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Biomedical subjects

David L Dunner

Publications and source records attributed to David L Dunner.

At least 37 records · Page 2Linked to original sources
PubMed2004

Lithium and valproic acid treatment effects on brain chemistry in bipolar disorder.

BACKGROUND: Prior work reported elevated gray matter (GM) lactate and Glx (glutamate + glutamine + GABA) concentrations in unmedicated patients with bipolar disorder (BP) compared with healthy controls (HC). This study examined whether lithium (Li) and valproic acid (VPA) treatment modulated these chemicals. METHODS: A subset of previously reported BP patients were treated with Li (n = 12, 3.6 +/- 1.9 months) or VPA (n = 9, 1.4 +/- 1.7 months) and compared untreated HC subjects (n = 12, 2.9 +/- 2.4 months) using proton echo-planar spectroscopic imaging. Regression analyses (voxel gray/white composition by chemistry) were performed at each time point, and change scores computed. Metabolite relaxation and regions of interest (ROI) were also examined. RESULTS: Across treatment, Li-treated BP subjects demonstrated GM Glx decreases (Li-HC, p =.08; Li-VPA p =.04) and GM myo-inositol increases (Li-HC p =.07; Li-VPA p =.12). Other measures were not significant. Serum Li levels were positively correlated with Glx decreases at the trend level. CONCLUSIONS: Li treatment of BP was associated with specific GM Glx decreases and myo-inositol increases. Findings are discussed in the context of cellular mechanisms postulated to underlie Li and VPA therapeutic efficacy.

Adult↗
PubMed2004

Frontal lobe gray matter density decreases in bipolar I disorder.

BACKGROUND: This study was conducted to explore differences in gray and white matter density between bipolar and healthy comparison groups using voxel-based morphometry (VBM). METHODS: Brain magnetic resonance imaging was performed for 39 subjects with bipolar I disorder and 43 comparison subjects. Images were registered into a proportional stereotaxic space and segmented into gray matter, white mater, and cerebrospinal fluid. Statistical parametric mapping was used to calculate differences in gray and white matter density between groups. RESULTS: Bipolar subjects had decreased gray matter density in left anterior cingulate gyrus (Brodmann's area [BA] 32, 7.3% decrease), an adjacent left medial frontal gyrus (BA 10, 6.9% decrease), right inferior frontal gyrus (BA 47, 9.2% decrease), and right precentral gyrus (BA 44, 6.2% decrease), relative to comparison subjects. CONCLUSIONS: The observation of a gray matter density decrease in the left anterior cingulate, which processes emotions, in bipolar subjects is consistent with prior reports that used region-of-interest analytic methods. Decreased gray matter density in the right inferior frontal gyrus, which processes nonverbal and intrinsic functions, supports nondominant hemisphere dysfunction as a component of bipolar disorder.

Adolescent↗
PubMed2004

Brain metabolic alterations in medication-free patients with bipolar disorder.

BACKGROUND: Bipolar disorder (BD) has substantial morbidity and incompletely understood neurobiological underpinnings. OBJECTIVE: To investigate brain chemistry in medication-free individuals with BD. DESIGN: Two-dimensional proton echo-planar spectroscopic imaging (PEPSI) (32 x 32, 1-cm(3) voxel matrix) acquired axially through the cingulate gyrus was used to quantify regional brain chemistry. SETTING: The Center for Anxiety and Depression at the University of Washington in Seattle and the Bipolar Research Programs at McLean Hospital and the Massachusetts General Hospital in Boston. PARTICIPANTS: Thirty-two medication-free outpatients with a diagnosis of BD type I (BDI) or BD type II (BDII), predominantly in a depressed or mixed-mood state, were compared with 26 age- and sex-matched healthy controls. MAIN OUTCOME MEASURES: Tissue type (white and gray) and regional analyses were performed to evaluate distribution of lactate; glutamate, glutamine, and gamma-aminobutyric acid (Glx); creatine and phosphocreatine (Cre); choline-containing compounds (Cho); N-acetyl aspartate; and myo-inositol. Chemical relationships for diagnosis and mood state were evaluated. RESULTS: Patients with BD exhibited elevated gray matter lactate (P =.005) and Glx (P =.007) levels; other gray and white matter chemical measures were not significantly different between diagnostic groups. Isolated regional chemical alterations were found. An inverse correlation between 17-item Hamilton Depression Rating Scale scores and white matter Cre levels was observed for BD patients. CONCLUSIONS: Gray matter lactate and Glx elevations in medication-free BD patients suggest a shift in energy redox state from oxidative phosphorylation toward glycolysis. The possibility of mitochondrial alterations underlying these findings is discussed and may provide a theoretical framework for future targeted treatment interventions.

Adult↗
PubMed2004

Cognitive-behavioral analysis system of psychotherapy as a maintenance treatment for chronic depression.

Although the efficacy of maintenance pharmacotherapy for the prevention of recurrence in major depressive disorder (MDD) is well documented, few studies have tested the efficacy of psychotherapy as a maintenance treatment. The authors examined the efficacy of the cognitive-behavioral analysis system of psychotherapy (CBASP) as a maintenance treatment for chronic forms of MDD. Eighty-two patients who had responded to acute and continuation phase CBASP were randomized to monthly CBASP or assessment only for 1 year. Significantly fewer patients in the CBASP than assessment only condition experienced a recurrence. The 2 conditions also differed significantly on change in depressive symptoms over time. These findings support the use of CBASP as a maintenance treatment for chronic forms of MDD.

Adolescent↗
PubMed2004

A review of antidepressant-induced hypomania in major depression: suggestions for DSM-V.

OBJECTIVES: To determine if the classification of 'antidepressant-induced hypomania' in DSM-IV is supported by available data. METHODS: We reviewed the available scientific literature to examine the incidence of mania and hypomania in non-bipolar patients who were treated with antidepressants. RESULTS: Eighty-nine per cent of studies of antidepressants in major depressive disorder patients reported no cases of treatment-induced hypomania. No instances of treatment-induced hypomania were reported in three large studies of patients with chronic forms of depression. CONCLUSIONS: The rate of antidepressant-induced hypomania in major depressive disorder is within the rate of misdiagnosis of bipolar depression as unipolar. Depressed patients who experience antidepressant-associated hypomania are truly bipolar.

Antidepressive Agents↗
PubMed2004

The effectiveness of St. John's Wort in major depressive disorder: a naturalistic phase 2 follow-up in which nonresponders were provided alternate medication.

BACKGROUND: A continuation study of an extract of St. John's wort (Hypericum perforatum) for depression was performed in follow-up to an acute study that found no significant difference between St. John's wort extract and placebo. METHOD: Seventeen subjects with DSM-IV-defined major depressive disorder who responded to St. John's wort extract in the acute-phase study (phase 1) were continued on double-blind treatment with the same preparation for 24 weeks. Ninety-five subjects who did not respond to either St. John's wort or placebo were treated with an antidepressant for 24 weeks. RESULTS: During antidepressant treatment, mean scores on the Hamilton Rating Scale for Depression for phase 1 nonresponders decreased significantly (p <.0001), with no significant difference between St. John's wort nonresponders and placebo nonresponders. Of the 17 subjects continued on treatment with St. John's wort extract, 5 (29.4%) relapsed. CONCLUSIONS: The subjects who did not respond to St. John's wort extract or placebo in phase 1 were, by and large, not resistant to antidepressant treatment. This suggests that the lack of efficacy found by Shelton et al. in the acute-phase study was unlikely to be the result of a high proportion of treatment-resistant subjects.

Adult↗
PubMed2004

Correlates of suicidal behavior and lithium treatment in bipolar disorder.

Individuals with bipolar and major depressive disorders have considerably higher suicide rates than the general population. However, estimating the risk of suicide is complicated, and there exists a general lack of consensus among researchers regarding whether suicide rates are higher in patients with unipolar, bipolar I, or bipolar II depressive disorders. Isolating the specific factors that contribute to the high risk of suicide in patients with affective disorders can be challenging as well; substance and alcohol abuse, family history of suicide, differences in allele distributions, comorbid anxiety, depression recurrence, seasonal effects, rapid cycling, and a history of hospitalizations for depression all appear to contribute to the likelihood that these patients will engage in suicidal behavior. Research does tend to agree that lithium is efficacious in decreasing suicidal behavior in patients with affective disorders.

Anticonvulsants↗
PubMed2003

Differential responses to psychotherapy versus pharmacotherapy in patients with chronic forms of major depression and childhood trauma.

Major depressive disorder is associated with considerable morbidity, disability, and risk for suicide. Treatments for depression most commonly include antidepressants, psychotherapy, or the combination. Little is known about predictors of treatment response for depression. In this study, 681 patients with chronic forms of major depression were treated with an antidepressant (nefazodone), Cognitive Behavioral Analysis System of Psychotherapy (CBASP), or the combination. Overall, the effects of the antidepressant alone and psychotherapy alone were equal and significantly less effective than combination treatment. Among those with a history of early childhood trauma (loss of parents at an early age, physical or sexual abuse, or neglect), psychotherapy alone was superior to antidepressant monotherapy. Moreover, the combination of psychotherapy and pharmacotherapy was only marginally superior to psychotherapy alone among the childhood abuse cohort. Our results suggest that psychotherapy may be an essential element in the treatment of patients with chronic forms of major depression and a history of childhood trauma.

Adolescent↗
PubMed2003

Randomized, placebo-controlled trial of nefazodone maintenance treatment in preventing recurrence in chronic depression.

BACKGROUND: Maintenance treatment to prevent recurrences is recommended for chronic forms of major depressive disorder (MDD), but few studies have examined maintenance efficacy of antidepressants with chronic MDD. This randomized, placebo-controlled study of the efficacy and safety of nefazodone in preventing recurrence was conducted for patients with chronic MDD. METHODS: A total of 165 outpatients with chronic, nonpsychotic MDD, MDD plus dysthymic disorder ("double-depression"), or recurrent MDD with incomplete inter-episode recovery, who achieved and maintained a clinical response during acute and continuation treatment with either nefazodone alone or nefazodone combined with psychotherapy, were randomized to 52 weeks of double-blind nefazodone (maximum dose 600 mg/day) or placebo. The occurrence of major depressive episodes during maintenance treatment was assessed with the 24-item Hamilton Rating Scale for Depression, a DSM-IV MDD checklist, and a blinded review of symptom exacerbations by a consensus committee of research clinicians. RESULTS: Application of a competing-risk model that estimated the conditional probability of recurrence among those patients remaining on active therapy revealed a significant (p =.043) difference between nefazodone (n = 76) and placebo (n = 74) when the latter part of the 1-year maintenance period was emphasized. At the end of 1 year, the conditional probability of recurrence was 30.3% for nefazodone-treated patients, compared with 47.5% for placebo-treated patients. Prior concomitant psychotherapy during acute/continuation treatment, although enhancing the initial response, was not associated with lower recurrence rates. Discontinuations due to adverse events were relatively low for both nefazodone (5.3%) and placebo (4.8%). Somnolence was significantly greater among the patients taking active medication (15.4%), compared with placebo (4.6%). CONCLUSIONS: Nefazodone is well-tolerated and is an effective maintenance therapy for chronic forms of MDD.

Acute Disease↗
PubMed2003

The effects of psychotherapy, nefazodone, and their combination on subjective assessment of disturbed sleep in chronic depression.

STUDY OBJECTIVES: The purpose of the study was to compare the effects of psychotherapy, nefazodone, and their combination on subjective measures of sleep in patients with chronic forms of major depression. DESIGN: Participants were randomized to receive 12 weeks of treatment with one of the three interventions. SETTING: The study was conducted in parallel at 12 academic institutions and was approved by the Human Subjects Committee at each site. PARTICIPANTS: 484 adult outpatients (65.29% female) who met DSM-IV criteria for one of three chronic forms of major depression. INTERVENTIONS: Psychotherapy (16-20 sessions) was provided by certified therapists following a standardized treatment manual for Cognitive Behavioral Analysis System of Psychotherapy (CBASP), a variant of cognitive psychotherapy developed for chronic depression. Pharmacotherapy consisted of open-label nefazodone, 300-600 mg per day in two divided doses prescribed by psychiatrists. The clinical management visits were limited to 15-20 minutes and followed a standardized protocol. Combination treatment consisted of both therapies. MEASUREMENTS AND RESULTS: Depression outcome was determined by the 24-item Hamilton Rating Scale for Depression and the 30-item Inventory of Depressive Symptomatology-Self Rating. Sleep outcome was measured prospectively with daily sleep diaries that were completed a week prior to HRSD assessments at baseline and after 1, 2, 3, 4, 8, and 12 weeks of treatment. Although nefazodone alone and CBASP alone had comparable impact on global measures of depression outcome, only monotherapy with nefazodone improved early morning awakening and total sleep time. Significant improvements in sleep quality, time awake after sleep onset, latency to sleep onset, and sleep efficiency were present in each of the three treatment groups. These improvements, however, occurred earlier in the course of treatment for participants receiving nefazodone, alone or in combination with CBASP. CONCLUSIONS: Nefazodone therapy may have a direct impact on disturbed sleep associated with depression beyond what would be expected if the improvements were all a consequence of improved depression.

Adolescent↗
PubMed2003

Duloxetine in treatment of anxiety symptoms associated with depression.

Most patients with major depressive disorder (MDD) have symptoms of anxiety associated with their depression. Duloxetine, a potent and balanced dual serotonin and norepinephrine reuptake inhibitor, is effective in the treatmentof depression. We investigated its effects in treating the symptoms of anxiety in depressed patients. This investigation includes all the placebo-controlled studies of duloxetine in MDD but focuses on four trials in which duloxetine was superior to placebo on the primary outcome measure of the 17-item Hamilton Depression Rating Scale (HAMD(17)) total score. Studies 1 and 2 included duloxetine at 60 mg/d (the recommended starting and therapeutic dose) and placebo. Study 3 included duloxetine 120 mg/d (administered as 60 mg b.i.d.), fluoxetine 20 mg/d, and placebo. Study 4 included duloxetine 40 mg/d (administered as 20 mg b.i.d.), duloxetine 80 mg/d (administered as 40 mg b.i.d.), paroxetine 20 mg/d, and placebo. Anxiety was assessed in all studies using the HAMD anxiety/somatization subfactor and the anxiety-psychic item (HAMD Item 10). Studies 3 and 4 also included the Hamilton Anxiety Rating Scale (HAMA). Across the four studies, duloxetine at doses of >/=60 mg was compared with placebo on 10 outcomes and with either paroxetine or fluoxetine on 6 outcomes. In 8 comparisons, mean improvement for duloxetine was significantly greater than placebo at the last study visit and/or across all study visits. In 3 comparisons, the mean improvement for duloxetine was significantly greater than paroxetine or fluoxetine. In these studies, duloxetine provided rapid relief of anxiety symptoms associated with depression. Previous reports have summarized duloxetine's efficacy in treating the core emotional symptoms and painful physical symptoms associated with depression. Duloxetine's efficacy in treating a broad spectrum of symptoms associated with depression, including mood, anxiety, and painful physical symptoms, may be attributed to dual reuptake inhibition of both serotonin and norepinephrine. Efficacy in these three key symptom domains may in turn explain the high probabilities of remission (43-57%) observed in these studies.

Adult↗
PubMed2003

Olanzapine in the acute treatment of bipolar I disorder with a history of rapid cycling.

BACKGROUND: A substantial proportion of patients with bipolar disorder are characterized by a rapidly cycling course and are particularly resistant to conventional treatment. METHODS: This secondary analysis, defined a priori, was conducted on a larger data set from patients with bipolar I disorder to determine the efficacy of a 3-week treatment with the atypical antipsychotic olanzapine (5-20 mg/day, n=19) versus placebo (n=26) in patients with >or=4 episodes in the preceding year. RESULTS: Significantly fewer placebo patients completed treatment (34.6 vs. 73.7%, P=0.016), and more than half discontinued due to lack of efficacy (53.8 vs. 21.1%, P=0.035). Olanzapine reduced Young Mania Rating Scale (YMRS) total scores significantly more than placebo (-13.9 vs. -4.1, P=0.011). Clinical responses, defined as >or=50% improvement in YMRS, were achieved in 58% of olanzapine patients, compared with 28% of placebo patients (P=0.066). Extrapyramidal symptoms were not significantly changed in either group. Somnolence was the most common adverse event in both groups (olanzapine: 52.6%, placebo: 23.1%; P=0.060). No event occurred significantly more frequently with olanzapine than with placebo. No patients discontinued due to an adverse event. LIMITATIONS: The duration of this study was limited to 3 weeks, precluding conclusions about long-term efficacy of olanzapine. Moreover, a sizeable placebo effect was obtained, possibly masking optimal therapeutic effect. Despite these limitations, treatment differences in efficacy were highly significant. CONCLUSIONS: These results indicate that olanzapine was effective in reducing symptoms of mania and well tolerated in patients with bipolar I disorder with a rapid-cycling course.

Adult↗
PubMed2003

Treatment considerations for depression in the elderly.

While an episode of depression can first present in late life, it is more likely to be a recurrence of a disorder that began earlier in life or a continuation of a chronic form of depression. Depression in the elderly often occurs in the context of ongoing medical conditions. The treatment for these medical conditions may pose problems in treatment of depression due to increased likelihood of drug interactions. This article discusses pharmacotherapeutic and psychotherapeutic approaches to the treatment of depression in the elderly population.

Aged↗
PubMed2003

Treatment-resistant bipolar disorder: a comparison of rapid cyclers and nonrapid cyclers.

BACKGROUND: We investigated clinical factors to determine their relationship to treatment resistance among bipolar patients who had a consultation at a tertiary care facility. METHODS: Patients were separated into two categories: rapid-cycling disorders and nonrapid-cycling disorders. We hypothesized that there would be less usage of lithium carbonate among nonrapid-cycling treatment-resistant patients than among rapid cyclers and also that there would be higher rates of comorbidity seen among nonrapid-cycling than rapid-cycling patients in order to account for these particular patients being treatment resistant. FINDINGS: Continued recycling and persistent depression characterized rapid cyclers, whereas persistent depression characterized nonrapid cyclers. Less than 30% of patients had adequate lithium treatment and there was no significant difference comparing rapid cyclers with nonrapid cyclers. Rates of comorbidity were also not significantly different between these groups. We also assessed a number of other factors. CONCLUSION: Some of these factors were significant, but when a Bonferonni correction was applied, these significant differences were not maintained. The study of treatment resistance among nonrapid-cycling bipolar patients merits further research.

Adult↗
PubMed2003

Clinical consequences of under-recognized bipolar spectrum disorder.

The prevalence of bipolar disorder is higher than previously believed, especially when bipolar spectrum disorders (BSD) are taken into account, and may approach rates as high as 5%. Difficulties in diagnosing bipolar II and BSD arise from complexities associated with defining and diagnosing hypomania. Additionally, bipolar disorder and BSD are often misdiagnosed because of symptoms that overlap with other psychiatric disorders, particularly unipolar depression. Recognition of the broader spectrum of bipolar disorders and their adequate treatment is paramount because bipolar disorder exacts such a high personal and societal toll, with high rates of suicide and interpersonal problems and a substantial economic burden. Recognition can be improved with active screening, and screening tools such as the Mood Disorders Questionnaire can be easily included in the initial assessment of patients who present with depressive symptoms. Depressive episodes are common in patients who experience BSDs, and increasingly treatment approaches designed specifically for bipolar depression are being studied.

Bipolar Disorder↗
PubMed2003

Efficacy of controlled-release paroxetine in the treatment of late-life depression.

BACKGROUND: Depression is the second most common neuropsychiatric disorder in older Americans, with significant clinical and public health costs. Despite advances in treatment, late-life depression remains a clinical challenge. Although the selective serotonin reuptake inhibitors (SSRIs) are the most common pharmacologic intervention for late-life depression, few placebo-controlled trials have assessed the efficacy of SSRIs for this condition. METHOD: In this 12-week, multicenter, placebo-controlled, flexible-dose, double-blind, randomized trial, 319 elderly patients (mean age = 70 years) were treated with controlled-release paroxetine (paroxetine CR) up to 50 mg/day (N = 104), immediate-release paroxetine (paroxetine IR) up to 40 mg/day (N = 106), or placebo (N = 109). Patients met DSM-IV criteria for major depressive disorder and had a total score of 18 or more on the 17-item Hamilton Rating Scale for Depression (HAM-D). The primary efficacy measure was change from baseline to endpoint in HAM-D total score. RESULTS: The primary efficacy analysis showed an adjusted difference between change from baseline in HAM-D score for paroxetine CR and placebo of -2.6 (95% confidence interval [CI] = -4.47 to -0.73, p = .007) at the week 12 last-observation-carried-forward (LOCF) endpoint. The adjusted difference between paroxetine IR and placebo was -2.8 (95% CI = -4.65 to -0.99, p = .003) at week 12. Paroxetine CR and IR were more effective than placebo, with mean +/- SD endpoint HAM-D total scores of 10.0 +/- 7.41 and 10.0 +/- 7.10, respectively, for the active treatments compared with 12.6 +/- 7.34 for placebo. Response, defined as a score of 1 or 2 on the Clinical Global Impressions-global improvement scale, was achieved by 72% of paroxetine CR patients (LOCF; p < .002 vs. placebo), 65% of paroxetine IR patients (p = .06 vs. placebo), and 52% of placebo patients. Remission, defined as a HAM-D total score < or = 7, was achieved by 43% of paroxetine CR patients (LOCF; p = .009 vs. placebo), 44% of paroxetine IR patients (p = .01 vs. placebo), and 26% of placebo patients. In a post hoc analysis, mean HAM-D improvement for paroxetine CR and paroxetine IR was greater than for placebo in both chronically depressed patients (duration > 2 years) and those with short-term (< or = 2 years) depression. Dropout rates due to adverse events were 12.5% for paroxetine CR, 16.0% for paroxetine IR, and 8.3% for placebo. CONCLUSION: Paroxetine CR and paroxetine IR are effective and well tolerated treatments for major depressive disorder in elderly patients, including those with chronic depression.

Aged↗
PubMed2003

Drug interactions of lithium and other antimanic/mood-stabilizing medications.

Treatments for bipolar disorder often consist of a combination of 2 or more medications that have mood-stabilizing properties. Lithium is the only agent that has shown efficacy for the treatment of acute mania and acute depression as well as for the prevention of recurrence of mania and depression in patients with bipolar disorder. Other agents frequently used as mood stabilizers in monotherapy and in combination with lithium are valproate and carbamazepine. Several other drugs that have mood-stabilizing properties are used in many combinations to effectively manage the spectrum of symptoms of bipolar disorder throughout the acute and maintenance phases. However, side effects and drug-interaction precautions accompany all agents used to treat bipolar disorder, and often it can be difficult to determine whether a patient is suffering from side effects of treatment or symptoms of the illness itself. It is important to use the lowest effective dose of any treatment medication, to monitor laboratory values closely, and to be familiar with the side effects and interaction precautions of each medication that a patient is taking. Successful management of medications for the patient with bipolar disorder is a challenge, but increased effort and vigilance by clinicians mean a reduced risk of hospitalization and fewer office visits for patients.

Anticonvulsants↗