The failure of anxiolytic therapies in early clinical trials: what needs to be done

Stewart, Adam; Nguyen, Michael; Poudel, Manoj K.; Warnick, Jason E.; Echevarria, David J.; Beaton, Elliott A.; Song, Cai; Kalueff, Allan V.

doi:10.1517/13543784.2015.1019063

Cited by 20 publications

(12 citation statements)

References 100 publications

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“… 129 , 130 Whereas animal models of pain use antinociception as a surrogate for analgesia, animal models of depression utilize tangible characteristics such as locomotor activity, aggression, preference for sucrose, and physiological responses (eg, electroencephalography to measure disturbances in circadian rhythm, laboratory tests to measure stress response, neuroimaging to measure CNS changes) to measure the subjective variable of mood. 131 For PTSD, the inherent challenges in translating a subjective condition to objective measures are equally challenging. 131 These factors may explain why most drugs shown to be beneficial in preclinical models of pain, depression, and PTSD fail in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

“… 131 For PTSD, the inherent challenges in translating a subjective condition to objective measures are equally challenging. 131 These factors may explain why most drugs shown to be beneficial in preclinical models of pain, depression, and PTSD fail in clinical trials. 18 , 131 , 132…”

Section: Discussionmentioning

confidence: 99%

“… 131 These factors may explain why most drugs shown to be beneficial in preclinical models of pain, depression, and PTSD fail in clinical trials. 18 , 131 , 132…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists

Cohen¹,

Bhatia

Buvanendran

et al. 2018

Regional Anesthesia and Pain Medicine

181

279

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show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists

Cohen¹,

Bhatia

Buvanendran

et al. 2018

Regional Anesthesia and Pain Medicine

181

279

View full text Add to dashboard Cite

show abstract

“…Identical issues hamper preclinical models of antidepressant activity. Solutions to improve not only the sensitivity, but also specificity, of preclinical anxiety and depression models have been proposed and apply similarly to all psychiatric domains in which CRF 1 antagonists have yet to show clinical efficacy (Haller et al 2013; Griebel et al 2013; Stewart et al 2015; Belzung 2014). …”

Section: Performance In Animal Modelsmentioning

confidence: 99%

Don’t stress about CRF: assessing the translational failures of CRF1antagonists

2017

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BACKGROUND Dr. Athina Markou sought treatments for a common neural substrate shared by depression and drug dependence. Antagonists of corticotropin-releasing factor (CRF) receptors, a target of interest to her, have not reached the clinic despite strong preclinical rationale and sustained translational efforts. METHODS We explore potential causes for the failure of CRF1 antagonists and review recent findings concerning CRF-CRF1 systems in psychopathology. RESULTS Potential causes for negative outcomes include: 1) poor safety and efficacy of initial drug candidates due to bad pharmacokinetic and physicochemical properties 2) specificity problems with preclinical screens, 3) the acute nature of screens vs late-presenting patients, 4.) positive preclinical results were limited to certain models and conditions with dynamic CRF-CRF1 activation not homologous to tested patients, 5) repeated CRF1 activation-induced plasticity that reduces the importance of ongoing CRF1 agonist stimulation, 6) therapeutic silencing may need to address CRF2 receptor or CRF-BP molecules, constitutive CRF1 activity, or molecules that influence agonist-independent activity or to target structural regions other than the allosteric site bound by all drug candidates We describe potential markers of activation towards individualized treatment, human genetic and functional data that still implicate CRF1 systems in emotional disturbance, sex differences, and suggestive clinical findings for CRF1 antagonists in food craving and CRF-driven HPA-axis overactivation. CONCLUSION The therapeutic scope of selective CRF1 antagonists now appears narrower than had been hoped. Yet, much remains to be learned about CRF’s role in the neurobiology of dysphoria and addiction and the potential for novel anti-CRF therapies therein.

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“…The conventional treatment for anxiety is based on the use of drugs belonging to psychoactive pharmacological classes such as benzodiazepines, barbiturates and modulators of the gamma-aminobutyric acid (GABA) receptors; drugs, which cause a wide range of side effects, such as ataxia, dizziness, sedation, and memory loss, besides being ineffective in some cases (STEWART AM, et al, 2015). Psychotherapy is also highly prescribed, since it assists in the individual's adaptation on how to deal with the stressful events of their daily life; however, pharmacological drugs are widely used for the reestablishment of the normal brain chemical composition, since these patients present levels of some neurotransmitters, such as noradrenaline and serotonin, compromised (STRAWN JR, et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Phytotherapy as treatment for anxiety: An alternative to minimize addiction and side effects

Pereira¹,

Meyer²,

Dantas³

et al. 2019

Acervo Saúde

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Objective: To describe the anxiolytic activity and possible mechanisms of action on the central nervous system of plants found in the region known as legal Amazon in the Brazilian territory. Bibliographic Review: For this, five plants popularly used as tranquilizers and to treat insomnia in the forms of teas and extracts were selected, they are: passion fruit, valerian, chamomile, lemon grass and bay leaf. A bibliographic survey of articles, mainly original research, reporting comparative studies of the anxiolytic effects of each plant against control groups, as well as its possible mechanisms of action on the nervous system through preclinical and clinical studies, was performed. Conclusion: All the selected plants exhibited comparable and even superior anxiolytic effects when compared to classes of drugs such as benzodiazepines, with minimization or elimination of side/adverse effects. In addition, all reviewed studies indicated some involvement of gamma-aminobutyric acid (GABA) receptors activation by plant chemical constituents in anxiolytic action. Due to the minimization of adverse effects and the absence of dependence, herbal medicine appears as an important alternative therapy to treat anxiety disorders.

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The failure of anxiolytic therapies in early clinical trials: what needs to be done

Cited by 20 publications

References 100 publications

Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists

Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists

Don’t stress about CRF: assessing the translational failures of CRF1antagonists

Phytotherapy as treatment for anxiety: An alternative to minimize addiction and side effects

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