Sara Siris Nash, MD

Patients with HIV infection are at risk of developing psychiatric symptoms and disorders similar to those seen in the general population. Even before infection, people at risk for HIV may come from certain populations--such as injection-drug users and others with substance abuse or dependence--in whom there is a higher than average risk for psychiatric illness (Pillard, 1988; Rounsaville et al., 1982). Symptoms of anxiety and depression may be related to apprehension about disease progression and death and sadness from the loss of health, friends and income (Forstein, 1984; Nichols, 1985; Ostrow, 1987).

Several studies have found a substantial risk for 

 major depression and adjustment disorders with anxious or depressed mood, which may occur during asymptomatic infection (Dilley et al., 1985; Holland and Tross, 1985). In addition, patients living with an underlying mental illness--especially severe and persistent mental or mood disorders--are at a disproportionately increased risk of developing infection with HIV due to sexual and substance use behaviors (Carey et al., 2004).

Shortly after the initial HIV infection, the virus enters the central nervous system and may cause meningitis or encephalitis. Other serious CNS complications tend to occur late in the course of disease, when immune function has significantly declined, though studies have reported conflicting results as to the predictive value of CD4 counts in assessing cognitive and motor performance (Bornstein et al., 1991; Goethe et al., 1989; Koralnik et al., 1990; McArthur et al., 1989; Miller et al., 1990; Saykin et al., 1988). Viral load is more closely associated with the degree of cognitive impairment. Patients with serum viral loads ≥30,000 copies/mL are 8.5 times more likely to develop dementia compared to patients with viral loads <3,000 copies/mL (Childs et al., 1999). In another study, a cerebrospinal fluid viral load >200 copies/mL was predictive of progression to neuropsychological impairment (Ellis et al., 2002).

Patients infected with HIV are at risk of developing dementia as a direct result of viral infection. This syndrome has been referred to by various names: 

 (Working Group of the American Academy of Neurology AIDS Task Force, 1991), 

HIV encephalopathy, subacute encephalitis

 (Navia et al., 1986b). HIV-associated dementia is defined as acquired cognitive abnormalities in two or more domains and is associated with functional impairment and acquired motor or behavioral abnormalities, in the absence of another etiology (

The clinical manifestations of HAD are predominantly those of subcortical dementia, with some similarity to those found in dementia associated with Huntington's disease and Parkinson's disease. Neuropathological evidence demonstrates that HIV-related diseases in the CNS are preferentially located in certain subcortical structures of the brain (e.g., white matter, basal ganglia and hippocampus) as well as in the spinal cord (Cummings, 1990; Navia et al., 1986a). Consistent with the subcortical nature of the dementing process, patients with HAD typically have disturbances in three neuropsychiatric spheres of functioning: cognitive, motor and behavioral.

The cognitive disturbance usually has a subtle onset and involves slowed thinking, memory impairment, forgetfulness and difficulty concentrating. Patients often complain that normal activities take longer or that they have to repeatedly reread paragraphs of text in order to understand them. As the dementia progresses, gross cognitive disturbances often occur, and patients begin to experience greater difficulty managing their financial affairs or shopping and caring for themselves.

Frank disorientation, confusion and muteness are observed late in the illness. Psychiatric symptoms, such as agitation, mania, hallucinations and paranoid delusions, are also not unusual in advanced disease stages. The management of these psychiatric disturbances needs to take into account the greater sensitivity to the extrapyramidal side effects of antipsychotic medications seen in patients with HIV infection (Perry, 1990). For this reason atypical antipsychotics with a low risk of EPS, such as quetiapine (Seroquel) and aripiprazole (Abilify), may be preferable in this population.

The motor disturbance begins with subtle signs such as slowed movements or hand tremor. Other common symptoms include decreased balance, lack of coordination, difficulty with rapid alternating movements, abnormal eye movements (including saccades and pursuit) and a sense of general clumsiness. For patients afflicted with vacuolar myelopathy or spinal cord involvement from HIV, motor signs include gait difficulty or bumping into things. When sitting, they may find themselves unexpectedly leaning or falling to one side in the absence of adequate postural support.

As the impairment progresses, patients experience weakness in their upper and lower extremities. In late stages of disease, paraplegia and urinary and bowel incontinence occur. When motor signs and symptoms occur in the absence of HIV dementia, the syndrome is known as 

Behavioral symptoms include social withdrawal, apathy, sleep disturbances, fatigue, headaches and decreased libido. These features may be difficult to distinguish from depressive symptoms, though the patient often lacks the dysphoria experienced in a clinical major depression. Perry (1990) has commented that the apathy, withdrawal and mental slowing found in HAD can be differentiated clinically from low self-esteem, irrational guilt and other features characteristic of depression. Nonetheless, these symptoms are important to recognize and should not be dismissed simply as emotional responses to the diagnosis of HIV infection. A less severe form of CNS disease associated with HIV infection is HIV-associated minor cognitive-motor disturbance, which is differentiated from HAD based upon the presence of fewer symptoms and little or no functional impairment (

Infection with HIV may indirectly lead to neuropsychiatric disturbances due to CNS opportunistic infections, neoplasms and metabolic disorders (

). These infections are unusual in the absence of HIV and tend to occur late in the course of illness, when immune function is waning, CD4+ cell counts fall to very low levels and viral load is rising. With the widespread use of highly active antiretroviral therapy (HAART), the incidence of opportunistic infections and other complications of HIV infection have fallen dramatically. The identification of the underlying cause of neuropsychiatric disturbance in an individual infected with HIV is very important because some of these conditions are responsive to treatment, and delayed diagnosis and treatment may result in permanent CNS damage.

The most common CNS opportunistic infections are cerebral toxoplasmosis, cryptococcal meningitis and progressive multifocal leukoencephalopathy. Less common CNS opportunistic infections include meningitis caused by 

 and other fungal CNS infections, such as candidiasis, coccidioidomycosis, aspergillosis and histoplasmosis. Opportunistic viral infections involving the CNS include cytomegalovirus, herpes simplex virus and varicella-zoster virus. Acute mental status changes can also occur as a result of metabolic disturbances, such as hypoxia, fever, dehydration, electrolyte disturbances, uremia and hepatic encephalopathy.

Central nervous system involvement also occurs as a result of primary CNS lymphoma, which tends to occur late in the course of HIV infection. Central nervous system manifestations of metastatic systemic lymphoma and Kaposi's sarcoma have been reported in patients with AIDS, but are uncommon.

Finally, many antibacterial, antifungal, antineoplastic and antiviral medications, in addition to the antiretroviral therapies, have CNS side effects. An awareness of the types of pharmacological treatments used and their potential side effects is important in the evaluation of psychiatric symptoms in patients who are HIV positive. Some of the drugs more commonly used in HIV and their neuropsychiatric side effects are listed in 

The incidence and prevalence of HAD has decreased since HAART first became widely available in 1996. Data from the Multicenter AIDS Cohort study show that the incidence fell from 21% with the use of monotherapy to 10.5% with HAART regimes (Sacktor et al., 2001). The prevalence of HAD had been variably estimated from 7% to 90% in the pre-HAART era, depending on the study (Dore et al., 1999). According to a study by Maschke and colleagues, it dropped from 17.1% to 11.2% between 1995-1996 and 1997-1998 (Maschke et al., 2000). Although HAART does not eliminate HAD, patients on this regimen have less impairment in cognition, concentration, memory and psychomotor speed than their nonmedicated counterparts, with benefits appearing within one to six months of treatment initiation (Ferrando et al., 1998).

Some antiretroviral agents are associated with neuropsychiatric side effects. The nucleoside reverse transcriptase inhibitor (NRTI) zidovudine (AZT, ZDV, Retrovir) was the earliest antiretroviral drug to be used in the management of HIV. A drug with good CNS penetration, it was initially given as monotherapy in doses of 2000 mg/day, and was associated with cases of acute mania (Wright et al., 1989). Now as a part of combination therapy, reports of mania are less common at doses of 600 mg/day.

The non-NRTI (NNRTI) efavirenz (Sustiva) has been associated with many neuropsychiatric side effects, including dizziness, headache, confusion, stupor, decreased concentration, agitation, amnesia, depersonalization, hallucinations, insomnia and night terrors. Symptoms usually occur within the first month of treatment and most resolve within six to 10 weeks. One study showed increased rates of depression, nervousness, abnormal dreaming and euphoria in patients treated with efavirenz (Ruiz et al., 1999). Compared to 27% of control participants, 54% of efavirenz-treated patients suffered from nervous system adverse events. There is some evidence that the plasma level of the drug correlates with the likelihood and severity of symptoms (Marzolini et al., 2001). The other members of the NNRTI medication class, delavirdine (Rescriptor) and nevirapine (Viramune), have not been associated with significant CNS adverse effects.

Antiretroviral medication decreases the morbidity and mortality associated with HIV and AIDS. The success of these medications, however, depends on their regular and appropriate use. Multiple factors influence adherence, including adverse effects of the medication, the number of pills required, dosing schedules and cost. Patients suffering from HAD or other types of cognitive impairment may simply forget to take their medication on a regular basis (Nath and Berger, 2004). Some studies have shown an association between nonadherence and depression, interpersonal problems, drug or alcohol abuse, and legal or employment problems. Axis II conditions, such as borderline personality disorder, also hinder antiretroviral compliance (Palmer et al., 2003). Riera et al. (2002) found that, in general, patients who were in psychiatric treatment, in a methadone maintenance program or depressed were more likely to be nonadherent than other patients. Health care workers need to be especially cognizant of the presence of depression or substance abuse because proper evaluation and treatment of these conditions may enhance adherence.

People with HIV infection are subject to the same forms of psychiatric illness and psychological distress as those without HIV. However, individuals with histories of drug abuse and dependence are at greater risk for a variety of psychiatric disorders. People with waning immunity and high viral loads may be at particular risk for the CNS complications of AIDS, such as HAD or CNS opportunistic infections and other causes of acute mental status changes. The unique biological, psychological and environmental factors involved in treating those with HIV infection require an awareness of these influences in order to arrive at appropriate psychiatric evaluation and effective treatment strategies.

Dr. Horwath is clinical professor of psychiatry at the Columbia University College of Physicians and Surgeons and medical director of the Columbia University HIV Mental Health Training Program, an affiliate of the NY/NJ AIDS Education and Treatment Center.

Dr. Nash is a PGY-I psychiatry resident at New York-Presbyterian Hospital and the Columbia University College of Physicians and Surgeons.

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Patients with HIV infection are at risk of developing psychiatric symptoms and disorders similar to those seen in the general population. What unique biological, psychological and environmental factors are involved in treating this population?

Sara Siris Nash, MD

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