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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    • "Due to its involvement in neuronal growth, maintenance and survival (specifically of dopaminergic neurons (Hyman et al., 1991)), BDNF may produce a neuroprotective mechanism against MA (Matsuzaki et al., 2004), and may thus contribute to the observed morphological abnormalities in MA-dependent individuals. It may be hypothesized that, in MAP, treatment with typical antipsychotics reduces inflammation or lowers BDNF (Pillai et al., 2006). Longitudinal studies are needed to determine whether MA dependence is associated with neuroplastic changes and higher gray matter thickness, and whether MAP in particular leads to a more Table 5Correlations between cortical thickness and Emotion Reactivity Scale scores. "
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    ABSTRACT: Methamphetamine (MA) has been shown to have neurotoxic effects associated with brain structure changes and schizophrenia-like psychotic symptoms. Although these abnormalities may in turn be related to cognitive impairment and increased aggression, their association with affect dysregulation is less well studied. We investigated cortical thickness and subcortical volumes in 21 participants with MA dependence, 19 patients with MA-associated psychosis (MAP), and 19 healthy controls. Participants' affect regulation abilities were assessed through self-report scales on emotion reactivity (ERS) and difficulties in emotion regulation (DERS) and correlated with differences in cortical thickness. MAP patients showed thinner cortices in the fusiform and inferior temporal gyrus (ITG), orbitofrontal (OFC) and inferior frontal gyrus (IFG), and insula, compared to the MA group. MAP also showed significantly lower hippocampal volumes relative to MA and CTRL. Both clinical groups showed impairment in affect regulation, but only in MAP was this dysfunction associated with thinner cortices in ITG, OFC and IFG. Our findings suggest significant differences in cortical thickness in MA dependence with and without psychosis. Lower fronto-temporal cortical thickness and smaller hippocampal volumes in MAP are consistent with neuroimaging findings in other psychotic disorders, supporting the notion of MAP being a useful model of psychosis.
    No preview · Article · Jan 2016 · Psychiatry Research: Neuroimaging
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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.
    Full-text · Article · Feb 2014 · PLoS ONE
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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. "

    Full-text · Article · Oct 2013 · Schizophrenia Research
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