The Role of Norepinephrine and Its α-Adrenergic Receptors in the Pathophysiology and Treatment of Major Depressive Disorder and Schizophrenia: A Systematic Review

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.

Keywords: antidepressants; antipsychotics; major depressive disorder; norepinephrine; pathophysiology; schizophrenia; valence systems; α-adrenergic receptors.

Figure 1

Overview of the actions of NE in neural synapses. Noradrenergic neurons originate from the locus coeruleus and project to regions of the forebrain, including the cortex and hypothalamus. NE is synthesized from the amino acids TYR and PHL and converted first to DOPA, DA, and further to NE by the enzymes TYR-H, AADC, and DA β-H, respectively, after which NE is stored in presynaptic vesicles. Following its release into the synaptic cleft, NE exerts its effects through binding to the adrenergic receptors (ARs): α_1A, α_1B, and α_1D; α_2A, α_2B, and α_2C; or β₁, β₂, and β₃. α₁- and β-ARs have a stimulatory effect on cell signaling, whereas α₂-ARs inhibit signaling. Also, while ARs are mainly located post-synaptically, α₂- and β₂-AR subtypes can also be localized pre-synaptically. NE is removed from the synaptic cleft by either reuptake via NET (expressed on the presynaptic terminals of NE neurons and glial cells), inactivation through the catabolic enzyme COMT to NM, or metabolism by MAO into several transitional metabolites, including its principal brain metabolite, MHPG. AADC, l-aromatic amino acid decarboxylase; cAMP, cyclic adenosine monophosphate; COMT, catechol O-methyltransferase; DA, dopamine; DA β-H, dopamine β-hydroxylase; DHPG, dihydroxyphenylglycol; DOPA, 3,4-dihydroxyphenylalanine; MAO, monoamine oxidase; MHPG, 3-methoxy-4-hydroxyphenylglycol; NE, norepinephrine; NET, NE transporter; NM, normetanephrine; PHL, phenylalanine; PHL-H, phenylalanine hydroxylase; PLC, phospholipase C; TYR, tyrosine; TYR-H, tyrosine hydroxylase.

Figure 2

Flow diagram of article selection. MDD, major depressive disorder; NE, norepinephrine; PK, pharmacokinetics.