Stephen J. Ferrando

Roles of the Akt/GSK-3 and Wnt Signaling Pathways in Schizophrenia and Antipsychotic Drug Action

Dopamine D(2) receptor antagonism is a unifying property of all antipsychotic drugs in clinical use. Remarkably, the effector molecules through which these medications exert their actions remain poorly characterized. Increasing attention is being focused on Akt/glycogen synthase kinase-3 (GSK-3) and wingless (Wnt) signaling pathways, which have been associated with schizophrenia in a number of genetic and postmortem studies. Antipsychotic medications may treat symptoms of psychosis, at least in part, through modulation of levels and activity of Akt, GSK-3, and Wnt-related intracellular signaling. The authors review evidence that Akt/GSK-3 and Wnt-related pathways are involved in the pathogenesis of schizophrenia as well as details of intracellular events related to these molecules mediated by both typical and atypical antipsychotic medications. Further study of Akt/GSK-3 and Wnt signaling may ultimately lead to alternative therapeutics of schizophrenia-related disorders.

Highly active antiretroviral treatment in Hiv infection: benefits for neuropsychological function

Objectives:To determine whether highly active antiretroviral therapy (HAART) is associated with reduced HIV-associated neuropsychological impairment. Design:Cross-sectional analysis in a natural history study of adaptation to HIV/AIDS. Method:A sample of 130 homo-/bisexual men with HIV/AIDS (mean age, 41 years; 42% non-white) were evaluated with a neuropsychological battery assessing attention, concentration, psychomotor speed, learning, memory and executive function. Subjects taking HAART were compared with those not taking HAART on demographics, CD4 cell count, viral load, scores on individual neuropsychological tests and proportion with neuropsychological impairment. Results:Sixty-nine (53%) subjects were taking HAART, and 48 (37%) were neuropsychologically impaired. Subjects taking HAART had lower mean CD4 cell counts than those not taking HAART (254 versus 342 × 106/l; P < 0.05), although they were more likely to have undetectable viral load (42 versus 20%; P < 0.01) and were less likely to be neuropsychologically impaired (22 versus 54%; P < 0.0001). Subjects taking HAART performed significantly better on tests of attention, concentration, learning, memory, and psychomotor speed. After excluding subjects with potential non-HIV confounders of neuropsychological function, those without neuropsychological impairment had significantly lower mean viral load levels and were more likely to have undetectable viral load than those with impairment. Conclusion:These preliminary findings suggest that HAART benefits neuropsychological function through the reduction of viral load.

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.

Fatigue in Hiv Illness: Relationship to Depression, Physical Limitations, and Disability

Objective This study was conducted to investigate the prevalence of clinical fatigue reported by gay/bisexual men at all HIV illness stages, and whether fatigue, while associated with depression, independently contributes to limitations in physical function and disability. Method HIV- men, HIV+ men with CD4 counts >500, HIV+ men with CD4 counts 200 to 500, and men with AIDS were compared on prevalence of clinical fatigue, as defined by a standardized instrument. Among HIV+ men, the relationships among fatigue, depressed mood, major depressive disorder, HIV illness markers (including CD4 count and HIV RNA viral load), physical limitations, and disability were assessed at baseline and after 1 year. Results The prevalence of clinical fatigue in men with CD4 counts <500 was 14%, significantly higher than HIV- men and HIV+ men with CD4 counts >500. However, fatigue was not directly correlated with CD4 count or HIV RNA. Fatigue was a chronic symptom that was associated with depressed mood, major depressive disorder, physical limitations, and disability. After 1 year, an increase in depressive symptoms predicted a small amount of variance in fatigue; however, depressive symptoms were not associated with physical limitations or disability after controlling for fatigue. Conclusion Fatigue is a chronic symptom that is more prevalent in advanced HIV illness, and which, although associated with depression, does not seem to be merely a symptom of depression. Because fatigue contributes independently to physical limitations and disability, it should be assessed and treated.

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.

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 Marins 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.

Psychiatric Morbidity, Illicit Drug Use and Adherence to Zidovudine (AZT) Among Injection Drug Users with HIV Disease

This study describes the relationship between the need for psychiatric consultation, illicit drug use, and zidovudine (AZT) adherence in HIV-infected injection drug users (IDUs) in methadone maintenance treatment (MMT). The treatment records of 57 IDUs in MMT who had been prescribed AZT between May and August of 1991 were reviewed. Those who required psychiatric consultation (P+, N = 46, 81%) were compared with those who did not require psychiatric consultation (P-, N = 11, 19%) on adherence to AZT treatment (using the mean corpuscular volume [MCV] as a biological marker), on recent illicit drug use, and on CD4 lymphocyte (T cell) count changes from the beginning to the end of AZT treatment. The P+ subjects were less likely than P- subjects to adhere to AZT treatment: fewer in the P+ group had an MCV outside of the normal range, and P+ subjects had a lower average monthly increase in MCV since the beginning of AZT treatment. Recent illicit drug use and CD4 lymphocyte count changes from the beginning to the end of AZT treatment did not show group differences. Psychiatric morbidity among HIV-infected IDUs in MMT is common, and may contribute to poor adherence to AZT treatment. Psychiatric screening and adherence-enhancing interventions should be targeted to IDUs entering drug treatment programs.

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.

The relationship between employment and neuropsychological impairment in HIV infection.

The relationship between neurocognitive impairment and employment in a cohort of 130 predominantly symptomatic individuals with HIV-1 infection was examined. Participants were classified as employed (full or part-time for pay) or unemployed (N = 64) and administered a neuropsychological test battery. When covarying for CD4 count, age, and physical limitations, the results revealed that unemployed men performed below that of employed participants on tasks of memory, set shifting-cognitive flexibility, and psychomotor speed. The results are discussed within the context of similar findings in other illnesses.

Treatment of depression in HIV positive individuals: A critical review

The primary goal of this paper is to provide a critical review of the literature on treatment of depression in HIV/AIDS. There is a substantial research literature documenting the efficacy of conventional antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), novel agents such as dehydroepiandrosterone, psychostimulants and some psychotherapies, particularly interpersonal and group psychotherapy for the treatment of depression in HIV. However, lack of comparative studies makes it difficult to draw a firm consensus regarding the best course of treatment. In devising a treatment plan, clinicians should take into account stage of HIV illness, co-morbid illnesses such as Hepatitis B and C, the potential for drug interactions with antiretroviral and other medications used to treat HIV and patient preference.