The use of placebos in unipolar major depression: the current status.
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Antidepressive Agents↗
Biomedical subjects
A J Rush
Publications and source records attributed to A J Rush.
Sleep electroencephalographic coherence abnormalities in individuals at high risk for depression: a pilot study.
BACKGROUND: Sleep electroencephalographic (EEG) studies of individuals with major depressive disorder have identified several microarchitectural features associated with the illness. These abnormalities are also found in clinically remitted individuals, raising the question of whether they are vulnerability markers of depression. This study evaluated the sleep EEG in high-risk individuals to see if abnormalities are present in the sleep EEG prior to the onset of illness. METHODS: A total of 26 subjects (13 males and 13 females) were recruited for study on the basis of 1) having a parent or grandparent treated for major depressive or bipolar affective disorder and 2) having no history of personal psychiatric illness. Polysomnographic data were collected and compared with gender- and age-matched healthy control subjects with no personal or family history of psychiatric illness. The primary outcome measures were interhemispheric and intrahemispheric coherence. RESULTS: Period analysis of the sleep EEG showed that beta-delta coherence was lower bilaterally in male high-risk subjects. Right-hemispheric theta-delta coherence was also lower in male high-risk subjects, with female high-risk subjects evidencing lower beta coherence. CONCLUSIONS: Sleep-EEG abnormalities associated with major depressive disorder are present in never mentally ill individuals at high risk for the illness. These markers may be useful in the prediction of illness and in family genetic studies of mood disorders.
Adolescent↗
Ultradian rhythms and temporal coherence in sleep EEG in depressed children and adolescents.
BACKGROUND: It has been suggested that a primary ultradian (80-120 minute) rhythm disturbance in EEG underlies sleep abnormalities in adults with depression. The present study evaluated ultradian rhythm disturbances in childhood and adolescent depression. METHODS: Sleep macroarchitecture and temporal coherence in quantitative EEG rhythms were investigated in 50 medication-free outpatients with major depression (25 children and 25 adolescents) and 15 healthy normal controls (5 children and 10 adolescents). RESULTS: Few of the macroarchitectural measures showed significant group effects. In fact, age and sex effects were stronger than disease-dependent components. Temporal coherence of EEG rhythms during sleep did differentiate those with MDD from controls. Both depressed children and adolescents had lower intrahemispheric coherence, whereas interhemispheric was only lower in depressed adolescents in comparison with controls. Gender differences were evident in adolescents, but not children, with MDD with lowest interhemispheric coherence in adolescent girls. CONCLUSIONS: These findings are in keeping with increased risk for depression in females beginning at adolescence and extending throughout adulthood. It was suggested that low temporal coherence in depression reflects a disruption in the fundamental basic rest-activity cycle of arousal and organization in the brain that is strongly influenced by gender.
Activity Cycles↗
Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study.
BACKGROUND: Vagus Nerve Stimulation (VNS) delivered by the NeuroCybernetic Prosthesis (NCP) System was examined for its potential antidepressant effects. METHODS: Adult outpatients (n = 30) with nonpsychotic, treatment-resistant major depressive (n = 21) or bipolar I (n = 4) or II (n = 5; depressed phase) disorders who had failed at least two robust medication trials in the current major depressive episode (MDE) while on stable medication regimens completed a baseline period followed by NCP System implantation. A 2-week, single-blind recovery period (no stimulation) was followed by 10 weeks of VNS. RESULTS: In the current MDE (median length = 4.7 years), patients had not adequately responded to two (n = 9), three (n = 2), four (n = 6), or five or more (n = 13) robust antidepressant medication trials or electroconvulsive therapy (n = 17). Baseline 28-item Hamilton Depression Rating Scale (HDRS(28)) scores averaged 38.0. Response rates (> or =50% reduction in baseline scores) were 40% for both the HDRS(28) and the Clinical Global Impressions-Improvement index (score of 1 or 2) and 50% for the Montgomery-Asberg Depression Rating Scale. Symptomatic responses (accompanied by substantial functional improvement) have been largely sustained during long-term follow-up to date. CONCLUSIONS: These open trial results suggest that VNS has antidepressant effects in treatment-resistant depressions.
Adolescent↗
Vagus nerve stimulation: a new tool for brain research and therapy.
Biological psychiatry has a long history of using somatic therapies to treat neuropsychiatric illnesses and to understand brain function. These methods have included neurosurgery, electroconvulsive therapy, and, most recently, transcranial magnetic stimulation. Fourteen years ago researchers discovered that intermittent electrical stimulation of the vagus nerve produces inhibition of neural processes, which can alter brain electrical activity and terminate seizures in dogs. Since then, approximately 6000 people worldwide have received vagus nerve stimulation for treatment-resistant epilepsy. We review the neurobiology and anatomy of the vagus nerve and provide an overview of the vagus nerve stimulation technique. We also describe the safety and potential utility of vagus nerve stimulation as a neuroscience research tool and as a putative treatment for psychiatric conditions. Vagus nerve stimulation appears to be a promising new somatic intervention that may improve our understanding of brain function and has promise in the treatment of neuropsychiatric disorders.
Brain↗
Platelet alpha2A-adrenoceptor function in major depression: Gi coupling, effects of imipramine and relationship to treatment outcome.
Studies suggest alpha2A-adrenoceptors (alpha(2A)AR) dysregulation in major depressive disorder (MDD). Platelet alpha(2A)ARs exist in high- and low-conformational states that are regulated by Gi protein. Although alpha(2A)AR coupling to Gi protein plays an important role in signal transduction and is modulated by antidepressants, it has not been previously investigated. Alpha2AR density in the high- and low-conformational states, agonist affinity and coupling efficiency were investigated in 27 healthy control subjects, 23 drug-free MDD patients and 16 patients after imipramine treatment using [3H]yohimbine saturation and norepinephrine displacement of [3H]yohimbine binding experiments. Coupling measures were derived from NE-displacement experiments. Patients had significantly higher alpha(2A)AR density, particularly in the high-conformational state, than control subjects. Coupling indices were normal in patients. High pre-treatment agonist affinity to the receptor in the high-conformational state and normal coupling predicted positive treatment outcome. Decreased coupling to Gi predicted a negative treatment outcome. Imipramine induced uncoupling (-11%) and redistribution of receptor density in treatment responders only, but had no effect on alpha(2A)AR coupling or density in treatment non-responders. Increased alpha(2A)AR density may represent a trait marker in MDD. The results provide indirect evidence for abnormal protein kinase A (PKA) and protein kinase C (PKC) in MDD which may be pursued in future investigations.
Adrenergic Uptake Inhibitors↗
Neutrophil beta(2)-adrenoceptor function in major depression: G(s) coupling, effects of imipramine and relationship to treatment outcome.
Abnormal beta(2)-adrenoceptor density and beta(2)-adrenoceptor-mediated cyclic adenosine monophosphate (cAMP) responses were inconsistently reported in major depressive disorder. Tricyclic antidepressants downregulate beta-adrenoceptor density and decrease coupling to G(s) protein. Abnormal beta-adrenoceptor coupling may exist in major depressive disorder and may relate to treatment response. We investigated beta(2)-adrenoceptor coupling to G(s) protein in 25 controls, 23 major depressive disorder drug-free patients and 16 major depressive disorder patients after chronic imipramine treatment using agonist displacement experiments. Pretreatment beta(2)-adrenoceptor coupling and density were normal in patients as a whole. Chronic imipramine induced beta(2)-adrenoceptor uncoupling. This effect was observed in treatment responders who had increased beta(2)-adrenoceptor density in the high-conformational state and supercoupling prior to treatment. Beta(2)-adrenoceptor density decreased after imipramine treatment. Treatment non-responders had seemingly normal pretreatment beta(2)-adrenoceptor function, which was not changed by imipramine. Differences in beta(2)-adrenoceptor regulation in major depressive disorder may underlie treatment response. The results indirectly implicate abnormal agonist-mediated beta(2)-adrenoceptor gene expression, protein kinase A, and protein kinase C in major depressive disorder.
Adrenergic Uptake Inhibitors↗
Characteristics of norepinephrine and clonidine displacement of [3H]yohimbine binding to platelet alpha2-adrenoreceptors in healthy volunteers.
Clonidine's estimates of platelet alpha2-adrenoreceptor (alpha2AR) density are substantially lower than yohimbine's. This discrepancy could have contributed to inconsistent results from studies on the role of alpha2AR in depression. Furthermore, few studies have investigated the relative distribution of alpha2AR between the high- and low-affinity states or their Gi protein coupling. [3H]yohimbine saturable binding to platelet alpha2AR, its displacement by norepinephrine and clonidine, and the effects of Gpp(NH)p on agonist displacement curves were investigated in 11 healthy volunteers. Clonidine estimates of alpha2AR density were close to norepinephrine estimates, and both were strongly correlated. Clonidine's K(L)/K(H) ratio was lower than norepinephrine's, consistent with its partial agonist nature. Norepinephrine and clonidine displacement curves revealed two affinity states. Gpp(NH)p induced a significant rightward shift to a single low-affinity state. When used in combination with a specific antagonist, clonidine's estimates of alpha2AR density were similar to those of norepinephrine's, and both were higher than previously reported, when clonidine was used alone. Re-evaluation of previous studies on alpha2AR in depression using clonidine is needed. The combined use of antagonist-saturation and agonist-displacement experiments to examine possible dysregulation in alpha2AR coupling to Gi protein in psychiatric disorders is recommended.
Adult↗
Platelet alpha2-adrenergic receptor coupling efficiency to Gi protein in subjects with post-traumatic stress disorder and normal controls.
Low platelet membrane alpha2-adrenergic receptor (alpha2AR) density and low basal and forskolin-stimulated cyclic adenosine monophosphate responses, which have been reported in post-traumatic stress disorder (PTSD), suggest either abnormal alpha2AR coupling to G(i) protein or dysregulation in post-receptor signal transduction mechanisms. alpha2AR density in the high- and low-conformational states, agonist affinity in both states and coupling to G(i) protein were investigated in 23 drug-free combat PTSD patients and 25 normal controls. alpha2AR coupling measures were not different between PTSD patients and controls. Total alpha2AR density was higher in PTSD patients than controls, due to a higher density of the receptor in the high-conformational state. There were no differences in agonist affinity to the receptor in either conformational state. Results rule out dysregulation in alpha2AR coupling to G(i) protein. Studies of post-receptor signal transduction mechanisms are warranted.
Adult↗
Neutrophil beta2-adrenergic receptor coupling efficiency to Gs protein in subjects with post-traumatic stress disorder and normal controls.
The symptomatology of post-traumatic stress disorder (PTSD) involves sympathetic hyperarousal. Several of these sympathetic symptoms are mediated through end-organ beta2-adrenergic receptors (beta2AR). Increased sympathetic activity in PTSD could therefore be due to increased betaAR function. This study investigated betaAR function in 30 healthy controls and 20 drug-free PTSD patients. BetaAR binding studies were conducted using antagonist-saturation and agonist-displacement experiments. Measures of beta2AR coupling to Gs protein were derived from agonist-displacement experiments. PTSD patients had significantly higher beta2AR density particularly in the high-conformational state and higher beta2AR coupling than controls, as reflected in a higher percentage of receptors in the high conformational state and a higher ratio of the agonist dissociaton constant from the receptor in the low/high-conformational state. Increased betaAR function in PTSD is consistent with the symptomatology of this disorder. Increased betaAR density and coupling may be consistent with downregulation of betaAR density and uncoupling by antidepressants and may underlie their partial efficacy in PTSD. Dysregulation in Gs protein function is postulated and, agonist-mediated regulation of betaAR expression and/or betaAR kinase activity in PTSD should be investigated in future studies.
Adult↗
Clinical and economic impact of newer versus older antipsychotic medications in a community mental health center.
This pilot study was conducted to compare both the clinical effectiveness and the treatment costs of newer (atypical) antipsychotic medications (clozapine and risperidone) with those of older (classic) neuroleptic medications (chlorpromazine and haloperidol) for psychosis in a community mental health care setting. The study used a retrospective, uncontrolled, open, nonrandomized, within-subjects design and relied on medical records as a data source for 37 clients. All clients received older antipsychotics for at least 1 year, newer antipsychotics for a transition period of 3 months, and the newer agents for at least an additional year. The newer antipsychotic medications were more effective and less costly (total cost of care, $3000 less per client per year [1997 dollars]) than the older medications. Effect-size estimates for the measured variables provide a guide for future research into the cost-effectiveness of these newer medications within the community mental health care setting. These findings can provide policy makers with guidance on treating people with major mental disorders in the most effective and efficient manner. Because of limited budgets, community mental health centers making the investment in newer, more expensive medications to improve client outcomes have to maintain the same or lower total cost of care. Results of the current study suggest that short-term investment in the newer medications by community mental health centers offers superior clinical effectiveness and lower long-term overall cost of care.
Adult↗
Prediction of response to fluoxetine and placebo in children and adolescents with major depression: a hypothesis generating study.
BACKGROUND: The results of multivariate analyses to identify potential predictors of response to fluoxetine or placebo separately in 96 child and adolescent outpatients with major depressive disorder from a recent controlled trial are presented. METHODS: A variety of clinical, demographic and laboratory factors were examined as possible predictors of response to fluoxetine or placebo using logistic regression models. RESULTS: No single variable or combination of variables strongly predicted response to fluoxetine. For the placebo group, a younger age, a shorter duration of depressive episode, and a lower socioeconomic status predicted response with an overall predictive power of 81%. CONCLUSIONS: This study is limited by the small sample size and should be considered hypothesis generating rather than confirming.
Adolescent↗
Age of onset in chronic major depression: relation to demographic and clinical variables, family history, and treatment response.
BACKGROUND: The clinical and etiological significance of the early-late onset distinction in chronic major depressive disorder was explored. METHOD: Subjects were 289 outpatients with DSM-III-R chronic major depression drawn from a multi-site study comparing the efficacy of sertraline and imipramine in the acute and long-term treatment of chronic depression. Patients received comprehensive evaluations using semi-structured interviews and rating scales. RESULTS: Early-onset chronic major depression was associated with a longer index major depressive episode and higher rates of recurrent major depressive episodes, comorbid personality disorders, lifetime substance use disorders, depressive personality traits, and a history of psychiatric hospitalization. In addition, more early-onset patients tended to have a family history of mood disorders. The early-late onset distinction was not associated with differences in symptom severity, functional impairment, or treatment response. LIMITATIONS: Family members were not interviewed directly; there were a large number of statistical comparisons; and interrater reliability of the assessments was not evaluated. CONCLUSIONS: Early-onset chronic major depression has a more malignant course and is associated with greater comorbidity than late-onset chronic major depression.
Adult↗
Adrenergic receptor function in panic disorder. I. Platelet alpha 2 receptors: Gi protein coupling, effects of imipramine, and relationship to treatment outcome.
Various studies suggest alpha 2-adrenergic receptor (alpha 2AR) dysregulation in panic disorder (PD). Platelet alpha 2-AR exist in high- and low-conformational states as a function of their coupling to Gi protein. alpha 2AR coupling is important in signal transduction and is modulated by antidepressants. alpha 2AR density in the high- and low-conformational states, agonist affinity, and coupling efficiency were investigated in 21 healthy controls, 21 drug-free PD patients, and eight imipramine-treated patients using norepinephrine displacement of 3H-yohimbine binding. Percentage of receptors in the high-conformational state (%RH) and the ratio of the agonist dissociation constant to the receptor in the low-/high-conformational state (KL/KH), calculated from displacement experiments, were used as coupling indices. Patients had high alpha 2AR density in both conformational states. %RH and KL/KH ratio were significantly different, particularly in patients with Hamilton scale for depression (HAMD) scores > or = 15. Imipramine treatment (29 weeks) had no effect on alpha 2AR density or coupling, despite improvement in anxiety ratings. High pretreatment alpha 2AR density and coupling predicted low severity of anxiety after treatment. Increased alpha 2AR density and abnormal coupling may represent an adaptive mechanism or trait marker in PD.
Adult↗
Effects of fluoxetine on the polysomnogram in outpatients with major depression.
This study investigated the effects of open-label fluoxetine (20 mg/d) on the polysomnogram (PSG) in depressed outpatients (n = 58) who were treated for 5 weeks, after which dose escalation was available (< or = 40 mg/d), based on clinical judgment. Thirty-six patients completed all 10 weeks of acute phase treatment and responded (HRS-D < or = 10). PSG assessments were conducted and subjective sleep evaluations were gathered at baseline and at weeks 1, 5, and 10. Of the 36 subjects who completed the acute phase, 17 were reevaluated after 30 weeks on continuation phase treatment and 13 after approximately 7 weeks (range 6-8 weeks) following medication discontinuation. Acute phase treatment in responders was associated with significant increases in REM latency, Stage 1 sleep, and REM density, as well as significant decreases in sleep efficiency, total REM sleep, and Stage 2 sleep. Conversely, subjective measures of sleep indicated a steady improvement during acute phase treatment. After fluoxetine was discontinued, total REM sleep and sleep efficiency were found to be increased as compared to baseline.
Adolescent↗
Hippocampal remodeling and damage by corticosteroids: implications for mood disorders.
Mood disorders are common, recurrent and disabling illnesses which are frequently associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation and memory loss. The hippocampus provides negative feedback to the HPA axis and has an important role in key aspects of spatial and declarative memory. Thus, hippocampal dysfunction could account for both the memory impairment and neuroendocrine abnormalities found in mood disorders. The critical role of the hippocampus in declarative memory, emotional processing, and vulnerability to stress has been demonstrated in both animal and human studies. Cellular processes in the hippocampus including long-term potentiation, neurogenesis, and dendritic remodeling are currently areas of intense study. Human studies report cognitive impairment consistent with hippocampal dysfunction in depression, bipolar disorder, Cushing's disease, and in those individuals receiving exogenous corticosteroids. This review examines data on the role of corticosteroids in hippocampal remodeling and atrophy in patients with mood disorders. Interventions to prevent or reverse the damaging effects of corticosteroids on the hippocampus are discussed.
Adrenal Cortex Hormones↗
Biological rhythm disturbance in depression: temporal coherence of ultradian sleep EEG rhythms.
BACKGROUND: Recent studies have suggested that major depressive disorders are associated with a breakdown in the organization of ultradian rhythm in sleep EEG. The present study used cross-spectral analysis of sleep EEG to confirm this finding, in a larger-scale study, evaluating the influence of gender and age on ultradian rhythms in depression. METHODS: Temporal coherence of ultradian (80-120 min) rhythms in beta, theta and delta, recorded from central and parietal sites, were compared in 120 symptomatic, unmedicated, depressed outpatients and 59 healthy normal controls. RESULTS: Few macro-architectural differences were noted between patients and controls. However, interhemispheric beta and theta coherence and intrahemispheric coherence between beta and delta rhythms were significantly lower in depressed patients. Coherence measures were lowest in women with depression and highest in men in the control group, but were not strongly influenced by age. Over 65% of depressed patients were > or = 2 standard deviations below normal on at least one coherence measure, in sharp contrast to less than 10% of patients on macro-architectural variables. CONCLUSIONS: It was concluded that dysregulation of ultradian rhythms characterizes the majority of depressed out-patients, primarily women, even when macro-architecture did not differentiate groups. The outcome of this study supports the view that the pathophysiology of depression is strongly influenced by gender. It was suggested that low temporal coherence in depression reflects a breakdown in the organization of sleep EEG rhythms within and between the two hemispheres.
Activity Cycles↗
Evidence for the segregation of a major gene for human plasma GABA levels.
Gamma-aminobutryic acid (GABA) is a major neurotransmitter in the central nervous system, and plasma levels of GABA may reflect brain GABA activity. In 35-40% of patients with mood disorders, plasma GABA levels are low compared to psychiatrically normal controls. Low plasma GABA in this subgroup of patients has characteristics of a biological trait marker for mood disorders. Low plasma GABA is also found in a subset of patients with alcohol dependence, but not in schizophrenia, anxiety, or eating disorders, suggesting some diagnostic specificity. Previous data from a small study of monozygotic twins are consistent with the hypothesis that plasma GABA levels are under genetic control. To better understand these mechanisms, we conducted a segregation analysis of plasma GABA levels in a sample of 157 individuals from 50 nuclear families. Analysis using the Class D regressive model indicated that the familial transmission of plasma GABA levels is compatible with the segregation of a recessive major gene. Our results suggest that plasma GABA levels are under single gene control. Future research should address the precise mechanisms which may account for the abnormality in GABA levels seen in a subset of patients with mood disorders.
Adolescent↗