Biological substrates underpinning diagnosis of major depression - PubMed (original) (raw)

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Biological substrates underpinning diagnosis of major depression

Etienne Sibille et al. Int J Neuropsychopharmacol. 2013 Sep.

Abstract

Major depression is characterized by low mood, a reduced ability to experience pleasure and frequent cognitive, physiological and high anxiety symptoms. It is also the leading cause of years lost due to disability worldwide in women and men, reflecting a lifelong trajectory of recurring episodes, increasing severity and progressive treatment resistance. Yet, antidepressant drugs at best treat only one out of every two patients and have not fundamentally changed since their discovery by chance >50 yr ago. This status quo may reflect an exaggerated emphasis on a categorical disease classification that was not intended for biological research and on oversimplified gene-to-disease models for complex illnesses. Indeed, genetic, molecular and cellular findings in major depression suggest shared risk and continuous pathological changes with other brain-related disorders. So, an alternative is that pathological findings in major depression reflect changes in vulnerable brain-related biological modules, each with their own aetiological factors, pathogenic mechanisms and biological/environment moderators. In this model, pathological entities have low specificity for major depression and instead co-occur, combine and interact within individual subjects across disorders, contributing to the expression of biological endophenotypes and potentially clinical symptom dimensions. Here, we discuss current limitations in depression research, review concepts of gene-to-disease biological scales and summarize human post-mortem brain findings related to pyramidal neurons, γ-amino butyric acid neurons, astrocytes and oligodendrocytes, as prototypical brain circuit biological modules. Finally we discuss nested aetiological factors and implications for dimensional pathology. Evidence suggests that a focus on local cell circuits may provide an appropriate integration point and a critical link between underlying molecular mechanisms and neural network dysfunction in major depression.

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Figures

Fig. 1

Schematic representation of a common trajectory towards chronic recurrent depression. Major depression frequently follows a lifelong and recurrent trajectory, with many features of a neuroprogressive disease, such as recurring episodes of increasing severity, reduced therapeutic response and shorter remission period. Depressive episodes are represented by the valleys in the curve (high on severity scale), whereas each peak represents periods of remission (high on improvement scale). MDD, Major depressive disorder.

Fig. 2

A multi-scale biological perspective on mechanisms of depression and its relationship to specificity of drug treatment and diagnoses. (a) The functionality of complex biological systems emerges from the integration of events occurring across hierarchical biological scales, starting from the bottom with genes, molecules, cells, microcircuits, and neural networks. Each scale depends on the function of level below, and determines the function of the level above. Feedback and modulation occur across levels and from the environment (not shown). Brain functions, behaviours, and endophenotypes emerge at the neural network levels, which then define individual symptoms and syndromes. Molecular and brain imaging studies investigate opposite ends of the spectrum (b) and can only speculate on mechanisms underlying causal links between those opposite ends (dashed lines). More direct links are provided by molecular genetics and imaging magnetic resonance spectroscopy (MRS) studies, but these studies do not inform on changes at intermediate scales. This results in inverse correlations between specificities of findings for disease and molecular/pharmacological studies (b). Therapeutic drugs have high specificities for their molecular targets, but lowest specificities in terms of treating complex behavioural syndromes; conversely, imaging and associated studies have high syndromal specificity (due to the Diagnostic and Statistical Manual of Mental Disorders-based clinical diagnosis), but low molecular target specificity (due to low consideration of biological phenotypes in diagnosis). GABA, γ-amino butyric acid.

Fig. 3

Complex biological pathways from gene to syndrome. In a linear gene-to-disease pathway (left), single genes code for syndromes in direct step-by-step upward trajectory, across all biological scales. However, in reality the biological complexity greatly increases with each higher scale. From the bottom-up, genes have multiple functions and coalesce in signalling pathways and structural entities in various combinations across cell types (left-to-right arrows). Cells assemble in local circuits, which are re-used, modified and repeated across brain regions. In turn, assemblies of these biological modules form the functional bases of brain areas and neural networks. The result is a massively interlinked and multi-scale network, whose output contributes to the expression of symptom dimensions, including mood, cognition and physiological changes in major depression (illustrated as various shades of colour). This redundancy in the use of genes and biological modules, combined with their putative distal impact on neural networks and putative symptom dimensions represents a core challenge in research on complex heterogeneous neuropsychiatric disorders, in which dominant roles of genes are rare and ambiguous, compared to neurodegenerative or peripheral organ diseases.

Fig. 4

Local circuit summary of depression-related pathological findings in human post-mortem brain cortex. (a) Human post-mortem studies suggest reduced oligodendrocyte (green spindles) number and/or integrity, reduced size, density or altered dendritic branching of pyramidal cells (grey triangles) in layers 3, 5 and 6, and reduced number and/or functionally-altered calbindin/somatostatin (SST)-positive γ-amino butyric acid (GABA) neurons (S-labelled red circle and grey circles). Calretinin- and parvalbumin-positive (C- and P-labelled red circles) GABA neurons are mostly unaffected. A close-up schematic of the large grey circle in (a) is shown in (b), representing synapses between an excitatory axonal terminal (green, with myelin sheath) and a GABAergic inhibitory terminal (red) onto a pyramidal dendritic spine (black). The close-up also depicts intercalated astrocytes (blue), which show evidence of deregulated function in depression. Sites of putative pathology are marked by blue arrows. The integrity of information transfer and processing, where ‘information’ is defined as excitatory output of pyramidal or principal cells, could be compromised at several levels: (1) decreased oligodendrocyte support of axonal function leading to suboptimal conduction of action potentials along the axon; (2) disruption of synaptic transfer of information, due to changes in the structure of pyramidal neurons and availability of glutamate; (3) suboptimal modulation or ‘fine-tuning’ of excitatory post-synaptic signals onto dendritic spines due to reduced SST-positive GABAergic dendritic targeted inhibition; (4) impaired astrocyte function resulting in decreased extracellular neurotransmitter clearance, affecting the homeostatic GABA/glutamate balance. Together, the various alterations may manifest as deregulated information transfer in corticocortical [thalamus (Thal)→layer 3/4→layer 5/6→layer 3], thalamocortical (Thal→layer 3/4→layer 5/6→Thal) and corticostriatal circuit loops within corticolimbic brain areas, leading to altered processing of emotion-salient information, and affect and mood symptoms. Structural variants of this schematic loop include lack of layer 4 in the anterior cingulate cortex and lack of cortical structure in the basolateral complex of the amygdala. Str, Striatum.

References

1. Agid Y, Buzsaki G, Diamond DM, Frackowiak R, Giedd J, Girault JA, Grace A, Lambert JJ, Manji H, Mayberg H, Popoli M, Prochiantz A, Richter-Levin G, Somogyi P, Spedding M, Svenningsson P, Weinberger D. How can drug discovery for psychiatric disorders be improved? Nat Rev Drug Discov. 2007;6:189–201. - PubMed
1. APA. Diagnostic and statistical manual of mental disorders: DSM-IV-TR. 4th edn. Washington, DC: American Psychiatric Association; 2000.
1. Arango V, Underwood MD, Mann JJ. Serotonin brain circuits involved in major depression and suicide. Prog Brain Res. 2002;136:443–453. - PubMed
1. Auer DP, Putz B, Kraft E, Lipinski B, Schill J, Holsboer F. Reduced glutamate in the anterior cingulate cortex in depression: an in vivo proton magnetic resonance spectroscopy study. Biol Psychiatry. 2000;47:305–313. - PubMed
1. Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, Kavalali ET, Monteggia LM. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature. 2011;475:91–95. - PMC - PubMed

Biological substrates underpinning diagnosis of major depression - PubMed (original) (raw)