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The pathophysiology of major depressive disorder (MDD) is thought to result from impaired connectivity between key brain networks. Gamma-aminobutyric acid (GABA) is the key inhibitory neurotransmitter in the brain, working primarily via GABAA receptors, with an important role in virtually all physiologic functions in the brain. Some neuroactive steroids (NASs) are positive allosteric modulators (PAMs) of GABAA receptors and potentiate phasic and tonic inhibitory responses via activation of synaptic and extrasynaptic GABAA receptors, respectively. This review first discusses preclinical and clinical data that support the association of depression with diverse defects in the GABAergic system of neurotransmission. Decreased levels of GABA and NASs have been observed in adults with depression compared with healthy controls, while treatment with antidepressants normalized the altered levels of GABA and NASs. Second, as there has been intense interest in treatment approaches for depression that target dysregulated GABAergic neurotransmission, we discuss NASs approved or currently in clinical development for the treatment of depression. Brexanolone, an intravenous NAS and a GABAA receptor PAM, is approved by the U.S. Food and Drug Administration for the treatment of postpartum depression (PPD) in patients 15 years and older. Other NASs include zuranolone, an investigational oral GABAA receptor PAM, and PH10, which acts on nasal chemosensory receptors; clinical data to date have shown improvement in depressive symptoms with these investigational NASs in adults with MDD or PPD. Finally, the review discusses how NAS GABAA receptor PAMs may potentially address the unmet need for novel and effective treatments with rapid and sustained antidepressant effects in patients with MDD.
The pathophysiology of major depressive disorder (MDD) is thought to result from impaired connectivity between key brain networks. Gamma-aminobutyric acid (GABA) is the key inhibitory neurotransmitter in the brain, working primarily via GABAA receptors, with an important role in virtually all physiologic functions in the brain. Some neuroactive steroids (NASs) are positive allosteric modulators (PAMs) of GABAA receptors and potentiate phasic and tonic inhibitory responses via activation of synaptic and extrasynaptic GABAA receptors, respectively. This review first discusses preclinical and clinical data that support the association of depression with diverse defects in the GABAergic system of neurotransmission. Decreased levels of GABA and NASs have been observed in adults with depression compared with healthy controls, while treatment with antidepressants normalized the altered levels of GABA and NASs. Second, as there has been intense interest in treatment approaches for depression that target dysregulated GABAergic neurotransmission, we discuss NASs approved or currently in clinical development for the treatment of depression. Brexanolone, an intravenous NAS and a GABAA receptor PAM, is approved by the U.S. Food and Drug Administration for the treatment of postpartum depression (PPD) in patients 15 years and older. Other NASs include zuranolone, an investigational oral GABAA receptor PAM, and PH10, which acts on nasal chemosensory receptors; clinical data to date have shown improvement in depressive symptoms with these investigational NASs in adults with MDD or PPD. Finally, the review discusses how NAS GABAA receptor PAMs may potentially address the unmet need for novel and effective treatments with rapid and sustained antidepressant effects in patients with MDD.
Background: Brain is the most sensitive organ, whereas brainstem is the most important part of Central Nervous System (CNS). It connects the brain and the spinal cord. However, a myriad of drugs and chemicals affects CNS with severe resultant effects on the brainstem. Methods: In view of this, a number of literature were assessed for information on the most sensitive part of brain, drugs and chemicals that act on the brainstem and clinical benefit and risk assessment of such drugs and chemicals. Results: Findings have shown that brainstem regulates heartbeat, respiration and because it connects the brain and spinal cord, all the drugs that act on the spinal cord may overall affect the systems controlled by the spinal cord and brain. The message is sent and received by temporal lobe, occipital lobe, frontal lobe, parietal lobe and cerebellum. Conclusion: Hence, the chemical functional groups of the brainstem and drugs acting on brainstem are complementary, and may produce either stimulation or depression of CNS.
The treatment of parasomnias and sleep related movement disorders is not always pharmacologic, indeed, some of these disorders respond to behavioral approaches without the risks of pharmaceuticals. This chapter endeavors to pull forward the disorders in which pharmacologic treatment is the best choice and lay out the pharmacologic properties of the treatments. It is not the goal of this chapter to present an encyclopedic review of the parasomnias and sleep related movement disorders. It is, however, the intent of this chapter to comprehensively review pharmacologic treatments used in the management of the disorders in which drug use is most necessary. The pharmacokinetic and pharmacodynamic properties and known risks of these pharmaceuticals are presented and discussed. When more than one pharmaceutical is used clinically within a class of drugs, thorough review of selected drugs is presented. The chapter includes investigations, mostly human studies, of the drugs discussed. The author’s extensive experience in pharmacology, neurology, and sleep medicine take the chapter through pharmacological information a clinician needs to guide the management of these disorders.
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