There are numerous psychiatric difficulties that can occur in the context of HIV infection, yet studies of the treatment of HIV-related psychiatric disorders are limited. This section summarizes the existing scientific literature on the treatment of specific psychiatric disorders for patients with concurrent HIV/AIDS.


1. Dementia and the spectrum of cognitive disorders

Most research studies on the treatment of cognitive disorders associated with HIV infection have focused on HIV-associated dementia. Fewer studies have looked at the benefits of intervention at earlier stages of cognitive decline despite the possibilities for treating disorders, such as minor cognitive motor disorder, that involve neuronal cell dysfunction rather than cell death. Treatment of neuropsychological impairment without clinical disorder has been studied to some extent, and protection against neuropsychological impairment has been studied least.

Pharmacologic treatment strategies for cognitive disorders can be divided into four types: 1) antiretroviral therapies, 2) therapies aimed at immunological measures or inflammatory mediators, 3) therapies aimed at bolstering the response of the brain to the onslaught of the infection (e.g., neurotransmitter manipulation), and 4) nutritional therapies. Most controlled studies have investigated the efficacy of antiretroviral therapies, and while these studies have advanced our knowledge about interventions for cognitive disorders, several key factors must be kept in mind. First is the fact that most published studies to date report on the treatment strategy of administering a single antiretroviral agent. Their findings are therefore difficult to interpret in light of the multidrug regimens that are now the standard of care in developed countries. Second, the reports vary widely with regard to the study population, since some studies enrolled subjects on the basis of established criteria for HIV-associated dementia or minor cognitive motor disorder but other studies enrolled cognitively impaired subjects without specifying whether they also met criteria for a clinical disorder. Third, the range of HIV clinical severity also varied widely in study subjects.

Whether antiretroviral agents penetrate the blood-brain barrier sufficiently to adequately suppress viral replication is a key issue that requires further study (379, 380). We know that near-perfect adherence to antiretroviral therapy is required to maintain plasma viral load at undetectable levels. Even in the best-case scenario, if decreased plasma viral load is achieved and levels of antiretroviral agents in CSF or brain tissue are optimized, it is not yet known whether complete suppression of replication in the CNS can be achieved (381). Another theoretical concern is that if antiretroviral resistance develops in the CNS, it is possible that resistant HIV could then reseed the peripheral circulation. This mechanism could potentially lead to increased prevalence of neurocognitive disorders as well as systemic progression of HIV disease.

a) Zidovudine treatment of cognitive disorders or dysfunction

Two randomized, placebo-controlled clinical trials have provided evidence for the effectiveness of zidovudine in reducing neuropsychological impairment for patients with HIV infection. Sidtis and colleagues (382) treated a group of 40 homosexual men (early-stage dementia and mean CD4 cell counts of 500 cells/mm3) with 1000 or 2000 mg/day of zidovudine or placebo. They found that both treatment groups demonstrated significant combined mean neuropsychological z score improvements when compared to the placebo group. In another randomized, placebo-controlled clinical trial, Schmitt and colleagues (383) used zidovudine to treat 281 subjects who did not necessarily have clear-cut signs of neuropsychological impairment or cognitive disorder but were stratified into two groups, AIDS or early asymptomatic HIV infection, on the basis of CD4 cell count. Significant improvements were found in attention, memory, visual-motor, and simple motor function at 4 months in both groups, which led to premature discontinuation of the study.

An open study of zidovudine in injection drug users found improvements in neuropsychological functioning on a number of subtests (384). Four case control studies retrospectively examined whether zidovudine treatment was associated with outcomes such as reduced leukoencephalopathy (385, 386), lower CSF 2-microglobulin levels (which are related to neuropsychological improvement) (387), or improved neuropsychological measures (388). Three of the four studies found that the zidovudine-treated patients had significantly positive findings compared to untreated patients.

While the above studies support the efficacy of zidovudine, they do not resolve the issue of optimal dosage nor zidovudine resistance (380). Doses of up to 2000 mg/day of zidovudine were used in some of the above studies, which are often associated with significant toxicity, including neutropenia and anemia. A typical zidovudine dose used now is 500–600 mg/day, and many patients cannot tolerate even these reduced doses (375). Patients can develop resistance to zidovudine, especially if used alone, and because zidovudine-resistant strains can be transmitted from one person to another, some HIV experts have considered the need for testing for zidovudine resistance before choosing which agents to use in treatment (389).

b) Other antiretroviral treatments of cognitive disorders or dysfunction

Treatment studies of antiretroviral agents other than zidovudine are fewer but illuminating. De Ronchi and colleagues (390) conducted a clinical trial (N=88) that compared zidovudine to didanosine to refusal of therapy in both symptomatic and asymptomatic HIV patients. They found that for subjects who were symptomatic for HIV disease, both zidovudine and didanosine treatment resulted in better performance on all neuropsychological subtests. In general, asymptomatic subjects did not show significant differences in neuropsychological performance compared to the untreated group. The findings suggest differences in effectiveness based on HIV clinical status.

A more recent placebo-controlled study involved the use of abacavir, a nucleoside analogue reverse transcriptase inhibitor with good CSF penetration, in 99 subjects with moderate to severe HIV-associated dementia (391). This study did not demonstrate significant differences in neuropsychological scores between abacavir and placebo groups, but a major limiting factor in this study design was that abacavir alone was added to an already failing antiretroviral treatment regimen.

Of currently available antiretroviral agents, the CSF penetration of stavudine is relatively high (0.4 ratio with serum), but a recent study indicated that stavudine nevertheless penetrates brain tissue poorly (392). The individual protease inhibitors have not been well studied for effects on neurocognitive impairment, and all but indinavir (0.16 ratio with serum) penetrate the CSF poorly (393). Regarding the nonnucleoside reverse transcriptase inhibitors, nevirapine has been shown to have a 0.45 CSF-to-serum ratio and therefore may be a good candidate to include in future controlled studies of HIV-associated cognitive disorders (381).

Ferrando and colleagues (394) studied the effects of various combination antiretroviral therapy regimens on measures of cognitive motor function. They found that tests of attention, concentration, psychomotor speed, learning, and memory were significantly better in those subjects taking antiretroviral therapy than in those who were untreated. Furthermore, they found that those without neuropsychological impairment had lower mean viral load levels, which suggests that antiretroviral treatment benefits neuropsychological functioning through lowering viral load. A similar conclusion was offered by Sacktor et al. (40).

c) Antiretroviral treatments to prevent HIV-associated dementia

A few studies have examined the use of antiretroviral medications to prevent HIV-associated dementia. Moore and colleagues (395) conducted a study of 863 homosexual men treated with zidovudine who were evaluated every 2 months for 2 years or until death. Development of HIV-associated dementia continued with zidovudine treatment but was significantly correlated with low CD4 cell count. Montforte and colleagues (396) used didanosine in a study of 1,047 subjects (median CD4 cell count of 47 cells/mm3 and mean prior zidovudine treatment of 19 months). Subjects were followed every 2 months to a clinical endpoint (AIDS-defining condition, severe adverse event, or death). They reported a very low incidence of HIV-associated dementia (11 subjects, or 1%), although no formal criteria for defining HIV-associated dementia were offered. One randomized clinical trial with 32 subjects that compared zidovudine treatment to placebo found no significant difference in rate of developing dementia by treatment assignment (397). HIV-associated dementia prevention requires further study, but it appears that treatment with antiretroviral medications may prevent the development of HIV-associated dementia and other cognitive motor disorders.

d) Interventions that affect inflammatory mediators

Although peptide T can be thought of as "antiretroviral," since it blocks the binding of envelope glycoprotein to CD4 receptors, it more likely exerts its effects through decrements in the deleterious effects of inflammatory mediators known as cytokines, such as tumor necrosis factor. A multisite, randomized, placebo-controlled clinical trial with intranasal peptide T was conducted on a sample of 215 patients with HIV-associated neurocognitive impairment, most of whom were taking a single antiretroviral agent or a two-drug combination regimen (398). The study found no statistically significant differences between treatment and placebo groups on global neuropsychological z scores. However, subgroup analyses showed that subjects with a CD4 count of 201–500 cells/mm3 and subjects with at least moderate neuropsychological impairment at baseline improved significantly with peptide T compared with those given placebo (p<0.05). In addition, peptide T was well tolerated with no clinically significant toxic effects.

Studies of inflammatory mediators are indicated because researchers have postulated that HIV-related neuronal injury involves the activation of voltage-dependent calcium channels and N-methyl-d-aspartate (NMDA) receptor-operated channels (399). Therefore, studies are underway using memantine (an NMDA antagonist), inhibitors of tumor necrosis factor-, thalidomide, pentoxifylline, and naloxone (an inhibitor of interferon-). Mapou and colleagues (400) conducted a clinical trial with interferon--n3 in 20 asymptomatic subjects with HIV infection and reported significant improvements in neuropsychological performance in selected subtests. While interferon has been associated with neuropsychological side effects, including depression, Skillman et al. (401) reported that such side effects are minimal.

Nimodipine is a voltage-dependent calcium channel antagonist that has been postulated to prevent HIV-related neuronal injury. Two controlled studies of nimodipine, one in combination with zidovudine (402) and one with nimodipine alone (403), found no significant differences in overall neuropsychological performance.

e) Treatments involving neurotransmitter manipulation

Stimulant drugs have been used as palliative agents to help manage symptoms of fatigue, decreased concentration, or memory deficits among patients with HIV-associated dementia or minor cognitive motor disorder. With regard to the specific effect of stimulants on neurocognitive impairment, there has been one randomized, placebo-controlled clinical trial of a small sample of eight opioid-dependent patients maintained on a regimen of methadone (404). This 7-day crossover study with sustained-release methylphenidate (20–40 mg/day) resulted in nonsignificant neuropsychological z score improvements from baseline with methylphenidate but not placebo. Fernandez and colleagues (321) presented case reports of treating patients with HIV-related disease with methylphenidate (30–90 mg/day) or dextroamphetamine (30–60 mg/day). All patients improved significantly; however, there was no placebo control group and the sample size was small. Similar data from a small trial are offered by Holmes et al. (405).

Studies of dopaminergic agonists are supported by preliminary data in the form of case studies of carbidopa and l-dopa (303). The Dana Consortium conducted a randomized, placebo-controlled clinical trial of 36 subjects with HIV-associated cognitive motor impairment who were given l-deprenyl, a putative antiapoptotic agent, and found that deprenyl-treated subjects showed an improvement in neuropsychological test performance, specifically in verbal memory (406). Investigation of the dopaminergic agent pramipexole is currently under way.

Other neurotransmitters such as serotonin and 5-hydroxyindoleacetic acid have been found to be decreased in CSF as HIV disease progresses (407). It is possible that increasing CNS serotonin levels through administration of agents such as SSRIs may be useful in the treatment of cognitive motor impairment.

f) Nutritional therapies and HIV-associated cognitive disorders

Nutritional therapies need to be considered as potential interventions for the cognitive motor symptoms associated with HIV infection. A case report of a subject with apparent late-stage HIV-associated dementia and a low cobalamin (vitamin B12) level due to decreased intrinsic factor secretion responded over 2 months to B12 replacement therapy with complete symptom resolution (408). Oxidative free radical scavengers such as vitamin E, the experimental antioxidant OPC-14117, and the trace mineral and antioxidant selenium may prove to be therapeutically useful.


2. Delirium

Antipsychotic medications have been the treatment of choice in treating delirious states that develop in patients with HIV infection, with most evidence arising from case reports or uncontrolled trials (409, 410). For patients with HIV infection, a prominent issue is the observed increased sensitivity to side effects (299, 300). This sensitivity applies to extrapyramidal side effects with higher-potency agents and also to cognitive side effects with lower-potency antipsychotics.

To date, only one randomized clinical trial has studied the treatment of delirium associated with HIV infection. Breitbart and colleagues (46) approached 244 hospitalized AIDS patients and monitored them for the development of delirium. Among the 30 subjects who went on to develop delirium, 310 episodes of delirium occurred that met both DSM-III-R and Delirium Rating Scale criteria (411). The 30 subjects were randomly assigned to receive haloperidol (N=11), chlorpromazine (N=13), or lorazepam (N=6). Because the six subjects taking lorazepam developed signs of toxicity (oversedation, disinhibition, ataxia, and increased confusion), this treatment was terminated prematurely. Both haloperidol and chlorpromazine treatment resulted in significantly reduced scores on the Delirium Rating Scale in the first 24 hours. The researchers did not report significant problems with extrapyramidal side effects in study patients, but mean daily doses were low.

Scattered case reports or series suggest that other antipsychotic agents may be useful for treating HIV-associated delirium. For instance, molindone (312), risperidone (315), and droperidol (412, 413) have been suggested as alternatives to the standard antipsychotic medication because of differences in side effect profile, onset of action, or potency.


3. Mood disorders

Disturbances of mood occur frequently in the context of HIV infection. Treatment studies are quite varied with regard to variables such as severity of mood disorder, methodology to categorize or diagnose mood disorders, outcome measures, and stage of HIV illness.

a) Acute treatment of depressive disorders—somatic treatments

Many studies, including randomized controlled trials, open-label trials, case series, and case reports, support the efficacy and safety of many antidepressants in the acute treatment of depressive disorders, including major depression, in a wide range of HIV-infected populations at all disease stages.

Wagner and colleagues (286) reported on a series of 6-week studies that used random assignment and placebo control to examine the efficacy of standard and alternative antidepressants for major depression in HIV-infected patients. The agents used at standard doses were fluoxetine, sertraline, imipramine, dextroamphetamine, and testosterone. Response rates to the different agents ranged from 70% to 93% and were significantly higher than placebo.

Similar findings were reported in a randomized, placebo-controlled clinical trial conducted by Elliot and colleagues (287) in 75 HIV patients (45% with AIDS) who had major depression. Both imipramine- and paroxetine-treated groups improved significantly compared to placebo at weeks 6, 8, and 12. The dropout rate due to side effects was higher for those receiving imipramine (48%) than it was for placebo (24%) or paroxetine (20%).

One randomized, placebo-controlled clinical trial (N=120) found that fluoxetine was an efficacious antidepressant agent among depressed HIV patients; the response rate for fluoxetine was 74% versus 47% for placebo (289). The same study reported significant differences between ethnic groups in terms of antidepressant efficacy; the response rates were 84% for white, 67% for Latino, and 50% for black subjects (414). Despite the effectiveness of fluoxetine in treating depression, because both placebo response and attrition were high, the researchers suggested that the addition of another medication in patients with serious medical illness who require multiple concomitant medications may be a significant barrier to the treatment of depression.

In a double-blind, placebo-controlled trial that compared desipramine to fluoxetine in 14 women with advanced HIV disease, both agents were linked to symptom improvement; however, for most of the women significant depressive symptoms remained after the 6-week trial (294). These findings are consistent with those of an open-label fluoxetine trial that compared HIV-positive and HIV-negative depressed men, which found that improvement in the HIV-positive cohort was significantly delayed beyond the 8-week trial compared to the HIV-negative patients (415).

The randomized trials are supported by uncontrolled studies of depression in HIV populations and confirm the effectiveness of fluvoxamine (295) and fluoxetine (293, 416, 417) in HIV-infected asymptomatic patients and of paroxetine, sertraline, and fluoxetine in symptomatic HIV patients (285, 418). In an open trial in which HIV-positive depressed women were given either fluoxetine or sertraline, both drugs were found to be effective treatments (419). Another open-label study found nefazodone effective in the treatment of depressed HIV-positive patients (288). One open-label trial of 32 patients with advanced HIV disease found venlafaxine effective among depressed patients who also had minor cognitive motor disorder (420).

The use of psychostimulants for treatment of major depression in HIV-infected outpatients has been supported in smaller studies, including five case reports, one open-label trial, and one placebo-drug-placebo clinical trial (321, 322, 421, 422). These studies suggest that methylphenidate, up to 35 mg/day, or dextroamphetamine, up to 10 mg/day, can improve major depression.

An open trial of testosterone replacement for hypogonadal men found that of 34 study participants with major depressive disorder, 79% had significant improvement in mood (126). There is a case report of a patient with HIV infection and comorbid major depressive disorder whose depression resolved with treatment with the antiretroviral agent zidovudine (423). For patients with severe major depression who are delusional or have failed medication treatment, ECT has been found to be safe and effective (424).

b) Acute treatment of depressive disorders—psychotherapy

Several studies of psychotherapeutic treatment of depression in HIV patients have been conducted. In a randomized, controlled trial, Targ and colleagues (425) compared structured group therapy plus fluoxetine to structured group therapy with placebo in 20 asymptomatic homosexual men with major depression or adjustment disorder and Hamilton Depression Rating Scale scores 16. Both groups showed significant improvements in depression after 6 weeks of treatment, but there were no differences between treatment groups (425). In contrast, another randomized, placebo-controlled clinical trial that compared the efficacy and safety of fluoxetine plus group psychotherapy versus group psychotherapy alone in 47 depressed HIV-positive men for 7 weeks found that fluoxetine in addition to group therapy was more efficacious than group psychotherapy alone. Differences were particularly apparent for patients whose initial depressive episodes were rated as severe (Hamilton depression score 24) (290).

Markowitz and colleagues (426) conducted a randomized, placebo-controlled clinical trial that compared 16-week interventions with interpersonal psychotherapy, cognitive behavior therapy, supportive psychotherapy, and supportive psychotherapy plus imipramine in 101 HIV patients with depressive symptoms (Hamilton depression score 15). Patients randomly assigned to interpersonal psychotherapy and supportive psychotherapy plus imipramine had significantly greater symptom improvement than those receiving supportive psychotherapy alone or cognitive behavior therapy.

In an earlier study (427), the Markowitz group demonstrated the benefits of interpersonal psychotherapy in HIV-positive, asymptomatic outpatients in an open study of men and women with DSM-III-R major depression or dysthymia. Twenty (87%) out of 23 patients achieved a full remission after 6 weeks by clinical assessment; mean Hamilton depression scores at baseline and follow-up were 25 and 6.8, respectively. Levine et al. (428) reported that four outpatients with major depression remained euthymic for 9 months with structured group psychotherapy after acute remission was achieved with fluoxetine, 20–40 mg/day.

Other studies such as two retrospective chart reviews (284, 429) and a prospective effectiveness study (430) support the findings from controlled and uncontrolled treatment studies of major depression that treatment with a number of different antidepressant agents is effective and generally tolerated in HIV patients.

c) Treatment of other types of depression

Other studies have investigated the efficacy of treatment for other types of depression in HIV patients. These studies generally use screening instruments (e.g., the Center for Epidemiologic Studies Depression Scale [CES-D Scale]) rather than structured interviews or clinical evaluations to diagnose specific depressive disorders. All involved ambulatory patients who had no significant clinical manifestations of HIV disease. In a study of patients with depression (CES-D Scale score >16) but with unknown psychiatric diagnoses, investigators compared cognitive behavior therapy and brief supportive group therapy to a waiting list control condition. Outpatients (N=68) were randomly assigned to an 8-week intervention of cognitive behavior therapy, support group, or a control group. While both types of psychotherapy were superior to the control condition, neither led to significant reductions on the CES-D Scale into the nondepressed range (431).

Eller (432) conducted a randomized, placebo-controlled clinical trial of alternative therapies for depression and assigned 81 male and female outpatients with HIV infection to guided imagery, relaxation therapy, or usual care. The sample had a mean CES-D Scale score of 19. There were no significant declines in CES-D Scale scores during treatment in any of the three groups.

d) Treatment of mania/bipolar disorder

One chart review (433) and one case report (434) have addressed the treatment of manic syndromes in HIV-infected patients. The chart review study identified seven male outpatients with mania who did not improve with lithium or neuroleptic treatment due to toxicity. Three patients had been treated with valproic acid (750–1750 mg/day), two with clonazepam (2 mg/day), one with phenytoin, and one with carbamazepine. All seven patients experienced remission of their manic syndrome with the agent used (433). The case report described the effectiveness of valproic acid in the treatment of acute mania in a patient with AIDS complicated by dementia (434). There are no published studies of maintenance treatments for mania or bipolar disorders in HIV-infected populations.


4. Substance use disorders

Clinical consensus has established the necessity of treating substance use disorders in order to produce optimal psychiatric and medical outcomes for patients with HIV infection. Despite this knowledge, remarkably few studies have investigated psychiatric treatment of substance use disorders in HIV-infected patients. This section will review the literature of the treatment of substance use disorders and associated syndromes.

a) Entry into a treatment program

Entry into a treatment program is probably one of the more critical steps for the assessment and treatment of substance use disorders. Guydish and colleagues (435) described a consultation-education-triage model program that referred drug users with HIV infection to follow-up care for substance use disorders. Of the 86 patients referred over an 8-month period, 81% were referred for further care to a substance use program, with 58% actually contacting the referral resource. Eighty percent had AIDS or symptomatic HIV disease; 37% of patients were dependent on alcohol, 36% were dependent on amphetamines, and 26% were dependent on heroin, marijuana, or cocaine.

b) Methadone maintenance

The Program for AIDS Counseling and Education in San Francisco is considered a model program for inner-city, poor, opiate-dependent, mostly minority men (436, 437). The program provides medical assessment and care, psychiatric treatment, methadone treatment, counseling, detoxification, and tolerance management for opiate addicts. Outcomes for patients enrolled in the Program for AIDS Counseling and Education have been reported in two conference papers. In one report, 29 opioid-dependent HIV patients with a mean of 28 days of drug use in the past month reduced their use to a mean of 5.9 days of use per month after 3 months in the program (438). The other report focused on clinical events related to drug use before and after enrollment for 62 patients in the program (439). Clinical events included medical complications and lapses in compliance with treatment. At baseline, patients experienced 0.72 clinically significant medical complications per 100 patient years, whereas the rate decreased significantly to 0.16 during enrollment in the Program for AIDS Counseling and Education. There was also a reduction in preventable HIV clinical events from 0.21 per 100 patient years to 0.02 per 100 patient years after starting the program. The reports provide some evidence that both the medical care as well as substance use behaviors of HIV-infected opioid addicts can benefit from a multidisciplinary, structured intervention.

c) Pharmacologic treatment of substance use disorders

One study of HIV-infected patients investigated the effect of antidepressant medications on symptoms of drug dependency, such as drug craving and comorbid depression. Batki (440) conducted a controlled trial that compared fluoxetine to placebo in 37 patients with cocaine and opiate dependency who were on a regimen of methadone maintenance. Of this sample, 41% also had major depression. Participants treated with fluoxetine (20–40 mg/day) had lower median measures of cocaine metabolites in urine and fewer mean days of cocaine use per week (1.6) compared to those given placebo (2.6); the fluoxetine-treated patients also reported reduced cocaine craving. Those with major depression showed significant improvement after the 12-week treatment.

d) Overall outcomes of psychiatric treatment

Lyketsos and colleagues (430) conducted a 14-month prospective effectiveness study of clinical outcomes in HIV patients who were referred to psychiatric treatment. Within the cohort, 110 patients had current (N=66) or recent (N=44) substance use disorders; there were high rates of polysubstance dependence, with only a small proportion of patients who abused alcohol. The psychiatric treatment took place within a primary care clinic and included treatment for substance abuse and concurrent psychiatric disorders. Psychiatric intervention led to a decrease in the use of substances and better clinical condition.


5. Anxiety disorders

Anxiety disorders are prevalent in the population of persons who have or are at risk for HIV infection, but studies of specific treatments for anxiety disorders in HIV patients are lacking. The literature provides only one retrospective chart review and two case reports that address the management of anxiety disorders in HIV-positive patients. There are no treatment studies of PTSD among HIV-infected patients, although PTSD rates are high in some HIV-affected groups (441).

A chart review study found that buspirone was an effective anxiolytic in opioid-dependent, HIV-positive patients who were on a regimen of methadone maintenance and who also had a comorbid anxiety disorder. The study additionally showed a modest reduction of urine tests positive for substances of abuse, from 42% to 30% (328).

McDaniel and Johnson (442) found fluoxetine to be effective in the treatment of obsessive-compulsive disorder (OCD) in two HIV-positive patients. Both patients tolerated the fluoxetine with minimal side effects and responded with resolution of OCD symptoms within 6–8 weeks.

A male patient with advanced AIDS complicated by comorbid trichotillomania and major depression was reported to have responded well to sertraline at a maximum dose of 150 mg/day. The patient reported experiencing a 70%–80% decrease in hair pulling and a modest improvement in depressed mood, with minimal medication side effects (443).


6. Psychotic disorders

Nine literature citations, two of them clinical trials and the remainder case reports, present evidence concerning the efficacy of psychotropic medication for the management of psychosis in the presence of HIV infection. The nine reports contain fewer than 100 subjects, approximately 90% of them male, and most with symptomatic HIV infection, usually AIDS. Where stated, the majority did not have a history of psychosis before HIV infection, and, where stated, the majority had cognitive impairment.

Antipsychotic medications were effective in treating psychosis whether or not cognitive dysfunction or delirium was present. One large case history series found that patients with manic psychosis showed more improvement than patients with schizophreniform psychosis (315). The two clinical trials (31, 444) found that positive symptoms responded better than negative symptoms. Across studies the subjects, who largely had advanced HIV disease, required lower doses of antipsychotic medication, similar to the pattern seen in the elderly. Lower doses were also useful due to increased sensitivity to side effects. If a patient did not respond to or tolerate one antipsychotic, it was useful to try another from a different class (300, 301, 310, 312).

In case reports, the use of adjunctive medications, including antianxiety drugs, antidepressants, and mood stabilizers, was a common practice and often useful in individual cases, but there have been no controlled studies on the efficacy of these combinations. Two case reports, each of a single male subject with AIDS, found that catatonia responded rapidly to lorazepam (445, 446). No side effects were noted.

Maintenance medication was not always necessary to sustain remission of psychotic symptoms (42, 312). In some cases it was specifically noted that symptoms of psychosis diminished as severe late-stage medical illness progressed (42). While it has been hypothesized that there is a window of vulnerability to psychosis or mania occurring early in the course of HIV-associated dementia (447), no data support this theory, and most patients treated for psychosis have continued their maintainance medication regimens.

There are few data on the treatment of psychosis in early-stage HIV infection or among women nor is there information concerning potential modifications in the treatment of preexisting psychotic illness, which might be necessary in the presence of advancing HIV infection.


7. Adjustment disorders

Two open-label clinical trials have assessed the effectiveness of psychotropic medications in the management of adjustment disorders in HIV-positive patients. As part of a larger study that examined the effectiveness of paroxetine in the treatment of depression in the context of HIV infection, Grassi and colleagues (418) included five patients with a diagnosis of adjustment disorder with depressed mood. All five patients received paroxetine (20 mg/day) and showed significant recovery as measured by the Hamilton depression scale at the 6-week endpoint.

Five male patients with neurocognitive impairment as well as a diagnosis of adjustment disorder with depressed mood were treated as part of a larger study of the effectiveness of psychostimulants in patients with HIV-associated dementia. Four of the five patients who received methylphenidate had moderate to marked improvement in symptoms; the one patient with minimal response was switched to dextroamphetamine and subsequently had a moderate response (405).


8. Sleep disorders

Numerous reports have documented disrupted sleep and altered sleep architecture in HIV patients (29, 448, 449), including one study which linked fatigue and sleep disturbances to morbidity and disability in homosexual men (450). While the etiologies remain unclear, some investigators have documented growth hormone dysregulation associated with sleep pathology (451), and one study found obstructive sleep apnea due to adenotonsillar hypertrophy to be a primary cause of sleep disruption in a cohort of HIV patients with excessive daytime sleepiness (452).

The treatment of sleep disorders in HIV-positive persons has been examined in only one open-label clinical trial of flurazepam in 12 patients (453). All patients were given a one-time dose of flurazepam, 30 mg, to examine changes in the patients' electroencephalographic recordings during sleep. Flurazepam mainly affected non-REM parameters, such as reduction of times awake during the night and increases in stage two and effective sleep time. As this study did not address treatment with flurazepam beyond a one-time dose, actual treatment recommendations cannot be made.


9. Disorders of infancy, childhood, and adolescence

Since HIV infection in childhood is associated with developmental delays or loss of acquired skills, it is hoped that early treatment will promote normal development. Currently, it appears that antiretroviral drug therapy reduces morbidity in children, especially in those with HIV-associated neurocognitive impairment. Several studies have reported a significant increase in mental ability, as measured by the WISC-R, the McCarthy Scales of Children's Abilities, or the Bayley Scales of Infant Development, in over 450 children during 12- and 36-month trials with zidovudine (58, 246, 454, 455). None of the studies included a control group.

The safety of zidovudine for children is similar to that for adults, although up to 40% of children experience hematological side effects that require dose alterations (246). The one published study of 54 children that did not find a significant improvement in cognitive functioning with zidovudine treatment did find a significant decrease in CD4 levels over the treatment period. No data were provided on adherence to treatment or zidovudine resistance (456). Other antiretroviral agents, such as didanosine, have been studied, with a multisite project showing that combination zidovudine and didanosine therapy was superior to either used as monotherapy for most of the CNS outcomes evaluated (457). Although combination antiretroviral therapy with three agents is standard practice with adults, there is only one case report of its use with a child (458). Caregivers noted the positive impact of this regimen on an 8-year-old boy's neurocognitive development.

The effectiveness of the treatment of other mental and behavioral disorders associated with HIV infection in children and adolescents is largely unstudied. Case reports of single patients suggest that attention deficit disorders and depressive disorders in those with HIV infection may be treated by using regimens that are standard for those without HIV infection (459). As in the treatment of adults, children with HIV infection may be especially sensitive to some treatment side effects, such as insomnia or appetite suppression associated with psychostimulant use.

Pain frequently accompanies pediatric HIV and can involve multiple organ systems (460). Clinicians should be aware that the inadequate verbal skills of younger children or the fact that some children are from non-English-speaking families can lead to the underrecognition and undertreatment of pain (461).


10. HIV-associated syndromes with psychiatric implications

A number of HIV-associated clinical syndromes have psychiatric implications, such as wasting syndrome, fatigue, pain, and sexual dysfunction. Because there are overlapping symptoms with these conditions and psychiatric disorders, it is useful for psychiatrists to be aware of treatment studies for such syndromes so that overall clinical outcomes can be improved.

a) Wasting syndrome

Several studies have focused on the use of testosterone for treatment of wasting syndrome in both patients with low testosterone levels and patients with "clinical hypogonadism" (normal hormone levels). Grinspoon and colleagues (462) conducted a double-blind, placebo-controlled study of hypogonadal HIV-positive men with wasting syndrome that demonstrated the safety and efficacy of testosterone replacement therapy (300 mg i.m. every 3 weeks). The treatment resulted in a significant increase of lean body mass, overall quality of life, and self-perception of appearance in treated subjects. Similar findings have been reported by Rabkin and colleagues (126, 343, 463), who conducted several randomized, placebo-controlled trials as well as open trials of testosterone replacement in men with clinical hypogonadism that led to significant positive effects on mood and weight (lean body mass). Another study that used oxymetholone, a testosterone derivative, demonstrated weight gain in cachectic men with AIDS (464). A controlled study of hypogonadal women with HIV infection that used transdermal testosterone replacement also reported improvement in lean body mass and quality of life (465).

Wagner and colleagues (466) reported an additional improvement of measures on the Brief Symptom Inventory and nutritional status for patients who exercised in addition to receiving testosterone replacement. In a double-blind, randomized, placebo-controlled trial, researchers found that resistance exercise in addition to testosterone and the anabolic steroid oxandrolone substantially increased lean body mass (467). Two open-label studies have reported that oxandrolone, 20 mg/day, in HIV patients with wasting syndrome led to significant weight gain, in particular, increases in body cell mass (334, 335).

Several clinical trials have used the recombinant growth hormone somatotropin for treatment of HIV-related wasting (336, 340). A large multicenter, double-blind, placebo-controlled study that used growth hormone in patients with AIDS wasting reported significant improvement in overall quality of life and weight gain, with no negative effect on virological or immunological markers (339). Treatment was well tolerated.

Since tumor necrosis factor- has been postulated to have a role in the pathogenesis of wasting syndrome, the effect of thalidomide, a selective inhibitor of tumor necrosis factor-, has been studied in patients with AIDS wasting syndrome. Two reports (a mail survey of thalidomide users and a small randomized, placebo-controlled clinical trial) have supported the positive effects of thalidomide on weight gain, appetite, and quality of life (341, 342).

b) Fatigue

Breitbart and colleagues (468) conducted a randomized, placebo-controlled clinical trial that used two psychostimulant medications, methylphenidate and pemoline, in treating fatigue among HIV patients. They found that both treatments were superior to placebo, with a stronger effect in the methylphenidate group. In addition, they reported that improvement in fatigue was associated with improvement in depressive symptoms and psychological distress. In an open trial of depressed patients with CD4 counts below 200, dextroamphetamine administration led to improvement of fatigue in 95% of patients along with reduction in depression scores (322). Testosterone replacement with dehydroepiandrosterone (DHEA) in HIV-infected hypogonadal men has also been found to improve symptoms of fatigue (469).

c) Pain

Studies of the frequency and adequacy of treatment for pain among patients with AIDS find wide variations in the effectiveness of interventions to manage pain. A study by Breitbart et al. (123) found that 85% of HIV patients in their ambulatory sample treated at a cancer center received inadequate pain therapy. Yet a different study reported that only 20% of their sample of AIDS patients treated in the hospital, home care, or nursing facility did not receive effective pain control (470).

While agents such as tricyclic antidepressants and anticonvulsant medications are often used to manage chronic pain from peripheral neuropathy, published treatment studies for HIV-associated peripheral neuropathy have not supported their use. Two randomized, controlled trials have focused on HIV-associated peripheral neuropathy; both trials used the agent mexiletine, an antiarrhythmic drug with local anesthetic properties that had been used in the treatment of diabetic neuropathy (317, 471). Neither study found pain relief different from that of placebo. Furthermore, Kieburtz et al. (317) did not find that treatment with amitriptyline provided significant pain relief compared to placebo. Shlay and colleagues (472) conducted a randomized, controlled trial that compared acupuncture, amitriptyline, and placebo for pain due to HIV-related peripheral neuropathy and found that neither acupuncture nor amitriptyline was more effective than placebo.

d) Sexual dysfunction

Sexual dysfunction is experienced commonly by HIV patients, both men and women, particularly with HIV disease progression. While no treatment trials are currently published, a cautionary note regarding sildenafil is clinically important. Sildenafil should be used judiciously in patients with erectile dysfunction who are also taking protease inhibitors, since the primary route of sildenafil metabolism is via the cytochrome P450 isoenzyme 3A4. One death has been reported in a 47-year-old male taking ritonavir and saquinavir who was administered 25 mg of sildenafil (473). The manufacturer of sildenafil has recommended that patients receiving ritonavir should not take more than a single sildenafil dose of 25 mg in a 48-hour period.


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