Serum BDNF levels and weight gain in schizophrenic patients on long-term treatment with antipsychotics
Introduction
Antipsychotic pharmacotherapy is associated with considerable weight gain (Allison et al., 1999, Baptista, 1999, Allison and Casey, 2001, Nasrallah, 2003, Correll and Malhotra, 2004). Weight gain severity appears to be dependent on the drug and the individual patient (Allison and Casey, 2001, Nasrallah, 2003). This problem has become more pronounced with increasing use of the newer atypical antipsychotics. Indeed, compared to conventional neuroleptics, atypical antipsychotic drugs have superior side effect profiles (Kane, 2001) and broader symptom efficacy (Buckley, 2001), and have become the first-line treatment for psychotic as well as many non-psychotic disorders (Correll et al., 2004). However, reports of significant weight gain with these new atypical antipsychotics have caused considerable concern (Allison et al., 1999, Baptista, 1999, Taylor and McAskill, 2000, Allison and Casey, 2001, Nasrallah, 2003, Correll and Malhotra, 2004). While all of the antipsychotic agents seem to share these effects as a group to varying degrees (McIntyre et al., 2001), clozapine and olanzapine appear to have the greatest potential to induce dramatic body weight gain (Allison et al., 1999, Baptista, 1999).
Antipsychotic-induced weight gain is a leading cause of non-compliance (Perkins, 1999, Weiden et al., 2004) in turn increasing the risk for relapse (Robinson, 1999, Nasrallah, 2003). Moreover, weight gain has serious implications for overall health and survival due to an increased risk for cardiovascular and malignant disorders (Calle et al., 2003) that is linked to greater morbidity, mortality, and decreased life expectancy (Blackburn, 2000, Nasrallah, 2003). Further, antipsychotic-induced weight gain affects psychological well being (Dietz, 1998), leading to lower quality of life (Blackburn, 2000, Nasrallah, 2003). The mechanisms underlying antipsychotic-induced body weight gain remain unknown, but most likely multifactorial involving both genetic and environmental factors.
Brain derived neurotrophic factor (BDNF) belongs to the neurotrophic factor family and is widely expressed in the adult mammalian brain. BDNF plays a key role in regulating neuronal survival during the development of the central nervous system and differentiation and maintenance of mature neurons (Lewin and Barde, 1996). BDNF is most abundant in the hippocampus and hypothalamus in the human brain (Thoenen, 1995, Nawa et al., 1995), and its tyrosine kinase receptor (TrkB) is expressed in various hypothalamic nuclei associated with eating behavior (Kernie et al., 2000). Several preclinical studies indicate involvement of BDNF in food intake, energy and glucose metabolism, body weight regulation and activity. For example, heterozygous Bdnf knockout mice (reduced BDNF levels) are hyperphagic, obese, and hypoactive. Central BDNF infusions can transiently reverse abnormal eating behavior and obesity (Lyons et al., 1999, Kernie et al., 2000). In rats, centrally administered BDNF leads to severe, dose-dependent appetite suppression and weight loss (Pelleymounter et al., 1995). Similarly, peripherally administered BDNF reduces food intake, lowers blood glucose to normoglycemic levels and decrease body weight in obese diabetic models (Tonra et al., 1999, Ono et al., 2000). A recent report also has shown that female patients with anorexia nervosa or bulimia have decreased levels of serum BDNF compared to healthy normal weight controls (Nakazato et al., 2003). Furthermore, a more recent study has shown a negative correlation of plasma cholesterol and body weight with plasma BDNF levels (Lommatzsch et al., 2005). Taken together, these studies lend support to the notion that BDNF may play an important role in the regulation of eating behavior and body weight.
Recent studies suggest that neurotrophins (i.e., BDNF) may also be involved in antipsychotic action in the central nervous system (Angelucci et al., 2000). For example, both atypical and typical antipsychotic drugs (such as haloperidol, clozapine and risperidone) decrease BDNF concentrations in the frontal and occipital cortex and hippocampus (Angelucci et al., 2000) and reduce the expression of BDNF mRNA in the hippocampus in rats (Lipska et al., 2001). In contrast, other studies have found that haloperidol down-regulates BDNF mRNA expression in the rat hippocampus compared to controls, whereas clozapine has the opposite effect (Chlan-Fourney et al., 2002, Bai et al., 2003). The exact mechanisms that underlie these divergent effects await to be assessed. Yet it is clear that antipsychotic pharmacotherapy affects BDNF on a number of levels.
Based on studies indicating a role for BDNF in body weight regulation and modulation by antipsychotics we determined if BDNF played a role in antipsychotic-induced weight gain. To our knowledge there have been no published studies examining this association. Considering the chronic nature of schizophrenia, it appears that long-term rather than transient effects of antipsychotics on body weight is most clinically significant (Sussman, 2001, Sussman, 2003). Therefore, we selected a representative sample of inpatients with schizophrenia undergoing long-term antipsychotic treatment. The purposes of this study were to determine if serum BDNF levels are altered in inpatients with chronic schizophrenia and if different antipsychotic drugs alter BDNF levels differentially. We also assessed whether there was an association between altered BDNF levels and antipsychotic-induced weight gain.
Section snippets
Subjects
One hundred and twenty-four patients met DSM-IV criteria of schizophrenia (American Psychiatric Association, 1994) by agreement of two senior psychiatrists using the Structured Clinical Interview for DSM-IV (SCID). They were recruited randomly from inpatients of Beijing Hui-Long-Guan Hospital, a Beijing City owned psychiatric hospital. All patients were of the chronic type, with an illness course of at least 5 years (mean 22.3 ± 7.2 years). The mean duration of hospitalization was 8.9 ± 6.9 years.
Demographic data
There was no significant difference between patient and normal controls in age (47.3 ± 5.8 years vs. 46.2 ± 4.7 years) and sex (patients: 91 males, 33 females; controls: 36 males, 14 females). Mean weight gain in patients since the onset of the illness was 8.5 ± 8.3 kg and mean BMI gain was 3.1 ± 3.0 kg/m2.
Serum BDNF levels
Serum BDNF levels were significantly lower in patients compared to normal controls, either in the total sample or when they were compared by gender (all p < 0.05; Table 1). Levels were significantly
Discussion
The major findings of the present study are that BDNF levels in patients with chronic schizophrenia were significantly decreased compared with those of age-, sex-matched normal control subjects but this difference dissipated when controlling for the patient’s current BMI or in a well-chosen group controlling for the effects of bodyweight; BDNF levels in female patients with schizophrenia negatively correlated with weight gain. To our knowledge, this is the first study determining serum BDNF
Acknowledgements
This study was funded by the National Key Technology Research and Development Program of China (2002BA711A07), and the National Basic Research Program of China (2004CB518601) (Y.S.), the Stanley Medical Institute Foundation 03T-459 (X.Y.Z.), and the Department of Veterans Affairs, VISN 1, Mental Illness Research, Education and Clinical Center (MIRECC) and National Institute on Drug Abuse K05-DA0454 and P50-DA18827 (T.R.K.).
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Drs. X.Y. Zhang, Y.L. Tan and D.F. Zhou contributed equally to this work.