A Review of Biomarkers in Mood and Psychotic Disorders: A Dissection of Clinical vs. Preclinical Correlates

Abstract

Despite significant research efforts aimed at understanding the neurobiological underpinnings of mood (depression, bipolar disorder) and psychotic disorders, the diagnosis and evaluation of treatment of these disorders are still based solely on relatively subjective assessment of symptoms as well as psychometric evaluations. Therefore, biological markers aimed at improving the current classification of psychotic and mood-related disorders, and that will enable patients to be stratified on a biological basis into more homogeneous clinically distinct subgroups, are urgently needed. The attainment of this goal can be facilitated by identifying biomarkers that accurately reflect pathophysiologic processes in these disorders. This review postulates that the field of psychotic and mood disorder research has advanced sufficiently to develop biochemical hypotheses of the etiopathology of the particular illness and to target the same for more effective disease modifying therapy. This implies that a "one-size fits all" paradigm in the treatment of psychotic and mood disorders is not a viable approach, but that a customized regime based on individual biological abnormalities would pave the way forward to more effective treatment. In reviewing the clinical and preclinical literature, this paper discusses the most highly regarded pathophysiologic processes in mood and psychotic disorders, thereby providing a scaffold for the selection of suitable biomarkers for future studies in this field, to develope biomarker panels, as well as to improve diagnosis and to customize treatment regimens for better therapeutic outcomes.

Fig. (1)

Glutamate-mediated effects on the cGMP-NO system leading to monoamine release that in turn can be targeted by pharmacological means, eg. PDE5 and NOS inhibitors, as well as known antidepressants. However this pathway can also lead to oxidative stress if excessive glutamate-mediated NO synthesis combines with O₂^- from aerobic metabolism. Also depicted is the effect of inflammatory mediators that promote iNOS-mediated NO synthesis thereby promoting the formation of cell-damaging reactive oxygen and nitrogen species. These pro-oxidative mechanisms can be abrogated by endogenous antioxidant systems such as superoxide dismutase (SOD) and glutathione that act as a sink to quench excessive NO and/or O₂^-. Abbreviations: calmodulin (Calm); cyclic guanosine monophosphate (cGMP); endoplasmic reticulum (ER); glutamate (Glu); glutathione peroxidase (glut peroxidase); guanosine triphosphate (GTP); inducible nitric oxide synthase (iNOS); l-arginine (L-arg); neuronal nitric oxide synthase (nNOS); nitric oxide (NO); NMDA receptor (NMDAR); phosphodiesterase (PDE); superoxide dismutase (SOD); superoxide (O₂^-); hydrogen peroxide (H₂O₂).

Fig. (2)

An overview of key neuroprotective and neurotoxic molecules involved in drug (antidepressant, lithium etc.)-induced neuroplasticity. The monoaminergic system mainly exerts its effect on BDNF expression via the cAMP cascade, while BDNF in turn exerts its effect on monoaminergic neurons through the TrkB-receptor via the MAPK/ERK cascade and the phospholipase C (PLC) signalling system. Adapted from [342]. Abbreviations: beta adrenoceptor (βAR); alpha-2 adrenoceptor (α2AR); BDNF receptor (TrkB), see text for further details/ abbreviations not noted here.

Fig. (3)

A simplified diagram of the kynurenine pathway, indicating the principle enzymes, IDO and tryptophan-2,3-dioxygenase (TDO), and the subsequent formation of kynurenine and its metabolites from TRP. The diagram indicates the inter-relationship of kynurenine metabolites, particularly QA, kynurenic acid and 3-hydroxyanthranilic acid. This diagram also depicts the activation and inhibition of IDO via pro- and anti-inflammatory cytokines respectively, as well as the influence of oxidative stress processes that will eventually determine cellular resilience or susceptibility to neurotoxic insults. Increased activity of the tryptophan-kynurenine synthesis (by TDO/IDO) will also diminish the availability of tryptophan for serotonin synthesis via tryptophan-5-hydroxylase, with resulting effects on mood and behavior. Abbreviations: glutathione (GSH); interferon (IFN)-γ; interleukin (IL)-2 and -4; nitric oxide synthase (NOS); reactive oxygen species (ROS); serotonin (5-HT); tumour necrosis factor (TNF)-α. Adapted from [452, 453].