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.

Metabolic and hormonal effects of oral DHEA in premenopausal women with HIV infection: a randomized, prospective, placebo-controlled pilot study.

Women with HIV infection use dehydroepiandrosterone (DHEA) because of its potential effects on mood and energy. We examined the effects of DHEA on the hypothalamic-pituitary-adrenal and gonadal axes and on insulin sensitivity. Fifteen HIV-positive women were randomized to receive placebo (6 subjects) or oral DHEA (9 subjects). ACTH-, CRF-, and GnRH-stimulation tests were performed before and after 8 weeks of treatment. DHEA, DHEA-S, dihydrotestosterone, total testosterone, free testosterone, sex hormone-binding globulin, estrone, estradiol, cortisol, insulin, IGF-1, IGFBP-1, IGFBP-3, and adiponectin in plasma or serum were measured. There was a significant increase in DHEA (p<0.004), DHEA-S (p<0.008), total testosterone (p<0.008), dihydrotestosterone (p<0.004), androstenedione (p<0.04), and estrone (p<0.03) from baseline within the DHEA group but not within the placebo group. There was a significant increase in DHEA (p<0.0006), DHEA-S (p<0.032), total testosterone (p<0.01), and dihydrotestosterone (p<0.005) in the DHEA group compared with the placebo group. Oral DHEA produces significant increases in circulating DHEA, DHEA-S, testosterone, DHT, and, possibly, androstenedione and estrone levels in premenopausal women with HIV infection. In the current pilot study these hormone changes did not affect the pituitary or adrenal axis or insulin/IGF indices. Long-term studies with larger groups of patients are needed to confirm these data and to determine their clinical significance.

Outcomes of antifungal prophylaxis in high-risk liver transplant recipients.

Antifungal prophylaxis for liver transplant recipients (LTRs) is common among patients considered at high risk of infection, but optimal prophylaxis duration and drug has not been defined. This study aimed to assess the effects of 14 days of antifungal therapy prophylaxis in reducing proven invasive fungal infections (IFI) in high-risk subjects. Eligible subjects who met 2 or more risk criteria were randomized 1:1 to the treatment arms (liposomal amphotericin B or fluconazole) and were followed for 100 days post transplantation for evidence of IFI. The study was designed to enroll 300 subjects, but was closed early for insufficient enrollment. A total of 71 subjects were enrolled and randomized. Two-thirds of subjects completed 14 days of study therapy. Ten subjects developed proven or probable IFI with Candida species (9 subjects) and Cryptococcus neoformans (1 subject); rates were similar in the 2 treatment arms. Eleven subjects died, but no death was attributed to study drug or IFI. In summary, high-risk LTRs tolerated antifungal prophylaxis well, and rates of IFI were lower than previously reported in untreated high-risk LTRs.

A 'second life' agenda. Psychiatric research issues raised by protease inhibitor treatments for people with the human immunodeficiency virus or the acquired immunodeficiency syndrome.

Seldom in the history of medicine has an entire generation of patients with an incurable, progressive, and ultimately fatal disease suddenly been offered the prospect of extended survival and even, perhaps, a "second life." The relatively simultaneous appearance of 2 major treatment developments has created profound changes in therapeutic options and outlook. The first development is an assay of serum levels of human immunodeficiency virus viral copies, providing a critical tool for clinical decision making. The second is the marketing between December 1995 and April 1997 of 4 human immunodeficiency virus protease inhibitors that, combined with previously available antiviral medications, achieve a new level of efficacy. With the advent of these changes come multiple psychiatric research and policy issues. These include the development of strategies to establish and maintain medication adherence. This is a critical task, given the complexity of combination therapy regimens and the rapid onset of viral resistance to protease inhibitors within days to weeks of missed or suboptimal dosing. The psychological issues to be studied include the process of restructuring lives and expectations in the event of clinical benefit or managing the distress associated with clinical failure. Other research questions include the effects of restored health on the appraisal of human immunodeficiency virus risk behaviors, assessment of effect of neurocognitive functioning, and unanswered questions about psychotropic or protease inhibitor drug interactions due to their shared metabolic pathways. Behavioral scientists can inform provision of care to patients who may be considered difficult to treat, such as those with severe and persistent mental illness or active substance abuse or the homeless. This includes the provision of empirical data regarding individual and situational characteristics that are likely to promote or impede adherence, as well as innovative provision systems. Psychiatry can make notable contributions during this turning point in human immunodeficiency virus therapeutics and research.

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.

Duration of antidepressant drug treatment. What is an adequate trial?

Data from three six-week placebo-controlled randomized antidepressant trials were pooled to test the hypothesis that a four-week trial is insufficient to reach a determination of drug failure in depressed patients. We compared global clinical ratings at weekly intervals for patients receiving drug and patients receiving placebo and calculated the proportion of patients whose clinical status changed over time. We predicted, and found, that a significant proportion of patients who showed no clear-cut response at four weeks would show much improvement at six weeks in drug but not placebo conditions. Baseline Research Diagnostic Criteria diagnosis, baseline illness severity, and drug dose adjustments after four weeks did not predict either late clinical improvement or relapse between four and six weeks. Additional placebo-controlled studies are needed to replicate our findings concerning the advantage of extending trials to five or six weeks in samples of patients of various depressive subtypes.

Identification of true drug response to antidepressants. Use of pattern analysis.

The purpose of this study was to develop a method for differentiating specific ("true") and nonspecific antidepressant drug response for the individual patient. Patterns of clinical response, based on weekly global ratings of clinical status, were generated for each of 185 patients participating in six-week placebo-controlled drug trials. We hypothesized and found that substantially more patients receiving active than placebo medication displayed treatment response patterns characterized both by two-week or greater delay in onset of initial improvement and nonfluctuating persistence of improvement once achieved. Identification of a distinctive pattern of clinical response to an active drug has both research and clinical applications. Pattern analysis may contribute to understanding the nature of drug mechanisms of action, may clarify some ambiguous treatment study outcomes, and in the individual case, may facilitate clinical management.

Use of pattern analysis to identify true drug response. A replication.

In any antidepressant study, placebo response in patients assigned active drug is a troubling source of variance. There have been few attempts to identify the patients whose conditions improve as a result of true drug effect, in contrast with improvement that is a result of nonspecific effects. In a previous report we demonstrated that true drug effect seemed to be characterized by a two-week delay in onset and persistence. We described a method of pattern analysis to identify such patients. In this report, we describe the use of pattern analysis to replicate our initial findings. Data from a new sample of 150 nonmelancholic patients support the hypothesis that true drug effect is characterized by a two-week delay in onset and persistence of improvement, once achieved. There was little evidence of the onset of antidepressant effect before two weeks. The theoretical and clinical implications of this work are discussed.

Depression, distress, lymphocyte subsets, and human immunodeficiency virus symptoms on two occasions in HIV-positive homosexual men.

We evaluated the extent to which depressive disorders, psychiatric distress, and psychosocial stressors are related to three measures of human immunodeficiency virus (HIV) illness, both cross-sectionally and during a 6-month period, in a community sample of 124 HIV-positive homosexual men. The dependent variables are immune status measured by CD4 and CD8 cell subsets, number of signs and symptoms commonly associated with HIV infection, and a cumulative index of HIV illness stage. We chose to focus on CD4 cell count because it is the immune marker most closely linked to the clinical consequences of HIV infection. We found no relationships between the independent variables and immune status or illness stage. The HIV-positive men who were depressed or distressed or who reported more life stressors had no greater immunosuppression or more advanced illness stage than did the others, either concurrently or across occasions. We did find a suggestive pattern of association between depressive disorders, distress, and stressors and the number of HIV-related symptoms, which warrants further study.

Multidisciplinary baseline assessment of homosexual men with and without human immunodeficiency virus infection. II. Standardized clinical assessment of current and lifetime psychopathology.

Despite numerous reports of the psychiatric consequences of human immunodeficiency virus infection, few reports describe systematic diagnostic assessments of people with human immunodeficiency virus infection. We studied the results of standardized clinical assessments of current and lifetime psychopathology in a large group of homosexual men whose serologic status was known. Results indicated low rates of current mental disorders but very high rates of lifetime major depression and alcohol and other psychoactive substance abuse and dependence disorders. Measures of severity of psychopathology and functioning also indicated, on the whole, good current functioning. No significant relationship was found between stage of medical illness or immune status and any measure of psychiatric disturbance.

Treatment outcome validation of DSM-III depressive subtypes. Clinical usefulness in outpatients with mild to moderate depression.

An algorithm for transcribing Research Diagnostic Criteria diagnoses for depressive disorders to similar categories in the DSM-III was applied to 103 depressed outpatients previously diagnosed by Research Diagnostic Criteria. All had Hamilton Depression Rating Scale scores of 18 or less. Among 64 patients completing a six-week, double-blind study comparing desipramine hydrochloride with placebo, desipramine was significantly more effective than placebo in patients with DSM-III major depression but not in those with dysthymic disorder. Among patients with major depression, a significant drug-placebo response difference was demonstrated even in those without melancholia. These findings support the clinical usefulness of the DSM-III in the treatment of depressed outpatients. Independent of DSM-III diagnosis, however, evidence of panic attacks seemed to identify patients who benefited from desipramine therapy. This suggests that the DSM-III hierarchy, which excludes consideration of panic in patients with major depression, may require revision.

Phenelzine and imipramine in mood reactive depressives. Further delineation of the syndrome of atypical depression.

Sixty patients who met Research Diagnostic Criteria for major, intermittent, or minor depressive disorder and had reactive mood without atypical symptoms were treated with imipramine hydrochloride, phenelzine sulfate, or a placebo. These patients, referred to as simple mood reactive depressives, were contrasted with previously published data from 180 atypical depressives. Atypical depressives had the presence of at least one vegetative atypical sign (hypersomnia, hyperphagia, leaden feeling, or rejection sensitivity) but were otherwise indistinguishable from simple mood reactive depressives. In contrast to the atypical depressives for whom phenelzine was effective and imipramine was relatively ineffective, both medications were equivalently good in simple mood reactive depressives. Since all groups did poorly when given a placebo and well when given phenelzine, the salient feature of atypical symptoms may be that they predict poor response to imipramine. Since the difference between imipramine and placebo depends on the diagnostic group, pharmacologic dissection suggests that atypical symptoms in patients with nonautonomous mood may delineate a qualitatively distinct subgroup.

Phenelzine v imipramine in atypical depression. A preliminary report.

Sixty patients meeting specific criteria for atypical depression completed six weeks of double-blind, randomly assigned treatment with phenelzine sulfate, imipramine hydrochloride, or placebo. The overall response rates were 67% with phenelzine, 43% with imipramine, and 29% with placebo. At week 6, phenelzine was superior to placebo on many measures, while the superiority of imipramine to placebo was confined to several variables. Phenelzine was superior to imipramine on the interpersonal sensitivity and paranoia factors of the 90-item Hopkins Symptom Checklist, with trends toward superiority on several other measures, while imipramine was not differentially superior on any measure. Atypical depressive patients with a history of spontaneous panic attacks and hysteroid dysphoric patients both showed extremely low rates of response to placebo and high rates of response to phenelzine. Conversely, those without panic or hysteroid dysphoric features responded equally to all three treatments. Responders to pheneizine also had greater platelet monoamine oxidase inhibition while receiving drug therapy than did nonresponders. Completion of the 120-patient sample will allow more detailed analyses.

Personality disorders predict onset of Axis I disorders and impaired functioning among homosexual men with and at risk of HIV infection.

BACKGROUND: A longitudinal study was conducted to investigate whether personality disorders (PDs) increase risk for the development of future Axis I disorders and serious functional impairment among human immunodeficiency virus (HIV)-seropositive and HIV-seronegative homosexual men. METHOD: Baseline assessments of PDs, Axis I disorders and symptoms, and Global Assessments of Functioning were conducted with a community sample of 107 (66 HIV-positive and 41 HIV-negative) homosexual men participating in a longitudinal study with semiannual interviews over 3 years. RESULTS: Logistic regression analysis indicated that PDs predicted onset of subsequent Axis I disorders after controlling for both HIV status and lifetime Axis I history (adjusted odds ratio, 4.31; P=.01; 95% confidence interval, 1.39 to 13.32). Of the 21 participants with PDs, 16 (76%) were subsequently diagnosed with Axis I disorders on at least one occasion. By contrast, only 36 (42%) of the 86 participants without PDs were subsequently diagnosed with Axis I disorders. Further, 33% of the participants with PDs, in comparison with only 8% of those without PDs, were assigned Global Assessments of Functioning scores of 50 or lower, indicating serious impairment during the postbaseline study period (adjusted odds ratio, 5.70; P<.005; 95% confidence interval, 1.66 to 19.53). CONCLUSION: Personality disorders may contribute to increased risk for onset of Axis I disorders and serious impairment among homosexual men regardless of HIV serologic status.

Multidisciplinary baseline assessment of homosexual men with and without human immunodeficiency virus infection. I. Overview of study design.

Although much is known about the virus believed by most experts to be the cause of the acquired immunodeficiency syndrome and about its pathogenic actions, major areas of ignorance remain. Among these are the reasons for the varying time between infection with human immunodeficiency virus and development of acquired immunodeficiency syndrome, the relationship between neurologic and medical aspects of the disease, the time course of neuropsychological findings, and the prevalence of psychiatric morbidity. We assessed 124 homosexual men who were positive for human immunodeficiency virus and 84 who were negative for the virus. In this article we describe the study design, method of recruitment, and medical and demographic characteristics of the cohort, which will be followed up for 5 years.

l-Deprenyl in atypical depressives.

We investigated the antidepressant efficacy of l-deprenyl (selegiline), a selective monoamine oxidase B inhibitor (MAOI), in a six-week open trial of 17 patients with atypical depression. Such patients have previously been shown to benefit from nonselective MAOIs such as phenelzine sulfate. Ten patients (59%) responded to l-deprenyl, but nine required dosages above the 10 to 20 mg/day used in previous investigations. l-Deprenyl was superior to six weeks of placebo administered to diagnostically similar patients in a separate double-blind study. In contrast with previous findings with pheneizine, responders to l-deprenyl differed from nonresponders by having lower baseline anxiety ratings. Even at high dosages, there appeared to be fewer side effects with l-deprenyl than with nonselective MAOIs.

Response to phenelzine and imipramine in placebo nonresponders with atypical depression. A new application of the crossover design.

We employed a study design that permitted a double-blind 12-week contrast of imipramine hydrochloride and phenelzine sulfate therapies in patients who met Columbia University criteria for atypical depression and were unresponsive to 7 weeks of treatment with placebo. These patients were found to benefit selectively from therapy with monoamine oxidase inhibitors compared with tricyclic drug therapy. This supports our observation about treatment response in depressed patients with reversed vegetative features. The design we utilized in this study has not previously been reported, to our knowledge. It was hypothesized that it would offer the advantage of the removal of a portion of placebo responders and serve to replicate our original findings. Treatment response to therapy with both imipramine and pheneizine in placebo nonresponders was uniformly lower (roughly 20% less than corresponding rates for patients who did not participate in the initial 6-week placebo trial). This is consistent with the view that the lower response rates were a result of the removal of some "placebo" responders in the drug groups. We think this is a useful design that should be considered in all studies of placebo and two active treatment regimens.

Antidepressant specificity in atypical depression.

One hundred nineteen patients who met specific criteria for atypical depression completed six weeks of double-blind, randomly assigned treatment with phenelzine sulfate, imipramine hydrochloride, or placebo. The overall response rates were 71% with phenelzine, 50% with imipramine, and 28% with placebo. Phenelzine was widely superior to placebo and also showed superiority to imipramine. Phenelzine superiority appeared even greater after an additional six-week continuation phase. Imipramine was only moderately effective in this atypical depressive sample. Unexpectedly, the superiority of either phenelzine or imipramine to placebo was largely confined to patients in subsets of the study sample who were prospectively judged to also have a history of spontaneous panic attacks and/or show hysteroid dysphoric features. This is consonant with some but not other recent findings and requires replication. Overall, the concept of atypical depression as a subtype that is preferentially responsive to monoamine oxidase inhibitors is supported.

The tyramine challenge test as a marker for melancholia.

A previous study reported that unipolar depressives excrete significantly lower amounts of urinary tyramine-O-sulfate following oral administration of a tyramine hydrochloride load than do normal control subjects. This study replicates and extends those findings by showing that within the heterogeneous group of unipolar depressives, patients with melancholia and bipolar patients with a history of melancholia manifest a tyramine excretion deficit. A small subgroup of medication-free patients in remission from episodes of melancholia had abnormally low tyramine sulfate excretion levels while they were euthymic, supporting the suggestion that reduced tyramine sulfate excretion following oral tyramine loading is a trait marker for depression. Further study of the role of trace amines in affective illness is warranted. Clinical application is not warranted until further evaluation of the sensitivity, specificity, and reproducibility of this oral tyramine challenge test.

Atypical depression, panic attacks, and response to imipramine and phenelzine. A replication.

In an initial study with 120 patients with reactive mood and associated atypical symptoms, phenelzine sulfate was superior to imipramine hydrochloride and placebo. Since their response to phenelzine appears to be unique, this suggests that atypical depression may be a distinct subgroup of unipolar depressive illness. Unexpectedly, the benefit of antidepressants was limited to patients who also had spontaneous panic attacks. To help establish the validity of this syndrome, a new sample of 90 atypical depressives was studied. The clinical and demographic characteristics of the original and replication sample were virtually identical at baseline. In addition, the treatment response with either placebo, imipramine, or phenelzine was also indistinguishable in the two patient groups. The outcome in the replication study supports the hypothesis that this may be a distinct unipolar depressive subgroup. In the replication sample, a history of panic attacks did not appear to be a relevant predictor. We discuss the explanations for this discrepancy in the two patient samples.