Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression.

BACKGROUND: Psilocybin is being studied for use in treatment-resistant depression. METHODS: In this phase 2 double-blind trial, we randomly assigned adults with treatment-resistant depression to receive a single dose of a proprietary, synthetic formulation of psilocybin at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. The primary end point was the change from baseline to week 3 in the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS; range, 0 to 60, with higher scores indicating more severe depression). Secondary end points included response at week 3 (≥50% decrease from baseline in the MADRS total score), remission at week 3 (MADRS total score ≤10), and sustained response at 12 weeks (meeting response criteria at week 3 and all subsequent visits). RESULTS: A total of 79 participants were in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group. The mean MADRS total score at baseline was 32 or 33 in each group. Least-squares mean changes from baseline to week 3 in the score were -12.0 for 25 mg, -7.9 for 10 mg, and -5.4 for 1 mg; the difference between the 25-mg group and 1-mg group was -6.6 (95% confidence interval [CI], -10.2 to -2.9; P<0.001) and between the 10-mg group and 1-mg group was -2.5 (95% CI, -6.2 to 1.2; P = 0.18). In the 25-mg group, the incidences of response and remission at 3 weeks, but not sustained response at 12 weeks, were generally supportive of the primary results. Adverse events occurred in 179 of 233 participants (77%) and included headache, nausea, and dizziness. Suicidal ideation or behavior or self-injury occurred in all dose groups. CONCLUSIONS: In this phase 2 trial involving participants with treatment-resistant depression, psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects. Larger and longer trials, including comparison with existing treatments, are required to determine the efficacy and safety of psilocybin for this disorder. (Funded by COMPASS Pathfinder; EudraCT number, 2017-003288-36; ClinicalTrials.gov number, NCT03775200.).

Treatment of HIV-related fatigue with armodafinil: a placebo-controlled randomized trial.

OBJECTIVE: To evaluate the efficacy and safety of armodafinil in the treatment of fatigue in HIV+ patients, and to assess its effect on depressive symptoms and behavior once fatigue remitted. METHOD: HIV+ patients with clinically significant fatigue were treated in a placebo-controlled randomized double-blind trial for 4 weeks. Armodafinil responders and placebo non-responders or relapsers were treated openly for a total of 16 weeks with armodafinil. The primary outcome measure for fatigue and depression was the Clinical Global Impressions-Improvement Scale, supplemented by the Fatigue Severity Scale, the Hamilton Depression Rating Scale, and the Beck Depression Inventory. Safety was assessed with assays of CD4 cell count and HIV RNA viral load and the SAFTEE side effects rating scale. Maximum trial dose of armodafinil was 250 mg/d. RESULTS: Seventy patients were enrolled. Attrition was 9%. In intention-to-treat analyses, fatigue response rate to armodafinil was 75% and to placebo, 26%. Armodafinil did not reduce depressive symptoms in the absence of improved energy, but of those patients with an Axis I depressive disorder at study entry whose energy improved, 82% experienced improved mood as well. Markers of immunologic suppression did not change during treatment. At 6 months, those still taking armodafinil had more energy and fewer depressive symptoms than those who were no longer taking it. CONCLUSIONS: As we found in our RCT of modafinil, armodafinil appears effective and well tolerated in treating fatigue in HIV+ patients. Side effects were minimal and most patients reported substantially improved energy and mood.

Comparison of counseling methods to promote employment for HIV+ ADULTS.

BACKGROUND: Despite improved health and during a strong job market (pre-COVID-19), a substantial proportion of HIV+ adults remained unemployed. This study sought to provide time-limited counseling to promote employment goals. OBJECTIVE: To determine whether behavioral activation (BA) or supportive counseling (SC), would be more effective in promoting vocational goals (full or part-time, paid or volunteer). METHODS: The study included two groups: those with clinically significant fatigue, who were first treated with armodafinil. Once their fatigue diminished, they were enrolled in the counseling program. Those without fatigue were enrolled directly. Both BA and SC interventions were manualized, consisting of eight individual sessions plus a follow-up. RESULTS: 116 participants entered counseling, including 87 assigned to BA and 29 to SC. Of these, 79 completed counseling or found a job by session eight. By follow-up, 51%of BA versus 41%of SC participants had found jobs, a non-significant difference either clinically or statistically. CONCLUSIONS: Multiple issues contributed to difficulty in employment, including gaps in resumes, loss of contact with former colleagues, and uncertainty about career direction. Ongoing barriers included substance use, housing instability, ambivalence about forfeiting government benefits, as well as inadequately treated depression. Success in employment for about half of participants is, in this context, a reasonable outcome.

Provigil (modafinil) plus cognitive behavioral therapy for methamphetamine use in HIV+ gay men: a pilot study.

OBJECTIVES: To evaluate the efficacy of modafinil combined with cognitive behavioral therapy (CBT) for treatment of methamphetamine (MA) dependence among HIV+ gay men. METHODS: In a single blind trial, modafinil was administered for 12 weeks, followed by a 4-week placebo phase. CBT was conducted for 18 sessions over the 16-week study. Primary outcome measures were self-reported use of days per week plus urine toxicology assays. Additional measures included the Beck Depression Inventory, Cravings Scale, and O/C Crystal Use Scale. Response was defined as > 50% decline in days used per week. Thirteen patients were enrolled over an 18-month period. RESULTS: Ten patients (77%) completed the trial, although two discontinued modafinil due to side effects. Six of the ten study completers reduced their MA use by > 50%. CONCLUSIONS: These preliminary results suggest good retention using combined medication and psychotherapy, and support further examination of modafinil and CBT in double-blind placebo controlled trials.

Returning to work after fatigue treatment and counseling in HIV/AIDS.

BACKGROUND: Employment rates for people with HIV/AIDS are low, compared to the general population. One widespread barrier is fatigue, accompanied by daytime sleepiness and a lack of stamina. Previous pharmacological studies have demonstrated improvement of fatigue-related symptoms without affecting work-related goal attainmentOBJECTIVE:In this pilot study, we sought to determine whether a pharmacologic-behavioral two-phase combined approach could facilitate returning to work. METHODS: HIV+ participants with fatigue were treated with armodafinil. If energy improved, 8 sessions of biweekly manualized Behavioral Activation (BA) counseling were added to medication maintenance. Outcome was assessed on a 3-point scale along with clinician and self-ratings. RESULTS: Of the 46 participants enrolled in BA, 15 (33%) did not complete all 8 sessions: 6 got jobs so they no longer needed counseling; 4 did not like BA, and 5 dropped out for reasons such as moving away or substance use relapse. Of the 46, 29 (63%) attained their vocational goal and showed significant changes on self-report scales. CONCLUSIONS: Our integrated treatment including armodafinil plus BA counseling significantly increased the success of achieving work-related goals. The two-phase medication plus counseling program was well-tolerated by participants and the manualized BA counseling was readily applied by counselors without advanced mental health training, making the method potentially feasible in community settings.

Trauma and Growth: Impact of AIDS Activism.

INTRODUCTION: Our goal was to assess the long-term impact of AIDS activism of ACT UP/New York on the current adjustment of those who were members during its peak years (1987-1992), including assessment of trauma sequelae as well as posttraumatic growth. METHODS: A 90-minute semistructured interview and 6 validated self-report scales were administered. We relied on purposive and snowball sampling to recruit potential participants. Areas covered include demographics, ACT UP participation, and psychiatric problems. Self-report scales provided approximate diagnoses of PTSD and depression, as well as coping, optimism, and related concepts. RESULTS: Participants included 102 men (40% HIV-positive) and 23 women. Seventeen percent reported current symptoms suggesting PTSD, slightly above the range in general population studies. Symptoms consistent with depression were reported by 8% overall, with higher rates for HIV+ men. Enhanced sense of self, belief in change, and empowerment were reported by 93% of respondents, independent of concurrent PTSD or depression. CONCLUSIONS: Twenty-eight years later, ACT UP study participants recall their activist days during the AIDS epidemic as the peak experience of their lives. While some continue to have symptoms of stress and depression, most found that their activism has enriched their subsequent lives.

Placebo-controlled trial of dehydroepiandrosterone (DHEA) for treatment of nonmajor depression in patients with HIV/AIDS.

OBJECTIVE: Subsyndromal major depressive disorder is common among HIV-positive adults. This study was designed to assess the efficacy of dehydroepiandrosterone (DHEA) as a potential treatment. METHOD: One hundred forty-five patients with subsyndromal depression or dysthymia were randomly assigned to receive either DHEA or placebo; 90% (69 of 77) of the DHEA patients and 94% (64 of 68) of the placebo patients completed the 8-week trial. The primary measure of efficacy was a Clinical Global Impression improvement rating of 1 or 2 (much or very much improved) plus a final Hamilton Depression Rating Scale score

Mood and substance use disorders in older adults with HIV/AIDS: methodological issues and preliminary evidence.

OBJECTIVE: To review methodological issues and available data regarding the prevalence of psychiatric disorders in HIV-positive people over the age of 50 years. RESULTS: We were unable to find any published data providing prevalence rates of depression and substance use disorders, the most common psychiatric disorders, for HIV-positive adults over 50 years, compared with HIV-seronegative adults over 50 years or HIV-positive adults under the age of 50 years. Epidemiological data from population studies in the United States and internationally consistently show a substantial decline in the rates of depression and substance use disorders with progressive age in the general population. Preliminary data in our small sample suggest that, unlike HIV-seronegative older adults whose rates of disorder decline substantially compared with younger adults, this decline was not observed for older HIV-positive adults. CONCLUSION: Given the relative infrequency of disorder and the need to control both for age and HIV status, a large-scale study with four groups is required: HIV-positive men and women under and over 50 years of age, and HIV-negative men and women under and over 50 years of age.

Modafinil treatment for fatigue in HIV+ patients: a pilot study.

BACKGROUND: Fatigue is widespread among human immunodeficiency virus-positive (HIV+) patients, yet few studies have assessed effective treatments. The authors conducted a pilot study to evaluate the efficacy of modafinil for fatigue in this clinical population. METHOD: Response was evaluated after a 4-week open-label trial. Data were collected from February 2003 through January 2004. Responders were offered 8 additional weeks of modafinil. Inclusion criteria included written approval from the primary care physician, clinically significant fatigue, current use of anti-retroviral medications, and the absence of treatable medical conditions known to cause fatigue. Exclusion criteria included untreated major depression and current substance abuse. Major outcome measures were the Fatigue Severity Scale, Chalder Fatigue Scale, Hamilton Rating Scale for Depression, Beck Depression Inventory, and neuropsychological tests assessing verbal memory, speed of processing, and executive function. Immunologic and virologic measures were performed at baseline and week 4 to assess safety of treatment. RESULTS: All 30 patients who enrolled completed 4 weeks of treatment; 24 (80%) were rated as responders. Responders showed statistically significant improvement on all measures of fatigue, depressive symptoms, and executive function, while nonresponders did not. Mean values of CD4 cell count and HIV RNA viral load did not change. The most common side effect was headache, followed by irritability and feeling "hyper." CONCLUSION: This pilot study shows encouraging results for modafinil in alleviation of fatigue in HIV+ patients. In addition, depressive symptoms were substantially reduced. Improvements on measures of verbal memory and executive function were significant, but in the absence of a placebo control, the magnitude of effect due to practice cannot be determined.

Modafinil treatment for fatigue in HIV/AIDS: a randomized placebo-controlled study.

OBJECTIVE: To evaluate the efficacy and safety of modafinil in the treatment of fatigue in patients with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) and to assess effect on depressive symptoms. METHOD: Patients who were HIV+ and had clinically significant fatigue (according to the Fatigue Severity Scale [FSS]) were included in a 4-week randomized, placebo-controlled, double-blind trial. This was followed by an additional 8 weeks of open-label treatment for modafinil responders and 12 weeks for placebo nonresponders. The primary outcome measure for fatigue and depression was the Clinical Global Impressions-Improvement scale, supplemented by the FSS, Hamilton Depression Rating Scale, and Beck Depression Inventory. Safety was assessed with assays of CD4 cell count and HIV ribonucleic acid (RNA) viral load. Visits were weekly for 4 weeks, then biweekly, with a follow-up visit at 6 months. Maximum trial dose of modafinil was 200 mg/d. Data for this study were collected between December 2004 and December 2008. RESULTS: 115 patients were randomly assigned. In intention-to-treat analyses, fatigue response rate to modafinil was 73% and to placebo, 28%. Attrition was 9%. Modafinil did not have an effect on mood alone in the absence of improved energy. At week 4, CD4 cell counts did not change significantly; HIV RNA viral load showed a trend decline for patients taking modafinil but not for those taking placebo. At 6 months, those still taking modafinil had more energy and fewer depressive symptoms than patients who were not taking modafinil, and only those still taking modafinil showed a significant decline from baseline in their HIV RNA viral load. CONCLUSIONS: Modafinil appears to be effective and well tolerated in treating fatigue in HIV+ patients. Consideration of its use is warranted considering the high prevalence of fatigue in the HIV community, its minimal side effects, and overall patient acceptance. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00118378.

Testosterone versus fluoxetine for depression and fatigue in HIV/AIDS: a placebo-controlled trial.

BACKGROUND: While testosterone's ameliorative effects on depressive disorders and fatigue in HIV-positive patients have been suggested in the literature, no placebo-controlled trial selecting for depressive disorders and including a standard antidepressant has been conducted. Accordingly, this double-blind trial was designed to determine whether testosterone, as well as fluoxetine, is superior to placebo for depression, fatigue, or both. METHOD: One hundred twenty-three men with HIV/AIDS with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition depressive disorder entered the 8-week trial and were randomized to testosterone (up to 400 mg IM testosterone cypionate biweekly), fluoxetine (up to 60 mg/d), or double placebo. Outcome variables were the Clinical Global Impressions Scale for mood and for fatigue, the Hamilton Rating Scale for Depression, and the Chalder Fatigue Scale. RESULTS: Ninety men completed the trial. In intention-to-treat analyses, mood response rates were 54%, 47%, and 44% for fluoxetine, testosterone, and placebo, respectively. Among completers, mood response rates were 70%, 57%, and 53%, respectively; in neither analysis were differences between treatments statistically significant. In contrast, testosterone was superior to fluoxetine and placebo for completers regarding fatigue. In intention-to-treat analysis, response rates were 39%, 56%, and 42% for fluoxetine, testosterone, and placebo, respectively, and for study completers, 41%, 63%, and 52%, respectively, (P < 0.05), CONCLUSION: While over 50% of patients treated with testosterone reported improved mood, this rate was not statistically superior to placebo. Thus, our findings do not support prescription of testosterone as a first-line treatment for depressive disorders in HIV-positive men. However, if validated in additional studies, testosterone may be a useful option for medically ill men experiencing significant fatigue as well as depression.