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Biomedical subjects

William J Burke

Publications and source records attributed to William J Burke.

At least 19 recordsLinked to original sources
PubMed2006

Number of risk genotypes is a risk factor for major depressive disorder: a case control study.

BACKGROUND: The objective of the study was to determine the genetic basis of Major Depressive Disorder, and the capacity to respond to antidepressant treatment. An association study of 21 candidate polymorphisms relevant to monoamine function and the mechanism of antidepressant response was conducted in 3 phenotypically distinct samples: a group with chronic or recurrent depression unable to respond to antidepressants (non-responders) (n = 58), a group capable of symptomatic improvement with or without treatment (responders) (n = 39), and volunteer controls (n = 85). The responders and non-responders constituted a larger group of depressed subjects. METHODS: A candidate gene approach was employed to asses the genetics basis of Major Depressive Disorder. The genotypic frequencies of selected polymorphisms were compared between the controls and depressed subjects. To asses the genetics basis of the capacity to respond to antidepressant treatment, the responders were compared to the non-responders. Candidate genes were chosen based on functional studies and proximity to whole genome linkage findings in the literature. Risk genotypes were identified by previous functional studies and association studies. RESULTS: A statistically significant difference in genotype frequency for the SLC6A4 intron 2 VNTR was detected between the subjects with a history of depression and controls (p = 0.004). Surprisingly, a statistically significant difference was detected between responders and non-responders for the DRD4 exon III VNTR genotype frequencies (p = 0.009). Furthermore, a difference between the controls and depressed subjects as well as between the controls and non-responders was detected for the number and distribution of risk genotypes in each group. CONCLUSION: An association between several monoamine-related genes and Major Depressive Disorder is supported. The data suggest that the two depressive phenotypes are genetically different, inferring that the genetic basis for the capacity to respond to standard antidepressant treatment, and the genetic susceptibility to Major Depressive Disorder may be independent. In addition, a proof of concept is provided demonstrating that the number of risk genotypes may be an indication of susceptibility of major depressive disorder and the severity of the disorder.

Journal Article↗
PubMed2005

Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial.

BACKGROUND: Vagus nerve stimulation (VNS) alters both concentrations of neurotransmitters or their metabolites and functional activity of central nervous system regions dysregulated in mood disorders. An open trial has suggested efficacy. METHODS: This 10-week, acute, randomized, controlled, masked trial compared adjunctive VNS with sham treatment in 235 outpatients with nonpsychotic major depressive disorder (n = 210) or nonpsychotic, depressed phase, bipolar disorder (n = 25). In the current episode, participants had not responded adequately to between two and six research-qualified medication trials. A two-week, single-blind recovery period (no stimulation) and then 10 weeks of masked active or sham VNS followed implantation. Medications were kept stable. Primary efficacy outcome among 222 evaluable participants was based on response rates (>/=50% reduction from baseline on the 24-item Hamilton Rating Scale for Depression [HRSD(24)]). RESULTS: At 10-weeks, HRSD(24) response rates were 15.2% for the active (n = 112) and 10.0% for the sham (n = 110) groups (p = .251, last observation carried forward [LOCF]). Response rates with a secondary outcome, the Inventory of Depressive Symptomatology - Self-Report (IDS-SR(30)), were 17.0% (active) and 7.3% (sham) (p = .032, LOCF). VNS was well tolerated; 1% (3/235) left the study because of adverse events. CONCLUSIONS: This study did not yield definitive evidence of short-term efficacy for adjunctive VNS in treatment-resistant depression.

Adult↗
PubMed2004

Neurotoxicity of MAO metabolites of catecholamine neurotransmitters: role in neurodegenerative diseases.

The monoamine oxidase (MAO) metabolites of norepinephrine (NE) or epinephrine (EPI) and of dopamine (DA) are 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) and 3,4-dihydroxyphenylacetaldehyde (DOPAL), respectively. The toxicity of these catecholamine (CA) MAO metabolites was predicted over 50 years ago. However, until our recent chemical synthesis of these CA aldehyde metabolites, the hypothesis about their toxicity could not be tested. The present paper reviews recent knowledge gained about these compounds. Topics to be reviewed include: chemical synthesis and properties of DOPEGAL and DOPAL; in vitro and in vivo toxicity of CA aldehydes; subcellular mechanisms of toxicity; free radical formation by DOPEGAL versus DOPAL; mechanisms of accumulation of CA aldehydes in Alzheimer's disease (AD) and Parkinson's disease (PD) and potential therapeutic targets in Alzheimer's disease and Parkinson's disease.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2004

Atomoxetine in the treatment of attention deficit hyperactivity disorder.

Atomoxetine (Strattera, Eli Lilly & Co.) is a highly selective noradrenaline reuptake inhibitor and the first nonstimulant medication to be approved for the treatment of attention deficit hyperactivity disorder. Currently, nine published clinical trials have documented the safety and efficacy of atomoxetine in the treatment of children, adolescents and adults with attention deficit hyperactivity disorder and data presented throughout the past year at national scientific meetings has further addressed its utility. This article reviews the available information on atomoxetine, accompanied by a discussion of its clinical use.

Adrenergic Uptake Inhibitors↗
PubMed2004

Escitalopram: better treatment for depression is through the looking glass.

Depression remains a common and often devastating illness. With the introduction of the selective serotonin reuptake inhibitors in the 1980s, patients were afforded treatment for depression that was both safer and better tolerated than any prior treatment modality offered. Although selective serotonin reuptake inhibitors quickly became the most widely used medications for the treatment of depression, no single agent has been recognized as an obvious first-line choice. Chirality potentially offers one method to improve upon the selective serotonin reuptake inhibitor class. For racemic compounds that differ in stereospecificity, separation into single enantiomers can result in significant changes in potency, tolerability and efficacy. One of the most widely prescribed selective serotonin reuptake inhibitors is citalopram, which exists as a racemic mixture of R- and S-enantiomers. The S-enantiomer escitalopram (Cipralex, Lundbeck) is the therapeutically active portion of the parent compound and has a proven antidepressant efficacy. The R-enantiomer lacks activity as an antidepressant and has been shown to inhibit the effect of the S-enantiomer when the two are combined. Escitalopram is the most selective member of its class and with minimal effects on the cytochrome P450 system, has a negligible potential for drug-drug interactions. In placebo-controlled trials, escitalopram has consistently demonstrated symptomatic improvement as early as the first to second week of treatment. In addition to antidepressant efficacy, escitalopram also appears to exhibit significant anxiolytic properties. It has also shown efficacy in treating panic disorder and generalized and social anxiety disorders. This is advantageous as many patients who suffer from depression also experience comorbid anxiety disorders.

Antidepressive Agents, Second-Generation↗
PubMed2004

The role of stimulants in the treatment of preschool children with attention-deficit hyperactivity disorder.

The symptoms of attention-deficit hyperactivity disorder (ADHD) can have an early onset, beginning before the age of 6 years. Despite the significant number of preschool-aged children that can be diagnosed with ADHD, there are limited controlled data available on the pharmacological interventions being increasingly used in this population. A 1990 review showed that 34% of paediatricians and 15% of family physicians had prescribed psychostimulant medications to preschoolers with ADHD, and pharmacoepidemiological studies indicate growing use of stimulants in preschoolers during the 1990s. Unfortunately, only six controlled trials, with a total enrollment of less than 200 children, have been conducted using these drugs in preschoolers. While these small studies provide some evidence of benefit from the use of methylphenidate in preschoolers with ADHD, more data are critically needed. Practice parameters developed by the American Academy of Child & Adolescent Psychiatry and the American Academy of Pediatrics provide some guidance regarding the diagnosis and treatment of young children with ADHD, but are mainly based upon research in children of primary-school age. The ongoing PATS (Preschool ADHD Treatment Study), funded by the National Institute of Mental Health, will provide important clinical guidance for diagnostic considerations and intervention strategies for children with ADHD aged 3-5 years. Pending the release of data from the PATS study, clinicians must rely on developmental assessment skills, available standardised rating instruments, reports about the child from multiple informants, and knowledge of the risks and benefits of available pharmacological and behavioural treatments, in order to treat preschool children with ADHD effectively.

Attention Deficit Disorder with Hyperactivity↗
PubMed2004

Selective versus multi-transmitter antidepressants: are two mechanisms better than one?

The issue of selectivity versus efficacy has now reappeared as newer agents have emerged that are less selective than the selective serotonin reuptake inhibitors (SSRIs) but more selective than the tricyclic antidepressants (TCAs). This article provides a critical examination of the clinical literature concerning what evidence there is for differential efficacy. Two broad areas will be discussed: (1) comparisons of SSRIs to TCAs and (2) comparisons of the SSRIs to a somewhat more selective compound (by comparison to the TCAs), venlafaxine. This review should caution one in accepting claims of superiority of any agent based on purported mechanism of action.

Antidepressive Agents, Tricyclic↗
PubMed2003

3,4-Dihydroxyphenylacetaldehyde is the toxic dopamine metabolite in vivo: implications for Parkinson's disease pathogenesis.

In Parkinson's disease (PD), there is a highly selective loss of dopamine (DA) neurons in the substantia nigra (SN) greater than in the ventral tegmental area (VTA). The simplest explanation for selective DA neuron loss in PD is that DA is toxic and, because only DA neurons contain significant amounts of DA, this highly localized synthesis of DOPAL accounts for selective vulnerability of DA neurons. However, the large concentrations of DA required to produce in vivo toxicity cast doubt on its role in PD pathogenesis. Alpha-synuclein (alpha-syn) is the major component of the Lewy body, the pathological marker of PD, and is genetically linked to the disease. Recent studies indicate that alpha-syn neurotoxicity is mediated by a free radical generating metabolite of DA. Here we test the hypothesis that 3,4-dihydroxyphenylacetaldehyde (DOPAL), the monamine oxidase metabolite of DA, mediates DA toxicity in vivo. We injected DOPAL, DA and its oxidative, reduced and methylated metabolites into rat SN and VTA. Five days post-surgery, the injection sites were evaluated in Nissl preparations and with tyrosine hydroxylase (for DA neurons), neuronal nuclear antigen (for neurons) and glial fibrillary acidic protein (for astrocytes) immunoreactivities. Lesion size in SN vs. VTA was compared using morphometry. DOPAL at concentrations as low as 100 ng was toxic to DA SN neurons>DA VTA neurons>glia. Neither DA nor its other metabolites showed evidence of neurotoxicity at fivefold higher doses. However, 20 microg of DA produced lesions in the SN and VTA. We conclude that DOPAL is the toxic DA metabolite in vivo. Implications for a unified hypothesis for PD pathogenesis are discussed.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2003

Focus on the locus.

Explore the source record for details and available documents.

Cognition Disorders↗
PubMed2003

Late-life mood disorders.

Mental disorders are not uncommon in late life. Although most psychiatric disorders occur less frequently in older populations compared with populations of younger adults, more than 10% of older adults have one or more psychiatric disorders. In addition, many older adults present with symptoms that do not meet the criteria for a specific disorder but nevertheless are clinically significant and affect quality of life. In this article the authors summarize the epidemiologic data for five psychiatric disorders and their subclinical forms: depression, anxiety, dementia, schizophrenia, and alcoholism. Also included is a discussion of risk factors and outcomes of these disorders.

Aged↗
PubMed2003

Diagnosis and treatment of alcohol dependence in older alcoholics.

Treatment of alcohol dependence among older alcoholic patients should be multidimensional to address as many potential relapse factors as possible. As the literature suggests, alcohol-related disorders often are under diagnosed and under treated. More efforts are needed to identify and improve diagnosis of these disorders in older alcoholic patients. For better outcomes, age-specific programs should be implemented. Furthermore, when treating elderly patients, basic therapeutic principles like respect for privacy and a respectful attitude should be adopted. Adequate medical, pharmacologic, and psychiatric treatment should be provided when appropriate. Medication to reduce cravings should be considered in patients without contraindications to its use. Participation in individual, group, and family therapy and attendance at self-help group meetings such as AA should be encouraged (Table 8). Despite the lack of empiric testing to validate these recommendations in an elderly population, clinical experience suggests that adherence to these recommendations will benefit elderly patients just as it has the general adult population. Research is necessary to explore the benefits of alcohol treatments in elderly patients. Until then, adherence to these recommendations should be the best available approach.

Aged↗
PubMed2003

Atomoxetine: a selective noradrenaline reuptake inhibitor for the treatment of attention-deficit/hyperactivity disorder.

Atomoxetine (Strattera, Eli Lilly & Co.) is a selective noradrenaline reuptake inhibitor that has been studied for use in the treatment of attention-deficit/hyperactivity disorder (ADHD). So far, two open-label and seven randomised, double-blind, placebo-controlled, clinical trials have been published, six in youths and three in adults. Each of these trials has shown a positive response as measured by the primary efficacy measures, the ADHD-IV Rating Scale (ADHD RS) or the Conners Adult ADHD Rating Scale (CAARS). Atomoxetine has generally been well tolerated. In November of 2002 the FDA approved atomoxetine for use in the US for the treatment of ADHD in children, adolescents and adults. Atomoxetine is the first nonstimulant approved by the FDA for the treatment of ADHD and the first medication approved for the treatment of adult ADHD.

Absorption↗
PubMed2002

Pharmacotherapy of childhood anxiety disorders.

Anxiety disorders are among the most common psychiatric disorders of childhood, yet limited data is available regarding the use of psychotropic medications for these conditions. Until recently, much of the data on the pharmacologic treatment of pediatric anxiety disorders has consisted of case reports and small open-label studies, with the exception of pediatric obsessive-compulsive disorder (OCD), which has had a comparatively rich literature consisting of several double blind trials. This void has been lessening, however, with four double blind, placebo-controlled studies published in the past year alone. Although the majority of pharmacologic studies of pediatric anxiety continue to focus on the treatment of OCD, additional reports on treatment of generalized anxiety disorder, panic disorder, social anxiety disorder, and separation anxiety disorder have recently been published. This article will review significant pharmacologic studies published in the prior year, and the role of pharmacotherapy in the treatment of pediatric anxiety disorders.

Anxiety Disorders↗
PubMed2002

Age at onset of major depressive disorder predicts reductions in NK cell number and activity.

BACKGROUND: Major depressive disorder (MDD) has been associated with altered immunologic parameters including reductions in natural killer cell activity (NKCA). It remains largely unknown, however, whether alterations in immune function characterize homogeneous sub-groups of MDD. The present study addressed the question of whether age at onset of index episode and/or duration of the present episode of MDD predicted alterations in NKCA and NK cell number. METHODS: Participants met DSM-IV criteria for MDD. Age at onset of MDD, duration of the present episode, demographics, and comorbidity were obtained by SCID for all subjects (n = 36). Severity and symptom pattern of MDD was assessed by the Hamilton Depression Rating Scale. NKCA was measured using a standard chromium-release cytotoxicity assay and NK number assessed by flow cytometry. RESULTS: Age at onset of MDD significantly predicted variance in NK cell number and NKCA. Consistent with previous studies, sleep disturbance and psychomotor retardation possessed significant explanatory power for variance in NK cell number and NKCA, respectively. LIMITATIONS: Measures of age at onset of MDD and duration of the present episode were obtained by self-report and thus recall bias may attenuate the reliability of the present findings. The present study design also precludes conclusions regarding the temporal association between alterations in NK cells and MDD. CONCLUSIONS: We propose that immunologic alterations, characterized by a suppression of NKCA and NK cell number concomitant with proinflammatory processes, may constitute an immunologic phenotype unique to early-age-onset depression and may be salient factors in the pathogenesis of depression.

Adult↗