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HIV, psychosis and aging: past, present and future

Dolder, Christian Ra,b; Patterson, Thomas La; Jeste, Dilip Va,b,c

Neuropsychiatric
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Objective: To review the clinical features, treatment issues, and research needs surrounding HIV infection in older adults with psychotic disorders and new-onset psychosis in HIV-infected individuals, while focusing on the implications of the highly active antiretroviral therapy (HAART) era and the use of atypical antipsychotic agents.

Design: We searched the Medline/HealthStar database for articles that had examined new-onset psychosis in HIV disease and existing HIV infection in adults with psychotic disorders.

Results: Individuals with psychotic disorders have an elevated risk of HIV infection. The risk factors for, prognosis for, and treatment of HIV disease may all be affected by older age. New-onset psychosis in HIV-infected individuals presents with a range of clinical features and is likely to remain a problem encountered in the near future, despite the treatment advances associated with HAART. Antipsychotic agents are the treatment of choice for psychosis in HIV-infected individuals. Research has demonstrated the sensitivity of HIV-infected individuals to the extrapyramidal side-effects of conventional antipsychotic agents, adverse effects that are reduced with the use of atypical antipsychotic agents.

Conclusion: HIV, psychosis, and aging represent a trio with important clinical implications. HIV-infected older adults, a growing portion of the HIV population, face challenges in terms of concomitant illness, treatment sensitivity, and the potential for increased morbidity and premature mortality. Atypical antipsychotic agents in low doses represent an advance over conventional antipsychotic agents, although they do have their own side-effects.

From the aDepartment of Psychiatry, University of California, San Diego, CA, USA; bPharmacy Service, and cPsychiatry Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.

Correspondence to: Dilip V. Jeste, MD, Geriatric Psychiatry Division 116A-1, VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA.

Tel: +1 858 552 8585 (ext 3046); fax: +1 858 552 7404.

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Introduction

Psychosis is a severe mental illness that markedly reduces functioning and affects thinking, perception, and cognition. Psychotic disorders are characterized by prominent delusions, hallucinations, disorganization, or negative symptoms (e.g. affective flattening, alogia, avolition). Psychotic disorders can be classified into primary (e.g. schizophrenia, schizoaffective disorder) or secondary (e.g. psychosis caused by a medical condition such as HIV infection) disorders [1].

Psychiatric symptoms may occur as a consequence of HIV disease and psychiatric illness may place individuals at an increased risk of contracting HIV infection. Psychotic disorders in individuals with HIV or AIDS are an important area with limited data and unanswered questions regarding incidence, prevalence, course, clinical features, and treatment.

The era of highly active antiretroviral therapy (HAART) has led to substantial gains in the development of more efficacious treatments for HIV and AIDS. HAART therapy has produced considerable delays in HIV disease progression, and has led to reductions in the incidence of opportunistic infections [2,3]. These developments, in combination with the aging of the United States population, should lead to an increase in individuals with HIV and AIDS surviving into old age, and may also lead to an increase in the incidence of older adults becoming infected with HIV. Whereas the positive outcomes of HAART therapy related to opportunistic infections are relatively consistent, the poor central nervous system (CNS) penetration of many antiretroviral agents [4] could reduce some of the beneficial effects of HAART on HIV-related CNS diseases and psychiatric symptoms.

With the discovery of the antipsychotic properties of chlorpromazine in the early 1950s, the modern era of antipsychotic pharmacotherapy began. Antipsychotic agents became and continue to be the pharmacological treatment of choice for psychosis. The pharmacological properties of chlorpromazine and similar medications led to the hypothesis of altered dopaminerigic transmission in schizophrenia and related disorders. To date, all of the currently marketed antipsychotic agents have significant activity at the dopamine-2 receptor [5].

The shortcomings of conventional antipsychotic agents such as chlorpromazine and haloperidol [e.g. side-effects including extrapyramidal symptoms and tardive dyskinesia (TD), as well as minimal efficacy against negative symptoms] led to the development of newer antipsychotic agents with modified pharmacological properties. These new or ‘atypical’ antipsychotic agents (i.e. clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole) have been shown to be at least as effective for treating the symptoms of schizophrenia and other psychotic disorders, while having a reduced risk of causing extrapyramidal side-effects (EPS) or TD when compared with the older conventional or ‘typical’ antipsychotic agents [6–10]. Antipsychotic agents with a reduced risk of motor side-effects have important treatment implications such as improved tolerability, acceptability, and adherence.

Although the efficacy and safety of antipsychotic agents in the treatment of schizophrenia have been relatively well studied, the use of antipsychotic agents in other populations, such as in older adults [11] or in individuals with new-onset psychosis as a result of HIV infection, has not been examined adequately. The anticipated increase in the numbers of older adults in the United States will be accompanied by an even more impressive increase in older adults with schizophrenia and other psychotic disorders during the next several decades [12]. These individuals will be at high risk of contracting HIV infection.

The purpose of this paper is to review the clinical features, treatment issues, and research needs surrounding HIV infection in older adults with psychotic disorders and new-onset psychosis in HIV infected individuals. Whereas our review includes relevant research from the pre-HAART era, the review focuses on HAART era implications and the use of atypical antipsychotic agents.

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Methods

We conducted a literature review to identify published articles that had examined new-onset psychosis in HIV disease and HIV infection in adults with psychotic disorders. Articles were limited to those published in English. We searched the Medline/HealthStar database (through September 2002) for keywords or title words containing combinations of ‘antipsychotic', ‘neuroleptic', ‘psychosis', ‘psychotic', ‘psychiatric', ‘clozapine', ‘risperidone', ‘olanzapine', ‘quetiapine', ‘ziprasidone', ‘HIV', and ‘AIDS'. In a second search, the words ‘age', ‘aging', ‘elderly', and ‘older’ were used to identify HIV-related manuscripts specific to older adults. A total of 86 papers were identified in this manner (31 on HIV and psychiatric disorders, i.e. schizophrenia or psychosis; 19 on antipsychotic agents and HIV; and 36 on HIV and aging), although only 41 were appropriate for inclusion in the current review (e.g. a number of animal studies and reviews were not used). References from articles identified through this search and citations from recent reviews were also examined to increase the comprehensiveness of the review.

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HIV/AIDS in older adults

Aging and HIV disease

Older patients (i.e. those at least 55 years of age) are one of the fastest-growing segments of the AIDS population [13]. According to the Centers for Disease Control and Prevention 2001 AIDS surveillance data, 5711 men and women were diagnosed with AIDS in the United States at the age of 50 years or older in 2000 (i.e. 11.3% of all patients diagnosed with AIDS) [14]. In contrast, 820 or 9.4% of all patients diagnosed with AIDS in 1985 were at least 50 years of age [14]. Although the reported number of older adults with AIDS has increased, these figures may be underestimates because early symptoms of the disease, such as fatigue, weight loss and diminished appetite, may be dismissed as part of the normal aging process [13].

Findings from published reports have suggested that individuals who become HIV infected in older age may have a worse prognosis than younger individuals. For example, older adults have been found to have a shorter observed AIDS-free interval and shorter survival, along with more HIV and non-HIV-related co-morbidity compared with younger individuals [15]. It has been suggested that such findings may result from a decrease in immune system functioning secondary to the aging process [16]. Some authors have also proposed that older age may potentiate or act as a risk factor for neurocognitive impairment in HIV disease [17].

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HIV disease and psychotic disorders

Individuals with severe mental illness have an elevated rate of HIV infection [17,18]. The apparent increased risk of HIV infection in severely mentally ill patients may be the result of elevations in risk behaviors such as hypersexuality, poor impulse control, self-destructive behavior, casual sexual relationships, lack of risk awareness, impaired judgment, substance abuse, and the potential for sexual victimization [19,20]. Questions arise about the effect a severe mental illness such as schizophrenia has on HIV and AIDS. In general, psychotic disorders may alter the course of HIV infection by impairing immune function or influencing behavior [17]; however, few studies have been published that examine the possible effects of schizophrenia on the progression of HIV-spectrum illness. According to Sewell [21], diseases such as HIV tend to lead to greater morbidity and mortality in patients with schizophrenia than in the general public because schizophrenia patients have: (i) difficulty complying with medical care; (ii) trouble explaining symptoms to medical personnel; and (iii) receive less attention from medical personnel about physical complaints. Anecdotal evidence has suggested a negative impact of HIV disease because individuals with schizophrenia may be more susceptible to the stresses related to HIV infection and have fewer resources to address these issues [21]. Interestingly, in an examination of claims histories of Medicaid beneficiaries with both HIV infection and schizophrenia (conducted before the widespread use of protease inhibitors), no difference was found in the likelihood of receiving antiretroviral medications between HIV-infected individuals with or without schizophrenia [22]. Although intriguing, findings from this retrospective study should be replicated before drawing any conclusions.

Aging may also impact individuals with psychiatric disorders and HIV. For example, some previous studies have suggested a survival disadvantage for older compared with younger adults with HIV [23]. As another example, in a multisite cohort of HIV-infected veterans, older HIV-infected patients (i.e. those at least 50 years of age) experienced a greater number of general medical co-morbidities than veterans younger than 50 years of age [24]. An increase in medical co-morbidities could contribute to negative outcomes in terms of morbidity and mortality.

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Highly active antiretroviral therapy era considerations

Most of the published reports assessing HIV, mortality, and aging have found a positive correlation between age and mortality; however, such studies were primarily conducted in the pre-HAART era. A few more recent examinations have suggested similar rates of mortality between older and younger adults with HIV infection. Wellons and colleagues [23] conducted a retrospective case–control study analysing data from 1993 to 1999 to compare antiretroviral use and outcomes between 101 HIV-infected patients aged 50 years and older and 101 matched younger HIV-infected controls. Contrary to the authors’ hypothesis, similar rates of use of nucleoside and non-nucleoside reverse transcriptase inhibitors and protease inhibitors were found in the two groups. Forty-two per cent of all patients were prescribed a protease inhibitor and 59 and 58% of older and younger patients were prescribed three or more antiretroviral agents, respectively. The older and younger groups had similar CD4 cell counts at baseline and similar increases in CD4 cell counts during follow-up; surprisingly, the older group had a higher percentage of individuals with plasma HIV-RNA levels of less than 400 copies/ml. These results suggest that with the prescription of similar HIV regimens for younger and older adults, treatment outcomes could be similar for the two age groups. Knobel et al. [25] compared the response to HAART therapy in patients aged 60 years or older (N = 28) with that of patients aged 40 years or younger (N = 671). After 24 months of follow-up, no significant differences between the two groups in terms of death, the proportion of patients with undetectable HIV-RNA levels, or the proportion of patients with increased CD4 cell counts from baseline were reported. Whereas these findings are promising, the methodological limitations and small number of older HIV-infected subjects limit the generalizability of the study results. Also noteworthy in that study was that lipodystrophy was reported by 63% of older patients compared with 33% of younger patients. This finding suggests that older adults may be more susceptible to some antiretroviral medication side-effects.

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Clinical and research considerations

McKinnon and colleagues [26] recommended targets for ongoing and future research on severe mental illness and HIV infection. Research must be broadened in order to determine the prevalence of HIV infection in populations such as older adults and those with psychiatric illness. As a result of treatment and outcome considerations, investigators must differentiate HIV-infected individuals with preexisting mental illness from those whose psychiatric illness occurs after HIV infection. Whereas retrospective and cross-sectional studies have provided some important contributions to the literature, more investigations using longitudinal designs are needed. There is also a need for multisite studies in urban, suburban, and rural locations in order to increase the external validity of study findings. Well-designed clinical trials are needed to gain a better understanding of how to treat individuals with HIV and psychotic illness safely and effectively. Barriers to HIV-related care for older adults with or without psychiatric illness should be identified in order to improve the delivery and quality of healthcare. Potential obstacles to HIV treatment in patients with mental illness include stigma, denial of illness, medication non-adherence, poor motivation, financial limitations, and familial constraints [26]. These barriers are likely to be magnified in older populations, in which the awareness of HIV disease is currently minimal.

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New-onset psychosis in HIV/AIDS

Clinical features

The reported prevalence of new-onset psychosis in patients with HIV infection has varied from 0.23 to 15.2% [21], a range that may reflect differences in symptom presentation. Harris and colleagues [27] conducted a literature review and retrospective chart review in HIV-infected patients to examine the clinical features of new-onset psychosis in HIV disease. Persecutory, grandiose, and somatic delusions were the most common symptoms, followed by hallucinations and affective disturbances. New-onset psychosis is thought generally to occur in AIDS or in later stages of HIV disease. Variability in the presentation of HIV- associated psychosis was exemplified by Sewell et al. [28], who described 20 HIV-infected men with non-iatrogenic new-onset psychosis who were not abusing drugs or alcohol at the time of investigation. Although all 20 men had delusions, auditory (n = 12) and visual hallucinations (n = 9) were the second most common psychotic symptom, and mood symptoms occurred in 65% of patients. The variability in the clinical picture led to a range of diagnoses based on the Diagnostic and Statistical Manual of Mental Disorders: psychosis not otherwise specified, bipolar mania, major depression with psychotic features, schizoaffective disorder, and schizophrenia. A variety of clinical courses were also reported in the investigation. Six patients had one discrete episode, three had multiple episodes, and the remaining 11 patients could not be maintained off conventional antipsychotic agents because of the recurrence or worsening of psychotic symptoms. In addition, the psychotic patients had a higher mortality rate when compared with 20 non-psychotic individuals (i.e. the mean survival time was 23 and 51 months for psychotic and non-psychotic patients, respectively) matched on a number of variables [28]. When one considers the clinical presentation of new-onset psychosis in HIV infection or AIDS, the absence or presence of HIV-related neurological disease or metabolic dysfunction should be taken into account in order to distinguish between primary and secondary psychosis [29]. The relatively small amount of literature describing new-onset psychosis in HIV infection makes it difficult to compare the clinical presentation of new-onset psychosis between younger and older adults (see Table 1).

Table 1

Table 1

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Etiology and co-morbidity

Studies comparing psychotic and non-psychotic HIV-seropositive patients have reported the following potential factors to be associated with the development of psychosis: psychiatric history (i.e. substance abuse disorder, affective disorder), untreated HIV infection, cognitive impairment, dementia, and a history of stimulant and sedative hypnotic abuse or dependence [28,30].

A number of hypotheses have been proposed in an attempt to explain the pathogenesis of new-onset psychosis in HIV infection: brain damage from some other opportunistic infection [28]; an inferior immune response in the CNS that allows for more damage from infectious pathogens [28]; subcortical neurodegeneration caused by HIV itself or in the presence of other viral infections [17]; psychosis secondary to HIV encephalopathy [31] or an underlying dementia [32]; and high levels of intracellular free calcium, leading to inappropriate neurotransmitter release [33]. It is unlikely that any one of these hypotheses fully explains the pathogenesis of new-onset psychosis in HIV disease. Nonetheless, continued examination of such hypotheses may provide valuable insight into the prevention and treatment of new-onset psychosis in HIV infection.

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Highly active antiretroviral therapy era considerations

The effects of HAART on new-onset psychosis are unclear. A dearth of studies of the prevalence of new-onset psychosis in the HAART era precludes any meaningful comparisons of rates between the pre-HAART and HAART eras. The reduction in opportunistic infections and in HIV-associated dementia attributed to the widespread use of HAART in HIV-infected individuals may be expected to reduce the risk of new-onset psychosis in these patients, especially psychosis secondary to dementia. The rates of dementia declined after the introduction of HAART, but not to the same extent as those of other AIDS-defining illnesses such as toxoplasmosis or cryptococcus infections [34,35]. This observation suggests that viral suppression in the periphery may not be sufficient treatment for HIV-related CNS disease and that the eradication of HIV within the brain might not be possible with current antiretroviral medications. Under these circumstances, the brain may serve as a reservoir for viral replication during HAART [36].

As discussed later in the treatment section, medication side-effects and drug–drug interactions are important considerations when patients are prescribed antipsychotic agents for the treatment of new-onset psychosis while concomitantly receiving HAART. For example, the enzymatic inhibition seen with protease inhibitors may lead to increased serum levels of antipsychotic agents and a greater potential for side-effects. Similarly, the ability of protease inhibitors and some atypical antipsychotic agents to cause weight gain and lipodystrophy may lead to negative long-term outcomes such as diabetes, hypercholesterolemia, and cardiovascular events. The long-term outcomes of these therapies should be considered in the light of the increased life expectancy of HIV-positive individuals receiving effective antiretroviral therapy. The ability of some antiretroviral agents (e.g. zidovudine, efavirenz) to cause CNS effects (e.g. nightmares, hallucinations) may also complicate the treatment of psychiatric disorders. Caution should thus be exercised when deciding on the pharmacological treatment of psychosis in HIV-infected individuals.

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Clinical and research considerations

The clinical evaluation of HIV-seropositive or AIDS patients with psychotic symptoms requires a comprehensive history and physical examination. Clinicians should rule out other known causes of psychosis. A careful history should include information about the onset and course of the patient's symptoms. Signs of medical illness, drug intoxication, or medication toxicity should be considered during the examination of the patient [37].

Case reports and cross-sectional studies conducted before the introduction of HAART comprise the majority of the literature describing new-onset psychosis in HIV infection. These investigations have provided interesting information. Nonetheless, a number of unanswered questions remain. Cross-sectional studies have suggested that psychosis may negatively impact the morbidity and mortality associated with physical disease, but longitudinal, prospective investigations are needed to address the relationship between psychosis, HIV disease progression, and mortality [38]. More rigorous trials of pharmacological therapies are also warranted.

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Treatment

Treatment for new-onset psychosis associated with HIV infection or existing psychosis in concomitant HIV infection requires a combination of pharmacological and psychosocial interventions. In either situation, atypical antipsychotic agents represent the pharmacological treatment of choice for psychosis, for reasons that will be discussed below.

In reviews of new-onset psychosis in HIV infection, Sewell [21] concluded that the use of an antipsychotic agent is usually necessary, regardless of the etiology, and Harris et al. [27] reported the successful use of a variety of conventional antipsychotic agents (e.g. haloperidol, thioridazine, chlorpromazine) at low doses. Results from published reports and anecdotal evidence suggest that HIV-infected patients with new-onset psychosis generally respond well to antipsychotic medications, but that these individuals are especially sensitive to their side-effects [17,21,39]. HIV-infected individuals are particularly susceptible to EPS and TD induced by conventional antipsychotic agents [37,40,41]. The likelihood of patients with AIDS developing EPS or TD from typical antipsychotic agents was reported to be more than twice that in non-AIDS patients after controlling for the mean medication dose and body weight [41]. In that study, the rate of developing EPS was very high in the relatively young group of subjects (i.e. 50 or 78% developed EPS depending on the antipsychotic dose) [41]. Furthermore, high rates of motor side-effects were seen with conventional antipsychotic agents at low doses (i.e. mean maximal chlorpromazine equivalent of 124 mg/day) in a 6-week study of haloperidol and thioridazine in the treatment of new-onset psychosis in HIV-seropositive adults [37]. The risk of developing EPS and TD has been reported to be greater in older compared with younger adults with schizophrenia [42], suggesting extra caution when treating older HIV-infected adults with antipsychotic agents.

The sensitivity of HIV-seropositive adults to EPS noted above is thought to result from the involvement of HIV on the basal ganglia, resulting in a loss of dopaminerigic neurons [43–46]. Because of their dopamine blocking activity in the nigrostriatum, conventional antipsychotic medications may produce or exacerbate EPS [44]. Unfortunately, current antiretroviral therapies do not seem to increase CNS levels of dopamine [47] or improve the clinical symptoms of parkinsonism in patients with HIV infection [48]. Antiretroviral therapies are thus not expected to decrease antipsychotic-induced EPS. An age-associated decrease in dopamine levels, dementia, and delirium may further predispose older patients with psychotic disorders to develop antipsychotic-induced EPS [1].

Large, randomized, controlled trials have demonstrated a reduced risk of developing EPS and TD [6–9,49–52] in HIV-negative patients with schizophrenia and related disorders with atypical antipsychotic compared with conventional agents. The improved side-effect profile of atypical antipsychotic agents has led clinicians to favor the use of these agents over conventional antipsychotic agents for the treatment of psychosis in HIV-infected individuals. Table 2 summarizes the published reports of atypical antipsychotic use for psychosis in patients with HIV or AIDS [53–59]. The most frequently investigated medication was risperidone, followed by clozapine and olanzapine. The use of atypical antipsychotic agents at relatively low doses was generally reported to lead to improvements in psychopathology without causing or exacerbating EPS. Nonetheless, the potential for antipsychotic-induced side-effects and overlapping toxicity between antiretroviral treatment and antipsychotic medications should lead to the careful selection of medications. For example, an agent such as clozapine, with the potential to cause bone marrow suppression, should be used cautiously in patients with HIV or AIDS. Findings from the studies included in Table 2 should be interpreted carefully because the investigations represent case reports, case series, and an open-label trial. In addition, the generalizability of these findings to older adults is limited. Even lower doses of atypical antipsychotic agents in older patients should be used cautiously.

Table 2

Table 2

In conclusion, HIV, psychosis, and aging represent a trio with important clinical implications. Advances in HIV treatment have allowed many HIV-infected individuals to live longer. In addition, HIV infection among older adults represents a growing portion of the HIV population. Unfortunately, HIV infection in older adults is accompanied by additional challenges in terms of concomitant illness, treatment sensitivity, and the potential for increased morbidity and premature mortality. New-onset psychosis in HIV-infected individuals may be difficult to treat, although atypical antipsychotic agents in low doses represent an advance over conventional antipsychotic agents.

Sponsorship: This work was partly supported by the National Institute of Mental Health grants MH49671, MH43693, MH59101, MH19934 and by the Department of Veterans Affairs.

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Keywords:

aging; AIDS; antipsychotic; HIV; psychosis

© 2004 Lippincott Williams & Wilkins, Inc.