Decreased serum BDNF levels in chronic institutionalized schizophrenia on long-term treatment with typical and atypical antipsychotics

https://doi.org/10.1016/j.pnpbp.2009.08.011Get rights and content

Abstract

Accumulating evidence showed that brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia. Decreased BDNF levels have been found in the serum of schizophrenic patients with mixed results. In the present study, we assessed serum BDNF levels in a large group of 364 schizophrenic patients (157 on clozapine, 89 on risperidone and 118 on typical antipsychotics), compared to 323 healthy control subjects matched for age and gender. The schizophrenia symptomatology was assessed by the Positive and Negative Syndrome Scale (PANSS), and serum BDNF levels were measured by sandwich ELISA. The results showed that BDNF levels were significantly lower in chronic patients with schizophrenia than in healthy control subjects (9.9 ± 2.0 ng/ml vs.11.9 ± 2.3 ng/ml, p < 0.0001). Lower BDNF levels were observed in patients treated with risperidone (9.3 ± 2.3 ng/ml) compared to those with clozapine (10.2 ± 2.0 ng/ml, p < 0.001) and typical antipsychotics (10.0 ± 2.1 ng/ml, p < 0.01). Furthermore, a stepwise multiple regression analysis identified types of antipsychotic drugs (beta =  0.37, t =  3.15, p = 0.001) and BDNF levels (beta =  0.26, t =  2.51, p = 0.014) as the influencing factor for the positive symptom subscore of PANSS. In addition, there was a sex difference in BDNF levels in patients with schizophrenia (9.7 ± 1.9 ng/ml for males vs.10.4 ± 2.1 ng/ml for female, p < 0.005), but not in normal controls. Our findings indicated decreased BDNF serum levels in chronic patients with schizophrenia, which may be related to clinical phenotypes, including gender, antipsychotic treatment and the severity of psychotic symptoms.

Introduction

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays an important role in the development, regeneration, survival and maintenance of function of neurons (Nawa et al., 2000, Karege et al., 2002). Recently, numerous studies have shown changes in BDNF levels in the blood of schizophrenic patients. For example, decreased serum or plasma BDNF levels have been reported in chronic antipsychotic-treated (Toyooka et al., 2002, Pirildar et al., 2004, Tan et al., 2005, Grillo et al., 2007, Ikeda et al., 2008), neuroleptic free (Palomino et al., 2006) or neuroleptic naive, first-episode schizophrenic patients (Buckley et al., 2007, Rizos et al., 2008). However, some authors failed to replicate these findings in both medicated and unmediated (Shimizu et al., 2003, Huang and Lee, 2006), or even found increased serum BDNF levels in treated schizophrenic patients (Gama et al., 2007, Reis et al., 2008) or in non-medicated schizophrenic patients with cannabis and multiple substance abuse (Jockers-Scherübl et al., 2004). Thus, the picture emerging is that BDNF levels deserve further examination in the peripheral blood of schizophrenia.

A few studies have examined the relationships between BDNF alteration and psychopathology in schizophrenia. For example, BDNF was found to be associated with positive symptoms (Buckley et al., 2007), negative symptoms (Zhang et al., 2007, Reis et al., 2008, Rizos et al., 2008), and TD (Tan et al., 2005). These findings provide evidence that BDNF may be involved in psychopathology of schizophrenia.

Some recent studies have found a differential regulation of BDNF mRNA expression in the rat hippocampus and neocortex by typical and atypical antipsychotic administration (Bai et al., 2003), and atypical antipsychotics specifically olanzapine or quetiapine appear to favorably modulate BDNF expression (Pillai et al., 2006, Park et al., 2008, Rizos et al., 2008) . Our previous study showed that serum BDNF levels were higher in chronic schizophrenic patients on clozapine or typical antipsychotic than those on risperidone (Tan et al., 2005). A more recent study also showed a trend for a significantly higher BDNF levels in chronic schizophrenic patients on clozapine than those on typical antipsychotics (Grillo et al., 2007). However, some longitude studies reported that lower serum BDNF levels did not elevate after several week treatment with risperidone or antipsychotics (Pirildar et al., 2004, Yoshimura et al., 2007). In addition, alteration of serum BDNF levels has been influenced by the duration of the antipsychotic medication. It seems that alteration of serum BDNF is different in short-term period treatment than in long-term period treatment (Pillai et al., 2006, Gama et al., 2007). Thus, the effects of antipsychotic agents on the BDNF levels deserve further examination in cases of schizophrenia. The true alteration of BDNF levels induced by different typical or atypical medications is still unknown.

Earlier studies featured comparatively small sample size, which often leads to false positive results. We recruited a larger sample of patients (n = 364) in the present study, which might provide us an enough power to elucidate the following questions: (1) whether serum BDNF levels were altered in chronic and medicated schizophrenic patients; (2) whether there was a differential effects of long-term treatment with typical and atypical antipsychotics on BDNF levels; and (3) whether there was a relationship between BDNF levels and psychopathological parameters, using the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987).

Section snippets

Subjects

Three hundred and sixty four physically healthy patients (male/female = 281/83) who met DSM-IV for schizophrenia were compared with 323 Chinese normal controls. All schizophrenic patients were recruited from among the inpatients of Beijing Hui-Long-Guan Hospital, a Beijing City owned psychiatric hospital. Diagnoses were made for each patient by two independent experienced psychiatrists. All schizophrenic patients were of the chronic type, with duration of illness for at least 5 years, age between

Demographic data

Table 1 shows the demographic data of the subjects in the present study. There was no significant difference between patient and normal control groups on any characteristic.

Within the normal controls, no significant correlation was observed between BDNF levels and gender, age, education, smoking and BMI. Within the patient group, there was a significant inverse relationship between age and BDNF levels (R =  0.19, df = 362, p = 0.003). No other parameters, including age of onset of psychosis, duration

Discussion

In the present study, the result of decreased BDNF levels in medicated patients with chronic schizophrenia is in accordance with some recently published studies (Grillo et al., 2007, Palomino et al., 2006, Pirildar et al., 2004, Tan et al., 2005, Zhang et al., 2007, Ikeda et al., 2008, Rizos et al., 2008). In contrast, some other studies failed to find any difference in serum BDNF levels between schizophrenia and normal controls (Shimizu et al., 2003, Huang and Lee, 2006), or even increased

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These three authors contributed equally to the study.

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