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Biomedical subjects

David J Kupfer

Publications and source records attributed to David J Kupfer.

At least 19 recordsLinked to original sources
PubMed2007

Diurnal variation in regional brain glucose metabolism in depression.

BACKGROUND: This study compared diurnal variation in mood and regional cerebral metabolic rate of glucose (rCMRglc) in depressed and healthy subjects. METHODS: Depressed and healthy subjects were investigated using [18F]-fluoro-deoxyglucose positron emission tomography scans during morning and evening wakefulness. All subjects completed subjective mood ratings at both times of day. Statistical parametric mapping was used to compare rCMRglc between the two groups across time of day. RESULTS: Depressed patients showed evening mood improvements compared with healthy subjects. Compared with healthy subjects, depressed patients showed smaller increases in rCMRglc during evening relative to morning wakefulness in lingual and fusiform cortices, midbrain reticular formation, and locus coeruleus and greater increases in rCMRglc in parietal and temporal cortices. Depressed patients had hypermetabolism in limbic-paralimbic regions and hypometabolism in frontal and parietal cortex at both times of day compared with healthy subjects. CONCLUSIONS: Variation in rCMRglc differs across times of day in depressed and healthy subjects. In depressed patients, evening mood improvements were associated with increased metabolic activity in ventral limbic-paralimbic, parietal, temporal, and frontal regions and in the cerebellum. This increased metabolic pattern during evening wakefulness may reflect partial normalization of primary and compensatory neural systems involved in affect production and regulation.

Adult↗
PubMed2006

Report by the ACNP Task Force on response and remission in major depressive disorder.

This report summarizes recommendations from the ACNP Task Force on the conceptualization of remission and its implications for defining recovery, relapse, recurrence, and response for clinical investigators and practicing clinicians. Given the strong implications of remission for better function and a better prognosis, remission is a valid, clinically relevant end point for both practitioners and investigators. Not all depressed patients, however, will reach remission. Response is a less desirable primary outcome in trials because it depends highly on the initial (often single) baseline measure of symptom severity. It is recommended that remission be ascribed after 3 consecutive weeks during which minimal symptom status (absence of both sadness and reduced interest/pleasure along with the presence of fewer than three of the remaining seven DSM-IV-TR diagnostic criterion symptoms) is maintained. Once achieved, remission can only be lost if followed by a relapse. Recovery is ascribed after at least 4 months following the onset of remission, during which a relapse has not occurred. Recovery, once achieved, can only be lost if followed by a recurrence. Day-to-day functioning and quality of life are important secondary end points, but they were not included in the proposed definitions of response, remission, recovery, relapse, or recurrence. These recommendations suggest that symptom ratings that measure all nine criterion symptom domains to define a major depressive episode are preferred as they provide a more certain ascertainment of remission. These recommendations were based largely on logic, the need for internal consistency, and clinical experience owing to the lack of empirical evidence to test these concepts. Research to evaluate these recommendations empirically is needed.

Clinical Trials as Topic↗
PubMed2006

Maintenance treatment of major depression in old age.

BACKGROUND: Elderly patients with major depression, including those having a first episode, are at high risk for recurrence of depression, disability, and death. METHODS: We tested the efficacy of maintenance paroxetine and monthly interpersonal psychotherapy in patients 70 years of age or older who had depression (55 percent of whom were having a first episode) in a 2-by-2, randomized, double-blind, placebo-controlled trial. Among patients with a response to treatment with paroxetine and psychotherapy, 116 were randomly assigned to one of four maintenance-treatment programs (either paroxetine or placebo combined with either monthly psychotherapy or clinical-management sessions) for two years or until the recurrence of major depression. Clinical-management sessions, conducted by the same nurses, social workers, and psychologists who provided psychotherapy, involved discussion of symptoms. RESULTS: Major depression recurred within two years in 35 percent of the patients receiving paroxetine and psychotherapy, 37 percent of those receiving paroxetine and clinical-management sessions, 68 percent of those receiving placebo and psychotherapy, and 58 percent of those receiving placebo and clinical-management sessions (P=0.02). After adjustment for the effect of psychotherapy, the relative risk of recurrence among those receiving placebo was 2.4 times (95 percent confidence interval, 1.4 to 4.2) that among those receiving paroxetine. The number of patients needed to be treated with paroxetine to prevent one recurrence was 4 (95 percent confidence interval, 2.3 to 10.9). Patients with fewer and less severe coexisting medical conditions (such as hypertension or cardiac disease) received greater benefit from paroxetine (P=0.03 for the interaction between treatment with paroxetine and baseline severity of medical illness). CONCLUSIONS: Patients 70 years of age or older with major depression who had a response to initial treatment with paroxetine and psychotherapy were less likely to have recurrent depression if they received two years of maintenance therapy with paroxetine. Monthly maintenance psychotherapy did not prevent recurrent depression. (ClinicalTrials.gov number, NCT00178100.).

Aged↗
PubMed2006

Smaller cingulate volumes in unipolar depressed patients.

BACKGROUND: The anterior cingulate cortex is a key structure in brain networks involved in mood regulation. Abnormalities in this brain region are possibly implicated in the pathophysiology of depression. This anatomical magnetic resonance imaging (MRI) study compared cingulate cortex volumes in unipolar depressed patients and age- and gender-matched healthy control subjects. METHODS: Thirty-one unmedicated DSM-IV unipolar patients (24 female, aged 39.2 +/- 11.9 years [mean +/- SD]) and 31 healthy control subjects (24 female, aged 36.7 +/- 10.7 years) were studied in a 1.5-T GE Signa magnet (General Electric Medical Systems, Milwaukee, Wisconsin). Cingulate volumes were compared by analysis of covariance with intracranial volume as the covariate. RESULTS: The unipolar patients had significantly smaller anterior and posterior cingulate volumes bilaterally compared with healthy control subjects. When patients were divided into currently depressed (n = 21) and remitted (n = 10) subgroups, currently depressed patients had significantly smaller anterior and posterior cingulate volumes bilaterally compared with healthy control subjects, whereas remitted patients had significantly smaller left anterior cingulate volumes compared with healthy individuals. CONCLUSIONS: Gray matter abnormalities in the cingulate cortex are implicated in the pathophysiology of unipolar depression. Smaller cingulate volumes in currently depressed patients support the hypothesis that cingulate cortex abnormalities are state dependent, whereas changes in left anterior cingulate might be trait related.

Adolescent↗
PubMed2006

Exploring risk factors for the emergence of children's mental health problems.

CONTEXT: Exploratory studies that generate testable models of how risk factors for childhood mental health problems work together over time are critical for developing effective prevention and treatment strategies. OBJECTIVE: To build models addressing the following 2 questions: (1) How early can we identify children at risk for mental health problems in third grade? (2) How do the risk factors work together over time? DESIGN AND PARTICIPANTS: We assessed a Wisconsin community sample 8 times, beginning during pregnancy. Three hundred seventy-nine families completed multi-informant reports (mothers, teachers, and children) of children's mental health symptoms in third grade. MAIN OUTCOME MEASURES: Symptom severity and directionality (externalizing vs internalizing). RESULTS: The hypothesis was generated that family socioeconomic status (SES) defined different pathways to symptom severity. In low/middle SES families, children were at risk if their mothers were distressed during the infancy period, which was then associated with more generalized maternal and child distress and dysregulation during the preschool period. In high SES families, the picture was more complex, beginning with parental histories of depression and family psychopathology, which then led to greater family stress in the infancy period and maternal and child distress and dysregulation during the preschool period. For all children, social and academic impairment during the school transition was an important mediator. Two pathways to later symptom directionality consisted of one beginning with child sex and the other with child temperament. CONCLUSIONS: Most risk factors predicted symptom severity and not directionality. The risk factors for internalizing and externalizing problems may be much the same, and the same preventive interventions might be effective for both classes of problems. Furthermore, at-risk children from high SES families might be identifiable as early as infancy, whereas those from lower SES families may be identifiable only as preschoolers.

Adult↗
PubMed2006

Early father involvement moderates biobehavioral susceptibility to mental health problems in middle childhood.

OBJECTIVE: To study how early father involvement and children's biobehavioral sensitivity to social contexts interactively predict mental health symptoms in middle childhood. METHOD: Fathers' involvement in infant care and maternal symptoms of depression were prospectively ascertained in a community-based study of child health and development in Madison and Milwaukee, WI. In a subsample of 120 children, behavioral, autonomic, and adrenocortical reactivity to standardized challenges were measured as indicators of biobehavioral sensitivity to social context during a 4-hour home assessment in 1998, when the children were 7 years of age. Mental health symptoms were evaluated at age 9 years using parent, child, and teacher reports. RESULTS: Early father involvement and children's biobehavioral sensitivity to context significantly and interactively predicted symptom severity. Among children experiencing low father involvement in infancy, behavioral, autonomic, and adrenocortical reactivity became risk factors for later mental health symptoms. The highest symptom severity scores were found for children with high autonomic reactivity that, as infants, had experienced low father involvement and mothers with symptoms of depression. CONCLUSIONS: Among children experiencing minimal paternal caretaking in infancy, heightened biobehavioral sensitivity to social contexts may be an important predisposing factor for the emergence of mental health symptoms in middle childhood. Such predispositions may be exacerbated by the presence of maternal depression.

Child↗
PubMed2006

Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report.

OBJECTIVE: This report describes the participants and compares the acute and longer-term treatment outcomes associated with each of four successive steps in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. METHOD: A broadly representative adult outpatient sample with nonpsychotic major depressive disorder received one (N=3,671) to four (N=123) successive acute treatment steps. Those not achieving remission with or unable to tolerate a treatment step were encouraged to move to the next step. Those with an acceptable benefit, preferably symptom remission, from any particular step could enter a 12-month naturalistic follow-up phase. A score of or=11 (HRSD(17)>or=14) defined relapse. RESULTS: The QIDS-SR(16) remission rates were 36.8%, 30.6%, 13.7%, and 13.0% for the first, second, third, and fourth acute treatment steps, respectively. The overall cumulative remission rate was 67%. Overall, those who required more treatment steps had higher relapse rates during the naturalistic follow-up phase. In addition, lower relapse rates were found among participants who were in remission at follow-up entry than for those who were not after the first three treatment steps. CONCLUSIONS: When more treatment steps are required, lower acute remission rates (especially in the third and fourth treatment steps) and higher relapse rates during the follow-up phase are to be expected. Studies to identify the best multistep treatment sequences for individual patients and the development of more broadly effective treatments are needed.

Adolescent↗
PubMed2006

Prevalence and clinical correlates of medical comorbidities in patients with bipolar I disorder: analysis of acute-phase data from a randomized controlled trial.

OBJECTIVE: We studied the relationship between number of medical comorbidities in patients with bipolar I disorder and their demographic and clinical characteristics. METHOD: Data were from 174 patients in the acute phase of the Pittsburgh Maintenance Therapies in Bipolar Disorder (MTBD) study, a randomized controlled trial comparing Interpersonal and Social Rhythm Therapy to an intensive clinical management approach for individuals with a lifetime diagnosis of bipolar I disorder or schizoaffective disorder, manic type, according to Research Diagnostic Criteria, who were receiving adjunctive protocol-driven pharmacotherapy. Patients entered the MTBD study from 1991 to 2000. We examined the acute-phase Hamilton Rating Scale for Depression (HAM-D) and Bech-Rafaelsen Mania Scale scores, demographics, clinical history, and medical comorbidities. RESULTS: Patients with a high number of medical comorbidities had longer duration of both lifetime depression (p = .02) and lifetime inpatient depression treatment (p = .04), had higher baseline HAM-D score (p = .01), and were more likely to be treated for a depressed clinical state during the acute phase of the MTBD study (p = .05). Moreover, higher severity of baseline medical comorbidities predicted slower decreases in HAM-D score among depressed (p = .004) and mixed/cycling (p = .003) patients even after controlling for baseline HAM-D score. CONCLUSIONS: Medical illness is correlated with several indicators of poorer prognosis and outcome in bipolar I disorder. Not only do preventing and treating medical comorbidities in bipolar patients decrease the morbidity and mortality related to physical illness, but they could also enhance psychological well-being and possibly improve the course of bipolar illness. Identification of characteristics in bipolar I patients that are correlated to increased risk for medical comorbidities is a fundamental step in understanding the nature of the relationship between bipolar disorder and medical illness.

Adult↗
PubMed2005

Size of treatment effects and their importance to clinical research and practice.

In randomized clinical trails (RCTs), effect sizes seen in earlier studies guide both the choice of the effect size that sets the appropriate threshold of clinical significance and the rationale to believe that the true effect size is above that threshold worth pursuing in an RCT. That threshold is used to determine the necessary sample size for the proposed RCT. Once the RCT is done, the data generated are used to estimate the true effect size and its confidence interval. Clinical significance is assessed by comparing the true effect size to the threshold effect size. In subsequent meta-analysis, this effect size is combined with others, ultimately to determine whether treatment (T) is clinically significantly better than control (C). Thus, effect sizes play an important role both in designing RCTs and in interpreting their results; but specifically which effect size? We review the principles of statistical significance, power, and meta-analysis, and commonly used effect sizes. The commonly used effect sizes are limited in conveying clinical significance. We recommend three equivalent effect sizes: number needed to treat, area under the receiver operating characteristic curve comparing T and C responses, and success rate difference, chosen specifically to convey clinical significance.

Area Under Curve↗
PubMed2005

Presenting characteristics of depressed outpatients as a function of recurrence: preliminary findings from the STAR*D clinical trial.

OBJECTIVES: Recurrent depression predicts risk for subsequent episodes, but it is unclear how it relates to demographic features, course of illness, and clinical presentation. METHODS: We report on the baseline data for the first 1500 patients enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study (www.star-d.org). Patients were required to have a DSM-IV diagnosis of nonpsychotic major depression and to score > or = 14 on the 17-item Hamilton rating scale for depression. Status with respect to recurrent depression and other aspects of illness course and demographic features were ascertained at intake, along with measures of depression and concurrent general medical illness. RESULTS: Patients with recurrent depression were older, had an earlier age of onset, and were more likely to have a positive family history of depression than first episode patients. However, recurrent patients were less likely to be chronic and reported shorter current episodes than first episode patients, something that was largely confined to females. Recurrent patients were more likely than first episode patients to report non-essential aspects of mood, cognition, and somatic symptoms, although largely as a consequence of greater overall depressive symptom severity. CONCLUSIONS: As compared to single episode depressions, recurrent depression was associated with greater symptom severity and illness characteristics suggestive of greater underlying risk, but not other demographic characteristics than age. Risk for recurrence appeared to be distinct from chronic depression. A subset of chronic first episode patients may lack the capacity to remit and may therefore be distinct from those with recurrent episodes.

Adolescent↗
PubMed2005

Structural brain changes in bipolar disorder using deformation field morphometry.

The objective of this study was to investigate anatomical brain abnormalities in adult bipolar patients using a deformation field morphometry technique. Our sample consisted of 32 right-handed bipolar I patients (men/women=16/16) and 32 right-handed, age and gender matched healthy controls. Deformation field morphometry analysis was performed on three-dimensional spoiled gradient recalled acquisition images. We found gender-specific structural differences between bipolar patients and healthy individuals. Bipolar men had significantly larger lateral ventricles (especially pronounced in the left hemisphere) and smaller left dorsolateral prefrontal cortex than healthy male controls. Our results are complementary to the findings of functional imaging and post-mortem studies that demonstrate abnormalities in the dorsolateral prefrontal cortex in bipolar patients.

Adolescent↗
PubMed2005

1H Magnetic resonance spectroscopy study of dorsolateral prefrontal cortex in unipolar mood disorder patients.

Neuroimaging and postmortem studies have suggested the involvement of the dorsolateral prefrontal cortex (DLPFC) in the pathophysioloy of unipolar disorder. We examined with in vivo 1H magnetic resonance spectroscopy (MRS) the levels of specific metabolites in the DLPFC of adult unipolar patients and the role of illness chronicity on DLPFC abnormalities. Nineteen unmedicated unipolar mood disorder patients and 19 age- and gender-matched healthy controls underwent a short echo-time 1H MRS examination localized to an 8-cm3 single voxel placed in the left DLPFC. There were no significant differences in metabolite levels, including N-acetylaspartate (NAA), phosphocreatine plus creatine (PCr+Cr) and choline-containing-compounds (GPC+PC), between the two groups. However, NAA/PCr+Cr ratios were significantly lower in the chronic than in the less chronically ill patients and healthy controls. The low levels of NAA/PCr+Cr ratios in the left DLPFC of unipolar patients who had been more chronically ill suggest a potential role for illness chronicity in neuronal abnormalities in the DLPFC in unipolar disorder. This could possibly be accounted for by neurodegenerative processes arising with the progression of the illness. Future 1H MRS investigations should longitudinally examine the role of illness chronicity on DLPFC abnormalities and their relationship with the symptoms of unipolar disorder.

Adult↗
PubMed2005

Alterations in regional cerebral glucose metabolism across waking and non-rapid eye movement sleep in depression.

BACKGROUND: Depression is associated with sleep disturbances, including alterations in non-rapid eye movement (NREM) sleep. Non-rapid eye movement sleep is associated with decreases in frontal, parietal, and temporal cortex metabolic activity compared with wakefulness. OBJECTIVE: To show that depressed patients would have less of a decrease than controls in frontal metabolism between waking and NREM sleep and to show that during NREM sleep, they would have increased activity in structures that promote arousal. DESIGN: Subjects completed electroencephalographic sleep and regional cerebral glucose metabolism assessments during both waking and NREM sleep using [(18)F]fluoro-2-deoxy-D-glucose positron emission tomography. SETTING: General clinical research center. PATIENTS: The study included 29 unmedicated patients who met the Structured Clinical Interview for DSM-IV criteria for current major depression and who had a score of 15 or greater on a 17-item Hamilton Rating Scale for Depression and 28 medically healthy subjects of comparable age and sex who were free of mental disorders. MAIN OUTCOME MEASURES: Electroencephalographic sleep and regional cerebral metabolism during waking and NREM sleep. RESULTS: Depressed patients showed smaller decreases than healthy subjects in relative metabolism in broad regions of the frontal, parietal, and temporal cortex from waking to NREM sleep. Depressed patients showed larger decreases than healthy subjects in relative metabolism in the left amygdala, anterior cingulate cortex, cerebellum, parahippocampal cortex, fusiform gyrus, and occipital cortex. However, in post hoc analyses, depressed patients showed hypermetabolism in these areas during both waking and NREM sleep. CONCLUSIONS: The smaller decrease in frontal metabolism from waking to NREM sleep in depressed patients is further evidence for a dynamic sleep-wake alteration in prefrontal cortex function in depression. Hypermetabolism in a ventral emotional neural system during waking in depressed patients persists into NREM sleep.

Adult↗
PubMed2005

Two-year outcomes for interpersonal and social rhythm therapy in individuals with bipolar I disorder.

CONTEXT: Numerous studies have pointed to the failure of prophylaxis with pharmacotherapy alone in the treatment of bipolar I disorder. Recent investigations have demonstrated benefits from the addition of psychoeducation or psychotherapy to pharmacotherapy in this population. OBJECTIVE: To compare 2 psychosocial interventions: interpersonal and social rhythm therapy (IPSRT) and an intensive clinical management (ICM) approach in the treatment of bipolar I disorder. DESIGN: Randomized controlled trial involving 4 treatment strategies: acute and maintenance IPSRT (IPSRT/IPSRT), acute and maintenance ICM (ICM/ICM), acute IPSRT followed by maintenance ICM (IPSRT/ICM), or acute ICM followed by maintenance IPSRT (ICM/IPSRT). The preventive maintenance phase lasted 2 years. SETTING: Research clinic in a university medical center. PARTICIPANTS: One hundred seventy-five acutely ill individuals with bipolar I disorder recruited from inpatient and outpatient settings, clinical referral, public presentations about bipolar disorder, and other public information activities. INTERVENTIONS: Interpersonal and social rhythm therapy, an adaptation of Klerman and Weissman's interpersonal psychotherapy to which a social rhythm regulation component has been added, and ICM. MAIN OUTCOME MEASURES: Time to stabilization in the acute phase and time to recurrence in the maintenance phase. RESULTS: We observed no difference between the treatment strategies in time to stabilization. After controlling for covariates of survival time, we found that participants assigned to IPSRT in the acute treatment phase survived longer without a new affective episode (P = .01), irrespective of maintenance treatment assignment. Participants in the IPSRT group had higher regularity of social rhythms at the end of acute treatment (P<.001). Ability to increase regularity of social rhythms during acute treatment was associated with reduced likelihood of recurrence during the maintenance phase (P = .05). CONCLUSION: Interpersonal and social rhythm therapy appears to add to the clinical armamentarium for the management of bipolar I disorder, particularly with respect to prophylaxis of new episodes.

Adult↗