous system (CNS) injury, CNS infection, and acute medical illness. HIV-associated dementia and other HIV-related CNS conditions can produce a flat, apathetic state often misdiagnosed as depression.

MANIA — Mania (table 2), which occurs in HIV-infected patients both as a component of bipolar illness and as the unique entity of AIDS mania, is associated with impulsivity, impaired judgment, and risk taking, all of which can lead to behavior that accelerates HIV-disease progression. Bipolar illness is broad in spectrum, ranging from a severely crippling and chronic mental illness to a mild disorder with alternating experiences of elevated or depressed mood. It is thus difficult to accurately measure the prevalence and incidence of bipolar disorder and it has also been difficult historically to distinguish severe bipolar illness from schizophrenia. Investigators looking at the relationship between HIV and mental illness have thus often simply employed the term "chronically mentally ill" for patients with severe disability from either schizophrenia or bipolar disorder. (See "Depression, mania, and schizophrenia in patients with HIV".)

AIDS mania is uniquely associated with late stage HIV infection. AIDS mania is characterized by typical mania and additional cognitive impairment in the setting of a lack of previous personal or family history of bipolar illness. AIDS mania has less euphoria and more irritability than the mania associated with illness, and is also far more chronic. In contrast to bipolar mania, AIDS mania usually does not remit if left untreated. The prevalence of AIDS mania has dropped significantly since the onset of potent antiretroviral therapy.

SCHIZOPHRENIA — Severe and chronic mental illness, historically encompassing schizophrenia (table 3) and bipolar I disorder, is estimated at prevalence rates from four to 19 percent in HIV patients. No evidence suggests that HIV causes schizophrenia, but data do suggest that schizophrenia contributes to high-risk behavior associated with HIV infection [16,17]. (See "Depression, mania, and schizophrenia in patients with HIV".)

SUBSTANCE USE DISORDER — Substance abuse adds a complex dimension to HIV-infected patients since addiction can serve as a primary vector for the spread of the virus but also greatly complicate treatment of HIV [9,10]. Extensive psychiatric, psychological, and medical comorbidities are associated with substance abuse and addiction in HIV disease. (See "Substance use disorder in patients with HIV".)

POSTTRAUMATIC STRESS DISORDER — The relationship between posttraumatic stress disorder (PTSD) and HIV infection is also complex. PTSD exacerbates HIV risk behaviors and worsens health outcomes. HIV risk behaviors, such as prostitution and drug abuse, may increase exposure to trauma associated with increased likelihood of developing PTSD, and likewise, PTSD from early trauma predisposes individuals to engage in sex or drug behaviors that increase the risk of HIV infection. For example, PTSD often coexists with depression and cocaine/opioid abuse [18], both of which are risk factors for HIV. Substance abuse may be either a relief strategy in response to traumatic experience, or a lifestyle that increases exposure to traumatic events like robbery or assault [19].

PERSONALITY DISTURBANCE — Personality disorders are more prevalent among HIV-infected (19 to 36 percent) and HIV at-risk (15 to 20 percent) individuals [20-22] than the general population (10 percent) [23]. Antisocial personality disorder is the most common personality disorder among HIV infected individuals [24], and has been shown to significantly increase risk of HIV infection [25].

Dimensional nature of personality — Personality in patients with HIV can be characterized along a spectrum of traits (dimensions), rather than categorized as discrete personality disorders. The dimensional approach emphasizes the assets as well as the maladaptive variants of personality and may help one more fully understand the behavior exhibited by patients. It also suggests intervention strategies and is less stigmatizing. In addition, a classification system based on a continuum approach may better predict HIV risk behavior than the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) categories [26].

The DSM-5-TR describes discreet personality disorders [27]. In addition, DSM-5-TR includes information about the dimensional nature of personality as part of an Alternative Model for Personality Disorders, which is based on impairments in personality functioning and the presence of pathological personality traits. (See "Dimensional-categorical approach to assessing personality disorder pathology".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topics (see "Patient education: HIV-associated neurocognitive disorders (The Basics)")

●Beyond the Basics topics (see "Patient education: Delirium (Beyond the Basics)")

SUMMARY

●Delirium – Delirium is characterized by inattention, disorganized thinking, confusion, emotional liability, and fluctuations in level of consciousness. The differential diagnosis of delirium in HIV-infected patients includes HIV-associated dementia, AIDS mania, minor cognitive motor disorder (MCMD), major depression, bipolar disorder, panic disorder, and schizophrenia. Delirium can usually be distinguished by its rapid onset, fluctuating level of consciousness, and link to a medical etiology. (See 'Delirium' above.)

●Dementia – HIV-associated dementia usually occurs in patients with a CD4 count nadir <200 cells/microL. Risks factors for HIV-associated dementia include high serum or cerebrospinal fluid HIV viral load, low educational level, advanced age, anemia, illicit drug use, and female sex. Since the introduction of potent antiretroviral therapy (ART), the incidence of HIV-associated dementia has declined. (See "HIV-associated neurocognitive disorders: Epidemiology, clinical manifestations, and diagnosis".)

●MCMD – MCMD is cognitive impairment that approaches but does not meet diagnostic criteria for dementia. MCMD is less severe than HIV-associated dementia and emerges earlier in HIV disease. It is not known whether MCMD predisposes to HIV-associated dementia. (See "HIV-associated neurocognitive disorders: Epidemiology, clinical manifestations, and diagnosis".)

●Major depression – Comorbid major depression (table 1) is common with HIV disease and hinders effective treatment of HIV-infected individuals, such that these patients are at significantly increased risk for HIV-disease progression and mortality. (See 'Major Depression' above and "Depression, mania, and schizophrenia in patients with HIV", section on 'Major depression'.)

●Mania – Mania (table 2) occurs in HIV-infected patients either as a component of bipolar illness, or as the unique entity of AIDS mania associated with late stage HIV infection. AIDS mania is characterized by typical mania and additional cognitive impairment in the setting of a lack of previous personal or family history of bipolar illness. The prevalence of AIDS mania has dropped significantly since the onset of potent ART. (See 'Mania' above and "Depression, mania, and schizophrenia in patients with HIV", section on 'Mania'.)

●Schizophrenia – No evidence suggests that HIV causes schizophrenia (table 3), but data indicate that schizophrenia contributes to high-risk behavior associated with HIV infection. (See "Depression, mania, and schizophrenia in patients with HIV", section on 'Schizophrenia and psychotic episodes'.)

●Substance use disorder – Substance dependence can serve as a primary vector for the spread of HIV and complicate HIV treatment. Numerous comorbidities are associated with substance use disorders in HIV disease. (See "Substance use disorder in patients with HIV".)

●Posttraumatic stress disorder (PTSD) – PTSD exacerbates HIV risk behaviors and worsens health outcomes. HIV risk behaviors (sex and drug use) may increase exposure to trauma associated with increased likelihood of developing PTSD. Likewise, PTSD from early trauma predisposes individuals to engage in behaviors that increase the risk of HIV infection. (See 'Posttraumatic stress disorder' above.)

●Personality disturbance – Personality disturbance in patients infected with HIV can be classified according to personality disorders as well as the dimensional constructs of extroversion-introversion (tendency to respond to stimuli with either excitation or inhibition) and emotional stability-instability (degree of emotional lability). Antisocial personality disorder is the most common personality disorder among HIV infected individuals. (See 'Personality disturbance' above.)