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Published online before print June 2, 2008, 10.1097/PSY.0b013e3181777190
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Psychosomatic Medicine 70:585-592 (2008)
© 2008 American Psychosomatic Society

TREATMENT AND PREVENTIVE INTERVENTIONS

Psychopharmacology in HIV-Infected Patients

Martin J. Repetto, MD, PhD and John M. Petitto, MD

From the Department of Psychiatry (M.J.R.), Provena Covenant Medical Center, Champaign, Illinois, and the Psychology Department, University of Illinois at Urbana-Champaign, Champaign, Illinois; and McKnight Brain Institute (J.M.P.), Departments of Psychiatry, Neuroscience, and Pharmacology, University of Florida College of Medicine, McKnight Brian Institute, Gainesville, Florida.

Address correspondence and reprint requests to Martin J. Repetto, Department of Psychiatry, Provena Covenant Medical Center; Psychology Department, University of Illinois at Urbana-Champaign, 407 E. University Avenue, Champaign, IL 61820. E-mail: RepettoM.D.Martin{at}provena.org.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 CONCLUSIONS
 NOTES
 REFERENCES
 
Neuropsychiatric disorders and syndromes may be underdiagnosed and inadequately treated in individuals infected with HIV. Depression in particular is among the most prevalent diagnoses, and data from controlled clinical studies have shown that antidepressant medications are efficacious and safe for treating depression in HIV-infected persons. A significant shortcoming of this literature is that most of the available data are from studies conducted before the advent of highly active antiretroviral therapy. In addition, apart from antidepressant medications, controlled studies systematically assessing efficacy and safety issues for other classes of psychotropic drugs (e.g., antipsychotic and anxiolytic medications) in HIV-infected persons are lacking. This review summarizes essential findings pertaining to the use of psychotropic medications to treat depression and other neuropsychiatric disorders in the context of HIV. It includes a discussion of clinically relevant treatment considerations (e.g., side effects, drug-drug interactions) derived from the existing literature as well as judgments that clinicians face in the absence of research data. Despite some shortcomings of the existing literature, overall there is compelling evidence that the appropriate use of psychotropic medications (coupled with behavioral therapy) can improve the quality of life of mentally ill HIV-infected individuals.

Key Words: neuropsychiatric disorders • depression • highly active antiretroviral therapy • psychotropic medications

Abbreviations: HAART = highly active antiretroviral therapy; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; SNRI = serotonin and norepinephrine reuptake inhibitor.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
CONCLUSIONS
 NOTES
 REFERENCES
 
Mentaldisorders are highly prevalent in HIV-infected individuals. The national HIV Costs and Service Utilization Study found that 48% of HIV-infected persons had a probable psychiatric disorder (1,2). Mental disorders like depression have been associated with increased risk of poor medication adherence (3,4) and HIV disease progression (5). Moreover, Pence et al. (6) suggested that patients, who are depressed or have an anxiety or substance abuse disorder at the time of initiating highly active antiretroviral therapy (HAART), have poorer virological responses to treatment. Improvement of depression after treatment has been shown to improve quality of life (7) and increase treatment adherence (8). Thus, there may be substantial health and economic benefits from psychiatric treatment of HIV-infected patients with depression and other mental health disorders.

Unfortunately, neuropsychiatric disorders in HIV-infected persons are frequently unrecognized and untreated (9). Although depressive disorders are the most frequent psychiatric conditions in HIV-infected persons estimated at about 36% in one national study (1), other disorders such as anxiety, psychosis, and dementia may also demand psychiatric intervention. The same study estimated generalized anxiety disorder at about 16% (1). High levels of anxiety have been found to compromise adherence with antiretroviral therapy (10). It has further been shown that psychiatric patients with chronic mental disorders, such as schizophrenia, are at higher risk for HIV infection than the general population (11).

This article summarizes essential findings pertaining to the use of psychotropic medications to treat depression and other neuropsychiatric disorders in HIV-infected persons. It includes a discussion of treatment considerations, such as the efficacy of medications, side effects, and interactions with HIV therapies. It is meant to help guide pharmacotherapeutic treatment decisions for HIV-infected persons. We focus here on pharmacotherapy, although it is important to note that there is literature showing that cognitive behavioral therapy and other psychological interventions are efficacious in reducing depression and anxiety (12). Substance abuse disorders can have major effects on treatment adherence and risk behavior (13,14). These important issues are covered elsewhere in this issue (4,15).

To ensure a complete review of the available literature on psychotropic medications for HIV-infected persons, we conducted PubMed searches combining HIV/AIDS with various keywords for psychiatric diagnoses and symptoms (i.e., depression, anxiety, dementia), and psychopharmacological agents—either individually or by class (i.e., fluoxetine, selective serotonin reuptake inhibitors (SSRIs), or antidepressants). The years covered by these searches included 1980 to 2007.

Pharmacological Treatments
Psychotropics are frequently used in the treatment of HIV-infected patients. Vitiello et al. (16) estimated that 27.2% of HIV patients received psychotropics in 1996, with antidepressants and anxiolytics being the most frequently prescribed. Depressed HIV-positive patients who receive antidepressants have higher levels of adherence to antiretroviral therapy than those who remain untreated (17). Antidepressants have also been useful in treating somatic problems frequently seen in HIV/AIDS patients, such as insomnia, and sometimes have positive effects on appetite, weigh loss, and pain (18). However, due to the elevated frequency of medical complications and the complexity of the antiretroviral drug regimens, special precautions must be taken when prescribing psychotropics to HIV-infected patients. This is discussed further below as it pertains to each specific class of psychotropic medications. Finally, it is important to note that the vast majority of cited research was performed before the discovery and use of HAART.

Tricyclic Antidepressants (TCAs)
Several studies have demonstrated that imipramine is an effective drug for treating depression in HIV-infected patients. In a double-blind, randomized, placebo-controlled study of 97 HIV-infected patients, Rabkin et al. (19) found treatment with imipramine efficacious in reducing depressive symptoms. In the sixth week of treatment, they found that the response rates were 74% for the imipramine group and 26% for the placebo group. No changes in CD4+ helper/inducer cell counts were found in imipramine-treated subjects. Adverse side effects, however, led to high discontinuation rates of imipramine during a 6-month follow-up. In spite of the evidence supporting the efficacy of TCAs in the treatment of depression in HIV-positive patients, the advent of newer antidepressant drugs with a more benign side effect profile has limited the use of TCAs to those patients who do not respond to more modern medications.

SSRIs
Research has established that SSRIs are as effective as TCAs with a more benign side effect profile. Elliott and co-workers (20) assigned blindly and randomly 75 HIV-positive individuals to imipramine, paroxetine, or placebo. Of the 75 subjects enrolled, 75% completed 6 weeks but only 45% completed the full 12-week trial. They found that both antidepressants were equally efficacious at 6, 8, and 12 weeks, and that both drugs were also significantly more efficacious than placebo. However, side effects of the TCAs markedly influenced attrition. The dropout rate in the imipramine group was 48% compared with 20% in the paroxetine group and 24% in the placebo group. Other placebo-controlled studies yielded similarly good results for SSRIs. For instance, in a randomized, placebo-controlled trial, Rabkin et al. (21) compared treatment response with fluoxetine and placebo in HIV-positive patients with major depression. They found that 74% of the participants who completed the study responded to fluoxetine. Interestingly, they also found a high response to placebo (47%). It is noteworthy that intention-to-treat analysis showed that the differences between the treatment groups were less remarkable (57% of HIV-positive subjects were responders compared with 41% of placebo group) and did not reach statistical significance. Fluoxetine did not alter CD4+ cell counts. Furthermore, in a double-blind, placebo-controlled study that involved 47 HIV-seropositive men, Zisook et al. (22) found that the combination of fluoxetine and group psychotherapy was more effective than psychotherapy alone in HIV patients with major depression.

In a 12-week open trial of fluoxetine, Rabkin and colleagues (23) evaluated HIV-infected depressed subjects who failed imipramine treatment (e.g., subjects who relapsed, did not tolerate side effects, no responders). Although the baseline levels of depression severity were lower in the fluoxetine study (Hamilton Depression Scale (HAM-D) average score = 12.5) compared with the initial imipramine study (HAM-D average score = 15.8), 83% of subjects treated with fluoxetine (15–60 mg/day) responded and exhibited significant reductions in depressive symptoms. Fluoxetine treatment again did not alter CD4+ counts. As expected, fluoxetine was better tolerated than imipramine.

An open trial of 28 depressed HIV-infected subjects found a 70% response rate among subjects that completed 8 weeks of treatment with sertraline (24). Side effects resulted in a loss of 18% of the total sample. Sertraline did not alter either CD4+ cell counts or natural killer (NK) cell counts. Ferrando and colleagues (18) conducted a 6-week open trial comparing paroxetine, fluoxetine, and sertraline in 33 symptomatic HIV-infected individuals with depression. Overall, 73% completed the trial, and 83% of those subjects were responders. Most of the subjects who dropped out of the study did so because of complaints of agitation, anxiety, and insomnia during the first half of the study. They found that depression as well as somatic symptoms perceived as related to HIV improved with SSRI treatment. Differences in the efficacy between the three SSRIs could not be ascertained reliably because of the design and small sample size (although the descriptive data suggested that fluoxetine was the most effective and well tolerated). More recently, a small open trial comparing fluoxetine (n = 21) and sertraline (n = 9) was performed exclusively in HIV-infected women (25). Studies in women have been lacking, in part due to such social factors as the need for childcare for single-parent mothers and financial difficulties. Only 14 participants in the fluoxetine group and 4 women in the sertraline group completed the trial. Seventy-eight percent of completers were responders (e.g., HAM-D scores decreased ≥50%). Grassi et al. (26) performed a 6-week open-trial investigation of the efficacy of paroxetine in 10 HIV-positive patients with major depression. Significant improvement in HAM-D scores was noted between weeks 2 through 6 of the study.

Another open-label, flexible-dose study involving 14 Hispanic patients reported that citalopram is well tolerated and effective in reducing symptoms of depression in HIV-infected Hispanic patients (27). Although the outcomes of these open-label studies are generally consistent with the available double-blind, randomized, placebo-controlled studies, these findings must nonetheless be interpreted cautiously.

Safety concerns have been raised regarding potential interactions between SSRIs and antiretroviral drugs. Protease inhibitors and nonnucleoside reverse transcriptase inhibitors may affect the activity of the cytochrome P450 (CYP450) izoenzymes, interacting with drugs metabolized by the same pathway including antidepressants, neuroleptics, and anticonvulsants (28). DeSilva and colleagues (29) reported four cases of serotoninergic syndrome in patients receiving fluoxetine in combination with antiretroviral agents that included ritonavir, efavirenz, or saquinavir. To avoid complications, a reduction of the initial dose of the SSRI, slow titration, and close monitoring for toxic reaction are recommended. A retrospective cohort study evaluated the interaction of fluvoxamine and fluoxetine with the nonnucleoside reverse transcriptase inhibitor nevirapine (30). This study found that fluvoxamine but not fluoxetine decreases the clearance for nevirapine whereas nevirapine was found to decrease fluoxetine plasma levels but did not affect fluvoxamine. In an open-label trial, Ouellet et al. (31) evaluated the interaction between fluoxetine and ritonavir. They found that fluoxetine and its major metabolite, norfluoxetine, produce a small but statistically significant increase in ritonavir levels due to an interaction at the level of the CYP450-2D6. However, due to the small magnitude of this interaction, no need for dose adjustment was recommended. Due to the short duration of this trial, the significance of this interaction needs further evaluation (32). Another open-label study evaluating the effects of ritonavir on the plasma levels of escitalopram in healthy participants showed no significant interactions between these two drugs (33).

New-Generation Antidepressants
The newer antidepressant drugs represent an attractive alternative to treat depression in HIV-infected patients. The serotonin and norepinephrine reuptake inhibitors (SNRI) venlafaxine and duloxetine are an interesting alternative in the treatment of depression in HIV-infected patients. One study showed that venlafaxine has a small effect on the cytochrome P450, decreasing the potential interaction with antiretroviral drugs (34). However, in a small open-label study involving nine patients, Levin et al. (35) found that venlafaxine lowers plasma levels of indinavir. Pain is frequently undertreated in HIV patients (36), and it is well established that SNRIs, such as venlafaxine and duloxetine, are effective agents to treat chronic pain. The use of duloxetine may cause elevation of liver enzymes (37). Caution is advised when prescribing duloxetine in patients with impaired liver function or HIV-positive patients coinfected with hepatitis C. More data from controlled studies is needed on the effectiveness and safety of SNRIs in treating patients with HIV.

An open-label study reported that bupropion is an effective and well-tolerated antidepressant for HIV-positive patients (38). However, nonnucleoside reverse transcriptase inhibitors such as efavirenz and protease inhibitors such as indinavir and saquinavir significantly interfere with the metabolism of bupropion by inhibiting the CYP2B6 (39). Another recent study reported that the combination of the protease inhibitors lopinavir and ritonavir significantly decrease plasma levels of bupropion. Dose adjustments of bupropion are needed when used in combination with lopinavir/ritonavir due to induction of the enzymes CYP2B6 and the UDP-glucuronosyl-transferase (40).

Nefazodone was found to be efficacious in an open trial of 15 outpatients, where 73% were found to be responders and few adverse side effects were noted (41). However, protease inhibitors may inhibit the metabolism of nefazodone. Patients treated with protease inhibitors require a reduction of nefazodone dosage (42). On the other hand, the coadministration of trazodone with ritonavir increases sedation, fatigue, and performance impairment compared with the effects of trazodone plus placebo (43). Mirtazapine was found to be an efficacious antidepressant with a profile that can benefit HIV-infected patients by promoting weight gain and decreasing nausea. In a 12-week open-label study, Elliott and Roy-Byrne (44) evaluated the antidepressant effects of mirtazapine in 12 HIV-positive patients diagnosed with major depression and dysthymia. Mirtazapine was effective and well tolerated. The participants in their study showed 66% full and 100% partial response rates as reflected in the HAM-D ratings. In spite of the sedating effects of mirtazapine, patients who participated in this study presented a significant reduction on heaviness, loss of energy, and fatigability after completing 4 weeks of treatment. More studies are needed to further examine the effects of newer antidepressants in HIV-infected individuals.

Psychostimulants and Novel Agents
In a 2-week randomized, placebo-controlled trial that was followed by a 24-week open-label study, Wagner and Rabkin (45) evaluated the effects of dextroamphetamine on 23 HIV-positive depressed men. The authors found a significant improvement in initiative and mood in 73% of the patients assigned to the drug group compared with 25% of the participants in the placebo group. In another randomized, double-blind, comparative study, Fernandez et al. (46) compared desipramine with methylphenidate in a treatment trial of 15 subjects. Both agents showed approximately a 50% response rate; however, subjects treated with desipramine experienced more adverse side effects including dry mouth, anxiety, and insomnia. In an open-trial study assessing the efficacy of dextroamphetamine in 24 individuals with AIDS that exhibited debilitating low energy and a DSM-III-R (Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition, Revised) diagnosis of depression, Wagner et al. (47) found that 75% of the subjects responded to treatment. Improvement in mood and energy coincided, and analyses revealed significant reductions in HAM-D scores in the second week of active treatment. Although systematic follow-up evaluations were not available, surprisingly they found that the treatment effect (improved mood and energy) was maintained for up to 2 years.

Several studies focused on the effects of hormone therapy in the treatment of fatigue and depression in HIV-positive patients. HIV-associated reductions in testosterone have been shown to correlate with changes in mood, appetite, energy, and sexual dysfunction (48). The results of a double-blind, placebo-controlled study showed that testosterone was effective in treating symptoms of depression and fatigue in HIV-positive patients (49). However, a more recent double-blind, placebo-controlled study comparing the effects of fluoxetine and testosterone on depression in HIV-infected patients found that testosterone was effective in treating fatigue but it was not superior to placebo in treating depression (50). In another double-blind, placebo-controlled trial (6-week trial followed by 12-week open-label maintenance), testosterone injections were effective in improving mood as well as libido, energy, and body muscle mass in 112 HIV-positive men with hypogonadal symptoms who completed the trial (51). Exercise was studied as a contributing factor favoring psychological well-being in patients receiving testosterone. Wagner et al. (52) found that exercise further improves psychological and nutritional status in HIV-positive individuals receiving testosterone therapy. Another placebo-controlled study evaluated the effects of dehydroepiandrosterone (DHEA) in the treatment of nonmajor depression (53). A group of 145 HIV-positive patients received either DHEA or placebo for a period of 8 weeks; 133 completed the trial. The authors found a significant improvement in the HAM-D scores of participants receiving DHEA. Patients who received DHEA showed a 62% decrease in their HAM-D scores compared with a 33% decrease in the placebo group. In an 8-week open-label pilot study of 45 HIV-positive subjects, the adrenal steroid DHEA also showed promise for improving mood as well as fatigue (54). A recent open-label study involving 30 HIV-positive patients evaluated the effects of modafinil in the treatment of fatigue. The study found that 80% of the participants presented a significant improvement in symptoms of depression and fatigue as well as in the performance of executive functions (55). In summary, there is evidence supporting the use of stimulants and hormonal therapy in the treatment of mood disorders and fatigue in HIV-positive patients.

Mood Stabilizers
Mood stabilizers are psychotropic agents used in the treatment and prevention of acute manic and depressive episodes (56). Some studies have raised concerns about the effects of valproic acid on the immune system and viral replication. For example, valproic acid was found to increase HIV-1 replication in vitro (57). However, clinical evidence indicates that valproic acid therapy does not affect viral load in vivo among HIV patients receiving adequate antiretroviral therapy (58). In a recent retrospective case control study that included 30 patients, Ances et al. (59) found that valproic acid does not affect plasma or cerebrospinal fluid viral load. An open-label clinical trial found no differences in plasma levels of efavirenz or the combination of lopinavir/ritonavir when administered separately or in combination with valproic acid (60). Controlled studies are needed to evaluate the efficacy and safety of valproic acid in HIV-infected patients. In any event, valproate blood levels, CD4+ counts, and the viral load must be closely monitored.

There is evidence of bidirectional interactions between carbamazepine and antiretroviral agents at the level of the cytochrome P450. On one hand, carbamazepine is a potent inducer of the CYP3A enzyme system increasing the metabolism of protease inhibitors, such as indinavir (61), and nonnucleoside reverse transcriptase inhibitors, such as delavirdine (62). On the other hand, another protease inhibitor, ritonavir, is a potent inhibitor of the same enzymatic system increasing the risk of carbamazepine toxicity (63).

Both in vivo and in vitro studies suggest that lithium does not influence the course of HIV infection. Evans et al. (64) found that lithium does not influence HIV replication in vitro. Moreover, a recent open-label study showed that lithium improves neuropsychological performance in HIV-infected patients receiving antiretroviral therapy (65). Parenti et al. (66) treated a group of 10 HIV-positive men with lithium using a serum concentration that ranged between 0.5 and 1.5 meq/L. The men who completed the study showed no significant changes in either CD4 count or viral titers.

The anticonvulsant lamotrigine is an effective and well-tolerated mood stabilizer. In HIV, a randomized, placebo-controlled study showed that lamotrigine is effective in treating neuropathic pain in 92 patients receiving antiretroviral therapy (67). Unfortunately, the antiretroviral drugs lopinavir and ritonavir decrease lamotrigine plasma levels. Dose adjustments must be considered in patients receiving this combination of drugs (68). Further studies on the use of mood stabilizers in the context of HIV disease are clearly warranted, especially those considering potential drug-drug interactions. Treatment plans must also take into consideration potential drug interactions of mood stabilizers with HIV medications.

Antiretroviral Therapy and Mood
There is clinical evidence showing that antiretroviral drugs are beneficial for the psychological health of HIV-infected persons. HAART has been shown to decrease the levels of psychological distress by improving overall physical well-being of HIV-infected persons (69). Fumaz and collaborators (70) evaluated the effects of antiretroviral regimens containing efavirenz on quality of life and emotional status in a prospective, randomized, controlled study that included 100 HIV-infected patients. The authors found that patients treated with a combination therapy that included efavirenz reported greater improvement in their emotional status and quality of life than those patients who did not receive efavirenz as part of their treatment.

Treatment Considerations With Antipsychotic Agents
Unfortunately, the treatment of psychotic disorders in HIV-infected patients has been less well studied than the treatment of mood disorders. Treating psychosis in patients with HIV represents a clinical challenge due to the lack of controlled efficacy studies, side effects of antipsychotic agents, and potential interactions with antiretroviral medications. For instance, due to subcortical motor slowing associated with HIV infection of the central nervous system, HIV-positive patients may be more sensitive to the extrapyramidal side effects of antipsychotics (71–74). Interactions between antipsychotics and antiretroviral drugs are also not well known. Lower starting doses and slower titration is recommended when treating psychosis in HIV-infected patients (75). In addition, the high risk for the development of displipidemias and hyperglycemia in HIV-infected patients receiving antiretroviral therapy (76) must be considered when prescribing atypical antipsychotics. Data obtained from the use of atypical antipsychotics in general psychiatry has shown that patients treated with clozapine and olanzapine are at high risk for developing metabolic complications, those treated with risperidone and quetiapine have intermediate risks, and those treated with ziprasidone and aripiprazole present minimal risk for metabolic problems (77).

However, several open-label and case reports support the use of antipsychotics in the treatment of psychosis in HIV-infected patients. For instance, a small open-label study involving six HIV-positive patients reported improvement of psychotic symptoms without inducing extrapyramidal syndromes using clozapine (78). In another study including 21 patients with HIV-related psychotic symptoms, Singh et al. found risperidone to be efficacious with fewer side effects than conventional antipsychotic drugs (79). A recent study evaluated the effects of ritonavir on plasma levels of the atypical antipsychotic olanzapine (80). The authors found that ritonavir significantly decreases olanzapine plasma levels by enhancing the activity of the liver enzymes CYP1A2 and UDP-glucoronyl transferase. Dose adjustments should be considered in patients receiving olanzapine and ritonavir (80). In summary, there is a paucity of data from controlled studies on the efficacy and safety of antipsychotic agents in HIV-infected persons. Caution and close monitoring of side effect are recommended when prescribing antipsychotic drugs to HIV-infected patients.

Medications Used in the Treatment of HIV-Associated Dementia (HAD)
The involvement of the central nervous system may induce devastating cognitive problems in HIV-infected patients. The clinical features of HAD include decreased memory, inability to concentrate, apathy, and psychomotor retardation. Patients in the initial stages of HAD exhibit difficulties in neuropsychological tests that evaluate executive functions, memory, and attention (81). Attention deficits are frequently seen in HIV-infected patients (82). Problems in complex motor and sequencing skills in patients with HAD have been associated to changes in the volume of the caudate nucleus (83). Changes in the hippocampus, however, seem not to be implicated in the cognitive deficits observed in HAD (84).

Early reports suggested that treatment with zidovudine could be beneficial for patients with HAD (85). Fortunately, combination antiretroviral therapies have also had a favorable impact on cognitive functioning in HIV-infected patients (86). In a multicenter cohort study, Sacktor et al. found a 50% decline in the incidence of AIDS dementia after the introduction of HAART (87). The reported incidence of HAD declined from 21.2 cases per 1000 persons per year before the introduction of HAART to 10.5 persons per year after HAART. Protease inhibitors may reverse white matter and basal ganglia abnormalities observed in patients with HAD (88). More recently, HAART was found to be effective not only in stabilizing but also in reversing cognitive deficits observed in many cases of HAD (89,90). By all accounts, adherence to antiretroviral therapy represents the most promising treatment for HAD. However, despite the beneficial effects of HAART on cognition, the occurrence of HAD is still associated with progression of the illness and death (91).

The effects of cognitive enhancers on HAD and AIDS encephalitis are under study. Animal studies suggested that the N-methyl-D-aspartic acid (NMDA) antagonist memantine could protect hippocampal neurons in AIDS encephalitis (92,93). Valproic acid was also suggested as a possible adjunctive treatment for HIV-related cognitive impairment (94). Controlled studies are needed to evaluate the potential benefits of NMDA antagonists and cholinesterase inhibitors in the treatment of HAD (95).


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 CONCLUSIONS
NOTES
 REFERENCES
 
The appropriate diagnosis and treatment of mental disorders in HIV-positive patients is of foremost importance. Neuropsychiatric disorders and syndromes may be underdiagnosed and inadequately treated in individuals infected with HIV. Mental health favors compliance with antiretroviral drugs; adherence with these drugs slows the progression of the illness, prevents medical complications, and improves quality of life. Appropriate adherence to antiretroviral therapy also has a favorable impact on the emotional and cognitive status of HIV-infected patients. Fortunately, psychopharmacological treatment is effective and can improve psychiatric problems in HIV-infected individuals.

Selective serotonin reuptake inhibitors and newer agents may be particularly well suited for use in depressed HIV-positive individuals because these agents lack significant side effects (e.g., anticholinergic, {alpha}-adrenergic, histaminergic, cardiac effects) exhibited by TCAs and other older classes of antidepressants (96). There are a number of shortcomings of the available literature, however, that clinicians must carefully consider. In particular, the vast majority of controlled studies were conducted before the advent of HAART. With the exception of antidepressant medications, controlled studies systematically assessing efficacy and safety issues for other classes of psychotropic drugs (e.g., antipsychotic and anxiolytic medications) in HIV-infected persons are lacking. Moreover, although it is well established that antidepressant drugs are effective for treating various anxiety disorders in HIV-negative individuals, controlled studies evaluating the efficacy of antidepressants for treating anxiety disorders in HIV-positive patients are also lacking. Benzodiazepines account for 66.3% of all anxiolytics prescribed to HIV-infected patients (16). Significant interactions have been reported between antiretroviral drugs and benzodiazepines. For instance, due to its inhibitory effects on the CYP3A isoenzyme, low doses of ritonavir can significantly impair the clearance of alprazolam (97). Controlled studies on the treatment of anxiety and bipolar disorder in HIV-positive patients are needed.

Where reliable data are unavailable, physicians must exercise their best judgment balancing the strengths and weaknesses of the available literature with the needs of their patients. Where studies are not available for HIV-infected persons, it is reasonable to employ the state-of-the-art treatments supported by controlled psychopharmacological investigations in patients not infected by HIV, so long as every effort is made to consider critical factors unique to HIV-infected persons (e.g., whether there are any data or rationale to indicate that the psychotropic drug chosen may affect the patient’s immune status or viral replication adversely, potential adverse interactions with antiviral therapies). The same rules of thumb regarding psychotropic drug treatment in the general population apply to treatment strategies in patients with HIV infection. Knowledge of the pharmacology of these agents can be used to therapeutic advantage as well to avoid untoward effects. Factors including drug interactions related to psychotropic drug metabolism and protein binding, half-life, and effects on appetite require careful consideration particularly in more debilitated HIV-infected patients. Significant interactions between psychotropic drugs and antiretroviral agents used in multidrug HIV therapy must be considered carefully by the clinician because the potential for drug interactions can be great. Mood stabilizers must be used cautiously. Psychotropic drugs, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors all serve as substrates for various cytochrome P450 enzymes in the liver. Each of these classes of compounds possesses enzyme-inducing and/or -inhibiting properties, and drugs such as the protease inhibitor, ritonavir, can simultaneously modify a number of these isoenzymes (28). Despite the paucity of controlled studies evaluating the safety and efficacy of atypical antipsychotics in HIV-infected patients, antipsychotics are widely used in the treatment of psychotic disorders, delirium, and agitation in these patients. Caution and close monitoring of side effects are particularly important until new studies become available.

Nontraditional, herbal psychotropic agents used to treat psychiatric syndromes must also be monitored closely in HIV-positive individuals. An open-label study revealed that the protease inhibitor, indinavir, was markedly reduced by the concomitant administration of St. John’s wort (98). The magnitude of the reduction of indinavir levels was estimated to be significant enough to lead to drug resistance and result in treatment failure.

Although psychotropic drugs have been shown to have bidirectional effects on various parameters of immune status, it is noteworthy that in some reports antidepressants were found to have beneficial effects. For example, peripheral blood mononuclear cells from clomipramine- treated patients were found to produce higher concentrations of several cytokines (interleukin (IL)-1β, IL-2, and IL-3) (99). Interestingly, fluoxetine was associated with greater increases in NK cells activity after treatment in those patients who exhibited lower baseline levels at study entry (100). Thus, it is conceivable that certain subgroups of HIV-infected patients could derive both behavioral and immunological benefits from appropriate psychopharmacological intervention. Given that psychotropic drugs such as antidepressants can improve quality of life in HIV-positive individuals, further research is needed to determine whether effective treatment can improve medical outcomes in select subsets of these patients.

In summary, newer psychotropic drugs, in conjunction with behavioral therapy, are effective and well tolerated. Appropriate psychiatric care of HIV-positive patients is likely to decrease the incidence of medical complications and improve quality of life, and in turn decrease the financial burden on the health system. Unfortunately, access to mental health services specialized in treating HIV-infected patients is frequently limited or not available. Mental health policies for HIV-infected patients need to focus on the development of outreach programs and the education of primary care and mental health providers on state-of-the-art treatment approaches. Often, clinicians focus on either psychopharmacological or behavioral interventions, but fail to recognize the added benefit of combining these treatment modalities (101,102). The combined use of antidepressants and behavioral therapy has been shown to be more effective than either treatment approach in depressed patients that are not infected with HIV. Despite some shortcomings of the existing literature, overall there is compelling evidence that the appropriate use of psychotropic medications (coupled with behavioral therapy) can improve the quality of life of mentally ill HIV-infected individuals.


   NOTES
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 ABSTRACT
 INTRODUCTION
 CONCLUSIONS
 NOTES
REFERENCES
 
The author(s) do not have an affiliation with or financial interest in a commercial organization that might pose a conflict of interest.

Received for publication July 5, 2007; revision received January 28, 2008.

DOI:10.1097/PSY.0b013e3181777190


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 CONCLUSIONS
 NOTES
 REFERENCES
 

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