Anilkumar Pillai

Neurotrophins and schizophrenia

Neurotrophins have established roles in neuronal development, synaptogenesis, and response to stress/anxious stimuli. Moreover, these agents are neuromodulators of monoaminergic, GABAergic, and cholinergic systems. Amidst a growing appreciation of the developmental neurobiology of schizophrenia--as well as the propensity for progressive brain changes--there is emergent information on abnormalities in the expression of neurotrophins in schizophrenia. This article reviews the literature on neurotrophins and schizophrenia. A schema for understanding the neurobiology of relapse in schizophrenia is offered.

Reduced folic acid, vitamin B12 and docosahexaenoic acid and increased homocysteine and cortisol in never-medicated schizophrenia patients: Implications for altered one-carbon metabolism

Abnormal one-carbon metabolism has long been suggested as one of the mechanisms for neuropathology and psychopathology of schizophrenia. Variable levels of components of one-carbon metabolism (folic acid and vitamin B12) and consequent altered levels of homocysteine and phospholipid docosahexaenoic acid (DHA) have been independently reported, mostly in medicated patients. This study examined the simultaneous levels of these key components of one-carbon metabolism and its consequences in unique, medication-naïve first-episode psychotic patients (FEP, n=31) and healthy controls (HC, n=48) matched for confounds such as race, diet and lifestyle to reduce the variability. Significantly lower levels of folate and vitamin B12 in plasma and folate in red blood cells were observed in FEP compared to HC. These reductions paralleled the significant increase in plasma homocysteine and cortisol levels. Significantly reduced levels of membrane DHA were also observed in FEP compared to HC. This study, using a unique cohort, provided a broader mechanism (disturbed folic acid-vitamin B12-DHA balance) of altered one-carbon metabolism and one of its key consequential components, an increased homocysteine level that together with cortisol, can contribute to the neuropathology of psychosis. These data may have important implications for the amelioration of psychopathology in schizophrenia.

Decreased BDNF levels in CSF of drug-naive first-episode psychotic subjects: Correlation with plasma BDNF and psychopathology

Brain-derived neurotrophic factor (BDNF), which plays an important role in neurodevelopmental plasticity and cognitive performance, has been implicated in neuropsychopathology of schizophrenia. We examined the levels of both cerebrospinal fluid (CSF) and plasma BDNF concomitantly in drug-naive first-episode psychotic (FEP) subjects with ELISA to determine if these levels were different from control values and if any correlation exists between CSF and plasma BDNF levels. A significant reduction in BDNF protein levels was observed in both plasma and CSF of FEP subjects compared to controls. BDNF levels showed significant negative correlation with the scores of baseline PANSS positive symptom subscales. In addition, there was a significant positive correlation between plasma and CSF BDNF levels in FEP subjects. The parallel changes in BDNF levels in plasma and CSF indicate that plasma BDNF levels reflect the brain changes in BDNF levels in schizophrenia.

Differential effects of long-term treatment with typical and atypical antipsychotics on NGF and BDNF levels in rat striatum and hippocampus

The results of mostly short-term treatment studies in human patients and animals suggest that second-generation antipsychotics (SGAs) such as risperidone (RISP) and olanzapine (OLZ) compared to first-generation antipsychotics (FGAs) such as haloperidol (HAL) and chlorpromazine (CPZ) have neuroprotective effects. The animal studies indicate that these effects are probably mediated through increased expression of neurotrophic factors such as nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF). However, since antipsychotics are commonly used for very long-term treatment periods, particularly in schizophrenic patients, it is important to measure the effects of chronic administration of antipsychotic drugs on the aforementioned growth factors. This study determined the effects of 90- and 180-day treatments with two FGAs, HAL and CPZ, and two SGAs, RISP and OLZ, on the levels of NGF and BDNF protein in hippocampus and striatum of rat. Furthermore, since a preliminary study showed that 90-day treatment of HAL caused significant reductions in the expression of both NGF and BDNF the HAL-treated animals were then switched to SGAs for the next 90 days to assess the potential for restoration of trophic factor levels. After the 90-day treatment, NGF levels in the hippocampus were reduced by 60-70% with HAL or CPZ, and by only 25-30% with RISP or OLZ compared to levels with vehicle only. After the 180-day treatment, NGF levels were further reduced with HAL, RISP, and OLZ, but not with CPZ. The magnitude of the NGF decreases in the striatum was larger (70-90%) with all the antipsychotics compared to the hippocampus. However, the pattern of BDNF changes in the hippocampus differed significantly from the striatum after 90- or 180-day treatment with the antipsychotics. In hippocampus, compared to controls, BDNF levels remained unchanged with OLZ both after 90 and 180 days of treatment. Whereas, larger decreases in BDNF levels were observed with HAL or CPZ and intermediate decreases were observed with RISP after 90 days of treatment that continued to decline up to 180 days. Furthermore, switching HAL animals after 90 days of treatment to either RISP or OLZ for the next 90 days significantly restored levels of both NGF and BDNF in both the brain regions. These data indicate that SGAs compared to FGAs induce less deleterious effects on neurotrophic factor levels in the brain and may also offer ability to reverse the more pronounced negative effects of FGAs as well. These data may have significant clinical implications for long-term antipsychotic selection as well as the common practice of antipsychotic switchover.

Brain-derived neurotrophic factor: findings in schizophrenia.

Purpose of review To review the role of brain-derived neurotrophic factor (BDNF) in neuroplasticity related to schizophrenia and the recent findings that have been reported on the status of BDNF in patients with schizophrenia and its association with the clinical measures. Recent findings Peripheral BDNF levels have been found altered in first-episode patients with psychosis and also in chronic schizophrenia patients. A few studies have reported changes in peripheral BDNF levels following antipsychotic treatment. The role of Val66Met polymorphism in BDNF has been shown to play an important role in structural and functional plasticity in schizophrenia. Summary Although peripheral BDNF levels hold promise for providing new perspectives for the development of novel therapeutic strategies for the treatment of schizophrenia, additional studies including efforts to prove its potential as a biomarker are warranted.

Decreased BDNF in Patients with Antipsychotic Naïve First Episode Schizophrenia

OBJECTIVE Brain-derived neurotrophic factor (BDNF) is a key factor known to mediate neuronal proliferation, differentiation, survival and response to stress. Decreases in BDNF levels have been reported in schizophrenia, but studies in treatment naïve patients are few. Herein we report on serum BDNF levels in a series of patients with first-episode treatment naïve psychoses in comparison to age matched healthy controls. METHOD Fasting serum BDNF levels were measured in 41 patients with treatment naive first episode psychosis (24 with schizophrenia, schizoaffective disorder or schizophreniform disorder, and 17 with non-schizophrenia psychotic disorders) and 41 age-matched healthy controls. RESULTS A three group analyses of covariance (ANCOVA) showed a diagnosis effect (p=.038) in which patients with schizophrenia had lesser serum BDNF levels than patient with non-schizophrenia psychosis, who in turn had lesser BDNF levels than matched healthy controls. Planned two-group ANCOVAs suggested that patients with schizophrenia had lower serum BDNF level than matched controls (p=.016), whereas patients with non-schizophrenia psychosis did not differ from controls. There were no age effects on BDNF, but there was a trend (p=.08) for a gender by group interaction with greater reductions in female patients with schizophrenia. The BDNF levels did not correlate with magnitude of smoking, body mass index, severity of positive and negative symptoms or overall functioning. CONCLUSIONS Serum BDNF may be reduced at the onset of psychosis but its role in the pathogenesis of schizophrenia remains unclear. Elucidating the role of BDNF in schizophrenia and related psychotic disorders may provide an important therapeutic target. Further studies are also needed to examine if patients with schizophrenia have more pronounced reductions in BDNF than those with affective psychosis.

Antioxidants as potential therapeutics for neuropsychiatric disorders

Oxidative stress has been implicated in the pathophysiology of many neuropsychiatric disorders such as schizophrenia, bipolar disorder, major depression etc. Both genetic and non-genetic factors have been found to cause increased cellular levels of reactive oxygen species beyond the capacity of antioxidant defense mechanism in patients of psychiatric disorders. These factors trigger oxidative cellular damage to lipids, proteins and DNA, leading to abnormal neural growth and differentiation. Therefore, novel therapeutic strategies such as supplementation with antioxidants can be effective for long-term treatment management of neuropsychiatric disorders. The use of antioxidants and PUFAs as supplements in the treatment of neuropsychiatric disorders has provided some promising results. At the same time, one should be cautious with the use of antioxidants since excessive antioxidants could dangerously interfere with some of the protective functions of reactive oxygen species. The present article will give an overview of the potential strategies and outcomes of using antioxidants as therapeutics in psychiatric disorders.

An inverse relationship between cortisol and BDNF levels in schizophrenia: Data from human postmortem and animal studies

Stress and stress-induced glucocorticoids have been implicated in many neuropsychiatric disorders including schizophrenia. In addition, the neurotrophin, brain derived neurotrophic factor (BDNF) has been shown to play an important role in stress-mediated changes in neuroplasticity, however, the exact relationship between glucocorticoid and BDNF levels in schizophrenia is unclear. Here, we measured the levels of cortisol (a major glucocorticoid hormone in humans) and BDNF in prefrontal cortex and CSF samples of postmortem schizophrenia subjects. We also assessed the levels of cortisol and BDNF in the frontal cortex and plasma from an animal model (the offspring of prenatally stressed rats), which demonstrates several behavioral and neuroendocrine abnormalities similar to schizophrenia. A significant increase in cortisol levels was found in prefrontal cortex and CSF samples from subjects with schizophrenia. The BDNF levels were significantly lower in prefrontal cortex and CSF samples of subjects with schizophrenia (compared to age-matched controls). Data from animal studies indicated that prenatally stressed offspring have significantly higher plasma and prefrontal cortex cortisol, whereas BDNF levels were significantly lower when compared to control, non-stressed offspring. Moreover, olanzapine treatment for 45 days starting at postnatal day 60 significantly attenuated prenatal stress-induced increase in cortisol levels in prefrontal cortex, but no change in BDNF levels was observed after olanzapine treatment. A significant negative correlation between BDNF and cortisol was observed in both human and animal studies. The above data from human and animal studies suggest that a negative association between stress hormone, cortisol and neuroprotective molecule, BDNF plays an important role in the pathophysiology of schizophrenia.

Prevention of oxidative stress-mediated neuropathology and improved clinical outcome by adjunctive use of a combination of antioxidants and omega-3 fatty acids in schizophrenia

Summary Schizophrenia is associated with a broad range of neurodevelopmental, structural and behavioral abnormalities that often progress with or without treatment. Evidence indicates that such neurodevelopmental abnormalities may result from defective genes and/or non-genetic factors such as pre-natal and neonatal infections, birth complications, famines, maternal malnutrition, drug and alcohol abuse, season of birth, sex, birth order and life style. Experimentally, these factors have been found to cause the cellular metabolic stress that often results in oxidative stress, such as increased cellular levels of reactive oxygen species (ROS) over the antioxidant capacity. This can trigger the oxidative cell damage (i.e., DNA breaks, protein inactivation, altered gene expression, loss of membrane lipid-bound essential polyunsaturated fatty acids [EPUFAs] and often apoptosis) contributing to abnormal neural growth and differentiation. The brain is preferentially susceptible to oxidative damage since it is under very high oxygen tension and highly enriched in ROS susceptible proteins, lipids and poor DNA repair. Evidence is increasing for increased oxidative stress and cell damage in schizophrenia. Furthermore, treatments with some anti-psychotics together with the lifestyle and dietary patterns, that are pro-oxidant, can exacerbate the oxidative cell damage and trigger progression of neuropathology. Therefore, adjunctive use of dietary antioxidants and EPUFAs, which are known to regulate the growth factors and neuroplasticity, can effectively improve the clinical outcome. The dietary supplementation of either antioxidants or EPUFAs, particularly omega-3 has already been found to improve some psychopathologies. However, a combination of antioxidants and omega-3 EPUFAs, particularly in the early stages of illness, when brain has high degree of neuroplasticity, potentially may be even more effective for long-term improved clinical outcome of schizophrenia.

Long-Term Continuous Corticosterone Treatment Decreases VEGF Receptor-2 Expression in Frontal Cortex

Objective Stress and increased glucocorticoid levels are associated with many neuropsychiatric disorders including schizophrenia and depression. Recently, the role of vascular endothelial factor receptor-2 (VEGFR2/Flk1) signaling has been implicated in stress-mediated neuroplasticity. However, the mechanism of regulation of VEGF/Flk1 signaling under long-term continuous glucocorticoid exposure has not been elucidated. Material and Methods We examined the possible effects of long-term continuous glucocorticoid exposure on VEGF/Flk1 signaling in cultured cortical neurons in vitro, mouse frontal cortex in vivo, and in post mortem human prefrontal cortex of both control and schizophrenia subjects. Results We found that long-term continuous exposure to corticosterone (CORT, a natural glucocorticoid) reduced Flk1 protein levels both in vitro and in vivo. CORT treatment resulted in alterations in signaling molecules downstream to Flk1 such as PTEN, Akt and mTOR. We demonstrated that CORT-induced changes in Flk1 levels are mediated through glucocorticoid receptor (GR) and calcium. A significant reduction in Flk1-GR interaction was observed following CORT exposure. Interestingly, VEGF levels were increased in cortex, but decreased in serum following CORT treatment. Moreover, significant reductions in Flk1 and GR protein levels were found in postmortem prefrontal cortex samples from schizophrenia subjects. Conclusions The alterations in VEGF/Flk1 signaling following long-term continuous CORT exposure represents a molecular mechanism of the neurobiological effects of chronic stress.