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3, 1996

Schizophrenia and HIV


by Daniel D. Sewell

Abstract There is very little published information regarding the co-occurrence of human immunodeficiency virus (HlV)-spectrum illness and psychotic illnesses, including schizophrenia, even though their coexistence in the same patient may severely affect the course of both illnesses. Estimates of the frequency of HIV infection in patients with preexisting mental illness range between 5 and 7 percent. Estimates of new-onset psychosis in patients with HIV-spectrum illness range between 0.2 and 15 percent and may increase as the stage of HIV illness progresses. Regardless of which illness camefirst,their occurrence together appears to be associated with more morbidity and mortality than would be expected with either illness alone. Patients with newonset psychosis respond to and tolerate relatively low doses of antipsychotic medication. Whether the presence of HIV decreases the effective daily dose of neuroleptic medication in patients with preexisting psychosis is not yet known. A clearly superior neuroleptic medication for patients with both psychosis and HIV infection has not yet been identified. Further systematic exploration is needed. Schizophrenia Bulletin, 22(3): 465-473,1996. Patients with schizophrenia or other psychotic illnesses and human immunodeficiency virus (HIV)-spectrum illness may be differentiated based on the temporal relationship between the onset of psychotic symptoms and the discovery of infection with HIV. One group is composed of patients who have a psychotic disorder and then become infected with HIV (preexisting psychosis), and the

second group consists of patients who have no past history of psychotic disorder but who develop a psychotic disorder after infection with HIV (new-onset psychosis). There are a number of reasons why the overlap of schizophrenia and other psychotic illnesses with HIVspectrum illness deserves discussion and study. First, those who have cared for patients with psychosis and HIV-spectrum illness generally agree that regardless of which came first, co-occurrence of these disorders leads to greater morbidity (and perhaps greater mortality) than would be associated with either disorder alone. Second, due to the everincreasing prevalence of HIV-spectrum illness, it appears that co-occurrence of these illnesses is likely to increase steadily. Last, the study of the co-occurrence of these illnesses has the potential to increase our understanding of the etiopathologic basis of psychosis in general and of schizophrenia in particular. Preexisting Psychotic Illness and HIV Infection Prevalence. Currently, there is a paucity of information about the prevalence of HIV-spectrum illness among patients with preexisting psychotic illness. Although there have been some studies of HIV infection among psychiatric patients, there appear to be no published studies that focus exclusively on patients with psychotic illness, including schizophrenia. Table 1 lists the seroprevalence of HIV antibodies in patients with psychiatric illness as Reprint requests should be sent to Dr. D.D. Sewell, Medical Director, Mission Valley Mental Health Clinic, San Diego Veterans Affairs Medical Center, 2022 Camino Del Rio North, San Diego, CA 92108.

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Table 1. Prevalence of human immunodeficiency virus (HIV) infection in populations of psychiatric inpatients
Number of patients 451 203 350 475 Percent with HIV(n) 5.5 (25) 6.4(13) 7.1 (25) 6.5(31)

Study Cournos et al. (1991) Empfield et al. (1993) Sacks et al. (1992) Zamperetti et al. (1990)

Location New York City New York City New York City Milan, Italy.

reported in the four published studies on the topic. Although these studies were conducted by a variety of scientists in two countries, they all share a common methodology. The subjects in each study were patients consecutively admitted to psychiatric hospitals. The prevalence of HTV infection in these studies ranged from 5.5 to 7.1 percent. Because the Empfield et al. (1993) study included only homeless patients, it is very likely that the study population had a high proportion of patients with schizophrenia and other psychotic illnesses. The work by Cournos et al. (1991) may most closely estimate the frequency of HIV in patients with preexisting psychotic illness: 81.8 percent of the patients in their sample had some type of psychotic illness (45.2% were diagnosed with schizophrenia). Risk Behavior in Patients With Preexisting Psychosis. Behaviors that place an individual at risk for acquiring HIV include needle-sharing and unprotected sex, except that which occurs within a monogamous relationship in which both individuals are known to be seronegative. Tynes et al. (1993) reviewed the literature regarding risk of HIV infection among patients with chronic mental illness, including patients with preexisting psychotic illness, and concluded that patients with chronic

severe mental illness may exhibit more risk behavior due to hypersexuality, poor impulse control, selfdestructive behavior, casual sexual relationships, lack of awareness of risks, impaired judgment, substance abuse, and potential for sexual victimization. A study of risk behavior among chronically mentally ill patients (Kelly et al. 1992) found that 62 percent had been sexually active during the 1-year period before entry into the study and that 42 percent of the men and 19 percent of the women reported multiple sexual contacts and infrequent use of condoms during intercourse. These findings indicate that a significant proportion of chronically mentally ill patients, including patients with psychosis, have either already been infected with HIV or may be likely to become infected due to high-risk behaviors. Impact on Course of Illness. No systematically obtained information is currently available regarding the impact of HTV infection on the course of illness in patients with a preexisting psychotic disorder. Anecdotal information suggests that, if there is an impact, it is generally negative. Patients with psychotic illnesses such as schizophrenia may be more vulnerable to the numerous stresses associated with HTV infection and may have less personal, financial, and social resources for addressing

the problems associated with HIVspectrum illness. Altamura et al. (1991) studied a group of 25 HIVpositive schizophrenia patients and found that neuroleptic treatment was associated with reduction in psychiatric symptoms but may also have been associated with more marked immune-system changes and a higher incidence of infectious diseases. In addition, these researchers found a deterioration in the cognitive performance of patients with schizophrenia and HIV. There appear to be no systematic published studies on the effect schizophrenia has on progression of HIVspectrum illness. Nonetheless, it is widely accepted that diseases generally tend to be more serious in patients with schizophrenia and that deaths from most causes are more frequent among persons with schizophrenia than among the general public (Torrey 1988). In the absence of data to the contrary, it seems reasonable to assume that both these generalizations apply to patients with schizophrenia and HTV-spectrum illness. The reasons for this higher morbidity and mortality are varied and include (1) the difficulty the patients have in complying with medical care, (2) a decreased ability to explain symptoms to medical personnel, (3) a tendency for medical personnel to pay less attention to the physical complaints of patients with schizophrenia, and (4) the presence in some patients with schizophrenia of an elevated pain threshold, which results in patients not complaining of symptoms until the disease has progressed to a critical stage. New-Onset Psychosis Associated With HIV Infection Although a causal relationship

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between the presence of HIV in the central nervous system (CNS) and the development of psychosis has not been established with certainty, a growing body of scientific information supports this possibility (Masdeu et al. 1991; Masliah et al. 1992). Prevalence. The frequency of newonset psychosis in HTV-infected patients is not well established but may vary according to stage of illness. Table 2 summarizes results from a number of studies that have attempted to estimate the frequency of new-onset psychosis in HIVinfected patients. Although there were methodological differences among the studies, including the use of different HIV illness classification systems, it is notable that the highest reported frequency of psychosis (15.2%) occurred in a population of 46 patients with acquired immunodeficiency syndrome (AIDS) dementia (Navia et al. 1986). In their study, ElMallakh et al. (1993) compared 60 individuals who were HlV-seropositive with 20 patients who met diagnostic criteria for AIDS and found that patients with AIDS had not only a higher incidence of AIDS-related dementia, as expected, but also a higher incidence of psychosis.

Characteristics of the Psychosis. Sewell et al. (1994a) reported a systematic study of 20 HIV-infected men who had noniatrogenic new-onset psychosis and who were not currently abusing drugs or alcohol. The researchers found that all 20 men had delusions, and two-thirds had more than one type of delusion. The most common types were paranoid, grandiose, and bizarre delusions. Auditory (n = 12) and visual (n - 9) hallucinations were also frequently present. They also found that mood symptoms (depression, euphoria, and mixed-mood symptoms) tended to occur prominently and frequently (65%). Classifying the patients according to criteria of DSM-IH-R (American Psychiatric Association 1987) proved challenging. When psychiatric diagnoses were made with the assumption that HTV was not etiologically related to the psychiatric symptoms, the following diagnoses were obtained: psychotic disorder not otherwise specified (n = 8); bipolar disorder, manic (n = 5); major depression with psychotic features (n = 4); schizoaffective disorder (n = 2); and schizophrenia, subchronic, undifferentiated type (n = 1). With regard to the stage of HIVspectrum illness, 12 of the patients

Table 2. Prevalence of new-onset psychosis in patients with human immunodeficiency virus (HIV)-spectrum illness
Stage of HIV1 Illness All stages All stages Stages A and B Stage C (AIDS) All stages Number of patients 80 2,200 124 46 573 Percent with

Study El-Mallakh et al. (1993) Halstead et al. (1988) Harris etal. (1991) Navia etaJ. (1986) Prieretal. (1991)

psychosis (n)
5.0 (4)2 0.23 (5) 3.2 (4) 15.2 (7) 1.2 (7)

with new-onset psychosis were in Centers for Disease Control (CDC; 1986,1992) Stage IV, 6 were in CDC Stage III, and 2 were in CDC Stage II at the time of onset of psychotic symptoms. The clinical course of these patients was variable. In 11 patients, attempts to discontinue treatment with antipsychotic medication were unsuccessful because of recurrence or worsening of psychotic symptoms. Six patients had one discrete episode of psychosis with complete recovery. Three patients had multiple discrete episodes (range = 2-4). El-Mallakh (1992) reported on the course of illness of four patients with HTV-associated psychosis. In two patients, it appeared that worsening of dementia was associated with remission of the psychotic symptoms. Based on this observation, El-Mallakh proposed a window of vulnerability to psychosis in patients with HIV infection that occurs in the setting of mild to moderate brain damage from HIV. In Sewell et al. (1994o), patients with new-onset psychosis were compared to 20 nonpsychotic HTVinfected men matched with respect to age, race, years of education, and CDC HIV stage. It was found that the psychotic subjects had a higher lifetime prevalence of stimulant and sedative-hypnotic abuse or dependence and a trend toward greater global neuropsychological impairment than did the nonpsychotic subjects. The psychotic patients also had a higher mortality rate. During the 3 years of the study, 11 psychotic patients and 3 nonpsychotic patients died. The mean survival time was 22.6 months for the psychotic patients and 50.8 months for the nonpsychotic patients. Etiopathology of New-Onset Psychosis. The etiopathology of new-

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'Classification system for HIV (Centers for Disease Control [CDC] 1986,1992). Includes two cases of 'secondary mania* and two cases of psychosis.



onset psychosis in individuals infected with HIV remains unclear; however, a number of hypotheses have been proposed (Harris et al. 1991). One hypothesis maintains that the psychosis is a direct effect of HIV infection of the brain, that is, the psychosis is secondary to HIV encephalopathy (Halstead et al. 1988). This theory is derived in part from a growing body of the literature suggesting that HIV can cause an array of nervous system disorders such as HIV dementia complex (Ostrow et al. 1988). Results of a study using singlephoton emission computed tomography also suggested that new-onset depression or psychosis in individuals infected with HIV might be associated with HIV encephalopathy (Masdeu et al. 1991). In the previously described study of 20 HIV-infected men who had noniatrogenic new-onset psychosis, the psychotic subjects had greater neuropsychological impairment, suggesting an association of encephalopathy with psychotic symptoms. Similarly, the work by El-Mallakh et al. (1993) points to an association between cognitive deterioration and severe brain dysfunction such as psychosis, mania, or dementia. The only available autopsy results from patients with new-onset HlV-associated psychosis (Sewell et al. 1994<J) tend to support this theory only partially, as three of the autopsied subjects had no detectable virus in their brains. It is possible that the quantity of the virus in the brain may vary over time and that the divergent findings are related to temporal sampling error. In addition, once the virus or its sequela (cytokine activation) has "damaged* the brain, symptoms could persist even without continued viral presence in the CNS. Lower cerebrospinal fluid (CSF) protein and white blood count

values in the psychotic patients (Sewell et al. 1994a) suggest that the psychotic patients may have a less robust immune response in the CNS, which would then allow more damage from the HIV or from some other infectious pathogen to occur and would thus predispose the psychotic patient to an encephalopathy and subsequent psychosis, followed by death. El-Mallakh (1991) speculates that intracellular free calcium accumulation may be responsible for newonset psychosis in patients infected with HIV, at least when the psychosis occurs along with manic symptoms. His idea is based on the work of Dubovsky et al. (1989), Dreyer et al. (1990), and El-Mallakh and Jaziri (1990). Dreyer et al. (1990) found that purified HIV coat protein, gpl20, increased intraneuronal free calcium in vitro in a dose-dependent manner. El-Mallakh and Jaziri (1990) hypothesize that increases in intracellular free calcium bring about increased and inappropriate neurotransmitter release, which may then lead to the production of manic and psychotic symptoms. Interestingly, Sierra-Honigmann et al. (1995) approached the relationship between psychosis and HIV, as well as other viruses, by studying patients with well-established schizophrenia rather than those with new-onset psychosis. They used viral-detection methods to test the viral etiology of schizophrenia. Specifically, they used polymerase chain reaction (PCR) to search for cytomegalovirus, HIV, influenza A, and several other viruses in the hippocampus (n = 3) or CSF (n = 48) or mononuclear cells (n = 9) of patients with well-documented schizophrenia. They found no virusspecific nucleic acids in any of the samples tested. Another theory to explain new-

onset psychosis in HIV-infected individuals is that it results from brain damage from some other "opportunistic" infectious agent such as herpes simplex virus or cytomegalovirus. The findings by Sewell et al. (1994a) did not support this hypothesis. In general, their patients had onset of psychotic symptoms while medically stable. One would expect that a patient with an opportunistic infection of the CNS might show systemic symptoms of illness, such as fever. In addition, one would expect evidence of infection to be apparent on magnetic resonance imaging (MRI) scans. This, however, was not the case for the psychotic patients studied. Last, although autopsy findings of Sewell et al. (1994a) revealed a variety of opportunistic pathogens, there was no association of a specific opportunistic infection with psychiatric or neuropsychological findings in their small sample. Still another theory proposes that the psychosis in these patients may result from one or more events that, singly or together, would be markedly stressful to almost anyone in similar circumstances in the person's culture (i.e., brief reactive psychosis). A case report by Boast and Coid (1994) supports this possible etiology. These authors conclude that the study of the psychodynamic aspects of acute psychotic disorders without evidence of cognitive impairment in HIV-infected patients has been neglected. Although the patients Sewell et al. (1994a) studied did experience multiple significant stresses, in all cases the symptoms lasted for more than a month and thus did not meet the DSM-Hl-R criteria for brief reactive psychosis. In addition, there was no evidence that the psychotic patients had more stresses or more severe stresses than the nonpsychotic comparison patients.

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One intriguing finding is that HIVinfected patients with new-onset psychosis may have a more frequent past history of stimulant and sedativehypnotic abuse or dependence than HIV-infected patients who are not psychotic (Sewell et al. 1994a). It is conceivable that such drug abuse increases a patient's susceptibility of developing psychosis when he or she is later infected with HIV. Other possible explanations exist for new-onset psychosis. The development of psychosis in HIV-infected individuals could simply be due to the coincidental occurrence of newonset schizophrenia or a psychotic mood disorder. Finally, a number of separate etiological factors mentioned above may act jointly and lead to psychosis in HIV-infected patients. Evaluation of Psychosis in Patients With HIV Infection The first step in the evaluation of HIV-infected patients with psychosis is to rule out known causes of psychosis such as a primary psychiatric illness (preexisting or new-onset), medical illness, or adverse reaction to medication. Table 3 lists many of the possible causes of psychosis in an HIV-infected patient. The causes are numerous and varied. For example, Daif et al. (1992) published a case report of a patient with AIDS and tuberculous meningitis who presented with paranoid psychosis. Evaluation should include a comprehensive history and a physical examination. In many instances, sources of history other than the patient will be needed. In addition to determining the onset and course of the patient's symptoms, information regarding a possible preexisting psychotic illness should be sought. Signs of medical illness, drug intoxication, or medication toxicity may be evi-

Table 3. Possible causes of psychosis in human immunodeficiency virus (HIV)-infected patients Primary psychiatric illnesses (preexisting or new-onset) Bipolar affective disorder with psychosis Brief psychotic disorder Delusional disorder Major depression with psychosis Schizoaffective disorder Schizophrenia Schizophreniform disorder Shared psychotic disorder Substance-induced psychotic disorder (amphetamine) Medical illnesses Autoimmune disorder Systemic lupus erythematosus Endocrine disorders Hyper- or hypoparathyroidism Hyper- or hypothyroidism Hypoadrenocorticism Hepatic diseases Neurological disorders Auditory nerve injury/deafness Central nervous system infections (e.g., tuberculous meningitis or cryptococcal infection) Central nervous system neoplasm (e.g., lymphoma) Cerebrovascular accidents Epilepsy Huntington's disease Migraine Renal diseases Medications Acyclovir Azidothymidine Buspirone Cydoserine Ganciclovir Interferons Isoniazid Predrusone Trimethoprim-sulfamethoxazole Vincristine dent on physical examination. The possibility that new-onset psychotic symptoms may result from medications deserves special consideration due to the number of prescribed medications and self-administered remedies that are often part of a patient's survival strategy. For example, Smith et al. (1994) described two patients with HIV-associated nephropathy who were treated with 60 mg of predrusone daily for 2-6 weeks and who subsequently developed psychosis, and Chen et al.

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(1992) reported a case of ganciclovirinduced visual hallucinations. In addition, a patient with HTV and severe anxiety developed psychosis after one 5-mg dose of buspirone (Trachman 1992). Focal neurologic deficits may herald the presence of stroke or CNS neoplasm. Lesions in certain brain regions such as the anterior frontal lobes may not cause focal deficits and, therefore, even in the absence of focal deficits, computed tomography (CT) or MRI scan is an important part of the evaluation of an HIV-infected patient with new-onset psychosis. With strict assessment criteria, it seems that electroencephalograms (EEGs) are normal in HIV-infected patients who have unimpaired neuropsychological status (Binnie and Prior 1994). In patients with AIDS dementia, 65 percent will have diffuse slowing, 22 percent will have focal slowing, and 11 percent will have paroxysmal slow and sharp activity. In the absence of cognitive deficits or signs and symptoms of delirium, EEGs probably are not a necessary part of the evaluation of new-onset psychosis; however, quantitative EEG assessment methods in longitudinal studies may provide a sensitive warning of impending neurological disease in asymptomatic patients (Binnie and Prior 1994). The evaluation of new-onset psychosis in patients infected with HIV should also include a general admission panel of laboratory tests, including electrolytes, a complete cell count, liver function tests, thyroid function tests, urinalysis, and some form of drug screening (urine or blood). Treatment of Psychosis in Patients With HIV Infection If the evaluation uncovers any under-

lying causes or contributing factors, then initial treatment efforts should be geared toward eliminating them. Frequently, addressing the underlying cause may result in resolution of the psychosis. Regardless of the etiology of the psychotic symptoms, symptomatic treatment with neuroleptic medication is usually necessary, at least initially. In their review of case reports, Harris et al. (1991) found that almost all commonly used neuroleptic medications have been prescribed to treat psychosis. Clinicians with experience treating new-onset psychosis in HTVinfected patients generally agree that these patients are unusually sensitive to both the benefits and the side effects associated with neuroleptic medications. Whether the presence of HIV increases this sensitivity is not known. Ostrow et al. (1988) recommends that low doses of highpotency neuroleptics be used because of the lower risk of anticholinergic side effects. Numerous reports suggest that HIV-infected patients may be especially vulnerable to extrapyramidal symptoms, including neuroleptic malignant syndrome and tardive dyskinesia (YD) (Shedlack et al. 1994). Fernandez and Levy (1993) reported a series of four patients with HIV infection and psychosis from various etiologies who had developed severe extrapyramidal symptoms from fluphenazine, haloperidol, perphenazine, thioridazene, and thiothixene. Each patient was ultimately switched to molindone, and each experienced significant therapeutic benefits without extrapyramidal side effects (EPS). Fernandez and Levy (1993) note that molindone does not appear to have the same propensity to induce side effects as do other neuroleptic agents (Markowitz and Brown 1987; Owen and Cole 1989);

this may be the result of its weak affinity to bind centrally to D, (Owen and Cole 1989) and D2 receptors (Richelson 1984) as well as to H, muscarinic and a, adrenergic receptors. Singh and Catalan (1994) successfully treated four psychotic male AIDS patients with risperidone. They found that low doses of risperidone (1 or 2 mg twice daily) were effective and did not cause EPS, even though two of the patients had previously developed EPS from haloperidol, chlorpromazine, and thioridazine. A rater-blind randomized study of the efficacy and side effects of haloperidol and thioridazine in the treatment of new-onset psychosis in HIV-positive individuals was reported by Sewell et al. (1994i>). The study included 13 men in whom the development of psychosis could not be attributed to delirium or to nonHlV-related organic factors such as recent drug or alcohol abuse or dependence. Patients who entered the study were evaluated with a number of rating scales of psychopathology and medication side effects and then were randomly assigned to treatment with haloperidol or thioridazine. The mean (± standard deviation [SD]) starting dose in chlorpromazine equivalents (CPZE) for patients treated with haloperidol was 48 (± 41) mg, and the mean (± SD) starting dose for patients treated with thioridazine in CPZE was 86 (± 46) mg. The optimal dose was established clinically by balancing maximum possible reduction in psychotic symptoms against minimal possible side effects. In general, each patient's dose was gradually increased over the 6-week study period. Patients were not treated prophylactically with an anti-EPS medication. Eight patients who were treated with haloperidol completed the study, and

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the mean maximum daily dose for these eight patients was 120 (± 61) mg CPZE. Five patients who were treated with thioridazine completed the study, and the mean maximum daily dose for these five patients was 131 (± 68) mg CPZE. The difference in mean maximum daily dose between the two groups was not significant. Both neuroleptics produced modest but significant reductions in overall level of psychosis and in positive symptoms, but not in negative symptoms. In terms of side effects, none of the patients experienced symptomatic orthostasis. All the haloperidoltreated patients developed EPS and required treatment with anticholinergic medication. One patient treated with haloperidol developed TD, and another patient experienced sedation. Three of the five patients treated with thioridazine had problematic side effects. One patient developed EPS, and another had noticeable sedation. A third patient experienced weight gain, dry mouth, and retrograde ejaculation and developed TD. Because of the risk of side effects, including TD, before beginning treatment patients should be educated about the risks and benefits of the use of neuroleptic medication, should have an opportunity to ask questions, and should indicate in writing their agreement with the treatment plans, including the use of neuroleptic medication. Of course, in emergency situations when patients are extremely agitated, neuroleptic treatment may have to be initiated before obtaining the patient's consent. In this case, written consent should be obtained as soon as the patient is clinically able to cooperate with the process. When a patient is initially too agitated to provide consent for neuroleptic medication, it is helpful to

determine if the patient has designated someone to make decisions on his or her behalf in the event that he or she is unable to do so (e.g., durable power of attorney for health care). If such a person exists, then consent for the use of neuroleptic medication should be obtained from this person. If no such person has been designated, then obtaining the approval from a partner or family member is recommended. Although obtaining the approval of a family member may not provide legal immunity, it seems ethically reasonable and helps achieve two important goals: establishing rapport with key individuals in the patient's support system and educating these individuals. Nonpharmacological treatment approaches are extremely important for patients with HIV-spectrum illness and psychosis. While the patient's symptoms are acute, it is usually helpful to include at least one member of the individual's support system for at least part of each appointment. Many patients with HIV-associated psychosis may benefit from participation in a support group for patients with HIV-spectrum illness and serious psychiatric illness. If a patient has drug or alcohol abuse or dependence, then participation in an active recovery program is essential. Once the psychosis has been effectively treated, some patients may benefit from couples' therapy to resolve issues such as the impact of HIV on the relationship. Patients with psychosis who are in the later stages of HIV-spectrum illness may benefit from an array of supportive services, including home meal delivery, day treatment center participation, or relocation to a board-and-care home for patients infected with HTV.

Summary The amount of published systematic information about preexisting psychosis and HIV-spectrum illness and about new-onset HIV-associated psychosis is limited. This article summarizes what is known and what is suspected about both of these conditions. Although neither condition is especially common, when they cooccur, they appear to be associated with more morbidity and mortality than would be expected if either condition was present alone. It appears that no matter which illness develops first, the combination may hasten a patient's death. The etiopathology of new-onset psychosis in patients infected with HTV remains unclear but seems likely to be possible sequela of HTV encephalopathy. The first and most important task in the evaluation of an HIV-infected patient with psychosis is to rule out known causes of psychosis. If an underlying reversible condition is discovered, then the initial treatment should attempt to treat this condition. Regardless of the etiology of the psychotic symptoms, neuroleptic medication is often needed. Neither the systematic studies by Sewell et al. (1994b) nor any of the other published reports dearly identify a preferred neuroleptic medication for this group of patients, although molindone and risperidone may ultimately prove to be superior to other neuroleptic medications. Patients with psychosis and HIV-spectrum illness appear to be unusually sensitive to both the therapeutic benefits and the side effects associated with neuroleptic medication. Further systematic exploration of these issues hopefully will lead to more effective interventions and may potentially shed light on the etiopathological basis of psy-

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chosis in general and of schizophrenia in particular.

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The Author Daniel D. Sewell, M.D., is Assistant Clinical Professor, Department of Psychiatry, University of California, San Diego, and Medical Director, Mission Valley Mental Health Clinic, San Diego Veterans Affairs Medical Center, San Diego, CA.

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