George R. Heninger

Bio: George R. Heninger is an academic researcher from United States Department of Veterans Affairs. The author has contributed to research in topics: Neurotransmitter receptor & Postsynaptic potential. The author has an hindex of 3, co-authored 6 publications receiving 738 citations. Previous affiliations of George R. Heninger include Yale University.

Receptor Sensitivity and the Mechanism of Action of Antidepressant Treatment: Implications for the Etiology and Therapy of Depression

Abstract: • Considerable evidence suggests that the acute effects of antidepressant treatments on brain norepinephrine (NE) and serotonin (5-HT) systems cannot account fully for their delayed therapeutic action. This review evaluates the effects of long-term antidepressant treatment on biogenic amine metabolism and on various indexes of presynaptic and postsynaptic receptor function. In contrast to variable effects on NE and 5-HT turnover and on presynaptic receptor sensitivity, almost all long-term antidepressant treatments produce consistent alterations in a number of measures of postsynaptic amine receptor sensitivity. Longterm treatment has been found to reduce β-adrenergic sensitivity while enhancing responses to serotonergic and α-adrenergic stimulation, suggesting that modulation of receptor sensitivity may be a mechanism of action common to tricyclic antidepressants, "atypical" antidepressants, monoamine oxidase inhibitors, and electroconvulsive therapy. These findings provide support for hypotheses of amine receptor abnormalities in depression and indicate the need for expanded studies of amine receptor function in patients.

Receptor sensitivity and the mechanism of action of antidepressant treatment: implications for the etiology and therapy of depression

Abstract: • Considerable evidence suggests that the acute effects of antidepressant treatments on brain norepinephrine (NE) and serotonin (5-HT) systems cannot account fully for their delayed therapeutic action This review evaluates the effects of long-term antidepressant treatment on biogenic amine metabolism and on various indexes of presynaptic and postsynaptic receptor function In contrast to variable effects on NE and 5-HT turnover and on presynaptic receptor sensitivity, almost all long-term antidepressant treatments produce consistent alterations in a number of measures of postsynaptic amine receptor sensitivity Longterm treatment has been found to reduce β-adrenergic sensitivity while enhancing responses to serotonergic and α-adrenergic stimulation, suggesting that modulation of receptor sensitivity may be a mechanism of action common to tricyclic antidepressants, "atypical" antidepressants, monoamine oxidase inhibitors, and electroconvulsive therapy These findings provide support for hypotheses of amine receptor abnormalities in depression and indicate the need for expanded studies of amine receptor function in patients

A molecular and cellular theory of depression

Abstract: Recent studies have begun to characterize the actions of stress and antidepressant treatments beyond the neurotransmitter and receptor level. This work has demonstrated that long-term antidepressant treatments result in the sustained activation of the cyclic adenosine 3',5'-monophosphate system in specific brain regions, including the increased function and expression of the transcription factor cyclic adenosine monophosphate response element-binding protein. The activated cyclic adenosine 3',5'-monophosphate system leads to the regulation of specific target genes, including the increased expression of brain-derived neurotrophic factor in certain populations of neurons in the hippocampus and cerebral cortex. The importance of these changes is highlighted by the discovery that stress can decrease the expression of brain-derived neurotrophic factor and lead to atrophy of these same populations of stress-vulnerable hippocampal neurons. The possibility that the decreased size and impaired function of these neurons may be involved in depression is supported by recent clinical imaging studies, which demonstrate a decreased volume of certain brain structures. These findings constitute the framework for an updated molecular and cellular hypothesis of depression, which posits that stress-induced vulnerability and the therapeutic action of antidepressant treatments occur via intracellular mechanisms that decrease or increase, respectively, neurotrophic factors necessary for the survival and function of particular neurons. This hypothesis also explains how stress and other types of neuronal insult can lead to depression in vulnerable individuals and it outlines novel targets for the rational design of fundamentally new therapeutic agents.

The relationship of depression to cardiovascular disease: epidemiology, biology, and treatment.

Abstract: This article reviews the burgeoning literature on the relationship of mood disorders and heart disease. Major depression and depressive symptoms, although commonly encountered in medical populations, are frequently underdiagnosed and undertreated in patients with cardiovascular disease (CVD). This is of particular importance because several studies have shown depression and its associated symptoms to be a major risk factor for both the development of CVD and death after an index myocardial infarction. This review of the extant literature is derived from MEDLINE searches (1966-1997) using the search terms "major depression," "psychiatry," "cardiovascular disease," and "pathophysiology." Studies investigating pathophysiological alterations related to CVD in depressed patients are reviewed. The few studies on treatment of depression in patients with CVD are also described. Treatment of depression in patients with CVD improves their dysphoria and other signs and symptoms of depression, improves quality of life, and perhaps even increases longevity. Recommendations for future research are proposed.

Serotonin Function and the Mechanism of Antidepressant Action: Reversal of Antidepressant-Induced Remission by Rapid Depletion of Plasma Tryptophan

Abstract: Brain serotonin content is dependent on plasma levels of the essential amino acid tryptophan. We investigated the behavioral effects of rapid tryptophan depletion in patients in antidepressant-induced remission. Twenty-one patients who were depressed by DSM-III-R criteria received a 24-hour, 160-mg/d, low-tryptophan diet followed the next morning by a 16-amino acid drink, in a double-blind, placebo-controlled (acute tryptophan depletion and control testing), crossover fashion. Total and free tryptophan levels decreased 87% and 91%, respectively, during acute tryptophan depletion. Fourteen of the 21 remitted depressed patients receiving antidepressants experienced a depressive relapse after the tryptophan-free amino acid drink, with gradual (24 to 48 hours) return to the remitted state on return to regular food intake. Control testing produced no significant behavioral effects. Free plasma tryptophan level was negatively correlated with depression score during acute tryptophan depletion. The therapeutic effects of some antidepressant drugs may be dependent on serotonin availability.

The neurobiology of depression

Abstract: Introduction or background: Depressive disorder is a long term, relapsing condition associated with high levels of disability and mortality. It has a neurobiological basis and is associated with functional and structural brain abnormalities. Sources of data: The data discussed have been obtained mainly from metaanalyses, randomized controlled clinical trials and key review papers as well as animal studies. Areas of agreement: Genetic vulnerability and stress are key factors in its aetiopathogenesis. Dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis reduces hippocampal volumes and prefrontal cortex (PFC) activity in depressed patients and disrupts homeostasis within the neurocircuit of depression. Antidepressant drugs increase brain-derived neurotrophin, restoring neuronal growth and activity and modulate interactions between the neurocircuit anatomical structures. Areas of controversy: It remains to be confirmed whether structural changes in the brain are purely abnormalities in neuroplasticity and are fully reversible, whether they predate depression and whether they increase in the long term. Growing points: Investigation of the molecular mechanisms mediating gene and environment interaction is a growing and potentially fruitful area of research in the neurobiology of depression. Further elucidation of the neuroanatomical and physiological connections between the limbic structures and PFC may help identify key areas to target in treatment. The role of the dysregulation of the HPA axis and identifiable stressors in the recent or remote past which are not always present in depression need further study. Areas timely for developing research: Prospective studies examining the interaction between changes in brain function and structure in relation to stress and identified relevant genes and how these may be influenced by antidepressant drug treatment and the long-term course of depression would help clarify their role in the pathophysiology of this disorder.