| Abstract|| |
Brain-derived neurotrophic factor (BDNF) plays a crucial role in neuroplasticity of the brain, and its role in alcohol dependence has been explored in the recent past. Animal studies suggest that BDNF may function as a protective factor in transition from social drinking to an alcohol use disorder. However, clinical studies have not been able to establish similar findings and have shown mixed results. In order to obtain a comprehensive understanding, the current review aims to evaluate the existing literature on the role of BDNF in alcohol dependence. Articles were retrieved using search engines PubMed and Google Scholar. Original research studies focusing on human participants, published in English till October 2018 were reviewed. Studies which measured BDNF levels in serum or plasma or both were included in this study. A total of 13 studies were found which compared BDNF levels in alcohol-dependent patients with control population. The studies have mixed findings. Seven studies measured BDNF levels across the abstinence period, and most of the studies show improving BDNF levels across the abstinence. The current review supports the notion that BDNF plays an important role in the neuroplasticity of alcohol dependence. However, it is premature at this stage to draw conclusions that BDNF may be used as a biomarker, as there have been inconclusive findings when compared with control population. Future studies with longer follow-ups, larger sample size, comparing early and late periods of alcohol abstinence are required for better understanding of the role BDNF in alcohol dependence.
Keywords: Alcohol dependence, brain-derived neurotrophic factor, plasma, review, serum
|How to cite this article:|
Kethawath SM, Jain R, Dhawan A, Sarkar S. A review of peripheral brain-derived neurotrophic factor levels in alcohol-dependent patients: Current understanding. Indian J Psychiatry 2020;62:15-20
|How to cite this URL:|
Kethawath SM, Jain R, Dhawan A, Sarkar S. A review of peripheral brain-derived neurotrophic factor levels in alcohol-dependent patients: Current understanding. Indian J Psychiatry [serial online] 2020 [cited 2021 Apr 21];62:15-20. Available from: https://www.indianjpsychiatry.org/text.asp?2020/62/1/15/274814
| Introduction|| |
Alcohol is a psychoactive substance with dependence-producing properties. Alcohol exposure and related withdrawal symptoms can result in structural and functional modifications at the synapse. Further, alcohol use disorder has been described as a disease of maladaptive plasticity. However, it is unclear whether structural plasticity and synaptic changes drive addictive behaviors, or they reflect homeostatic compensations to drug use. Attempts have been made to understand the neurobiological basis of alcohol dependence from various fronts, including the evaluation of the structural changes, alterations in the size, functioning of the cell groups, and changes in brain neurochemicals. In this pursuit of understanding the neurobiological genesis of alcohol dependence, growth factors and neurotrophic factors have received attention in the recent past, and their role in patients with alcohol dependence is being explored.
Brain-derived neurotrophic factor (BDNF), being the most prevalent growth factor in the central nervous system, plays a crucial role in the development and plasticity of the brain. Recently, researchers have begun to appreciate the potential role of BDNF as a protective gatekeeper in the transition from casual drinking to compulsive alcohol consumption. Animal models suggest that BDNF signaling in corticostriatal pathways may act to keep alcohol consumption in moderation through mechanisms related to habit learning and compulsive behaviors, while the risk for transition to uncontrolled drinking may occur when BDNF levels in the medial prefrontal cortex are reduced. Thus, there exists a relatively vast amount of literature from animal studies whereas those from the clinical studies are smaller in number, although with an increasing trend. From animal studies, it can be seen that BDNF has a pivotal role in alcohol dependence and studies are being done to replicate the findings in human population. Meta-analyses of genetic association studies in human population suggest that the BDNF Val66Met polymorphism may not be linked to the development of alcohol use disorders. A vast amount of literature is available regarding the role of BDNF at the genetic level. However, there is limited literature on the peripheral BDNF levels in alcohol-dependent patients. The alteration of peripheral BDNF levels not only helps in understanding the neurobiology of alcohol dependence but could also provide new directions for evaluating it as a therapeutic measure. Thus, in view of its potential role demonstrated in animal studies, a review of peripheral BDNF levels in alcohol-dependent patients is necessary to have a better understanding of the neurobiology of alcohol dependence. Such a synthesis would be helpful in determining the future directions of research. Hence, we present here a review of the studies assessing BDNF levels among humans with alcohol dependence to obtain a comprehensive understanding the role of BDNF in alcohol dependence.
| Materials and Methods|| |
The current literature review focused on recent studies relevant to BDNF in alcohol-dependent subjects. Articles were retrieved using search engines such as PubMed and Google Scholar and search terms included individually as well as combinations of “BDNF,” “alcohol,” and “serum” or “plasma.” Original research studies focusing on human participants and published in English from 2007 to October 2018 were reviewed. We have included only clinical studies with various methodologies for the estimation of BDNF levels. However, we restricted our literature to studies which measured peripheral BDNF values, i.e., serum or plasma or either. We did not include studies on central BDNF levels, because from the literature it is apparent that BDNF protein can cross the blood–brain barrier in both directions,, and studies in rodent models have reported significant positive correlations between levels of BDNF found in serum or whole blood with levels of BDNF in brain tissue. We included studies exclusively done on alcohol-dependent patients with or without nicotine dependence. Studies published in language other than English or did not present the quantitative data on BDNF levels were excluded. Human studies assessing BDNF levels in patients with alcohol dependence have compared the BDNF levels with controls and have assessed changes over time. We included case–control studies for better comparison with respect to healthy individuals. All studies which measured BDNF levels either in serum or plasma or both were included.
| Results|| |
A total of 13 studies were found which compared BDNF levels in alcohol-dependent patients with control population and are summarized in [Table 1]. Seven studies were found which looked into a change in BDNF levels over the course of the abstinence period. The details are summarized in [Table 2]. Totally 9 studies measured BDNF levels in serum sample whereas, three studies measured in plasma. However, two studies were found which measured BDNF levels in both serum and plasma. Most of the studies were case–control studies, which were done by comparing cases with a healthy control population or by comparing the BDNF levels over the detoxification process within the alcohol-dependent patients. Similarly, the findings of currently available literature are discussed as follows:
|Table 1: Summary of studies comparing brain-derived neurotrophic factor levels among patients with alcohol dependence and controls|
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|Table 2: Summary of studies comparing changes in brain-derived neurotropic factor levels over the course of abstinence|
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Studies comparing brain-derived neurotrophic factor levels between cases and controls
Of 13 studies, five studies found significantly lower BDNF values compared to control population. Initial study by Joe et al. found that plasma BDNF levels among alcohol-dependent patients were significantly lower when compared to that of healthy controls. They compared it in plasma levels which might not give an accurate estimation of BDNF levels in the body since the plasma levels would be about 100 folds lesser when compared to serum levels. However, they assessed BDNF values after 1 month of abstinence from alcohol and not while the patient was actively consuming the alcohol. Further, they found that BDNF levels were consistently lower in patients with a positive family history of alcohol dependence than in those with a negative family history of alcohol dependence, suggesting that BDNF expression might be decreased by chronic alcohol intake, especially in patients having genetic predispositions to alcohol dependence. Subsequently, Huang et al. found significantly lower BDNF levels in alcohol-dependent patients when compared to controls. In this study, they noted that BDNF levels were further decreased in alcohol-dependent patients with delirium tremens as presentation compared to other alcohol-dependent patients without delirium as presentation. Another study by Zanardini et al. also found similar significant findings in the serum samples. In this study, authors compared BDNF values in serum as well as plasma; however, they found a significant decrease in serum samples only. They claimed that serum levels might better reflect the whole blood content since the BDNF is also released into the circulation from the platelets during clotting. However, in this study, six out of 30 alcohol-dependent patients had comorbid major depression and 13 patients were receiving serotonin selective reuptake inhibitor (SSRI) antidepressant drugs. Serum BDNF levels were known to be decreased in depressive patients and some SSRIs were found to increase the peripheral BDNF levels during acute management of depression. Cavus et al. minimized the above limitations and yet found similar results. However, in their study, patients were consuming 164.2 ± 46.2 g of pure ethanol, i.e., severe dependence in a day in their past 1 month. Since their study could not include patients with mild/moderate alcohol dependence, it might be difficult to generalize their findings. Moreover, the study was done exclusively on male alcohol-dependent patients, so one should interpret the findings cautiously. In another study by Köhler et al., similar results were found. They measured BDNF in serum and included both male and female alcohol-dependent patients. However, comorbid psychiatric conditions were not assessed, which is a major limitation as BDNF levels alter with psychiatric conditions.
Two out of 13 studies found contrary findings. An earlier study found that BDNF levels in alcohol-dependent patients were significantly increased in contrast to the above-mentioned studies. Authors claimed several factors, including BDNF values, might have increased as a part of neuroadaptation against the neurotoxicity caused by alcohol. They also claimed that alcohol-dependent patients may have various inflammatory processes such as hepatic, pancreatic, gastric, pulmonary, and cardiovascular that could be a different source of BDNF. However, in this study, the authors did not discuss the comorbid alcohol-related physical conditions. Later, another study also found significant increase in BDNF levels in 4 weeks alcohol abstinent individuals compared to controls. The study measured BDNF levels in both serum and plasma; however, they found significant changes in serum samples only. They claimed that the serum elevation is not due to higher BDNF exposure but might be due to other sources of BDNF such as platelets which are a potential source of BDNF. However, this study did not measure the baseline BDNF levels in alcohol patients, and controls were social drinkers who were consuming <25 drinks/month. Thus, findings cannot be interpreted precisely.
Six out of 13 other studies found nonsignificant changes in alcohol-dependent patients compared to controls. Two of these studies found increasing trend in BDNF values in alcohol-dependent patients when compared to controls, and three of the studies found decreasing trend of the same,, whereas one study had similar findings as that of controls.
Studies comparing brain-derived neurotrophic factor level over the course of detoxification
Huang et al. have found a significant increase in serum BDNF levels after 1 week of alcohol withdrawal; however, Heberlein et al. found no change during alcohol withdrawal from day 1 to day 7 and day 14 (P > 0.05). In the latter study, withdrawal symptoms were treated by oxcarbazepine and clomethiazole unlike in the former where only lorazepam was used for the detoxification. Another study found that the serum BDNF levels of the abstinent group at 6 months of abstinence were significantly higher than those of the nonabstinent group (P = 0.034). Authors hypothesize that abstinence might have restored the homeostasis of BDNF dysregulation due to chronic alcohol use resulting in increased BDNF synthesis and serum concentrations. However, since the BDNF levels were compared over 6 months' duration, various additional factors might have confounded the findings. For example, in this study, some of the patients were on antidepressants, and their depressive status might influence the BDNF levels. Some others found positive urine toxicology for cannabis both at baseline and at 6 months of alcohol abstinence. From the literature, it is apparent that BDNF levels are altered with cannabis use and depression. Köhler et al. found that mean BDNF concentrations decreased slightly from day 1 (7.8 ng/ml) to day 2 (9.0 ng/ml), and day 3 (7.0 ng/ml) but then increased slightly to day 8 (7.5 ng/ml) and increased on day 14 (9.0 ng/ml). Mean BDNF concentrations showed a tendency to increase from day 3 to day 14 (P = 0.078) but did not change from day 3 to day 8 (P = 0.173). However, the study did not screen for other psychiatric comorbidities which can alter the expression of BDNF. Cavus et al. found a significant decrease in BDNF values on day 7 compared to day 1 (P < 0.001). Authors claimed that a significant decrease may be due to the long latency for increase in BDNF; thus, more time might be required for BDNF levels to improve, and the initial withdrawal symptoms might have confounded the results. A recent study found that serum BNDF levels on day 14 were significantly higher than those on day 1 (P = 0.016). However, there was no significant difference between day 1 and day 7 (P = 0.363) or between day 7 and day 14 (P = 0.677). Further, BDNF levels were negatively correlated with the severity of alcohol withdrawal; thus, BDNF may play a role in neuroadaptation during alcohol withdrawal. Another recent study also found that serum BDNF values at 6 months were significantly increased when compared to baseline (P < 0.001). However, more than half of the cases had comorbid other psychiatric comorbidities and were receiving psychotropic medications.
| Discussion|| |
In the modern era, research in the field of alcohol has gained an increasing appreciation for the involvement of growth factors. The alcohol dependence syndrome has been characterized as a disease of maladaptive plasticity. The role of BDNF in animal studies have demonstrated that BDNF may directly influence the transition from light to compulsive drinking through actions in the dorsal striatum and prefrontal cortex. At the same time, its role in human population is becoming an interesting area for research due to the hypothetical implication of BDNF as a biological marker. Thus, there has been a recent increase in the number of studies examining these issues in human participants.
The current review on peripheral BDNF levels in alcohol-dependent patients shows that most of the studies were done in serum thus, giving an accurate estimation of the BDNF values as compared to studies done in plasma. Further, some studies have been done in both serum and plasma., These studies have established the importance of measuring BDNF in serum, as even the BDNF stored in platelets gets released into the peripheral circulation.
The present literature has indicated a significant difference in BDNF levels between patients with alcohol dependence and healthy controls.,,,, However, some of the studies have not detected any significant difference.,,,, Contrarily, two studies found a significant increase in BDNF levels in alcohol-dependent patients compared to controls., Similarly, there have been variable results in studies which have followed up patients with alcohol dependence during abstinence periods. Most of the studies indicate increasing levels of BDNF over the course of abstinence.,,,, However, one study found a significant decrease in BDNF levels over the abstinence period.
Most of the studies show increasing levels of BDNF during the abstinence period. The levels might be increasing to protect against the alcohol-induced neurodegeneration and thus, playing a pivotal role in neuroplasticity. This would mean that monitoring serum BDNF levels might have a diagnostic value. It could serve as a potential biomarker which would have significant implications for preventive and therapeutic intervention strategies. However, similar evidence could not be obtained when compared to healthy population as the current findings are mixed.
The different findings across these case-control studies could be due to heterogeneity in the studies and various confounding factors. Some of the factors for heterogeneity were different age and duration of alcohol dependence across the studies. Further, BDNF measurements during variable periods of abstinence across the studies could have led to heterogeneous results.
Various confounding factors identified across the studies were: low sample size, single-sex population, relatively stress-free atmosphere, comorbid other psychiatric conditions, concurrent nicotine use, use of psychotropic medications, different methods of detoxification, family history of alcohol dependence, sample collection during different periods of alcohol abstinence, all of which are known to influence BDNF expression and thus which could be potential confounders.
Despite the above limitations, the current review supports the notion that BDNF plays an important role in the neuroplasticity of alcohol dependence. However, it is premature at this stage to draw a conclusion that BDNF may be used as a biomarker. As the current study has not pooled data of the various studies, it cannot comment on the quantitative differences in BDNF levels in cases when compared to control. Similarly, with the current review, we cannot quantify the change in BDNF over the course of alcohol detoxification. Therefore, in the future, a meta-analysis could help in addressing these queries. Furthermore, in view of the existence of multiple confounding factors, further research is warranted with the possible elimination of the above-mentioned confounding factors. Studies measuring central and peripheral BDNF levels in the same population may further add to the literature. Further studies evaluating BDNF levels with a longer follow-up; including the early and late periods of alcohol abstinence, and with larger sample sizes, in both genders, using a standardized medication schedule to manage alcohol withdrawal are required for a better understanding the role of BDNF in alcohol dependence.
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Dr. Shanti Mohan Kethawath
Department of Psychiatry, Gandhi Medical College, Secunderabad, Telangana
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2]