Prevalence, diagnosis, and pharmacological treatment of mood disorders in HIV disease

Prevalence, Diagnosis, and Pharmacological Treatment of Mood Disorders in HIV Disease Dean G. Cruess, Dwight L. Evans, Martin J. Repetto, David Gettes, Steven D. Douglas, and John M. Petitto Human immunodeficiency virus seropositive (HIV⫹) individuals are at a heightened risk of developing mood disorders and related syndromes. Over the past several decades, increased rates of mood disorders, including depression and mania, have been reported among HIV⫹ individuals. Because alterations in mood may impact on quality of life and perhaps reduce adherence to antiretroviral treatment regimens that are critical for preventing disease progression, recognition and effective treatment of mood disorders is essential. There are accumulating data showing that antidepressants and mood stabilizers, as well as other novel agents, might benefit HIV⫹ individuals suffering from a concomitant mood disturbance. This review highlights the relevant studies that have examined prevalence rates of mood disorders in HIV⫹ individuals, characteristics of HIV disease that influence the diagnosis and psychopharmacologic treatment of mood disorders, including complex interactions with antiretroviral medications, as well as the available evidence regarding the efficacy of agents used to treat depression and mania in the context of HIV disease. Biol Psychiatry 2003;54: 307–316 © 2003 Society of Biological Psychiatry Key Words: Human immunodeficiency virus, mood disorders, prevalence, diagnosis, treatment

positive for major depression, and more than one quarter for dysthymia. It should be noted that these rates were based on screening instruments and significantly exceed clinical interview-based diagnostics assessments; however, mood disturbances are often viewed as one of the most common psychiatric symptoms reported by HIV⫹ individuals, and clinicians need to actively identify those individuals at risk and ensure the availability of appropriate treatments. This review summarizes studies examining the prevalence of mood disorders and the use of psychotropic medications to treat depression and mania in the context of HIV disease. This includes a discussion of clinically significant treatment considerations (e.g., efficacy, side effects, drug– drug interactions) derived from the existing literature. We also discuss some of the complexities in diagnosing mood disorders in this population. Overall, there is compelling evidence that mood disorders are at higher prevalence rates in HIV⫹ individuals than in the general population, and that psychopharmacologic interventions can improve mood during the course of HIV disease.

Diagnostic Considerations Introduction

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uman immunodeficiency virus seropositive (HIV⫹) individuals may be at an increased risk of developing psychiatric disorders. A recent epidemiologic study assessed a nationally representative sample of 2864 HIV⫹ patients during the past year, and found that nearly half screened positive for a psychiatric disorder, including major depression, dysthymia, and generalized anxiety disorder (Bing et al 2001). More than one third screened

Departments of Psychology (DGC), Psychiatry (DLE, DG), Medicine (DLE), Neuroscience (DLE), and Pediatrics (SDD), University of Pennsylvania, Philadelphia, Pennsylvania; and the McKnight Brain Institute, Departments of Psychiatry, Neuroscience, and Pharmacology, University of Florida College of Medicine (MJR, JMP), Gainesville, Florida. Address reprint requests to Dean G. Cruess, Ph.D., University of Pennsylvania, Department of Psychology, 3815 Walnut Street, Philadelphia, PA 19104-6196. Received December 2, 2002; revised February 21, 2003; accepted March 14, 2003.

© 2003 Society of Biological Psychiatry

Psychiatric disorders among HIV⫹ individuals are frequently unrecognized and untreated (Evans et al 1996). The assessment of mood disorders during HIV disease poses a number of unique challenges, including that mood disorders can be considered primary or secondary to the medical illness. Treisman et al (1998) have noted that the primary group may or may not have a previous history of a mood disorder but have prevalence rates similar to traditional risk groups, such as homosexual men and injection drug users. Those with mood disorders secondary to HIV do not necessarily have a prior history or a familial history, and the affective disturbance most likely results from viral infection and central nervous system (CNS) brain involvement. There is no consistent evidence that depressive symptoms increase as HIV disease progresses. Although Lyketsos et al (1996) found an increase in depressive symptoms 0006-3223/03/$30.00 doi:10.1016/S0006-3223(03)00318-4

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approximately 1.5 years before the onset of acquired immunodeficiency syndrome (AIDS), Rabkin et al (1997b) showed that depression did not increase despite worsening HIV infection over a 4-year period. Goggin et al (1997) found that HIV⫹ depressed and nondepressed men did not differ on global neurocognitive impairment, although the depressed individuals exhibited greater memory impairment. The clinician must also consider the possibility of a spontaneous onset of first-episode as well as a recurrence of depression in a recently diagnosed HIV⫹ individual. Distinguishing between primary and secondary mood disorders among HIV⫹ patients requires a thorough assessment of affective symptoms both current and past and a comprehensive evaluation of medical and neurologic contributions. Diagnosing major depression among HIV⫹ individuals is also complicated by the fact that several symptoms of depression (e.g., fatigue, sleep disturbance, and weight loss) are also common symptoms of HIV disease (Norman et al 1992; Perkins et al 1995). Depressive symptoms may also mirror symptoms associated with a comorbid substance-related disorder (Regier and Farmer 1990). Because of overlapping symptom features, mood disorders may be under-diagnosed and inadequately treated. Thus, a thorough medical and psychiatric assessment is warranted. Due to this potential for under-diagnosis, an inclusive approach in diagnosing depression is generally recommended in patients with comorbid medical illness.

Prevalence of Mood Disorders in HIV Infection Depression HIV⫹ seropositive individuals have reported depressive symptoms since the genesis of this disease, but there has been a wide range of reported prevalence rates. These rates have ranged between 5% and 20% across the majority of studies (Atkinson et al 1988; Lipsitz et al 1994; Perkins et al 1994; Stern et al 1992). This variability is likely due to differences in patient samples, especially with regard to demographics, disease stage and treatment status, assessment strategies, and comorbidity of other psychiatric conditions. Reported rates of depression are higher among asymptomatic, HIV⫹ homosexual men compared with heterosexual men in the general population but are similar to HIV⫺ homosexual men (Atkinson et al 1988; Evans and Perkins 1990; Williams et al 1991). Perkins et al (1994) estimated that between 4% and 9% of HIV⫹ (and HIV⫺) homosexual men report a major depressive episode in the past month, and that roughly 6% develop a major depression in the subsequent 6-month period. Rabkin et al (1997a) assessed 112 HIV⫹ men with AIDS, 61 HIV⫹

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men without AIDS, and 84 HIV⫺ homosexual men and reported that rates of major depression were generally in the 5%–10% range. Rates of dysthymia were also elevated among men with CD4 cell counts ⬍ 500, and cumulative rates of any current depressive disorder were in the 15%-20% range. Although the majority of men assessed in these studies seem to effectively adjust to HIV disease, a significant number experience mood disturbances. Thus, HIV⫹ patients should be routinely assessed and appropriately treated for depression. Although it is well documented that women report higher rates of depression than men in the general population (Blazer et al 1994), most of the prevalence studies of depression in HIV disease have focused almost exclusively on men. A few studies have examined rates of depression among samples including both men and women. Rabkin et al (1997c) examined an intravenous drug-using cohort of 121 men (69 HIV⫹, 52 HIV⫺) and 66 women (36 HIV⫹, 30 HIV⫺) over 3 years. At baseline assessment, rates of major depression and dysthymia ranged from 15% (HIV⫺ men) to 33% (HIV⫹ men and HIV⫺ women). For HIV⫹ individuals, degree of mood improvement over time was related to HIV progression (i.e., those who remained healthier based on CD4 count and illness stage showed mood improvement over time). In a five-site World Health Organization study including both men and women, prevalence rates of major depression ranged from 4.0% to 18.4% among HIV⫹ symptomatic individuals and 3.0% to 10.9% among asymptomatic individuals (Maj 1996). In two sites, women had higher depression scores than men, but complete data on gender differences across all five sites was unavailable. Ciesla and Roberts (2001) conducted a meta-analysis of 10 studies comparing HIV⫹ and at-risk, HIV⫺ men and women and reported that the frequency of major depressive disorder among the HIV⫹ participants was almost twofold that of the at-risk, HIV⫺ individuals, but only three studies included women. Prevalence rates of major depression among exclusively HIV⫹ women have varied widely. Rates among clinical samples have ranged from 1.9% to 35% (Boland et al 1999; Goggin et al 1998; McDaniel et al 1995; Taylor et al 1996) and from 30% to 60% among community samples (Moore et al 1999; Smith et al 1996). The range of prevalence rates of depression among HIV⫹ women is most likely the result of differing methodologies and study populations and in some cases the use of small samples. Larger-scale prevalence studies of HIV⫹ women are starting to emerge. Ickovics et al (2001) studied 765 HIV⫹ women and reported that 42% had chronic depressive symptoms and 35% had intermittent depressive symptoms. Morrison et al (2002) examined 93 HIV⫹ and 62 HIV⫺ women who were not current substance abusers

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and found that HIV⫹ women had a significantly higher prevalence rate of major depressive disorder (19.4%) compared with HIV⫺ control subjects (4.8%). Overall, these prevalence studies suggest that HIV⫹ women are at significantly greater risk of major depressive disorder compared with demographically similar groups of HIV⫺ women.

Mania Mania can occur at any time in HIV disease, but often clusters into two categories: a preexisting bipolar disorder that often manifests early in the course of disease but that can also occur later on as well and the late-stage (or AIDS) mania, which is less likely associated with a preexisting condition or family history and most likely results from HIV dementia and related cognitive deficits (Lyketsos et al 1997; Treisman et al 1998). These researchers point out, however, that AIDS mania (or secondary mania) seems to have a different clinical profile than traditional bipolar mania (or primary mania), including marked cognitive slowing or dementia that often complicates diagnosis, more pronounced irritable mood as opposed to euphoric states, and greater severity in presentation and course. The differences between the early-onset and late-onset types of mania may reflect different etiologies within the context of HIV disease and warrants further investigation. The majority of studies report a relationship between the onset of manic symptoms and the development of cognitive impairment associated with CNS involvement. Lyketsos et al (1993) conducted a chart review and reported that manic syndromes affected roughly 8% of patients across a 17-month study period. Patients with manic episodes occurring later in disease course (e.g., CD4 cell counts ⬍ 200) were less likely to have a family history of mood disorder and more likely to have concurrent dementia or other cognitive impairment than those with manic episodes occurring earlier (e.g., CD4 cell counts ⬎ 200). Kieburtz et al (1991) also described a manic syndrome among eight patients with AIDS and suggested that the manic syndrome was secondary to HIV infection, because the patients also developed simultaneous cognitive impairments. In a case– control study of 19 patients with HIV-associated mania and 57 HIV⫹ control subjects, incident AIDS dementia was significantly more common in patients with mania (Mijch et al 1999). Ellen et al (1999) screened all patients referred to an HIV consultation-liaison psychiatry service over a 29-month period for manic symptoms and identified 23 patients with mania, of whom 19 were considered to have secondary mania. The prevalence of secondary mania over the study period was 1.2% for HIV⫹ individuals and 4.3% for those with AIDS. Overall, these studies provide support for an

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association between HIV neuropathology and the development of mania. Some studies have also reported bipolar episodes in HIV⫹ individuals. Perretta et al (1998) compared 46 HIV⫹ patients with index major depressive episode to an equal number of demographically matched HIV⫺ index major depressive episode patients on rates of bipolar subtypes. The authors found that HIV⫹ and HIV⫺ clinic patients had a comparable history of familial mood disturbance, although the HIV⫹ patients had a higher family history of alcohol use. The authors also reported a significantly higher proportion of HIV⫹ patients with lifetime bipolar II disorder (78%) and associated cyclothymic (52%) and hyperthymic (35%) temperaments. The authors argue that premorbid impulsive risk-taking traits associated with these temperaments may have played a role in needle-sharing drug use and/or unprotected sexual behavior; however, because of the methodologic limitations noted, including that assessors were not blind to the affective diagnoses and family history of patients, and the comparison group employed was a convenience sample, continued investigation is warranted. Furthermore, more large-scale, prospective studies are needed to determine the exact prevalence rates of mania and bipolar disorders among HIV⫹ individuals.

Pharmacologic Management of Mood Disorders in HIV Infection The existence of a co-occurring psychiatric disorder can complicate treatment among medically ill patients. For example, medical patients with depression show reduced treatment compliance and increased use of health care services (Carney et al 1995). Psychiatric disorders such as depression are also related to greater risk of HIV infection and reduced adherence to treatments. Increased incidence and severity of side effects and interactions between psychotropic and antiretroviral medications and medical conditions in HIV disease further complicate pharmacologic treatment. Although these complexities exist, data linking depression and HIV disease progression are emerging (Leserman et al 2002; Patterson et al 1995), and considerable health and economic benefits might result from effectively treating mood disorders in HIV⫹ individuals. Several studies have also reported that antidepressant treatment in HIV⫹ patients produces a beneficial effect on psychosocial functioning. For example, Elliot et al (2002) demonstrated that reducing depressive symptoms in HIV⫹ individuals has a positive impact on health-related quality of life and also further enhances adherence. Overall, depression is among the most prevalent psychiatric diagnoses observed in the context of HIV disease, and there is now increasing

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data demonstrating the efficacy of various antidepressant medications among HIV⫹ individuals. Below, we briefly summarize the pertinent data and issues guiding current research related to specific pharmacologic therapies for mood disorders in HIV disease.

Tricyclic Antidepressants The tricyclic antidepressants (TCAs) have been effective for treating depressive symptoms in HIV⫹ patients, but their side effect profile may lead to discontinued use. In a double-blind, randomized, placebo-controlled study of imipramine in 97 HIV⫹ patients, Rabkin et al (1994a) found that after 6 weeks response rates were 74% for the imipramine group and 26% for the placebo group; however, the authors reported that adverse side effects led to a greater likelihood of discontinuation of imipramine within 6 months. Although TCAs such as imipramine are an effective therapeutic option for HIV⫹ patients with depression, the apparent increased sensitivity to side effects that can exacerbate existing conditions may interfere with adherence to treatments. For example, dry mouth is a frequent complaint among HIV⫹ persons (Younai et al 2001), and the TCAs might further increase such complaints. Therefore, clinicians should consider the anticholinergic side effects of the TCAs when prescribing them to HIV⫹ patients.

Selective Serotonin Reuptake Inhibitors Several studies of depressed, HIV⫹ patients have shown that selective serotonin reuptake inhibitors (SSRIs) are as effective as TCAs but produce a less severe side effect profile. Elliott et al (1998) blindly and randomly assigned 75 HIV⫹ individuals to imipramine, paroxetine, or a placebo control. Seventy-five percent completed 6 weeks of treatment, but only 45% completed the full 12-week trial. Both active treatments were equally effective at 6, 8, and 12 weeks and were also significantly more effective than placebo; however, side effects of imipramine influenced attrition, and the dropout rate in the imipramine group was 48% compared with only 20% in the paroxetine group and 24% in the placebo group. In a randomized, placebo-controlled study of fluoxetine, Zisook et al (1998) also found that severely depressed HIV⫹ patients responded favorably to treatment with few side effects. In another study, Rabkin et al (1999) conducted a randomized, placebo-controlled trial comparing fluoxetine with placebo in HIV⫹ individuals with major depression and reported that 74% of participants responded to fluoxetine. Interestingly, they also reported a relatively high response rate in the placebo group (47%), and intent-to-treat analysis showed that differences between the fluoxetine and placebo groups were less remarkable.

Open-label studies of SSRIs have generated results similar to the controlled studies outlined above. Rabkin et al (1994b) enrolled HIV⫹ depressed individuals who failed imipramine treatment (e.g., relapsed, did not tolerate side effects, nonresponders) in a 12-week open trial of fluoxetine. Eighty-three percent treated with fluoxetine responded to treatment and exhibited significant reductions in depression scores, and the patients reported tolerating fluoxetine better than imipramine. In an open trial of 28 depressed HIV⫹ individuals, a 70% response rate was reported among those completing an 8-week open trial of sertraline (Rabkin et al 1994c), with side effects resulting in a loss of only 18% of participants. Ferrando et al (1997) conducted a 6-week open trial comparing paroxetine, fluoxetine, and sertraline among 33 symptomatic, depressed HIV⫹ individuals and reported that 73% of participants completed the trial and that 83% responded to treatment. Most of the dropouts did so because of complaints of agitation, anxiety, and insomnia during weeks 1-3. Differences in the efficacy of the three SSRIs could not be ascertained reliably owing to the open trial design and small sample size. Grassi et al (1997) conducted a 6-week open trial of paroxetine in 10 HIV⫹ patients with major depression and noted significant improvement in depression scores between weeks 2 and 6 of the study. In one of the few studies of antidepressant treatment among HIV⫹ women, Ferrando et al (1999) conducted an open trial comparing fluoxetine (n ⫽ 21) and sertraline (n ⫽ 9). Sixty percent of the women completed the trial, and 78% responded to treatment (e.g., HAM-D scores decreased by 50% or more). Although the outcomes of these open-label studies are generally consistent with the available controlled studies, these findings must be interpreted with caution. There is evidence that HIV⫹ patients receiving antiretroviral and SSRI therapy may be at heightened risk of developing serotonin syndrome (DeSilva et al 2001). Protease inhibitors and reverse transcriptase inhibitors decrease the activity of cytochrome P450 (CYP450) enzymes, potentially interfering with the metabolism of SSRIs. For example, the protease inhibitor ritonavir can simultaneously modify a number of these enzymes (Tseng and Foisy 1999). Thus, this potential drug interaction should be taken into consideration when prescribing SSRI therapies for HIV⫹ individuals concurrently on these HIV medications.

Newer Generation Antidepressants Newer antidepressant medications represent a potential alternative to treating depression, although there is a paucity of controlled studies in the context of HIV disease. Nefazodone was found to be efficacious in a 12-week,

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open trial of 15 HIV⫹ outpatients, in which 73% of patients responded to treatment with relatively few adverse effects (Elliot et al 1999); however, the authors pointed out the potential for drug interactions between nefazodone and protease inhibitors, such as delavirdine and efavirenz. Several cases of nefazodone-induced hepatitis have also been reported, which is relevant to HIV⫹ patients because of the frequent comorbidity of HIV and viral hepatitis. Although not a controlled trial, one study reported that mirtazapine is an efficacious antidepressant with a profile that can benefit HIV⫹ patients by promoting weight gain during HIV wasting disease and also by decreasing nausea (Elliot and Roy-Byrne 2000), although its sedating properties may complicate existing complaints of asthenia. Venlafaxine has demonstrated limited effects at the level of the CYP450 enzymes, perhaps decreasing the potential interaction with antiretroviral medication (Ereshefsky and Dugan 2000); however, Klesmer and Badescu (2002) advise that because venlafaxine is metabolized by CYP450 2D6, doses should be reduced when used concurrently with ritonavir. Bupropion may be an alternative for anergic HIV⫹ patients because of its potential activating effects; however, in vitro studies have shown that HIV medications, such as ritonavir, efavirenz, and nelfinavir, significantly interfere with the metabolism of bupropion by inhibiting CYP450 2B6 (Hesse et al 2001). Overall, controlled studies are needed to further examine the effects and potential drug interactions of these new-generation antidepressants among HIV⫹ individuals.

Psychostimulants Psychostimulants have also been prescribed for depressed HIV⫹ patients. Fernandez et al (1995) compared methylphenidate to desipramine in a randomized, double-blind trial, and both drugs showed approximately a 50% response rate; however, patients treated with desipramine experienced more adverse side effects, including dry mouth, anxiety, and insomnia. A placebo-controlled trial of dextroamphetamine for depression in HIV⫹ individuals also reported a significant improvement in mood in 73% of patients, compared with 25% in the placebo group (Wagner and Rabkin 2000). In an open trial of dextroamphetamine among 24 depressed AIDS patients also exhibiting low energy, Wagner et al (1997) found that 75% of the patients responded to treatment. Improvement in mood and energy occurred in parallel, with significant reductions in depression scores achieved as early as the second week of treatment. Although complete follow-up evaluations were unavailable, the authors found that treatment benefits were maintained for up to 2 years in some patients. The use of stimulants in the treatment of depression in HIV disease should consider alterations in weight, and the

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potential for abuse should be monitored. Although some controlled trials have not demonstrated that stimulants are effective in treating primary depression (Satel and Nelson 1989), they may be useful adjunctive agents for select HIV⫹ individuals and warrant further evaluation.

Hormonal Therapies Because HIV-related reductions in testosterone are related to changes in mood, appetite, energy, and sexual dysfunction, hormonal therapies have also been employed to treat depression. In a double-blind, placebo-controlled trial (6-week trial followed by 12-week open-label maintenance), Rabkin et al (2000c) found that testosterone injections were effective in improving mood as well as libido, energy, and body muscle mass among 70 HIV⫹ hypogonadal men. Seventy-nine percent of patients reported a mood improvement, comparable to that of antidepressant therapy. In an 8-week, open-label study among 45 HIV⫹ men, Rabkin et al (2000b) reported that dehydroepiandrosterone also improved mood as well as anabolic and androgenic parameters. Thus, androgen replacement may hold promise in ameliorating depressive symptoms among HIV⫹ individuals, especially among those suffering from wasting disease and anergic symptoms, although side effects should be monitored.

Mood Stabilizers Several studies have examined the efficacy of mood stabilizers for treating manic symptoms among HIV⫹ individuals. An in vitro study showed that lithium had no adverse effects on HIV replication or virus-associated reverse transcriptase activity (Evans et al 1993). Parenti et al (1988) treated 10 HIV⫹ homosexual men with lithium, but 7 patients discontinued treatment because of significant adverse side effects. el-Mallakh (1991) described 14 cases and reported that AIDS-associated manic states are responsive to available antimanic agents (e.g., lithium) but that AIDS patients with associated neurologic and cognitive dysfunction may be more prone to neurocognitive side effects. Further studies of mood stabilizers in the context of HIV disease are clearly required. Anticonvulsant medications may represent a promising alternative for treating manic symptoms in HIV⫹ individuals. Halman et al (1993) conducted a retrospective chart review identifying 11 HIV⫹ patients with an acute manic episode and found that among those with poor tolerance of lithium and neuroleptics, anticonvulsants were an effective alternative treatment. A number of factors must be taken into consideration when prescribing anticonvulsants to HIV⫹ individuals. Although there is in vitro evidence that

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valproic acid increases HIV replication (Moog et al 1996), the clinical significance of these findings are not known. A recent retrospective in vivo clinical trial indicated that valproic acid treatment does not affect viral load among HIV⫹ patients also receiving appropriate antiretroviral therapy (Maggi and Halman 2001). Prospective study of this issue is warranted, whereby viral load would be monitored systematically over the course of treatment for those taking valproate as well as other mood stabilizers. Blood levels of valproate must also be closely monitored, as well as conditions such as hypoalbuminemia or the simultaneous use of certain antibiotics (e.g., trimethoprim, sulfamethoxazole), which can elevate the drug’s blood concentration. Bidirectional interactions between carbamazepine and antiretroviral medications have been reported at the level of the CYP450 enzymes. On the one hand, carbamazepine is a potent promoter of the CYP3A enzyme system, increasing the metabolism of protease inhibitors such as indinavir (Hugen et al 2000) and nonnucleoside reverse transcriptase inhibitors such as delavirdine (Tran et al 2001). On the other hand, another protease inhibitor, ritonavir, is a potent inhibitor of the same enzyme system, increasing the risk of carbamazepine toxicity (BerbelGarcia et al 2000). Thus, consideration of potential drug– drug interactions is warranted when prescribing these types of agents in HIV⫹ individuals on these HIV medications.

Antipsychotic Agents Psychotic symptoms may also present among HIV⫹ patients with mood disorders, but special precautions must be taken when using antipsychotic medications. Several reports have noted that HIV⫹ patients are more sensitive to the extrapyramidal side effects associated with dopamine receptor antagonists (Hriso et al 1991; Sewell et al 1994). This may be related to subcortical motor slowing associated with advancing HIV disease. Although AIDS patients may have increased sensitivity to the newer, atypical antipsychotic agents as well, an open-label study using clozapine reported improvement of psychotic symptoms among HIV⫹ patients without extrapyramidal symptoms (Zirulnik 1999). In addition, in a case series of 21 patients with psychotic symptoms (12 of whom had mania), risperidone was efficacious and led to fewer side effects than did conventional antipsychotic drugs (Singh et al 1997). Despite these initial observations, compared with trials of antidepressants there is a paucity of data from controlled studies on the effects of antipsychotic agents in HIV disease. Thus, more controlled studies are needed in this area, especially among individuals with concurrent mania.

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Psychotropic Medications in HIV: Clinical Considerations and Comments Similar rules regarding the prescription of psychotropic drugs to medically healthy persons apply to treatment strategies among HIV⫹ patients, although extra care is often required because HIV disease presents some unique challenges to prescribing physicians. Knowledge of pharmacology can often be used to therapeutic advantage as well to avoid adverse interactions. Drug interactions related to psychotropic drug metabolism and protein binding, half-life, and effects on appetite, among others, may require careful consideration, particularly among more advanced symptomatic HIV⫹ patients. The physician must carefully monitor significant interactions between psychotropic drugs and antiretroviral agents used in combination therapies. The clinician should be mindful that psychotropic drugs, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors all serve as substrates for various CYP450 enzymes in the liver, and as noted throughout this review, each of these classes of compounds possesses enzyme inducing and/or inhibiting properties. In addition to these potential drug interactions, depression and substance abuse frequently co-occur in HIV⫹ individuals, and the use of intravenous illicit substances may further increase the risk of adverse drug interactions and also increase the risk of acquiring hepatitis. Even with the advent of advanced combination treatments, many patients are also resorting to complementary and alternative medicine strategies as well. Nontraditional, herbal psychotropic agents used by HIV⫹ patients experiencing mood symptoms must be closely monitored. An open-label study recently revealed that serum concentrations of the protease inhibitor indinavir were markedly reduced by the concomitant administration of hypericum (St. John’s Wort), a potent inducer of CYP450 3A4 (Piscitelli et al 2000). The magnitude of the reduction of indinavir levels was estimated to be significant enough to lead to drug resistance and result in treatment failure. Based on the available evidence, antidepressant medications are effective in reducing depressive symptoms and thus may also improve the quality of life of HIV⫹ individuals. Patients with AIDS may experience adverse effects more frequently with certain agents, such as TCAs, than will patients with AIDS-related complex and asymptomatic HIV-positive patients (Fernandez et al 1989). Selective serotonin reuptake inhibitors may be particularly well suited for use in depressed HIV⫹ patients, because they have a less severe side effect profile, such as the anticholinergic, ␣-adrenergic, histaminergic, and other cardiac effects exhibited by TCAs (Wagner et al 1996); however, further controlled studies are required, particu-

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larly with the newer agents that appear promising but lack rigorous testing in the context of immunodeficiency. In addition, other physical symptoms related to HIV disease may also present along with mood complaints. For example, pain may be frequently under-treated in HIV disease (Breitbart et al 1996). Because adjuvant analgesic drugs, such as antidepressant medications, are often effective in treating many pain syndromes in noninfected populations, they may also be helpful for HIV⫹ patients. Further research is needed to determine whether these medications can improve pain and other related physical symptoms as well. Studies of antidepressants or mood stabilizing medications in HIV disease must also take into consideration the ever-changing HIV medication regimens. There is some clinical evidence that antiretroviral medications alone are beneficial for improving mood. For example, the relief of physical symptoms due to highly active antiretroviral therapy has been found to also decrease psychological distress (Rabkin et al 2000a), and antiretroviral drugs may also directly improve the mood of HIV⫹ patients (LowBeer et al 2000). Fumaz et al (2002) found that patients treated with a combination therapy including efavirenz reported a better improvement in emotional status and quality of life than did patients who did not receive it. Prescribing antidepressant and mood stabilizing medications to HIV⫹ patients requires continuous monitoring of drug interactions in an environment of rapidly changing treatment regimens.

General Conclusions and Future Directions Mood disorders, especially depression, continue to be the most observed psychiatric diagnoses among HIV⫹ individuals and warrant thorough assessment and treatment. Prevalence of mania also seems elevated, especially in the more advanced stages of HIV disease, as CNS involvement becomes more pronounced. Additional large-scale studies are needed to determine the exact prevalence rates of mania during HIV disease. There are relatively few controlled trials of antidepressant medication among HIV⫹ individuals and virtually no large-scale, controlled studies of mood stabilizing medications. Overall, the few published controlled trials of antidepressant medication document their effectiveness among HIV⫹ individuals. The available evidence suggests that the SSRIs reduce depressive symptoms and are also better tolerated by HIV⫹ individuals than are older antidepressants; however, care must be taken to limit the occurrence of drug interactions regardless of the medication. The majority of the antidepressant treatment trials, to date, have been conducted on relatively small samples.

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Future trials should be designed to address potential methodologic issues by studying larger samples and employing long-term follow-up assessments of both mood and HIV-disease progression. In addition, further evaluation of other novel antidepressant agents is warranted. Recent evidence has shown promising effects of glucocorticoid antagonists, such as mifepristone (RU486), as well as substance P antagonists in treating depression among medically healthy persons (Belanoff et al 2001; Stout et al 2001). Perhaps these types of agents may also help alleviate depressive symptoms among HIV⫹ individuals. Recent data showing that depressive symptoms are associated with increased mortality in HIV⫹ women (Ickovics et al 2001) and influence disease progression among HIV⫹ men (Leserman et al 2002) highlights the need for more controlled studies. It is noteworthy that the majority of studies, to date, have examined treatment effects on HIV⫹ men. Future studies should consider the changing demographic landscape of HIV disease and examine treatment of mood disorders among HIV⫹ women (Evans et al 2002), as well as other groups at increased risk, such as adolescents and children, especially among minority and low socioeconomic status groups. Finally, though not covered in this brief review, it should be noted that psychotherapy may provide additional benefits to HIV⫹ individuals.

Aspects of this work were presented at the conference, “The Diagnosis and Treatment of Mood Disorders in the Medically Ill,” November 12–13, 2002 in Washington, DC. The conference was sponsored by the Depression and Bipolar Support Alliance through unrestricted educational grants provided by Abbott Laboratories, Bristol-Myers Squibb Company, Cyberonics, Inc., Eli Lilly and Company, Forest Laboratories, Inc., GlaxoSmithKline, Janssen Pharmaceutica Products, Organon Inc., Pfizer Inc., and Wyeth Pharmaceuticals.

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