Glucocorticoid Receptor Antagonists Hasten and Augment Neurochemical Responses to a Selective Serotonin Reuptake Inhibitor Antidepressant

Johnson, Daniel A.; Grant, Emma J.; Ingram, C.D.; Gartside, Sarah E.

doi:10.1016/j.biopsych.2007.05.003

Cited by 38 publications

(35 citation statements)

References 51 publications

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“…Continued or repeated cortisol hypersecretion leads to over-exposure of corticosteroid receptors, which in turn may be downregulated. This premise has been the source of a number of studies evaluating the efficacy of glucocorticoid inhibitors (Belanoff et al, 2001(Belanoff et al, , 2002Jahn et al, 2004;Flores et al, 2006) and glucocorticoid receptor antagonists (Bachmann et al, 2003;Johnson et al, 2007) as anti-depressants. Thus, it is possible that there are differences in the autoregulatory feedback of GAD and comparison subjects due to corticosteroid receptor performance.…”

Section: Discussionmentioning

confidence: 99%

Salivary cortisol is associated with diagnosis and severity of late-life generalized anxiety disorder

Mantella

Butters

Amico

et al. 2008

Psychoneuroendocrinology

186

151

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SummaryAge-associated alterations in hypothalamic-pituitary-adrenal (HPA) axis functioning may make individuals more susceptible to HPA dysregulation in the context of mood and anxiety disorders. Little to no research has been done to examine HPA axis function in generalized anxiety disorder (GAD), particularly in late-life GAD, the most prevalent anxiety disorder in the elderly. The study sample consisted of 71 GAD subjects and 40 nonanxious comparison subjects over 60 years of age. We examined the hypotheses that elderly individuals with GAD will have elevated salivary cortisol levels compared to nonanxious subjects, and that elevated cortisol levels in GAD will be associated with measures of symptom severity. We report that late-life GAD is characterized by elevated basal salivary cortisol levels, with higher peak cortisol levels and larger areas under the curve, compared to nonanxious subjects. Additionally, severity of GAD as measured by the GAD Severity Scale and the Penn State Worry Questionnaire are positively correlated with cortisol levels. These data demonstrate HPA axis dysfunction in late-life GAD and suggest the need for additional research on the influence of aging on HPA axis function in mood and anxiety disorders.

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Section: Discussionmentioning

confidence: 99%

Salivary cortisol is associated with diagnosis and severity of late-life generalized anxiety disorder

Mantella

Butters

Amico

et al. 2008

Psychoneuroendocrinology

186

151

View full text Add to dashboard Cite

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“…Chronic exposure to the SSRI escitalopram attenuates the anxiety phenotype in 1473G/G mice to levels similar to less anxious 1473C/C mice, thus mirroring the selective effect of chronic SSRI treatment in anxiety patients. Recently, increasing evidence has accumulated that the major mechanism of SSRIs in relieving anxiety-and depression-related symptoms is not simply increasing extracellular 5-HT concentrations via reuptake inhibition, but that chronic treatment with drugs like escitalopram, citalopram, or fluoxetine causes a complex modulation of the entire serotonergic neurotransmission, in which the desensitization of 5-HT 1A autoreceptors is one of the major changes observed (Blier and de Montigny, 1994;El Mansari et al, 2005;Johnson et al, 2007;Le Poul et al, 2000). In 1473G/G mice, we could identify normal extracellular 5-HT levels and a functional desensitization of 5-HT 1A autoreceptors before escitalopram treatment.…”

Section: Efficient Treatment Of Anxiety By Chronic Escitaloprammentioning

confidence: 99%

A Functional Tph2 C1473G Polymorphism Causes an Anxiety Phenotype via Compensatory Changes in the Serotonergic System

Berger

Weber

Perreau-Lenz

et al. 2012

Neuropsychopharmacol

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The association of single-nucleotide polymorphisms (SNPs) in the human tryptophan hydroxylase 2 (TPH2) gene with anxiety traits and depression has been inconclusive. Observed inconsistencies might result from the fact that TPH2 polymorphisms have been studied in a genetically heterogeneous human population. A defined genetic background, control over environmental factors, and the ability to analyze the molecular and neurochemical consequences of introduced genetic alterations constitute major advantages of investigating SNPs in inbred laboratory mouse strains. To investigate the behavioral and neurochemical consequences of a functional C1473G SNP in the mouse Tph2 gene, we generated congenic C57BL/6N mice homozygous for the Tph2 1473G allele. The Arg 447 substitution in the TPH2 enzyme resulted in a significant reduction of the brain serotonin (5-HT) in vivo synthesis rate. Despite decreased 5-HT synthesis, we could detect neither a reduction of brain region-specific 5-HT concentrations nor changes in baseline and stress-induced 5-HT release using a microdialysis approach. However, using a [ 35 S]GTP-g-S binding assay and 5-HT 1A receptor autoradiography, a functional desensitization of 5-HT 1A autoreceptors could be identified. Furthermore, behavioral analysis revealed a distinct anxiety phenotype in homozygous Tph2 1473G mice, which could be reversed with chronic escitalopram treatment. Alterations in depressive-like behavior could not be detected under baseline conditions or after chronic mild stress. These findings provide evidence for an involvement of functional Tph2 polymorphisms in anxiety-related behaviors, which are likely not caused directly by alterations in 5-HT content or release but are rather due to compensatory changes during development involving functional desensitization of 5-HT 1A autoreceptors.

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“…3,196 Finally, GR antagonists hasten and augment the induction of 5-HT levels elicited by chronic fluoxetine, possibly by accelerating desensitization of 5-HT 1A autoreceptors. 208 These observations support interest in combined inhibitors of 5-HT reuptake plus suppressors of glucocorticoid synthesis or GR receptor antagonists. 197,206 There are caveats, however: 1) clinical data remain in need of consolidation; 2) only certain patients, such as those with psychotic depression, may be sensitive to treatment, whereas others with atypical depression and seasonal affective disorder show blunted HPA axis activity; 3) the HPA axis is regulated around a set-point, so its activity should not be too strongly compromised; 3,167,196,197,206 and 4), it would prove challenging to integrate GR blockade and 5-HT reuptake inhibition into a single structure.…”

Section: Innovative Neuroendocrine Mechanisms: Calming Hpa Axis Overdmentioning

confidence: 56%

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

Millan¹

2009

Neurotherapeutics

176

122

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Summary:The past decade of efforts to find improved treatment for major depression has been dominated by genomedriven programs of rational drug discovery directed toward highly selective ligands for nonmonoaminergic agents. Selective drugs may prove beneficial for specific symptoms, for certain patient subpopulations, or both. However, network analyses of the brain and its dysfunction suggest that agents with multiple and complementary modes of action are more likely to show broad-based efficacy against core and comorbid symptoms of depression. Strategies for improved multitarget exploitation of monoaminergic mechanisms include triple inhibitors of dopamine, serotonin (5-HT) and noradrenaline reuptake, and drugs interfering with feedback actions of monoamines at inhibitory 5-HT 1A , 5-HT 1B and possibly 5-HT 5A and 5-HT 7 receptors. Specific subsets of postsynaptic 5-HT receptors mediating antidepressant actions are under study (e.g., 5-HT 4 and 5-HT 6 ). Association of a clinically characterized antidepressant mechanism with a nonmonoaminergic component of activity is an attractive strategy. For example, agomelatine (a melatonin agonist/5-HT 2C antagonist) has clinically proven activity in major depression. Dual neurokinin 1 antagonists/5-HT reuptake inhibitors (SRIs) and melanocortin 4 antagonists/SRIs should display advantages over their selective counterparts, and histamine H 3 antagonists/SRIs, GABA B antagonists/SRIs, glutamatergic/SRIs, and cholinergic agents/SRIs may counter the compromised cognitive function of depression. Finally, drugs that suppress 5-HT reuptake and blunt hypothalamo-pituitary-adrenocorticotrophic axis overdrive, or that act at intracellular proteins such as GSK-3␤, may abrogate the negative effects of chronic stress on mood and neuronal integrity. This review discusses the discovery and development of dual-and tripleacting antidepressants, focusing on novel concepts and new drugs disclosed over the last 2 to 3 years.

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Glucocorticoid Receptor Antagonists Hasten and Augment Neurochemical Responses to a Selective Serotonin Reuptake Inhibitor Antidepressant

Cited by 38 publications

References 51 publications

Salivary cortisol is associated with diagnosis and severity of late-life generalized anxiety disorder

Salivary cortisol is associated with diagnosis and severity of late-life generalized anxiety disorder

A Functional Tph2 C1473G Polymorphism Causes an Anxiety Phenotype via Compensatory Changes in the Serotonergic System

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

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