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Abstract
Norepinephrine (NE) is recognized as having a key role in the pathophysiology of major depressive disorder (MDD) and schizophrenia, although its distinct actions via α-adrenergic receptors (α-ARs) are not well defined. We performed a systematic review examining the roles of NE and α-ARs in MDD and schizophrenia. PubMed and ProQuest database searches were performed to identify English language papers published between 2008 and 2015. In total, 2,427 publications (PubMed, n = 669; ProQuest, n = 1,758) were identified. Duplicates, articles deemed not relevant, case studies, reviews, meta-analyses, preclinical reports, or articles on non-target indications were excluded. To limit the review to the most recent data representative of the literature, the review further focused on publications from 2010 to 2015, which were screened independently by all authors. A total of 16 research reports were identified: six clinical trial reports, six genetic studies, two biomarker studies, and two receptor studies. Overall, the studies provided indirect evidence that α-AR activity may play an important role in aberrant regulation of cognition, arousal, and valence systems associated with MDD and schizophrenia. Characterization of the NE pathway in patients may provide clinicians with information for more personalized therapy of these heterogeneous diseases. Current clinical studies do not provide direct evidence to support the role of NE α-ARs in the pathophysiology of MDD and schizophrenia and in the treatment response of patients with these diseases, in particular with relation to specific valence systems. Clinical studies that attempt to define associations between specific receptor binding profiles of psychotropics and particular clinical outcomes are needed.
Highlights
Major depressive disorder (MDD) and schizophrenia affect 151.2 and 26.3 million people worldwide, respectively, and are associated with high rates of morbidity and mortality [1]
We found that direct clinical evidence for the role of NE at α-adrenergic receptors (α-adrenergic receptors (ARs)) in the symptomatology of major depressive disorder (MDD) and schizophrenia is limited
Six clinical trials were identified, none of which were designed a priori to compare the effect of compounds with differing pharmacological profiles on outcomes of the study
Summary
Major depressive disorder (MDD) and schizophrenia affect 151.2 and 26.3 million people worldwide, respectively, and are associated with high rates of morbidity and mortality [1]. These disorders exert a large mental health burden and socioeconomic cost across the world, accounting for 24.5 α-ARs: MDD and Schizophrenia and 5.3%, respectively, of disability-adjusted life-years attributed to all mental, neurological, and substance use disorders [2]. Α1- and β-ARs have a stimulatory effect on cell signaling, as they have been shown to increase intracellular phospholipase C or cyclic adenosine monophosphate (cAMP), respectively, whereas α2-ARs suppress intracellular cAMP and generally have an inhibitory influence on signaling (Figure 1) [6]. NE has the highest affinity for α2-ARs [5] so low-level NE release may inhibit neuronal activity, whereas increased neural transmission arising from NE binding to stimulatory α1- and β-ARs only occurs at higher NE concentrations [7]
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