- Email: [email protected]
A Prospective Trial of Sustained-Release Bupropion for Depression in HIV-Seropositive and AIDS Patients
A Prospective Trial of Sustained-Release Bupropion for Depression in HIV-Seropositive and AIDS Patients M. BEATRIZ CURRIER, M.D. GERMAN MOLINA, M.D. MARTHA KATO, M.D.
To date, the authors know of no prospective studies of sustained-release bupropion in depressed HIV-seropositive patients. The purpose of this study was to evaluate the efficacy and tolerability of sustained-release bupropion in 20 depressed HIV-positive adult outpatients. Twenty outpatients with HIV spectrum illness, a DSM-IV-diagnosed major depressive disorder confirmed with the Structured Clinical Interview for DSM-IV, and Mini-Mental State Examination scores ⬎20 were recruited into a 6-week, open-label, flexible-dose study of sustained-release bupropion (100– 300 mg/day). Twelve patients (60%) responded to sustained-release bupropion at a mean dose of 265 mg/day. Five patients (25%) discontinued study participation secondary to adverse events. Preliminary findings suggest that sustained-release bupropion is effective for the treatment of depression in HIV-positive patients, regardless of HIV clinical staging. Furthermore, it appears to be well tolerated in patients with AIDS-related medical conditions. (Psychosomatics 2003; 44:120–125)
D
epressive disorders account for the most common psychiatric comorbidity among HIV-positive patients. The lifetime prevalence of depression in this medical population ranges from 22% to 45%, which is twofold higher than in the general population.1 Although consistent findings to suggest a direct negative impact of depression on the immune function or survivorship of this population are lacking,2,3 depression may indirectly hasten HIV disease progression by influencing poor compliance with medical treatment regimens. Despite the high prevalence of depressive disorders,
Presented in part at the 154th annual meeting of the American Psychiatric Association, New Orleans, May 5–10, 2001. Received June 24, 2002; accepted July 24, 2002. From the Department of Psychiatry and Behavioral Sciences, Division of Consultation Psychiatry, University of Miami School of Medicine. Address reprint requests to Dr. Currier, Department of Psychiatry (D-79), Division of Consultation Psychiatry, University of Miami/Jackson Memorial Medical Center, 1400 N.W. 10 Ave., Suite 704A, Miami, FL 33136; [email protected] (e-mail). Copyright 䉷 2003 The Academy of Psychosomatic Medicine.
120
few studies have systematically investigated the pharmacological treatment of depression among HIV-positive and AIDS patients. Double-blind, placebo-controlled studies with fluoxetine,4 imipramine,5 and paroxetine6 and several open studies evaluating sertraline7 and nefazodone8 in HIV-positive depressed patients have demonstrated an overall positive clinical response rate ranging from 45% to 80%. A retrospective review of 52 patients treated with bupropion (dose: mean⳱200 mg/day)9 revealed that 63% of the patients had a favorable clinical response. Because of the anticholinergic adverse effects of tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs) have been considered the first-line treatment for depression in the HIV population. Several SSRIs, however, have potential drug interactions with antiretroviral and antifungal medication regimens (by means of cytochrome P450 oxidase system 3A4 and 2D6 isoenzyme inhibition) and adverse effects such as asthenia, nausea, diarrhea, and sexual dysfunction that may interfere with patient compliance and quality of life.10–12 Psychosomatics 44:2, March-April 2003
Currier et al. HIV infection may affect CSF dopamine levels. In a controlled study,13 mean CSF dopamine levels were significantly lower in HIV-positive patients with or without neurological disease than in HIV-negative comparison subjects. The catecholaminergic profile of sustained-release bupropion may offer direct advantages over SSRIs by modulating dopaminergic transmission in this population.14–16 Bupropion may have a relatively low potential for serious drug interactions with protease inhibitors. Despite earlier warnings to the contrary, there is no empirical evidence to support the contraindication of bupropion with ritonavir therapy.17 Specifically, ritonavir, a potent 3A4 and 2D6 inhibitor, may increase the concentration and toxicity of the antidepressants metabolized by these isoenzymes. Early concerns arose regarding the impact of 3A4 inhibition on the metabolism of bupropion, which prompted contraindication warnings for bupropion and ritonavir therapy.17 Other data,18 however, has revealed that the primary metabolic pathway of sustained-release bupropion in the P450 oxidase system is the 2B6 isoenzyme rather than the 3A4 isoenzyme. The 3A4 isoenzyme plays a minor secondary role in its metabolism. In vitro data have demonstrated that selective 3A4 inhibitors have minimal impact on bupropion concentrations.18 To date, no serious drug interactions have been reported between sustained-release bupropion and protease inhibitors in the HIV-positive population, to our knowledge. To date, we know of no prospective studies of sustained-release bupropion performed among depressed HIV-positive patients. The purpose of this study was to determine the efficacy and tolerability of sustained-release bupropion in the treatment of depressed HIV-positive patients. In addition, we wanted to determine if HIV clinical variables such as disease staging, CD4 cell count, viral load (number of HIV RNA copies in plasma), and depression severity and chronicity are significantly associated with depression treatment response. METHOD Study Group Outpatients with HIV spectrum illness, ages 18–75 years, who were seeking medical treatment at the University of Miami/Jackson Memorial Medical Center’s Special Immunology Clinic were screened with the Beck Depression Inventory19 and the Mini-Mental State Examination (MMSE)20 for participation in this prospective, Psychosomatics 44:2, March-April 2003
6-week, open-label, flexible-dose antidepressant study with sustained-release bupropion (100–300 mg/day). Eligible participants included those with a baseline Beck Depression Inventory score ⬎15, a baseline MMSE score ⬎20, and a DSM-IV diagnosis of major depressive disorder confirmed with the Structured Clinical Interview for DSM-IV. Psychiatric exclusion criteria included an active axis I disorder other than major depressive disorder, a current risk for suicide, and current treatment with another antidepressant. Medical exclusion criteria included a history of seizure disorder or traumatic brain injury and current risk factors for seizure—such as a CNS opportunistic infection, current CNS lymphoma, or current use of an antipsychotic medication. Study Design and Assessments All of the patients provided written informed consent to participate in this 6-week, open-label, flexible-dose antidepressant study. Baseline assessment included the following: administration of the mood disorder module of the Structured Clinical Interview for DSM-IV,21 a semistructured review of demographic variables, medical and psychiatric histories, a listing of antidepressant therapies, neuroimaging studies, a listing of current medications, HIV illness markers (CD4 cell count, viral load),22 and HIV disease staging, as outlined by the Centers for Disease Control and Prevention.23 Criteria for the three stages of HIV illness include the following: asymptomatic (CD4 ⬎500 cells/mm3 and no symptoms), symptomatic (CD4 of 200– 500 cells/mm3 and past or current symptoms without opportunistic infections), and AIDS (CD4 less than 200 cells/mm3 and past or current AIDS-defining opportunistic infection or malignancy). Baseline depression measures included the Beck Depression Inventory, the 17-item Hamilton Depression Rating Scale,24 and the Clinical Global Improvement (CGI) severity scale.25 Baseline cognitive performance measures included the MMSE and Trail Making Tests A and B.26,27 Sustained-release bupropion was dispensed at each visit, with an initial dose of 100 mg/day for 1 week. At week 2, the dose was increased to 100 mg b.i.d. for 2 weeks, and at week 4, the dose was increased to 150 mg b.i.d. for the remaining 3 weeks of the study. Since the study incorporated a flexible-dose design, sustained-release bupropion was adjusted as clinically indicated and tolerated. The patients’ assessments were made at baseline and at weeks 2, 4, and 6. The outcome measures administered 121
Bupropion for Depression in HIV/AIDS Patients at the follow-up visits and final assessment included the Beck Depression Inventory, the Hamilton depression scale, the MMSE, Trail Making Tests A and B, the CGI, and repeat immunological measurements (if available). Spontaneous reporting of treatment-emergent adverse events was documented and rated for severity at each visit. The responders were defined by a CGI score of very much improved or much improved and a 50% reduction in baseline scores on the Beck Depression Inventory and the Hamilton depression scale. Remission was defined by a Hamilton depression scale score ⬍8. Data Analysis Treatment responders were compared with nonresponders by using t tests for continuous variables and chisquare analysis for categorical variables. Fisher’s exact test was used if the expected cell size was ⬍5. All data analysis was performed by using the Statistical Package for Social Sciences (SPSS, Chicago) 10.0 software program. The patients who did not complete the trial but underwent at least one postbaseline assessment while taking medication were included in the intent-to-treat analysis. Response and remission rates were assessed. Paired t tests were used to assess baseline and endpoint continuous outcome measures for treatment outcome. Independent t tests were used to examine differences in depression (i.e., chronicity and severity) and HIV illness progression (i.e., CD4 cell count, viral load, staging) between the two treatment outcome groups to identify the clinical variables significantly associated with treatment response to sustained-release bupropion. RESULTS Patient Demographic and Clinical Characteristics Twenty patients were enrolled in the study. The group consisted of six women and 14 men with a mean age of 40.95 years (SD⳱7.00, range⳱26–54). Thirteen patients were Hispanic, and two were Haitian. There were no significant differences in demographic variables between the treatment outcome groups. In terms of psychiatric clinical variables, 11 patients (55%) suffered from recurrent major depressive disorder, and eight patients (40%) had received prior antidepressant pharmacotherapy. The mean duration of the current episode of depression was 27.35 months (SD⳱24.28, range⳱1– 122
80). Nine patients (45%) had developed depression within 6 months (range⳱1–144) of testing HIV seropositive. Five patients (25%) reported a prior history of substance abuse. Baseline depression severity scores revealed a mean Hamilton depression scale score of 23.80 (SD⳱3.83, range⳱ 16–29), a mean Beck Depression Inventory score of 30.10 (SD⳱8.39, range⳱16–48), and a mean CGI severity score of 4.80 (SD⳱0.77, range⳱4–6). Baseline cognitive measures revealed a mean MMSE score of 28.90 (SD⳱0.91, range⳱27–30), a mean Trail Making Test A score of 2.35 (SD⳱0.75, range⳱2–5), and a mean Trail Making Test B score of 2.55 (SD⳱0.69, range⳱1–4). Both mean scores on Trail Making Tests A and B indicated average to borderline motor and cognitive performance. There were no significant differences in baseline depression measures (i.e., severity or chronicity) and baseline cognitive performance (i.e., on the MMSE and Trail Making Tests A and B) between the responders and the nonresponders. In terms of clinical variables for HIV illness, 10 patients (50%) reported man-to-man sexual contact as the risk factor for HIV transmission, eight patients (40%) reported heterosexual contact, and two patients (10%) reported needle-sharing contact associated with drug abuse as the risk factor for transmission. The HIV-positive group included asymptomatic patients (N⳱9, 45%), symptomatic patients (N⳱4, 20%), and AIDS patients (N⳱7, 35%). The mean duration of HIV illness was 65.28 months (SD⳱47.18, range⳱1–156). The mean CD4 cell count was 503 cells/mm3 (SD⳱546, range⳱10–2,390). No viral load was detected in 12 patients (60%); however, the remaining eight patients had a range of 1,800 to 441,715 HIV RNA copies/ml plasma, as detected by polymerase chain reaction. All but two patients were taking antiretroviral medications, and 14 patients (70%) were taking protease inhibitors plus two antiretroviral drugs. One patient was taking ritonavir. HIV clinical variables were compared between responders and nonresponders. The treatment outcome groups differed significantly in baseline immune status. The treatment responders had a significantly lower (t⳱ –2.50, df⳱19, p⬍0.02) mean baseline CD4 cell count (mean⳱277 cells/mm3, SD⳱219) than the nonresponders (mean⳱843 cells/mm3, SD⳱719). This difference remained significant (t⳱–2.54, df⳱18, p⬍0.03) when we excluded an outlier in the nonresponder treatment group with a high CD4 cell count (2,390 cells/mm3). Other HIV clinical variables (e.g., viral load, HIV disease staging, and duration of HIV-positive status) were comparable between the treatment groups. Psychosomatics 44:2, March-April 2003
Currier et al. 219) than the nonresponders (mean⳱843 cells/mm3, SD⳱719) (t⳱–2.59, df⳱18, p⬍0.02). Regression analysis, however, revealed no correlation between CD4 cell count and treatment response (coefficient⳱0.006 [SD⳱ 0.003], df⳱1, p⬍0.08). No HIV clinical variables were significantly associated with depression treatment response. Furthermore, there was no significant association between depression clinical variables and treatment response to sustained-release bupropion.
Efficacy Twenty patients were treated with sustained-release bupropion. At week 6, 75% of the completers (9 of 12) had responded to sustained-release bupropion at 300 mg/ day. In an intent-to-treat analysis in which all patients with a postbaseline visit were included, 60% of the patients (12 of 20) were rated as responders. More than half of the responders (7 of 12) achieved remission (Hamilton depression scale score ⬍8). The mean effective dose of sustained-release bupropion was 265 mg/day (SD⳱65). There was no significant difference in endpoint dose between the two groups (t⳱1.36, df⳱18, p⳱0.19). The responders demonstrated a significant improvement between mean baseline and final scores on the Beck Depression Inventory (t⳱10.12, df⳱11, p⬍0.001) and the Hamilton depression scale (t⳱10.64, df⳱11, p⬍0.001) (Table 1). The nonresponders demonstrated no significant difference between mean baseline and final scores on the Beck Depression Inventory and the Hamilton depression scale. Despite comparable baseline cognitive performance between the two treatment groups, the responders demonstrated significant improvement in motor/cognitive performance between baseline and final scores on the Trail Making Test A (t⳱2.35, df⳱11, p⬍0.04) and the Trail Making Test B (t⳱3.92, df⳱11, p⳱0.002), whereas the nonresponders demonstrated no significant change (Table 1). There was no significant difference in mean baseline and final MMSE scores between the two treatment groups and no significant improvement at endpoint within either group. The treatment responders had significantly lower mean baseline CD4 cell counts (mean⳱277 cells/mm3, SD⳱
TABLE 1.
Adverse Effects Fourteen patients (70%) reported treatment-emergent adverse events. Five patients (25%) discontinued study participation secondary to adverse events (headaches, panic attacks, irritability) that occurred at 100 mg/day (N⳱2), 200 mg/day (N⳱2), and 300 mg/day (N⳱1). In the total group, the most frequently reported adverse events included headaches (N⳱5, 25%), insomnia (N⳱4, 20%), anxiety/irritability (N⳱2, 10%), dry mouth (N⳱2, 10%), and edema of the lower extremities (N⳱2, 10%). Most of the adverse events reported were mild and transient. No serious adverse events were reported, and no seizures occurred. There was no significant difference in the incidence of adverse events between the responders and the nonresponders. The patients who completed the study were compared with those who dropped out secondary to adverse events. No significant differences in demographic, psychiatric, or HIV-related variables—including CD4 cell count, protease inhibitors, and HIV disease severity staging— were noted between the two groups.
Outcome Measures in a 6-Week, Open-Label, Flexible-Dose Study of Sustained-Release Bupropion in Depressed HIV-Positive Patients Score Baseline
Group and Measure Responders (N⳱12) Beck Depression Inventory Hamilton Depression Rating Scale Trail Making Test Aa Trail Making Test Ba Nonresponders (N⳱8) Beck Depression Inventory Hamilton Depression Rating Scale Trail Making Test Aa Trail Making Test Ba
Endpoint
Analysis
Mean
SD
Mean
SD
Paired Samples t
df
p (two-tailed)
30.33 22.00 2.58 2.58
5.57 3.98 0.90 0.79
11.42 6.08 2.22 2.00
8.89 3.87 1.09 0.15
10.12 10.64 2.35 3.92
11 11 11 11
⬍0.001 ⬍0.001 ⬍0.04 0.002
29.63 24.00 2.00 2.50
12.05 3.51 0.00 0.53
27.25 19.88 2.13 2.50
12.42 7.20 0.35 0.76
1.28 2.08 ⳮ1.00 0.00
7 7 7 7
⬍0.25 ⬍0.08 ⬍0.36 1.00
a
A score of 2 indicates average motor/cognitive performance; a score of 3 indicates borderline motor/cognitive performance.
Psychosomatics 44:2, March-April 2003
123
Bupropion for Depression in HIV/AIDS Patients DISCUSSION Sustained-release bupropion was found to be effective for the treatment of major depressive disorder in HIV-positive and AIDS patients in this 6-week open-label study. The efficacy rate of 75% in subjects completing the 6-week study, and 60% in the intent-to-treat group, is comparable with the efficacy range of SSRIs in this medical population.4–8 Furthermore, 45% of the group achieved remission (Hamilton depression scale score ⬍8) during the 6-week study. The mean effective dose of sustained-release bupropion was 265 mg/day (SD⳱65). This antidepressant efficacy may be due to the catecholaminergic effects of sustained-release bupropion and the relationship between immunosuppression and lower CSF dopamine levels in HIV-positive patients. Several investigators have found lower levels of CSF dopamine and its metabolite, homovanillic acid, in HIV-positive and AIDS patients.13,28,29 Berger et al.13 compared the CSF dopamine levels (measured by high-performance liquid chromatography) of 17 HIV-positive patients with those of five HIV-negative comparison subjects. The HIV-positive patient group was further divided into those who were asymptomatic and those who had neurological complications, including mild cognitive/motor deficits, peripheral neuropathies, and dementia (one patient). They found significantly lower mean CSF dopamine levels in all of the HIV-positive patients, compared to the HIV-negative comparison subjects. In addition, a strong correlation existed between lower CSF dopamine levels and lower CD4 cell counts among the neurologically impaired HIV-positive patients. The strong correlation found between lower CSF dopamine levels and immunosuppression in HIV-positive patients, coupled with the catecholaminergic effects of sustained-release bupropion, may provide indirect evidence to support CSF catecholamine depletion as a possible etiology for mood disorders in HIV-positive patients. We found no HIV illness or depression variables that were significantly associated with depression treatment response. The lack of significant findings with these clinical variables has been noted in most antidepressant studies.4,5,7,8 This study further investigated the impact of depression treatment response on the patients’ cognitive and mo-
tor performance. Outcome assessments included Trail Making Tests A and B, which serve as sensitive screening tools for detecting deficits in information processing speed and psychomotor response in HIV-positive patients.26 Of interest, this study demonstrated significant improvement in these deficits among the treatment responders, whereas the nonresponders had no change or worsening of their cognitive and motor performance. This finding highlights the importance of aggressively treating depression in this population. Dopamine transmission in the mesolimbic, mesocortical, and nigrostriatal pathways may ameliorate mood disturbances as well as the depression-related mild cognitive/motor deficits that need to be distinguished from the early subcortical deficits related to HIV illness. An antidepressant that modulates catecholamines may be more effective in ameliorating depression-induced motor/cognitive deficits in this medical population with lower CSF dopamine levels. Five patients (25%) discontinued the study secondary to adverse events (headaches, panic attacks, and irritability). Most side effects were mild and transient. No seizures or serious side effects were reported. This discontinuation rate was comparable to the 27% rate reported in an openlabel study comparing three SSRIs.30 There was no evidence of clinical toxicity with sustained-release bupropion when it was coadministered with protease inhibitors that inhibit the 3A4 isoenzyme. On the basis of this small group of patients, it appears that sustained-release bupropion is well tolerated in this medically complex population. The limitations of this study include the small group size, the open-label format, and the lack of a comparison or placebo group. Since this is the first prospective study of sustained-release bupropion in the HIV-positive population that we know of, large double-blind, placebo-controlled studies are needed to confirm these findings. Furthermore, comparative placebo-controlled antidepressant studies are needed to identify possible biochemical markers (e.g., CSF levels of dopamine and 5-hydroxyindoleacetic acid), immunological markers (e.g., CD4 cell counts and viral load), and HIV clinical markers (e.g., HIV disease staging and presence of neurological complications) that may distinguish antidepressant treatment response in HIV-infected patients. Sponsored by GlaxoSmithKline.
References
1. Maj M, Jansen R, Starace F, Zaudig M, Satz P, Sughondhabirom B, Luabeya MA, Riedel R, Ndetei D, Calil HM, et al: WHO Neuropsychiatric AIDS Study, cross sectional phase I: study de-
124
sign and psychiatric findings. Arch Gen Psychiatry 1994; 51: 39–49 2. Lyketsos CG, Hoover DR, Guccione M, Senterfitt W, Dew MA,
Psychosomatics 44:2, March-April 2003
Currier et al. Wesch J, VanRaden MJ, Treisman GJ, Morgenstern H: Depressive symptoms as predictors of medical outcomes in HIV infection: Multicenter AIDS Cohort Study. JAMA 1993; 270:2563–2567 3. Burack JH, Barrett DC, Stall RD, Chesney MA, Ekstrand ML, Coates TJ: Depressive symptoms and CD4 lymphocyte decline among HIV-infected men. JAMA 1993; 270:2568–2573 4. Rabkin JG, Wagner GJ, Rabkin R: Fluoxetine treatment for depression in patients with HIV and AIDS: a randomized, placebocontrolled trial. Am J Psychiatry 1999; 156:101–107 5. Rabkin JG, Rabkin R, Harrison W, Wayne G: Effect of imipramine on mood and enumerative measures of immune status in depressed patients with HIV illness. Am J Psychiatry 1994; 151:516–523 6. Elliott AJ, Uldall KK, Bergam K, Russo J, Claypoole K, RoyByrne PP: Randomized, placebo-controlled trial of paroxetine versus imipramine in depressed HIV-positive outpatients. Am J Psychiatry 1998; 155:367–372 7. Rabkin JG, Wagner G, Rabkin R: Sertraline effects on mood and immune status in patients with major depression and HIV illness: an open trial. J Clin Psychiatry 1994; 55:433–439 8. Elliott AJ, Russo J, Bergam K, Claypoole K, Uldall KK, RoyByrne PP: Antidepressant efficacy in HIV-seropositive outpatients with major depressive disorder: an open trial of nefazodone. J Clin Psychiatry 1999; 60:226–231 9. Fernandez F, Levy JK: Psychopharmacotherapy of psychiatric syndromes in asymptomatic and symptomatic HIV infections. Psychiatr Med 1991; 9:377–394 10. Greenblatt DJ, vonMolke LL, Harmatz JS, Shadler RI: Drug interactions with newer antidepressants: role of human cytochrome P450. J Clin Psychiatry 1998; 59(suppl 15):19–27 11. Nemeroff CB, DeVane CL, Pollock BG: Newer antidepressants and the cytochrome P450 system. Am J Psychiatry 1996; 153:311–320 12. Penzak SR, Reddy YS, Grimsley SR: Depression in patients with HIV infection. Am J Health Syst Pharm 2000; 57:376–386 13. Berger JR, Kumar M, Kumar A, Fernandez JB, Levin B: Cerebrospinal fluid dopamine in HIV-1 infections. AIDS 1994; 8:67–71 14. Ferris RM, Cooper BR: Mechanism of antidepressant activity of bupropion. J Clin Psychiatry Monogr 1993; 11:2–14 15. Ascher JA, Cole JO, Colin JN, Feighner JP, Ferris RM, Fibiger HC, Golden RN, Martin P, Potter WZ, Richelson E, et al: Bupropion: a review of its mechanism of antidepressant activity. J Clin Psychiatry 1995; 56:395–401
Psychosomatics 44:2, March-April 2003
16. Goodnick PJ: Pharmacokinetics of second-generation antidepressants: bupropion. Psychopharmacol Bull 1991; 27:513–519 17. Norvir (ritonavir) product instruction brochure. Chicago, Abbot Laboratories, 1995 18. Wellbutrin SR (bupropion SR) product information brochure. Research Triangle Park, NC, Glaxo Wellcome, 1999 19. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J: An inventory for measuring depression. Arch Gen Psychiatry 1961; 4:561– 571 20. Folstein MF, Folstein SE, McHugh PR: “Mini-Mental State”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12:189–198 21. Spitzer RL, Williams JBW, Gibbon M, First MB: Structured Clinical Interview for DSM-IV (SCID). New York, New York State Psychiatric Institute, Biometrics Research, 1995 22. Yerly S, Perneger TV, Hirschel B, Dubuis O, Matter L, Malinverni R, Furrer H, Perrin L: A critical assessment of the prognostic value of HIV-1 RNA levels and CD4 cell counts in HIV-infected patients: the Swiss HIV Cohort Study. Arch Intern Med 1998; 158:247–252 23. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Morb Mortal Wkly Rep 1992; 41(RR-17):1–19 24. Williams JBW: A structured interview guide for the Hamilton Depression Rating Scale. Arch Gen Psychiatry 1988; 45:742–747 25. Guy W (ed): ECDEU Assessment Manual for Psychopharmacology: Publication ADM 76-338. Washington, DC, US Department of Health, Education, and Welfare, 1976, pp 217–222 26. Reitan RM, Wolfson D: The Halstead-Reitan Neuropsychological Test Battery. Tucson, Ariz, Neuropsychology Press, 1985 27. Wilkie FL, Eisdorfer C, Morgan R: Cognition in early human immunodeficiency virus infection. Arch Neurol 1990; 47:433–440 28. Britton GB, Cote L, Alstiel L: Cerebrospinal fluid biogenic amine metabolism in patients with AIDS (abstract). Neurology 1989; 39(suppl):380 29. Larrson M, Hagberg L, Forsman A, Norkrans G: Cerebrospinal fluid catecholamine metabolites in HIV-1 infected patients. J Neurosci Res 1991; 28:406–409 30. Fernando SJ, Goldman JD, Charness WE: Selective serotonin reuptake inhibitor treatment of depression in symptomatic HIV infection and AIDS: improvements in affective and somatic symptoms. Gen Hospital Psychiatry 1997; 19:89–97
125
To date, the authors know of no prospective studies of sustained-release bupropion in depressed HIV-seropositive patients. The purpose of this study was to evaluate the efficacy and tolerability of sustained-release bupropion in 20 depressed HIV-positive adult outpatients. Twenty outpatients with HIV spectrum illness, a DSM-IV-diagnosed major depressive disorder confirmed with the Structured Clinical Interview for DSM-IV, and Mini-Mental State Examination scores ⬎20 were recruited into a 6-week, open-label, flexible-dose study of sustained-release bupropion (100– 300 mg/day). Twelve patients (60%) responded to sustained-release bupropion at a mean dose of 265 mg/day. Five patients (25%) discontinued study participation secondary to adverse events. Preliminary findings suggest that sustained-release bupropion is effective for the treatment of depression in HIV-positive patients, regardless of HIV clinical staging. Furthermore, it appears to be well tolerated in patients with AIDS-related medical conditions. (Psychosomatics 2003; 44:120–125)
D
epressive disorders account for the most common psychiatric comorbidity among HIV-positive patients. The lifetime prevalence of depression in this medical population ranges from 22% to 45%, which is twofold higher than in the general population.1 Although consistent findings to suggest a direct negative impact of depression on the immune function or survivorship of this population are lacking,2,3 depression may indirectly hasten HIV disease progression by influencing poor compliance with medical treatment regimens. Despite the high prevalence of depressive disorders,
Presented in part at the 154th annual meeting of the American Psychiatric Association, New Orleans, May 5–10, 2001. Received June 24, 2002; accepted July 24, 2002. From the Department of Psychiatry and Behavioral Sciences, Division of Consultation Psychiatry, University of Miami School of Medicine. Address reprint requests to Dr. Currier, Department of Psychiatry (D-79), Division of Consultation Psychiatry, University of Miami/Jackson Memorial Medical Center, 1400 N.W. 10 Ave., Suite 704A, Miami, FL 33136; [email protected] (e-mail). Copyright 䉷 2003 The Academy of Psychosomatic Medicine.
120
few studies have systematically investigated the pharmacological treatment of depression among HIV-positive and AIDS patients. Double-blind, placebo-controlled studies with fluoxetine,4 imipramine,5 and paroxetine6 and several open studies evaluating sertraline7 and nefazodone8 in HIV-positive depressed patients have demonstrated an overall positive clinical response rate ranging from 45% to 80%. A retrospective review of 52 patients treated with bupropion (dose: mean⳱200 mg/day)9 revealed that 63% of the patients had a favorable clinical response. Because of the anticholinergic adverse effects of tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs) have been considered the first-line treatment for depression in the HIV population. Several SSRIs, however, have potential drug interactions with antiretroviral and antifungal medication regimens (by means of cytochrome P450 oxidase system 3A4 and 2D6 isoenzyme inhibition) and adverse effects such as asthenia, nausea, diarrhea, and sexual dysfunction that may interfere with patient compliance and quality of life.10–12 Psychosomatics 44:2, March-April 2003
Currier et al. HIV infection may affect CSF dopamine levels. In a controlled study,13 mean CSF dopamine levels were significantly lower in HIV-positive patients with or without neurological disease than in HIV-negative comparison subjects. The catecholaminergic profile of sustained-release bupropion may offer direct advantages over SSRIs by modulating dopaminergic transmission in this population.14–16 Bupropion may have a relatively low potential for serious drug interactions with protease inhibitors. Despite earlier warnings to the contrary, there is no empirical evidence to support the contraindication of bupropion with ritonavir therapy.17 Specifically, ritonavir, a potent 3A4 and 2D6 inhibitor, may increase the concentration and toxicity of the antidepressants metabolized by these isoenzymes. Early concerns arose regarding the impact of 3A4 inhibition on the metabolism of bupropion, which prompted contraindication warnings for bupropion and ritonavir therapy.17 Other data,18 however, has revealed that the primary metabolic pathway of sustained-release bupropion in the P450 oxidase system is the 2B6 isoenzyme rather than the 3A4 isoenzyme. The 3A4 isoenzyme plays a minor secondary role in its metabolism. In vitro data have demonstrated that selective 3A4 inhibitors have minimal impact on bupropion concentrations.18 To date, no serious drug interactions have been reported between sustained-release bupropion and protease inhibitors in the HIV-positive population, to our knowledge. To date, we know of no prospective studies of sustained-release bupropion performed among depressed HIV-positive patients. The purpose of this study was to determine the efficacy and tolerability of sustained-release bupropion in the treatment of depressed HIV-positive patients. In addition, we wanted to determine if HIV clinical variables such as disease staging, CD4 cell count, viral load (number of HIV RNA copies in plasma), and depression severity and chronicity are significantly associated with depression treatment response. METHOD Study Group Outpatients with HIV spectrum illness, ages 18–75 years, who were seeking medical treatment at the University of Miami/Jackson Memorial Medical Center’s Special Immunology Clinic were screened with the Beck Depression Inventory19 and the Mini-Mental State Examination (MMSE)20 for participation in this prospective, Psychosomatics 44:2, March-April 2003
6-week, open-label, flexible-dose antidepressant study with sustained-release bupropion (100–300 mg/day). Eligible participants included those with a baseline Beck Depression Inventory score ⬎15, a baseline MMSE score ⬎20, and a DSM-IV diagnosis of major depressive disorder confirmed with the Structured Clinical Interview for DSM-IV. Psychiatric exclusion criteria included an active axis I disorder other than major depressive disorder, a current risk for suicide, and current treatment with another antidepressant. Medical exclusion criteria included a history of seizure disorder or traumatic brain injury and current risk factors for seizure—such as a CNS opportunistic infection, current CNS lymphoma, or current use of an antipsychotic medication. Study Design and Assessments All of the patients provided written informed consent to participate in this 6-week, open-label, flexible-dose antidepressant study. Baseline assessment included the following: administration of the mood disorder module of the Structured Clinical Interview for DSM-IV,21 a semistructured review of demographic variables, medical and psychiatric histories, a listing of antidepressant therapies, neuroimaging studies, a listing of current medications, HIV illness markers (CD4 cell count, viral load),22 and HIV disease staging, as outlined by the Centers for Disease Control and Prevention.23 Criteria for the three stages of HIV illness include the following: asymptomatic (CD4 ⬎500 cells/mm3 and no symptoms), symptomatic (CD4 of 200– 500 cells/mm3 and past or current symptoms without opportunistic infections), and AIDS (CD4 less than 200 cells/mm3 and past or current AIDS-defining opportunistic infection or malignancy). Baseline depression measures included the Beck Depression Inventory, the 17-item Hamilton Depression Rating Scale,24 and the Clinical Global Improvement (CGI) severity scale.25 Baseline cognitive performance measures included the MMSE and Trail Making Tests A and B.26,27 Sustained-release bupropion was dispensed at each visit, with an initial dose of 100 mg/day for 1 week. At week 2, the dose was increased to 100 mg b.i.d. for 2 weeks, and at week 4, the dose was increased to 150 mg b.i.d. for the remaining 3 weeks of the study. Since the study incorporated a flexible-dose design, sustained-release bupropion was adjusted as clinically indicated and tolerated. The patients’ assessments were made at baseline and at weeks 2, 4, and 6. The outcome measures administered 121
Bupropion for Depression in HIV/AIDS Patients at the follow-up visits and final assessment included the Beck Depression Inventory, the Hamilton depression scale, the MMSE, Trail Making Tests A and B, the CGI, and repeat immunological measurements (if available). Spontaneous reporting of treatment-emergent adverse events was documented and rated for severity at each visit. The responders were defined by a CGI score of very much improved or much improved and a 50% reduction in baseline scores on the Beck Depression Inventory and the Hamilton depression scale. Remission was defined by a Hamilton depression scale score ⬍8. Data Analysis Treatment responders were compared with nonresponders by using t tests for continuous variables and chisquare analysis for categorical variables. Fisher’s exact test was used if the expected cell size was ⬍5. All data analysis was performed by using the Statistical Package for Social Sciences (SPSS, Chicago) 10.0 software program. The patients who did not complete the trial but underwent at least one postbaseline assessment while taking medication were included in the intent-to-treat analysis. Response and remission rates were assessed. Paired t tests were used to assess baseline and endpoint continuous outcome measures for treatment outcome. Independent t tests were used to examine differences in depression (i.e., chronicity and severity) and HIV illness progression (i.e., CD4 cell count, viral load, staging) between the two treatment outcome groups to identify the clinical variables significantly associated with treatment response to sustained-release bupropion. RESULTS Patient Demographic and Clinical Characteristics Twenty patients were enrolled in the study. The group consisted of six women and 14 men with a mean age of 40.95 years (SD⳱7.00, range⳱26–54). Thirteen patients were Hispanic, and two were Haitian. There were no significant differences in demographic variables between the treatment outcome groups. In terms of psychiatric clinical variables, 11 patients (55%) suffered from recurrent major depressive disorder, and eight patients (40%) had received prior antidepressant pharmacotherapy. The mean duration of the current episode of depression was 27.35 months (SD⳱24.28, range⳱1– 122
80). Nine patients (45%) had developed depression within 6 months (range⳱1–144) of testing HIV seropositive. Five patients (25%) reported a prior history of substance abuse. Baseline depression severity scores revealed a mean Hamilton depression scale score of 23.80 (SD⳱3.83, range⳱ 16–29), a mean Beck Depression Inventory score of 30.10 (SD⳱8.39, range⳱16–48), and a mean CGI severity score of 4.80 (SD⳱0.77, range⳱4–6). Baseline cognitive measures revealed a mean MMSE score of 28.90 (SD⳱0.91, range⳱27–30), a mean Trail Making Test A score of 2.35 (SD⳱0.75, range⳱2–5), and a mean Trail Making Test B score of 2.55 (SD⳱0.69, range⳱1–4). Both mean scores on Trail Making Tests A and B indicated average to borderline motor and cognitive performance. There were no significant differences in baseline depression measures (i.e., severity or chronicity) and baseline cognitive performance (i.e., on the MMSE and Trail Making Tests A and B) between the responders and the nonresponders. In terms of clinical variables for HIV illness, 10 patients (50%) reported man-to-man sexual contact as the risk factor for HIV transmission, eight patients (40%) reported heterosexual contact, and two patients (10%) reported needle-sharing contact associated with drug abuse as the risk factor for transmission. The HIV-positive group included asymptomatic patients (N⳱9, 45%), symptomatic patients (N⳱4, 20%), and AIDS patients (N⳱7, 35%). The mean duration of HIV illness was 65.28 months (SD⳱47.18, range⳱1–156). The mean CD4 cell count was 503 cells/mm3 (SD⳱546, range⳱10–2,390). No viral load was detected in 12 patients (60%); however, the remaining eight patients had a range of 1,800 to 441,715 HIV RNA copies/ml plasma, as detected by polymerase chain reaction. All but two patients were taking antiretroviral medications, and 14 patients (70%) were taking protease inhibitors plus two antiretroviral drugs. One patient was taking ritonavir. HIV clinical variables were compared between responders and nonresponders. The treatment outcome groups differed significantly in baseline immune status. The treatment responders had a significantly lower (t⳱ –2.50, df⳱19, p⬍0.02) mean baseline CD4 cell count (mean⳱277 cells/mm3, SD⳱219) than the nonresponders (mean⳱843 cells/mm3, SD⳱719). This difference remained significant (t⳱–2.54, df⳱18, p⬍0.03) when we excluded an outlier in the nonresponder treatment group with a high CD4 cell count (2,390 cells/mm3). Other HIV clinical variables (e.g., viral load, HIV disease staging, and duration of HIV-positive status) were comparable between the treatment groups. Psychosomatics 44:2, March-April 2003
Currier et al. 219) than the nonresponders (mean⳱843 cells/mm3, SD⳱719) (t⳱–2.59, df⳱18, p⬍0.02). Regression analysis, however, revealed no correlation between CD4 cell count and treatment response (coefficient⳱0.006 [SD⳱ 0.003], df⳱1, p⬍0.08). No HIV clinical variables were significantly associated with depression treatment response. Furthermore, there was no significant association between depression clinical variables and treatment response to sustained-release bupropion.
Efficacy Twenty patients were treated with sustained-release bupropion. At week 6, 75% of the completers (9 of 12) had responded to sustained-release bupropion at 300 mg/ day. In an intent-to-treat analysis in which all patients with a postbaseline visit were included, 60% of the patients (12 of 20) were rated as responders. More than half of the responders (7 of 12) achieved remission (Hamilton depression scale score ⬍8). The mean effective dose of sustained-release bupropion was 265 mg/day (SD⳱65). There was no significant difference in endpoint dose between the two groups (t⳱1.36, df⳱18, p⳱0.19). The responders demonstrated a significant improvement between mean baseline and final scores on the Beck Depression Inventory (t⳱10.12, df⳱11, p⬍0.001) and the Hamilton depression scale (t⳱10.64, df⳱11, p⬍0.001) (Table 1). The nonresponders demonstrated no significant difference between mean baseline and final scores on the Beck Depression Inventory and the Hamilton depression scale. Despite comparable baseline cognitive performance between the two treatment groups, the responders demonstrated significant improvement in motor/cognitive performance between baseline and final scores on the Trail Making Test A (t⳱2.35, df⳱11, p⬍0.04) and the Trail Making Test B (t⳱3.92, df⳱11, p⳱0.002), whereas the nonresponders demonstrated no significant change (Table 1). There was no significant difference in mean baseline and final MMSE scores between the two treatment groups and no significant improvement at endpoint within either group. The treatment responders had significantly lower mean baseline CD4 cell counts (mean⳱277 cells/mm3, SD⳱
TABLE 1.
Adverse Effects Fourteen patients (70%) reported treatment-emergent adverse events. Five patients (25%) discontinued study participation secondary to adverse events (headaches, panic attacks, irritability) that occurred at 100 mg/day (N⳱2), 200 mg/day (N⳱2), and 300 mg/day (N⳱1). In the total group, the most frequently reported adverse events included headaches (N⳱5, 25%), insomnia (N⳱4, 20%), anxiety/irritability (N⳱2, 10%), dry mouth (N⳱2, 10%), and edema of the lower extremities (N⳱2, 10%). Most of the adverse events reported were mild and transient. No serious adverse events were reported, and no seizures occurred. There was no significant difference in the incidence of adverse events between the responders and the nonresponders. The patients who completed the study were compared with those who dropped out secondary to adverse events. No significant differences in demographic, psychiatric, or HIV-related variables—including CD4 cell count, protease inhibitors, and HIV disease severity staging— were noted between the two groups.
Outcome Measures in a 6-Week, Open-Label, Flexible-Dose Study of Sustained-Release Bupropion in Depressed HIV-Positive Patients Score Baseline
Group and Measure Responders (N⳱12) Beck Depression Inventory Hamilton Depression Rating Scale Trail Making Test Aa Trail Making Test Ba Nonresponders (N⳱8) Beck Depression Inventory Hamilton Depression Rating Scale Trail Making Test Aa Trail Making Test Ba
Endpoint
Analysis
Mean
SD
Mean
SD
Paired Samples t
df
p (two-tailed)
30.33 22.00 2.58 2.58
5.57 3.98 0.90 0.79
11.42 6.08 2.22 2.00
8.89 3.87 1.09 0.15
10.12 10.64 2.35 3.92
11 11 11 11
⬍0.001 ⬍0.001 ⬍0.04 0.002
29.63 24.00 2.00 2.50
12.05 3.51 0.00 0.53
27.25 19.88 2.13 2.50
12.42 7.20 0.35 0.76
1.28 2.08 ⳮ1.00 0.00
7 7 7 7
⬍0.25 ⬍0.08 ⬍0.36 1.00
a
A score of 2 indicates average motor/cognitive performance; a score of 3 indicates borderline motor/cognitive performance.
Psychosomatics 44:2, March-April 2003
123
Bupropion for Depression in HIV/AIDS Patients DISCUSSION Sustained-release bupropion was found to be effective for the treatment of major depressive disorder in HIV-positive and AIDS patients in this 6-week open-label study. The efficacy rate of 75% in subjects completing the 6-week study, and 60% in the intent-to-treat group, is comparable with the efficacy range of SSRIs in this medical population.4–8 Furthermore, 45% of the group achieved remission (Hamilton depression scale score ⬍8) during the 6-week study. The mean effective dose of sustained-release bupropion was 265 mg/day (SD⳱65). This antidepressant efficacy may be due to the catecholaminergic effects of sustained-release bupropion and the relationship between immunosuppression and lower CSF dopamine levels in HIV-positive patients. Several investigators have found lower levels of CSF dopamine and its metabolite, homovanillic acid, in HIV-positive and AIDS patients.13,28,29 Berger et al.13 compared the CSF dopamine levels (measured by high-performance liquid chromatography) of 17 HIV-positive patients with those of five HIV-negative comparison subjects. The HIV-positive patient group was further divided into those who were asymptomatic and those who had neurological complications, including mild cognitive/motor deficits, peripheral neuropathies, and dementia (one patient). They found significantly lower mean CSF dopamine levels in all of the HIV-positive patients, compared to the HIV-negative comparison subjects. In addition, a strong correlation existed between lower CSF dopamine levels and lower CD4 cell counts among the neurologically impaired HIV-positive patients. The strong correlation found between lower CSF dopamine levels and immunosuppression in HIV-positive patients, coupled with the catecholaminergic effects of sustained-release bupropion, may provide indirect evidence to support CSF catecholamine depletion as a possible etiology for mood disorders in HIV-positive patients. We found no HIV illness or depression variables that were significantly associated with depression treatment response. The lack of significant findings with these clinical variables has been noted in most antidepressant studies.4,5,7,8 This study further investigated the impact of depression treatment response on the patients’ cognitive and mo-
tor performance. Outcome assessments included Trail Making Tests A and B, which serve as sensitive screening tools for detecting deficits in information processing speed and psychomotor response in HIV-positive patients.26 Of interest, this study demonstrated significant improvement in these deficits among the treatment responders, whereas the nonresponders had no change or worsening of their cognitive and motor performance. This finding highlights the importance of aggressively treating depression in this population. Dopamine transmission in the mesolimbic, mesocortical, and nigrostriatal pathways may ameliorate mood disturbances as well as the depression-related mild cognitive/motor deficits that need to be distinguished from the early subcortical deficits related to HIV illness. An antidepressant that modulates catecholamines may be more effective in ameliorating depression-induced motor/cognitive deficits in this medical population with lower CSF dopamine levels. Five patients (25%) discontinued the study secondary to adverse events (headaches, panic attacks, and irritability). Most side effects were mild and transient. No seizures or serious side effects were reported. This discontinuation rate was comparable to the 27% rate reported in an openlabel study comparing three SSRIs.30 There was no evidence of clinical toxicity with sustained-release bupropion when it was coadministered with protease inhibitors that inhibit the 3A4 isoenzyme. On the basis of this small group of patients, it appears that sustained-release bupropion is well tolerated in this medically complex population. The limitations of this study include the small group size, the open-label format, and the lack of a comparison or placebo group. Since this is the first prospective study of sustained-release bupropion in the HIV-positive population that we know of, large double-blind, placebo-controlled studies are needed to confirm these findings. Furthermore, comparative placebo-controlled antidepressant studies are needed to identify possible biochemical markers (e.g., CSF levels of dopamine and 5-hydroxyindoleacetic acid), immunological markers (e.g., CD4 cell counts and viral load), and HIV clinical markers (e.g., HIV disease staging and presence of neurological complications) that may distinguish antidepressant treatment response in HIV-infected patients. Sponsored by GlaxoSmithKline.
References
1. Maj M, Jansen R, Starace F, Zaudig M, Satz P, Sughondhabirom B, Luabeya MA, Riedel R, Ndetei D, Calil HM, et al: WHO Neuropsychiatric AIDS Study, cross sectional phase I: study de-
124
sign and psychiatric findings. Arch Gen Psychiatry 1994; 51: 39–49 2. Lyketsos CG, Hoover DR, Guccione M, Senterfitt W, Dew MA,
Psychosomatics 44:2, March-April 2003
Currier et al. Wesch J, VanRaden MJ, Treisman GJ, Morgenstern H: Depressive symptoms as predictors of medical outcomes in HIV infection: Multicenter AIDS Cohort Study. JAMA 1993; 270:2563–2567 3. Burack JH, Barrett DC, Stall RD, Chesney MA, Ekstrand ML, Coates TJ: Depressive symptoms and CD4 lymphocyte decline among HIV-infected men. JAMA 1993; 270:2568–2573 4. Rabkin JG, Wagner GJ, Rabkin R: Fluoxetine treatment for depression in patients with HIV and AIDS: a randomized, placebocontrolled trial. Am J Psychiatry 1999; 156:101–107 5. Rabkin JG, Rabkin R, Harrison W, Wayne G: Effect of imipramine on mood and enumerative measures of immune status in depressed patients with HIV illness. Am J Psychiatry 1994; 151:516–523 6. Elliott AJ, Uldall KK, Bergam K, Russo J, Claypoole K, RoyByrne PP: Randomized, placebo-controlled trial of paroxetine versus imipramine in depressed HIV-positive outpatients. Am J Psychiatry 1998; 155:367–372 7. Rabkin JG, Wagner G, Rabkin R: Sertraline effects on mood and immune status in patients with major depression and HIV illness: an open trial. J Clin Psychiatry 1994; 55:433–439 8. Elliott AJ, Russo J, Bergam K, Claypoole K, Uldall KK, RoyByrne PP: Antidepressant efficacy in HIV-seropositive outpatients with major depressive disorder: an open trial of nefazodone. J Clin Psychiatry 1999; 60:226–231 9. Fernandez F, Levy JK: Psychopharmacotherapy of psychiatric syndromes in asymptomatic and symptomatic HIV infections. Psychiatr Med 1991; 9:377–394 10. Greenblatt DJ, vonMolke LL, Harmatz JS, Shadler RI: Drug interactions with newer antidepressants: role of human cytochrome P450. J Clin Psychiatry 1998; 59(suppl 15):19–27 11. Nemeroff CB, DeVane CL, Pollock BG: Newer antidepressants and the cytochrome P450 system. Am J Psychiatry 1996; 153:311–320 12. Penzak SR, Reddy YS, Grimsley SR: Depression in patients with HIV infection. Am J Health Syst Pharm 2000; 57:376–386 13. Berger JR, Kumar M, Kumar A, Fernandez JB, Levin B: Cerebrospinal fluid dopamine in HIV-1 infections. AIDS 1994; 8:67–71 14. Ferris RM, Cooper BR: Mechanism of antidepressant activity of bupropion. J Clin Psychiatry Monogr 1993; 11:2–14 15. Ascher JA, Cole JO, Colin JN, Feighner JP, Ferris RM, Fibiger HC, Golden RN, Martin P, Potter WZ, Richelson E, et al: Bupropion: a review of its mechanism of antidepressant activity. J Clin Psychiatry 1995; 56:395–401
Psychosomatics 44:2, March-April 2003
16. Goodnick PJ: Pharmacokinetics of second-generation antidepressants: bupropion. Psychopharmacol Bull 1991; 27:513–519 17. Norvir (ritonavir) product instruction brochure. Chicago, Abbot Laboratories, 1995 18. Wellbutrin SR (bupropion SR) product information brochure. Research Triangle Park, NC, Glaxo Wellcome, 1999 19. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J: An inventory for measuring depression. Arch Gen Psychiatry 1961; 4:561– 571 20. Folstein MF, Folstein SE, McHugh PR: “Mini-Mental State”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12:189–198 21. Spitzer RL, Williams JBW, Gibbon M, First MB: Structured Clinical Interview for DSM-IV (SCID). New York, New York State Psychiatric Institute, Biometrics Research, 1995 22. Yerly S, Perneger TV, Hirschel B, Dubuis O, Matter L, Malinverni R, Furrer H, Perrin L: A critical assessment of the prognostic value of HIV-1 RNA levels and CD4 cell counts in HIV-infected patients: the Swiss HIV Cohort Study. Arch Intern Med 1998; 158:247–252 23. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Morb Mortal Wkly Rep 1992; 41(RR-17):1–19 24. Williams JBW: A structured interview guide for the Hamilton Depression Rating Scale. Arch Gen Psychiatry 1988; 45:742–747 25. Guy W (ed): ECDEU Assessment Manual for Psychopharmacology: Publication ADM 76-338. Washington, DC, US Department of Health, Education, and Welfare, 1976, pp 217–222 26. Reitan RM, Wolfson D: The Halstead-Reitan Neuropsychological Test Battery. Tucson, Ariz, Neuropsychology Press, 1985 27. Wilkie FL, Eisdorfer C, Morgan R: Cognition in early human immunodeficiency virus infection. Arch Neurol 1990; 47:433–440 28. Britton GB, Cote L, Alstiel L: Cerebrospinal fluid biogenic amine metabolism in patients with AIDS (abstract). Neurology 1989; 39(suppl):380 29. Larrson M, Hagberg L, Forsman A, Norkrans G: Cerebrospinal fluid catecholamine metabolites in HIV-1 infected patients. J Neurosci Res 1991; 28:406–409 30. Fernando SJ, Goldman JD, Charness WE: Selective serotonin reuptake inhibitor treatment of depression in symptomatic HIV infection and AIDS: improvements in affective and somatic symptoms. Gen Hospital Psychiatry 1997; 19:89–97
125