Relationship of birth cohort and early age at onset of illness in a bipolar disorder case registry

OBJECTIVE: Utilizing data from a previously characterized registry of subjects with bipolar illness, the authors examined age at onset of the first illness episode in cohorts of subjects born from 1900 through 1939 and from 1940 through 1959. METHOD: Demographic and clinical characteristics at the first full episode of bipolar disorder of subjects in a diagnostically validated voluntary bipolar disorder registry (N=1,218) were reviewed and subjected to statistical analyses. RESULTS: The median age at onset of the first episode of bipolar illness was lower by 4.5 years in subjects born during or after 1940 (median age=19 years), compared with subjects born before 1940 (median age=23.5 years). The proportion of subjects with bipolar disorder presenting with a prepubertal onset was significantly higher in the later birth-year cohort than in the earlier birth-year cohort. More than 50% of male and female subjects in both cohorts had a depressive episode as the first episode of bipolar illness. Subjects in each cohort who had a parent with major depression, bipolar disorder, or schizophrenia experienced their first episode nearly 4 to 5 years earlier than the other subjects in the cohort. CONCLUSIONS: Prospective epidemiological studies conducted with bipolar disorder subjects are needed to either affirm or refute these data on age at illness onset. If the results are affirmed, the early recognition of prepubertal bipolar disorder will be important, so that the condition can be treated with appropriate medications and medications that could potentially worsen the illness course can be avoided. Similarly, early recognition of bipolar illness is important, especially in women, to minimize use of antidepressant monotherapy for patients with bipolar illness. Among young people presenting with major depression as the first illness episode, a parental history of major depression, bipolar disorder, or psychosis may be a useful pointer to future bipolar disorder. Early recognition and appropriate treatment of bipolar illness may prevent the development of chronicity and serious functional impairment.     

Occurrence and course of suicidality during short-term treatment of late-life depression

BACKGROUND: Elderly persons (> or =65 years) have the highest rate of suicide; still, little is known about the occurrence, course, and responsivity of suicidal ideation during treatment of depression in late life and how suicidality affects treatment response. METHODS: This study was undertaken to determine (1) how suicidal ideation changes during short-term depression treatment and (2) whether treatment response differs among 3 groups of patients based on their levels of suicidality at baseline and during treatment (those with a recent suicide attempt or current suicidal ideation [high-risk group; n = 46], those with recurrent thoughts of death [moderate-risk group; n = 143], or those with no suicide attempt, suicidal ideation, or thoughts of death [low-risk group; n = 206]). This is a secondary analysis of pooled data from 3 treatment studies of late-life major depression. Participants were 395 elderly persons with a current major depressive episode, treated as inpatients or outpatients under protocolized conditions with paroxetine hydrochloride or nortriptyline hydrochloride, with or without interpersonal psychotherapy. Changes in suicidal ideation over time, rate of responses, and time to response in each group were compared. RESULTS: Suicidal ideation decreased rapidly early in the course of treatment, with more gradual change thereafter. At the beginning of treatment, 77.5% of the patients reported suicidal ideation, thoughts of death, or feelings that life is empty. After 12 weeks of treatment, suicidal ideation had resolved in all treated patients; 4.6% still reported thoughts of death. However, 6-week (P =.001) and 12-week (P =.02) rates of response were significantly lower in high-risk patients than in low- and moderate-risk patients. High- and moderate-risk patients needed a significantly (P<.001) longer time to respond than low-risk patients (median time to response, 6 and 5 vs 3 weeks). CONCLUSIONS: While suicidal ideation resolves rapidly, the resolution of thoughts about death is more gradual. Suicidal elderly persons with depression require special attention during depression treatment because they have a lower response rate and need a longer time to respond.     

Decreased working memory and processing speed mediate cognitive impairment in geriatric depression

BACKGROUND: While neuropsychological dysfunction is common in geriatric depression, not all aspects of cognition are equally affected. It has been suggested that depressed patients are impaired only in tasks that make heavy demands on processing resources and that a resource decrement therefore underlies the neuropsychological decrements seen in geriatric depression. The present study examined whether processing resources in the form of working memory and information processing speed are decreased in depression and whether a decrease in these resources actually mediates neuropsychological impairment. METHODS: Measures of processing resources were administered to elderly depressed patients prior to treatment and to age-matched controls. Patients whose depression remitted were retested as were the controls. Subjects also received neuropsychological tests of episodic memory and visuospatial performance. RESULTS: Depressed patients performed significantly worse on measures of both processing speed and working memory. While performance on these measures improved in patients whose depression remitted, the amount of improvement was no greater than that seen in the controls with repeat testing. Hierarchical regression analyses showed that depression explained a significant amount of variance on the neuropsychological tasks. However, if the variance associated with processing resources was removed first, depression no longer accounted for a significant amount of neuropsychological variance. CONCLUSIONS: Processing resources are decreased in elderly depressed patients and this decrease in resources appears to mediate impairments in several areas of neuropsychological functioning including episodic memory and visuospatial performance. The resource decrement persists after remission of the depression and thus may be a trait marker of geriatric depression.     

Sensitivity of Escherichia coli (MutT) and human (MTH1) 8-oxo-dGTPases to in vitro inhibition by the carcinogenic metals, nickel(II), copper(II), cobalt(II) and cadmium(II)

The toxicity of Ni(II), Co(II) and Cu(II) in animals, and that of Cd(II) in cultured cells, has been associated with generation of the promutagenic lesion 8-oxo-7,8-dihydroguanine (8-oxoguanine) in DNA, among other effects. One possible source of this base may be 8-oxo-7,8- dihydro-2'-deoxyguanosine-5'-triphosphate (8-oxo-dGTP), a product of oxidative damage to the nucleotide pool, from which it is incorporated into DNA. To promote such incorporation, the metals would have to inhibit specific cellular 8-oxo-dGTPases that eliminate 8-oxo-dGTP from the nucleotide pool. The present study was designed to test such inhibition in vitro on 8-oxo-dGTPases from two different species, the human MTH1 protein and Escherichia coli MutT protein. In the presence of Mg(II), the natural activator of 8-oxo-dGTPases, all four metals were found to inhibit both enzymes. For MTH1, the IC50 values (+/- SE; n = 3-4) were 17 +/- 2 microM for Cu(II), 30 +/- 8 microM for Cd(II), 376 +/- 71 microM for Co(II) and 801 +/- 97 microM for Ni(II). For MutT, they were 60 +/- 6 microM for Cd(II), 102 +/- 8 microM for Cu(II), 1461 +/- 96 microM for Ni(II) and 8788 +/- 1003 microM for Co(II). Thus, Cu(II) and Cd(II) emerged as much stronger inhibitors than Ni(II) and Co(II), and MTH1 appeared to be generally more sensitive to metal inhibition than MutT. Interestingly, in the absence of Mg(II), the activity of the enzymes could be restored by Co(II) to 73% of that with Mg(II) alone for MutT, and 34% for MTH1, the other metals being much less or non-effective. The difference in sensitivity to metal inhibition between the two enzymes may reflect the differences in the amino acid ligands, especially the cysteine ligand, outside their evolutionarily conserved Mg(II)-binding active sites, which might indicate predominantly non-competitive or uncompetitive mechanism of the inhibition. The overall results suggest that inhibition of 8-oxo- dGTPases may be involved in the mechanisms of induction of the 8- oxoguanine lesion in DNA by the metal ions studied, especially the non- redox-active Cd(II) cation.      

Localized muscular mucormycosis in a child with acute leukemia

Mucormycosis is a rare fungal infection of childhood, occurring mainly in patients with chronic illnesses such as diabetes and malignancies. The fungus seldom grows in culture and confirmation of the diagnosis depends on histologic examination of infected tissues. To date, the reported natural history of the disease has been rapid progression and a fatal outcome. Therefore, the importance of early diagnosis by tissue biopsy and early treatment with surgical debridement and systemic antifungal therapy cannot be overemphasized. The pulmonary system is the most common site for mucormycosis in patients with leukemia. We report what we believe to be the first successfully treated case of isolated muscular mucormycosis occurring in a child with biphenotypic acute leukemia. The diagnosis was made promptly by tissue examination at the time of surgical debridement. The patient was also given systemic amphotericin-B therapy.      

Reliable discrimination of elderly depressed and demented patients by electroencephalographic sleep data

Using electroencephalographic sleep data from a sample of 235 elderly subjects, discriminant function analyses of sleep alterations in depression and dementia were performed. Overall, 80% of patients were correctly classified using a backward discriminant function analysis, and 81% with a general stepwise discriminant function analysis. Four measures contributed to the separation of depressed and demented patients: rapid eye movement (REM) sleep latency (lower in depressives); REM sleep percent (higher in depressives); indeterminate non-REM sleep percent (higher in demented patients, reflecting greater loss of spindles and K complexes); and early morning awakening (more marked in depressives). When both discriminant functions were subjected to cross-validation in independent subsamples, both procedures correctly identified 78% of patients. The classification functions derived from nondemented depressed and nondepressed demented patients were applied to a mixed-symptom group (n = 42). Overall, 27 patients (64%) with either depressive pseudodementia or dementia with depressive features were correctly classified using the same four predictor variables. These findings suggest that sleep physiological alterations of depression and dementia reflect between-group differences in sleep continuity, sleep architecture, and REM sleep temporal distribution, and that the differences are statistically reliable, in both diagnostically pure and mixed clinical presentations. These findings are discussed in the context of current hypotheses of sleep regulation and its mechanisms.