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PSYCHIATRY IN THE MEDICALLY ILL

0193–953X/02 $15.00 ‫ ם‬.00

PRACTICAL PSYCHOPHARMACOLOGY IN HIV-1 AND ACQUIRED IMMUNODEFICIENCY SYNDROME
Michael J. Robinson, MD, and Roula B. Qaqish, PharmD

Psychiatric disorders, including mood disorders, anxiety disorders, substance use disorders, cognitive disorders, personality disorders, psychotic disorders, and delirium, are highly prevalent among patients infected with HIV-1. HIV-1 infection rates among patients with psychiatric disorders also appear to be high. Psychopathology may have an important impact on treatment adherence, quality of life, HIV-1 risk factors, social and adaptive functioning, and possibly HIV-1 illness progression. For these reasons, psychiatrists treating patients infected with HIV-1 have many important roles, as listed in Table 1. The psychopharmacologic treatment of patients infected with HIV1 follows the same principles of using psychotropics in other medical populations. Patients with HIV-1/acquired immunodeficiency syndrome (AIDS) may be at increased risk for side effects and drug–drug interactions with combination antiretroviral regimens and other commonly used medications (e.g., antituberculous agents, antifungal agents, antimicrobial agents). This article reviews the psychopharmacologic treatment of major psychiatric syndromes in patients infected with HIV-1. The first section outlines the use of psychotropic medications for depression, anxiety, mania, psychosis and delirium, and cognitive disorders. The second section specifically focuses on known, potential and theoretic drug–drug interactions between psychotropics and antiretrovirals. A discussion of potential psychotropic drug–drug interactions with other

From the Division of Consultation-Liaison Psychiatry, Department of Psychiatry, Queen’s University, Kingston, Ontario, Canada (MJR); and the Division of Pharmacy, St. Louis College of Pharmacy, St. Louis, Missouri (RBQ)

THE PSYCHIATRIC CLINICS OF NORTH AMERICA
VOLUME 25 • NUMBER 1 • MARCH 2002

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Table 1. POTENTIAL ROLES OF THE PSYCHIATRIST IN CARE OF THE HIVINFECTED PATIENT Establishing and maintaining a therapeutic alliance Collaboration and coordination of care with other mental health and medical providers Diagnosing and treating all associated psychiatric disorders Facilitating adherence to the overall treatment plan Providing education about psychological, psychiatric and neuropsychiatric disorders Providing risk reduction strategies Maximize psychological and social adaptive functioning Considering the role of religion and spirituality Preparing the patient for issues of disability, death and dying Advising significant others/family regarding sources of care and support
Adapted from American Psychiatric Association, Work Group on HIV/AIDS. Practice guideline for the treatment of patients with HIV/AIDS. Am J Psychiatry 157:1–62, 2000; with permission.

medications commonly prescribed for HIV-1 infected patients (e.g., antimicrobials and antifungals) is beyond the scope of this article. PSYCHOTROPIC MEDICATIONS FOR PSYCHIATRIC SYNDROMES Depressive Disorders In the absence of delirium, clinical depression in HIV-1 patients should be treated, regardless of the stage of disease, and a trial of an antidepressant is usually warranted. Antidepressants have been underused in HIV-1/AIDS patients, as in other severely medically ill patients, because some clinicians overascribe depressive symptoms to a ‘‘normal reaction to illness.’’ Many studies (i.e., randomized, controlled trials; open-labeled trials; case series; and case reports) of the treatment of depressive disorders in HIV-1 infection support safety and efficacy of many antidepressant agents61; however, potential drug–drug interactions always should be considered when prescribing antidepressants to a patient with HIV-1 (see section on drug–drug interactions).30 Many of the treatment trials to date were completed before currently recommended, complex, highly active antiretroviral therapy (HAART). Thus, the generalizability of antidepressant safety under HAART remains to be determined. Table 2 summarizes the randomized, controlled trials, with effect size calculations, in the treatment of major depression in HIV-1 infection. Data from randomized trials support efficacy with a calculated high median effect size; however, the effect size for placebo response is also fairly high, as is typical of trials in uncomplicated depression. Literature from uncontrolled clinical trials of several newer antidepressant agents (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, nefazodone, mirtazapine, and venlafaxine) also supports their reported efficacy and tolerability.*
*References 2, 15, 17, 18, 26, 30, 32, 48, 61, 64, and 65.

Table 2. RANDOMIZED TRIALS Study Year Medication Effect Size* Depression Measures Findings

Antidepressants and Stimulants 2000 Dextroamphetamine Wagner GJ, et al85 Placebo

1.66 (11) SCID (DSM-IV), 0.84 (11) HAM-D, BSI, BHS, VAS, CGI 1.50 (8) 0.60 (6)

Schwartz JA, et al77 1999 Fluoxetine Desipramine

Rabkin JG, et al68 Markowitz JC, et al51

1999 Fluoxetine Placebo 1998 Imipramine (SWI) IPT Supportive psychotherapy CBT 1998 Fluoxetine Placebo

2.79 (81) 2.04 (39) 1.55 1.89 0.98 1.13 (26) (24) (24) (27)

Zisook S, et al89

1.89 (25) 0.69 (22)

At baseline, 53% major depression, 13% dysthymia, 35% minor depression or subthreshold major depression; 73% of the dextroamphetamine group and 27% of the placebo group responded to treatment; Note: dextroamphetamine was less effective in those who had major depression compared with those who had more mild depression. SCID (DSMStudy participants were women only, with advanced HIV IIIR), HAM-D, disease, and most had prior depressive episodes by history; CGI insufficient power to detect differences between treatment groups; 38% of fluoxetine group and 33% of desipramine group had a partial response defined as 50% reduction in HAM-D score at 6 weeks, whereas 25% and 17% respectively for full response defined as HAM-D score Ͻ8. CGI, HAM-D, In completers there was a 74% response rate to fluoxetine, and BSI a 47% response rate to placebo; Intent to treat analysis, however, showed no significant difference (57% vs. 41%). SCID (DSMOnly 53% of the sample met DSM-IIIR criteria for depression IIIR), BDI, on SCID, and about half the sample population had an axis HAM-D, PDE II disorder and a lifetime substance abuse history; scores on HAM-D decreased significantly for all groups, and BDI scores fell significantly only for IPT and SWI groups. SCID (DSMOf the 79% who completed the trial, 64% of fluoxetine treated IIIR), HAM-D, vs. 23% of placebo had a Ͼ50% decrease in HAM-D score. BDI-13, CGI-I, Differences were particularly apparent for those whose CGI-S depressive episodes were rated as severe (HAM-D Ͼ 24). Table continued on following page

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Table 2. RANDOMIZED TRIALS (Continued) Study Elliot AJ, et al
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Year

Medication

Effect Size*

Depression Measures

Findings

1998 Paroxetine Imipramine Placebo

Fernandez F, et al23 1995 Desipramine Methylphenidate

Rabkin et al65

1994 Imipramine Placebo

Not SCID (DSMOnly 45% of the subjects completed the 12-week trial. Of the readily IIIR), HAM-D, group that completed treatment, response rates (Ͼ 50% calculated CGI reduction in HAM-D) were 62%, 64%, and 90% for placebo, paroxetine, & imipramine respectively after 12 weeks of treatment. Rates for full response (HAM-D Ͻ 8), respectively, were 23%, 55%, and 80%. No significant difference in response rates for paroxetine and imipramine. 3.18 (10) DSM-IIIR, 47% of the DMI group and 43% of the MPD group had a Ͼ 1.98 (10) HAM-D, 50% reduction in HAM-D score at 6 weeks; significant side POMS, BSI, effects were reported by 22% of the DMI group and 16% of MMPI the MPD group, with treatment emergent side effects more common for MPD early in treatment, and later for DMI. 2.14 (47) SCID (DSM-IIR), 74% of IMI group versus 26% of the placebo group responded 1.00 (42) HAM-D, CGI, according to HAM-D and CGI scores; of the placebo BSI, BHS nonresponders, open treatment with IMI led to 53% response rate after 6 weeks; no consistent relationship between response rate and illness severity, as measured by CD4 count; IMI had no adverse effect on immune status as measured by CD4 count; Note: nearly 20% of IMI responders chose to discontinue treatment before 6 months secondary to side effects. 0.73 (26) BDI, 57% with BDI Ͼ 18 were hypogonadal by free testosterone 0.67 (26) antidepressant levels, versus 24% with BDI Ͻ 18; The BDI score was not use was different between treatment groups; the BDI score decreased recorded significantly in testosteone group, but not among patients receiving placebo.

Testosterone Grinspoon S, et al34 2000 Testosterone Placebo

Rabkin JG, et al69

2000 Testosterone Placebo

0.80 (38) SCID (DSM-IV), ‫מ‬0.49 (32) HAM-D, BDI, BSI

Rabkin JG, et al67

1999 Testosterone Placebo

Of the 26 completers with current syndromal mood disorder, 58% randomized to testosterone and 14% randomized to placebo were ‘‘mood’’ responders based on CGI score. Mood disordered patients randomized to testosterone showed significantly more improvement on all measures of HAM-D than placebo treated except the affective subscale. Note: patients taking antidepressants were included in the trial. 1.50† (37) SCID (DSM56% had depressed mood at study baseline, and of these 54% 0.03† (40) IIIR), HAM-D, had major depression and the remaining had elevated CGI, BSI scores on HAM-D, but no current axis I depressive disorder; during open treatment phase, 79% with axis I depressive disorder showed significant improvement in mood; during double-blind discontinuation phase, measures of mood showed no decline in those receiving testosterone versus a quick and significant decline for those on placebo. 2.02 (203) 1.82 (21) 0.73 (101) 0.84 (214) 1.51 (51)

Median effect size Antidepressent Stimulant Testosterone Placebo CBT/IPT

*Effect sizes for depression scores were calculated for open trials and randomized trials in the same according to the following formula ((Mean(pre-test) ‫ מ‬Mean(post-test)/ standard deviation(pre-test)) within each treatment condition. The sign of the effect sizes was adjusted so that a positive effect size reflected improvement on the measure. For uniformity across randomized trials and open trials, estimates of standard deviation were not pooled across conditions. As a check, effect sizes in the randomized trials were calculated using estimates of the standard deviation pooled across the pre-tests of all conditions in the study. This approach produced similar results. †Effect sizes adjusted so that the larger value reflected the greatest retained improvement following the cessation of treatment in the discontinuation trial. SCID ‫ ס‬Structured Clinical Interview for DSM; DSM ‫ ס‬Diagnostic and Statistical Manual of Mental Disorders; HAM-D ‫ ס‬Hamilton Depression Rating Scale; BDI ‫ ס‬Beck Depression Inventory; BDI-13 ‫ ס‬Beck Depression Inventory-13 Item Short Version; BSI ‫ ס‬Brief Symptom Inventory; BHS ‫ ס‬Beck Hopelessness Scale; CGI ‫ ס‬Clinical Global Impression; VAS ‫ ס‬Visual Analog Scale; MMPI ‫ ס‬Minnesota Multiphasic Personality Inventory; PDE ‫ ס‬Personality Disorders Examination; POMS ‫ ס‬Profile of Mood States: IMI ‫ ס‬Imipramine; DMI ‫ ס‬Desipramine; MPD ‫ ס‬Methylphenidate; CBT ‫ ס‬Cognitive-behavioral therapy; IPT ‫ ס‬Interpersonal psychotherapy; SWI ‫ ס‬Supportive psychotherapy with imipramine.

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Newer antidepressant agents (i.e., fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, venlafaxine, nefazodone, and bupropion) are often better tolerated than tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), but side effects may still limit their use. Side effects from serotonergic agents may result from stimulation of 5-HT2A (e.g., insomnia, anxiety or agitation, and sexual dysfunction), 5-HT2C (e.g., irritability and decreased appetite), and 5-HT3 (e.g., nausea, vomiting, and headache) receptors. Side effects from newer agents also may result from noradrenergic receptor stimulation (e.g., tachycardia, blood pressure effects, dry mouth, and sweating) and from interactions at other receptors, including muscarinic, histaminergic, and postsynaptic ␣1-adrenergic receptors (e.g., dry mouth, sedation, postural hypotension).70 It is important to keep these potential side effects in mind when choosing an antidepressant for a patient with HIV-1/AIDS. In particular, if patients are on HAART, with a large pill burden, selecting an agent that is well tolerated with low risk for drug–drug interactions is important to promote medication adherence. Clinical pearls regarding the use of antidepressants in patients with HIV-1 are listed in Table 3. In addition to traditional antidepressant agents, testosterone treatment has been found to be effective for depressive symptoms, which occur in the context of men with hypogonadal symptoms (e.g., diminished libido, depressed mood, low energy, and depleted muscle mass). Table 2 summarizes the results from randomized trials. Their efficacy also is supported in nonrandomized trials. Psychostimulants, including methylphenidate, dextroamphetamine, and pemoline, may be useful in the treatment of HIV-1–infected patients for depression with or without cognitive impairment and for pain syndromes. In advanced HIV-1 disease, psychostimulants have been shown to improve cognitive performance, apathy, fatigue, withdrawal, anorexia, suicidal ideation, and self-care.52 Stimulants are preferable to traditional antidepressants in terminally ill HIV-1 patients because of their quicker onset of action. Based on reports of the development of irreversible abnormal involuntary movements in depressed patients with HIV-1– associated dementia, the current recommendation is to avoid dextroamphetamine in this population.20 Methylphenidate can be given by mouth, feeding tube, or suppository. The advantage of pemoline is its availability in a tablet form that can be dissolved in the mouth and absorbed through the buccal mucosa for patients who are on NPO (nothing-bymouth) restrictions.82 Potential disadvantages of pemoline are delayed onset of action (2–3 weeks) and need to monitor liver function because of idiosyncratic toxicity.9 Side effects may include movement disorders, psychosis, and seizures. Although clinical experience with psychostimulants in the medically ill, including HIV-1/AIDS, suggests a low tendency toward tolerance and abuse, all psychostimulants have abuse potential and should be used judiciously in patients with a history of substance abuse.

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Table 3. USING NEWER ANTIDEPRESSANT AGENTS IN PATIENTS WITH HIV/AIDS, CLINICAL PEARLS Medication Nefazodone Clinical Pearls in HIV/AIDS Patients

Inhibitor of CYP3A4—use caution when combining with protease inhibitors (see section on drug interactions for more information). Venlafaxine Higher rates of nausea and anorexia may not be well tolerated by patients with HIV/acquired immunodeficiency syndrome (AIDS); dosedependent increase in blood pressure. Bupropion Use with caution in patients with intracranial pathology (e.g., toxoplasmosis, CNS lymphoma, CMV) as there may be an increased seizure risk; no longer contraindicated with protease inhibitor Ritonavir Mirtazapine May promote weight gain (useful in patients with significant AIDS wasting). May alleviate nausea (by way of its 5-HT23 blockade); useful for patients with poor sleep; now available in an orally disintegrating tablet, which may be useful in severely ill patients; lack of sexual dysfunction, minimal GI side effects. Fluvoxamine One study in HIV patients found that it was poorly tolerated despite showing efficacy; may not be a first-line agent. Fluoxetine Well tolerated and clinically effective in studies to date; due to its activating properties, it may not be first line medication in patients with significant comorbid anxiety or insomnia; no reported effect on immune function, when studied. Paroxetine Mild secondary muscurinic-antagonistic properties may make this drug a second-time choice in an HIV/AIDS patient with cognitive impairment. Sertraline Well tolerated and clinically effective in studies to date; no reported effect on immune function, when studied. Citalopram Most selective SSRI, with no secondary properties which limits nonserotinergic side effects. TCAs Anticholinergic side effects may cause urinary retention, paralytic ileus, dry mouth (which may increase risk for oral opportunistic infections such as candidiasis), cognitive dysfunction and may worsen confusion; other side effects may be problematic including orthostatic hypotension, and cardiac arrythmogenicity. MAOIs Avoid due to the complex, often changing drug regimen and the potential for fatal hypertensive crisis, and drug–drug interactions.
CYP ‫ ס‬cytochrome P-450; CNS ‫ ס‬central nervous system; CMV ‫ ס‬cytomegalovirus; 5HT ‫ ס‬5hydroxytryptamine; GI ‫ ס‬gastrointestinal; SSRI ‫ ס‬selective serotonin reuptake inhibitor.

Anxiety Syndromes Anxiety, as a symptom, is prevalent in the HIV-1/AIDS population, and may be multifactorial in etiology. It may be a symptom of an anxiety disorder, adjustment disorder, depressive disorder, delirium, or other cognitive disorder. In addition, anxiety may be a side effect of medications used in patients with HIV-1/AIDS. Psychopharmacologic treatment options for anxiety states include benzodiazepines (BDZs), non-BDZ anxiolytics (buspirone), antidepressants (particularly trazodone), and neuroleptics. Neuroleptics generally are preferred for severe anxiety states associated with delirium and other cognitive disorders. BDZs may be used in patients with HIV-1/AIDS, as in other patients with medical illnesses. They are best used for short periods to minimize the risk for habituation, tolerance, abuse, and dependence. BDZs with

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short to intermediate half-lives are preferred to decrease the potential for accumulation and side effects, such as oversedation, disinhibition, cognitive impairment, and confusion. The biggest concern when using BDZs is the potential for drug–drug interactions.30 Buspirone, an alternative to BDZs, was found to be tolerated in patients with HIV-1 for the treatment of generalized anxiety.5 It has the advantages of being nonsedating and nonaddictive, and it has few known drug–drug interactions in patients with HIV-1/AIDS. Disadvantages include a slow onset of action (usually 2 to 3 weeks), and it has not been well studied in the medically ill in general. One case of buspirone-induced psychosis with manic features in a patient with HIV-1 has been reported.83 Other cases of buspirone-induced mania in patients without HIV-1 also have been reported.54, 55, 63 Despite these limited case reports, it seems to be a reasonable alternative in treatment of general anxiety in HIV-1/AIDS. The antidepressant trazodone, in low dosage (25 to 200 mg/d), is useful for the treatment of anxiety, agitation, and insomnia. It is usually well tolerated, with an immediate sedating and ‘‘calming’’ effect, unlike buspirone. Although it poses a small risk for priapism, it generally lacks significant systemic side effects, although in higher doses, the risk for hypotension and sedation is increased. Other antidepressants to consider for the treatment of generalized anxiety include venlafaxine, which has received a clinical indication for generalized anxiety disorder from the US Food and Drug Administration. The suggestions outlined in the preceding section on depression are also appropriate when treating other anxiety disorders in which antidepressant medications are often first-line treatments (e.g., panic disorder, obsessive-compulsive disorder, social anxiety disorder, and posttraumatic stress disorder). Manic Syndromes Manic syndromes in patients with HIV-1 may be considered primary or secondary. Primary manic syndromes are those that occur in HIV-1 patients with a preexisting personal or family history of bipolar disorder and may occur at any time during the course of HIV-1 infection. Treatment of primary mania is not substantially different from the usual treatment of bipolar mania in patients without HIV-1. Secondary mania (HIV-1–associated mania, or AIDS mania) most often occurs late in the course of HIV-1 infection and is thought to result from HIV-1 brain involvement. HIV-1–associated mania may be differentiated from primary mania in HIV-1–infected patients by its late onset in the course of HIV-1 infection and its common association with cognitive decline or AIDS dementia. Frequently, no prior personal or family history of bipolar disorder is found. Of course, it is also possible for an HIV-1 patient to have a manic episode that has primary and secondary characteristics. Clinically, HIV-1–associated mania tends to present with more irritability

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and has a more chronic course, few spontaneous remissions, and frequently relapses with cessation of treatment. Treatment of secondary mania differs in some regards, as is discussed later. Finally, evaluating a patient with HIV-1 infection who presents with manic symptoms, one also should consider a medical cause (e.g., AIDS-associated CNS infection or neoplasm) or a side effect of medications (e.g., didanosine or zidovudine).11, 14, 49, 88 Lithium commonly is used to treat primary mania of bipolar disorder in HIV-1 patients. The use of lithium may be complicated because of unstable fluid status with diarrhea, dehydration, and poor fluid intake. These patients also may develop HIV-1 nephropathy, a generally irreversible condition, which may impair lithium clearance.2 Lithium levels and renal function need to be monitored closely. Although it does not require hepatic metabolism and is therefore free of significant metabolic drug–drug interactions, the previously mentioned difficulties limit its clinical use. Because of the risks of toxicity, even in small doses, lithium should generally be avoided in the treatment of secondary or HIV-1–associated mania. Valproic acid (or divalproex sodium) is a common mood stabilizer used in the treatment of manic syndromes. Valproic acid may be used for manic syndromes in HIV-1 with some caution. Recently, its use has been questioned because of in vitro evidence that valproate may lead to activation of HIV-1 and cytomegalovirus replication and thus acceleration of viral disease; however, the clinical relevance of this interaction is unclear.36, 40, 41, 42 A retrospective review of 11 HIV-1 patients treated with valproate and adequate antiretrovirals found no evidence of increased viral load in these patients.50 Therefore, the use of valproate in HIV-1 patients receiving antiretroviral should be with caution until further data are available. Until further study, the authors recommend regular monitoring of viral load in patients receiving valproic acid or divalproex sodium. It is also well known that valproic acid may cause hepatic toxicity, usually asymptomatic and transient. Recently, a case of hepatitis caused by the use of valproic acid, ritonavir, and nevirapine in a patient with HIV-1 was reported.13 The frequency of liver function monitoring should be individualized. As with any medication that is primarily metabolized through the liver, there are potential drug–drug interactions with antiretroviral medications. Carbamazepine is now less commonly used as a treatment alternative for mania, especially in patients with HIV-1, and generally should be avoided in the treatment of secondary mania. Because of its potential for bone marrow toxicity (leukopenia or aplastic anemia), it should be avoided in patients who are immunocompromised. Carbamazepine has potent effects on the cytochrome P-450 system that may cause significant drug–drug interactions in patients with HIV-1.38 Gabapentin, lamotrigine, and topiramate are additional alternative, off-label mood-stabilizing therapies for mania. No data are available about the use of these agents for mania HIV-1–infected patients. In other populations, gabapentin is fairly well tolerated, with the main side

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effects including sedation, fatigue, and dizziness. It is not metabolized by the liver or protein bound, and is devoid of significant drug–drug interactions; however, it is entirely renally excreted, and therefore its dosage may need to be adjusted if creatinine clearance is reduced.7 Gabapentin has been used successfully in patients with HIV-1 to treat neuropathic pain.60 Lamotrigine has been used effectively as a moodstabilizing, or anticycling, agent in patients without HIV-1.19 Its use in HIV-1 may be complicated by severe dermatologic side effects and the potential for drug–drug interactions. Lamotrigine too has been used successfully in patients with HIV-1 for the treatment of HIV-1–associated neuropathy.79 Gabapentin and lamotrigine, although used as mood stabilizing, or anticycling, agents, have not been shown to be effective individually in the acute treatment of mania in bipolar disorder. Topiramate, in preliminary studies of non–HIV-1 patients, shows more promise as both an adjunctive anticycling and antimanic agent.44 Potential side effects of concern for the HIV-1 population include psychomotor slowing with impaired concentration, somnolence, and fatigue. Other potential side effects include confusion, memory problems, and increased irritability. Topiramate also may cause decreased appetite with weight loss, a potentially undesirable side effect in the HIV-1 population. The authors cannot currently recommend its use in this population until additional research is performed. The treatment of secondary mania deserves special attention. Because it typically occurs in patients with advanced HIV-1 infection, management is more difficult. Single-agent therapy is a goal to minimize the risk for potential drug–drug interactions and to promote treatment adherence. Low-dose, high-potency neuroleptics and atypical neuroleptics (e.g., risperidone, olanzapine, and quetiapine) may be effective in secondary mania.14, 80 For more information about the details of using these neuroleptics in patients with HIV-1, please see the next section on treatment of psychotic syndromes. Some emerging evidence shows that antiretrovirals that have good CNS penetration may provide some protection against the development of secondary mania.58

Psychosis and Delirium Psychotic symptoms may occur in HIV-1 infection either as a primary disorder, such as schizophrenia, or as part of mania, delirium, HIV1–associated dementia, or other ‘‘organic’’ syndromes. The treatment of new-onset psychotic symptoms in HIV-1–infection always should begin with thorough medical and neurologic evaluation. Psychopharmacologic treatment primarily includes neuroleptics. In patients with asymptomatic HIV-1 infection whose immune function is competent and who are not receiving antiretroviral medication, the use of neuroleptics is no different that in the non–HIV-1 population. For all patients who are receiving antiretroviral medication, particularly

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the protease inhibitors (PIs), it is important to be aware of potential drug–drug interactions with neuroleptics. The risk for neuroleptic-induced extrapyramidal symptoms (EPS) in patients with advanced HIV-1 infection is much higher than in patients without HIV-1.37, 58 Patients with HIV-1 are also at higher risk for movement disorders, such as Parkinsonism and dystonia, unrelated to neuroleptic exposure, perhaps because of damage to the basal ganglia.2 Therefore, atypical neuroleptics are preferred, especially in patients with HIV1–associated dementia. Baseline examination for a abnormal movements always should be performed before initiating any neuroleptic. It is important always to use the lowest effective dose of either a conventional or atypical neuroleptic. With conventional neuroleptics, high-potency agents may pose greater risk for EPS, but low-potency neuroleptics have much greater anticholinergic activity. This may increase the risk for worsening confusion and may precipitate delirium, particularly in those with HIV-1– associated dementia; however, one study comparing chlorpromazine (average maintenance dosage, 36 mg/d) and haloperidol (average maintenance dosage, 1.4 mg/d) in the treatment of delirium in patients with AIDS found no statistically significant difference in treatment emergent side effects.10 Also, molindone was reported to be effective and well tolerated in four patients with HIV-1 infection and psychosis of various causes, refractory to conventional neuroleptic treatments, and suffering from severe EPSs.22 In addition to EPSs, neuroleptic malignant syndrome has occurred in HIV patients with both conventional and atypical neuroleptics.8, 25, 73 HIV-1–infected patients seem to be at higher risk for neuroleptic malignant syndrome. Atypical neuroleptics seem to be better tolerated in patients with HIV-1 during both early and advanced infection, but no systematic studies of atypical neuroleptic use in patients with HIV-1 have been performed.6, 80 Therefore, recommendations are drawn mainly from clinical experience in HIV-1 and other medically ill populations and from limited case reports and uncontrolled clinical trials. To date, the literature supports tolerability and efficacy of risperidone. One case of neuroleptic malignant syndrome in HIV-1 with risperidone, possibly secondary to a drug–drug interaction with PIs ritonavir and indinavir, has been reported.45 This highlights the vigilance regarding potential drug–drug interactions that one needs to maintain when prescribing any medication to patients with HIV-1 who are on complex multidrug regimens. Atypical neuroleptics, clozapine, and remoxipride (not available in North America), have been used successfully in patients with HIV-14, 46; however, they should be used with caution because they can produce undesirable hematologic side effects, such as agranulocytosis and aplastic anemia, respectively. Weight gain, a common side effect among many atypical neuroleptics, may be less problematic, even an advantage, in patients with anorexia or HIV-1–related wasting syndromes. Less is known about the use of olanzapine, quetiapine, ziprasidone, and zotepine (not available in North America) in patients with HIV-1. Clinically,

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the authors have successfully used olanzapine in the treatment of delirious patients with advanced HIV-1. General clinical pearls guiding the use of neuroleptics in the context of HIV-1/AIDS are listed in Table 4. HIV-1–Associated Cognitive Disorders Potential CNS manifestations of HIV-1 infection are numerous. Cognitive disorders in HIV-1 mainly consist of HIV-1–associated dementia and HIV-1–associated minor cognitive motor disorder. Diagnostic criteria for these disorders are displayed in Tables 5 and 6, respectively. An extensive review of the neuropsychiatric aspects of HIV-1–associated cognitive disorders, including epidemiology, pathogenesis, staging, diagnosis, neuropathology, neuroimaging, and treatment, can be found in the article by Whitaker.86 There have been four major treatment approaches are (1) antiretroviral drugs, (2) interventions that affect inflammatory mediators and neuroprotective therapies, (3) neurotransmitter manipulation, and (4) nutritional therapies. Most of the research to date has focused on antiretroviral drugs; however, over the past few years, the optimal treatment of HIV-1 has changed drastically with HAART, and this makes it difficult to draw conclusions from earlier research. Also,
Table 4. CLINICAL PEARLS FOR PRESCRIBING NEUROLEPTICS IN PATIENTS WITH HIV-1 Medication General Clinical Pearl HIV-infected patients are at increased risk for side effects, including EPS, NMS, and TD; use lowest effective dose; always be aware of potential drug–drug interactions; Low potency conventional and atypical (clozapine, olanzapine, and quetiapine) neuroleptics, increased risk for postural hypotension which may be a significant problem in dehydrated or weak HIV patients. High potency, increased risk for EPS; those with high anticholinergic properties may worsen confusion, precipitate delirium, and dry mucous membranes presdisposing to oral candidiasis; molindone may be useful and well tolerated, based on four case reports; low potency, increased risk for postural hypotension which may be a significant problem in dehydrated or weak HIV patients. Appear to be effective and better tolerated than conventional neuroleptics; limited data other than uncontrolled trials and case reports; risperidone has been safe and effective; potential undesirable hematological side effects of clozapine and remoxipride, use with caution; olanzapine’s muscarinic antagonistic properties theoretically may make this unfavorable for use in patients with cognitive dysfunction, but it is now available in a orally disintegrating tablet formulation that may be helpful in patients who are unable to take medication per os; quetiapine may be the least likely to cause EPS.

Conventional neuroleptics

Atypical neuroleptics

NMS ‫ ס‬neuroleptic malignant syndrome; EPS ‫ ס‬extrapyramidal symptom; TD ‫ ס‬tardive dyskinesia.

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Table 5. DEFINITIONAL CRITERIA FOR HIV-1–ASSOCIATED DEMENTIA Criterion 1. Acquired abnormality in at least two of the following cognitive abilities (present for Ն 1 month): Attention/concentration; speed of processing; abstraction/reasoning; visuospatial skills; memory learning; speech/language Description Cognitive decline verified by history and mental status examination; when possible, history should be obtained from an informant and examination should be supplemented by neuropsychological testing; the cognitive dysfunction must cause impairment of work or in activities of daily living, with impairment not attributable solely to severe systemic illness Abnormality verified by physical examination, neuropsychological tests, or both

2. At least one of the following: A. Acquired abnormality in motor function or performance B. Decline in motivation or emotional control or change in social behavior 3. Absence of clouding of consciousness during a period long enough to establish the presence of criterion 1

4. Exclusion of another etiology by history, physical, and psychiatric examination and appropriate laboratory and radiologic tests

Change characterized by any of the following: apathy, inertia, irritability, emotional lability, or new-onset impaired judgment characterized by socially inappropriate behavior or disinhibition Alternate possible etiologies include active central nervous system opportunistic infections or malignancy, psychiatric disorders (e.g., depressive disorders), active substance abuse, or acute or chronic substance withdrawal

From American Psychiatric Association, Work Group on HIV/AIDS: Practice Guideline for the treatment of patients with HIV/AIDS. Am J Psychiatry 157:1–62, 2000; with permission.

Table 6. DEFINITIONAL CRITERIA FOR HIV-1–ASSOCIATED MINOR COGNITIVE/ MOTOR DISORDER Criterion*† 1. Acquired cognitive/motor/behavioral abnormalities, verified by both a reliable history and by neurologic tests 2. Mild impairment of work or activities of daily living 3. Does not meet criteria for HIV-1 associated dementia or HIV myelopathy 4. No other cause present
*A probable diagnosis must meet all four criteria. †A possible diagnosis of MCMD can be given if criteria 1–3 are present and either (1) an alternate etiology is present and the cause of number 1 is not certain or (2) the etiology of criterion 1 cannot be determined because of an incomplete evaluation. Adapted from American Psychiatric Association, Work Group on HIV/AIDS: Practice Guidelines for the treatment of patients with HIV/AIDS. Am J Psychiatry 157:1–62, 2000; with permission.

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the populations studied have varied widely in both diagnostic definitions and clinical severity. Recently, increased understanding of the neuropathology of HIV-1–associated cognitive disorders has led to increased research involving anti-inflammatory and neuroprotective therapies as adjuncts to viral suppression with antiretrovirals.86 Zidovudine has been found to be effective in the treatment of cognitive disorders or dysfunction in HIV-1. This comes from two randomized, placebo-controlled trials that demonstrated improvements in neuropsychological impairment, as well as open-labeled trials.76, 78 Other antiretroviral drugs that have been studied in the treatment of HIV1–associated cognitive disorders include stavudine, nevirapine, didanosine, and abacavir. A key question is whether antiretroviral agents penetrate the blood brain barrier sufficiently to adequately suppress HIV-1 replication, and if so, what dosage of medication is required to achieve this.53, 56, 86 Theoretically, if there is incomplete suppression of viral replication, then there may be the potential for antiretroviral resistance to develop within the CNS and potentially worsen neurocognitive disorders. This also raises the possibility of resistant viral reseeding from the CNS to the peripheral circulation.2 This explains the preferred use of antiretroviral agents with good CNS penetration (e.g., zidovudine, stavudine, abacavir, and nevirapine). Combination antiretroviral treatments have been shown to improve tests of neurocognitive function compared with no treatment.24 Whether antiretroviral treatment helps to prevent HIV-1–associated cognitive disorders remains unclear, although a few clinical trials have suggested that this may be the case.12, 35, 81 It has been postulated that HIV-1–associated neuronal injury may result from activation of voltage-dependent calcium channels and Nmethyl-D-aspartate (NMDA) receptor -operated channels. This has led to the investigation of NMDA antagonists (e.g., memantine, see www.memantine.com/inhalte/s1.html for more information), and calcium channel blockers (e.g., nimodipine).39, 86 Nimodipine has significantly reduced HIV-1–associated cognitive deficits.28, 59 Still other neuroprotective therapies studied include antioxidants (e.g., OPC-14117 and thioctic acid) and platelet-activating factor antagonist (e.g., lexipafant).75 Few treatment trials have involved interventions that are thought to exert their effect through modulating inflammatory mediators. These have included peptide T, inhibitors of tumor necrosis factor-␣ (e.g., pentoxifylline and thalidomide), interleukin-1 receptor blockers, and interferon-␣ inhibitors (e.g., naloxone).86 A detailed discussion of these therapies is beyond the scope of this article. Nutritional therapies also have been used as possible interventions in the treatment of HIV-1–associated cognitive disorders. These have included vitamin B12, vitamin B6, and zinc. Vitamin B12 has been found to be low in many HIV-1-infected individuals. Deficiencies can be associated with impairments on tests of neurocognitive functioning, and normalization can lead to improvement. Zinc deficiency has been found to be associated with a more rapid general progression of HIV-1, which

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includes CNS progression. Other nutritional therapies may include vitamin E, an antioxidant.2, 86 Other treatments that have been found to be helpful in the treatment of HIV-1–associated neurocognitive disorders include agents that manipulate neurotransmitter systems. Psychostimulants are used as palliative agents in the care of patients with HIV-1–associated dementia or minor cognitive motor disorder. They are effective at relieving symptoms of fatigue, apathy, decreased concentration, and memory deficits.2 The use of psychostimulants is outlined in the section on depression. When using psychostimulants in patients with HIV-1–associated cognitive disorders, one must beware of the potential to exacerbate psychotic symptoms, especially as dementia progresses. Psychostimulants also may exacerbate the risk for seizures and movement disorders. Of the psychostimulants used in the treatment of HIV-1–associated cognitive disorders, methylphenidate is considered first line, followed by dextroamphetamine and pemoline. Other dopaminergic-enhancing agents are currently being investigated for use in HIV-1–associated cognitive disorders (e.g., pramipexole, as dopamine agonist).2 Selegiline, a MAOI-B, which enhances dopamine, has been shown to reverse deficits in mild HIV-1–associated cognitive impairment.72, 74 Serotonin 5-hydroxyindoleacetic acid has been found to be decreased in the cerebrospinal fluid as HIV-1 progresses. Theoretically, the administration of serotonergic agents, such as selective serotonin reuptake inhibitors (SSRIs), may be useful in the treatment of HIV-1–associated cognitive dysfunction. Some recent evidence indicates that some serotonin reuptake inhibitors (e.g., paroxetine, femoxetine [not available in North America]) inhibit HIV-1 replication but require further study.43 PSYCHOTROPIC-ANTIRETROVIRAL DRUG–DRUG INTERACTIONS Drug–drug interactions are pharmacodynamic or pharmacokinetic in nature. Pharmacodynamic interactions involve alterations in the pharmacologic response to or effect by a drug without pharmacokinetic changes. Pharmacokinetic interactions include altered absorption, distribution, metabolism, or excretion and can result in changing the drug concentration in tissues. Hepatic metabolism is divided into phase 1 and phase 2 reactions. A group of monooxygenase enzymes, called the cytochrome P-450 (CYP450) enzyme system, catalyze phase 1 reactions and are responsible for most of the metabolic drug interactions. Eleven CYP450 enzyme families exist, of which three are important in humans (e.g., CYP1, CYP2, and CYP3). The families are subclassified into subfamilies that are identified by a capital letter (i.e., CYP3A). The subfamilies are further subclassified into isozymes based on the homology between the subfamily proteins and are denoted by a number following the capital letter (i.e., CYP3A4). A substrate is an agent or a drug the metabolism of

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which is catalyzed by CYP isozymes. An inducer is an agent or a drug that increases the catalytic activity of the enzyme, allowing for increased rate of metabolism, whereas an inhibitor decreases the catalytic activity of an enzyme, resulting in the opposite effect on the enzyme. Phase 2 reactions are conjugation reactions, which couple oxidized substrates to glucuronate for excretion (e.g., glucuronidation).62 The three classes of antiretroviral agents used to treat HIV-1 infection are shown in Table 7. Many of the clinically relevant pharmacokinetic interactions involving psychotropics and the PIs or the non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolic in nature. The nucleoside reverse transcriptase inhibitors (NRTIs) are eliminated by the kidneys, thus involving fewer pharmacokinetic interactions.62 Many psychotropic agents are metabolized (e.g., substrates) by the CYP3A4 and the CYP2D6 isozymes. Table 8 includes a list of psychotropic and antiretroviral substrates, inducers, and inhibitors of the most relevant isoenzymes. The HIV-1 PIs and NNRTIs are substrates of CYP3A4. In addition to being substrates of CYP3A4, nelfinavir is substrate of CYP2C19, ritonavir is a substrate of CYP2D6, and efavirenz and nevirapine are substrates of CYP2B6. The PIs inhibit the CYP3A4 isozymes at varying degrees. Ritonavir is the most potent inhibitor of CYP3A4, followed by indinavir, amprenavir, and nelfinavir as moderate inhibitors and saquinavir and lopinavir are the weakest inhibitors. The combination of lopinavir–ritonavir (Kaletra) may have greater inhibitory effects on CYP3A4 because of the ritonavir component. In addition, ritonavir inhibits CYP2D6, which is an important isoenzyme for the metabolism of many psychotropics (Table 8), CYP2C9 and CYP2C19. Ritonavir and nelfinavir are weak inducers of CYP3A4 and glucuronyl transferase, whereas ritonavir is also an inducer of CYP1A2, CYP2C9.

Table 7. HIV-1 ANTIRETROVIRAL MEDICATIONS BY CLASS Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Abacavir (ABC) (Zigen) Didanosine (ddI) (Videx) Lamivudine (3TC) (Epivir) Stavudine (d4T) (Zerit) Zalcitabine (ddC) (Hivid) Zidovudine (ZDV or AZT) (Retrovir) Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Delavirdine (DLV) (Rescriptor) Nevirapine (NVP) (Viramune) Efavirenz (EFV) (Sustiva) Protease Inhibitors (PIs) Amprenavir (APV) (Agenerase) Indinavir (IDV) (Crixivan) Lopinavir/Ritonavir (Kaletra) Nelfinavir (NFV) (Viracept) Saquinavir mesylate (SQV) (Invirase) Saquinavir (SQV) (Fortovase) Ritonavir (RTV) (Norvir)

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Table 8. PSYCHOTROPIC AND ANTIRETROVIRAL* SUBSTRATES, INHIBITORS AND INDUCERS OF THE CYTOCHROME P-450 ISOENZYMES CYP Isoforms 1A2 Substrates Clomipramine Clozapine Fluvoxamine Haloperidol Imipramine Mirtazapine Olanzapine Zotepine Bupropion Efavirenz Nevirapine Diazepam Diazepam Nelfinavir Amitriptyline Chlorpromazine Clomipramine Clozapine Desipramine Fluoxetine Fluvoxamine Haloperidol Imipramine Methylphenidate Mirtazapine Alprazolam Amprenavir Buspirone Carbamazepine Citalopram Clomipramine Clonazepam Delavirdine Efanirenz Imipramine Indinavir Lopinavir Lorazepam Olanzapine Paroxetine Perphenazine Risperidone Thioridazine Trazodone Trimipramine Venlafaxine Zotepine Midazolam Nefazodone Nelfinavir Nevirapine Pimozide Quetiapine Ritonavir Saquinavir Temazepam Trazodone Ziprasidone Zotepine Inhibitors Fluvoxamine Paroxetine Olanzapine Inducers Ritonavir

2B6 2C9 2C19 2D6

Ritonavir Efavirenz Ritonavir Efavirenz Fluoxetine Ritonavir Fluoxetine Fluvoxamine Nelfinavir Norfluoxetine Olanzapine Paroxetine Perphenazine Ritonavir Sertraline Venlafaxine Ziprasidone Amprenavir Delvirdine Efavirenz Fluvoxamine Indinavir Lopinavir Nefazodone Nelfinavir Norfluoxetine Ritonavir Saquinavir Thioridazine

Nevirapine

3A4

Carbamazepine Efavirenz Nevirapine Ritonavir St. John’s wort

*Italics ‫ ס‬antiretroviral medications. CYP ‫ ס‬cytochrome P-450.

The NNRTIs efavirenz and nevirapine are substrates of CYP3A4 and CYP2B6. Both are inducers of CYP3A4 and nevirapine is an inducer of CYP2B6. In vitro, efavirenz seems to be an inhibitor of CYP3A4, CYP2C9, and CYP2C19, whereas delavirdine is a potent inhibitor of CYP3A4.29 Many of the potential metabolic interactions between the psychotropics and the antiretrovirals have not been studied; however, based on the current understanding of how the psychotropic agents are metabolized,

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the potential for interactions with these antiretrovirals exists. Practical management recommendations concerning the documented and theoretic interactions are summarized in Tables 9 to 11. Antidepressants Many of the TCAs and non-tricyclic antidepressants (non-TCAs) are substrates of the CYP2D6 isoenzyme. The TCAs have minimal inhibitory effects on the CYP450 isoenzyme pathway. The PI ritonavir is a substrate and an inhibitor of CYP2D6; thus, interactions between the TCAs and many of the non-TCAs can be predicted. Ritonavir was found to double the serum concentration of desipramine.1 Therefore, patients receiving the combination of ritonavir and any of the TCAs should be monitored carefully for side effects of TCAs (e.g., dry mouth, urinary retention, sedation, and blurred vision), delayed cardiac conduction, and orthostasis. Although the SSRIs are generally well tolerated, their coadministration with ritonavir may lead to serotonin syndrome, presumably by inhibiting CYP2D6.30 Although the SSRIs can inhibit CYP2D6 to a lesser extent than can ritonavir, patients still should be monitored for increased ritonavir toxicity (i.e., gastrointestinal disturbances). The remaining PIs and the NNRTIs have minimal or no effects on CYP2D6; thus, metabolic interactions are unlikely. Conversely, nefazodone and citalopram are substrates of CYP3A4; thus, a potential for interactions with the all PIs and the NNRTIs exists. Nefazodone, fluvoxamine, and the metabolite of fluoxetine (norfluoxetine) are inhibitors of CYP3A4 isoenzyme.84 Thus a decrease in the metabolism of all PIs and the NNRTIs is possible, and patients should be monitored for side effects of these agents. The coadministration of venlafaxine and indinavir has resulted in a decrease in indinavir serum levels. Based on the established metabolic pathways of these agents, how such an interaction occurred is unclear. Likewise, whether the same could happen (e.g., a decrease in serum levels) with the other PIs or any of the NNRTIs is unknown. Nonetheless, the combination of indinavir and venlafaxine should be avoided at this time, and patients receiving venlafaxine and other antiretrovirals should be monitored for virologic control.47 Previously, bupropion was thought to be a substrate of CYP2D6; however, recently it has been shown that it is metabolized by CYP2B6.71 Because the NNRTI nevirapine is a substrate and inducer of CYP2B6, a decrease in bupropion serum levels is predicted, thus potentially limiting its efficacy. Anxiolytics and Sedative-Hypnotics The BDZs and buspirone are substrates of CYP3A4. The NNRTIs, nevirapine and efavirenz, may decrease the serum levels of buspirone and the BDZs by inducing CYP3A4. Conversely, metabolic interactions involving the PIs, NNRTIs, delavirdine, and perhaps even efavirenz, and

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Table 9. ANTIDEPRESSANT AND ANTIRETROVIRAL DRUG-DRUG INTERACTIONS
Mechanism of Interaction with the Protease Inhibitors or the NNRTIs Inhibition of CYP2D6 by the PI, ritonavir

Antidepressants TCAs Amitriptyline, clomipramine, desipramine, imipramine, nortriptyline, trimipramine Non-TCAs Fluoxetine (norfluoxetine), fluvoxamine, mirtazapine paroxetine, sertraline, trazodone, venlafaxine

Comment Coadministration with ritonavir may increase serum concentrations of TCAs, resulting in TCA toxicity.

Documentation Potential; minimal documentation

Inhibition of CYP2D6 by the PI, ritonavir Inhibition of CYP3A4 by fluoxamine and norfluoxetine

Coadministration with ritonavir may increase serum concentrations of SSRIs, resulting in SSRI toxicity. Fluvoxamine and norfluoxetine are inhibitors of CYP3A4, thus may increase the levels of the PIs or NNRTI resulting in increased toxicity of the PI or NNRTI Coadministration with any of the protease inhibitor, delavirdine or efavirenz may increase serum concentrations of SSRIs, resulting in SSRI toxicity.

Potential; minimal documentation Theoretic

Citalopram, nefazodone

Inhibition of CYP3A4 by all the PIs and or NNRTIs, delavirdine, and possibly efavirenz

Theoretic interaction between citalopram and the PIs and NNRTIs; minimal documentation on interation between ritonavir and nefazodone Theoretic interactions for both psychotropics Theoretic

Induction of CYP3A4 by the NNRTIs, nevirapine, and efavirenz Inhibition of CYP3A4 by nefazodone

Administration with nevirapine or efavirenz may decrease the serum concentration of the SSRI, resulting in decrease in response to the SSRI. Nefazodone is an inhibitor of CYP3A4, thus may increase the levels of the PIs or NNRTI resulting in a increased toxicity of the PI or NNRTI. Coadministration with the NNRTI, nevirapine, or efavirenz, may decrease the serum concentrations of buproprion, compromising the response to buproprion. Coadministered ritonavir may increase serum concentrations of bupropion, potentially increasing risk for seizures.

Bupropion

Induction of CYP2B6 by the NNRTI, nevirapine

Theoretic

Inhibition of metabolism by ritonavir

Potential; minimal documentation

CYP ‫ ס‬cytochrome P-450; SSRI ‫ ס‬selective serotonin reuptake inhibitor; NNRTI ‫ ס‬non-nucleoside reverse transcriptase inhibitor; PI ‫ ס‬protease inhibitor; TCA ‫ ס‬tricyclic antidepressant.

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Table 10. ANXIOLYTIC/SEDATIVE-HYPNOTIC AND ANTIRETROVIRAL DRUG–DRUG INTERACTIONS
Anxiolytic and SedativeHypnotics Buspirone Mechanism of Interaction with the Protease Inhibitors or the NNRTIs Inhibition of CYP3A4 by all PI, delavirdine, and possibly efavirenz Induction of CYP3A4 by nevirapine and efavirenz Benzodiazepines Midazolam, triazolam

Comment Coadministration may increase serum concentrations of buspirone, resulting in buspirone toxicity. Coadministration may decrease serum concentrations of buspirone, resulting in subtherapeutic buspirone. Both are contraindicated with PIs, efavirenz, and delavirdine because of a significant rise in serum levels of these agents and increased excessive sedation and respiratory depression. Coadministration may increase BZD serum concentration, resulting in excessive sedation and respiratory depression Coadministration may decrease BZD serum concentration, resulting in BZD withdrawal. Coadministration may decrease BZD serum concentration, resulting in BZD withdrawal. Coadministration may decrease BZD serum concentration, resulting in BZD withdrawal. Coadministration may increase BZD serum concentration, resulting in excessive sedation and respiratory depression.

Documentation Potential

Theoretic

Inhibition of CYP3A4 by all PIs, delavirdine, and possibly efavirenz

Well documented

Alprazolam, clonazepam, lorazepam, temazepam

Inhibition of CYP3A4 by all PIs, delavirdine, and possibly efavirenz

Potential; minimal documentation

Induction of CYP3A4 by nevirapine and efavirenz Lorazepam, oxazepam, temazapam Diazepam Induction of glucuronyl transferase by ritonavir and nelfinavir Induction of CYP2C9 by ritonavir Inhibition of CYP2C9 and 2C19 by efavirenz

Theoretic

Potential

Theoretic

Theoretic

NNRTIs ‫ ס‬non-nucleoside reverse transcriptase inhibitors; PIs ‫ ס‬protease inhibitors; BZD ‫ ס‬benzodiazepine; CYP ‫ ס‬cytochrome P-450.

buspirone or the BDZs occur presumably by the inhibition of the CYP3A4 isozymes. The combination of midazolam or triazolam is contraindicated with the PIs and the two NNRTIs, efavirenz and delavirdine, because of the potential for excessive sedation resulting in respiratory depression.2, 57 Initially, low-dose ritonavir seems to decrease the clearance of the BDZ alprazolam,33 but chronically, ritonavir increases the clearance of alprazolam, resulting in a 10% to 15% decrease in its expected serum levels.27 Thus the use of ritonavir in a patient already on alprazolam may initially cause BDZ toxicity and, later, signs of BDZ

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Table 11. NEUROLEPTIC AND ANTIRETROVIRAL DRUG–DRUG INTERACTIONS
Mechanism of Interaction with the Protease Inhibitors or the NNRTIs

Neuroleptics Typical CYP2D6 substrate Chlopromazine, haloperidol, perphenazine, thioridazine CYP3A4 substrate Pimozide

Comment

Documentation

Inhibition of CYP206 by the PI, ritonavir

Coadministration may increase serum concentrations of the typical neuroleptics, resulting in increased risk of EPS and NMS. Coadministration may decrease serum concentrations of pimozide resulting in subtherapeutic levels. Contraindicated combination serum concentrations of pimozide may increase resulting in increased cardiotoxicity risk (QTc prolongation).

Potential

Induction of CYP3A4 by NNRTIs, nevirapine and efavirenz Inhibition of CYP3A4 by all PIs, delavirdine, and possibly efavirenz

Theoretic

Potential

Atypical CYP1A2 substrate Clozapine, olanzapine, zotepine CYP2D6 substrate Clozapine, risperdone, zotepine

Induction of CYP1A2 by ritonavir

Coadministration may decrease serum concentration of neuroleptic; Monitor for clinical response. Coadministration may increase neuroleptic serum concentration, resulting in excessive side effects; increased clozapine serum concentrations, monitor for agranulocytosis. Coadministration may increase serum levels of those neuroleptics; monitor for increased side effects; use caution when coadministering with zotepine and possibly ziprasidone for potential risk of increased serum levels and QTc interval. Coadministration may decrease serum levels of neuroleptics, thus monitor clinical response.

Theoretic

Inhibition of CYP2D6 by the PIs, ritonavir

Theoretic

CYP3A4 substrate Quetiapine, ziprasidone, zotepine

Inhibition of CYP3A4 by all PIs, delavirdine, and possibly efavirenz

Potential

Induction of CYP3A4 by NNRTIs, nevirapine and efavirenz

CYP ‫ ס‬cytochrome P-450; EPS ‫ ס‬extrapyramidal side symptoms; NMS ‫ ס‬neuroleptic malignant syndrome; NNRTI ‫ ס‬non-nucleoside reverse transcriptase inhibitors; PI ‫ ס‬protease inhibitor.

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withdrawal. Ritonavir and nelfinavir are inducers of the phase 2 enzyme glucuronyl transferase and might decrease serum levels of the BDZs that undergo glucuronidation (e.g., oxazepam, lorazepam, and temazepam).30 Mood Stabilizers Carbamazepine and valproate may be used in HIV-1–infected patients with bipolar disorders. The metabolism of valproate is not fully understood, but valproate has been found to inhibit the phase 2 enzyme glucuronyl transferase. The nucleoside reverse transcriptase inhibitor zidovudine is glucuronidated using this enzyme; thus, combination with valproate may result in decreased zidovudine clearance and increased zidovudine toxicity (i.e., bone marrow toxicities). Carbamazepine is a substrate of CYP3A4 isozyme. Like some other anticonvulsants (e.g., phenobarbital and phenytoin), carbamazepine is a potent inducer of CYP3A4. Thus, theoretically, carbamazepine could enhance the clearance of the PIs and the NNRTIs and perhaps result in decreased serum concentration of the antiretrovirals, thereby decreasing viral suppression. Therefore, the viral load should be monitored closely. In the other discussion, the PIs could decrease the metabolism of carbamazepine, thereby increasing its serum concentration and toxicities. Thus, patients receiving carbamazepine in combinations with antiretrovirals should undergo regular monitoring of carbamazepine serum concentrations.2 Newer anticonvulsants have been used off-label for the treatment of mood disorders in HIV-1 patients. These include gabapentin, lamotrigine, and topiramate. As mentioned earlier, metabolic interactions with gabapentin are minimal. Lamotrigine is metabolized by glucuronyl transferase, which is induced by the PIs ritonavir and nelfinavir. This theoretically could lead to increased metabolism of lamotrigine and decrease its serum concentrations. Although topiramate is primarily renally eliminated, the authors do not recommend its combination with the antiretrovirals at this time (see section about manic syndromes). Lithium carbonate has been used in HIV-1 patients with primary bipolar disorders. Similar to gabapentin, lithium is primarily renally eliminated and hepatic metabolism is not required. This in turn results in insignificant metabolic interactions with HIV-1 antiretrovirals; however, it should be avoided in patients with AIDS mania or advanced HIV because of the increased risk for toxicity in this population (see section about manic syndromes). Neuroleptics The typical neuroleptics, haloperidol, chlorpromazine, perphenazine, and thioridazine, are substrates of CYP2D6 that are inhibited by the PI ritonavir. Because serum levels of these agents may be increased

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by ritonavir inhibiting CYP2D6, the risk for EPSs also is exacerbated. Therefore, patients should receive lower doses of these agents and be monitored for EPS. The neuroleptic pimozide is a substrate of CYP3A4; thus, its metabolism can be inhibited by all the PIs, delavirdine, and possibly efavirenz. Consequently, this could result in increasing pimozide serum levels and cardiotoxicity (e.g., QTc prolongation); thus, the combination of pimozide with any of the PIs, delavirdine, and efavirenz are contraindicated. Atypical antipsychotics are better tolerated than antipsychotics in the HIV population. Clozapine and olanzapine are primarily metabolized by CYP1A2, of which ritonavir is a weak inducer, whereas risperidone and, to a lesser extent, clozapine are metabolized by CYP2D6 (inhibited by ritonavir).84 Thus, patients receiving the combination of ritonavir and olanzapine or clozapine should be monitored for antipsychotic response. Conversely, the combination of ritonavir with clozapine or risperidone may result in increased side effects. SUMMARY HIV-1 infection poses a challenge for psychiatrists of the medically ill. Many factors concerning the care of HIV-1–infected patients need to be considered when prescribing psychotropics. These include careful diagnosis, taking into account medical disorders associated with HIV-1 that can present with psychiatric symptoms, as well as medications that HIV-1 patients may be taking that can cause a variety of neuropsychiatric side effects. Another important issue is the potential for drug–illness interactions. In general, HIV-1 patients seem to be more sensitive to the development of adverse drug reactions than do non–HIV-1 patients, especially as the illness progresses. It is also important to be cognizant of the complex multidrug regimens that many HIV-1 patients are on to avoid known drug–drug interactions and be on the alert for other potential interactions when using psychotropic medications.
ACKNOWLEDGMENT
The authors would like to acknowledge the assistance of Paul R. Davidson, PhD, CPsych, from the Department of Psychiatry at Queen’s University, for his help in the development of Table 2.

References
1. Abbott Laboratories: Norvir Prescribing Information. Abbott Park, IL, Abbot Laboratories, March 1997 2. American Psychiatric Association, Work Group on HIV/AIDS. Practice guideline for the treatment of patients with HIV/AIDS. Am J Psychiatry 157:1–62, 2000 4. Ayuso Mateos JL, Singh AN, Catalan J: Drug treatment of HIV associated neuropsychiatric syndromes. Neurologia 15:164–171, 2000

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5. Batki SL: Buspirone in drug users with AIDS or AIDS-related complex. J Clin Psychopharmacol 10(suppl):111–115, 1990 6. Belzie LR: Risperidone for AIDS-associated dementia: A case series. AIDS Patient Care STDs 10:246–249, 1996 7. Blum RA, Comstock TJ, Sica DA, et al: Pharmacokinetics of gabapentin in subjects with various degrees of renal function. Clin Pharmacol Ther 56:154–159, 1994 8. Breitbart W, Marotta RF, Call P: AIDS and neuroleptic malignant syndrome. Lancet 2:1488–1489, 1988 9. Breitbart W, Mermelstein H: Pemoline: An alternative psychostimulant for the management of depressive disorders in cancer patients. Psychosomatics 33:352–356, 1992 10. Breitbart W, Marotta R, Platt MM, et al: A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. Am J Psychiatry 153:231–237, 1996 11. Brouillette MJ, Chouinard G, Lalonde R: Didanosine-induced mania in HIV infection. Am J Psychiatry 151:1839–1840, 1994 12. Clifford DB: Human immunodeficiency virus-associated dementia. Arch Neurol 57:321–324, 2000 13. Cozza KL, Swanton EJ, Humphreys CW: Hepatotoxicity with combination of valproic acid, ritonavir, and nevirapine: A case report. Psychosomatics 41:452–453, 2000 13a. DHHS Panel on Clinical Practices for Treatment of HIV Infection: Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents [online]. Washington, DC, Department of Health and Human Services and Henry J. Kaiser Family Foundation, 2001. Available: www.hivatis.org [May 2, 2001] 14. Ellen SR, Judd FK, Mijch AM, et al: Secondary mania in patients with HIV infection. Aust N Z J Psychiatry 33:353–360, 1999 15. Elliott AJ, Roy-Byrne PP: Major depressive disorder and HIV-1 infection: A review of treatment trials. Semin Clin Neuropsychiatry 3:137–150, 1998 16. Elliott AJ, Uldall KK, Bergam K, et al: Randomized, placebo-controlled trial of paroxetine versus imipramine in depressed HIV-positive outpatients. Am J Psychiatry 155:367– 372, 1998 17. Elliott AJ, Russo J, Bergam K, et al: Antidepressant efficacy in HIV-seropositive outpatients with major depressive disorder: An open trial of nefazodone. J Clin Psychiatry 60:226–231, 1999 18. Elliott AJ, Roy-Byrne PP: Mirtazapine for depression in patients with human immunodeficiency virus. J Clin Psychopharmacol 20:265–267, 2000 19. Engle PM, Heck AM: Lamotrigine for the treatment of bipolar disorder. Ann Pharmacother 34:258–262, 2000 20. Fernandez F, Levy JK, Galizzi H: Response of HIV-related depression to psychostimulants: Case reports. Hosp Community Psychiatry 39:628–631, 1988 21. Fernandez F: Psychopharmacological interventions in HIV infections. New Dir Ment Health Serv 48:43–53, 1990 22. Fernandez F, Levy JK: The use of molindone in the treatment of psychotic and delirious patients infected with the human immunodeficiency virus: Case reports. Gen Hosp Psychiatry 15:31–35, 1993 23. Fernandez F, Levy JK, Samley HR, et al: Effects of methylphenidate in HIV-related depression: A comparative trial with desipramine. Int J Psychiatry Med 25:53–67, 1995 24. Ferrando S, van Gorp W, McElhiney M, et al: Highly active antiretroviral treatment in HIV infection: Benefits for neuropsychological function. AIDS 12:F65–F70, 1998 25. Ferrando SJ, Eisendrath SJ: Adverse neuropsychiatric effects of dopamine antagonist medications: Misdiagnosis in the medical setting. Psychosomatics 32:426–432, 1991 26. Ferrando SJ, Rabkin JG, de Moore GM, et al: Antidepressant treatment of depression in HIV-seropositive women. J Clin Psychiatry 60:741–746, 1999 27. Frye R: Effect of ritonavir on the pharmacokinetics and pharmacodynamics of alprazolam [abstract]. In Abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1997 28. Galgani S, Balestra P, Narciso P, et al: Nimodipine plus zidovudine versus zidovudine alone in the treatment of HIV-1–associated cognitive deficits. AIDS 11:1520–1521, 1997 29. Gerber JG: Using pharmacokinetics to optimize antiretroviral drug–drug interactions

PRACTICAL PSYCHOPHARMACOLOGY IN HIV-1 AND AIDS

173

30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47.

48. 49. 50. 51. 52. 53.

in the treatment of human immunodeficiency virus infection. Clin Infect Dis 30(suppl 2):123–129, 2000 Gillenwater DR, McDaniel JS: Rational psychopharmacology for patients with HIV infection and AIDS. Psychiatr Ann 31:28–34, 2001 Grassi B, Gambini O, Scarone S: Notes on the use of fluvoxamine as treatment of depression in HIV-1–infected subjects. Pharmacopsychiatry 28:93–94, 1995 Grassi B, Gambini O, Garghentini G, et al: Efficacy of paroxetine for the treatment of depression in the context of HIV infection. Pharmacopsychiatry 30:70–71, 1997 Greenblatt DJ, von Moltke LL, Harmatz JS, et al: Alprazolam-ritonavir interaction: implications for product labeling. Clin Pharmacol Ther 67:335–341, 2000 Grinspoon S, Corcoran C, Stanley T, et al: Effects of hypogonadism and testosterone administration on depression indices in HIV-infected men. J Clin Endocrinol Metab 85:60–65, 2000 Groothuis DR, Levy RM: The entry of antiviral and antiretroviral drugs into the central nervous system. J Neurovirol 3:387–400, 1997 Hardy MA, Nardacci D: Does valproate pose a threat to human immunodeficiency virus-infected patients? J Clin Psychopharmacol 19:189–190, 1999 Hriso E, Kuhn T, Masdeu JC, et al: Extrapyramidal symptoms due to dopamineblocking agents in patients with AIDS encephalopathy. Am J Psychiatry 148:1558– 1561, 1991 Hugen PW, Burger DM, Brinkman K, et al: Carbamazepine–indinavir interaction causes antiretroviral therapy failure. Ann Pharmacother 34:465–470, 2000 Jain KK: Evaluation of memantine for neuroprotection in dementia. Expert Opin Invest Drugs 9:1397–1406, 2000 Jefferson JW: Possible risks associated with valproate treatment of AIDS-related mania. J Clin Psychiatry 59:317, 1998 Jennings HR, Romanelli F: The use of valproic acid in HIV-positive patients. Ann Pharmacother 33:1113–1116, 1999 Jennings HR, Romanelli F: Comment: Potential risk of valproic acid therapy in patients who are HIV-positive. Ann Pharmacother 34:1348–1349, 2000 Kristiansen JE, Hansen JB: Inhibition of HIV replication by neuroleptic agents and their potential use in HIV infected patients with AIDS related dementia. Int J Antimicrob Agents 14:209–213, 2000 Kusumaker V, Kutcher SP: Pharmacological treatment for bipolar disorder: An update. CPA Bulletin 32:111–113, 2000 Lee SI, Klesmer J, Hirsch BE: Neuroleptic malignant syndrome associated with use of risperidone, ritonavir, and indinavir: A case report. Psychosomatics 41:453–454, 2000 Lera G, Zirulnik J: Pilot study with clozapine in patients with HIV-associated psychosis and drug-induced parkinsonism. Mov Disord 14:128–131, 1999 Levin GM, Nelson LA, Devane CL, et al: Venlafaxine and indinavir: Results of pharmacokinetic interaction study [abstract 661]. In Abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC, American Society for Microbiology, 1999 Levine S, Anderson D, Bystritsky A, et al: A report of eight HIV-seropositive patients with major depression responding to fluoxetine. J AIDS 3:1074–1077, 1990 Lyketsos CG, Schwartz J, Fishman M, et al: AIDS mania. J Neuropsychiatry Clin Neurosci 9:277–279, 1997 Maggi JD, Halman MH: The effect of divalproex sodium on viral load: A retrospective review of HIV-positive patients with manic syndromes. Can J Psychiatry 46:359–362, 2001 Markowitz JC, Kocsis JH, Fishman B, et al: Treatment of depressive symptoms in human immunodeficiency virus-positive patients. Arch Gen Psychiatry 55:452–457, 1998 Masand PS, Tesar GE: Use of stimulants in the medically ill. Psychiatr Clin North Am 19:515–547, 1996 McArthur JC, Sacktor N, Selnes O: Human immunodeficiency virus-associated dementia. Semin Neurol 19:129–150, 1999

174

ROBINSON & QAQISH

54. McDaniel JS, Ninan PT, Magnuson JV: Possible induction of mania by buspirone. Am J Psychiatry 147:125–126, 1990 55. McIvor R, Sinanan K: Buspirone-induced mania. Br J Psychiatry 158:136–137, 1991 56. Melton ST, Kirkwood CK, Ghaemi SN: Pharmacotherapy of HIV dementia. Ann Pharmacother 31:457–473, 1997 57. Merry C, Mulcahy F, Barry M, et al: Saquinavir interaction with midazolam: Pharmacokinetic considerations when prescribing protease inhibitors for patients with HIV disease. AIDS 11:268–269, 1997 58. Mijch AM, Judd FK, Lyketsos CG, et al: Secondary mania in patients with HIV infection: are antiretrovirals protective? J Neuropsychiatry Clin Neurosci 11:475–480, 1999 59. Navia BA, Dafni U, Simpson D, et al: A phase I/II trial of nimodipine for HIV-related neurologic complications. Neurology 51:221–228, 1998 60. Newshan G: HIV neuropathy treated with gabapentin. AIDS 12:219–221, 1998 61. Penzak SR, Reddy YS, Grimsley SR: Depression in patients with HIV infection. Am J Health Syst Pharm 57:376–386, 2000 62. Piscitelli SC, Gallicano KD: Interactions among drugs for HIV and opportunistic infections. N Engl J Med 344:984–996, 2001 63. Price WA, Bielefeld M: Buspirone-induced mania. J Clin Psychopharmacol 9:150–151, 1989 64. Rabkin JG, Wagner G, Rabkin R: Effects of sertraline on mood and immune status in patients with major depression and HIV illness: An open trial. J Clin Psychiatry 55:433–439, 1994 65. Rabkin JG, Rabkin R, Harrison W, et al: Effect of imipramine on mood and enumerative measures of immune status in depressed patients with HIV illness. Am J Psychiatry 151:516–523, 1994 66. Rabkin JG, Rabkin R, Wagner G: Effects of fluoxetine on mood and immune status in depressed patients with HIV illness. J Clin Psychiatry 55:92–97, 1994 67. Rabkin JG, Wagner GJ, Rabkin R: Testosterone therapy for human immunodeficiency virus-positive men with and without hypogonadism. J Clin Psychopharmacol 19:19– 27, 1999 68. Rabkin JG, Wagner GJ, Rabkin R: Fluoxetine treatment for depression in patients with HIV and AIDS: A randomized, placebo-controlled trial. Am J Psychiatry 156:101–107, 1999 69. Rabkin JG, Wagner GJ, Rabkin R: A double-blind, placebo-controlled trial of testosterone therapy for HIV-positive men with hypogonadal symptoms. Arch Gen Psychiatry 57:141–147, 2000 70. Robinson MJ: Are newer antidepressants really ‘‘better tolerated’’? Can J Psychiatry 46:286–287, 2001 71. Rotzinger S, Bourin M, Akimoto Y, et al: Metabolism of some ‘‘second’’- and ‘‘fourth’’generation antidepressants: Iprindole, viloxazine, bupropion, mianserin, maprotiline, trazodone, nefazodone, and venlafaxine. Cell Mol Neurobiol 19:427–442, 1999 72. Roesler R, Quevedo J, Walz R, et al: A randomized, double-blind, placebo-controlled trial of deprenyl and thiotic acid in HIV-associated cognitive impairment. Neurology 52:1920–1921, 1999 73. Rosebush P, Stewart T: A prospective analysis of 24 episodes of neuroleptic malignant syndrome. Am J Psychiatry 146:717–725, 1989 74. Sacktor N, Schifitto G, McDermott MP, et al: Transdermal selegiline in HIV-associated cognitive impairment: Pilot, placebo-controlled study. Neurology 54:233–235, 2000 75. Schifitto G, Sacktor N, Marder K, et al: Randomized trial of the platelet-activating factor antagonist lexipafant in HIV-associated cognitive impairment. Neurological AIDS Research Consortium. Neurology 53:391–396, 1999 76. Schmitt FA, Bigley JW, McKinnis R, et al: Neuropsychological outcome of zidovudine (AZT) treatment of patients with AIDS and AIDS-related complex. N Engl J Med 319:1573–1578, 1988 77. Schwartz JA, McDaniel JS: Double-blind comparison of fluoxetine and desipramine in the treatment of depressed women with advanced HIV disease: A pilot study. Depress Anxiety 9:70–74, 1999

PRACTICAL PSYCHOPHARMACOLOGY IN HIV-1 AND AIDS

175

78. Sidtis JJ, Gatsonis C, Price RW, et al: Zidovudine treatment of the AIDS dementia complex: results of a placebo- controlled trial. AIDS Clinical Trials Group. Ann Neurol 33:343–349, 1993 79. Simpson DM, Olney R, McArthur JC, et al: A placebo-controlled trial of lamotrigine for painful HIV-associated neuropathy. Neurology 54:2115–2119, 2000 80. Singh AN, Golledge H, Catalan J: Treatment of HIV-related psychotic disorders with risperidone: A series of 21 cases. J Psychosom Res 42:489–493, 1997 81. Swindells S, Zheng J, Gendelman HE: HIV-associated dementia: new insights into disease pathogenesis and therapeutic interventions. AIDS Patient Care STDs 13:153– 163, 1999 82. Thompson D, Dimartini A: Nonenteral routes of administration for psychiatric medications. A literature review. Psychosomatics 40:185–192, 1999 83. Trachman SB: Buspirone-induced psychosis in a human immunodeficiency virusinfected man. Psychosomatics 33:332–335, 1992 84. Tseng AL, Foisy MM: Significant interactions with new antiretrovirals and psychotropic drugs. Ann Pharmacother 33:461–473, 1999 85. Wagner GJ, Rabkin R: Effects of dextroamphetamine on depression and fatigue in men with HIV: A double-blind, placebo-controlled trial. J Clin Psychiatry 61:436–440, 2000 86. Whitaker R: Neuropsychiatry of HIV-associated dementia. Psychiatric Times 17:57–61, 2001 87. White JC, Christensen JF, Singer CM: Methylphenidate as a treatment for depression in acquired immunodeficiency syndrome: An n-of-1 trial. J Clin Psychiatry 53:153– 156, 1992 88. Wright JM, Sachdev PS, Perkins RJ, et al: Zidovudine-related mania. Med J Aust 150:339–341, 1989 89. Zisook S, Peterkin J, Goggin KJ, et al: Treatment of major depression in HIV-seropositive men. HIV Neurobehavioral Research Center Group. J Clin Psychiatry 59:217–224, 1998 Address reprint requests to Michael J Robinson, MD Division of Consultation-Liaison Psychiatry Kingston General Hospital 76 Stuart Street, Connell 4, Room 2-486 Kingston, Ontario K7L 2V7 Canada e-mail: mjr4@post.queensu.ca