Modafinil and armodafinil treatment for fatigue for HIV-positive patients with and without chronic hepatitis C.

Fatigue is prevalent among patients with hepatitis C virus (HCV) and with HIV/AIDS but there are no established fatigue treatments for either condition or their combination. We analysed data from three trials of modafinil or armodafinil for HIV-positive patients with fatigue, including 36 co-infected with HCV, to compare treatment response and safety parameters related to HCV status. One hundred and twenty patients received active drug and 70 were randomized to placebo. Fatigue response rate to modafinil/armodafinil was 100% for patients with HCV (18/18) and 73% (74/102) for patients without HCV. Placebo response rate was 28% (5/18) and 29% (15/52), respectively. Depressive symptoms improved only when energy improved. Viral load declined from baseline after 12 and 26 weeks of active medication. CD4 cell count did not change, nor did alanine transaminase and aspartate aminotransferase for patients with HCV. Patients with haematocrit below the reference range responded, as well as patients whose values were within the reference range. Modafinil and armodafinil appear effective and well tolerated for treating fatigue among both HCV-positive and HCV-negative patients with HIV/AIDS, suggesting that they may hold promise for HIV-positive patients considering alpha interferon/ribavirin treatment for HCV. Further investigation in a focused trial is warranted.

Prevalence of fatigue and depression in ALS patients and change over time.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) patients report both fatigue and depression. It is not clear how frequently each occurs, to what extent they occur together, how each relates to ALS disease status, or their stability over time. OBJECTIVE: To assess frequency and persistence of fatigue and depression, and relationship to ALS disease status, for patients attending an ALS interdisciplinary centre for routine 3-month visits. METHOD: Measures included the Fatigue Severity Scale, Patient Health Questionnaire-9. ALS Functional Rating Scale -- Revised and forced vital capacity, rate of disease progression, and bulbar/nonbulbar disease onset. RESULTS: 223 patients completed the ratings once; of these, 113 completed them twice, and 65 on three visits. At baseline, 44% (99/223) had clinically significant fatigue, including 34 patients who also had a depressive disorder; 7% (16/223) had major or minor depression only, and 48% (108/223) had neither condition. Fatigue was associated with greater ALS severity, but depression was not. Among the 113 patients seen 3 months later, 75% (33/44) who were fatigued at Time 1 remained fatigued, while 48% (10/21) remained depressed. New-onset fatigue was reported by 22% (25/113), and new-onset depression by 6% (7/113). For the 65 patients seen a third time, rates remained nearly the same. CONCLUSION: Fatigue was more prevalent and persistent than depression, although 15% (34/223) of patients had both conditions. Fatigue but not depression was associated with ALS severity. The two conditions appear to be independent, although sometimes co-occurring, and both warrant consideration in evaluating patient functioning and treatment.

Prevalence of depressive disorders and change over time in late-stage ALS.

OBJECTIVE: To determine the prevalence of depressive disorders and symptoms in patients with late-stage ALS, to identify possible risk and protective factors associated with depression, and to determine whether depression increases as death approaches. METHODS: Semistructured interviews were conducted monthly with hospice-eligible patients with ALS and caregivers until the study endpoints of death or tracheostomy. Standardized measures were administered to assess depressive disorders and symptoms, hopelessness, spiritual beliefs, attitudes toward hastened death, quality of life, and related constructs. RESULTS: Sixty-three percent of eligible patients were enrolled. Of the 80 participants, 17 were seen only once; the number of monthly assessments for the others ranged from 2 to 18. For the 53 patients who died, median interval between last assessment and death was 30 days. At study baseline, 81% had no depressive disorder, 10% had minor depression, and 9% had symptoms consistent with major depression. Diagnoses of depression were made on 16% of 369 monthly assessments. Fifty-seven percent of patients never had a depression diagnosis at any visit, and 8% were depressed at all visits. There was no trend toward increasing depression as death approached. Presumed protective factors including spiritual beliefs, spouse as care partner, financial situation, depression in caregiver, and hospice participation did not distinguish between those who were depressed and those who were not. CONCLUSIONS: Results of multiple measures of depression and distress converged to indicate that major depression in people with late-stage ALS is rare, although transient depressive symptoms may occur, and depression does not generally increase as death approaches.

Wish to die in end-stage ALS.

BACKGROUND: In retrospective studies, estimates of hastened dying among seriously ill patients range from <2% in one national survey to as much as 20% in end-stage disease cohorts. OBJECTIVE: To examine, in prospective studies, dying patients in the months before death, in order to understand the wish to die. METHODS: Patients with advanced ALS with a high likelihood of death or need for tracheostomy within 6 months were identified. Patients were assessed monthly with an extensive psychosocial interview, including a diagnostic interview for depression. Family caregivers were interviewed on the same schedule and also after patient deaths. RESULTS: Eighty patients with ALS were enrolled, 63% of eligible patients; 53 died over follow-up. Ten (18.9%) of the 53 expressed the wish to die, and 3 (5.7%) hastened dying. Patients expressing the wish to die did not differ in sociodemographic features, ALS severity, or perceived burden of family caregivers. They were more likely to meet criteria for depression, but differences were smaller when suicidality was excluded from the depression interview. Patients who expressed the wish to die reported less optimism, less comfort in religion, and greater hopelessness. Compared with patients unable to act on the wish to die, patients who hastened dying reported reduction in suffering and increased perception of control over the disease in the final weeks of life. CONCLUSION: These findings suggest caution in concluding that the desire to hasten dying in end-stage disease is simply a feature of depression.

Disparities in perceptions of distress and burden in ALS patients and family caregivers.

OBJECTIVES: To examine agreement between end-stage ALS patients and their family caregivers on indicators of physical and psychological status at the end of life. METHODS: Patient-caregiver pairs completed monthly interviews in patient homes. Patients were asked to rate their current pain, energy, suffering, depression, control over ALS, optimism, interest in hastened death, weariness from ALS, will to live, and how burdened they thought caregivers were on Visual Analogue Scales. Caregivers completed identical ratings of patients as well as a measure of their own burden. Both independently completed the ALS Functional Rating Scale-Rev. (ALSFRS-R), a measure of patient disability and physical function. RESULTS: A total of 69 patient-caregiver pairs participated. For measures of physical function, kappa ranged from 0.49 to 0.83, indicating moderate to excellent agreement. Patient and caregiver composite ALSFRS-R scores were highly correlated (r = 0.92, p < 0.001). Agreement between patients and caregivers was high for ratings of patient pain, control over ALS, optimism, and will to live, and this level of agreement remained high over multiple assessments. In pairwise analyses, caregivers rated patients as having less energy, greater suffering, and greater weariness than patients indicated for themselves, whereas patients rated caregivers as more burdened than caregivers reported for themselves. CONCLUSIONS: Caregivers can accurately report information about a patient's physical function at the end of life. However, patients and caregivers each overestimated the psychosocial impact of the disease on the other.

A female perspective on living with HIV disease.

The study discussed in this article explored women's views of the positive and negative aspects of life with HIV. Even in the face of a stigmatizing physical illness and with elevated levels of depression and anxiety, the 55 women interviewed for the study were able to identify a large number of positive events; for many, HIV served as a motivating force for positive change. Common negative experiences included physical symptoms, a limited life span, alienation, and stigma. Results suggest that whereas women demonstrate a remarkable capacity to adapt, there are a number of specific areas where social services and community interventions can be targeted.

Hopelessness as a mediator of the association between social support and depressive symptoms: findings of a study of men with HIV.

Data from a prospective longitudinal study were used to investigate whether hopelessness mediates the association between social support and depression, as hypothesized by L. Y. Abramson, G. I. Metalsky, and L. B. Alloy (1989). Measures of hopelessness, social support, and depression were administered to 103 HIV-infected men and readministered 6 months later. Findings indicated that low baseline social support predicted increases in hopelessness and depression. Increases in hopelessness predicted increases in depression after controlling for baseline social support. Low baseline social support did not predict increased depression when hopelessness was controlled statistically.

Health locus of control, distress, and utilization of protease inhibitors among HIV-positive men.

OBJECTIVE: To investigate the relationship between health locus of control (HLOC), distress, and protease inhibitor (PI) utilization in gay/bisexual men in all stages of HIV illness. METHOD: A total of 173 men participating in a longitudinal study of the psychological effects of HIV illness were administered a number of psychological distress measures and the HLOC scale. The association between the HLOC subscales, distress, and PI utilization was evaluated. RESULTS: In addition to physical symptoms, the attribution of health status to chance or fate significantly predicted depressive symptoms, feelings of hopelessness, and recent life stress. Results also demonstrated a significant relationship between strong, positive beliefs in doctors and other health care professionals and PI utilization. CONCLUSION: The results of this study point to a strong association between beliefs that health status is related to chance or fate and distress. In addition, beliefs in physicians and other health care providers appear to contribute to decisions to initiate PI therapy.

Measuring medication adherence: are missed doses reported more accurately then perfect adherence?

Self-reports overestimate adherence compared to more objective measures such as electronic monitoring. However, self-report is the most feasible method for clinical settings; therefore, it is important to identify the context in which this method can provide an accurate assessment. To address whether self-reports are more accurate when missed doses are reported, we conducted a secondary analysis of data from a methodological study comparing multiple measures of adherence (including self-report and electronic monitoring) to a two-week placebo regimen mimicking HAART among 30 HIV-positive patients not on HAART. Results indicated a mean adherence of 85% and 62%, as measured by self-report and electronic monitoring, respectively. Self-report and electronic monitoring were not significantly correlated in the measurement of proportion of prescribed doses taken among the sub-group of 17 patients who reported missed doses (r = 0.22), nor among those who reported no missed doses, or the group as a whole. Using electronic monitoring as the validity criterion, these findings indicate that self-reports overestimate adherence even among patients who report missed doses.

Relationships among apathy, depression, and cognitive impairment in HIV/AIDS.

This study was designed to determine whether apathy is associated with neurocognitive symptoms and/or depressive symptoms in HIV/AIDS and also whether apathy is associated with patient expectancies about antiretroviral medication adherence. Seventy-five HIV+ homosexual men and 58 HIV+ women were assessed for depressive disorders and symptoms. Neuropsychological tests measured attention, concentration, learning, memory, executive function, and psychomotor speed. Other measures included Marin's Apathy Evaluation Scale, the Adherence Determinants Questionnaire, CD4 cell count, and HIV RNA viral load. Apathy was consistently related to depression and unrelated to neuropsychological impairment. Patient expectancies regarding medication adherence were unrelated to apathy when the analysis was controlled for depressive symptoms.

Psychological and physical health correlates of body cell mass depletion among HIV+ men.

OBJECTIVE: To assess whether significant body cell mass depletion related to HIV is associated with declines in physical health and psychological well-being. METHODS: As part of a 2-year prospective HIV study, semiannual assessments included measures of body composition, psychological status, and physical health. RESULTS: As measured by bioelectric impedance analysis, 58 (31%) of 187 enrolled HIV+ men had significant body cell mass depletion at some point during the study, of who 23 subsequently lost at least an additional 5% of body cell mass in the 6 months between any two consecutive study visits. This additional body cell mass depletion was associated with significant increase in fatigue, global distress and depressive symptomatology, and reduced life satisfaction. CONCLUSION: These data illuminate the importance of monitoring body weight and body cell mass, and the need for awareness of the association between malnutrition, mental health, and quality of life.

Anxiety syndromes and symptoms among men with AIDS: a longitudinal controlled study.

This 2-year longitudinal study assessed prevalence of Axis I anxiety disorders and anxiety symptoms and their relationship to manifestations of HIV illness in a sample of nonintravenous drug users. The sample included 173 homosexual men with HIV or AIDS (HIV+/AIDS) and 84 homosexual men negative for HIV or AIDS (HIV-). Data were compared with national prevalence rates to provide a framework for interpretation. No significant differences were observed. However, compared with the general population, both HIV+/AIDS and HIV- men reported more anxiety symptoms and stress. For the HIV+/AIDS group there was a positive relationship between anxiety and HIV symptoms, fatigue, and physical limitations. No changes in rates or levels of anxiety were observed in those whose immunologic markers improved or worsened over the 2 years.

Psychological effects of HAART: a 2-year study.

OBJECTIVE: The objectives of this study were to evaluate the psychological consequences of combination antiretroviral treatment in terms of mood, hope, and life satisfaction in men with symptomatic human immunodeficiency virus (HIV) infection or acquired immune deficiency syndrome and to compare those whose health improved with those whose health did not improve. METHODS: One hundred seventy-three HIV+ gay or bisexual men with symptomatic HIV illness (40% nonwhite) were evaluated semiannually in a university-affiliated research program between July 1995 and December 1997. The primary outcome measures were the Structured Clinical Interview for DSM-IV, Beck Depression Inventory, Endicott Quality of Life Enjoyment and Satisfaction Questionnaire, and Beck Hopelessness Scale. RESULTS: Psychological distress in this sample was mild to moderate at baseline. During the first 2 years that highly active antiretroviral therapy became widely available, we observed a statistically significant but clinically modest reduction in distress in the sample as a whole, with significant covariates of CD4 cell count, HIV symptoms, and social support in a mixed-effects model. Rates of clinical depression declined. However, this generalized mental health improvement was not related to individual medical improvement of markers of HIV illness progression; those classified as improved were no more likely than those who remained unimproved to report greater declines in measures of distress and hopelessness. Number of self-reported physical symptoms were directly related to distress levels. CONCLUSIONS: A cohort effect was observed, with overall psychological improvement. Physical symptoms were more strongly related to psychological distress than were laboratory markers. Consequently, those whose CD4 cell count and HIV RNA viral load reflected successful treatment were no more likely than others to be relieved of the psychological burdens of illness.

Resilience and distress among amyotrophic lateral sclerosis patients and caregivers.

OBJECTIVES: The objectives of this study were to assess the prevalence of depressive disorders and symptoms and their correlates in patients with amyotrophic lateral sclerosis (ALS) and caregiver spouses and to identify dimensions of resilience as well as distress. METHODS: Fifty-six patients with ALS and 31 caregivers were interviewed on one occasion, and 20 patients were subsequently reinterviewed during a scheduled medical visit at an ALS center. Major measures included the Structured Clinical Interview for DSM-IV, the Beck Depression Inventory, the Schedule of Attitudes Toward Hastened Death, quality of life, spirituality, and degree of hopelessness. The ALS Functional Rating Scale, spirometry measures of forced vital capacity, and the Karnofsky Performance Index were used to assess physical status. RESULTS: Neither patients nor caregivers displayed significant psychopathology with respect to either current depressive disorders or scores on symptom scales. Depressive symptoms and psychological distress were not related to time since diagnosis, degree of disability, or illness progression during the period of observation. More interest in hastened death was associated with greater distress, but willingness to consider assisted suicide was not. Among caregivers, perceived caregiver burden was significantly associated with finding positive meaning in caregiving. Concordance between patient and caregiver distress was high, suggesting that attention to the mental health needs of caregivers may alleviate the patient's distress as well. CONCLUSIONS: Clinical depression or significant depressive symptomatology is not an inevitable or common outcome of life-threatening illness, even in the presence of major disability.

Difficulties in interpersonal relationships associated with personality disorders and axis I disorders: a community-based longitudinal investigation.

A longitudinal study was conducted to investigate the association between Axis I and Axis II psychiatric disorders, interpersonal relationships, and global functioning among men in the community. Structured clinical interviews assessing Axis I and Axis II psychiatric disorders, global assessments of functioning, and questionnaires assessing social support, social conflict, and loneliness were administered to a community sample of 95 HIV+ and 45 HIV- men. The questionnaires were readministered 1 year later. Results indicated that (a) Personality disorders (PDs) and unipolar depressive disorders were associated with loneliness, social conflict, and low levels of social support after HIV status was controlled statistically; (b) PDs were associated with interpersonal and global impairment after HIV status and co-occurring Axis I disorders were controlled statistically; (c) Axis I disorders were associated with global impairment, but were not associated with interpersonal difficulties after HIV status and PDs were controlled statistically; (d) PDs, but not Axis I disorders, predicted increases in social conflict and global impairment after HIV status was controlled statistically; (e) PDs continued to predict increases in global impairment after both Axis I disorders and HIV status were controlled statistically; and (f) HIV+ men reported more loneliness, less social support, and had a higher prevalence of substance use disorders than HIV- men. The present findings are of particular interest because they suggest that PDs are associated with loneliness, social conflict, and a lack of social support among men in the community, whether or not Axis I disorders are present.

Validity of clinical trials of antidepressants.

OBJECTIVE: Recent reports have criticized the design of antidepressant studies and have questioned their validity. These critics have concluded that antidepressants are no better than placebo treatment and that their illusory superiority depends on methodologically flawed studies and biased clinical evaluations. It has been suggested that the blind in randomized trials is penetrable-since clinician's guesses exceed chance-and that only active placebo can appropriately camouflage the difference between drug and placebo response. Furthermore, evidence has been cited to suggest that psychotherapy is as effective as antidepressants in both the acute and maintenance treatment of depression. These positions are often accepted as valid and have been broadly discussed in both the lay press and scientific literature. The purpose of this review is to reassess the cited data that support these assertions. METHOD: The authors examined the specific studies that were cited in these reports, evaluated their methodology, and conducted aggregate analyses. RESULTS: Analyses of the original sources failed to substantiate 1) that standard antidepressants are no more effective than placebo, 2) that active placebo offers an advantage over inactive placebo, or 3) that substantial evidence of a medication bias is suggested by raters' treatment guesses exceeding chance. The authors also note that some researchers have suggested that the interpretation of psychotherapy trials can be complicated by "allegiance effects." CONCLUSIONS: The issue of bias or allegiance effects for both antidepressant and psychotherapy research is real. Investigators of all orientations must guard against potential bias. However, studies cited as supporting the questionable validity of antidepressant trials fail upon closer examination to support assertions that these trials are invalid.

A double-blind, placebo-controlled trial of testosterone therapy for HIV-positive men with hypogonadal symptoms.

BACKGROUND: The goal was to evaluate the efficacy of testosterone in alleviation of hypogonadal symptoms (diminished libido, depressed mood, low energy, and depleted muscle mass) in men with symptomatic human immunodeficiency virus illness. METHODS: Seventy-four patients were enrolled in a double-blind, placebo-controlled 6-week trial with bi-weekly testosterone injections, followed by 12 weeks of open-label maintenance treatment. Major outcome measures were Clinical Global Impressions Scale ratings for libido, mood, energy, and erectile function; Hamilton Depression Rating Scale scores, and Chalder Fatigue Scale scores. Body composition changes were assessed with bioelectric impedance analysis. RESULTS: Seventy men completed the 6-week trial. Response rates, defined as much or very much improved libido, were 74% (28/38) for patients randomized to testosterone, and 19% (6/32) for placebo-treated patients (P<.001). Of the 62 completers with fatigue at baseline, 59% (20/34) receiving testosterone and 25% (7/28) receiving placebo reported improved energy (P<.01). Among the 26 completers with an Axis I depressive disorder at baseline, 58% of the testosterone-treated patients reported improved mood compared with 14% of placebo-treated patients (Fisher exact test = .08). With testosterone treatment, average increase in muscle mass over 12 weeks was 1.6 kg for the whole group, and 2.2 kg for the 14 men with wasting at baseline. Improvement on all parameters was maintained during subsequent open-label treatment for up to 18 weeks. CONCLUSION: Testosterone is well tolerated and effective in the short-term treatment of symptoms of clinical hypogonadism in men with symptomatic human immunodeficiency virus illness, restoring libido and energy, alleviating depressed mood, and increasing muscle mass.

DHEA treatment for HIV+ patients: effects on mood, androgenic and anabolic parameters.

The goal of this pilot study was to evaluate the effect of dehydroepiandrosterone (DHEA) on depressed mood and fatigue in HIV+ men and women, unselected for baseline DHEA level. Secondary questions concerned treatment effects on libido and body cell mass, on serum testosterone levels, and elicitation of short-term side effects. Treatment consisted of an open-label 8-week trial using DHEA doses from 200 to 500 mg/day. Mood responders were maintained for another 4 weeks, then randomized to a double blind placebo controlled 4-week discontinuation trial. Forty-five patients, including six women, entered the trial. Of 32 week 8 completers, mood was much improved in 72%, and 81% were rated responders with respect to fatigue. Response on either parameter was unrelated to baseline serum DHEA level. Twenty-one patients entered the double blind discontinuation phase. No differences in relapse rate between placebo and DHEA groups were observed for either mood or fatigue. Body cell mass increased significantly by week 8, and this improvement was maintained throughout the double blind phase for patients in both treatment conditions. Libido increased significantly as well. DHEA therapy did not have an effect on CD4 cell count or on serum testosterone levels in men. In conclusion, DHEA may be a promising treatment for HIV+ patients with depressed mood and fatigue, although persistence of response even in placebo-treated patients during the discontinuation phase leaves unresolved questions. A parallel group double blind clinical trial is indicated as the next step to more clearly identify therapeutic efficacy.