Toward a biaxial model of “bipolar” affective disorders: Spectrum phenotypes as the products of neuroelectrical and neurochemical alterations

Based upon a synthesis of findings related to affective illness, a pathophysiologic hypothesis and possible nosology are proposed. The authors reviewed recent (2001–2004) phenomenologic, diagnostic and treatment literature for pathophysiologic implications and selectively reviewed genetic, neuroimaging, neurochemical and neuropathological studies (1966–2004) that might inform the hypothesized model. Modern DSM nosology of affective illness is based upon the accumulation of observations in the purely descriptive tradition and has little pathophysiologic basis. A new perspective, that of the bipolar spectrum, deriving from clinical, theoretical and epidemiologic considerations, appears more promising for building bridges with the emerging neurobiology of bipolar disorder. Research seeking associations between structural alterations (molecular, cellular and system-level) and behavioral-level pathophysiologic processes has provided many clues, but no population-wide, major genetic loci have been identified. Three general hypotheses have emerged in the literature implicating: 1) presynaptic electrical signaling, an early suggestion which has received less recent consideration, 2) neurotransmitter–receptor systems (first messenger) and 3) post-receptor neurochemical signaling systems (second- and third messenger). The current ‘biaxial’ hypothesis proposes: 1) affective regulation may be understood in terms of two primary functional spectra: mood range and mood tonicity, 2) these spectra, in turn, are determined by neurochemical capacity and neuroelectrical modulation–and their functional interaction, and 3) proposed cellular pathophysiology suggests primary molecular loci, that may predict phenomenologic patterns and treatment responsiveness.