Biomedical subjects
Publications and source records attributed to David J Kupfer.
Patients whose depression is complicated by a lifetime history of panic symptoms display a poorer treatment response to both psychotherapeutic and pharmacologic interventions. A newly adapted psychosocial treatment for depression with lifetime panic spectrum symptoms was evaluated in an open pilot study.
BACKGROUND: We sought to develop a series of assessment measures of psychiatric spectrum conditions associated with major DSM-IV mood and anxiety disorders that might capture the true phenotypes underlying these disorders. The specific objective of this report was to describe the methods we employed to create instruments that could cross linguistic and national boundaries and to evaluate the comparability of results obtained when one of these instruments, the Structured Clinical Interview for Panic-Agoraphobic Spectrum (SCI-PAS), was administered in the United States and in Italy. METHOD: After developing, in parallel, the English and the Italian versions of the SCI-PAS, identical protocols were conducted in patients and control samples at the University of Pittsburgh and the University of Pisa to examine the reliability and validity of the interview. RESULTS: Total and domain scores on the SCI-PAS were strikingly similar in the US and Italian patient groups and in controls. In addition, similarly high levels of inter-rater and test-retest reliability were found at the two sites. Finally, virtually identical patterns of relationships were found between the domains of the SCI-PAS and established measures of the same constructs. CONCLUSIONS: The SCI-PAS displays similar reliability and validity properties in the two versions. This suggests that the instrument taps a phenotype that is consistent in American and Italian patient and control populations.
This commentary focuses on the current dilemma regarding the application of dimensional models for research and diagnosis. Four articles are used to review the positive contributions of dimensional approaches. Although categorical approaches are integral in deciding the characteristics of the group to be studied (i.e., development of inclusion/exclusion criteria), the generation of cutpoints for categorical classification is, in reality, working with dimensional data. Ultimately, new methodological strategies need to be incorporated that address both categorical and dimensional aspects of the overall diagnostic framework. These refinements will be vital in determining the extent and reality of co-occurrence of disorder and the determination of boundaries across specific disorders.
The pathogenesis of bipolar disorder may involve, at least in part, aberrations in serotonergic neurotransmission. Hence, serotonergic genes are attractive targets for association studies of bipolar disorder. We have reviewed the literature in this field. It is difficult to synthesize results as only one polymorphism per gene was typically investigated in relatively small samples. Nevertheless, suggestive associations are available for the 5HT2A receptor and the serotonin transporter genes. With the availability of extensive polymorphism data and high throughput genotyping techniques, comprehensive evaluation of these genes using adequately powered samples is warranted. We also report on our investigations of the serotonin transporter, SLC6A4 (17q11.1-q12). An insertion/deletion polymorphism (5HTTLPR) in the promoter region of this gene has been investigated intensively. However, the results have been inconsistent. We reasoned that other polymorphism/s may contribute to the associations and the inconsistencies may be due to variations in linkage disequilibrium (LD) patterns between samples. Therefore, we conducted LD analyses, as well as association and linkage using 12 polymorphisms, including 5HTTLPR. We evaluated two samples. The first sample consisted of 135 US Caucasian nuclear families having a proband with bipolar I disorder (BDI, DSM IV criteria) and available parents. For case-control analyses, the patients from these families were compared with cord blood samples from local Caucasian live births (n = 182). Our second, independent sample was recruited through the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD, 545 cases, 548 controls). No significant associations were detected at the individual polymorphism or haplotype level using the case-control or family-based analyses. Our analyses do not support association between SLC6A4 and BDI families. Further studies using sub-groups of BDI are worthwhile.
Abnormalities in circadian rhythms are prominent features of bipolar I disorder (BD1). To investigate circadian variation in BD1, we evaluated morningness-eveningness (M/E), a stable trait reflecting circadian phase, using the composite scale (CS) among BD1 patients (DSM IV criteria; n = 75), unscreened controls (n = 349), and patients with schizophrenia (SZ) or schizoaffective disorder (SZA) (n = 81). Our analyses showed that CS scores correlated significantly with age but did not differ by gender among the controls. BD1 patients differed significantly from controls and from SZ/SZA patients when age was considered. CS scores were distributed bi-modally among BD1 cases. There are several possible reasons for the observed heterogeneity. Younger BD1 patients, and those with rapid mood swings, were significantly more likely to have lower CS scores (i.e., to score in the 'evening' range and to have later circadian phase). CS scores were also positively correlated with the age at onset and the duration of the most severe depressive episodes. These relationships were not observed among the SZ/SZA groups. Thus, distinct patterns of M/E were noted among BD1 patients and among BD1 subgroups. The impact of medication, mood state, and chronicity on CS scores needs to be considered.
In the management of late-life depression, a major set of issues concerns the terms or language used to describe the course of illness and response to treatment. There appear to be considerable advantages in the application of standardized remission criteria. If one is primarily concerned with symptomatic remission and the resolution of a single or initial episode of depression, then a moderately strict criterion is sufficient, for example, Hamilton Rating Scale for Depression (HRSD) < or = 10. However, as the goal of treatment is to achieve complete recovery, which may reduce the risk for either relapse or recurrence, then there may be a strong advantage in applying a more stringent remission criterion such as HRSD < or = 6 or 7. The characteristics of the response pattern (ie, trajectory of clinical course) also can provide important prognostic information. Such pattern characteristics can be modeled with newer statistical methods, which in turn can better inform the course of future treatment. Finally, there is growing recognition that standardized remission criteria can be valuable for establishing treatment guidelines for late-life depression, as well as for educating clinicians and consumers.
OBJECTIVES: The goal of this paper was to compare clinical characteristics and treatment history of African-American and Caucasian participants in a bipolar disorder registry. METHODS: The Western Pennsylvania Bipolar Disorder Registry used several recruitment methods to reach individuals self-identified as having bipolar disorder. Individuals who contacted and joined the registry completed an interviewer-administered questionnaire on clinical characteristics and treatment history. A sample of 2,718 registry participants was analyzed in order to compare these characteristics and history by race. RESULTS: African-Americans in the registry reported a greater number of inpatient hospitalizations (9.8 versus 4.4) than Caucasians, as well as a higher suicide attempt rate (64% versus 49%). African-American participants were more likely to report a family member with schizophrenia. With respect to psychotropic medication, African-Americans were less likely to report taking antimanic medication or benzodiazepines, but more likely to report taking antipsychotics than Caucasians. CONCLUSIONS: The present findings reinforce previous reports regarding the chronicity and severity of bipolar disorder among African-Americans. They also support previous studies that found high rates of attempted suicide among African-Americans with bipolar disorder. These findings provide further impetus for specific community and mental health services delivery efforts to reduce barriers to early accurate diagnosis and to appropriate ambulatory treatment for bipolar disorder.
BACKGROUND: Typical experimental categorizations of treatment responses in bipolar disorder (BPD) patients may have limited relationship to clinical recovery or functional status, and there is inadequate research on such clinically important outcomes. METHODS: We analyzed data from a study of open continuation of olanzapine treatment following a 3-week placebo-controlled trial involving initially hospitalized adult subjects with DSM-IV BP-I mania to estimate rates and times to symptomatic remission (low scores on standardized symptomatic assessments) and clinical recovery (remission sustained>or=8 weeks), associated clinical factors, and functional outcomes. RESULTS: During treatment with olanzapine for 27.9+/-20.1 weeks, symptomatic remission was attained by 70% of subjects, half by 8 weeks (95% CI 6-10) weeks, and later lost by 82% of remitted subjects; remitted (versus non-remitted) subjects had slightly lower baseline clinical global impression scores and greater trial-completion. Sustained clinical recovery was attained by only 40 of 113 (35%) of subjects, half by 36 (95% CI 20-40) weeks, and later lost by 45%. Subjects with above-median (>12) initial Hamilton-Depression rating scale depression scores were half as likely to recover (p=0.016) and did so much later (36 versus 12 weeks) than those with lower scores. At final assessment, self-rated well being (SF-36 psychosocial functioning scores) improved substantially more among recovered versus non-recovered subjects (mean changes: 87% versus 23%), and two-thirds of recovered subjects remained unemployed-for-pay while half received disability-compensation. CONCLUSIONS: Clinically meaningful symptomatic remission and recovery in relatively severely ill adult bipolar I manic patients were achieved slowly and sustained by only some patients within an average of 7 months of continuous treatment. These clinically relevant outcomes were worse with relatively high initial dysphoria ratings. Well-being was rated higher by recovered subjects, but their ability to work and live independently were markedly impaired. These findings underscore the emerging view that BPD can often be severe, slow to remit, and disabling, particularly in association with prominent depression-dysphoria symptoms. Improved treatments for BPD are needed, guided by longitudinal assessments of clinically meaningful measures of symptomatic recovery and functional outcome.
OBJECTIVES: The purpose of this study was to evaluate functional impairment in a group of patients with bipolar disorder in remission and to determine the extent of relationships between overall functioning and current depressive, manic and panic spectrum symptoms. METHOD: A subset of the patient population at the Pittsburgh site of the Systematic Treatment Enhancement Program in Bipolar Disorder (STEP-BD) study was evaluated in this study. The subsample comprises 103 male and female subjects with bipolar I disorder (n = 70), bipolar II disorder (n = 24), schizoaffective disorder - bipolar type (n = 4), or bipolar disorder NOS (n = 5). Subjects were evaluated in a period of remission (at least 4 weeks with no more than two depressive or manic symptoms). Subjects were assessed for overall functional status using the Work and Social Adjustment Scale (WSAS) and for current bipolar and panic spectrum symptoms using the Mood Spectrum Self-Report questionnaire (MOODS-SR) and Panic-Agoraphobic Spectrum Self-Report questionnaire (PAS-SR). RESULTS: The median WSAS total score in these remitted subjects was 14, indicating significant functional impairment. Regressing WSAS on current depressive, manic, and panic spectrum total scores, we observed a highly significant depressive spectrum effect (t = 4.9, df = 94, p < 0.0001), but non-significant panic and manic spectrum effects (t = 1.3, df = 94, p = 0.19 and t = -1.8, df = 94, p = 0.07, respectively). CONCLUSION: Bipolar disorder is associated with functional deficits even during periods of sustained and substantial remission. The degree of functional impairment is correlated with the degree of depressive spectrum symptoms.
OBJECTIVE: This study sought to evaluate the presence of the metabolic syndrome in a group of 171 patients with bipolar disorder who were consecutively recruited in the Bipolar Disorder Center for Pennsylvanians. METHODS: Data were collected from participants entering the Bipolar Disorder Center for Pennsylvanians protocol between 2003 and 2004. The study focused on the presence of the metabolic syndrome, as defined by the National Cholesterol Education Program Expert Panel on Detection, Evaluation And Treatment of High Blood Cholesterol in Adults (NCEP ATP III). RESULTS: Thirty percent of the sample met the NCEP ATP III criterion for the metabolic syndrome, 49% met the criterion for abdominal obesity, 41% met the criterion for hypertriglyceridemia, 48% met the criterion for hypertriglyceridemia or were on a cholesterol-lowering medication, 23% met the criterion for low high-density lipoprotein cholesterol, 39% met the criterion for hypertension and 8% met the criterion for high fasting glucose or antidiabetic medication use. Patients with the metabolic syndrome and patients endorsing the obesity criterion were more likely (p = 0.05 and p = 0.004, respectively) to report a lifetime history of suicide attempt/s. CONCLUSIONS: The prevalence of the metabolic syndrome in patients with bipolar disorder is alarmingly high, as it is for the general population. The prevalence of obesity is even higher than the already very high prevalence that has been estimated for the US general population. Our findings are a reason for concern, considering the difficulty in implementing prevention and treatment programs in the bipolar population. We strongly support the development and testing of interventions specifically designed for preventing and treating the metabolic syndrome and its components in patients with bipolar disorder.
OBJECTIVE: The authors investigated the influence of body pain on 1) time to treatment response and 2) suicidal ideation, in late-life depression. They hypothesized that higher levels of body pain would predict a longer time to and lower likelihood of response, and increased levels of suicidal ideation. METHODS: Subjects (N=187) were older adult outpatients (age > or =69 years), with current episodes of major depression, who were openly treated with paroxetine up to 40 mg daily and weekly interpersonal psychotherapy. Response was defined as 3 consecutive weeks of Hamilton Rating Scale for Depression at < or =10. Body pain was measured with the Bodily Pain Index of the SF-36 quality-of-life assessment. Authors used survival-analysis models on the responder sample to test the effect of body pain on response, after controlling for severity of depression. RESULTS: Overall response rate was 75.4%. Nonresponders reported more severe pain at baseline. After covarying for severity of baseline depression, no effect was found for physical pain on time-to-response or degree of suicidality. Bodily pain remained stable during acute treatment for responders, independent of depression response to combination psychotherapy and antidepressant treatment. CONCLUSIONS: Older adult patients with higher levels of physical pain can still respond to antidepressant treatment; however, reported bodily pain may be associated with a more difficult-to-treat depression.
OBJECTIVE: The authors sought to determine the feasibility of treating elderly adults with bipolar disorder under standardized-treatment conditions. METHODS: Thirty-one patients age 60 and older with bipolar disorder were treated in standardized pathways. Mood state was checked at each study visit with the Hamilton Rating Scale for Depression-17 item (Ham-D-17) and the Young Mania Rating Scale (YMRS). RESULTS: Defining "well days" as both Ham-D and YMRS scores of <or=10, the mean percentage of well days was 72.5 (range: 0%-100%) over study participation. CONCLUSIONS: Treating older adults with bipolar disorder under standardized treatment is feasible and is associated with low symptom levels. However, most older adults with bipolar disorder do not experience sustained recovery.
INTRODUCTION: Pain and depression are mutually exacerbating. We know that both of these syndromes predict the future occurrence of the other. It has not been shown, however, whether the presence of pain slows the effect of treatment for depression. We hypothesized that greater pain and somatic scores prior to treatment with imipramine and interpersonal psychotherapy would predict a slowed time to remission from depression. METHOD: We performed secondary data analyses of an archived study. Subjects (N = 230) were between 21 and 65 years of age and were enrolled in a study of maintenance treatment for recurrent unipolar depression. Patients had to meet Research Diagnostic Criteria (RDC) for a major depressive episode and historical requirements for at least 3 prior episodes and clear remissions (according to RDC). Patients were also required to have a minimum Hamilton Rating Scale for Depression score of 15 and a minimum score of 7 on the Raskin Severity of Depression Scale. This report describes the acute treatment phase, during which all subjects received combination therapy consisting of imipramine hydrochloride (150 to 300 mg) and interpersonal psychotherapy. Pain and somatization were measured with the Hopkins Symptom Checklist. RESULTS: Higher levels of both pain and somatization predicted a longer time to remission. After controlling for baseline severity of depression, only pain was still significant in predicting a longer time to remission. Headache and muscle soreness were the 2 variables from the pain index whose presence independently predicted a slower remission. Both pain and somatization improved during acute treatment. Subjects with more pain and somatization, after controlling for severity of depression, reported more suicidality. Women reported more pain than men. CONCLUSIONS: Pain, but not somatization, predicted a longer time to remission and may be a marker of a more difficult-to-treat depression. Adults with recurrent depression should be screened for the presence of pain prior to treatment, as the presence of these symptoms may require more aggressive treatment or may be a marker for suicidality or the use of dual-mechanism antidepressants.
Depressive disorders are common, recurrent, and chronic, and require treatment A review of the symptom picture and current drug targets demonstrates the need for accurate assessment of depression severity, including suicidality. The initial focus of treatment is rapid resolution of symptoms during an acute phase, followed by continuation. Maintenance treatment is indicated if the risk of recurrence is high. The range of available medications is considerable and the benefit/risk ratio is acceptable. Depression is diagnosable across the life span and treatable at every age (although recent disagreement has arisen with regard to young patients). Comorbidity, both psychiatric and medical, need to be assessed, as does the possible presence of two subtypes of depression (psychotic and bipolar) often requiring different interventions. It is expected that the next generation of antidepressants would be associated with more specific disease and outcome biomarkers.
This review focuses on information concerning antidepressants and psychotherapy in the treatment of both acute and chronic forms of unipolar depression in the English language literature. In it, we address the use of combination therapy, both from the outset of treatment and in a variety of sequences, ie, we examine the potential advantages of adding a targeted psychotherapy to an incompletely effective pharmacotherapy and the potential advantages of adding pharmacotherapy to an incompletely effective psychotherapy. The number of research reports available to address these questions is small relative to their importance for clinical practice. There is a clear need for more information about the relative efficacy of pharmacotherapy-psychotherapy combinations or sequences versus either pharmacotherapy or psychotherapy provided as monotherapies.
Previous studies have suggested abnormal cerebral lateralization in major depressive disorder (MDD). Few controlled MRI studies have investigated the corpus callosum (CC), the largest commissura connecting the two cerebral hemispheres, in MDD. This study investigated anatomical abnormalities in the CC and its subdivisions in MDD patients. Twenty-two unmedicated MDD patients and 39 healthy subjects underwent brain magnetic resonance imaging (MRI). Measurements of the CC and its sub-regions were performed with a semi-automated software (NIH Image, version 1.62). ANCOVA with age, gender, and intra-cranial volume (ICV) as covariates showed no significant differences in CC measurements between patients and controls (df=1,56; p>0.05). However, patients with familial MDD had a significantly larger middle genu area (F(1,45)=4.252; p=0.045) compared to healthy controls, and significantly larger middle genu (F(1,13)=5.366; p=0.037), anterior splenium (F(1,13)=6.27; p=0.026), and middle splenium areas (F(1,13)=4.706; p=0.049) compared to patients with non-familial MDD. Although preliminary, our findings suggest that anatomical abnormalities in CC may be restricted to patients with familial MDD, with possible enlargement of CC in this particular sub-group. The possible role of callosal abnormalities in the pathogenesis of mood disorders should be further examined.
Morphometric MRI studies suggest decreased hippocampal volumes in currently depressed patients, with conflicting findings for the amygdala. We studied these temporal lobe structures and superior temporal gyrus (STG) in patients with current and remitted major depression. We scanned 31 unmedicated depressed patients (21 currently depressed, 10 remitted) and 31 matched healthy controls with a 3D SPGR sequence in a 1.5 Tesla GE Signa Imaging System. There was a trend towards smaller left amygdala volumes in all depressed patients compared with healthy controls. We found significantly smaller hippocampal volumes bilaterally in currently depressed patients than in remitted patients. Furthermore, we found a statistically significant inverse correlation between length of illness and left hippocampus volumes and right superior temporal gyrus volumes. Our finding of smaller hippocampi in currently depressed patients is consistent with the hypothesis that hypercortisolism could result in hippocampal neurotoxicity in major depression. A smaller hippocampal size may be more characteristic of the depressive state and not be present in remitted patients.
STUDY OBJECTIVES: The mechanisms that maintain wakefulness across the day, in the face in increasing sleep drive, are largely unknown. The goal of this pilot study was to examine regional relative brain glucose metabolism during morning and evening wakefulness in healthy humans. DESIGN: [18F]-fluorodeoxyglucose positron emission tomography scans were conducted during quiet wakefulness in the morning and in the evening. Statistical parametric mapping was used to compare relative regional glucose metabolism during the 2 scans. Subjects also completed subjective ratings of alertness. SETTING: University of Pittsburgh General Clinical Research Center and Positron Emission Tomography Facility. PATIENTS OR PARTICIPANTS: Thirteen healthy adults (10 women, 3 men; mean age, 37 years) INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Relative regional glucose metabolism was significantly higher in the evening than in the morning in a large cluster of midline and brainstem structures. Volumes of interest centered on the pontine reticular formation, midbrain reticular formation, midbrain raphe, locus coeruleus, and posterior hypothalamus also showed higher relative metabolism in the evening than in the morning. Relative glucose metabolism was significantly lower in the evening than in the morning in clusters that included structures in the right temporal cortex and occipital lobe, including cuneus and medial occipital gyrus. CONCLUSIONS: Evening wakefulness is associated with increased relative metabolism in brainstem and hypothalamic arousal systems and decreased relative metabolism in posterior cortical regions. These patterns may reflect input from the circadian timing system to promote wakefulness, and/or the effects of increasing homeostatic sleep drive.