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Serum brain-derived neurotrophic factor levels and psychotic symptoms in heroin dependence
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ScienceDirect Comprehensive Psychiatry 62 (2015) 80 – 85 www.elsevier.com/locate/comppsych
Serum brain-derived neurotrophic factor levels and psychotic symptoms in heroin dependence B. Han a , X.Y. Zhang b, c , D.Y. Wang a, d , W.W. Ren a , Y.Y. Gu a , L. Zhu a , Y.L. Chang a , L.P. Wang a , C.W. Wu a , Q.Q. Jin a , C. Chen a , D.Z. Lyu a , J.Y. Zhao a , B. Shao a , J.C. He a,⁎ a
Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, China b Beijing HuiLongGuan Hospital, Peking University, Beijing, BJ 100096, PR China c Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX 77030, USA d Department of Psychiatry, People’s Hospital of Yueqing, Wenzhou, 325600, China
Abstract Objectives: Psychotic symptoms are commonly observed among heroin users. Low serum brain-derived neurotrophic factor (BDNF) levels have been reported in schizophrenia and psychosis; however, studies assessing the relationship between serum BDNF levels and psychotic symptoms in heroin dependence are lacking. Method: A total of 31 heroin-dependent patients who had never experienced psychotic symptoms during heroin consumption and 21 patients with a history of psychotic symptoms were consecutively recruited. We measured by enzyme-linked immunosorbent assay (ELISA) serum BDNF levels during early abstinence. A gender- and age-matched sample of healthy controls was also recruited and underwent measurement of BDNF. Results: BDNF levels were significantly lower in patients with psychotic symptoms than in those without psychotic symptoms (P b 0.001). BDNF levels were not found to be correlated with sex, age, age of onset, duration of heroin use, average daily dose of heroin use, frequency of heroin use, SDS scores, BAI scores and BDI scores in the psychotic subsamples (all P N 0.05). Conclusions: Our findings suggest that heroin-dependent patients with psychotic symptoms share some of the neurotrophic insult that characterizes schizophrenia and psychosis. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Coexisting psychotic symptoms in heroin users have been frequently mentioned in previous literatures [1–4]. The prevalence of psychotic symptoms associated with opiates consumption has been reported to range from 6.7% to 58.2% [4]. The presence of psychotic symptoms has been associated with increased severity of the substance use [4,5], greater psychosocial problems and lower quality of life. However, risk factors for the trait are unclear until now. Brain-derived neurotrophic factor (BDNF) is the most broadly distributed neurotrophin in the human brain and it Abbreviations: BDNF, brain-derived neurotrophic factor; SDS, Severity of Dependence Scale; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory. ⁎ Corresponding author. Tel./fax: +86 577 55579363. E-mail address: [email protected] (J.C. He). http://dx.doi.org/10.1016/j.comppsych.2015.06.008 0010-440X/© 2015 Elsevier Inc. All rights reserved.
regulates neuronal development, survival and function and neural plasticity [6–8]. BDNF has also been shown to be involved in synaptic neurotransmission, with special effect on dopamine, GABA and glutamate, three neurotransmitter systems that play a critical role in the pathophysiology and treatment of schizophrenia [9,10]. Low serum BDNF levels have been reported in medicated and non-medicated patients with schizophrenia [11–13] while further studies focus on the involvement of BDNF in the pathophysiology and treatment of schizophrenia [9,14]. Moreover, the Val66Met single nucleotide polymorphism (SNP) of the BDNF gene has been associated with cognitive impairment in chronic schizophrenic patients [15]. The polymorphism may also contribute to the development of schizophrenia, regarding the pathophysiology, symptoms and medication [16–18]. Recently, Corominas-Roso et al. [19] found that cocaine-dependent patients with a history of cocaine-induced psychosis exhibited a significant decrease in serum BDNF levels during early abstinence.
B. Han et al. / Comprehensive Psychiatry 62 (2015) 80–85
However, to our best knowledge, no study has examined this association between serum BDNF levels and psychotic symptoms in heroin dependence. The objective of our study is to examine the involvement of BDNF in heroin-dependent patients with psychotic symptoms. We evaluate whether serum BDNF levels during early abstinence may be capable of differentiating between patients with and without psychotic symptoms during heroin consumption.
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2. Method
were under the influence of heroin? Patients were considered as having psychotic symptoms if they were marked positively in any of the above questions. We interviewed heroin-dependent patients to gather variables related to heroin consumption, including age of onset, duration of heroin use, average daily dose of heroin use, and frequency of heroin use (b1 time per week; 2–5 times per week; 1–2 times per day; ≥3 times per day). The Severity of Dependence Scale (SDS) measured the degree of dependence. The Beck Depression Inventory (BDI-13) [20] and Beck Anxiety Inventory (BAI) [21] assessed depression and anxiety symptoms respectively.
2.1. Participants
2.3. Determination of BDNF concentrations in serum
Fifty-two heroin-dependent patients were consecutively recruited from Sanyang Detoxification Institute in Wenzhou city in the Zhejiang province. Recruited patients, with an average abstinent period of 4.62 ± 2.27 days, had no access to alcohol or drugs. The inclusion criteria were: (1) age 18 years or older; (2) fulfillment of the Diagnostics and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria for heroin dependence; (3) positive urine test for opiates on admission; (4) heroin abstinence within 7 days; (5) signed informed consent. The exclusion criteria included: (1) history of psychotic, mood, anxiety or substance abuse disorder except heroin or nicotine; (2) neurological illness; (3) history of cranial trauma; (4) being seropositive for HIV; (5) metabolic, cardiac or any medical illness that can interfere with the serum levels of BDNF. To manage withdrawal symptoms, heroin-dependent subjects received initial dosages of methadone in the range of 30– 40 mg/day and then slowly tapered by 5 mg/day. Methadone was administrated orally and once daily. All participants took no other medications during heroin abstinence. Clinical diagnosis was performed by a trained psychiatrist. A subgroup of 31 subjects reported never having experienced psychotic symptoms during their heroin consumption, whereas a subgroup of 21 subjects had experienced psychotic symptoms while using heroin. A gender-and age-matched sample of 57 normal controls met the aforementioned inclusion criteria. Our study was approved by the Human Research and Ethics Committee of Wenzhou Medical University. Written informed consent was obtained from all participants.
For serum sampling, 5 ml of blood was collected from the antecubital vein in anticoagulant-free tubes. All samples were collected between 8 and 10 AM to limit a possible rhythm variance bias. The samples were allowed to clot at room temperature for 4 h and then centrifuged at 3500 rpm for 10 min immediately. We collected serum and then stored it at −80 °C until conducting the BDNF assay. Serum levels of BDNF were measured using DuoSet ELISA Development System (Catalog number DY248, R&D Systems, USA). The measurements were performed by trained operators blind to our research design. All assays were performed in duplicate and expressed as pg/ml. The detection range of the assay was 20–4000 pg/ml. The intra-assay and inter-assay coefficients were b5% and b10% respectively.
2.2. Measures To evaluate the psychotic symptoms associated with heroin consumption, a structured interview was performed. The questions based in DSM IV-TR were as follows: (1) Have you ever heard something that wasn’t actually there? Did it happen while you were under the influence of heroin? (2) Have you ever seen something that wasn’t really there? Did it happen under the influence of heroin? (3) Have you ever felt anything abnormal on your body or on your skin? Did it happen while you were under the influence of heroin? (4) Have you thought that people were spying on you, or that someone was plotting against you, or trying to hurt you? Did it happen while you
2.4. Data analysis The categorical variables were compared with the Pearson χ 2 test. If any of the expected counts were b5, Fisher’s exact test was used instead. Kolmogorov–Smirnov test was used to analyze for normality, and then Levene test was used to verify homogeneity of group variances. Student t test and one-way analysis of variance (ANOVA) were employed for the normally distributed variables, while the Mann–Whitney U test was employed for variables that did not pass the test for normality. Post hoc tests were conducted to determine the difference between groups, followed by Fisher’s least significant difference (LSD) test. The effect of age and sex was tested by adding these variables to the analysis model as covariates. Correlations between serum BDNF and demographic and clinical parameters were examined by bivariate correlation (Pearson or Spearman rank correlation). Bonferroni corrections were applied to each test to adjust for multiple testing. All analyses were performed with SPSS software (version 17.0, SPSS Inc., Chicago, IL.). A two-tailed P value of less than 0.05 was considered to be statistically significant. 3. Results 3.1. Demographic and clinical features of heroin-dependent patients and controls The demographic features of the control, non-psychotic and psychotic subsamples are shown in Table 1. No gender
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B. Han et al. / Comprehensive Psychiatry 62 (2015) 80–85
Table 1 Demographic features of patients (with or without psychotic symptoms) and controls. No psychotic symptoms (n = 31) Age, mean ± SD Gender a (F), n a b
35.71 ± 7.90 2 (6.5%)
Psychotic symptoms (n = 21) 36.00 ± 7.95 1 (4.8%)
Controls (n = 57)
Statistic
P
35.91 ± 7.85 4 (7.0%)
χ = 0.109
0.947 b
2
No statistical test was performed due to the low number in the female subsample. Pearson χ 2 test.
or age differences were found among groups. Table 2 shows the clinical information of psychotic and non-psychotic patients. There was no significant difference in any of clinical variables (age of onset, duration of heroin use, average daily dose of heroin use, frequency of heroin use, SDS scores, BAI scores and BDI scores) between the non-psychotic and psychotic subsamples.
heroin use, frequency of heroin use, SDS scores, BAI scores and BDI scores (all P N 0.05). Similarly, these variables were not found to be correlated with serum BDNF levels in the psychotic subsamples (all P N 0.05).
3.2. Serum BDNF levels among normal controls and heroin-dependent with and without psychotic symptoms
In the present study, we found increased serum levels of BDNF during early abstinence in both patient groups, which replicate our previous study [22] and are consistent with others [23,24]. However, Angelucci et al. [25] reported decreased serum BDNF levels in heroin users. The relatively small sample size in Angelucci et al.’ study may have resulted in the contradictory results. Additionally, factors such as nicotine and alcohol use [26], depression [27] and stress [28], which have been associated with serum BDNF levels, may also have contributed to these differences. The neurobiological significance of the increase of serum BDNF levels in early abstinent heroin-dependent patients compared to normal controls was discussed in more detail in our previous study [22]. To the best of our knowledge, this is the first report investigating the serum BDNF levels in heroin-dependence patients with psychotic symptoms. We found that serum BDNF levels during early abstinence were significantly lower in patients with psychotic symptoms than in those without psychotic symptoms. In this context, decreased
There was a significant intergroup difference in serum BDNF levels (F = 46.418, df = 2, P b 0.001). When the effect of age and sex was examined by adding them to the ANOVA as covariates, a significant intergroup difference was still observed (F = 44.908, df = 4, P b 0.001). Post hoc comparisons indicate that mean serum BNDF levels were significantly lower in patients with psychotic symptoms than in those without psychotic symptoms (1549.95 ± 338.80 vs. 1920.27 ± 300.92 pg/ml, P b 0.001) and both patient groups were higher than the controls (1271.87 ± 288.92 pg/ml; both P b 0.001). 3.3. Correlation of serum BDNF levels with demographic and clinical features In the non-psychotic subsample, no significant correlations were found between serum BDNF levels and sex, age, age of onset, duration of heroin use, average daily dose of
4. Discussion
Table 2 Clinical information of heroin-dependent patients.
Age of onset, years Duration of heroin use, months Average daily dose of heroin use, g Frequency of heroin use b1 time per week 2–5 times per week 1–2 times per day ≥3 times per day SDS scores BAI scores BDI scores
No psychotic symptoms (n = 31)
Psychotic symptoms (n = 21)
Statistic
P
26.00 ± 7.55 102.66 ± 78.82 0.49 ± 0.20
25.84 ± 5.96 108.14 ± 84.42 0.37 ± 0.09
t = −0.088 z = −0.299 z = −0.970 χ 2 = 2.257
0.930 a 0.765 b 0.332 b 0.521 c
5 (16.1%) 4 (12.9%) 10 (32.3%) 12 (38.7%) 12.79 ± 3.43 32.72 ± 12.56 15.72 ± 8.44
3 (14.3%) 2 (9.5%) 11 (52.4%) 5 (23.8%) 14.52 ± 2.68 31.05 ± 9.22 18.48 ± 6.80
z = −1.916 z = −0.128 t = 1.232
0.055 b 0.898 b 0.224 a
Values are shown as number (percentage) except where noted. Abbreviations: SDS, Severity of Dependence Scale; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory. a Student t test. b Mann–Whitney U–test used. c Fisher’s Exact Test.
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serum BDNF levels have been shown in chronic antipsychotic-treated and first-episode and drug-naïve schizophrenic patients [11–13]. Low serum BDNF levels are involved in cognitive impairment, especially immediate memory, in patients with a chronic form of schizophrenia [15], and interestingly, serum BDNF levels increase in chronic schizophrenic patients after cognitive training [29]. Additionally, the Val66Met SNP of the BDNF gene has been reported to alter the intracellular tracking and packaging of pro-BDNF and, thus, to affect serum levels of BDNF [30,31] and hippocampal-dependent learning [32]. The polymorphism may also contribute to the pathogenesis of schizophrenia, its psychopathological symptoms and therapeutic response [16–18]. Recently, Corominas-Roso et al. [19] reported that cocaine-dependent subjects with a history of cocaine-induced psychosis showed a significant decrease in serum levels of BDNF during early abstinence, when compared to cocaine-dependent patients without a history of cocaine-induced psychosis, which suggests that BDNF may play an important role in the psychotic symptoms associated with cocaine consumption. Taken together, these data suggest that heroin-dependent patients with psychotic symptoms may share some of the BDNF insult that characterizes schizophrenia and psychosis. The origins of circulating BDNF are not fully clear. To date, platelet and brain neurons are considered to be putative sources. It was shown that BDNF crosses the blood–brain barrier in both directions [33], and that BDNF levels in the serum and brain have been reported to undergo similar alterations in both rodent and clinical studies [34–36]. These results demonstrate that serum BDNF levels might in part reflect the BDNF levels in the brain. BDNF has been shown to be involved in the regulation of long-term activity-dependent synaptic plasticity underlying learning and memory in the hippocampus [37,38]. Several preclinical studies have revealed impairments in long-term potentiation (LTP), a widely studied form of synaptic plasticity, in hippocampal slices extracted from BDNF knockout mice [39,40]. Recently, reduced BDNF levels have been reported to be implicated in the pathophysiology of schizophrenia through its regulation on synaptic plasticity [9]. BDNF is synthesized and released in response to afferent activity, and dopaminergic and glutamatergic activity significantly alteration in heroin users [41]. Therefore, we hypothesize that the psychotic symptoms associated with heroin dependence might be reflecting plasticity deficits to some extent. The possible effect of demographic and clinical variables on the response of BDNF during early abstinence was also analyzed. No significant differences were found between the psychotic and non-psychotic subsamples in consumption variables, SDS scores, BAI scores and BDI scores. Moreover, no significant correlations were found between demographic and clinical variables and serum BDNF levels in the psychotic and non-psychotic subsamples. Therefore, these data demonstrate that demographic and clinical variables do not explain the differences in
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serum levels of BDNF between the psychotic and nonpsychotic subsamples. There are several limitations in the present study. First, we did not measure platelet BDNF level in the present study, which is one of the main limitations of our study. The main source of serum BDNF is from platelet that appears to bind, store and release serum BDNF via the clotting process or upon activation [42]. Therefore, the limitation should be remedied in a further study. Second, all heroin-dependent patients received methadone administration during early abstinence, which may affect the withdrawal process [43]. Moreover, methadone, which is similar to heroin, may also have a significant effect on serum levels of BDNF. Third, the limited number of heroin-dependent patients included in the protocol reduced the statistical power of the study. In this regard, it is necessary to mention the difficulty in recruiting subjects for various reasons. In summary, our study indicated that serum BDNF levels during early abstinence were significantly lower in patients with psychotic symptoms than in those without psychotic symptoms, suggesting that patients with psychotic symptoms share some of the neurotrophic insult that characterizes schizophrenia and psychosis. Further studies are necessary to confirm the finding, which may be used as a novel therapeutic target in heroin-dependent patients with psychotic symptoms.
Contributors Han B and He JC conceived of the study, supervised the statistical analyses, and prepared manuscript, and wrote the protocol and the paper. Zhang XY, Wang DY, Ren WW, Gu YY, Zhu L, Chang YL, Wang LP, Wu CW, Jin QQ, Chen C, Lyu DZ, Zhao JY and Shao B were responsible for clinical data collection and the statistical analyses. All authors gave final approval for submission of the manuscript. Dr. He JC (the lead author) had full access to all of the data in the study and takes responsibility for the integrity of the data and accuracy of the data analyses.
Conflicts of interest None.
Acknowledgment This work was funded by the grant from National Key Technology R&D Program in the 11th Five year Plan of China (2009BAI77B06) and Wenzhou Municipal Sci-Tech Bureau Program (H20100021). These sources had no further role in study design, data collection and analysis, preparation of the article, or decision to publish.
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ScienceDirect Comprehensive Psychiatry 62 (2015) 80 – 85 www.elsevier.com/locate/comppsych
Serum brain-derived neurotrophic factor levels and psychotic symptoms in heroin dependence B. Han a , X.Y. Zhang b, c , D.Y. Wang a, d , W.W. Ren a , Y.Y. Gu a , L. Zhu a , Y.L. Chang a , L.P. Wang a , C.W. Wu a , Q.Q. Jin a , C. Chen a , D.Z. Lyu a , J.Y. Zhao a , B. Shao a , J.C. He a,⁎ a
Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, China b Beijing HuiLongGuan Hospital, Peking University, Beijing, BJ 100096, PR China c Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX 77030, USA d Department of Psychiatry, People’s Hospital of Yueqing, Wenzhou, 325600, China
Abstract Objectives: Psychotic symptoms are commonly observed among heroin users. Low serum brain-derived neurotrophic factor (BDNF) levels have been reported in schizophrenia and psychosis; however, studies assessing the relationship between serum BDNF levels and psychotic symptoms in heroin dependence are lacking. Method: A total of 31 heroin-dependent patients who had never experienced psychotic symptoms during heroin consumption and 21 patients with a history of psychotic symptoms were consecutively recruited. We measured by enzyme-linked immunosorbent assay (ELISA) serum BDNF levels during early abstinence. A gender- and age-matched sample of healthy controls was also recruited and underwent measurement of BDNF. Results: BDNF levels were significantly lower in patients with psychotic symptoms than in those without psychotic symptoms (P b 0.001). BDNF levels were not found to be correlated with sex, age, age of onset, duration of heroin use, average daily dose of heroin use, frequency of heroin use, SDS scores, BAI scores and BDI scores in the psychotic subsamples (all P N 0.05). Conclusions: Our findings suggest that heroin-dependent patients with psychotic symptoms share some of the neurotrophic insult that characterizes schizophrenia and psychosis. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Coexisting psychotic symptoms in heroin users have been frequently mentioned in previous literatures [1–4]. The prevalence of psychotic symptoms associated with opiates consumption has been reported to range from 6.7% to 58.2% [4]. The presence of psychotic symptoms has been associated with increased severity of the substance use [4,5], greater psychosocial problems and lower quality of life. However, risk factors for the trait are unclear until now. Brain-derived neurotrophic factor (BDNF) is the most broadly distributed neurotrophin in the human brain and it Abbreviations: BDNF, brain-derived neurotrophic factor; SDS, Severity of Dependence Scale; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory. ⁎ Corresponding author. Tel./fax: +86 577 55579363. E-mail address: [email protected] (J.C. He). http://dx.doi.org/10.1016/j.comppsych.2015.06.008 0010-440X/© 2015 Elsevier Inc. All rights reserved.
regulates neuronal development, survival and function and neural plasticity [6–8]. BDNF has also been shown to be involved in synaptic neurotransmission, with special effect on dopamine, GABA and glutamate, three neurotransmitter systems that play a critical role in the pathophysiology and treatment of schizophrenia [9,10]. Low serum BDNF levels have been reported in medicated and non-medicated patients with schizophrenia [11–13] while further studies focus on the involvement of BDNF in the pathophysiology and treatment of schizophrenia [9,14]. Moreover, the Val66Met single nucleotide polymorphism (SNP) of the BDNF gene has been associated with cognitive impairment in chronic schizophrenic patients [15]. The polymorphism may also contribute to the development of schizophrenia, regarding the pathophysiology, symptoms and medication [16–18]. Recently, Corominas-Roso et al. [19] found that cocaine-dependent patients with a history of cocaine-induced psychosis exhibited a significant decrease in serum BDNF levels during early abstinence.
B. Han et al. / Comprehensive Psychiatry 62 (2015) 80–85
However, to our best knowledge, no study has examined this association between serum BDNF levels and psychotic symptoms in heroin dependence. The objective of our study is to examine the involvement of BDNF in heroin-dependent patients with psychotic symptoms. We evaluate whether serum BDNF levels during early abstinence may be capable of differentiating between patients with and without psychotic symptoms during heroin consumption.
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2. Method
were under the influence of heroin? Patients were considered as having psychotic symptoms if they were marked positively in any of the above questions. We interviewed heroin-dependent patients to gather variables related to heroin consumption, including age of onset, duration of heroin use, average daily dose of heroin use, and frequency of heroin use (b1 time per week; 2–5 times per week; 1–2 times per day; ≥3 times per day). The Severity of Dependence Scale (SDS) measured the degree of dependence. The Beck Depression Inventory (BDI-13) [20] and Beck Anxiety Inventory (BAI) [21] assessed depression and anxiety symptoms respectively.
2.1. Participants
2.3. Determination of BDNF concentrations in serum
Fifty-two heroin-dependent patients were consecutively recruited from Sanyang Detoxification Institute in Wenzhou city in the Zhejiang province. Recruited patients, with an average abstinent period of 4.62 ± 2.27 days, had no access to alcohol or drugs. The inclusion criteria were: (1) age 18 years or older; (2) fulfillment of the Diagnostics and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria for heroin dependence; (3) positive urine test for opiates on admission; (4) heroin abstinence within 7 days; (5) signed informed consent. The exclusion criteria included: (1) history of psychotic, mood, anxiety or substance abuse disorder except heroin or nicotine; (2) neurological illness; (3) history of cranial trauma; (4) being seropositive for HIV; (5) metabolic, cardiac or any medical illness that can interfere with the serum levels of BDNF. To manage withdrawal symptoms, heroin-dependent subjects received initial dosages of methadone in the range of 30– 40 mg/day and then slowly tapered by 5 mg/day. Methadone was administrated orally and once daily. All participants took no other medications during heroin abstinence. Clinical diagnosis was performed by a trained psychiatrist. A subgroup of 31 subjects reported never having experienced psychotic symptoms during their heroin consumption, whereas a subgroup of 21 subjects had experienced psychotic symptoms while using heroin. A gender-and age-matched sample of 57 normal controls met the aforementioned inclusion criteria. Our study was approved by the Human Research and Ethics Committee of Wenzhou Medical University. Written informed consent was obtained from all participants.
For serum sampling, 5 ml of blood was collected from the antecubital vein in anticoagulant-free tubes. All samples were collected between 8 and 10 AM to limit a possible rhythm variance bias. The samples were allowed to clot at room temperature for 4 h and then centrifuged at 3500 rpm for 10 min immediately. We collected serum and then stored it at −80 °C until conducting the BDNF assay. Serum levels of BDNF were measured using DuoSet ELISA Development System (Catalog number DY248, R&D Systems, USA). The measurements were performed by trained operators blind to our research design. All assays were performed in duplicate and expressed as pg/ml. The detection range of the assay was 20–4000 pg/ml. The intra-assay and inter-assay coefficients were b5% and b10% respectively.
2.2. Measures To evaluate the psychotic symptoms associated with heroin consumption, a structured interview was performed. The questions based in DSM IV-TR were as follows: (1) Have you ever heard something that wasn’t actually there? Did it happen while you were under the influence of heroin? (2) Have you ever seen something that wasn’t really there? Did it happen under the influence of heroin? (3) Have you ever felt anything abnormal on your body or on your skin? Did it happen while you were under the influence of heroin? (4) Have you thought that people were spying on you, or that someone was plotting against you, or trying to hurt you? Did it happen while you
2.4. Data analysis The categorical variables were compared with the Pearson χ 2 test. If any of the expected counts were b5, Fisher’s exact test was used instead. Kolmogorov–Smirnov test was used to analyze for normality, and then Levene test was used to verify homogeneity of group variances. Student t test and one-way analysis of variance (ANOVA) were employed for the normally distributed variables, while the Mann–Whitney U test was employed for variables that did not pass the test for normality. Post hoc tests were conducted to determine the difference between groups, followed by Fisher’s least significant difference (LSD) test. The effect of age and sex was tested by adding these variables to the analysis model as covariates. Correlations between serum BDNF and demographic and clinical parameters were examined by bivariate correlation (Pearson or Spearman rank correlation). Bonferroni corrections were applied to each test to adjust for multiple testing. All analyses were performed with SPSS software (version 17.0, SPSS Inc., Chicago, IL.). A two-tailed P value of less than 0.05 was considered to be statistically significant. 3. Results 3.1. Demographic and clinical features of heroin-dependent patients and controls The demographic features of the control, non-psychotic and psychotic subsamples are shown in Table 1. No gender
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Table 1 Demographic features of patients (with or without psychotic symptoms) and controls. No psychotic symptoms (n = 31) Age, mean ± SD Gender a (F), n a b
35.71 ± 7.90 2 (6.5%)
Psychotic symptoms (n = 21) 36.00 ± 7.95 1 (4.8%)
Controls (n = 57)
Statistic
P
35.91 ± 7.85 4 (7.0%)
χ = 0.109
0.947 b
2
No statistical test was performed due to the low number in the female subsample. Pearson χ 2 test.
or age differences were found among groups. Table 2 shows the clinical information of psychotic and non-psychotic patients. There was no significant difference in any of clinical variables (age of onset, duration of heroin use, average daily dose of heroin use, frequency of heroin use, SDS scores, BAI scores and BDI scores) between the non-psychotic and psychotic subsamples.
heroin use, frequency of heroin use, SDS scores, BAI scores and BDI scores (all P N 0.05). Similarly, these variables were not found to be correlated with serum BDNF levels in the psychotic subsamples (all P N 0.05).
3.2. Serum BDNF levels among normal controls and heroin-dependent with and without psychotic symptoms
In the present study, we found increased serum levels of BDNF during early abstinence in both patient groups, which replicate our previous study [22] and are consistent with others [23,24]. However, Angelucci et al. [25] reported decreased serum BDNF levels in heroin users. The relatively small sample size in Angelucci et al.’ study may have resulted in the contradictory results. Additionally, factors such as nicotine and alcohol use [26], depression [27] and stress [28], which have been associated with serum BDNF levels, may also have contributed to these differences. The neurobiological significance of the increase of serum BDNF levels in early abstinent heroin-dependent patients compared to normal controls was discussed in more detail in our previous study [22]. To the best of our knowledge, this is the first report investigating the serum BDNF levels in heroin-dependence patients with psychotic symptoms. We found that serum BDNF levels during early abstinence were significantly lower in patients with psychotic symptoms than in those without psychotic symptoms. In this context, decreased
There was a significant intergroup difference in serum BDNF levels (F = 46.418, df = 2, P b 0.001). When the effect of age and sex was examined by adding them to the ANOVA as covariates, a significant intergroup difference was still observed (F = 44.908, df = 4, P b 0.001). Post hoc comparisons indicate that mean serum BNDF levels were significantly lower in patients with psychotic symptoms than in those without psychotic symptoms (1549.95 ± 338.80 vs. 1920.27 ± 300.92 pg/ml, P b 0.001) and both patient groups were higher than the controls (1271.87 ± 288.92 pg/ml; both P b 0.001). 3.3. Correlation of serum BDNF levels with demographic and clinical features In the non-psychotic subsample, no significant correlations were found between serum BDNF levels and sex, age, age of onset, duration of heroin use, average daily dose of
4. Discussion
Table 2 Clinical information of heroin-dependent patients.
Age of onset, years Duration of heroin use, months Average daily dose of heroin use, g Frequency of heroin use b1 time per week 2–5 times per week 1–2 times per day ≥3 times per day SDS scores BAI scores BDI scores
No psychotic symptoms (n = 31)
Psychotic symptoms (n = 21)
Statistic
P
26.00 ± 7.55 102.66 ± 78.82 0.49 ± 0.20
25.84 ± 5.96 108.14 ± 84.42 0.37 ± 0.09
t = −0.088 z = −0.299 z = −0.970 χ 2 = 2.257
0.930 a 0.765 b 0.332 b 0.521 c
5 (16.1%) 4 (12.9%) 10 (32.3%) 12 (38.7%) 12.79 ± 3.43 32.72 ± 12.56 15.72 ± 8.44
3 (14.3%) 2 (9.5%) 11 (52.4%) 5 (23.8%) 14.52 ± 2.68 31.05 ± 9.22 18.48 ± 6.80
z = −1.916 z = −0.128 t = 1.232
0.055 b 0.898 b 0.224 a
Values are shown as number (percentage) except where noted. Abbreviations: SDS, Severity of Dependence Scale; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory. a Student t test. b Mann–Whitney U–test used. c Fisher’s Exact Test.
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serum BDNF levels have been shown in chronic antipsychotic-treated and first-episode and drug-naïve schizophrenic patients [11–13]. Low serum BDNF levels are involved in cognitive impairment, especially immediate memory, in patients with a chronic form of schizophrenia [15], and interestingly, serum BDNF levels increase in chronic schizophrenic patients after cognitive training [29]. Additionally, the Val66Met SNP of the BDNF gene has been reported to alter the intracellular tracking and packaging of pro-BDNF and, thus, to affect serum levels of BDNF [30,31] and hippocampal-dependent learning [32]. The polymorphism may also contribute to the pathogenesis of schizophrenia, its psychopathological symptoms and therapeutic response [16–18]. Recently, Corominas-Roso et al. [19] reported that cocaine-dependent subjects with a history of cocaine-induced psychosis showed a significant decrease in serum levels of BDNF during early abstinence, when compared to cocaine-dependent patients without a history of cocaine-induced psychosis, which suggests that BDNF may play an important role in the psychotic symptoms associated with cocaine consumption. Taken together, these data suggest that heroin-dependent patients with psychotic symptoms may share some of the BDNF insult that characterizes schizophrenia and psychosis. The origins of circulating BDNF are not fully clear. To date, platelet and brain neurons are considered to be putative sources. It was shown that BDNF crosses the blood–brain barrier in both directions [33], and that BDNF levels in the serum and brain have been reported to undergo similar alterations in both rodent and clinical studies [34–36]. These results demonstrate that serum BDNF levels might in part reflect the BDNF levels in the brain. BDNF has been shown to be involved in the regulation of long-term activity-dependent synaptic plasticity underlying learning and memory in the hippocampus [37,38]. Several preclinical studies have revealed impairments in long-term potentiation (LTP), a widely studied form of synaptic plasticity, in hippocampal slices extracted from BDNF knockout mice [39,40]. Recently, reduced BDNF levels have been reported to be implicated in the pathophysiology of schizophrenia through its regulation on synaptic plasticity [9]. BDNF is synthesized and released in response to afferent activity, and dopaminergic and glutamatergic activity significantly alteration in heroin users [41]. Therefore, we hypothesize that the psychotic symptoms associated with heroin dependence might be reflecting plasticity deficits to some extent. The possible effect of demographic and clinical variables on the response of BDNF during early abstinence was also analyzed. No significant differences were found between the psychotic and non-psychotic subsamples in consumption variables, SDS scores, BAI scores and BDI scores. Moreover, no significant correlations were found between demographic and clinical variables and serum BDNF levels in the psychotic and non-psychotic subsamples. Therefore, these data demonstrate that demographic and clinical variables do not explain the differences in
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serum levels of BDNF between the psychotic and nonpsychotic subsamples. There are several limitations in the present study. First, we did not measure platelet BDNF level in the present study, which is one of the main limitations of our study. The main source of serum BDNF is from platelet that appears to bind, store and release serum BDNF via the clotting process or upon activation [42]. Therefore, the limitation should be remedied in a further study. Second, all heroin-dependent patients received methadone administration during early abstinence, which may affect the withdrawal process [43]. Moreover, methadone, which is similar to heroin, may also have a significant effect on serum levels of BDNF. Third, the limited number of heroin-dependent patients included in the protocol reduced the statistical power of the study. In this regard, it is necessary to mention the difficulty in recruiting subjects for various reasons. In summary, our study indicated that serum BDNF levels during early abstinence were significantly lower in patients with psychotic symptoms than in those without psychotic symptoms, suggesting that patients with psychotic symptoms share some of the neurotrophic insult that characterizes schizophrenia and psychosis. Further studies are necessary to confirm the finding, which may be used as a novel therapeutic target in heroin-dependent patients with psychotic symptoms.
Contributors Han B and He JC conceived of the study, supervised the statistical analyses, and prepared manuscript, and wrote the protocol and the paper. Zhang XY, Wang DY, Ren WW, Gu YY, Zhu L, Chang YL, Wang LP, Wu CW, Jin QQ, Chen C, Lyu DZ, Zhao JY and Shao B were responsible for clinical data collection and the statistical analyses. All authors gave final approval for submission of the manuscript. Dr. He JC (the lead author) had full access to all of the data in the study and takes responsibility for the integrity of the data and accuracy of the data analyses.
Conflicts of interest None.
Acknowledgment This work was funded by the grant from National Key Technology R&D Program in the 11th Five year Plan of China (2009BAI77B06) and Wenzhou Municipal Sci-Tech Bureau Program (H20100021). These sources had no further role in study design, data collection and analysis, preparation of the article, or decision to publish.
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