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

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Abstract

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.

Introduction

Bipolar disorder represents a leading cause of disability worldwide (Murray and Lopez, 1996), and innovative treatments are urgently required. In addition to the extraordinarily high rates of suicide (Angst et al., 2002, Rihmer and Kiss, 2002), and suicide attempts (Davidson et al., 2002) relative to the general or other mentally ill populations, the amount of time spent ill, severity of illness, rates of comorbidity (McElroy et al., 2001) psychosocial impairment (Judd and Akiskal, 2003) and stigmatization (Morselli et al., 2004) have a tremendous impact on quality of life. Additionally, depressive, subsyndromal and interepisode morbidity are often exacerbated by under- or late diagnosis (Ghaemi et al., 2001, Ghaemi et al., 2002). Development of more effective preventive, acute and maintenance treatments requires synthesis of the ever-expanding body of research findings.

It is critical that any such synthesis meets the important general criteria of causal inference (Bradford-Hill, 1966), particularly testability. Summarizing recommendations from researchers in the field, future hypotheses must: 1) consider molecular candidates–in addition to those involved in neurochemical transduction–that are localized within neuronal membranes, in a widely-distributed system likely responsible for stimulus gating, and subserving integrated cognitive, emotional and motoric functioning (Goodwin and Jamison, 1990, pp. 593–594); and 2) address neurobiology at the molecular, cellular, and systems levels, that is manifested in the behavioral expression of unstable, episodic and progressive illness (Manji and Lenox, 2000, p.518). This paper addresses these imperatives.

Section snippets

Historical background: defining essential traits in affective disorders

Years of phenomenologic observations have produced an array of illness conceptualizations and nosologies attempting to address the question of whether clinically-distinct affective subtypes are different manifestations of a common pathophysiology or derive from unique etiologic sources. After several decades (1883–1920) of clinical observation, Kraepelin ultimately described a broad spectrum of phenomenology that encompassed all observed illness forms. In contrast, Carl Wernicke advocated for

Theoretical background: deriving affective pathophysiologic hypotheses

Current pathophysiologic hypotheses attempting to explain these observations posit explanations at the cellular level and may fall into three general categories: 1) electrical signaling (especially presynaptic), 2) parasynaptic neurotransmitter–receptor signaling systems (first messenger), and 3) post-receptor neurochemical signaling systems (second and third messenger).

The latter two subcellular systems have received significant attention in recent decades. Research into the potential

The biaxial model

The biaxial model offers a new conceptualization of genetic, cellular, system and behavioral level bases of affective functioning and disease (see Fig. 1, Fig. 2). Moreover, by distinguishing between individual- and population-level effects, at each of the four neurobiological levels, the model provides an explanation and a new lens for interpretation of the widespread inconsistencies across studies.

In summary, the biaxial model proposes that: 1) of the 10,000+ neuronally-expressed genes, the

Evidence in the pathophysiology of affective disorders

The ultimate validation of this hypothesis will be the prospective demonstration of proposed biaxial genetic alterations, their impact on corresponding proteomic complements, system functioning, and phenotypic correlation. Nonetheless, a wealth of data at all four levels is very consistent with the biaxial hypothesis.

Genetic studies

Rapidly evolving technologies, such as DNA chip/array sequencing platforms (Mir and Southern, 2000, Califano et al., 2000), can be applied on a large scale, to identify and sequence polymorphic variations across neuroelectrical genes, which can then be used in linkage analyses and as screening markers in genome-wide associational studies. Building upon systems biology theory (Aderem, 2005), a database (currently under development) in which all potentially relevant genes, are classified

Conclusions

Current evidence does not support an exclusive pathophysiologic role for neurochemical alterations in affective disorders. A high degree of inconsistency is found across published investigations; most positive studies to date are insufficient to support more than system-level neurochemical alterations; and those genetic studies suggesting an etiologic connection in ‘bipolar’ subjects to neurochemical systems apply to narrow phenotypic subsets.

Although a few genetic studies have

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