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Biomedical subjects

David J Kupfer

Publications and source records attributed to David J Kupfer.

At least 55 records · Page 3Linked to original sources
PubMed2004

Reduced left anterior cingulate volumes in untreated bipolar patients.

BACKGROUND: Functional and morphologic abnormalities of the cingulate cortex have been reported in mood disorder patients. To examine the involvement of anatomic abnormalities of the cingulate in bipolar disorder, we measured the volumes of this structure in untreated and lithium-treated bipolar patients and healthy control subjects, using magnetic resonance imaging (MRI). METHODS: The volumes of gray matter at the right and left anterior and posterior cingulate cortices were measured in 11 bipolar patients not taking any psychotropic medications (aged 38 +/- 11 years, 5 women), 16 bipolar patients treated with lithium monotherapy (aged 33 +/- 11 years, 7 women), and 39 healthy control subjects (aged 37 +/- 10 years, 14 women). Volumetric measurements were made with T1-weighted coronal MRI images, with 1.5-mm-thick slices, at 1.5T, and were done blindly. RESULTS: Using analysis of covariance with age and intracranial volume as covariates, we found that untreated bipolar patients had decreased left anterior cingulate volumes compared with healthy control subjects [2.4 +/-.3 cm3 and 2.9 +/-.6 cm3, respectively; F(1,58) = 6.4, p =.042] and compared with lithium-treated patients [3.3 +/-.5 cm3; F(1,58) = 11.7, p =.003]. The cingulate volumes in lithium-treated patients were not significantly different from those of healthy control subjects. CONCLUSIONS: Our findings indicate that anatomic abnormalities in left anterior cingulate are present in bipolar patients. Furthermore, our results suggest that lithium treatment might influence cingulate volumes in bipolar patients, which could possibly reflect postulated neuroprotective effects of lithium.

Adult↗
PubMed2004

Anatomic evaluation of the orbitofrontal cortex in major depressive disorder.

BACKGROUND: The orbitofrontal cortex (OFC) plays a major role in neuropsychologic functioning including exteroceptive and interoceptive information coding, reward-guided behavior, impulse control, and mood regulation. This study examined the OFC and its subdivisions in patients with MDD and matched healthy control subjects. METHODS: Magnetic resonance imaging (MRI) was performed on 31 unmedicated MDD and 34 control subjects matched for age, gender, and race. Gray matter volumes of the OFC and its lateral and medial subdivisions were measured blindly. RESULTS: The MDD patients had smaller gray matter volumes in right medial [two-way analysis of covariance F(1,60) = 4.285; p =.043] and left lateral OFC [F(1,60) = 4.252; p =.044]. Left lateral OFC volume correlated negatively with age in patients but not in control subjects. Male, but not female patients exhibited smaller left and right medial OFC volumes compared with healthy control subjects of the same gender. CONCLUSIONS: These findings suggest that patients with MDD have reduced OFC gray matter volumes. Although this reduction might be important in understanding the pathophysiology of MDD, its functional and psychopathologic consequences are as yet unclear. Future studies examining the relationship between specific symptomatic dimensions of MDD and OFC volumes could be especially informative.

Adult↗
PubMed2004

Increased activation of anterior paralimbic and executive cortex from waking to rapid eye movement sleep in depression.

BACKGROUND: Depression is associated with sleep disturbances, including alterations in rapid eye movement (REM) sleep, that may relate to the neurobiology of the disorder. Given that REM sleep activates limbic and anterior paralimbic cortex and that depressed patients demonstrate increases in electroencephalographic sleep measures of REM, we hypothesized greater activation of these structures during waking to REM sleep in depressed patients. DESIGN: Subjects completed electroencephalographic sleep and regional cerebral glucose metabolism assessments during both waking and REM sleep using [(18)F]fluoro-2-deoxy-D-glucose positron emission tomography. SETTING: Patients and healthy subjects recruited from the general community to participate in a research study of depression at an academic medical center. Patients Twenty-four unmedicated patients who met the Structured Clinical Interview for DSM-IV criteria for current major depression and who had a score of 15 or higher on a 17-item Hamilton Rating Scale for Depression; 14 medically healthy subjects of comparable age and sex who were free of mental disorders. MAIN OUTCOME MEASURES: Electroencephalographic sleep, semiquantitative and relative regional cerebral metabolism during waking and REM sleep. RESULTS: Depressed patients showed greater REM sleep percentages. While both healthy and depressed patients activated anterior paralimbic structures from waking to REM sleep, the spatial extent of this activation was greater in the depressed patients. Additionally, depressed patients showed greater activation in bilateral dorsolateral prefrontal, left premotor, primary sensorimotor, and left parietal cortices, as well as in the midbrain reticular formation. CONCLUSIONS: Increased anterior paralimbic activation from waking to REM sleep may be related to affective dysregulation in depressed patients. Increased activation of executive cortex may be related to a cognitive dysregulation. These results suggest that altered function of limbic/anterior paralimbic and prefrontal circuits in depression is accentuated during the REM sleep state. The characteristic sleep disturbances of depression may reflect this dysregulation.

Adult↗
PubMed2004

Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design.

STAR*D is a multisite, prospective, randomized, multistep clinical trial of outpatients with nonpsychotic major depressive disorder. The study compares various treatment options for those who do not attain a satisfactory response with citalopram, a selective serotonin reuptake inhibitor antidepressant. The study enrolls 4000 adults (ages 18-75) from both primary and specialty care practices who have not had either a prior inadequate response or clear-cut intolerance to a robust trial of protocol treatments during the current major depressive episode. After receiving citalopram (level 1), participants without sufficient symptomatic benefit are eligible for randomization to level 2 treatments, which entail four switch options (sertraline, bupropion, venlafaxine, cognitive therapy) and three citalopram augment options (bupropion, buspirone, cognitive therapy). Those who receive cognitive therapy (switch or augment options) at level 2 without sufficient improvement are eligible for randomization to one of two level 2A switch options (venlafaxine or bupropion). Level 2 and 2A participants are eligible for random assignment to two switch options (mirtazapine or nortriptyline) and to two augment options (lithium or thyroid hormone) added to the primary antidepressant (citalopram, bupropion, sertraline, or venlafaxine) (level 3). Those without sufficient improvement at level 3 are eligible for level 4 random assignment to one of two switch options (tranylcypromine or the combination of mirtazapine and venlafaxine). The primary outcome is the clinician-rated, 17-item Hamilton Rating Scale for Depression, administered at entry and exit from each treatment level through telephone interviews by assessors masked to treatment assignments. Secondary outcomes include self-reported depressive symptoms, physical and mental function, side-effect burden, client satisfaction, and health care utilization and cost. Participants with an adequate symptomatic response may enter the 12-month naturalistic follow-up phase with brief monthly and more complete quarterly assessments.

Adolescent↗
PubMed2004

Morningness-eveningness and lifestyle regularity.

The relation between morningness (M) - eveningness (E) and lifestyle regularity was studied in a convenience sample of 100 healthy subjects aged between 20 and 59 yrs (47 males and 53 females; mean age 33.6 yrs). Morningness-eveningness was measured by a single administration of the 13-item Composite Scale for Morningness (CSM). Lifestyle regularity was measured by requiring subjects to complete a five-item Social Rhythm Metric diary (SRM-5) each evening for two weeks. Each week of SRM-5 was analyzed separately and the two SRM scores averaged to yield the lifestyle regularity measure for the subject. Subjects were categorized by morningness into top and bottom quartiles of CSM score (denoted M-types and E-types, respectively), with the remaining 50% of subjects denoted as intermediate (I-types). Mean SRM scores significantly differed between the three morningness groups (p <0.001) in the order E-types (SRM = 3.6), then I-types (SRM=4.0), then M-types (SRM=4.9), with higher scores indicating greater daily lifestyle regularity. The effect size of the E-type versus M-type difference was approximately 1.3. The relationship between the CSM and SRM scores was also confirmed using a correlational analysis (rho = 0.428; p < 0.001). This correlational finding was substantially weaker when age was partialed out (r=0.186; p=0.065), although there was still a trend toward a significan relationship. Thus it appears that morning types appear to be more regular in their daily lifestyle than are evening types, suggesting a relationship between these two aspects of human circadian behavior.

Adult↗
PubMed2004

von Willebrand's disease and psychotic disorders: co-segregation and genetic associations.

OBJECTIVES: To evaluate co-segregation and genetic associations between von Willebrand's disease (vWD) and psychotic disorders. METHODS: The study was initiated following ascertainment of a nuclear family in which four members were diagnosed with vWD and psychotic/mood disorders. As co-segregation was uncertain in the extended pedigree, we also investigated population-based linkage and association using polymorphisms of vWF, the gene conferring susceptibility to vWD. Three common vWF polymorphisms were investigated among 194 patients with psychotic disorders (bipolar I disorder, BD I; schizoaffective disorder, SZA and schizophrenia, SZ) and their parents. The cases were also compared with unrelated population-based controls (n = 183). RESULTS: The transmission disequilibrium test and related analyses suggested nominally significant transmission distortion of one allele and related haplotypes to the probands from their parents. The most significant results were obtained among patients with BD I, and similar trends were also evident in the SZ sample. Comparisons between the cases and population-based controls did not reveal associations, though marginally significant case-control differences were obtained in the BD I sample. CONCLUSIONS: These studies are consistent with association and linkage between vWF and BD I. However, given the relatively small sample, stochastic variation is an alternative explanation.

Adult↗
PubMed2004

The prevalence of the metabolic syndrome in patients with schizoaffective disorder--bipolar subtype.

OBJECTIVES: To evaluate the point prevalence of the metabolic syndrome in patients with schizoaffective disorder--bipolar type. METHODS: Consenting patients who were participants in an ongoing clinical trial of adjunctive topiramate treatment for schizoaffective disorder, bipolar type were evaluated at baseline for the point prevalence of the metabolic syndrome. The criteria for the metabolic syndrome included: (a) waist circumference > 102 cm (40 inches) in males, or > 88 cm (35 inches) in females; (b) fasting serum triglyceride levels > or = 150 mg/dL; (c) fasting high density lipoproteins (HDL) cholesterol <40 mg/dL in men or <50 mg/dL in women; (d) blood pressure > or = 130/85 mmHg; and (e) fasting glucose > or = 110 mg/dL. Subjects who had at least three of these five criteria were defined as meeting criteria for the metabolic syndrome. RESULTS: Thirty-six subjects (males = 15, females = 21) were evaluated, and three were excluded for missing data. Among those 33 subjects with complete data, 14 subjects (42.4%, males = 7, females = 7, African Americans = 6, Caucasians = 8) met criteria for the metabolic syndrome. Not unexpectedly, those with the metabolic syndrome were significantly more likely to be obese, and have significantly higher mean systolic and diastolic blood pressure, mean fasting triglyceride levels and larger mean waist circumferences, and significantly lower HDL cholesterol levels; and a trend toward higher fasting blood glucose levels. Furthermore, the fasting mean total cholesterol in those with the metabolic syndrome was 217 mg/dL (+/-46). CONCLUSIONS: This preliminary report suggests that the point prevalence of the metabolic syndrome in patients with schizoaffective disorder appears to be higher than that reported in the general population of the USA. Targeted weight reduction and life style change strategies (increased exercise, smoking cessation, stress reduction) may provide useful interventions to decrease the morbidity and mortality that accompanies the presence of the metabolic syndrome in patients with psychiatric illnesses.

Adult↗
PubMed2004

Neurobiology of non-REM sleep in depression: further evidence for hypofrontality and thalamic dysregulation.

OBJECTIVE: Sleep disturbances characterize depression and may reflect the abnormal persistence of brain activity from wakefulness into non-REM sleep. The goal of this study was to investigate the functional neuroanatomical correlates of non-REM sleep relative to presleep wakefulness in depressed patients and healthy subjects. METHOD: Twelve medication-free depressed patients and 13 healthy subjects underwent polysomnography and [(18)F]fluorodeoxyglucose positron emission tomography scans during presleep wakefulness and non-REM sleep. Statistical parametric mapping contrasts were performed to detect differences in relative regional cerebral glucose metabolism between presleep wakefulness and non-REM sleep in each group as well as interactions across states and between groups. RESULTS: Relative to healthy subjects, depressed patients showed less of a decrease in relative regional cerebral glucose metabolism from presleep wakefulness to non-REM sleep in the left and right laterodorsal frontal gyri, right medial prefrontal cortex, right superior and middle temporal gyri, insula, right posterior cingulate cortex, lingual gyrus, striate cortex, cerebellar vermis, and left thalamus. CONCLUSIONS: Patterns of relative regional cerebral glucose metabolism changes from presleep wakefulness to non-REM sleep differ in healthy subjects and depressed patients. Specifically, the transition from wakefulness to non-REM sleep was characterized by the relative persistence of elevated metabolic activity in frontoparietal regions and thalamus in depressed patients compared with healthy subjects. These findings suggest that abnormal thalamocortical network function may underlie sleep anomalies and complaints of nonrestorative sleep in depressed patients.

Adult↗
PubMed2004

Randomized, placebo-controlled trial of fluoxetine for acute treatment of minor depressive disorder.

OBJECTIVE: Minor depressive disorder is both common and associated with significant psychosocial impairment. This study examined antidepressant treatment efficacy in a large group of patients with minor depressive disorder. METHOD: One hundred sixty-two patients with minor depressive disorder were randomly assigned to receive fluoxetine or placebo in a 12-week, double-blind study; 73% (59 of 81) of the patients in each treatment group completed the study. Patients were evaluated weekly with standard depression rating instruments and measures of psychosocial impairment. Hypotheses were tested by last-observation-carried-forward analysis of variance (ANOVA) and confirmed by mixed (random-effects) regression analysis. RESULTS: At baseline, minor depressive disorder patients were mildly to moderately depressed, with a corresponding degree of functional impairment. Over 12 weeks of treatment, both ANOVA and mixed regression showed fluoxetine to be superior to placebo as indicated by significantly greater improvement of fluoxetine-treated patients in scores on the 30-item clinician-rated Inventory of Depressive Symptomatology, the 17-item and 21-item Hamilton Depression Rating Scale, the Beck Depression Inventory, and the Clinical Global Impression severity scale. Improvement in Global Assessment of Functioning Scale score was significantly greater for the fluoxetine group in mixed regression analysis only. Patients in both treatment groups reported a similar number and severity of adverse events during the 12-week treatment period. CONCLUSIONS: Clinicians frequently encounter minor depressive disorder either as a prodromal or residual phase of illness in major depressive disorder or as de novo minor depressive disorder episodes. Fluoxetine is significantly superior to placebo in reducing minor depressive disorder symptoms within a 12-week period. Improvement in psychosocial function with fluoxetine may take longer than 12 weeks.

Adaptation, Psychological↗
PubMed2004

Relationship of variability in residual symptoms with recurrence of major depressive disorder during maintenance treatment.

OBJECTIVE: To investigate how residual symptoms from an index episode of major depressive disorder may be associated with recurrence, the authors conducted a trial involving four maintenance treatment approaches and examined 1) whether the level and variability of residual symptoms differed among the maintenance treatment conditions and 2) whether greater symptom variability is associated with a higher likelihood of recurrence and more rapid recurrence. METHOD: Patients enrolled in a maintenance treatment study (N=114) were randomly assigned to one of four maintenance treatment conditions: imipramine plus interpersonal psychotherapy, imipramine alone, interpersonal psychotherapy alone, or no active treatment. Residual symptoms were characterized both as continuous variables (mean values and coefficients of variation for Hamilton Depression Rating Scale and Global Assessment Scale [GAS] scores) and as a categorical variable, the percentage of maintenance evaluations with a Hamilton depression scale score > or =8 (e.g., with a symptom peak). RESULTS: Analysis of variance revealed no differences among the four treatment conditions in patients' levels of residual symptoms or symptom variability assessed as a continuous variable, but patients in the combined treatment group had fewer symptom peaks, compared to those in the placebo and interpersonal psychotherapy groups. Cox proportional hazards modeling showed that higher coefficients of variation for both the Hamilton depression scale and the GAS scores and a greater percentage of evaluations with symptom peaks were associated with shorter survival times. CONCLUSIONS: A higher level of symptom variability during maintenance treatment is associated with higher risk for recurrence of depression and may provide a specific target for maintenance treatments.

Adult↗
PubMed2004

Functional neuroimaging evidence for hyperarousal in insomnia.

OBJECTIVE: The authors investigated the neurobiological basis of poor sleep and daytime fatigue in insomnia. METHOD: [(18)F]Fluorodeoxyglucose positron emission tomography was used to assess regional cerebral glucose metabolism of seven patients with insomnia and 20 healthy subjects. RESULTS: Compared with healthy subjects, patients with insomnia showed greater global cerebral glucose metabolism during sleep and while awake, a smaller decline in relative metabolism from waking to sleep states in wake-promoting regions, and reduced relative metabolism in the prefrontal cortex while awake. CONCLUSIONS: Subjectively disturbed sleep in patients with insomnia is associated with greater brain metabolism. The inability to fall asleep may be related to a failure of arousal mechanisms to decline in activity from waking to sleep states. Further, daytime fatigue may reflect decreased activity in the prefrontal cortex resulting from inefficient sleep.

Adult↗
PubMed2004

Cognitive functioning in late-life bipolar disorder.

OBJECTIVE: This study characterized cognitive functioning in elderly patients with bipolar disorder. METHOD: The cognitive functioning of 18 euthymic patients with a history of bipolar disorder I or II, ages 60 years and older, was tested with the Mini-Mental State Examination (MMSE), the Mattis Dementia Rating Scale, and the Executive Interview. Cognitive functioning in these subjects was compared with that of an age- and education-matched group of 45 comparison subjects without mood disorders. RESULTS: Approximately half of the bipolar subjects scored one or more standard deviations below the mean of the comparison subjects on the MMSE (N=8, 44%) and the Mattis Dementia Rating Scale total (N=10, 56%). On the Executive Interview, three subjects (17%) scored between one and two standard deviations below the mean of the comparison subjects. CONCLUSIONS: A significant proportion of older bipolar subjects exhibited neuropsychological deficits when they were clinically euthymic.

Aged↗
PubMed2004

The mood spectrum in unipolar and bipolar disorder: arguments for a unitary approach.

OBJECTIVE: This study examined the extent to which individuals with a lifetime diagnosis of recurrent unipolar disorder endorse experiencing manic/hypomanic symptoms over their lifetimes and compared their reports with those of patients with bipolar I disorder. METHOD: The study group included 117 patients with remitted recurrent unipolar depression and 106 with bipolar I. Subjects had their clinical diagnosis confirmed by the Mini International Neuropsychiatric Interview and were administered the Structured Clinical Interview for the Mood Spectrum, which assesses lifetime symptoms, traits, and lifestyles that characterize threshold and subthreshold mood episodes as well as "temperamental" features related to mood dysregulation. RESULTS: The patients with recurrent unipolar depression endorsed experiencing a substantial number of manic/hypomanic symptoms over their lifetimes. In both patients with recurrent unipolar depression and patients with bipolar I disorder, the number of manic/hypomanic items endorsed was related to the number of depressive items endorsed. In the group with recurrent unipolar depression, the number of manic/hypomanic items was related to an increased likelihood of endorsing paranoid and delusional thoughts and suicidal ideation. In the bipolar I group, the number of lifetime manic/hypomanic items was related to suicidal ideation and just one indicator of psychosis. CONCLUSIONS: The presence of a significant number of manic/hypomanic items in patients with recurrent unipolar depression seems to challenge the traditional unipolar-bipolar dichotomy and bridge the gap between these two categories of mood disorders. The authors argue that their mood spectrum approach is useful in making a more accurate diagnostic evaluation in patients with mood disorders.

Adult↗
PubMed2004

Utility of sparse concentration sampling for citalopram in elderly clinical trial subjects.

The objective of this study was to evaluate whether the disposition of the selective serotonin reuptake inhibitor, citalopram, could be robustly captured using 1 to 2 concentration samples per subject in 106 patients participating in 2 clinical trials. Nonlinear mixed-effects modeling was used to evaluate the pharmacokinetic parameters describing citalopram's disposition. Both a prior established 2-compartment model and a de novo 1-compartment pharmacokinetic model were used. Covariates assessed were concomitant medications, race, sex, age (22-93 years), and weight. Covariates affecting disposition were assessed separately and then combined in a stepwise manner. Pharmacokinetic characteristics of citalopram were well captured using this sparse sampling design. Two covariates (age and weight) had a significant effect on the clearance and volume of distribution in both the 1- and 2-compartment pharmacokinetic models. Clearance decreased 0.23 L/h for every year of age and increased 0.14 L/h per kilogram body weight. It was concluded that hyper-sparse sampling designs are adequate to support population pharmacokinetic analysis in clinically treated populations. This is particularly valuable for populations such as the elderly, who are not typically available for pharmacokinetic studies.

Administration, Oral↗
PubMed2004

Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone.

BACKGROUND: Few controlled studies have examined the use of atypical antipsychotic drugs for prevention of relapse in patients with bipolar I disorder. Aims To evaluate whether olanzapine plus either lithium or valproate reduces the rate of relapse, compared with lithium or valproate alone. METHOD: Patients achieving syndromic remission after 6 weeks'treatment with olanzapine plus either lithium (0.6-1.2 mmol/l) or valproate (50-125 microg/ml) received lithium or valproate plus either olanzapine 5-20 mg/day (combination therapy) or placebo (monotherapy), and were followed in a double-masked trial for 18 months. RESULTS: The treatment difference in time to relapse into either mania or depression was not significant for syndromic relapse (median time to relapse: combination therapy 94 days, monotherapy 40.5 days; P=0.742), but was significant for symptomatic relapse (combination therapy 163 days, monotherapy 42 days; P=0.023). CONCLUSIONS: Patients taking olanzapine added to lithium or valproate experienced sustained symptomatic remission, but not syndromic remission, for longer than those receiving lithium or valproate monotherapy.

Adult↗
PubMed2004

A pilot study of subjective daytime alertness and mood in primary insomnia participants using ecological momentary assessment.

This pilot study compared daytime symptom ratings in primary insomniacs (n = 7) and age-matched controls (n = 8). Participants completed sleep diaries and rated their daytime symptoms using a Daytime Symptom Diary (DSD) 4 times per day for 1 week. DSD responses were collapsed into 4 domains: mood, subjective alertness, energy, and concentration. The level and variability of DSD domains, and correlations between the domains and sleep diary characteristics, were examined. Significant Group x Time of Day interactions were observed in values for each DSD domain, with the most consistent group differences occurring in the morning. Coefficients of variation for DSD domains were greater in the insomnia group. Frequent measures of daytime symptoms may be useful outcomes in insomnia studies.

Adult↗
PubMed2004

Suicide attempts and ideation in patients with bipolar I disorder.

BACKGROUND: Suicidal thinking and behavior are common in individuals with bipolar disorder. METHOD: Suicidal ideation and suicide attempts were examined in 175 patients with bipolar I disorder (diagnosis confirmed with the Schedule for Affective Disorders and Schizophrenia or the Structured Clinical Interview for DSM-IV) participating in the Pittsburgh Study of Maintenance Therapies in Bipolar Disorder. Patients who attempted suicide before entering the study were compared with those who did not attempt suicide with respect to clinical and demographic characteristics. RESULTS: Twenty-nine percent of the patients had attempted suicide prior to entering the study. Suicide attempts happened at a relatively young age and in the first period of the illness. Greater severity of bipolar disorder, as indicated by a greater number of previous depressive episodes (p =.0009) and higher HAM-D-25 scores (p =.04), and higher body mass index (p =.03) were significantly correlated with a history of suicide attempts. None of the patients with a history of suicide attempt attempted suicide again. However, 5 patients without a history of suicide attempt did attempt suicide. Four of these patients did not display severe suicidal ideation at the assessment that preceded the suicide attempt. No subject completed suicide during the 11 years of the study. CONCLUSION: Greater severity of bipolar disorder and higher body mass index are significantly correlated with a history of suicide attempts. However, a treatment program in a maximally supportive clinical environment can reduce suicidal behavior in high-risk patients. In some cases, suicide risk is transient and may be preceded by a period of severe suicidal ideation that lasts only a few minutes or hours. In such cases, mental health professionals are unable to predict suicide attempts.

Adult↗