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Although reducing psychotic symptoms in schizophrenia has been a major focus of therapeutic interventions for decades, improving cognition is considered a better predictor of functional outcomes. However, the most commonly prescribed antipsychotic drugs (APDs) show only marginal beneficial effects on cognition in patients with schizophrenia. The neural mechanisms underlying cognitive disturbances in schizophrenia remain unknown that making drug development efforts very challenging. Since neurotrophic factors are the primary architects of neurogenesis, synaptic plasticity, learning, and memory, the findings from preclinical and clinical studies that assess changes in neurogenesis and neurotrophic factors and their relationship to cognitive performance in schizophrenia, and how these mechanisms might be impacted by APD treatment, may provide valuable clues in developing therapies to combat cognitive deficit in schizophrenia. Numerous evidence produced over the years suggests a deficit in a wide spectrum of neurotrophic factors in schizophrenia. Since schizophrenia is considered a neurodevelopmental disorder, early intervention with neurotrophic factors may be more effective in ameliorating the cognitive deficits and psychopathological symptoms associated with this pathology. In this context, results from initial clinical trials with neurotrophic factors and their future potential to improve cognition and psychosocial functioning in schizophrenia are discussed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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. However, now these and several other atypical antipsychotics that differ in their neurotransmitter receptor affinity profiles are being used for a long-term treatment of schizophrenia. Therefore, understanding of their long-term treatment effects on the expression of antioxidant enzymes and oxidative neural cell injury in rats may be important to explain the possible differential mechanisms underlying their long-term clinical and side effects profiles. The effect of 90 and 180 day exposure to haloperidol (HAL, 2mg/kg/day), a representative typical antipsychotic was compared to exposure to chlorpromazine (CPZ, 10mg/kg/day), ziprasidone (ZIP, 12mg/kg/day), risperidone (RISP, 2.5mg/kg/day), clozapine (CLOZ, 20mg/kg/day) or olanzapine (OLZ, 10mg/kg/day) on the expression of antioxidant defense enzymes and levels of lipid peroxidation in the rat brain. The drug-induced effects on various antioxidant defense enzymes; manganese-superoxide dismutase (MnSOD), copper-zinc superoxide dismutase (CuZnSOD) and catalase (CAT) were assessed by determination of their enzymatic activity and protein content. Immunohistochemical analysis was also carried out to assess the cellular levels of MnSOD and CuZnSOD and cellular morphology. The oxidative membrane damage was assessed by determination of levels of the lipid peroxidation product, hydroxyalkanals (HAEs) in the rat brain. Both 90 and 180 days of HAL treatment very significantly decreased the levels of MnSOD (50%) and CuZnSOD (80%) and increased the levels of HAEs compared to vehicle treatment. Smaller reduction was found in CAT (25%) and no change in the glutathione peroxidase (GSHPx). The levels of enzymatic activity correlated generally well with the levels of enzyme protein indicating that the changes were in the expression of net protein. Though atypical antipsychotics like ZIP, RISP and OLZ did not show any change in the HAEs levels up to 90 days, further treatment up to 180 days resulted in significantly increased levels of HAEs in CPZ, ZIP and RISP, but not in OLZ treated rats. Post-treatment with several atypical antipsychotics (OLZ=CLOZ>RISP) for 90 days after 90 day of HAL treatment significantly restored the HAL-induced loss in MnSOD and CuZnSOD activities and increase in lipid peroxidation products as well as cellular morphology. These data may be very helpful in planning long-term use as well as switch over of these antipsychotics for the management of schizophrenia.

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. Seven and 14 days of treatment with either HAL or ZIP resulted in a notable increase in NGF and ChAT immunoreactivity in the dentate gyrus (DG), CA1, and CA3 areas of the hippocampus. After 45 days, NGF and ChAT immunoreactivity had abated to control levels in ZIP-treated animals, but it was markedly reduced in HAL-treated subjects. After 90 days of treatment, NGF and ChAT levels were substantially lower than controls in both antipsychotic groups. Furthermore, after 90 days of treatment and a drug-free washout period, water maze performance (but not PPI) was impaired in both antipsychotic groups, although the decrement was greater in the HAL group. Several NGF-related and cholinergic proteins were diminished in the brains of subjects treated with either neuroleptic as well. These data support the premise that, although ZIP (given chronically) seems somewhat superior to HAL due to less pronounced behavioral effects and a more delayed appearance of neurochemical deficits, both antipsychotics produce time-dependent deleterious effects on NGF, cholinergic markers (i.e., important neurobiological substrates of memory), and cognitive function.

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. Male Wistar rats (250-300 g) were exposed to HAL (2.0 mg/kg/day), RISP (2.5 mg/kg/day), or CLOZ (20 mg/kg/day) for 45 days or a pre-treatment regimen consisting of administering either RISP/HAL (i.e., RISP followed by HAL) or CLOZ/HAL, or a post-treatment regimen consisting of administering: HAL/RISP or HAL/CLOZ. The duration of each treatment in the crossover study was also 45 days. NGF and ChAT immunoreactivity were measured by quantitative immunohistochemistry in some sub-cerebral cortical regions and NBM after drug exposures. NGF protein was also measured by an enzyme-linked ImmunoSorbent assay (ELISA) in rat sensorimotor cortex. The results indicated that HAL (but not RISP or CLOZ) significantly reduced NGF levels in some sub-cortical regions and ChAT immunoreactivity in both cortex and NBM. However, pre-treatment with CLOZ prevented the HAL-associated decreases in NGF and ChAT, while post-treatment with either RISP or CLOZ (i.e., after the administration of HAL) appeared to restore NGF and ChAT to control levels. These data indicate that antipsychotic drugs exert dissimilar effects on the levels of NGF and ChAT in the brain, which may contribute to their differential effects on cognitive function. The crossover data further suggest that certain atypical antipsychotic drugs (e.g., clozapine) may have the potential to prevent or reverse the deleterious effects of HAL on important neurochemical substrates of cognitive function.

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. positive effects on nerve growth factor (NGF), which is known to regulate the brain cholinergic activity as well as cognitive function. Therefore, the effects of chronic exposure to HAL, RISP, or OLZ on the expression of NGF and choline acetyltransferase (ChAT) in the hippocampus (i.e. a brain area well known to be involved in cognitive function and known to receive major cholinergic projections from the medial septum) were compared., Methods: Rats were treated with HAL (1 or 2 mg/kg per day), RISP (1.25 or 2.5 mg/kg per day), or OLZ (5 or 10 mg/kg per day) for 45 days in drinking water. NGF and ChAT were measured by immunohistochemistry and NGF protein was also measured by an enzyme-linked ImmunoSorbent assay., Results: Compared to controls, HAL exposure resulted in a marked reduction in NGF immunoreactivity in the hippocampal dentate gyrus (DG), CA1 and CA3 areas. In contrast, RISP did not alter, while OLZ significantly increased levels of NGF. These changes in NGF levels corresponded well with changes in ChAT immunoreactivity in the hippocampus and the medial septum., Conclusions: These preclinical data, combined with previously published behavioral results, support the premise that OLZ and RISP, in contrast to HAL, preserve cholinergic pathways and cognitive function via superior effects on NGF expression and are thus therapeutically superior for extended use.

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. OLZ was administered after 45 days of HAL exposure. HAL, but not OLZ, significantly reduced the levels of BDNF in hippocampus. These changes in BDNF paralleled the levels of TrkB receptors. Furthermore, post-treatment with OLZ markedly restored the HAL treatment associated reductions in both BDNF and TrkB receptors in hippocampus.

A role of indices of oxidative stress, oxidative injury, and abnormal membrane phospholipid, specifically the phospholipid essential polyunsaturated fatty acids (EPUFAs) metabolism has been suggested based on studies in separate groups of patients with or without medication. The current study investigated the relationship between these biochemical measures in first-episode psychotic patients (N=16) at baseline and after 6 months of antipsychotic treatment (N=5 each with risperidone and olanzapine) and compared them to matched normal subjects. The indices of oxidative stress included: antioxidant enzymes; superoxide dismutase, glutathione peroxidase and catalase; and the oxidative injury as the levels of plasma lipid peroxides. The key membrane EPUFA's been; linolenic acid, arachidonic acid, nervonic acid, docosapentaenoic acid and docosahexaenoic acid. Furthermore, the changes in these biochemical measures were correlated with clinical symptomatology. Data indicated that, at baseline, reduced levels of antioxidant enzymes were associated with increased plasma lipid peroxides and reduced membrane EPUFAs, particularly omega-3 fatty acids. Furthermore, these biochemical measures normalized after 6 months of antipsychotic treatment. Parallel-improved psychopathology indicated that membrane EPUFA status might be partly affected by oxidative damage, which together may contribute to the pathophysiology and thereby, psychopathology of schizophrenia. These data also support the augmentation of antipsychotic treatment by supplementation with a combination of antioxidants and omega-3 fatty acids.

Apolipoprotein-D (apoD), a member of the lipocalin family of proteins, binds to arachidonic acid and cholesterol among other hydrophobic molecules. Recently, elevated apoD levels have been reported in the post-mortem brains, as well as plasma, of schizophrenic patients and in rodent brains after chronic treatment with clozapine (CLOZ). These findings and the evidence for altered membrane lipid metabolism in schizophrenia suggest that apoD may have a role in the pathophysiology of illness, and also in the differential clinical outcome following treatment with typical and atypical antipsychotic drugs. Here, we compared the effects of these antipsychotics on the expression of apoD in rat brain. Chronic treatment with typical antipsychotic, haloperidol (HAL) reduced apoD expression in hippocampus, piriform cortex and caudate-putamen (p = 0.027-0.002), whereas atypical antipsychotics, risperidone (RISP) and olanzapine (OLZ) increased (p = 0.051 to < 0.001 and p = 0.048 to < 0.001, respectively) apoD expression. In hippocampus, HAL-induced changes were present in CA1, CA3 and dentate gyrus, however, apoD levels in motor cortex were unchanged. There were also very dramatic effects of HAL on the neuronal morphology, particularly, cellular shrinkage and disorganization with the loss of neuropil. Post-treatment, either with RISP or OLZ, was very effective in restoring the HAL-induced reduction of apoD, as well as cellular morphology. Similarly, pre-treatments were also effective, but slightly less than post-treatment, in preventing HAL-induced reduction of apoD. The increased expression of apoD by atypical antipsychotics may reflect a novel molecular mechanism underlying their favorable effects compared with HAL on cognition, negative symptoms and extra-pyramidal symptoms in schizophrenia.

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). NGF levels were determined in plasma by Enzyme-Linked ImmunoSorbent Assay (ELISA). Plasma NGF levels were significantly lower in both FEP and medicated chronic patients as compared to normal subjects (P<0.001). However, NGF levels were significantly higher in chronic schizophrenic patients, which were treated with antipsychotics as compared to FEP (P<0.05). Moreover, NGF levels in chronic patients treated with atypical antipsychotics were markedly higher as compared to patients treated with typical antipsychotics (P<0.05). Lower NGF levels in FEP patients at the onset of psychosis may have implications for the neurodevelopmental abnormalities. However, higher NGF levels in chronic patients treated with atypical antipsychotics may have implications for the treatment outcome.

Typical and atypical antipsychotics significantly differ in their neurotransmitter receptor affinity profiles, and their efficacy and side effects in schizophrenic patients. Typical antipsychotics have been found to increase the oxidative (i.e. free radical-mediated) cellular injury in rats. Since schizophrenia also involves oxidative injury, the understanding of differential effects of these antipsychotics on expression of antioxidant enzymes and oxidative injury may be very critical. The effect of chronic exposure of haloperidol (HAL), a typical antipsychotic, was compared to effects of risperidone (RIS) or clozapine (CLZ) or olanzapine (OLZ), atypical antipsychotics on antioxidant defense enzymes and lipid peroxidation in the rat brain. The levels of antioxidant enzymes and hydroxyalkenals (HAEs) were measured in rat brain cytosol and fatty acids were measured in brain cell membranes. Chronic HAL treatment for both 45 and 90 days significantly decreased manganese-superoxide dismutase (MnSOD), copper-zinc superoxide dismutase (CuZnSOD) and catalase (CAT) activity with parallel marked increase in (HAEs), a marker of lipid peroxidation in rat brain. The levels of enzymatic activity very well correlated with the levels of enzyme proteins indicating that the changes were probably in the expression of net protein. However, RIS, CLZ and OLZ treatments did not produce any alterations in the levels of antioxidant enzymes and HAEs, both after 45 and 90 days. There were no alterations in the levels of saturated as well as polyunsaturated fatty acids in brain membranes. These findings indicate that chronic administration of HAL, but none of the studied atypicals induce oxidative stress by persistent changes in the levels of antioxidant enzymes and cause membrane lipid peroxidation.