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

Progress in Neuro-Psychopharmacology & Biological Psychiatry xxx (2009) xxx–xxx Progress in Neuro-Psychopharmacology & Biological j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p n p Decreased serum BDNF levels in chronic institutionalized schizophrenia onlong-term treatment with typical and atypical antipsychotics Mei Hong Xiu 1 , Li Hui 1 , Yu Feng Dang ,1 , Tian De Hou , Chong Xi Zhang You Lan Zheng Da Chun Chen Thomas R. Kosten Xiang Yang Zhang a Center for Biological Psychiatry, Beijing HuiLongGuan Hospital, Beijing, PR Chinab College of Life Science, Northwest Normal Unversity Lanzhou, Gansu Province, PR Chinac College of Chinese Medicinal Material, Jilin Agricultural University, ChangChun, PR Chinad Shandong University at Weihai Shandong Weihai 264209, PR Chinae Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas, USA 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 andNegative 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 sexdifference 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 patientswith schizophrenia, which may be related to clinical phenotypes, including gender, antipsychotic treatment andthe severity of psychotic symptoms.
2009 Elsevier Inc. All rights reserved.
chronic antipsychotic-treated (neuroleptic free Brain-derived neurotrophic factor (BDNF), a member of the ) or neuroleptic naive, first-episode schizophrenic neurotrophin family, plays an important role in the development, regeneration, survival and maintenance of function of neurons ( failed to replicate these findings in both medicated and unmediated changes in BDNF levels in the blood of schizophrenic patients. For serum BDNF levels in treated schizophrenic patients example, decreased serum or plasma BDNF levels have been reported in or in non-medicated schizophrenic patients withcannabis and multiple substance abuse ).
Thus, the picture emerging is that BDNF levels deserve further Abbreviations: ANOVA, analysis of variance; BBB, blood-brain barrier; BDNF, brain- examination in the peripheral blood of schizophrenia.
derived neurotrophic factor; BMI, body mass index; DA, dopamine; ELISA, enzyme- A few studies have examined the relationships between BDNF linked immunosorbent assay; PANSS, Positive and Negative Syndrome Scale; TD, alteration and psychopathology in schizophrenia. For example, BDNF tardive dyskinesia; 5-HT, serotonin.
⁎ Corresponding authors. Kosten is to be contacted at VA Medical Center, Research was found to be associated with positive symptoms Building 110, Room 229, 2002 Holcombe Boulevard, Houston, Texas, 77030, USA. Tel.: +1 713 794 7032; fax: +1 713 794 7938. Zhang, VA Medical Center, Research Building ), and TD ). These findings provide evidence 109, Room 130, 2002 Holcombe Boulevard, Houston, Texas, 77030, USA. Tel.: +1 713 that BDNF may be involved in psychopathology of schizophrenia.
791 1414x5824; fax: +1 713 794 7938.
Some recent studies have found a differential regulation of BDNF E-mail addresses: (T.R. Kosten), (X.Y. Zhang).
1 These three authors contributed equally to the study.
mRNA expression in the rat hippocampus and neocortex by typical and 0278-5846/$ – see front matter 2009 Elsevier Inc. All rights reserved.
doi: Please cite this article as: Xiu MH, et al, Decreased serum BDNF levels in chronic institutionalized schizophrenia on long-term treatment withtypical and atypical antipsychotics, Prog Neuro-Psychopharmacol Biol Psychiatry (2009), doi: M.H. Xiu et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry xxx (2009) xxx–xxx atypical antipsychotic administration ), and atypical Neither the schizophrenic patients nor the control subjects suffered from antipsychotics specifically olanzapine or quetiapine appear to favorably drug or alcohol abuse/dependence. All subjects gave signed, informed consent to participate in the study, which was approved by the . Our previous study showed that serum BDNF levels were Institutional Review Board, Beijing HuiLongGuan hospital.
higher in chronic schizophrenic patients on clozapine or typicalantipsychotic than those on risperidone (. A more recent study also showed a trend for a significantly higher BDNF levels inchronic schizophrenic patients on clozapine than those on typical The patient's psychopathology was assessed on the day of the antipsychotics (). However, some longitude studies blood sampling by four psychiatrists who were blind to the clinical reported that lower serum BDNF levels did not elevate after several status with the PANSS. To ensure consistency and reliability of rating week treatment with risperidone or antipsychotics across the study, these four psychiatrists who had worked at least In addition, alteration of serum BDNF levels has 5 years in clinical practice simultaneously attended a training session been influenced by the duration of the antipsychotic medication. It in the use of the PANSS before the start of the study. After training, a seems that alteration of serum BDNF is different in short-term period correlation coefficient greater than 0.8 was maintained for the PANSS treatment than in long-term period treatment total score by repeated assessments during the course of the study.
). Thus, the effects of antipsychotic agents on the BDNF levelsdeserve further examination in cases of schizophrenia. The truealteration of BDNF levels induced by different typical or atypical med- Earlier studies featured comparatively small sample size, which Ten ml of blood samples were collected into sterile empty tube often leads to false positive results. We recruited a larger sample of without anticoagulant and allowed to clot at room temperature.
patients (n = 364) in the present study, which might provide us an Serum was separated by centrifugation at 3000 rpm for 10 min and enough power to elucidate the following questions: (1) whether serum BDNF levels were altered in chronic and medicated schizo- Serum BDNF levels were measured by sandwich enzyme-linked phrenic patients; (2) whether there was a differential effects of long- immunosorbent assay (ELISA) using a commercially available kit term treatment with typical and atypical antipsychotics on BDNF (BanDing Biomedical, Chinese Academy of Sciences, Beijing, China). A levels; and (3) whether there was a relationship between BDNF levels full description of the assays has been given in our previous report ( and psychopathological parameters, using the Positive and Negative ). Briefly, standard 96-well plates were coated with the mouse monoclonal anti-BDNF immunoglobulin and incubated over-night. After washing, the samples and standards (concentration 0.1– 256 ng/well) were incubated overnight. The plates were then washedthree times with washing buffer, followed by incubation with chick anti- BDNF overnight. After three washes, a 1:1000 dilution of peroxidaselabeled anti-chick antibody were added. After further washing, the Three hundred and sixty four physically healthy patients (male/ reaction was developed at room temperature with tetramethylbenzi- female = 281/83) who met DSM-IV for schizophrenia were compared dine (TMB) and stopped with phosphoric acid. Absorbencies were with 323 Chinese normal controls. All schizophrenic patients were measured by a microtiter plate reader (absorbency at 450 nm).
recruited from among the inpatients of Beijing Hui-Long-Guan Hospital, All samples were assayed by a technician blind to the clinical a Beijing City owned psychiatric hospital. Diagnoses were made for each situation. The identity of all subjects was indicated by a code number patient by two independent experienced psychiatrists. All schizophrenic maintained by the principal investigator until all biochemical analyses patients were of the chronic type, with duration of illness for at least were completed. Inter- and intra-assay variation coefficients were 7 5 years, age between 25 and 70 years (mean 51.3 ± 9.2 years). All patients had been receiving stable dose of oral neuroleptic medicationsfor at least 12 months prior to entry into the study. Antipsychotic treatment consisted mainly of monotherapy with clozapine (n = 157),risperidone (n = 89), and other typical antipsychotics (n = 118) Initial analysis included all subjects. BDNF data was analyzed with a including haloperidol (n = 31), chlorpromazine (n = 21), perphenazine 2 × 2 ANOVA representing the between-subject group factors (patients (n = 26), sulpiride (n = 27) or others (n = 13). The mean dose of each vs. healthy controls) and sex (male vs. female). Secondary analyses antipsychotic drug used in the study were 243 ± 119 mg/day for consisted of 4 × 3 analysis of covariance (ANCOVA) with the between- clozapine, 4.2 ± 3.4 mg/day for risperidone, 21± 16 mg/day for halo- factors of subtype (4 levels: paranoid, disorganized, undifferentiated, or peridol, 373 ± 167 mg/day for chlorpromazine, 26 ± 19 mg/day for residual) and antipsychotic drugs (3 levels: clozapine, risperidone or perphenazine, and 544 ± 287 mg/day for sulpiride. Mean antipsychotic typicals). For the main models, ANCOVAs were constructed with dose (as chlorpromazine equivalents) was 446 ± 341 mg/day. The mean subtype or antipsychotic drug as the independent variables, and BDNF duration of each antipsychotic drug was 5.9± 3.8 years for clozapine, as dependent variables, with sex, age, education, smoking, body mass 2.8 ± 2.0 for risperidone, 5.3 ± 5.1 for haloperidol, 6.1 ± 6.3 for index (BMI), illness course, age of onset, dose of drug (equivalent to chlorpromazine, 4.6 ± 3.3 for perphenazine and 4.8 ± 3.8 years for chlorpromazine) and duration of antipsychotic treatment as the sulpiride. The average duration of the current antipsychotic treatment covariates. Post hoc comparisons between subtypes or antipsychotic was 5.5 ± 4.9 years at the time of the investigation.
drugs were made using the Fisher's least significant difference (LSD) Normal controls (male/female = 228/95) were recruited from the procedure. In addition, t-tests were used to compare the differences local community, and matched for age and gender. Current mental status between male and female groups. Finally, correlation between variables and personal or family history of any mental disorder was assessed by a was studied using Pearson product moment correlations. Bonferroni clinical psychiatrist. None of the healthy control subjects presented a corrections were applied to each test to adjust for multiple testing.
personal or family history of psychiatric disorder. All subjects were Han Stepwise multiple regression analysis was performed to investigate the Chinese being recruited at the same period from Beijing area.
relationships between psychotic symptoms and clinical variables and A complete medical history and physical examination were obtained BDNF levels. Two-tailed significance values were used and significance from all subjects. Any subjects with physical abnormalities were excluded.
Please cite this article as: Xiu MH, et al, Decreased serum BDNF levels in chronic institutionalized schizophrenia on long-term treatment withtypical and atypical antipsychotics, Prog Neuro-Psychopharmacol Biol Psychiatry (2009), doi: M.H. Xiu et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry xxx (2009) xxx–xxx Table 2The effects of gender on BDNF levels in schizophrenia and normal controls.
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 ob- Note: The data presented here are mean ± SD.
served between BDNF levels and gender, age, education, smoking and a Indicates the comparison between male patients and male controls: p <0.001.
b BMI. Within the patient group, there was a significant inverse Indicates the comparison between female patients and female controls: p < 0.001.
relationship between age and BDNF levels (R = −0.19, df = 362,p = 0.003). No other parameters, including age of onset of psychosis,duration of illness, hospitalizations, dose of antipsychotics (equivalent effect of schizophrenia subtype (F=0.69, df =3, 361, p>0.05) and the to chlorpromazine), duration of antipsychotic treatment and BMI non-significant effect of drug×subtype (F=0.51, df =6, 361, p>0.05).
were found to be associated with BDNF levels (all p > 0.05). Fur- Post hoc comparisons indicate significantly decreased BDNF thermore, analysis of individual antipsychotic drug dose in patients levels in the risperidone subgroup compared to the clozapine sub- did not show any association with BDNF levels (all p > 0.05). Hence, group(9.3 ± 2.3 ng/ml vs. 10.2 ± 2.0 ng/ml, p < 0.01), and compared age was adjusted as potentially confounding covariate in the to the typical antipsychotic subgroup (10.0 ± 2.1 ng/ml, p < 0.01).
However, no significant difference was found between the clozapinegroup and the typical antipsychotic group (p = 0.59). Furthermore,we did not find any differences in serum BDNF between different 3.2. BDNF levels in schizophrenia and normal controls agents of typical antipsychotics (all p > 0.05).
Two-way ANOVA showed that there was a significant differ- 3.4. Relationship between BDNF levels and psychopathology ence between schizophrenia and control groups in BDNF serum levels (9.9 ± 2.0 ng/ml vs.11.9 ± 2.3 ng/ml; F = 80.0, p < 0.0001), a trendtoward significant sex effect (F = 3.53, p = 0.07), but there was no Correlation analysis revealed a significantly negative association significant group × sex (F = 1.5, p = 0.22).
between BDNF levels and the PANSS negative subscore (R = −0.15, Now that there was a trend toward significant sex effect, we fur- df = 1, 358, p < 0.05). However, this result did not pass Bonferroni ther analyze the sex difference in BDNF levels in patients and controls separately. There was no significant difference in BDNF serum levels A simultaneous entry regression analysis was conducted first to between male and female subjects in control group (11.9 ± 2.4 ng/ml vs.
identify the possible contribution of the BDNF, with all these param- 12.0 ± 2.3 ng/ml, p > 0.05). However, a significantly lower BDNF levels eters as independents. The overall analysis was statistically significant were noted in male than female patients (9.7 ± 1.9 ng/ml vs. 10.4 ± for the PANSS total score (R2 = 0.11, adjusted R2 = 0.07, F = 2.42, p = 0.004), or for the PANSS positive subscore (R2 = 0.09, adjustedR2 = 0.04, F = 1.97, p = 0.02).
Next, a stepwise multiple regression analysis identified BDNF levels 3.3. BDNF levels in different forms of schizophrenia treated with typical (beta = −0.29, t=−2.71, p=0.008) and types of antipsychotic drugs (beta= −0.25, t=−2.35, p=0.021) as the influencing factor for thePANSS total score. Similarly, a stepwise multiple regression analysis Clinical subtypes of schizophrenia were as follows: paranoid, 139 (38%); disorganized 25 (7%); undifferentiated, 26 (7%); and residualschizophrenia, 174 (48%). There was a significant difference in BDNF levelsbetween antipsychotic types, as supported by the significant effect ofantipsychotic types (F=5.72, df =2, 361, p=0.004), the non-significant Table 1Demographics of patients and normal control subjects.
Fig. 1. Serum BDNF levels were significantly lower in schizophrenia patients (Sch, n=364) than normal controls (NC, n=323) (p<0.0001). Further, there was a significantly lower BDNF levels in male (MS, n=281) than female (FS, n=83) patients (p<0.005), but no Patient group did not differ from control group on any characteristic by χ2 test and significant difference between male (MN, n=228) and female normal (FN, n=95) controls (p>0.05). ***p<0.0001, **p<0.005.
Please cite this article as: Xiu MH, et al, Decreased serum BDNF levels in chronic institutionalized schizophrenia on long-term treatment withtypical and atypical antipsychotics, Prog Neuro-Psychopharmacol Biol Psychiatry (2009), doi: M.H. Xiu et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry xxx (2009) xxx–xxx identified types of antipsychotic drugs (beta = −0.37, t =−3.15, ween age and BDNF levels in patient group (p = 0.003). Some studies p = 0.001) and BDNF levels (beta = −0.26, t=−2.51, p=0.014) as have showed that peripheral BDNF levels decreased significantly with the influencing factor for the positive subscore of the PANSS. No variables were shown to influence negative subscore of the PANSS comparatively older age of patients (mean 51.3 years) in our current study might be related to reduced BDNF levels. However, we did notfind the association between age and BDNF levels in normal controls.
The reasons for this differential effect of aging on the serum BDNFlevels between patients and normal controls deserve further In the present study, the result of decreased BDNF levels in medicated patients with chronic schizophrenia is in accordance with Our present study showed a significant difference in BDNF levels between antipsychotic types. Interestingly, risperidone was found to produce a more robust effect on BDNF compared to clozapine and In contrast, some other studies failed to typical antipsychotics. and our previous study find any difference in serum BDNF levels between schizophrenia and ) also found that clozapine may be associated with somewhat higher BDNF levels as compared to typical antipsychotics or risperidone. Furthermore, serum BDNF levels were positively Several factors, such as differences in techniques of measuring correlated with clozapine dose Some recent neurotrophin levels, differences in tested material (serum vs. plasma), animal studies found that haloperidol down-regulated BDNF mRNA sampling of patients in different stages of disease progression (acute expression in the rat hippocampus compared with controls, while vs. chronic or active phase vs. remission), different illness courses, clozapine and olanzapine up-regulated it ( exposure for different type, dosage and length of antipsychotics, the subtypes of schizophrenic patients recruited, or the biological het- quetiapine prevented stress-induced decrease in levels of BDNF erogeneity may be responsible for the discrepancy. Our recent studies protein. A more recent study in rats have shown that BDNF levels presented other confusing effects such as the body mass index (BMI), remained unchanged in hippocampus with olanzapine both after 90 smoking status or tardive dyskinesia on BDNF levels and 180 days of treatment. Whereas, larger decreases in BDNF levels were observed with haloperidol or chlorpromazine and intermediate The decreased BDNF serum levels in the present study are decreases were observed with risperidone after 90 days of treatment concordant with that observed in the brain of schizophrenic patients that continued to decline up to 180 days ). These or animal model of schizophrenia. For example, a significant reduction studies suggest that the differential (acute vs. long-term) effects of in BDNF mRNA and protein was found in the hippocampus or typical and atypical antipsychotic drugs on BDNF levels in the brain, prefrontal cortex of patients with schizophrenia in postmortem and atypical antipsychotics may favorably modulate BDNF expression.
However, it is worthy of mentioning that risperidone reduced more Thus, lower serum levels of BDNF are consistent with the serum BDNF than typical antipsychotics did in the present study. The hypothesis that a deficit in this neurotrophic factor may contribute to underlying mechanisms for this finding are still unknown. Although the structural and functional alterations of brain underlying in the this result might be related to their differential pharmacological mechanisms, we currently could not offer a reasonable explanation.
), supporting the hypothesis of neurodegenera- Furthermore, although clozapine and risperidone have the similar pharmacological mechanisms, with a potent blockade of both DA D2 However, it is noteworthy that the origins of serum BDNF remain and 5-HT2A receptors, there was a substantially differential effect on not yet completely understood. Although BDNF is highly concentrated BDNF levels. Probably risperidone and clozapine may produce the in the nervous system, it is also produced in various peripheral tissues effect on BDNF through the other neurotransmitter systems other (). Recently, Karege et al. reported that brain and than DA or 5-HT, which deserves further investigation.
serum BDNF levels underwent similar changes during maturation and Also, we found that there was a significantly positive relationship aging process in rats. They also found a positive correlation between between BDNF levels and the PANSS total score, as well as the PANSS serum and cortical BDNF levels suggesting that positive subscore. These results show that the BDNF may play a role in blood BDNF levels may reflect BDNF in the brain. Furthermore, BDNF total schizophrenia psychopathology, suggesting that the decreased is transported across the blood-brain barrier (BBB) in a mice model BDNF levels in schizophrenia are not just an epiphenomenon but are (although whether such transport of BDNF may related to the pathomechanism of the disorder. Further, we found a occur in humans is still unknown. However, whether a decrease in positive correlation between BDNF and the positive symptoms. Some peripheral BDNF levels might possibly influence the cascade relevant recent reports examined the correlations between BDNF levels and in the pathophysiology of schizophrenia also in the central nervous characteristic psychopathology, with mixed results. For example, system remained to be elucidated in further investigation.
BDNF levels have been associated with positive symptoms ( One possibility to explain our results of reduced BDNF levels would be due to antipsychotic treatment. In our present study, the patients were all chronically ill and had been taking antipsychotic drugs for a others did not find any clinical parameters to be correlated with BDNF long-term period. Recently, some studies have reported that both levels (A previous study with first-episode and atypical and typical antipsychotic drugs (such as haloperidol, clozapine drug-naive patients with schizophrenia found significant negative and risperidone) decreased BDNF concentrations in frontal and occipital correlations between serum BDNF levels and PANSS positive ( cortex and hippocampus suggesting that the Our present finding of the positive correlation between effect of antipsychotic drugs on BDNF levels may be due to a direct action BDNF and positive symptoms is in conflict with this report. The of long-term antipsychotic treatment. However, we did not find a possible reasons for this difference may be related to clinical status of correlation between BDNF levels and antipsychotic dosages in the patients; for example, the subjects in Buckley's study were signifi- patient group, suggesting that antipsychotic treatment may influence cantly younger and first-episode, drug-naïve compared to those older BDNF levels, but not in a dose-dependent manner.
and chronic patients with long-term antipsychotic treatment in our In addition, the effects of age on reduced BDNF levels should be study. Moreover, the testing material was different in our study and considered, because we found a significant inverse relationship bet- Buckley's (serum vs. plasma). In addition, interethnic differences in Please cite this article as: Xiu MH, et al, Decreased serum BDNF levels in chronic institutionalized schizophrenia on long-term treatment withtypical and atypical antipsychotics, Prog Neuro-Psychopharmacol Biol Psychiatry (2009), doi: M.H. Xiu et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry xxx (2009) xxx–xxx the allelic frequencies of the BDNF gene polymorphisms may play an Grillo RW, Ottoni GL, Leke R, Souza DO, Portela LV, Lara DR. Reduced serum BDNF levels in schizophrenic patients on clozapine or typical antipsychotics. J Psychiatr Res important role; for example, genotype frequencies of BDNF Val66Met polymorphism were significantly different between Easter and Huang TL, Lee CT. Associations between serum brain-derived neurotrophic factor levels and clinical phenotypes in schizophrenia patients. J Psychiatr Res 2006;40(7):664–8.
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Please cite this article as: Xiu MH, et al, Decreased serum BDNF levels in chronic institutionalized schizophrenia on long-term treatment withtypical and atypical antipsychotics, Prog Neuro-Psychopharmacol Biol Psychiatry (2009), doi:


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