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.

Reduced cerebrospinal fluid and plasma nerve growth factor in drug-naïve psychotic patients.

Impaired expression and function of several major neurotrophic factors such as nerve growth factor (NGF) has been proposed to contribute to the neurodevelopmental pathology of schizophrenia. However, the evidence in the majority of studies is based on variable and inconsistent levels of plasma NGF in diverse populations of early psychosis or medicated patients with chronic schizophrenia. We report here the first study comparing NGF levels in cerebrospinal fluid (CSF) and plasma from a unique patient cohort (unmedicated, early psychotic patients with similar racial and dietary patterns) and matched healthy controls.

Antipsychotic drugs: comparison in animal models of efficacy, neurotransmitter regulation, and neuroprotection.

Various lines of evidence indicate the presence of progressive pathophysiological processes occurring within the brains of patients with schizophrenia. By modulating chemical neurotransmission, antipsychotic drugs may influence a variety of functions regulating neuronal resilience and viability and have the potential for neuroprotection. This article reviews the current literature describing preclinical and clinical studies that evaluate the efficacy of antipsychotic drugs, their mechanism of action and the potential of first- and second-generation antipsychotic drugs to exert effects on cellular processes that may be neuroprotective in schizophrenia.

Cystamine prevents haloperidol-induced decrease of BDNF/TrkB signaling in mouse frontal cortex.

The role of brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology as well as treatment outcome of schizophrenia. Rodent studies indicate that several antipsychotic drugs have time-dependent (and differential) effects on BDNF levels in the brain. Earlier studies from our laboratory have indicated that long-term treatment with haloperidol (HAL) decreases BDNF, reduced GSH and anti-apoptotic marker, Bcl-xl protein levels and increases the expression of pro-apoptotic proteins in rat frontal cortex.

Increased truncated TrkB receptor expression and decreased BDNF/TrkB signaling in the frontal cortex of reeler mouse model of schizophrenia.

Heterozygous reeler mouse has been used as an animal model for schizophrenia based on several neuropathological and behavioral abnormalities homologous to schizophrenia. Since some of these abnormalities are primarily associated with altered BDNF signaling we investigated BDNF signaling in the frontal cortex of reeler mice in order to shed some light on the neuropathology and treatment of schizophrenia. BDNF, TrkB receptor isoforms (full-length and truncated), reelin, GAD67, GAD65, p75NTR, and NRH-2 levels were measured in the frontal cortex samples from reeler (B6C3Fe a/a-Reln rl/+) and wild-type (WT) mice.

Opposite changes in predominantly docosahexaenoic acid (DHA) in cerebrospinal fluid and red blood cells from never-medicated first-episode psychotic patients.

Variable levels of essential polyunsaturated fatty acids (EPUFAs) reported in schizophrenia are likely due to differences in age, sex, ethnicity, diet, life style and treatments. The present study examined the EPUFAs levels in plasma, RBC and CSF in never-medicated first-episode psychotic patients and normal controls matched for ethnicity, diet and life style. The plasma EPUFAs levels were similar in both groups.

Sensitivity of fetus and pups to excess levels of maternal intakes of alpha linolenic acid at marginal protein levels in Wistar rats.

There is growing interest in the role omega 3 fatty acids (n3), in promoting fetal growth. Present study examined whether alpha linolenic acid, primary vegetarian dietary omega 3 fatty acid source and precursor to cellular membrane phospholipid eicosapentaenoic acid and docosahexaenoic acid, can improve birth outcome. Pregnant dams from three groups (seven in each) were fed: control diet (18% protein with 7% soybean oil, normal alpha linolenic acid), or two treatment diets at marginal protein level of 12%; one with 7% soybean oil (Treatment I, normal alpha linolenic acid), and other with 3% flax oil and 4% soybean oil (Treatment II, four times normal alpha linolenic acid) during gestation.

Erythropoietin prevents haloperidol treatment-induced neuronal apoptosis through regulation of BDNF.

Functional alterations in the neurotrophin, brain-derived neurotrophic factor (BDNF) have recently been implicated in the pathophysiology of schizophrenia. Furthermore, animal studies have indicated that several antipsychotic drugs have time-dependent (and differential) effects on BDNF levels in the brain. For example, our previous studies in rats indicated that chronic treatment with the conventional antipsychotic, haloperidol, was associated with decreases in BDNF (and other neurotrophins) in the brain as well as deficits in cognitive function (an especially important consideration for the therapeutics of schizophrenia).

Time-dependent cognitive deficits associated with first and second generation antipsychotics: cholinergic dysregulation as a potential mechanism.

Although cognitive dysfunction is considered one of the more debilitating symptoms of schizophrenia, there is a fundamental gap in our knowledge of how the primary pharmacologic treatments of this disease, first- and second-generation antipsychotics (FGAs and SGAs, respectively), affect cognition, particularly over extended periods of time. Moreover, it has been known for decades that chronic treatment with FGAs can lead to imbalances in cholinergic function in the striatum that result in movement disorders; however, there is a growing body of evidence to suggest that both FGAs and SGAs can lead to cholinergic alterations in brain areas more traditionally considered as memory-related, such as cortical and hippocampal regions. Data from our laboratories in rodents indicate that some SGAs (if administered for sufficient periods of time) can be associated with impairments in memory-related task performance as well as alterations in the cholinergic enzyme choline acetyltransferase, the vesicular acetylcholine transporter, and nicotinic (alpha(7)) and muscarinic (M(2)) acetylcholine receptors.

Differential effects of haloperidol and olanzapine on the expression of erythropoietin and its receptor in rat hippocampus and striatum.

Compared with first-generation antipsychotics (FGAs), second-generation antipsychotics (SGAs) seem to be neuroprotective and trigger neuroplasticity. Because neuroplasticity is regulated by a variety of neurotrophic factors we studied differential effects of haloperidol (HAL, a FGA) and olanzapine (OLZ, a SGA) on temporal expression of erythropoietin (EPO), a potent neuroprotective factor and its receptor (EPOr) in rat brain. Rats (8-10/group) were treated with HAL or OLZ for 14 days (HAL-14 or OLZ-14) or 45 days (HAL-45 or OLZ-45).

Differential effects of haloperidol and olanzapine on levels of vascular endothelial growth factor and angiogenesis in rat hippocampus.

Compared to first-generation antipsychotics (FGAs) such as haloperidol, second-generation antipsychotics (SGAs) such as olanzapine are found superior to improve cognitive performance and reduce negative symptoms with no extrapyramidal symptoms (EPS). These clinical effects of SGAs have been reported to be associated with the most replicated phenomenon, favorable changes in brain regional blood flow and volume. The changes in brain regional blood flow are shown to parallel changes in angiogenesis, which is primarily mediated by vascular endothelial growth factor (VEGF) through its receptor, Flk-1, on endothelial cells.

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.

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.

Time-dependent effects of haloperidol and ziprasidone on nerve growth factor, cholinergic neurons, and spatial learning in rats.

In this rodent study, we evaluated the effects of different time periods (7, 14, 45, and 90 days) of oral treatment with haloperidol (HAL; 2.0 mg/kg/day) or ziprasidone (ZIP; 12.0 mg/kg/day) on nerve growth factor (NGF) and choline acetyltransferase (ChAT) levels in the hippocampus, and we subsequently assessed water maze task performance, prepulse inhibition (PPI) of the auditory gating response, and several NGF-related proteins and cholinergic markers after 90 days of treatment.

Long-term antipsychotic treatments and crossover studies in rats: differential effects of typical and atypical agents on the expression of antioxidant enzymes and membrane lipid peroxidation in rat brain.

Short-term (<45 days) treatment studies in rats have reported increased oxidative stress and oxidative (i.e., oxygen free radical-mediated) neural cell injury with typical antipsychotics such as haloperidol, but not with the atypicals such as clozapine, olanzapine or risperidone.

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.

Thiobarbituric acid reactive substances in the cerebrospinal fluid in schizophrenia.

Increased levels of lipid peroxidation products (thiobarbituric acid reactive substances [TBARS]) are reported in plasma/serum from patients with schizophrenia. CSF TBARS levels were assessed in 10 neuroleptic-free patients with schizophrenia and in 9 normal controls. Controlling for duration of storage, CSF TBARS content was significantly lower in patients with schizophrenia vs.

Differential effects of typical and atypical antipsychotics on nerve growth factor and choline acetyltransferase expression in the cortex and nucleus basalis of rats.

Previously we reported that chronic exposure to haloperidol (HAL), but not the atypical antipsychotics risperidone (RISP) or clozapine (CLOZ), resulted in reductions in brain choline acetyltransferase (ChAT) immunoreactivity and impaired water maze task performance in rats. In the present study, we compared the effects of these antipsychotic drugs on the expression of nerve growth factor (NGF) as well ChAT the in the rat cortex and nucleus basalis of Meynert (NBM) in an effort to determine the underlying mechanism for the differential drug effects observed previously. We also evaluated the effects of these compounds in a crossover design to evaluate specific neurochemical consequences of switching between typical and atypical antipsychotics, a common practice observed in the clinical setting.

Olanzapine counteracts reduction of brain-derived neurotrophic factor and TrkB receptors in rat hippocampus produced by haloperidol.

Recently, we have reported studies in rats showing that the atypical antipsychotic olanzapine (OLZ), in contrast to haloperidol (HAL), was not associated with reduction of markers of central cholinergic neurons as well as decrements in cognitive performance after chronic exposure. We compared the effect of 45 day chronic exposure of HAL (2 mg/kg per day) to OLZ (10 mg/kg per day) on brain-derived neurotrophic factor (BDNF)) and its high affinity receptor TrkB in rat hippocampus. Since the use of OLZ is presently preferred over HAL in patients, effects of its post-treatment on HAL-induced changes in the expression of BDNF and its TrkB receptor were also investigated.

Decreased antioxidant enzymes and membrane essential polyunsaturated fatty acids in schizophrenic and bipolar mood disorder patients.

Oxidative stress-mediated cell damage has been considered in the pathophysiology of schizophrenia. Abnormal findings have often been considered related to differences in ethnicity, life style, dietary patterns and medications, all of which influence indices of oxidative stress and oxidative cell damage. To minimize these confounds, schizophrenic patients were compared with age-matched control subjects with the same ethnic background and similar lifestyle, as well as with bipolar mood disorder (BMD) patients.

Modulation of nerve growth factor and choline acetyltransferase expression in rat hippocampus after chronic exposure to haloperidol, risperidone, and olanzapine.

Rationale: Recently, we reported that compared to haloperidol, chronic exposure to either the risperidone (RISP) or olanzapine (OLZ) resulted in superior effects on spatial learning performance as well as the cholinergic neurons, although the mechanism for these effects was not addressed.

Objectives: The objective of this study was to investigate one plausible mechanism whereby RISP and OLZ exert superior effects on cholinergic neurons, i.e.

Supplementation with a combination of omega-3 fatty acids and antioxidants (vitamins E and C) improves the outcome of schizophrenia.

Reduced levels of membrane essential polyunsaturated fatty acids (EPUFAs), namely, arachidonic acid (AA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acids (DHAs), and their association with psychopathology have been consistently reported in both chronic-medicated schizophrenic patients as well as in never-medicated patients soon after the first episode of psychosis. Past supplementation studies with either omega-6 or omega-3 or both EPUFAs generally in chronic-medicated-older patients have reported varying degrees of therapeutic effects, and have suggested that supplementation with primarily omega-3 EPUFAs (EPA>DHA) may be preferable. We report the supplementation with a mixture of EPA/DHA (180:120 mg) and antioxidants (vitamin E/C, 400 IU:500 mg) orally morning and evening to schizophrenic patients (N=33) for 4 months.

Is schizophrenia a metabolic brain disorder? Membrane phospholipid dysregulation and its therapeutic implications.

The dysregulation of membrane phospholipid metabolism exists throughout the body from the onset of psychosis in schizophrenic patients. This dysregulation is primarily due to altered contents of phospholipid bound EPUFAs, AA and DHA. These EPUFAs are highly enriched in the brain and are crucial for brain and behavioral development.

Nerve growth factor in never-medicated first-episode psychotic and medicated chronic schizophrenic patients: possible implications for treatment outcome.

Nerve growth factor (NGF) has been found to play a crucial role in the neuroplasticity of predominantly cholinergic neurons in brain development, and neuronal survival following brain injury, which reflect in cognitive performance. Wide ranges of neurodevelopmental abnormalities have been reported in schizophrenic patients, who also show poor cognitive performance. We report plasma NGF levels in never-medicated first-episode psychotic (FEP; N=24) and chronic medicated schizophrenic patients (N=24).

Differential effects of haloperidol, risperidone, and clozapine exposure on cholinergic markers and spatial learning performance in rats.

Haloperidol (HAL), a potent typical antipsychotic, continues to be a frequently prescribed medication for behavioral disturbances associated particularly with schizophrenia despite well-documented adverse effects associated with its chronic use. Animal experiments have even indicated that HAL can damage cholinergic pathways and thus could be especially deleterious to those experiencing cognitive deficits. However, several recent clinical studies indicate that atypical antipsychotics may actually improve cognitive function in some patients, although this assertion requires further investigation.

Essential polyunsaturated fatty acid and lipid peroxide levels in never-medicated and medicated schizophrenia patients.

Background: Reduced levels of membrane essential polyunsaturated fatty acids (EPUFAs) and increased levels of lipid peroxidation products (thiobarbituric acid reactive substances; TBARS) have been observed in chronic medicated schizophrenics. The relationship of EPUFA and TBARS to psychopathology is unclear, since their levels may be altered differentially by duration of illness and antipsychotic treatment. To minimize these confounds, their levels were compared among never-medicated patients in early illness, medicated patients and control subjects with similar lifestyle and common ethnic background.