Pregnenolone-progesterone-allopregnanolone pathway as a potential therapeutic target in first-episode antipsychotic-naïve patients with schizophrenia.

Neurosteroids are both endogenous and exogenous steroids that rapidly alter neuronal excitability through interactions with ligand-gated ion channels and other cell surface receptors. They are originated from cholesterol and have important implications for schizophrenia (SZ) pathophysiology and treatment strategies. Specifically, pregnenolone (PREG), progesterone (PROG) and allopregnanolone (ALLO) exhibit similar psychotropic properties.

Associations between purine metabolites and monoamine neurotransmitters in first-episode psychosis.

Schizophrenia (SZ) is a biochemically complex disorder characterized by widespread defects in multiple metabolic pathways whose dynamic interactions, until recently, have been difficult to examine. Rather, evidence for these alterations has been collected piecemeal, limiting the potential to inform our understanding of the interactions amongst relevant biochemical pathways. We herein review perturbations in purine and neurotransmitter metabolism observed in early SZ using a metabolomic approach.

Associations between purine metabolites and clinical symptoms in schizophrenia.

Background: The antioxidant defense system, which is known to be dysregulated in schizophrenia, is closely linked to the dynamics of purine pathway. Thus, alterations in the homeostatic balance in the purine pathway may be involved in the pathophysiology of schizophrenia.

Methodology/principal Findings: Breakdown products in purine pathway were measured using high-pressure liquid chromatography coupled with a coulometric multi-electrode array system for 25 first-episode neuroleptic-naïve patients with schizophrenia at baseline and at 4-weeks following initiation of treatment with antipsychotic medication.

3-Hydroxykynurenine and clinical symptoms in first-episode neuroleptic-naive patients with schizophrenia.

One branch of the tryptophan catabolic cascade is the kynurenine pathway, which produces neurotoxic [3-hydroxykynurenine (3-OHKY), quinolinic acid] and neuroinhibitory (kynurenic acid) compounds. Kynurenic acid acts as a competitive antagonist at the glycine site of N-methyl-d-asparate receptors at high concentrations and as a non-competitive antagonist on the α7-nicotinic acetylcholine receptor at low concentrations. Kynurenine compounds also influence cognitive functions known to be disrupted in schizophrenia.

Homeostatic imbalance of purine catabolism in first-episode neuroleptic-naïve patients with schizophrenia.

Background: Purine catabolism may be an unappreciated, but important component of the homeostatic response of mitochondria to oxidant stress. Accumulating evidence suggests a pivotal role of oxidative stress in schizophrenia pathology.

Methodology/principal Findings: Using high-pressure liquid chromatography coupled with a coulometric multi-electrode array system, we compared 6 purine metabolites simultaneously in plasma between first-episode neuroleptic-naïve patients with schizophrenia (FENNS, n = 25) and healthy controls (HC, n = 30), as well as between FENNS at baseline (BL) and 4 weeks (4w) after antipsychotic treatment.

Age-related changes of n-3 and n-6 polyunsaturated fatty acids in the anterior cingulate cortex of individuals with major depressive disorder.

Accumulating evidence finds a relative deficiency of peripheral membrane fatty acids in persons with affective disorders such as unipolar and bipolar depression. Here we sought to investigate whether postmortem brain fatty acids within the anterior cingulate cortex (BA-24) varied according to the presence of major depression at the time of death. Using capillary gas chromatography we measured fatty acids in a depressed group (n=12), and in a control group without lifetime history of psychiatric diagnosis (n=14).

Semantic memory in schizophrenia: association with cell membrane essential fatty acids.

Introduction: Semantic memory and language deficits are associated with schizophrenia. Understanding how these systems operate in this disorder will likely require a multi-factorial model that explains their linkages with cognition and modulation by dopamine. A biological factor that may provide causal convergence for these connections is cell membrane composition and dynamics.

Reduced platelet serotonergic responsivity as assessed by dense granule secretion in first-episode psychosis.

Objectives: To determine whether blunted serotonergic responsivity, indicated by decreased platelet dense granule secretion (DGS), occurs in neuroleptic-naïve patients with schizophrenia, as observed previously in chronic schizophrenia.

Design And Methods: Serotonin (5-HT)-amplified DGS was examined in 40 first-episode neuroleptic-naïve patients (24 with schizophrenia and 16 with mood disorders) and 24 healthy subjects.

Results: Healthy controls showed robustly increased DGS.

Reduced red blood cell membrane essential polyunsaturated fatty acids in first episode schizophrenia at neuroleptic-naive baseline.

There is emerging evidence in schizophrenia of membrane abnormalities, primarily reductions in the essential omega-3 and omega-6 series of polyunsaturated fatty acids (PUFA). Because previous studies have largely been in chronic patients, it is not known whether these membrane abnormalities also occur early in illness. In the present study, red blood cell membrane fatty acid levels were determined by capillary gas chromatography from 24 neuroleptic-naive patients with first episode schizophrenia or schizoaffective disorder and 31 age-matched normal controls.

Increased nitric oxide radicals in postmortem brain from patients with schizophrenia.

Alterations in antioxidant status in schizophrenia suggest free radical-mediated neurotoxicity; this finding can be a consequence of increased free radical production. There are multiple pathways to excess free radical generation and subsequent oxidative stress. One such pathway is the formation of peroxynitrite by a reaction of nitric oxide (NO) and superoxide radical.

Metabolic investigation in psychiatric disorders.

A multiplicity of theories have been proposed over the years that aim to conceptualize the pathophysiology of neuropsychiatric disorders, including impaired neurotransmission, viral infections, genetic mutation, energy metabolism deficiency, excitotoxicity, oxidative stress, and others. It is likely that complex disorders such as schizophrenia, bipolar disorder, and major depression are associated with multiple etiologies and pathogenetic mechanisms. In light of the interwoven biochemistry of human organs, identifying a network of multiple interacting biochemical pathways that account for the constellation of clinical and biological features would advance our understanding of these disorders.

Association of plasma apolipoproteins D with RBC membrane arachidonic acid levels in schizophrenia.

Apolipoprotein D (apoD) is a member of the lipocalin superfamily of transporter proteins that bind small hydrophobic molecules, including arachidonic acid (AA). The ability of apoD to bind AA implicates it in pathways associated with membrane phospholipid signal transduction and metabolism. Recent findings of an increased expression of apoD in the mouse brain after clozapine treatment suggested a role for apoD in the pharmacological action of clozapine.

Effects of omega-3 fatty acid on platelet serotonin responsivity in patients with schizophrenia.

Studies suggest that the omega-3 fatty acid supplementation may be beneficial in reducing symptom severity in schizophrenia. The mechanism(s) underlying the clinical effect is not known. Serotonin (5-HT) has been implicated in the pathophysiology of schizophrenia and in the mechanism of some antipsychotic agents.

Environmental factors and membrane polyunsaturated fatty acids in schizophrenia.

There is accumulating evidence of reductions in red blood cell membrane essential fatty acids in patients with schizophrenia. The mechanisms that may underlie these reductions have yet to be determined. It is possible that the observed membrane fatty acid deficits are associated with the development of schizophrenia.

Membrane pathology in schizophrenia: implication for arachidonic acid signaling.

Schizophrenia is a major mental disorder with no clearly identified pathophysiology. A variety of theories has been proposed to explain the pathophysiology of schizophrenia. One approach that is finding empirical support is the investigation of membrane composition and function.

Correlations between peripheral polyunsaturated fatty acid content and in vivo membrane phospholipid metabolites.

Background: There is evidence for membrane abnormalities in schizophrenia. It is unclear whether the observed membrane deficits in peripheral cells parallel central membrane phospholipid metabolism. To address this question we examined the relations between red blood cell polyunsaturated fatty acids and brain phospholipid metabolites from different regions of interest in schizophrenia and healthy subjects.