Biological Markers for Treatment Response in First-Episode Psychosis

Stress and infalmmatory BiomarkersBy Mohamed GhamryBioMarkers for Treatment Response in First-Episod Psychosis

Biomarkers are objective measures that can provide information on a variety of different clinical characteristics, such as an individual's normal biology, pathology, including the trajectory of illness, or the response to a therapeutic intervention.

pathology biomarkers have been highly informative for understanding the neural and genomic heterogeneity of neuropsychiatric disorders and appear promising for the identification of individuals at ultrahigh risk for developing psychosis .

Inflammatory biomarkers

Cytokines as Biomarkers for Anti-inflammatory Treatments

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The effect on glutamine synthetase (found only in astrocytes) which is one of the factors protecting neurons from glutamate induced excitotoxicity

the effect of excitotoxicity on neurons is to decrease the activity of choline acetyl transferase (ChAT) in cholinergic neurons and to decrease the activity of glutamate decarboxylase (GAD) in GABAergic neurons. IL-6 (10 units) reduces the first effect, but not the second.

IL-6 appears to have multiple effects, some neuroprotective, and others damaging. The effects depend on the duration of exposure and the cell type. IL-6 is known to protect from NMDA induced excitotoxicity under some conditions, but to elevate calcium currents that can lead to increased neuronal stress/death in other cases

Cytokines and psychosis

In first-episode psychosis, there have been a number of studies to report increased levels of cytokines including interleukin (IL)-1, IL-6, IL-12, interferon (IFN)-, tumor necrosis factor (TNF)-, transforming growth factor- and more recently IL-17, the complement protein C1Q activation, leukocyte activation, and adiponectin.

All these baseline immune-inflammatory disturbances may be biomarkers of interest for future anti-inflammatory add-on therapy. The adjunction of celecoxib( a cyclooxygenase-2 inhibitor), to amisulpride in first-episode psychosis improved the clinical outcome as assesseby diminished PANSS (positive, negative, and general subscores).

Several studies have so far assessed the association between cytokine levels and treatment response in first episode psychosis: decreased IL-6 levels, increased levels of IL-10, and normalization of Th17 cells were all associated with positive treatment response.Cytokines & ttt response

Hormonal Stress Biomarkers

Stress is known to play a key role in the development and course of many psychiatric disorders, including psychosis. Hypothalamo-pituitary-adrenal (HPA) axis function is often altered in the major psychiatric disorders

Multiple studies, but not all, found a basal overactivity of the HPA axis in male patients with first-episode psychosis that was, however, only inconsistently associated with disease severity. HPA functioning was also found to be impaired in the ultra-high-risk stages of illness, with elevated cortisol levels indicating increased risk for transition.

HPA disturbances may be maintained and worsened all along the illness progression and correlated with severity of illness and aggressive behavior in male patients with first-episode psychosis.Antipsychotics drugs were found to normalize diurnal cortisol hypersecretion but not the blunted cortisol awakening response in patients with first-episode psychosis.

Dehydroepiandrosterone (DHEA) and its sulphated form (DHEAS) are major circulating corticosteroids that exert multiple effects on the central nervous system and have antistress and neuroprotective properties.

DHEA has potent antiglucocorticoid actions on the brain and can protect hippocampal neurons from glucocorticoid-induced neurotoxicity. The corelease of DHEA in the acute stress response is thought to protect against the potentially damaging effects of excessive cortisol activity.

LOWERED CORTISOL AWAKENING RESPONSE

For the study, saliva and blood samples were taken from 68 patients presenting with early psychosis and 57 healthy controls. In order to establish whether symptoms had improved following the first course of antipsychotic medication, responses to treatment were measured at the beginning of the study and 12 weeks later.Those who did not respond to early treatment showed lower levels of cortisol awakening response (CAR). CAR refers to an increase of around 50 per cent in levels of cortisol 20-30 minutes after waking in the morning.

Individuals at the onset of psychosis typically show increased levels of cortisol throughout the day but a blunted CAR.The study also found higher levels of inflammatory markers, in particularIL-6and IFN-, among those who did not respond to treatment. These differences in cortisol and inflammatory biomarkers were found to persist over the first 12 weeks of treatment.