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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.

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Schizophrenia is a life altering disease with a complex etiology and pathophysiology, and although antipsychotics are valuable in treating the disorder, certain symptoms and/or sufferers remain resistant to treatment. Our poor understanding of the underlying neuropathological mechanisms of schizophrenia hinders the discovery and development of improved pharmacological treatment, so that filling these gaps is of utmost importance for an improved outcome. A vast amount of clinical data has strongly implicated the role of inflammation and oxidative insults in the pathophysiology of schizophrenia. Preclinical studies using animal models are fundamental in our understanding of disease development and pathology as well as the discovery and development of novel treatment options. In particular, social isolation rearing (SIR) and pre- or postnatal inflammation (PPNI) have shown great promise in mimicking the biobehavioral manifestations of schizophrenia. Furthermore, the "dual-hit" hypothesis of schizophrenia states that a first adverse event such as genetic predisposition or a prenatal insult renders an individual susceptible to develop the disease, while a second insult (e.g., postnatal inflammation, environmental adversity, or drug abuse) may be necessary to precipitate the full-blown syndrome. Animal models that emphasize the "dual-hit" hypothesis therefore provide valuable insight into understanding disease progression. In this Review, we will discuss SIR, PPNI, as well as possible "dual-hit" animal models within the context of the redox-immune-inflammatory hypothesis of schizophrenia, correlating such changes with the recognized monoamine and behavioral alterations of schizophrenia. Finally, based on these models, we will review new therapeutic options, especially those targeting immune-inflammatory and redox pathways.

Schizophrenia is causally associated with early-life environmental stress, implicating oxidative stress in its pathophysiology. N-acetyl cysteine (NAC), a glutathione precursor and antioxidant, is emerging as a useful agent in the adjunctive treatment of schizophrenia and other psychiatric illnesses. However, its actions on brain monoamine metabolism are unknown. Social isolation rearing (SIR) in rats presents with face, predictive and construct validity for schizophrenia. This study evaluated the dose-dependent effects of NAC (50, 150 and 250 mg/kg/day × 14 days) on SIR- vs. socially reared induced changes in cortico-striatal levels of dopamine (DA), serotonin (5-HT) noradrenaline (NA) and their associated metabolites. SIR induced significant deficits in frontal cortical DA and its metabolites, 3,4-dihydroxyphenylacetic acid (Dopac) and homovanillic acid (HVA), reduced 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and reduced levels of the NA metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG). In addition, significant elevations in frontal cortical NA and striatal DA, Dopac, HVA, 5-HT, 5-HIAA, NA and MHPG were also observed in SIR rats. NAC at 150 and 250 mg/kg reversed all cortico-striatal DA, Dopac, HVA, 5-HT, 5-HIAA and striatal NA alterations in SIR animals, with 250 mg/kg of NAC also reversing alterations in cortico-striatal MHPG. In conclusion, SIR profoundly alters cortico-striatal DA, 5-HT and NA pathways that parallel observations in schizophrenia, while these changes are dose-dependently reversed or abrogated by sub-chronic NAC treatment. A modulatory action on cortico-striatal monoamines may explain NACs' therapeutic use in schizophrenia and possibly other psychiatric disorders, where redox dysfunction or oxidative stress is a causal factor.

Anxiety disorders are severely disabling, while current pharmacological treatments are complicated by delayed onset, low remission rates and side-effects. Sex is also noted to contribute towards illness severity and treatment response. Agomelatine is a melatonin (MT/MT) agonist and serotonin (5-HT) antagonist purported to be anxiolytic in clinical and some pre-clinical studies. We undertook a detailed analysis of agomelatine's anxiolytic activity in a neurodevelopmental model of anxiety, the social isolation reared rat. Rats received sub-chronic treatment with vehicle or agomelatine (40 mg/kg per day intraperitoneally at 16:00 h for 16 days), with behaviour analysed in the open field test, social interaction test and elevated plus maze. The contribution of corticosterone and sex was also studied. Social isolation rearing increased locomotor activity and reduced social interaction in the social interaction test, and was anxiogenic in the elevated plus maze in males and females. Agomelatine reversed these behaviours. Male and female social isolation reared rats developed anxiety-like behaviours to a similar degree, although response to agomelatine was superior in male rats. Social isolation rearing decreased plasma corticosterone in both sexes and tended to higher levels in females, although agomelatine did not affect corticosterone in either sex. Concluding, agomelatine is anxiolytic in SIR rats, although correcting altered corticosterone could not be implicated. Sex-related differences in the response to agomelatine are evident.