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Biomedical subjects

A F Schatzberg

Publications and source records attributed to A F Schatzberg.

At least 19 recordsLinked to original sources
PubMed2005

Nocturnal sleep apnea/hypopnea is associated with lower memory performance in APOE epsilon4 carriers.

The authors investigated the relationship between obstructive sleep apnea/hypopnea (OSAH) and cognition in 36 older adults, 18 APOE epsilon4 carriers, and 18 non-carriers. Greater numbers of respiratory events negatively impacted memory function in epsilon4 carriers only. This is the first study to provide preliminary evidence for a negative interaction of APOE epsilon4 and OSAH on memory in older adults, which may have important implications for treating cognitive decline and delaying dementia onset.

Aged↗
PubMed2003

Functional brain imaging of olfactory processing in monkeys.

As a step toward bridging the gap between human and animal studies of olfactory brain systems, we report results from an fMRI study of olfaction in squirrel monkeys. High-resolution fMRI images at 3 T with 1.25 x 1.25 x 1.2 mm(3) voxels were obtained covering the whole brain using an 8-cm-diameter birdcage coil and a gradient-echo spiral pulse sequence. Data were acquired from six sedated adult males using a standard block design. All fMRI data were spatially normalized to a common template and analyzed at the individual and group levels with statistical parametric and nonparametric methods. Robust odorant-induced activations were detected in several brain regions previously implicated in conscious human olfactory processing, including the orbitofrontal cortex, cerebellum, and piriform cortex. Consistent with human data, no stimulus intensity effects were observed in any of these regions. Average signal changes in these regions exceeded 0.6%, more than three times the expected signal change based on human fMRI studies of olfaction adjusting for differences in voxel size. These results demonstrate the feasibility of studying olfaction in sedated monkeys with imaging techniques commonly used at 3 T in humans and help promote direct comparisons between humans and nonhuman primates. Our findings, for example, provide novel support for the hypothesis that the cerebellum is involved in sensory acquisition. More broadly, this study suggests that olfactory processing in sedated monkeys and nonsedated humans shares similar neural substrates both within and beyond the primary olfactory system.

Animals↗
PubMed2001

Early life stress and inherited variation in monkey hippocampal volumes.

BACKGROUND: Opportunities for research on the causes and consequences of stress-related hippocampal atrophy are limited in human psychiatric disorders. Therefore, this longitudinal study investigated early life stress and inherited variation in monkey hippocampal volumes. METHODS: Paternal half-siblings raised apart from one another by different mothers in the absence of fathers were randomized to 1 of 3 postnatal conditions that disrupted diverse aspects of early maternal care (n = 13 monkeys per condition). These conditions were previously shown to produce differences in social behavior, emotional reactivity, and neuroendocrine stress physiology. Hippocampal volumes were subsequently determined in adulthood by high-resolution magnetic resonance imaging. RESULTS: Adult hippocampal volumes did not differ with respect to the stressful postnatal conditions. Based on paternal half-sibling effects, the estimated proportion of genetic variance, ie, heritability, was 54% for hippocampal size. Paternal half-siblings with small adult hippocampal volumes responded to the removal of all mothers after weaning with initially larger relative increases in cortisol levels. Plasma cortisol levels 3 and 7 days later, and measures of cortisol-negative feedback in adulthood were not, however, correlated with hippocampal size. CONCLUSIONS: In humans with mood and anxiety disorders, small hippocampal volumes have been taken as evidence that excessive stress levels of cortisol induce hippocampal volume loss. Results from this study of monkeys suggest that small hippocampi also reflect an inherited characteristic of the brain. Genetically informed clinical studies should assess whether inherited variation in hippocampal morphology contributes to excessive stress levels of cortisol through diminished neuroendocrine regulation.

Animals↗
PubMed2001

Sertraline versus imipramine to prevent relapse in chronic depression.

BACKGROUND: Chronic depressions are common, disabling and under-treated, and long-term treatment is little studied. We report the continuation phase results from a long-term treatment study. METHODS: After 12 weeks of acute phase treatment in a double-blind, randomized, parallel-group, multi-center trial of sertraline or imipramine, patients with chronic depression (> or = 2 years in major depression, or major depression superimposed on dysthymia) continued study drug for 16 weeks. Initially, 635 patients were randomized to sertraline or imipramine in a 2:1 ratio. Nonresponders after 12 weeks entered a 12-week double-blind crossover trial of the alternate medication. Entry into continuation treatment required at least a satisfactory response (partial remission) to initial or crossover treatment. RESULTS: Of 239 acute or crossover responders to sertraline, 60% entered continuation in full remission and 40% with a partial remission. These proportions were identical for imipramine patients (n = 147). For both drug groups, over two-thirds of those entering in full remission retained it. For those entering in partial remission, over 40% achieved full remission. Patients requiring crossover treatment were less likely to maintain or improve their response during continuation treatment. The two drugs did not differ significantly in response distribution, drop out rates or discontinuation due to side effects during continuation treatment. LIMITATIONS: The absence of a placebo group constrains interpretation of our results, but chronic depressions have low placebo response rates. CONCLUSIONS: Most chronic depression patients who remit with 12 weeks of sertraline or imipramine treatment maintain remission during 16 weeks of continuation treatment. Most patients with a satisfactory therapeutic response (partial remission) after 12 weeks of treatment maintain it or further improve. Patients treated with imipramine experienced more side effects, but both drugs were well tolerated.

Adult↗
PubMed2001

Rapid reversal of psychotic depression using mifepristone.

The rationale for treating psychotic major depression with glucocorticoid receptor (GR) antagonists is reviewed. Five patients with psychotic major depression were given 600 mg of mifepristone in a 4-day, double-blind, placebo-controlled crossover study. All the patients completed the protocol and adverse effects were not observed or reported. All of the five patients showed substantial improvements in their Hamilton Rating Scale for Depression scores while they were receiving mifepristone, and four of the five patients showed substantial improvement in their Brief Psychiatric Rating Scale scores. Little, if any, improvement was seen with placebo. These preliminary results suggest that short-term use of GR antagonists may be effective in the treatment of psychotic major depression and that additional study, perhaps using higher doses or more treatment days, seems warranted.

Adolescent↗
PubMed2001

Cortisol activity and cognitive changes in psychotic major depression.

OBJECTIVE: The theory that psychotic major depression is a distinct syndrome is supported by reports of statistically significant differences between psychotic and nonpsychotic major depression in presenting features, biological measures, familial transmission, course and outcome, and response to treatment. This study examined differences in performance on a verbal memory test and in cortisol levels between patients with psychotic and nonpsychotic major depression and healthy volunteers. METHOD: Ten patients with psychotic major depression, 17 patients with nonpsychotic major depression, and 10 healthy volunteers were administered the Wallach Memory Recognition Test and had blood drawn at half-hour intervals over the course of an afternoon to assay cortisol levels. RESULTS: Subjects with psychotic major depression had a higher rate of errors of commission on the verbal memory test (incorrectly identified distracters as targets) than did subjects with nonpsychotic major depression or healthy volunteers; errors of omission were similar among the three groups. Subjects with psychotic major depression had higher cortisol levels throughout the afternoon than subjects with nonpsychotic major depression or healthy volunteers. This effect became even more pronounced later in the afternoon. CONCLUSIONS: Psychotic major depression is endocrinologically different from nonpsychotic major depression and produces cognitive changes distinct from those seen in nonpsychotic major depression.

Adult↗
PubMed2001

Cortisol feedback during the HPA quiescent period in patients with major depression.

OBJECTIVE: The authors tested the hypothesis that patients with major depression have a defect in the mechanism by which cortisol exerts negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis during the HPA axis quiescent period. METHOD: Twenty-nine patients with major depression and 25 healthy comparison subjects were randomly assigned to administration of 15 mg cortisol or placebo infused over 2 hours beginning at 7:00 p.m. Cortisol and ACTH levels were measured at baseline and every 30 minutes from 7:30 p.m. to 11:00 p.m. RESULTS: Differences between the patients and the comparison subjects in the ACTH response to the cortisol infusion, relative to the ACTH response to placebo, were not found. CONCLUSIONS: The results provide some evidence that patients with major depression do not have an abnormality of cortisol feedback during the HPA axis quiescent period.

Adrenocorticotropic Hormone↗
PubMed2000

Stress-level cortisol treatment impairs inhibitory control of behavior in monkeys.

Most studies of cortisol-induced cognitive impairments have focused on hippocampal-dependent memory. This study investigates a different aspect of cognition in a randomized placebo-controlled experiment with monkeys that were treated with cortisol according to a protocol that simulates a prolonged stress response. Young adult and older adult monkeys were assigned randomly to placebo or chronic treatment with cortisol in a 2 x 2 factorial design (n = 8 monkeys per condition). Inhibitory control of behavior was assessed with a test shown previously in primates to reflect prefrontal cortical dysfunction. Failure to inhibit a specific goal-directed response was evident more often in older adults. Treatment with cortisol increased this propensity in both older and young adult monkeys. Age-related differences in response inhibition were consistent across blocks of repeated test trials, but the treatment effects were clearly expressed only after prolonged exposure to cortisol. Aspects of performance that did not require inhibition were not altered by age or treatment with cortisol, which concurs with effects on response inhibition rather than nonspecific changes in behavior. These findings lend support to related reports that cortisol-induced disruptions in prefrontal dopamine neurotransmission may contribute to deficits in response inhibition and play a role in cognitive impairments associated with endogenous hypercortisolism in humans.

Adrenocortical Hyperfunction↗
PubMed2000

Use of placebo control groups in evaluating efficacy of treatment of unipolar major depression.

Double-blind, random-assignment placebo-controlled trials are routinely used in evaluating efficacy of potential antidepressant agents. In recent years concern has risen that placebo response rates in unipolar depression are too high, and this has eroded confidence in both old and new agents. At the same time, the use of placebos has been questioned by patients and their advocates. We review factors that have been commonly explored as associated with placebo response (e.g., length of episode, severity, subtype), as well as issues in methodology (e.g., interrater reliability, statistical artifacts). We discuss possible methods of dealing with the problem of placebo response, emphasizing reconceptualizing effect sizes to design more powerful single trials and a systematic sequence of trials to achieve the right answers.

Antidepressive Agents↗
PubMed2000

24-Hour monitoring of cortisol and corticotropin secretion in psychotic and nonpsychotic major depression.

BACKGROUND: Considerable research has been devoted to the hypothalamic-pituitary-adrenal (HPA) axis in depression, but relatively little attention has been given to intensive monitoring of hormone secretion over time. Such research is potentially important because the HPA axis has prominent circadian and ultradian periodicity. Comparison of depressed patients with and without psychotic features is also important because HPA axis abnormalities may be especially pronounced in psychotic depressed patients. METHODS: Eleven patients with psychotic major depression (PMD patients), 38 patients with nonpsychotic major depression (NPMD patients), and 33 healthy control subjects, all drug free, were studied. Patients with PMD and NPMD were outpatients recruited primarily by advertisement. Subjects were admitted to a General Clinical Research Center and had blood drawn through an intravenous line for determination of cortisol and corticotropin (ACTH) levels every hour for 24 hours. RESULTS: Among NPMD patients, the 24-hour cortisol amplitude was significantly (P =.02) reduced in comparison with control subjects, while ACTH indices did not differ between NPMD patients and the control group. Among PMD patients, the ACTH 24-hour mean was significantly (P =.03) increased compared with controls, while PMD patients and the control group did not differ significantly in cortisol indices. CONCLUSION: In the population studied, PMD and NPMD patients have distinct profiles of HPA axis dysregulation.

Adrenocorticotropic Hormone↗
PubMed2000

Pharmacotherapy of depression and mixed states in bipolar disorder.

The treatment of bipolar depression requires the resolution of depression and the establishment of mood stability. A basic problem is that the treatments used in treating bipolar depression were developed and proven effective for other disease states: antidepressants for unipolar depression, and mood stabilizers for mania. The panel addressed four unresolved questions regarding depression in relation to bipolar disorder: (1) the relative effectiveness of different antidepressant treatments; (2) the relative likelihood of mood destabilization with different antidepressant treatments; (3) the effectiveness and role of mood-stabilizing medicines as antidepressants; and (4) the optimal approach to mixed states. The selection of an antidepressant depends both on its relative lack of mania- or hypomania-provoking potential and on its effectiveness against bipolar depression. There is little definitive evidence distinguishing effectiveness of the major groups of antidepressive agents, so side-effect profiles and pharmacokinetics are major considerations. The underlying bipolar disorder should be treated with mood stabilizers started simultaneously with any antidepressive treatments. Lithium, divalproex sodium and carbamazepine have all been found to be helpful, to some extent, in treating bipolar depressive episodes as well as for long-term mood stabilization. There is little evidence for long-term benefits of antidepressive agents in bipolar disorder, and some evidence that they may destabilize the disorder. Therefore, in contrast to the long-term use of mood-stabilizers, antidepressant use is recommended on a temporary basis. The duration of antidepressant treatment is determined by past history in terms of liability for mood destabilization, and by the ability of the patient to tolerate gradual antidepressant discontinuation without return of depression. Mixed states, where symptoms of depression and mania coexist, are regarded as a predictor of relatively poor response to lithium, and divalproex has been found to be more effective. Carbamazepine may too be useful in mixed states. Most patients with mixed states in actual practice require combinations of mood stabilizers, though there is little controlled data regarding such co-prescription, especially from a long-term perspective.

Antidepressive Agents↗
PubMed2000

Gender differences in chronic major and double depression.

BACKGROUND: While the sex difference in prevalence rates of unipolar depression is well established, few studies have examined gender differences in clinical features of depression. Even less is known about gender differences in chronic forms of depression. METHODS: 235 male and 400 female outpatients with DSM-III-R chronic major depression or double depression (i.e., major depression superimposed on dysthymia) were administered an extensive battery of clinician-rated and self-report measures. RESULTS: Women were less likely to be married and had a younger age at onset and greater family history of affective disorder compared to men. Symptom profile was similar in men and women, with the exception of more sleep changes, psychomotor retardation and anxiety/somatization in women. Women reported greater severity of illness and were more likely to have received previous treatment for depression with medications and/or psychotherapy. Greater functional impairment was noted by women in the area of marital adjustment, while men showed more work impairment. LIMITATIONS: Since our population consisted of patients enrolling in a clinical trial, study exclusion criteria may have affected gender-related differences found. CONCLUSIONS: Chronicity of depression appears to affect women more seriously than men, as manifested by an earlier age of onset, greater family history of affective disorders, greater symptom reporting, poorer social adjustment and poorer quality of life. These findings represent the largest study to date of gender differences in a population with chronic depressive conditions.

Adult↗
PubMed2000

Impaired transactivation of the glucocorticoid receptor cloned from the Guyanese squirrel monkey.

Squirrel monkeys are among a diverse group of New World primates that demonstrate unusually high levels of circulating corticosteroids and glucocorticoid receptor (GR) insensitivity. Recent evidence suggests that overexpression of an immunophilin impairs dexamethasone binding to GR in the Bolivian squirrel monkey (Saimiri boliviensis). Here we describe the cloning, expression, and functional characterization of GR from the closely related Guyanese squirrel monkey (S. sciureus). The cloned Guyanese squirrel monkey GR (gsmGR) cDNA closely resembles human GR (hGR) cDNA, and yields a high affinity dexamethasone binding receptor when expressed in COS-1 cells. Transactivation analysis of hGR and gsmGR expressed in CV-1 cells and cultured squirrel monkey kidney (SMK) cells indicates that: (1) SMK cells elaborate a functional high activity GR from human GR cDNA; (2) gsmGR is an order of magnitude less efficient than hGR at transactivation in CV-1 and SMK cells; and (3) maximal transactivation by gsmGR is attenuated in both cell lines. Glucocorticoid resistance in S. sciureus is at least partly attributable to a naturally occurring mutation in the GR gene that results in impaired GR transactivation.

Animals↗
PubMed2000

Dilative cardiomyopathy leading to congestive heart failure in a male squirrel monkey (Saimiri sciureus).

A 17-year-old, 1-kg, colony-housed, male squirrel monkey (Samiri sciureus) developed clinical signs of congestive heart failure. The monkey presented with lethargy, increased heart and respiratory rates, and mild abdominal distention. The clinical history, laboratory analysis, and radiographic findings were consistent with heart failure due to dilative cardiomyopathy. Gross and microscopic examination of the heart confirmed a dilative cardiomyopathy. This is the first report describing congestive heart failure caused by dilative cardiomyopathy in a squirrel monkey. Spontaneous dilative cardiomyopathy may be infrequently observed in the squirrel monkeys because they are not routinely housed in the research environment during their advancing years.

Aging↗
PubMed2000

Early environmental regulation of glucocorticoid feedback sensitivity in young adult monkeys.

Variations in maternal care induce in neonatal rodents life-long changes in glucocorticoid feedback regulation of the hypothalamic-pituitary-adrenal axis. This aspect of plasticity in neuroendocrine development has not been established in primates. We assessed, in young adult squirrel monkeys, postnatal rearing effects on cortisol-induced suppression of corticotropin-releasing factor (CRF) stimulated secretion of adrenocorticotropic hormone (ACTH). Offspring of randomly bred monkeys were periodically removed from natal groups between 13 and 21 weeks of age. In two other postnatal rearing conditions, systematic differences in maternal availability were produced by manipulating the effort required of lactating mothers to successfully find food. All offspring were subsequently administered, 3-5 years later on two occasions, an intravenous ovine CRF injection preceded 60 min earlier by placebo or cortisol pretreatment. The difference between CRF-stimulated time-integrated secretion of ACTH following placebo vs cortisol pretreatment served as an index of glucocorticoid negative feedback. Difference scores were greatest in monkeys previously separated from natal groups. This finding was not attributable to significant rearing condition differences in plasma cortisol levels achieved following pretreatment with exogenous cortisol, nor plasma ACTH levels produced when the CRF injection was preceded by pretreatment with placebo. The results suggest that postnatal experiences altered glucocorticoid feedback in monkeys at least through early adulthood. This conclusion supports retrospective reports indicating that, for humans with major mood and anxiety disorders, systematic differences in glucocorticoid feedback may reflect neural mechanisms in development linking early life stress with psychopathology in adulthood.

Adaptation, Physiological↗
PubMed2000

Cognitive-behavioral group therapy for social phobia in female adolescents: results of a pilot study.

OBJECTIVES: To examine the efficacy of cognitive-behavioral group therapy for adolescents (CBGT-A) in females with social phobia and the effect of this treatment on the risk for major depression. METHOD: Female adolescents with social phobia (N = 35) were randomly assigned to treatment (n = 12) or no treatment (n = 23) groups. Assessments were conducted at baseline, after treatment, and at a 1-year follow-up. RESULTS: Eleven subjects completed treatment. Sixteen weeks of treatment produced a significant improvement in interference and reduction in symptoms of social anxiety. There was a significant reduction in the number of subjects meeting DSM-IV criteria for social phobia in the CBGT-A versus the untreated group; however, at the 1-year follow-up there were no significant differences by treatment condition. There was also suggestive evidence that treatment of social phobia lowers the risk for relapse of major depression among those with a history of major depression. Combining social phobia and major depression as the outcome produced more robust treatment effects in the 1-year follow-up. CONCLUSIONS: This pilot study provides evidence for a moderate short-term effect of CBGT-A for treating female adolescents suffering from social phobia and indicates that treatment of social phobia may result in a reduction of major depression.

Adolescent↗