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Original Article |

Association of the Brain-Derived Neurotrophic Factor Val66Met Polymorphism With Reduced Hippocampal Volumes in Major Depression FREE

Thomas Frodl, MD; Cornelius Schüle, MD; Gisela Schmitt, MD; Christine Born, MD; Thomas Baghai, MD; Peter Zill, PhD; Ronald Bottlender, MD; Rainer Rupprecht, MD; Brigitta Bondy, MD; Maximilian Reiser, MD; Hans-Jürgen Möller, MD; Eva M. Meisenzahl, MD
[+] Author Affiliations

Author Affiliations: Department of Psychiatry and Psychotherapy (Drs Frodl, Schüle, Schmitt, Baghai, Zill, Rupprecht, Bondy, Möller, and Meisenzahl) and Radiology (Drs Born and Reiser), Ludwig-Maximilians University, Munich, Germany, and East London and the City Mental Health NHS Trust, Department of Psychiatry, Newham Centre for Mental Health, London, United Kingdom (Dr Bottlender).


Arch Gen Psychiatry. 2007;64(4):410-416. doi:10.1001/archpsyc.64.4.410.
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Context  Brain-derived neurotrophic factor (BDNF) modulates hippocampal plasticity, which is believed to be altered in patients with major depression.

Objective  To examine the effect of the BDNF Val66Met polymorphism on hippocampal and amygdala volumes in patients with major depression and in healthy control subjects.

Design  Cross-sectional comparison between patients and controls.

Setting  Inpatients with major depression from the Department of Psychiatry and Psychotherapy and healthy controls from the community were recruited.

Participants  The study population of 120 subjects included 60 patients with major depression and 60 healthy controls.

Main Outcome Measures  Using a combined strategy, hippocampal and amygdala volumes were estimated on high-resolution magnetic resonance images, and genotyping was performed for the BDNF Val66Met polymorphism.

Results  Patients had significantly smaller hippocampal volumes compared with controls (P = .02). Significantly smaller hippocampal volumes were observed for patients and for controls carrying the Met-BDNF allele compared with subjects homozygous for the Val-BDNF allele (P = .006). With respect to amygdala volumes, no significant differences between patients and controls and no significant main effects for the BDNF Val66Met polymorphism were observed.

Conclusions  These genotype-related alterations suggest that Met-BDNF allele carriers might be at risk to develop smaller hippocampal volumes and may be susceptible to major depression. This study supports findings from animal studies that the hippocampus is involved in brain development and plasticity.

Figures in this Article

Major depression is one of the most frequent human diseases, with a lifetime prevalence of 16% and a 12-month prevalence of 6.6%.1 Dysfunction of neuronal plasticity or remodeling could contribute to the pathophysiology of mood disorders.2 This hypothesis is supported by preclinical and clinical investigations demonstrating that stress and depression lead to reduction of the total volume of the hippocampus and to atrophy and loss of neurons in the adult hippocampus. Experimental studies3,4 found that prolonged stress decreases the number of apical dendritic branch points and the length of apical dendrites, particularly in the laminar CA3 region of the hippocampus. This effect was glucocorticoid dependent and emerged after 3 weeks of experimental corticosterone treatment. Moreover, antidepressants suppress the toxic effects of stress on the hippocampus and increase hippocampal neurogenesis.5 In vivo investigations detected reduced hippocampal volumes in older patients6,7 and in younger patients810 with major depression. Two meta-analytic studies11,12 confirmed that the hippocampus is consistently reduced in volume in patients with major depression, although there were some negative findings.

With respect to the neurotrophin hypothesis of depression, brain-derived neurotrophic factor (BDNF) is of major importance because it modulates hippocampal plasticity in physiological models and in animals.13 Depressive states in animal models have been shown to be associated with reduced BDNF levels in the brain, and central administration of BDNF has been demonstrated to reverse such depressive states.14 However, BDNF also seems to be important for the manifestation of depressive states. In mice, BDNF function was required for the development of persistent social aversion in a social defeat paradigm. Chronic treatment then restored social functioning, and blockade of BDNF activity in the ventral tegmental area and projections to the nucleus accumbens exerted antidepressant-like effects.15

Haplotype analysis of the BDNF gene showed a robust association with major depression and with schizophrenia in the presence of depressive symptoms.16 In another study,17 no significant association was found between BDNF and unipolar depression. A common single nucleotide polymorphism consisting of a missense change (G196A) that produces a nonconservative amino acid change (valine to methionine) in the coding exon of BDNF at position 66 (Val66Met) was recently described as a functional polymorphism.18 In a large community sample of 441 subjects, the Val-BDNF allele was associated with a high neuroticism score, which is a risk factor for depression. Other investigators failed to replicate this finding in 3 large populations.19 Patients with geriatric depression in a Taiwanese veterans population showed a significant excess of the Met-BDNF allele compared with control subjects,20 whereas no significant associations were detected in a Chinese population21,22 or in a German population.16 The BDNF Val66Met polymorphism was associated with cognitive performance during the Wisconsin Card Sorting Test in patients with bipolar disorder; patients homozygous for the Val-BDNF allele had a higher percentage of correct reaction in the task.23 Recently, patients with schizophrenia carrying the Met-BDNF allele were observed to have more visuospatial impairment.24 Overall, there is great diversity in the findings regarding the association between BDNF and depression.

The BDNF Val66Met polymorphism in BDNF in the 5′ signal domain has been shown to affect intracellular packaging and regulation of BDNF secretion25 and human hippocampal function.26 Healthy Met-BDNF allele carriers had substantial relative decreases in hippocampal volume that are gender and age independent, suggesting that these changes may occur before adulthood.27,28 The Met-BDNF allele may be a vulnerability factor for the development of disease processes associated with dysfunction of this brain region. However, an exaggerated age-related volume reduction of the dorsolateral prefrontal cortex was found in healthy Met-BDNF allele carriers; therefore, subjects with the Met-BDNF allele might be more vulnerable to aging than individuals homozygous for the Val-BDNF allele.29 Furthermore, stress decreases the expression of BDNF in the hippocampus.30 So far, there is no study available (to our knowledge) that has investigated the effect of the BDNF polymorphism on hippocampal volumes in patients with depression and in healthy control subjects. A possible association between the BDNF polymorphism and hippocampal reductions that in turn have an effect on the development of depression may enhance our knowledge of the neurotrophic and neurogenic hypothesis of depression.31

Herein, we used a combined strategy of neuroimaging techniques and genetic analysis to identify the effect of the BDNF polymorphism on the hippocampus and amygdala in patients with major depression and in healthy controls. In a sample of 40 patients and 40 controls, patients with major depression carrying the L/L genotype in the promoter region of the serotonin transporter gene (5-HTTLPR) were found to have reduced hippocampal volumes compared with healthy controls.32 In the present study, we sought to test the following hypotheses: (1) In this large sample, hippocampal and amygdala volumes are reduced in patients with major depression compared with healthy controls. (2) Reduced hippocampal or amygdala volumes are related to the BDNF polymorphism among the patients.

PARTICIPANTS

Sixty inpatients with major depression from the Department of Psychiatry and Psychotherapy, Ludwig-Maximilians University, Munich, Germany, were recruited (age range, 18-65 years; mean ± SD age, 44.2 ± 11.8 years) (Table 1). Psychiatric diagnoses based on DSM-IV criteria and on the Structured Clinical Interview for DSM-IV were determined by a consensus of at least 2 psychiatrists. Clinical variables were documented using the 21-item Hamilton Depression Rating Scale.33

Table Graphic Jump LocationTable 1. Demographic and Clinical Characteristics of Study Subjects*

All patients were inpatients. Thirty patients had a first depressive episode, and 30 patients had recurrent episodes. There were 8 patients with 1 earlier admission to a psychiatric hospital, 5 patients with 2 earlier admissions, 2 patients with 3 earlier admissions, and 1 patient each with 4, 7, 12, and 15 earlier admissions. Almost all patients, except those not taking antidepressant medication, were in an outpatient service and were treated with antidepressants before the current admission. They were hospitalized because their conditions did not improve. Magnetic resonance imaging was performed in the first 2 weeks after admission to the hospital.

On the day of magnetic resonance imaging, patients were taking the following medications: 17 patients were taking serotonin reuptake inhibitors (sertraline [n = 7], citalopram hydrobromide [n = 7], paroxetine hydrochloride [n = 2], and fluvoxamine maleate [n = 1]), 11 patients were taking tricyclic antidepressants (amitriptyline hydrochloride [n = 4], doxepin hydrochloride [n = 5], maprotiline hydrochloride [n = 1], and trimipramine maleate [n = 1]), and 23 patients were taking other antidepressants (venlafaxine hydrochloride [n = 7], reboxetine [n = 9], and mirtazapine [n = 7]). Nine patients were not taking antidepressant medication at the time of magnetic resonance imaging. Patients taking antidepressants had a mean ± SD duration of treatment of 15.2 ± 12.9 days.

For comparison, 60 healthy controls were matched with respect to gender, handedness, and age (age range, 22-64 years; mean ± SD age, 41.6 ± 12.3 years) (Table 1). A structured interview was used to assess medical history, trauma, and other exclusion criteria. Neither the control subjects nor their first-degree relatives had a history of neurological or mental illness. Exclusion criteria for patients and controls were previous head injury with loss of consciousness, cortisol medication in the medical history, and previous alcohol or other substance abuse. Other mental illnesses including personality disorders as well as neurological diseases were also exclusion criteria. No subject had received electroconvulsive therapy. Handedness was determined using the Edinburgh Inventory.34

After an extensive description of the study to the patients with major depression and the healthy controls, written informed consent was obtained. The study design was approved by the local ethics committee and was prepared in accord with the ethical standards laid down in the Declaration of Helsinki.

MAGNETIC RESONANCE IMAGING PROCEDURES

Magnetic resonance images were obtained (1.5-T Magnetom Vision; Siemens, Erlangen, Germany) using a coronal T2-weighted and proton density–weighted dual-echo sequence (repetition time, 3710 milliseconds; echo times, 22 milliseconds [first echo] and 90 milliseconds [second echo]; total acquisition time, 9 minutes; number of acquisitions, 1; field of view, 230 mm; matrix, 240 × 256 pixels; and section thickness, 3 mm) and a 3-dimensional magnetization prepared rapid acquisition gradient-echo sequence (repetition time, 11.6 milliseconds; echo time, 4.9 milliseconds; total acquisition time, 9 minutes; number of acquisitions, 1; field of view, 230 mm; matrix, 512 × 512 pixels; and section thickness, 1.5 mm). A commercial software package was used for further image processing (Analyze; Biomedical Imaging Resource, Mayo Foundation, Rochester, Minn), with size reduction from 16 to 8 bits and transformation to a uniform matrix of 256 × 256 pixels on 192 sections of 1.0-mm thickness. All data sets were realigned and resampled 3-dimensionally for the anterior commissure to posterior commissure line according to Talairach coordinates using a software program (BRAINS; Brain Research: Analysis of Images, Networks and Systems; developed by Andreasen et al35). This program allowed control of the regions of interest for the sagittal and transverse sections simultaneously, as well as control of the segmentation for calculating intracranial content and gray and white matter volumes (in cubic centimeters) within the defined region of interest.

DEFINITION OF THE HIPPOCAMPAL AND AMYGDALA FORMATION

We used the definition of the hippocampus according to Niemann et al36 and the detection of the hippocampal-amygdala border from the description of Convit et al.37 The evaluation staff (T.F.) was blinded to each subject's study group status. The amygdala was outlined manually using a mouse-driven cursor. The definition of the amygdala according to the criteria established by Convit et al37 was applied. To obtain the most anterior boundary, the definition in accord with Altshuler et al38 was used (for a detailed description, see Frodl et al9,39). The hippocampus and amygdala are illustrated in Figure 1.

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Figure 1.

Magnetic resonance imaging sections. A and B, Coronal sections through occipitorostral parts of the hippocampus. The shape of the hippocampus may be compared with that of a rabbit with the head directed vertically (B). C, Section through the posteromedial part of the amygdala. D, Section through the anteromedial part of the amygdala.

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For determination of interrater reliability, 10 brains were randomly chosen, and regions of interest were determined by 2 raters independently. The intraclass correlations for the interrater reliability and the intrarater reliability in randomly chosen brains were high.9,39

LABORATORY ANALYSIS

DNA was extracted from a 5-mL blood sample using a kit (QIAamp Blood Isolation Kit; QIAGEN GmbH, Hilden, Germany) following the instructions of the supplier. All genotypings were performed by the fluorescence resonance energy transfer method using a commercially available system (Light Cycler System; Roche Diagnostics, Mannheim, Germany). For the G196A polymorphism in BDNF, the following conditions were applied: forward primer, 5′-TCA TAC TTT GGT TGC ATG AAG G-3′; reverse primer, 5′-AGA AGA GGA GGC TCC AAA GG-3′; and acceptor hybridization probe, 5′-LCRed604-TGT TGG ATG AGG ACC AGA AAG TTC GGC-p-3′. Polymerase chain reaction was performed using 50 ng of DNA in a total volume of 20 μL containing 2 μL of reaction mix (0.4μM each primer, 0.2μM each hybridization probe, and 2μM magnesium chloride) according to the manufacturer's instructions for 40 cycles of denaturation (95°C for 0 seconds), annealing (64°C for 10 seconds), and extension (72°C for 10 seconds), with ramp rates of 20°C/s. After amplification, a melting curve was generated by holding the reaction at 40°C for 20 seconds and then by heating slowly to 95°C with a ramp rate of 0.2°C/s. The fluorescence signal was plotted against temperature to give melting curves of each sample. Peaks were obtained at 52°C for the A allele and at 57°C for the G allele.

STATISTICAL ANALYSIS

All statistical tests were considered significant at P<.05. Morphometric measurements in both study groups were tested for normal distribution and for homogeneity of variance. Departure from Hardy-Weinberg equilibrium was tested using χ21 test. t Test and analysis of variance were used to test for differences in demographic variables between patients and controls and among the genotypes. χ2 Test was used to compare the genotype frequencies between patients and controls. Hippocampal and amygdala volumes were subjected to analysis of covariance assessing the main and interaction effects of the within-subject factor of hemisphere (left or right) and the between-subject factors of diagnosis (patients or controls) and BDNF allele (Met carriers or Val/Val) using intracranial content as the cofactor. Post hoc analyses were carried out using analysis of covariance and t test to test hippocampal and amygdala volumes for differences between genotypes.

Patients and controls did not differ with regard to demographic variables (Table 1). The BDNF Val66Met genotype distributions for the patients and controls were in Hardy-Weinberg equilibrium. Age and weight were not different between patients and controls for each BDNF allele group (Met carriers or Val/Val). Illness duration (F1,58 = 3.3, P = .07), age at onset (F1,58 = 1.7, P = .20), and depression severity (Hamilton Depression Rating Scale, F1,58 = 0.01; P = .91) were not significantly different between patients who were Met-BDNF allele carriers and patients who were homozygous for the Val-BDNF allele.

Furthermore, the antidepressant medications taken (none, serotonin reuptake inhibitors, tricyclic antidepressants, or other antidepressants) were not significantly different among patients with the various BDNF genotypes (χ258 = 2.1, P = .50). The BDNF genotype frequencies are given in Table 1. They did not differ between patients and controls.

HIPPOCAMPUS

The analysis of covariance results for the gray matter and the white matter of the hippocampus are given in Table 2. A significant main diagnosis effect was found indicating smaller hippocampal gray and white matter volumes in patients with major depression compared with healthy controls. Moreover, there was a significant effect of BDNF allele on the hippocampal gray matter volume (Figure 2).

Place holder to copy figure label and caption
Figure 2.

Scattergram of left and right hippocampal gray matter volumes showing BDNF (brain-derived neurotrophic factor) polymorphisms of patients with depression and of healthy control subjects. Horizontal lines indicate the mean for each group. P values are shown with intracranial content as a cofactor in the analysis of covariance. For the numbers of subjects in each group, see Table 1.

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Table Graphic Jump LocationTable 2. Repeated-Measures Analysis of Covariance Results for Hippocampal Volumes

In an exploratory analysis, the factor of first depressive episode vs recurrent episodes did not reveal significant interactions for hippocampal gray matter volume. However, there was a significant 3-way interaction between diagnosis, BDNF allele, and the factor episode for hippocampal white matter volume (F1,111 = 5.1, P = .03). Post hoc testing revealed a significant effect among the patients with a first depressive episode that demonstrated smaller hippocampal white matter volume in patients carrying the Met-BDNF allele (F1,27 = 11.2, P = .003), without a significant effect in matched controls (F1,27 = 0.08, P = .78). In patients with recurrent episodes, no significant effect was found for BDNF allele (F1,27 = 0.81, P = .38). An effect between diagnosis and the factor of first depressive episode vs recurrent episodes was not detected.

AMYGDALA

Left and right amygdala volumes did not show a significant effect for diagnosis (F1,115 = 1.9, P = .20) or for BDNF allele (F1,115 = 1.1, P =.31). Nor did they show a significant interaction between BDNF allele and diagnosis (F1/115 = 1.1, P = .31).

In an exploratory analysis, gender had a significant effect on these results. There was a significant 3-way interaction between diagnosis, BDNF allele, and gender for amygdala volumes (F1,111 = 3.8, P = .05). Post hoc analysis detected that women had a significant interaction between diagnosis and BDNF allele (F1,53 = 6.4, P = .01), whereas men did not show such an effect (F1,57 = 0.19, P = .66). Female patients with the Val/Val genotype had significantly larger amygdala volumes compared with female controls with the same genotype (F1,27 = 8.9, P = .006), whereas this was not the case for female patients with the Met allele compared with female controls with the same allele (F1,25 = 0.3, P = .62). The exploratory analysis that included the factor of first depressive episode vs recurrent episodes did not show any significant interactions for amygdala volumes.

CORRELATIONS TO CLINICAL VARIABLES

There were no significant correlations between hippocampal or amygdala volume and illness duration. Furthermore, there was no significant correlation between hippocampal or amygdala volume and severity of depression as measured by the Hamilton Depression Rating Scale.

HIPPOCAMPUS

Our study identified for the first time (to our knowledge) an effect of the functional variation in the Val66Met locus in the 5′ prodomain of BDNF on hippocampal morphologic structure in patients with major depression. The observed decreases in hippocampal volumes were independent of whether subjects were depressed or not and may occur during development of the hippocampus. This view is supported by the finding that the reduction of hippocampal volumes in healthy Met-BDNF allele carriers is age and gender independent.27 The BDNF Val66Met polymorphism seems to be associated with altered hippocampal morphologic structure, which might have an effect on the susceptibility to or the expression of illnesses such as major depression that involve hippocampal neuronal integrity. Indeed, reduced hippocampal volumes affect the course of depressive illnesses,40 they are related to executive dysfunctioning,41 and changes in hippocampal neuronal integrity are associated with poor episodic memory.25

Patients with a first depressive episode did not differ from patients with recurrent episodes for hippocampal gray matter volumes and for the association between the BDNF Val66Met polymorphism and hippocampal gray matter volumes. However, hippocampal white matter volumes were smaller in patients with a first depressive episode who were Met carriers compared with those with the Val/Val genotype, whereas no such difference was detected in patients with recurrent episodes. The number of subjects may have been too small for a subgroup analysis, so this result should be interpreted with caution. In patients with recurrent episodes, other depression-related effects on hippocampal volumes may be present,6 whereas this may not be the case at the beginning of the disease. Therefore, patients with a first depressive episode may show a greater effect of the BDNF polymorphism on hippocampal volumes.

It can be theorized that synaptic and cellular plasticity changes in the hippocampus might result in cognitive deficits. Brain-derived neurotrophic factor seems to play an important role in the early and late phases of long-term potentiation.13 In the late phase, cyclic adenosine monophosphate– and the cyclic adenosine monophosphate–responsive element binding protein signaling pathway are recruited to direct protein synthesis–dependent changes in structure and function of the hippocampal synapsis.42 In vitro investigations demonstrated that depolarization-induced secretion was reduced in Met-BDNF–transfected neurons compared with Val-BDNF analogues, leading to decreased BDNF activity in subjects with the Met-BDNF allele compared with those with the Val-BDNF allele.25 Therefore, Met-BDNF allele carriers might manifest decreased synaptic and cellular plasticity during development and may have reduced hippocampal volumes.

The L/L genotype of the serotonin transporter polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) was associated with reduced hippocampal volumes in patients with major depression but not in control subjects.32 Moreover, patients with late-onset geriatric depression who were homozygous for the L allele of 5-HTTLPR exhibited smaller hippocampal volumes than other subject groups, whereas a significant association between the S allele of 5-HTTLPR and smaller hippocampal volumes was observed in patients with early onset.43 Disease-specific effects other than a genetic susceptibility might contribute to this effect of 5-HTTLPR. Stress may be a prominent factor that can result in neuroplastic changes in the hippocampus.2

The presence of the Met-BDNF allele may independently reduce hippocampal volumes and increase the susceptibility to develop depression via altered hippocampal functioning. However, this is weakened by a study18 among a community sample demonstrating that the Val-BDNF allele was associated with a high neuroticism score (which may be a risk factor for depression), by another study19 that showed no association between the BDNF Val66Met polymorphism and neuroticism. In line with our hypothesis, another study20 found an association between the Met-BDNF allele and geriatric depression. Moreover, among patients with bipolar disorder, the Met-BDNF allele was associated with executive dysfunctioning.23 However, in another population, no significant relationship between the BDNF polymorphism and depression was found.21,22 Our investigation supports the view that the Met-BDNF allele results in reduced hippocampal volumes (eg, via neuroplastic effects), which, in turn, increases the risk for depression. This indirect relationship may explain the inconsistent findings among previous BDNF studies.

AMYGDALA

We found no significant differences between patients and controls with respect to amygdala volumes in this largest sample of patients and controls to date (to our knowledge). Two other studies failed to find altered total amygdala volumes. The first study44 did not show significantly smaller total amygdala volumes in 20 patients with depression compared with 20 healthy controls, whereas amygdala core volumes were found to be significantly smaller in the patients. In the second study10 among 34 drug-resistant patients with major depression, no significant differences in amygdala volumes were observed compared with 17 age-matched healthy controls. In an earlier investigation, no significant differences in amygdala volumes in patients with recurrent depression compared with healthy controls were observed.45

However, larger amygdala volumes have been detected in patients with a first episode of major depression,39 in patients with bipolar disorder,46 and in patients with borderline personality disorder.47 An explanation for differences between patients with a first depressive episode and those with recurrent episodes may be an increased amygdala volume at the beginning of the disease and a reduction to normal size during the course of the disease.45 In the present study, we focused on the genetic effects among patients and not on the differences between patients with a first depressive episode and those with recurrent episodes.

There was no significant main effect of the BDNF polymorphism in patients or in controls. In an exploratory analysis, there was a significant 3-way interaction between diagnosis, BDNF allele, and gender. However, this result should be interpreted with caution because a statistical correction for a post hoc analysis would result in nonsignificant post hoc effects. This finding must be replicated before it can be interpreted.

The primary limitation of this study is its case-control design, which is sensitive to population stratification. This is unlikely to be problematic herein because the patients and controls with each BDNF allele did not differ for age, gender, origin, illness duration, age at onset, or medication use. There was a small number of subjects with the Met-BDNF allele. It could be argued that equal numbers of individuals with the genetic subtype should have been sampled. This would have required a very large number of subjects.

Our findings suggest that Met-BDNF allele carriers may be at risk of developing smaller hippocampal volumes and might be susceptible to developing major depression. The association between hippocampal volumes and the BDNF Val66Met polymorphism underline the hippocampal involvement in brain development and plasticity. This in vivo study confirms in vitro findings that BDNF is required for neuroplastic changes and brain development and further supports the neurotrophic and neurogenic hypothesis of depression.31

Correspondence: Thomas Frodl, MD, Department of Psychiatry and Psychotherapy, Ludwig-Maximilians University, Nussbaumstrasse 7, 80336 Munich, Germany (Thomas.Frodl@med.uni-muenchen.de).

Submitted for Publication: May 16, 2006; final revision received July 28, 2006; accepted July 31, 2006.

Financial Disclosure: None reported.

Funding/Support: This study was supported by the German Federal Research Ministry within the German Research Networks in Medicine promotion as part of the German Research Network on Depression project.

Acknowledgment: We would like to thank Anton Strauß, MD, and Bernhard Burgermeister for technical support.

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Ho  BCMilev  PO’Leary  DSLibrant  AAndreasen  NCWassink  TH Cognitive and magnetic resonance imaging brain morphometric correlates of brain-derived neurotrophic factor Val66Met gene polymorphism in patients with schizophrenia and healthy volunteers. Arch Gen Psychiatry 2006;63731- 740
PubMed Link to Article
Egan  MFKojima  MCallicott  JHGoldberg  TEKolachana  BSBertolino  AZaitsev  EGold  BGoldman  DDean  MLu  BWeinberger  DR The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003;112257- 269
PubMed Link to Article
Hariri  ARGoldberg  TEMattay  VSKolachana  BSCallicott  JHEgan  MFWeinberger  DR Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci 2003;236690- 6694
PubMed
Pezawas  LVerchinski  BAMattay  VSCallicott  JHKolachana  BSStraub  REEgan  MFMeyer-Lindenberg  AWeinberger  DR The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. J Neurosci 2004;2410099- 10102
PubMed Link to Article
Bueller  JAAftab  MSen  SGomez-Hassan  DBurmeister  MZubieta  JK BDNF Val66Met allele is associated with reduced hippocampal volume in healthy subjects. Biol Psychiatry 2006;59812- 815
PubMed Link to Article
Nemoto  KOhnishi  TMori  TMoriguchi  YHashimoto  RAsada  TKunugi  H The Val66Met polymorphism of the brain-derived neurotrophic factor gene affects age-related brain morphology. Neurosci Lett 2006;39725- 29
PubMed Link to Article
Vollmayr  BKeck  SHenn  FASchloss  P Acute stress decreases serotonin transporter mRNA in the raphe pontis but not in other raphe nuclei of the rat. Neurosci Lett 2000;290109- 112
PubMed Link to Article
Warner-Schmidt  JLDuman  RS Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment. Hippocampus 2006;16239- 249
PubMed Link to Article
Frodl  TMeisenzahl  EMZill  PBaghai  TRujescu  DLeinsinger  GBottlender  RSchüle  CZwanzger  PEngel  RRRupprecht  RBondy  BReiser  MMöller  HJ Reduced hippocampal volumes associated with the long variant of the serotonin transporter polymorphism in major depression. Arch Gen Psychiatry 2004;61177- 183
PubMed Link to Article
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;2356- 62
PubMed Link to Article
Oldfield  RC The assessment and analysis of handedness: the Edinburgh Inventory. Neuropsychologia 1971;997- 113
PubMed Link to Article
Andreasen  NCCohen  GHarris  GCizadlo  TParkkinen  JRezai  KSwayze  VW  II Image processing for the study of brain structure and function: problems and programs. J Neuropsychiatry Clin Neurosci 1992;4125- 133
PubMed
Niemann  KHammers  ACoenen  VAThron  AKlosterkotter  J Evidence of a smaller left hippocampus and left temporal horn in both patients with first episode schizophrenia and normal control subjects. Psychiatry Res 2000;9993- 110
PubMed Link to Article
Convit  AMcHugh  PWolf  OTde Leon  MJBobinski  MDe Santi  SRoche  ATsui  W MRI volume of the amygdala: a reliable method allowing separation from the hippocampal formation. Psychiatry Res 1999;90113- 123
PubMed Link to Article
Altshuler  LLBartzokis  GGrieder  TCurrran  JMintz  J Amygdala enlargement in bipolar disorder and hippocampal reduction in schizophrenia: an MRI study demonstrating neuroanatomic specificity. Arch Gen Psychiatry 1998;55663- 664
PubMed
Frodl  TMeisenzahl  EZetzsche  TBottlender  RBorn  CGroll  CJager  MLeinsinger  GHahn  KMöller  HJ Enlargement of amygdala volumes in patients with a first episode of major depression. Biol Psychiatry 2002;51708- 714
PubMed Link to Article
Frodl  TMeisenzahl  EMZetzsche  THohne  TBanac  SSchorr  CJager  MLeinsinger  GBottlender  RReiser  MMöller  HJ Hippocampal and amygdala changes in patients with major depressive disorder and healthy controls during a 1-year follow-up. J Clin Psychiatry 2004;65492- 499
PubMed Link to Article
Frodl  TSchaub  ABanac  SCharypar  MJäger  MKümmler  PBottlender  RZetzsche  TLeinsinger  GReiser  MMöller  HJMeisenzahl  EM Reduced hippocampal volume correlates with executive dysfunctioning in major depression. J Psychiatry Neurosci 2006;31316- 323
PubMed
Kandel  ER The molecular biology of memory storage: a dialogue between genes and synapses. Science 2001;2941030- 1038
PubMed Link to Article
Taylor  WDSteffens  DCPayne  MEMacFall  JRMarchuk  DASvenson  IKKrishnan  KR Influence of serotonin transporter promoter region polymorphisms on hippocampal volumes in late-life depression. Arch Gen Psychiatry 2005;62537- 544
PubMed Link to Article
Sheline  YIGado  MHPrice  JL Amygdala core nuclei volumes are decreased in recurrent major depression. Neuroreport 1998;92023- 2028
PubMed Link to Article
Frodl  TMeisenzahl  EMZetzsche  TBorn  CJäger  MGroll  CBottlender  RLeinsinger  GMöller  HJ Larger amygdala volumes in first depressive episode as compared to recurrent major depression and healthy control subjects. Biol Psychiatry 2003;53338- 344
PubMed Link to Article
Strakowski  SMDelBello  MPSax  KWZimmerman  MEShear  PKHawkins  JMLarson  ER Brain magnetic resonance imaging of structural abnormalities in bipolar disorder. Arch Gen Psychiatry 1999;56254- 260
PubMed Link to Article
Zetzsche  TFrodl  TPreuss  UWSchmitt  GSeifert  DLeinsinger  GBorn  CReiser  MMöller  HJMeisenzahl  EM Amygdala volume and depressive symptoms in patients with borderline personality disorder. Biol Psychiatry 2006;60302- 310
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Magnetic resonance imaging sections. A and B, Coronal sections through occipitorostral parts of the hippocampus. The shape of the hippocampus may be compared with that of a rabbit with the head directed vertically (B). C, Section through the posteromedial part of the amygdala. D, Section through the anteromedial part of the amygdala.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Scattergram of left and right hippocampal gray matter volumes showing BDNF (brain-derived neurotrophic factor) polymorphisms of patients with depression and of healthy control subjects. Horizontal lines indicate the mean for each group. P values are shown with intracranial content as a cofactor in the analysis of covariance. For the numbers of subjects in each group, see Table 1.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Demographic and Clinical Characteristics of Study Subjects*
Table Graphic Jump LocationTable 2. Repeated-Measures Analysis of Covariance Results for Hippocampal Volumes

References

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PubMed Link to Article
Mervaala  EFohr  JKononen  MValkonen-Korhonen  MVainio  PPartanen  KPartanen  JTiihonen  JViinamaki  HKarjalainen  AKLehtonen  J Quantitative MRI of the hippocampus and amygdala in severe depression. Psychol Med 2000;30117- 125
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Berton  OMcClung  CADileone  RJKrishnan  VRenthal  WRusso  SJGraham  DTsankova  NMBolanos  CARios  MMonteggia  LMSelf  DWNestler  EJ Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 2006;311864- 868
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Schumacher  JJamra  RABecker  TOhlraun  SKlopp  NBinder  EBSchulze  TGDeschner  MSchmal  CHofels  SZobel  AIllig  TPropping  PHolsboer  FRietschel  MNothen  MMCichon  S Evidence for a relationship between genetic variants at the brain-derived neurotrophic factor (BDNF) locus and major depression. Biol Psychiatry 2005;58307- 314
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Oswald  PDel-Favero  JMassat  ISouery  DClaes  SVan Broeckhoven  CMendlewicz  J No implication of brain-derived neurotrophic factor (BDNF) gene in unipolar affective disorder: evidence from Belgian first and replication patient-control studies. Eur Neuropsychopharmacol 2005;15491- 495
PubMed Link to Article
Sen  SNesse  RMStoltenberg  SFLi  SGleiberman  LChakravarti  AWeder  ABBurmeister  M A BDNF coding variant is associated with the NEO personality inventory domain neuroticism, a risk factor for depression. Neuropsychopharmacology 2003;28397- 401
PubMed Link to Article
Willis-Owen  SAGFullerton  JSurtees  PGWainwright  NWJMiller  SFlint  J The Val66Met coding variant of the brain-derived neurotrophic factor (BDNF) gene does not contribute toward variation in the personality trait neuroticism. Biol Psychiatry 2005;58738- 742
PubMed Link to Article
Hwang  JPTsai  SJHong  CJYang  CHLirng  JFYang  YM The Val66Met polymorphism of the brain-derived neurotrophic-factor gene is associated with geriatric depression. Neurobiol Aging 2006;271834- 1837
PubMed Link to Article
Tsai  SJCheng  CYYu  YWChen  TJHong  CJ Association study of brain-derived neurotrophic-factor genetic polymorphism and major depressive disorders, symptomatology, and antidepressant response. Am J Med Genet B Neuropsychiatr Genet 2003;12319- 22
PubMed Link to Article
Hong  CJHuo  SJYen  FCTung  CLPan  GMTsai  SJ Association study of brain-derived neurotrophic-factor genetic polymorphism and mood disorders, age of onset and suicidal behavior. Neuropsychobiology 2003;48186- 189
PubMed Link to Article
Rybakowski  JKBorkowska  ASkibinska  MSzczepankiewicz  AKapelski  PLeszczynska-Rodziewicz  ACzerski  PMHauser  J Prefrontal cognition in schizophrenia and bipolar illness in relation to Val66Met polymorphism of the brain-derived neurotrophic factor gene. Psychiatry Clin Neurosci 2006;6070- 76
PubMed Link to Article
Ho  BCMilev  PO’Leary  DSLibrant  AAndreasen  NCWassink  TH Cognitive and magnetic resonance imaging brain morphometric correlates of brain-derived neurotrophic factor Val66Met gene polymorphism in patients with schizophrenia and healthy volunteers. Arch Gen Psychiatry 2006;63731- 740
PubMed Link to Article
Egan  MFKojima  MCallicott  JHGoldberg  TEKolachana  BSBertolino  AZaitsev  EGold  BGoldman  DDean  MLu  BWeinberger  DR The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003;112257- 269
PubMed Link to Article
Hariri  ARGoldberg  TEMattay  VSKolachana  BSCallicott  JHEgan  MFWeinberger  DR Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci 2003;236690- 6694
PubMed
Pezawas  LVerchinski  BAMattay  VSCallicott  JHKolachana  BSStraub  REEgan  MFMeyer-Lindenberg  AWeinberger  DR The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. J Neurosci 2004;2410099- 10102
PubMed Link to Article
Bueller  JAAftab  MSen  SGomez-Hassan  DBurmeister  MZubieta  JK BDNF Val66Met allele is associated with reduced hippocampal volume in healthy subjects. Biol Psychiatry 2006;59812- 815
PubMed Link to Article
Nemoto  KOhnishi  TMori  TMoriguchi  YHashimoto  RAsada  TKunugi  H The Val66Met polymorphism of the brain-derived neurotrophic factor gene affects age-related brain morphology. Neurosci Lett 2006;39725- 29
PubMed Link to Article
Vollmayr  BKeck  SHenn  FASchloss  P Acute stress decreases serotonin transporter mRNA in the raphe pontis but not in other raphe nuclei of the rat. Neurosci Lett 2000;290109- 112
PubMed Link to Article
Warner-Schmidt  JLDuman  RS Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment. Hippocampus 2006;16239- 249
PubMed Link to Article
Frodl  TMeisenzahl  EMZill  PBaghai  TRujescu  DLeinsinger  GBottlender  RSchüle  CZwanzger  PEngel  RRRupprecht  RBondy  BReiser  MMöller  HJ Reduced hippocampal volumes associated with the long variant of the serotonin transporter polymorphism in major depression. Arch Gen Psychiatry 2004;61177- 183
PubMed Link to Article
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;2356- 62
PubMed Link to Article
Oldfield  RC The assessment and analysis of handedness: the Edinburgh Inventory. Neuropsychologia 1971;997- 113
PubMed Link to Article
Andreasen  NCCohen  GHarris  GCizadlo  TParkkinen  JRezai  KSwayze  VW  II Image processing for the study of brain structure and function: problems and programs. J Neuropsychiatry Clin Neurosci 1992;4125- 133
PubMed
Niemann  KHammers  ACoenen  VAThron  AKlosterkotter  J Evidence of a smaller left hippocampus and left temporal horn in both patients with first episode schizophrenia and normal control subjects. Psychiatry Res 2000;9993- 110
PubMed Link to Article
Convit  AMcHugh  PWolf  OTde Leon  MJBobinski  MDe Santi  SRoche  ATsui  W MRI volume of the amygdala: a reliable method allowing separation from the hippocampal formation. Psychiatry Res 1999;90113- 123
PubMed Link to Article
Altshuler  LLBartzokis  GGrieder  TCurrran  JMintz  J Amygdala enlargement in bipolar disorder and hippocampal reduction in schizophrenia: an MRI study demonstrating neuroanatomic specificity. Arch Gen Psychiatry 1998;55663- 664
PubMed
Frodl  TMeisenzahl  EZetzsche  TBottlender  RBorn  CGroll  CJager  MLeinsinger  GHahn  KMöller  HJ Enlargement of amygdala volumes in patients with a first episode of major depression. Biol Psychiatry 2002;51708- 714
PubMed Link to Article
Frodl  TMeisenzahl  EMZetzsche  THohne  TBanac  SSchorr  CJager  MLeinsinger  GBottlender  RReiser  MMöller  HJ Hippocampal and amygdala changes in patients with major depressive disorder and healthy controls during a 1-year follow-up. J Clin Psychiatry 2004;65492- 499
PubMed Link to Article
Frodl  TSchaub  ABanac  SCharypar  MJäger  MKümmler  PBottlender  RZetzsche  TLeinsinger  GReiser  MMöller  HJMeisenzahl  EM Reduced hippocampal volume correlates with executive dysfunctioning in major depression. J Psychiatry Neurosci 2006;31316- 323
PubMed
Kandel  ER The molecular biology of memory storage: a dialogue between genes and synapses. Science 2001;2941030- 1038
PubMed Link to Article
Taylor  WDSteffens  DCPayne  MEMacFall  JRMarchuk  DASvenson  IKKrishnan  KR Influence of serotonin transporter promoter region polymorphisms on hippocampal volumes in late-life depression. Arch Gen Psychiatry 2005;62537- 544
PubMed Link to Article
Sheline  YIGado  MHPrice  JL Amygdala core nuclei volumes are decreased in recurrent major depression. Neuroreport 1998;92023- 2028
PubMed Link to Article
Frodl  TMeisenzahl  EMZetzsche  TBorn  CJäger  MGroll  CBottlender  RLeinsinger  GMöller  HJ Larger amygdala volumes in first depressive episode as compared to recurrent major depression and healthy control subjects. Biol Psychiatry 2003;53338- 344
PubMed Link to Article
Strakowski  SMDelBello  MPSax  KWZimmerman  MEShear  PKHawkins  JMLarson  ER Brain magnetic resonance imaging of structural abnormalities in bipolar disorder. Arch Gen Psychiatry 1999;56254- 260
PubMed Link to Article
Zetzsche  TFrodl  TPreuss  UWSchmitt  GSeifert  DLeinsinger  GBorn  CReiser  MMöller  HJMeisenzahl  EM Amygdala volume and depressive symptoms in patients with borderline personality disorder. Biol Psychiatry 2006;60302- 310
PubMed Link to Article

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