Psychopharmacology (2010) 209:213–215 DOI 10.1007/s00213-010-1781-3
LETTER TO THE EDITORS
BDNF plasma levels decrease during benzodiazepine withdrawal in patients suffering from comorbidity of depressive disorder and benzodiazepine dependence Annemarie Heberlein & Bernd Lenz & Marc Muschler & Helge Frieling & Rebecca Buechl & Michael Gröschl & Johannes Kornhuber & Stefan Bleich & Thomas Hillemacher
Received: 3 January 2010 / Accepted: 12 January 2010 / Published online: 6 February 2010 # Springer-Verlag 2010
Abstract Rationale Alterations in the expression of neurotrophic growth factors like brain-derived neuronal factor (BDNF) and glial cell line-derived neuronal growth factor (GDNF) have been frequently associated with affective disorders. Indeed, benzodiazepine dependence is typically combined with affective disorders. Aim of the study was to investigate plasma levels of the neuronal growth factors BDNF and GDNF during benzodiazepine withdrawal in patients suffering from comorbidity of benzodiazepine dependence and depressive disorder. Methods In total, 11 patients were included in the study. Seven patients completed benzodiazepine withdrawal. Results We found that BDNF plasma levels were significantly increased in the benzodiazepine-dependent patients (p=0.011) compared to a healthy control group (14 ageand sex-matched persons) and decreased significantly (p=0.029) due to benzodiazepine withdrawal, whereas A. Heberlein : B. Lenz : M. Muschler : H. Frieling : R. Buechl : J. Kornhuber : S. Bleich : T. Hillemacher Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University of Erlangen–Nuremberg, Erlangen, Germany A. Heberlein (*) : M. Muschler : H. Frieling : S. Bleich : T. Hillemacher Department of Psychiatry, Social Psychiatry and Psychotherapy, Center of Addiction Research, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany e-mail:
[email protected] M. Gröschl Department of Pediatrics, University Hospital Erlangen, Erlangen, Germany
GDNF plasma levels did not differ (p=0.886) and change (p=0.180) significantly. Conclusion In conclusion, we assume that benzodiazepines may partly act by similar neurobiological mechanisms like antidepressant medication, which may explain the high frequency of benzodiazepine dependence in affective disorders. Keywords BDNF . GDNF . Benzodiazepine dependence . Benzodiazepine withdrawal . Depression . Comorbidity Affective disorders have been associated with volumetric reductions in the cortex and the limbic system (Campbell and MacQueen 2006; Campbell et al. 2004). Therefore, the so-called neurotrophic hypothesis of affective disorders has been widely discussed. It describes the inability of neuronal cells to exhibit appropriate adaptive plasticity, which is hypothesized to underlie affective disorders like depression (Altar 1999). This hypothesis is supported by various study reports that show alterations of neurotrophic neuropeptides like brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) in patients suffering from affective disorders because both neuropeptides have been implicated in the maintenance and structural integrity of the adult brain (Michel et al. 2008). Benzodiazepines have been frequently reported to show neuroprotective properties regarding seizures (Qashu et al. 2010) and ischemia (Corbett et al. 2008). Therefore, the assumption that benzodiazepines may also affect neuronal growth factors seems conclusive. Moreover, there is a frequent comorbidity of benzodiazepine dependence and affective disorders (Michelini et al. 1996). Therefore, we investigated the hypotheses that plasma levels of BDNF and GDNF are altered in patients suffering from depression and benzodiaz-
214
epine dependence and that plasma levels of both neurotrophic neuropeptides change during benzodiazepine withdrawal. The present study was approved by the local ethics committee of the University of Erlangen-Nuremberg. The investigation was conducted in accordance with the Declaration of Helsinki of 1975 (revised in 1983). Each participant gave written informed consent. In total, we investigated BDNF and GDNF plasma levels of 11 patients that suffered from depressive disorder and comorbid benzodiazepine dependence according to International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) and were admitted for detoxification treatment (Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Germany). Seven of the 11 patients completed benzodiazepine withdrawal. Benzodiazepine withdrawal was done by dose tapering of the benzodiazepine patients took usually (lorazepam in six patients, diazepam in five patients, bromazepam in one patient). Diazepam equivalent doses ranged from 2.5 to 45 mg on admission (mean 16.79, SD 12.88). Patients suffering from any other axis one diagnosis, severe somatic illnesses like hypothalamic–pituitary– adrenal dysregulation and patients that showed a positive history of cerebral damage (e.g., ischemia) were not enrolled in the study. Patients receiving electroconvulsive treatment and transcranial magnetic stimulation during benzodiazepine withdrawal were excluded from the study. As a control group, we enrolled age- and sex-matched healthy persons that did not suffer from any current somatic disease (14 persons). Controls were negative for alcohol abuse, alcohol dependence, or other mental diseases according to ICD-10. For further analysis, fasting blood samples were taken directly at admission between 8 and 10 a.m. All blood samples were centrifuged and stored at −80°C immediately after collection. BDNF and GDNF plasma levels were investigated on admission (day0) and 7 days (day2) after benzodiazepine withdrawal was completed. BDNF and GDNF plasma levels were assessed using the DuoSet enzyme-linked immunosorbent assay Development System (DY248, DY212 E, R&D Systems, WiesbadenNordenstadt, Germany). All the assays were performed according to the manufacturer’s description. The lower limits of determination were 26 pg/mL (GDNF) and 21 pg/mL (BDNF), respectively. The intra-assay and interassay coefficients of variation were 7.0 and 10.3% (GDNF) and 5.0 and 8.7% (BDNF). BDNF and GDNF were normally distributed by means of the Kolmogorov–Smirnov test. Data were analyzed employing PASWTM for Windows 17. 0 and Graph Pad PrismTM 5.0 (Graph Pad Software Inc., San Diego, CA, USA). We found significantly increased BDNF plasma levels on admission compared to the healthy control group (t=
Psychopharmacology (2010) 209:213–215
2.991, p=0.011). BDNF (t=2.842, p=0.029) plasma levels decreased significantly during benzodiazepine withdrawal (see Fig. 1). After completion of benzodiazepine withdrawal, BDNF plasma levels of the patient’s group and the healthy control group did not differ significantly any longer (t=1.600, p=0.127). GDNF plasma levels were slightly but not significantly decreased in the patient’s group compared to the healthy control group (t=−0.145 p=0.886). GDNF plasma level decreased slightly but not significantly during benzodiazepine withdrawal (t=1.557, p=0.180). BDNF and GDNF plasma levels were not associated to duration of benzodiazepine dependence or to daily benzodiazepine dosage. In conclusion, our results show for the first time that neurotrophic growth factors are affected in patients suffering from depressive disorder and comorbid benzodiazepine dependence. Whereas GDNF plasma levels were not altered in benzodiazepine dependent patients, BDNF plasma levels were significantly elevated in patients suffering from benzodiazepine dependence. Unfortunately, all the patients investigated received stable doses of antidepressive medication. Therefore, the initial elevation of BDNF plasma levels may contribute to antidepressant medication (Shimizu et al. 2003). However, in addition with the finding that BDNF levels decreased significantly during benzodiazepine withdrawal obtained in this study, our results show that benzodiazepines similar to antidepressant medication affect the expression of BDNF. GDNF plasma levels were not significantly changed in the benzodiazepine-dependent patients. Similar to BDNF, GDNF levels decreased slightly but not significantly during benzodiazepine withdrawal. This may point toward an affection of GDNF expression by benzodiazepines. Anyway, our study had not enough power to show an equal and significant difference. Unfortunately, the explanatory power of this study is limited by the small number of patients included. However, the data presented here show for the first time that neuro-
Fig. 1 Alteration of BDNF plasma levels during benzodiazepine withdrawal compared to the healthy control group. BDNF plasma levels decrease significantly from admission (day0) to end (day2) of benzodiazepine withdrawal (p=0.029)
Psychopharmacology (2010) 209:213–215
trophic growth factors—in particular BDNF—are affected by benzodiazepine dependence and benzodiazepine withdrawal. In respect of study results reporting an association between the symptomatology of depression and the alterations of peripheral blood levels of neurotrophic neuropeptides, this study may help to enlighten the underlying coherencies of the typical comorbidity of benzodiazepine dependence and affective disorders. Assuming that benzodiazepines may increase expression of neuropeptides that are decreased due to depressive disorders would explain the positive effects of benzodiazepines particularly in this patient’s group. Acknowledgment We gratefully acknowledge the support by a grant (A.H., T.H.) from ELAN funds (“Erlanger Leistungsbezogene Anschubfinanzierung und Nachwuchsförderung”), Friedrich-AlexanderUniversity of Erlangen–Nuremberg, Germany. None of the authors has a financial or personal conflict of interest.
References Altar CA (1999) Neurotrophins and depression. Trends Pharmacol Sci 20:59–61
215 Campbell S, MacQueen G (2006) An update on regional brain volume differences associated with mood disorders. Curr Opin Psychiatry 19:25–33 Campbell S, Marriott M, Nahmias C, MacQueen GM (2004) Lower hippocampal volume in patients suffering from depression: a meta-analysis. Am J Psychiatry 161:598–607 Corbett D, Larsen J, Langdon KD (2008) Diazepam delays the death of hippocampal CA1 neurons following global ischemia. Exp Neurol 214:309–314 Michel TM, Frangou S, Camara S, Thiemeyer D, Jecel J, Tatschner T, Zoechling R, Grunblatt E (2008) Altered glial cell line-derived neurotrophic factor (GDNF) concentrations in the brain of patients with depressive disorder: a comparative post-mortem study. Eur Psychiatry 23:413–420 Michelini S, Cassano GB, Frare F, Perugi G (1996) Long-term use of benzodiazepines: tolerance, dependence and clinical problems in anxiety and mood disorders. Pharmacopsychiatry 29:127–134 Qashu F, Figueiredo TH, Aroniadou-Anderjaska V, Apland JP, Braga MF (2010) Diazepam administration after prolonged status epilepticus reduces neurodegeneration in the amygdala but not in the hippocampus during epileptogenesis. Amino Acids 38(1): 189–197 Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C, Nakazato M, Watanabe H, Shinoda N, Okada S, Iyo M (2003) Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry 54:70–75
