Pillai A, Terry Jr AV, Mahadik SP. Differential effects of long-term treatment with typical and atypical antipsychotics on NGF and BDNF levels in rat striatum and hippocampus. Schizophr Res 82: 95-106

Psychiatry and Health Behavior, Medical College of Georgia, Augusta, GA, USA.
Schizophrenia Research (Impact Factor: 3.92). 03/2006; 82(1):95-106. DOI: 10.1016/j.schres.2005.11.021
Source: PubMed


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.

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    • "However, other studies have found no effects of antipsychotic treatment on BDNF levels [11]–[13]. In addition to antipsychotic treatment, other factors such as stage of illness, gender and genetic makeup seem to play a role in BDNF levels of patients with schizophrenia [14]–[16]. "
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    ABSTRACT: Schizophrenia is associated with structural and functional abnormalities of the hippocampus, which have been suggested to play an important role in the formation and emergence of schizophrenia syndrome. Patients with schizophrenia exhibit significant bilateral hippocampal volume reduction and progressive hippocampal volume decrease in first-episode patients with schizophrenia has been shown in many neuroimaging studies. Dysfunction of the neurotrophic system has been implicated in the pathophysiology of schizophrenia. The initiation of antipsychotic medication alters the levels of serum Brain Derived Neurotrophic Factor (BDNF) levels. However it is unclear whether treatment with antipsychotics is associated with alterations of hippocampal volume and BDNF levels. In the present longitudinal study we investigated the association between serum BDNF levels and hippocampal volumes in a sample of fourteen first-episode drug-naïve patients with schizophrenia (FEP). MRI scans, BDNF and clinical measurements were performed twice: at baseline before the initiation of antipsychotic treatment and 8 months later, while the patients were receiving monotherapy with second generation antipsychotics (SGAs). We found that left hippocampal volume was decreased (corrected left HV [t = 2.977, df = 13, p = .011] at follow-up; We also found that the higher the BDNF levels change the higher were the differences of corrected left hippocampus after 8 months of treatment with atypical antipsychotics (Pearson r = 0.597, p = 0.024). The association of BDNF with hippocampal volume alterations in schizophrenia merits further investigation and replication in larger longitudinal studies.
    PLoS ONE 02/2014; 9(2):e87997. DOI:10.1371/journal.pone.0087997 · 3.23 Impact Factor
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    • "Paliperidone (5 mg/kg/day) or vehicle (saline) was administered via continuous subcutaneous infusion (ALZET) in order to mimic the profile of LAI paliperidone ER in clinical studies (Marchese et al., 2010). The dose and duration of drug treatment were selected based on previous studies (Pillai et al., 2006; McNamara et al., 2011). Risperidone and paliperidone were provided by Janssen Scientific Affairs, LLC. "
    Schizophrenia Research 10/2013; 151(1-3). DOI:10.1016/j.schres.2013.09.027 · 3.92 Impact Factor
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    • "Several studies have shown that BDNF mRNA and protein content in the hippocamus are decreased during AAD-induced weight gain (20, 21). Risperidone has been shown to significantly decrease BDNF concentration in the frontal cortex, occipital cortex, and hippocampus of rats (21). However, neither the study by Angelucei et al. (20) nor the present study showed an effect of risperidone on BDNF in the hypothalamus of rats and mice, questioning whether BDNF expression in the hypothalamus is involved in the integrative regulation of energy metabolism during AAD treatment. "
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    ABSTRACT: Objective To investigate the effect of risperidone on energy expenditure and weight gain in female C57BL/6J mice. Design and Methods Body weight and composition, food intake, energy expenditure, and activity were determined weekly. mRNA expression of uncoupling protein 1 in brown adipose tissue, orexin and brain-derived neurotrophic factor in the hypothalamus were quantified by Real-Time PCR. Results Risperidone tended to induce a greater body weight gain (P=0.052) and significantly higher food intake (P=0.038) relative to the placebo-treated group. Risperidone-treated mice had a higher resting energy expenditure (P=0.001), and total energy expenditure (P=0.005) than the placebo group. There were no effects of treatment, time, and treatment by time on NREE between groups. Risperidone-treated mice showed a significantly lesser locomotor activity than placebo-treated mice over 3 weeks (P<0.001). Risperidone induced a higher UCP1 mRNA (P=0.003) and a lower orexin mRNA (P=0.001) than placebo. Discussion Risperidone-induced weight gain is associated with hyperphagia and a reduction in locomotor activity in C57BL/6J mice. Additionally, higher total and resting energy expenditure were accompanied by higher levels of UCP1 mRNA in BAT. The increased total energy expenditure could not offset the total intake of energy through risperidone-induced hyperphagia, therefore resulting in weight gain in female C57BL/6J mice.
    Obesity 05/2013; 21(9). DOI:10.1002/oby.20350 · 3.73 Impact Factor
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