Original Paper Received: September 19, 2014 Accepted after revision: January 12, 2015 Published online: April 25, 2015
Neuropsychobiology 2015;71:140–148 DOI: 10.1159/000375311
Decreased Right Hippocampal Volumes and Neuroprogression Markers in Adolescents with Bipolar Disorder F. Neslihan Inal-Emiroglu a Halil Resmi b Nuri Karabay c Handan Guleryuz d Burak Baykara a Nagihan Cevher a, d Aynur Akay a
a
Child and Adolescent Psychiatry Department, b Medical Biochemistry Department, and c Radiology Department, Dokuz Eylül University Medical School, and d Behçet Uz Children’s Hospital, Izmir, Turkey
Abstract Objectives: The aim of the present study was to assess differences and correlations between the hippocampal volumes (HCVs), serum nerve growth factor (NGF), and brainderived neurotrophic factor (BDNF) levels in adolescents with bipolar disorder (BP) compared to healthy controls. Methods: Using structural magnetic resonance imaging, we compared HCVs of 30 patients with euthymic BP who were already enrolled in a naturalistic clinical follow-up. For comparison, we enrolled 23 healthy controls between the ages of 13 and 19. The boundaries of the hippocampus were outlined manually. The BDNF and NGF serum levels were measured with the sandwich ELISA. Results: The groups did not differ in the right or left HCVs or in the NGF or BDNF serum levels. However, negative correlations were found between the right HCVs and the duration of the disorder and medication and positive correlations were found between the duration of the medications and the NGF and BDNF levels in the patient group. Additionally, positive correlations were found between the follow-up period and left normalized HCVs in both the BP and lithium-treated groups. Conclusions: The
© 2015 S. Karger AG, Basel 0302–282X/15/0713–0140$39.50/0 E-Mail [email protected] www.karger.com/nps
right HCVs may vary with illness duration and the medication used to treat BP; NGF and BDNF levels may be affected by long-term usage. Further research is needed to determine whether these variables and their structural correlates are associated with clinical or functional differences between adolescents with BP and healthy controls. © 2015 S. Karger AG, Basel
Introduction
Bipolar disorder (BP) is almost always characterized by a chronic and severe disorder in children and adolescents. Although the pathophysiology of BP is not adequately understood, evidence suggests that children and adolescents with BP show progressive changes in symptomatology over the course of their illness according to their age at onset [1, 2]. Over the past few years, a link between clinical observations and emerging neuroimaging findings on the progression of the disorder in children and adolescents with BP has been investigated by researchers, hoping to understand whether these data indicate aberrant neurodevelopmental processes [3]. A limbic-thalamic-cortical circuitry consisting of the amygdala, the mediodorsal nucleus of the thalamus, and F. Neslihan Inal-Emiroglu Department of Child and Adolescent Psychiatry Dokuz Eylül University Medical School TR–35340 Narlidere-Izmir (Turkey) E-Mail neslihan.emiroglu @ deu.edu.tr
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Key Words Hippocampal volumes · Adolescents · Bipolar disorder · Brain-derived neurotrophic factor · Nerve growth factor
HCVs and Neuroprogression in Adolescents with Bipolar Disorder
of neuroplasticity is still evolving rapidly during childhood and adolescence, and the effects of BDNF and NGF on neuroprogression are largely unknown. Previous hippocampal structural findings have been various and controversial in children and adolescents with BP. Notably, the effects of time and illness exposure on children and adolescents with BP have been inadequately studied. Although our study was not a prospective or longitudinal study, we followed all of our patients before and after the research process in a naturalistic way. For this reason, we had a good level of knowledge and data regarding the progression of our subjects’ illnesses. The aim of the present study was to assess differences and correlations between the HCVs, NGF, and BDNF serum levels in adolescents with BP. We hypothesized that bipolar adolescents would have smaller HCVs than healthy control subjects. We also expected to find a negative correlation between the serum levels of NGF, BDNF and HCVs in adolescents with BP as a consequence of the neuroprogressive effects of the illness.
Materials and Methods In this study, the case and healthy groups consisted of adolescents within the age range of 13–19 years. We considered that agerelated changes in the BDNF and NGF levels may occur due to different neurodevelopmental stages. In a study evaluating the agerelated changes in the serum BDNF levels of healthy individuals, the serum BDNF levels within the first 10 years were found to be the same as in the 30- to 39-year group, representing a level acceptable for adults. However, the BDNF levels began to decrease significantly within 10–19 years after reaching the adult level [22]. Experimental studies have shown age-dependent decreases in the NGF and BDNF levels in rats [23]. For that reason, our sample was divided into two groups according to age at onset before and after 15 years for some of our evaluations. Preliminary findings from this study, consisting of only HCVs for 17 adolescents with BP and for 13 healthy adolescents, were published in 2012 [24]. Here, we aimed to provide more precise results with inclusion of almost twofold increased sample size for the HCV analysis, as well as serum levels of BDNF and NGF from the entire sample. Subjects The study includes 30 adolescents with DSM-IV BP aged between 13 and 19 years. All patients at the Dokuz Eylül University Medical School, Department of Child and Adolescent Psychiatry who were already enrolled in a naturalistic clinical follow-up between June 2008 and September 2013 were included in the study. This study was approved by Dokuz Eylül University Local Ethics Committee. Diagnoses were made using the Kiddie and Young Adult Schedule for Affective Disorders and Schizophrenia Present and Lifetime Version (K-SADS P/L). This interview was translated into and adapted to Turkish, and a reliability and validity study has
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the medial and ventrolateral prefrontal cortex has been proposed to play a crucial role in the pathophysiology of mood disorders. A core area in these networks is the hippocampus (HC), which is involved in the memory and emotional regulation deficits that often accompany mood disorders [4, 5]. Child- and adolescent-onset BP may comprise more severe forms than adult-onset BP; the similarities between early-onset and treatment-resistant adult-type BP and the continuity of early-onset BP with the adult form of the illness remain unresolved [6]. Interestingly, although most studies of adults with BP found no decreases in hippocampal volume (HCV) [7, 8], the results from studies of children and adolescents have been controversial. Some studies have identified HCV decreases in young patients with BP [9–11]. In contrast, some of these studies found no differences in global HCV between children with BP and controls [12–14]. A significant positive correlation was found between hippocampal size and age in patients with bipolar disorder, whereas healthy controls showed an inverse relation [15]. The neurotrophin family consists of regulatory factors that mediate the differentiation and survival of neurons and modulate synaptic transmission and plasticity. Two members of this neurotrophin family are the nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). These factors are thought to be secreted constitutively or transiently, often in an activity-dependent manner [16]. Since these factors are essential for neuronal function and survival, it has been suggested that neuronal viability might be influenced in cases where there were persistent reductions [16]. The neurodevelopmental and neurodegenerative models of hippocampal formation structure changes and the complex relationship between HCV/neurogenesis and neurotrophic factors such as NGF and BDNF should therefore be studied in children and adolescents with BP. The HC contains the highest brain levels of neurotrophic factors [17]. Altar et al. [18] also found significant binding in the HC, in the subiculum, and in the cingulate, frontal, parietal, and occipital cortex using the techniques of radiolabeled NGF binding to brain sections. Diminished hippocampal BDNF activity impairs stem cells in the dentate gyrus, a depression-related change [19]. Indeed, unmedicated depressive patients have decreased hippocampal serum concentrations of BDNF [20]. In an animal model of mania induced by ouabain, Jornada et al. [21] found decreased BDNF levels in the HC and amygdala. The role of BDNF and NGF in BP pathophysiology has yet to be elucidated. Furthermore, the development
Medical Treatment of the Patients At the time of the MRI scanning, 11 participants were taking lithium (mean serum lithium level = 0.78 ± 0.25 mmol/l; range: 0.24–1.10 mmol/l, 2 missing). The mean duration of lithium treatment was 2.4 ± 1.37 years (range: 0.5–3), with 9 receiving concomitant treatment with a second-generation antipsychotic (SGA; risperidone, olanzapine, quetiapine, or aripiprazole). Sixteen participants were receiving sodium valproate (VPA; mean serum VPA level: 77.7 ± 15.2 mmol/l; range: 34–97 mmol/l). The mean VPA medication duration was 2.4 ± 1.2 years (range: 0.5–3); 13 of these patients also received SGA (risperidone, quetiapine, olanzapine, or aripiprazole) and 3 received VPA, SGA and lamotrigine concomitantly. Two participants were taking carbamazepine and SGA in combination (olanzapine and aripiprazole), and the remaining patient was not on medication. MRI Scans and Image Processing Subjects were scanned on a 1.5-tesla MR scanner with an 8-channel head coil (Intera, Philips, The Netherlands). Axial and coronal T1-weighted images of the whole brain were acquired
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using a three-dimensional spoiled gradient recalled echo sequence (TR = 15 ms, TE = 4.2 ms, FA = 20°, matrix = 256 × 256, 150 slices, slice thickness = 1 mm, no slice gap, FoV = 23 cm, 1 signal average and voxel size: 0.90 × 0.89 × 1.00 mm). T1-weighted images were preferred due to their superior contrast between gray and white matter. Images were transferred to a ViewForum postprocessing console and processed with Easy Vision CT/MR software (Philips Medical Systems, Eindhoven, The Netherlands) for the segmentation of tissue compartments and definition of the regions of interest. Anatomical, T1-weighted three-dimensional high-resolution coronal images acquired perpendicular to the long axis of the HC were used for HCV measurements because of the clearly superior visibility of the borders of the HC. The sagittal and axial planes were used as required, and the boundaries of the HC were outlined manually. To reduce manual tracing errors, the axial T1 MR images were magnified 4 times. The area of interest was determined by combining a thresholding technique with a region-growing algorithm for segmentation and manual tracing with a mouse-guided cursor. We used the criteria defined by Konrad et al. [30] to delineate the HC. The boundaries of the HC were defined as follows: anteriorly, the alveus was used to differentiate the amygdala from the hippocampal head, and the posterior border was defined as being bordered laterally by the white matter of the fornix, medially by cerebrospinal fluid, inferiorly by white matter, and superiorly by the splenium of the corpus callosum. All scans were reviewed by a clinical neuroradiologist to rule out gross pathology. Brain Extraction Tool (BET) software working on the FMRIB Software Library (FSL) was used to measure the whole brain volume. BET software deletes non-brain tissue from an image of the whole head. The ratio of hippocampal to whole brain volumes was used for normalized HCVs (nHCVs). Laboratory Assay All subjects underwent blood sample collection between 09: 00 a.m. and 10: 00 a.m. after overnight fasting. BDNF (Millipore, ChemiKine, CYT306) and NGF (Boster) serum levels were measured with sandwich ELISA using a commercial kit. After patients gave their blood samples, they underwent an MRI scan within 24–72 h [31].
Statistical Analyses Statistical analysis was performed using SPSS 15.0 software. Mann-Whitney U and univariate analyses of variance (ANOVA) were employed for the continuous variables, and χ2 tests for the categorical demographic variables. The Kolmogorov-Smirnov test was used to evaluate whether the data on quantitative variables (BDNF, NGF levels and HCVs) were normally distributed. Pearson’s correlations were calculated based on whether there was any relationship between two variables in both populations. Pearson’s correlations were measured for age, treatment duration (only BP group), illness duration (only BP group), and the BDNF, NGF levels, and HCVs. Spearman’s correlations were calculated for the treatment groups. The correlation among BDNF, NGF and the HCV was also investigated after the HCVs were normalized by intracranial volume to obtain a more precise relationship between the serum levels of BDNF, NGF, and HCVs. Both nHCV and nonnormalized hippocampal volume results are presented in order to increase the generalizability of our findings. A p value of less than 0.05 was considered significant.
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been conducted [25]. The affective module of Washington University at St. Louis-Kiddie and Young Adult Schedule for Affective Disorders and Schizophrenia-Present State and Lifetime (WASH-U-K-SADS) was also used. This interview was also translated into and adapted to Turkish [26]. Diagnosis was made according to DSM-IV and information from the K-SADS P/L; the affective module of WASH-U-K-SADS was used to obtain detailed mood symptomatology and chronology. In the patient group, a history of seizures, severe head injury causing a loss of consciousness longer than 10 min, history of psychostimulants, antipsychotic or antidepressant usage within 3 months before diagnosis, history of pregnancy, schizophrenia, pervasive developmental disorders, intellectual disability (total IQ ≤70), the presence of a chronic medical disorder and ongoing substance abuse were deemed exclusionary criteria. Patients who had comorbid anxiety or disruptive behavior disorders and patients who received medical treatment were still included. The comparison group consisted of 23 adolescents between 13 and 19 years of age without any psychiatric diagnosis or substance abuse, as assessed by the K-SADS P/L. They were selected from an epidemiologic catchment area of the university. In the control group, the presence of a psychiatric disorder in first-degree relatives, intellectual disability (≤70 IQ), a chronic medical condition, history of seizure, and any severe head injury that caused a loss of consciousness for longer than 10 min were exclusionary criteria. MRI data and serum samples were acquired from patients when they were euthymic. Euthymia was defined as Young Mania Rating Scale (YMRS) and Hamilton Depression Rating Scale (17item HAM-D) scores below 7. HAM-D was used and validated in adolescents with depression [27]. We also preferred the YMRS for ratings of manic symptoms. The YMRS achieved good discriminative validity when classifying children and adolescents with BP compared to other disorders [28]. According to a cohort study, the optimal YMRS severity threshold of 25 (positive predictive value = 83.0%; negative predictive value = 66.0%) was determined. In this cohort, a YMRS score of 20 (typical cutoff for randomized clinical trial inclusion criteria) corresponds to a positive predictive value of 74.6% and to a negative predictive value of 77.6%, meaning that the majority of patients included would be classified as severely ill [29].
Table 1. Clinical demographic characteristics, BDNF/NGF levels and HCVs of the BP and comparison groups
Characteristics
BP group (n = 30)
Age, years Gender Male/female Family history Onset before age 15 Duration of disorder, months Duration of medications, months Follow-up period, months HCV, mm3 Right Left nHCV, mm3 Right Left Total intracranial volume, mm3 Serum BDNF Serum NGF
Healthy comparison group (n = 23)
p
16.37±1.326
16.30±1.105
0.752
12/18 15 17 31±16.3 23.7±15.1 30±10.3
12/11
0.416
13 – –
2,987.5±297.6 2,921.4±374.7
3,067.0±432.6 2,961.9±363.8
0.542 0.590
2.2±0.2 2.1±0.2 11,305±113.0 1,734.5±899.2 29.0±10.9
2.2±0.2 2.2±0.3 13,521±124.1 2,000.0±1,160.4 25.8±12.8
0.720 0.858 0.914 0.604 0.095
Mean ± SD; χ2 (demographic variables), Mann-Whitney U (continuous variables).
Table 2. BDNF/NGF levels and HCVs of the lithium-treated and VPA-treated groups
Characteristics HCV, mm3 Right Left nHCV, mm3 Right Left Total intracranial volume, mm3 Serum BDNF Serum NGF
Lithium-treated (n = 11)
Other group (n = 19)
p
VPA-treated (n = 16)
Other group (n = 14)
p
3,102.4±385.7 2,918.5±405.2
2,920.96±217.3 2,923.08±367.3
0.237 0.753
2,941.4±208.5 2,955.4±375.6
3,040.2±376.5 2,882.5±383.7
0.430 0.747
2.2±0.2 2.1±0.2 13,677±114 1,472.8±861.6 31.5±10.0
2.1±0.2 2.1±0.3 13,489±114 1,886.0±907.8 27.5±11.4
0.232 0.703 0.832 0.071 0.144
2.2±0.2 2.2±0.3 13,416±111 1,807.7±912.5 30.9±11.1
2.2±0.2 2.1±0.2 13,719±116 1,650.9±910.4 26.8±10.7
0.697 0.313 0.448 0.373 0.989
Mean ± SD; Mann-Whitney U (continuous variables).
Demographics, Neurotrophic Factors and HCV Characteristics The demographic and other characteristics of the 30 bipolar subjects and 23 healthy comparison subjects are presented in table 1. These groups did not differ in terms of demographic variables, HCVs, nHCVs or BDNF or NGF serum levels. Univariate ANOVA with gender as a cofactor revealed that the HCV (right: F = 0.47, d.f. = 1, HCVs and Neuroprogression in Adolescents with Bipolar Disorder
p = 0.5; left: F = 2.63, d.f. = 1, p = 0.1) and nHCV (right: F = 0.079, d.f. = 1, p = 0.8; left: F = 1.3, d.f. = 1, p = 0.2) in each hemisphere did not differ significantly among the groups. Effects of Medications on Results The lithium-treated and VPA-treated groups did not differ in terms of HCVs, nHCVs or BDNF or NGF serum levels when compared to the other treatment groups. The results of this analysis are presented in table 2. Neuropsychobiology 2015;71:140–148 DOI: 10.1159/000375311
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Results
2.75
Right nHCVs
2.50
2.25
2.00
1.75 R2 linear = 0.192 0.000
1.000 2.000 3.000 4.000 Total duration of disorder (years)
5.000
Fig. 1. Correlations between the right nHCVs (×10–3 mm3) and
2.75
Lithium-nontreated group
Scale 3.0 2.5 2.0 1.5 1.0
Spearman’s r: 142, p: 0.5
Color version available online
total duration in the BP group.
Left nHCVs
2.50
2.25
2.00
1.75 R2 linear = 0.016 10.00
15.00
20.00 25.00 30.00 Follow-up period (months)
35.00
40.00
Fig. 2. Correlations between the right nHCVs (×10–3 mm3) and
total duration in the lithium-nontreated group.
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Bivariate Correlations The Kolmogorov-Smirnov test was conducted to evaluate the data on quantitative variables. According to the results of the Kolmogorov-Smirnov tests, no difference from a normal distribution was noted for BDNF levels (p = 0.4), NGF levels (p = 0.3), left nHCVs (p = 0.7), or right nHCVs (p = 0.5). There was a positive correlation between NGF and BDNF levels in the patient group (r = 0.405, p = 0.027). There were also positive correlations between the duration of medications and the NGF (r = 0.486, p = 0.006) and BDNF levels (r = 0.479, p = 0.007) in the patient group. There were negative correlations between the right nHCVs and the durations of the disorder (r = –0.43, p = 0.015; fig. 1) and medications (r = –0.43, p = 0.016). Further, a positive correlation was noted between the follow-up period and left nHCVs (r = 0.40, p = 0.02) in the BP group. In terms of treatment groups different from lithiumnontreated group (fig. 3), there was a positive correlation between the follow-up period and left nHCVs in the lithium-treated BP group (Spearman’s r = 0.76, p = 0.006; fig. 2). A negative correlation between the right nHCV and the duration of the disorder was noted in the VPA-treated group (Spearman’s r = –0.597, p = 0.001).
Discussion
The main finding of this study was a lack of significant difference between the right and left HCVs and serum levels of NGF and BDNF when comparing patients with BP with the healthy controls. We aimed to evaluate the long-term effects of the disorder, of age and treatment on hippocampal losses, as well as any potential relationship among the consequences of these effects, neurotrophins and brain plasticity. Although our study was not a prospective or longitudinal study, we followed all of our patients before and after the research process in a naturalistic way. For this reason, we had a good level of knowledge and data regarding the progression of our subjects’ illnesses. To the best of our knowledge, this is the first study to report such a relationship in adolescents with BP. To evaluate the relationships among structural changes, neurotrophins and the long-term effects of the disorder, we conducted a bivariate correlational analysis and found a positive correlation between the NGF and BDNF serum levels, as well as between both serum levels and the duration of the medication. We found a negative correlaInal-Emiroglu/Resmi/Karabay/Guleryuz/ Baykara/Cevher/Akay
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r: –0.43, p: 0.015
Color version available online
BP group
HCVs and Neuroprogression in Adolescents with Bipolar Disorder
Neuropsychobiology 2015;71:140–148 DOI: 10.1159/000375311
2.75
Left nHCVs
2.50
Scale 4.0 3.5 3.0 2.5 2.0 1.5 1.0
Spearman’s r: 0.76, p: 0.006
2.25
2.00
1.75 R2 linear = 0.741 0.00
10.00
20.00 30.00 40.00 Follow-up period (months)
50.00
Fig. 3. Correlations between the right nHCVs (×10–3 mm3) and
total duration in the lithium-treated group.
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Color version available online
tion between the right HCVs and the durations of the disorder and medications. In addition to this correlation, we found a positive relationship between the follow-up period and left nHCVs in the patient and lithium-treated groups. The hippocampal findings in youths with BP have been somewhat contradictory. Decreased HCV may be more prominent in cases of pediatric as opposed to adult BP [9, 11, 15, 32, 33]. On the other hand, some studies found no structural differences for HCVs in youths with BP, similar to our results [12–14]. However, even though we did not find any differences in terms of decreased HCVs and nHCVs between BP and healthy groups, we did find a decrease in the volume of right nHCVs over the course of illness and medication duration. Although the mechanism underlying the observed structural abnormalities is not sufficiently understood, the HC is one of the regions of the brain that is most vulnerable to neuronal loss. In fact, the HC may be one of the earliest structures to be negatively impacted by the disorder [34]. A recent study using three-dimensional modeling found significant volume reductions in HCV among
youths with BP and alterations in the volumetric changes associated with age [15]. Nevertheless, the findings of cross-sectional structural MRI studies in children and youths have been controversial. Whereas some studies have identified HCV decreases in young patients with BP [9–11], others found no differences in global HCV between children with BP and controls [12–14]. Our results suggest that youths with BP may exhibit a later development of the HC structures with continued decreases over time with a longer exposure to the illness. It seems difficult to establish a connection with the general findings of decreased volume, although this challenge may be related to alterations in the timing of normal hippocampal development in youths with BP. Furthermore, it remains possible that there are heterogeneous alterations in HCVs over time; future research should explore the reasons behind this possibility. Although illness-related changes in children and adolescents with BP are often interpreted as evidence of neurodevelopmental abnormalities, the role of the underlying neurophysiological progression related to recurrent affective episodes has not been sufficiently investigated as a reason for potential alterations in the neurodevelopmental trajectories or in other progressive changes by evaluating the correlations of structural measurements with age or with measures of illness burden and treatment (e.g., duration of illness and medication). Furthermore, we tested the associations among these biological variables and such clinical measures as the duration of the disorder, age at onset and treatment. There are positive correlations between the duration of the medications and both the NGF and BDNF levels in a patient group. Limited studies and results exist regarding BDNF and NGF in the pathophysiology of children and adolescents with BP. One previous study on youths with BP found that the BDNF mRNA levels in the lymphocytes and BDNF protein levels in the platelets of drug-free subjects were significantly lower compared to those of normal control subjects and that long-term treatment with mood-stabilizing drugs significantly increased the levels of BDNF mRNA in subjects with BP [35]. Our study indicated that long-term exposure to lithium and VPA may lead to greater increases in the BDNF and NGF levels of youths with early-onset BP. Recently, it has been shown that chronic treatment with either mood stabilizers, such as lithium, or VPA increases BDNF immunoreactivity in rat frontal cortices, potentially enhancing the synaptic plasticity related to BDNF [36, 37]. Furthermore, a considerable amount of evidence suggests that aberrations in the regulation of
Lithium-treated group
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mates from our preliminary findings [24]. We followed these patients for a long time in a naturalistic manner. However, for more reliable results, further longitudinal follow-up studies are needed with large enough sample sizes to sort out developmental and medication influences on the brain structures over time in the BP population. Since all BP patients are in a euthymic state, this study also attempted to determine the state-trait plasticity of HC. Even though we had a good level of knowledge regarding the follow-up of our BP patients, the main limitation of the current study is its cross-sectional design as adolescent brains are developing and it would be difficult to differentiate the impact of an illness or of psychiatric medications on a developing brain. In addition, larger sample sizes are needed to produce more reliable results, according to power analysis. All observed correlations between two or more variables may not represent causality and there may be unexplained variance due to variables not included in the analysis. Different durations of exposure to lithium and VPA, in addition to the effects of polypharmacy from using several atypical antipsychotics, may have led to heterogeneous effects on the brain structures. Additionally, the 1.5-tesla scanner is not powerful enough for hippocampal imaging compared to 3- and 7-tesla scanners in terms of resolution. Further research is needed to determine the structural correlates associated with clinical, treatment or functional differences in early-onset BP.
Acknowledgments The authors acknowledge Dr. Ellen Leibenluft for her invaluable editorial contributions and Drs. Hulya Ellidokuz and Ahmet Topuzoglu for their invaluable help during statistical analyses. The manuscript was edited by American Journal Experts (AJE) editing services in terms of language and grammatical rules. However, the authors are entirely responsible for the scientific content of the article. This study was supported by the Dokuz Eylül University Foundation of Scientific Research Projects (BAP) and was partly supported by the Research Support Award 2008 of the International Society for Bipolar Disorders-affiliated Society for Bipolar Disorders-Turkey.
Disclosure Statement Drs. Inal-Emiroglu, Resmi, Karabay, Guleryuz, Baykara, and Cevher have no potential conflict of interest. Dr. Akay is a member of the scientific council of Janssen Cilag and Lilly drug companies in Turkey.
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neurotrophic signaling play a role in the pathophysiology of BP and certainly appear to be relevant targets for the action of mood stabilizers. These data raise the possibility that early intervention to prevent certain atrophic changes via neurotrophic factors, such as BDNF and NGF, could have major beneficial effects on the course and trajectory of BP. The available data suggest that lithium or VPA might have utility in the treatment of degenerative disorders. Although such drugs would certainly not ‘cure’ these illnesses, any impact that they might have on slowing down disease progression should prove worthwhile [16]. In our cases, psychotropic agents (atypical antipsychotics) and mood stabilizers (lithium and VPA) were potentially found to act via NGF and BDNF as neurotrophic factors, compensating for the destructive effects of this disorder. On the other hand, although both BDNF and NGF serum levels were increased in the course of illness along with medication usage, these increases could not prevent the loss in the right HCVs over time. Inversely, in all BP groups and the lithium-treated group, there was a relationship between increased left HCVs and the follow-up period that could reflect the positive effects of treatment and, especially, of lithium treatment. The neuroprotective effects of lithium have been well documented in experimental animal models [38, 39], and several neuroimaging studies have reported findings suggestive of similar effects of lithium in humans [40–44]. A recent meta-analysis found significantly smaller bilateral HCVs in nontreated lithium patients with BP compared to healthy controls and lithium-treated patients with BP [45]. Another study investigated the effects of lithium, anticonvulsants and antipsychotics on brain structure in BP, finding gray matter in the subgenual anterior cingulate gyrus on the right (extending into the hypothalamus) and in the postcentral gyrus. The HC/amygdala complex and the insula on the left were greater in BP patients on lithium treatment when compared to all other treatment groups [46]. In our study, we found a decreased right HCV when the duration of the illness and medication usage were increasing, but we did not see the same results in the lithium-treated group and healthy groups, similar to previous studies. These findings support a neuroprotective role for lithium against early-onset BP. The child- and adolescent-onset BP group has the advantage of being able to reflect the early neurodevelopmental period of the illness as well as the fact that longterm effects, including medication effects, have not yet to be seen. To fully investigate these effects, we increased our sample size in order to increase the precision of our esti-
References
HCVs and Neuroprogression in Adolescents with Bipolar Disorder
14
15
16
17
18
19 20 21
22
23
24
van MS, Ryan ND, Birmaher B, Soares JC: Cross-sectional study of abnormal amygdala development in adolescents and young adults with bipolar disorder. Biol Psychiatry 2004; 56:399–405. Dickstein DP, Milham MP, Nugent AC, Drevets WC, Charney DS, Pine DS, Leibenluft E: Frontotemporal alterations in pediatric bipolar disorder: results of a voxel-based morphometry study. Arch Gen Psychiatry 2005; 62:734–741. Bearden CE, Soares JC, Klunder AD, Nicoletti M, Dierschke N, Hayashi KM, Narr KL, Brambilla P, Sass RB, Axelson D, Ryan N, Birmaher B, Thompson PM: Three-dimensional mapping of hippocampal anatomy in adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 2008;47:515– 525. Shaltiel G, Chen G, Manji HK: Neurotrophic signaling cascades in the pathophysiology and treatment of bipolar disorder. Curr Opin Pharmacol 2007;7:22–26. Suzuki F, Junier MP, Guilhem D, Sorensen JC, Onteniente B: Morphogenetic effect of kainite on adult hippocampal neurons associated with a prolonged expression of brain-derived neurotrophic factor. Neurosciences 1995;64:665–674. Altar CA, Dugich-Djordjevic M, Armanini M, Bakhit C: Medial-to-lateral gradient of neostriatal NGF receptors: relationship to cholinergic neurons and NGF like immunoreactivity. J Neurosci 1991;11:828–836. Duman RS, Monteggia LM: A neurotrophic model for stress-related mood disorders Biol Psychiatry 2006;59:1116–1127. Groves JO: Is it time to reassess the BDNF hypothesis of depression? Mol Psychiatry 2007; 12:1079–1088. Jornada LK, Moretti M, Valvassori SS, Ferreira CL, Padilha PT, Arent CO, Fries GR, Kapczinski F, Quevedo J: Effects of mood stabilizers on hippocampus and amygdala BDNF levels in an animal model of mania induced by ouabain. J Psychiatr Res 2010; 44: 506–510. Katoh-Semba R, Wakako R, Komori T, Shigemi H, Miyazaki N, Ito H, Kumagai T, Tsuzuki M, Shigemi K, Yoshida F, Nakayama A: Age-related changes in BDNF protein levels in human serum: differences between autism cases and normal controls. Int J Dev Neurosci 2007;25:367–372. Perovic M, Tesic V, Djordjevic AM, Smiljanic K, Loncarevic-Vasiljkovic N, Ruzdijic S, Kanazir S: BDNF transcripts, proBDNF and proNGF, in the cortex and hippocampus throughout the life span of the rat. Age 2013; 35:2057–2070. Baykara B, Inal-Emiroglu N, Karabay N, Çakmakçı H, Cevher N, Şentürk Pilan B, Alşen S: Increased HCVs in lithium treated adolescents with bipolar disorders: a structural MRI study. J Affect Disord 2012;138:433–439.
25 Gökler B, Ünal F, Pehlivantürk B, ÇengelKültür E, Akdemir D, Taner Y: Reliability and validity of schedule for affective disorders and schizophrenia for school age children present and lifetime version – Turkish version (KSADS-PL-T). Çocuk ve Gençlik Ruh Saglıgı Dergisi 2004;11:109–116. 26 Inal-Emiroglu FN, Baykara B, Miral S: A case series of Turkish children and adolescents with bipolar spectrum disorder: a naturalistic clinical phenomenological follow-up. Minerva Pediatr 2008;60:51–57. 27 Robbins DR, Alessi NE, Colfer MV, Yanchyshyn GW: Use of the Hamilton Rating Scale for Depression and the Carroll Self-Rating Scale in adolescents. Psychiatry Res 1985; 14:123–129. 28 Yee AM, Algorta GP, Youngstrom EA, Findling RL, Birmaher B, Fristad MA; The Lams Group: Unfiltered administration of the YMRS and CDRS-R in a clinical sample of children. J Clin Child Adolesc Psychol 2014;2:1–16. 29 Lukasiewicz M, Gerard S, Besnard A, Falissard B, Perrin E, Sapin H, Tohen M, Reed C, Azorin JM; Emblem Study Group: Young Mania Rating Scale: how to interpret the numbers? Determination of a severity threshold and of the minimal clinically significant difference in the EMBLEM cohort. Int J Methods Psychiatr Res 2013;22:46–58. 30 Konrad C, Ukas T, Nebel C, Arolt V, Toga AW, Narr KL: Defining the human hippocampus in cerebral magnetic resonance images – an overview of current segmentation protocols. Neuroimage 2009;47:1185–1195. 31 Lang UE, Hellweg R, Seifert F, Schubert F, Gallinat J: Correlation between serum brainderived neurotrophic factor level and an in vivo marker of cortical integrity. Biol Psychiatry 2007;62:530–535. 32 Frazier JA, Ahn MS, DeJong S, Bent EK, Breeze JL, Giuliano AJ: Magnetic resonance imaging studies in early-onset bipolar disorder: a critical review. Harv Rev Psychiatry 2005;13:125–140. 33 MacMaster FP, Carrey N, Langevin LM, Jaworska N, Crawford S: Disorder-specific volumetric brain difference in adolescent major depressive disorder and bipolar depression. Brain Imaging Behav 2014;8:119–127. 34 Sapolsky RM: The possibility of neurotoxicity in the hippocampus in major depression: a primer on neuron death. Biol Psychiatry 2000;48:755–765. 35 Pandey GN, Hooriyah SR, Yogesh D, Pavuluri MN: Brain-derived neurotrophic factor gene expression in pediatric bipolar disorder: effects of treatment and clinical response. J Am Acad Child Adolesc Psychiatry 2008; 9: 1077–1085. 36 Einat H, Yuan P, Gould TD, Li J, Du J, Zhang L, Manji HK, Chen G: The role of the extracellular signal-regulated kinase signaling pathway in mood modulation. J Neurosci 2003;23: 7311–7316.
Neuropsychobiology 2015;71:140–148 DOI: 10.1159/000375311
147
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1 Axelson D, Birmaher B, Strober M, Gill MK, Valeri S, Chiappetta L, Ryan N, Leonard H, Hunt J, Iyengar S, Bridge J, Keller M: Phenomenology of children and adolescents with bipolar spectrum disorders. Arch Gen Psychiatry 2006;63:1139–1148. 2 Birmaher B, Axelson D, Goldstein B, Strober M, Gill MK, Hunt J, Houck P, Ha W, Iyengar S, Kim E, Yen S, Hower H, Esposito-Smythers C, Goldstein T, Ryan N, Keller M: Four-year longitudinal course of children and adolescents with bipolar spectrum disorders: the Course and Outcome of Bipolar Youth (COBY) study. Am J Psychiatry 2009; 166: 795–804. 3 Schneider MR, DelBello MP, McNamara RK, Strakowski SM, Adler CM: Neuroprogression in bipolar disorder. Bipolar Disord 2012; 14: 356–374. 4 Kronmüller KT, Schröder J, Köhler S, Götz B, Victor D, Unger J, Giesel F, Magnotta V, Mundt C, Essig M, Pantel J: Hippocampal volume in first episode and recurrent depression. Psychiatry Res 2009;174:62–66. 5 Soares JC, Mann JJ: The anatomy of mood disorders – review of structural neuroimaging studies. Biol Psychiatry 1997;41:86–106. 6 Goldstein BI, Birmaher B: Prevalence, clinical presentation and differential diagnosis of pediatric bipolar disorder. Isr J Psychiatry Relat Sci 2012;49:3–14. 7 Brambilla P, Glahn DC, Balestrieri M, Soares JC: Magnetic resonance findings in bipolar disorder. Psychiatr Clin North Am 2005; 28: 443–467. 8 McDonald C, Zanelli J, Rabe-Hesketh S, Ellison-Wright I, Sham P, Kalidindi S, Murray RM, Kennedy N: Meta-analysis of magnetic resonance imaging brain morphometry studies in bipolar disorder. Biol Psychiatry 2004; 56:411–417. 9 Blumberg HP, Kaufman J, Martin A, Whiteman R, Zhang JH, Gore JC, Charney DS, Krystal JH, Peterson BS: Amygdala and HCVs in adolescents and adults with bipolar disorder. Arch Gen Psychiatry 2003; 60: 1201–1208. 10 Brambilla P, Hatch JP, Soares JC: Limbic changes identified by imaging in bipolar patients. Curr Psychiatry Rep 2008;10:505–509. 11 Frazier JA, Chiu S, Breeze JL, Makris N, Lange N, Kennedy DN, Herbert MR, Bent EK, Koneru K, Dieterich ME, Hodge SM, Rauch SL, Grant PE, Cohen BM, Seidman LJ, Caviness VS, Biederman J: Structural brain magnetic resonance imaging of limbic and thalamic volumes in pediatric bipolar disorder. Am J Psychiatry 2005;162:1256–1265. 12 Chang K, Karchemskiy A, Barnea-Goraly N, Garrett A, Simeonova DI, Reiss A: Reduced amygdalar gray matter volume in familial pediatric bipolar disorder. J Am Acad Child Adolesc Psychiatry 2005;44:565–573. 13 Chen BK, Sassi R, Axelson D, Hatch JP, Sanches M, Nicoletti M, Brambilla P, Kesha-
148
McDonald C: Structural magnetic resonance imaging in bipolar disorder: an international collaborative mega-analysis of individual adult patient data. Biol Psychiatry 2011; 69: 326–335. 41 Moore GJ, Bebchuk JM, Wilds IB, Chen G, Manji HK: Lithium-induced increase in human brain gray matter. Lancet 2000; 356: 1241–1242. 42 Moore GJ, Bebchuk JM, Hasanat K, Chen G, Seraji-Bozorgzad N, Wilds IB, Faulk MW, Koch S, Glitz DA, Jolkovsky L, Manji HK: Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2’s neurotrophic effects? Biol Psychiatry 2000;48:1–8. 43 Sassi RB, Nicoletti M, Brambilla P, Mallinger AG, Frank E, Kupfer DJ, Keshavan MS, Soares JC: Increased gray matter volume in lithium-
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treated bipolar disorder patients. Neurosci Lett 2002;329:243–245. 44 Yucel K, McKinnon MC, Taylor VH, Macdonald K, Alda M, Young LT, MacQueen GM: Bilateral hippocampal increases after longterm lithium treatment in patients with bipolar disorder: a longitudinal MRI study. Psychopharmacology (Berl) 2007;195:357–367. 45 Hajek T, Kopecek M, Höschl C, Alda M: Smaller hippocampal volumes in patients with bipolar disorder are masked by exposure to lithium: a meta-analysis. J Psychiatry Neurosci 2012;37:333–343. 46 Germana C, Kempton MJ, Sarnicola A, Christodoulou T, Haldane M, Hadjulis M, Girardi P, Tatarelli R, Frangou S: The effects of lithium and anticonvulsants on brain structure in bipolar disorder. Acta Psychiatr Scand 2010;122:481–487.
Inal-Emiroglu/Resmi/Karabay/Guleryuz/ Baykara/Cevher/Akay
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37 Fukumoto T, Morinobu S, Okamoto Y, Kagaya A, Yamawaki S: Chronic lithium treatment increases the expression of brain-derived neurotrophic factor in the rat brain. Psychopharmacology (Berl) 2001;158:100–106. 38 Gould TD, Picchini AM, Einat H, Manji HK: Targeting glycogen synthase kinase-3 in the CNS: implications for the development of new treatments for mood disorders. Curr Drug Targets 2006;7:1399–1409. 39 Zarate CA Jr, Singh J, Manji HK: Cellular plasticity cascades: targets for the development of novel therapeutics for bipolar disorder. Biol Psychiatry 2006;59:1006–1020. 40 Hallahan B, Newell J, Soares JC, Brambilla P, Strakowski SM, Fleck DE, Kieseppä T, Altshuler LL, Fornito A, Malhi GS, McIntosh AM, Yurgelun-Todd D, Labar KS, Sharma V, MacQueen GM, Murray RM,
Neuropsychobiology 2015;71:140–148 DOI: 10.1159/000375311
Decreased Right Hippocampal Volumes and Neuroprogression Markers in Adolescents with Bipolar Disorder F. Neslihan Inal-Emiroglu a Halil Resmi b Nuri Karabay c Handan Guleryuz d Burak Baykara a Nagihan Cevher a, d Aynur Akay a
a
Child and Adolescent Psychiatry Department, b Medical Biochemistry Department, and c Radiology Department, Dokuz Eylül University Medical School, and d Behçet Uz Children’s Hospital, Izmir, Turkey
Abstract Objectives: The aim of the present study was to assess differences and correlations between the hippocampal volumes (HCVs), serum nerve growth factor (NGF), and brainderived neurotrophic factor (BDNF) levels in adolescents with bipolar disorder (BP) compared to healthy controls. Methods: Using structural magnetic resonance imaging, we compared HCVs of 30 patients with euthymic BP who were already enrolled in a naturalistic clinical follow-up. For comparison, we enrolled 23 healthy controls between the ages of 13 and 19. The boundaries of the hippocampus were outlined manually. The BDNF and NGF serum levels were measured with the sandwich ELISA. Results: The groups did not differ in the right or left HCVs or in the NGF or BDNF serum levels. However, negative correlations were found between the right HCVs and the duration of the disorder and medication and positive correlations were found between the duration of the medications and the NGF and BDNF levels in the patient group. Additionally, positive correlations were found between the follow-up period and left normalized HCVs in both the BP and lithium-treated groups. Conclusions: The
© 2015 S. Karger AG, Basel 0302–282X/15/0713–0140$39.50/0 E-Mail [email protected] www.karger.com/nps
right HCVs may vary with illness duration and the medication used to treat BP; NGF and BDNF levels may be affected by long-term usage. Further research is needed to determine whether these variables and their structural correlates are associated with clinical or functional differences between adolescents with BP and healthy controls. © 2015 S. Karger AG, Basel
Introduction
Bipolar disorder (BP) is almost always characterized by a chronic and severe disorder in children and adolescents. Although the pathophysiology of BP is not adequately understood, evidence suggests that children and adolescents with BP show progressive changes in symptomatology over the course of their illness according to their age at onset [1, 2]. Over the past few years, a link between clinical observations and emerging neuroimaging findings on the progression of the disorder in children and adolescents with BP has been investigated by researchers, hoping to understand whether these data indicate aberrant neurodevelopmental processes [3]. A limbic-thalamic-cortical circuitry consisting of the amygdala, the mediodorsal nucleus of the thalamus, and F. Neslihan Inal-Emiroglu Department of Child and Adolescent Psychiatry Dokuz Eylül University Medical School TR–35340 Narlidere-Izmir (Turkey) E-Mail neslihan.emiroglu @ deu.edu.tr
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Key Words Hippocampal volumes · Adolescents · Bipolar disorder · Brain-derived neurotrophic factor · Nerve growth factor
HCVs and Neuroprogression in Adolescents with Bipolar Disorder
of neuroplasticity is still evolving rapidly during childhood and adolescence, and the effects of BDNF and NGF on neuroprogression are largely unknown. Previous hippocampal structural findings have been various and controversial in children and adolescents with BP. Notably, the effects of time and illness exposure on children and adolescents with BP have been inadequately studied. Although our study was not a prospective or longitudinal study, we followed all of our patients before and after the research process in a naturalistic way. For this reason, we had a good level of knowledge and data regarding the progression of our subjects’ illnesses. The aim of the present study was to assess differences and correlations between the HCVs, NGF, and BDNF serum levels in adolescents with BP. We hypothesized that bipolar adolescents would have smaller HCVs than healthy control subjects. We also expected to find a negative correlation between the serum levels of NGF, BDNF and HCVs in adolescents with BP as a consequence of the neuroprogressive effects of the illness.
Materials and Methods In this study, the case and healthy groups consisted of adolescents within the age range of 13–19 years. We considered that agerelated changes in the BDNF and NGF levels may occur due to different neurodevelopmental stages. In a study evaluating the agerelated changes in the serum BDNF levels of healthy individuals, the serum BDNF levels within the first 10 years were found to be the same as in the 30- to 39-year group, representing a level acceptable for adults. However, the BDNF levels began to decrease significantly within 10–19 years after reaching the adult level [22]. Experimental studies have shown age-dependent decreases in the NGF and BDNF levels in rats [23]. For that reason, our sample was divided into two groups according to age at onset before and after 15 years for some of our evaluations. Preliminary findings from this study, consisting of only HCVs for 17 adolescents with BP and for 13 healthy adolescents, were published in 2012 [24]. Here, we aimed to provide more precise results with inclusion of almost twofold increased sample size for the HCV analysis, as well as serum levels of BDNF and NGF from the entire sample. Subjects The study includes 30 adolescents with DSM-IV BP aged between 13 and 19 years. All patients at the Dokuz Eylül University Medical School, Department of Child and Adolescent Psychiatry who were already enrolled in a naturalistic clinical follow-up between June 2008 and September 2013 were included in the study. This study was approved by Dokuz Eylül University Local Ethics Committee. Diagnoses were made using the Kiddie and Young Adult Schedule for Affective Disorders and Schizophrenia Present and Lifetime Version (K-SADS P/L). This interview was translated into and adapted to Turkish, and a reliability and validity study has
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the medial and ventrolateral prefrontal cortex has been proposed to play a crucial role in the pathophysiology of mood disorders. A core area in these networks is the hippocampus (HC), which is involved in the memory and emotional regulation deficits that often accompany mood disorders [4, 5]. Child- and adolescent-onset BP may comprise more severe forms than adult-onset BP; the similarities between early-onset and treatment-resistant adult-type BP and the continuity of early-onset BP with the adult form of the illness remain unresolved [6]. Interestingly, although most studies of adults with BP found no decreases in hippocampal volume (HCV) [7, 8], the results from studies of children and adolescents have been controversial. Some studies have identified HCV decreases in young patients with BP [9–11]. In contrast, some of these studies found no differences in global HCV between children with BP and controls [12–14]. A significant positive correlation was found between hippocampal size and age in patients with bipolar disorder, whereas healthy controls showed an inverse relation [15]. The neurotrophin family consists of regulatory factors that mediate the differentiation and survival of neurons and modulate synaptic transmission and plasticity. Two members of this neurotrophin family are the nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). These factors are thought to be secreted constitutively or transiently, often in an activity-dependent manner [16]. Since these factors are essential for neuronal function and survival, it has been suggested that neuronal viability might be influenced in cases where there were persistent reductions [16]. The neurodevelopmental and neurodegenerative models of hippocampal formation structure changes and the complex relationship between HCV/neurogenesis and neurotrophic factors such as NGF and BDNF should therefore be studied in children and adolescents with BP. The HC contains the highest brain levels of neurotrophic factors [17]. Altar et al. [18] also found significant binding in the HC, in the subiculum, and in the cingulate, frontal, parietal, and occipital cortex using the techniques of radiolabeled NGF binding to brain sections. Diminished hippocampal BDNF activity impairs stem cells in the dentate gyrus, a depression-related change [19]. Indeed, unmedicated depressive patients have decreased hippocampal serum concentrations of BDNF [20]. In an animal model of mania induced by ouabain, Jornada et al. [21] found decreased BDNF levels in the HC and amygdala. The role of BDNF and NGF in BP pathophysiology has yet to be elucidated. Furthermore, the development
Medical Treatment of the Patients At the time of the MRI scanning, 11 participants were taking lithium (mean serum lithium level = 0.78 ± 0.25 mmol/l; range: 0.24–1.10 mmol/l, 2 missing). The mean duration of lithium treatment was 2.4 ± 1.37 years (range: 0.5–3), with 9 receiving concomitant treatment with a second-generation antipsychotic (SGA; risperidone, olanzapine, quetiapine, or aripiprazole). Sixteen participants were receiving sodium valproate (VPA; mean serum VPA level: 77.7 ± 15.2 mmol/l; range: 34–97 mmol/l). The mean VPA medication duration was 2.4 ± 1.2 years (range: 0.5–3); 13 of these patients also received SGA (risperidone, quetiapine, olanzapine, or aripiprazole) and 3 received VPA, SGA and lamotrigine concomitantly. Two participants were taking carbamazepine and SGA in combination (olanzapine and aripiprazole), and the remaining patient was not on medication. MRI Scans and Image Processing Subjects were scanned on a 1.5-tesla MR scanner with an 8-channel head coil (Intera, Philips, The Netherlands). Axial and coronal T1-weighted images of the whole brain were acquired
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using a three-dimensional spoiled gradient recalled echo sequence (TR = 15 ms, TE = 4.2 ms, FA = 20°, matrix = 256 × 256, 150 slices, slice thickness = 1 mm, no slice gap, FoV = 23 cm, 1 signal average and voxel size: 0.90 × 0.89 × 1.00 mm). T1-weighted images were preferred due to their superior contrast between gray and white matter. Images were transferred to a ViewForum postprocessing console and processed with Easy Vision CT/MR software (Philips Medical Systems, Eindhoven, The Netherlands) for the segmentation of tissue compartments and definition of the regions of interest. Anatomical, T1-weighted three-dimensional high-resolution coronal images acquired perpendicular to the long axis of the HC were used for HCV measurements because of the clearly superior visibility of the borders of the HC. The sagittal and axial planes were used as required, and the boundaries of the HC were outlined manually. To reduce manual tracing errors, the axial T1 MR images were magnified 4 times. The area of interest was determined by combining a thresholding technique with a region-growing algorithm for segmentation and manual tracing with a mouse-guided cursor. We used the criteria defined by Konrad et al. [30] to delineate the HC. The boundaries of the HC were defined as follows: anteriorly, the alveus was used to differentiate the amygdala from the hippocampal head, and the posterior border was defined as being bordered laterally by the white matter of the fornix, medially by cerebrospinal fluid, inferiorly by white matter, and superiorly by the splenium of the corpus callosum. All scans were reviewed by a clinical neuroradiologist to rule out gross pathology. Brain Extraction Tool (BET) software working on the FMRIB Software Library (FSL) was used to measure the whole brain volume. BET software deletes non-brain tissue from an image of the whole head. The ratio of hippocampal to whole brain volumes was used for normalized HCVs (nHCVs). Laboratory Assay All subjects underwent blood sample collection between 09: 00 a.m. and 10: 00 a.m. after overnight fasting. BDNF (Millipore, ChemiKine, CYT306) and NGF (Boster) serum levels were measured with sandwich ELISA using a commercial kit. After patients gave their blood samples, they underwent an MRI scan within 24–72 h [31].
Statistical Analyses Statistical analysis was performed using SPSS 15.0 software. Mann-Whitney U and univariate analyses of variance (ANOVA) were employed for the continuous variables, and χ2 tests for the categorical demographic variables. The Kolmogorov-Smirnov test was used to evaluate whether the data on quantitative variables (BDNF, NGF levels and HCVs) were normally distributed. Pearson’s correlations were calculated based on whether there was any relationship between two variables in both populations. Pearson’s correlations were measured for age, treatment duration (only BP group), illness duration (only BP group), and the BDNF, NGF levels, and HCVs. Spearman’s correlations were calculated for the treatment groups. The correlation among BDNF, NGF and the HCV was also investigated after the HCVs were normalized by intracranial volume to obtain a more precise relationship between the serum levels of BDNF, NGF, and HCVs. Both nHCV and nonnormalized hippocampal volume results are presented in order to increase the generalizability of our findings. A p value of less than 0.05 was considered significant.
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been conducted [25]. The affective module of Washington University at St. Louis-Kiddie and Young Adult Schedule for Affective Disorders and Schizophrenia-Present State and Lifetime (WASH-U-K-SADS) was also used. This interview was also translated into and adapted to Turkish [26]. Diagnosis was made according to DSM-IV and information from the K-SADS P/L; the affective module of WASH-U-K-SADS was used to obtain detailed mood symptomatology and chronology. In the patient group, a history of seizures, severe head injury causing a loss of consciousness longer than 10 min, history of psychostimulants, antipsychotic or antidepressant usage within 3 months before diagnosis, history of pregnancy, schizophrenia, pervasive developmental disorders, intellectual disability (total IQ ≤70), the presence of a chronic medical disorder and ongoing substance abuse were deemed exclusionary criteria. Patients who had comorbid anxiety or disruptive behavior disorders and patients who received medical treatment were still included. The comparison group consisted of 23 adolescents between 13 and 19 years of age without any psychiatric diagnosis or substance abuse, as assessed by the K-SADS P/L. They were selected from an epidemiologic catchment area of the university. In the control group, the presence of a psychiatric disorder in first-degree relatives, intellectual disability (≤70 IQ), a chronic medical condition, history of seizure, and any severe head injury that caused a loss of consciousness for longer than 10 min were exclusionary criteria. MRI data and serum samples were acquired from patients when they were euthymic. Euthymia was defined as Young Mania Rating Scale (YMRS) and Hamilton Depression Rating Scale (17item HAM-D) scores below 7. HAM-D was used and validated in adolescents with depression [27]. We also preferred the YMRS for ratings of manic symptoms. The YMRS achieved good discriminative validity when classifying children and adolescents with BP compared to other disorders [28]. According to a cohort study, the optimal YMRS severity threshold of 25 (positive predictive value = 83.0%; negative predictive value = 66.0%) was determined. In this cohort, a YMRS score of 20 (typical cutoff for randomized clinical trial inclusion criteria) corresponds to a positive predictive value of 74.6% and to a negative predictive value of 77.6%, meaning that the majority of patients included would be classified as severely ill [29].
Table 1. Clinical demographic characteristics, BDNF/NGF levels and HCVs of the BP and comparison groups
Characteristics
BP group (n = 30)
Age, years Gender Male/female Family history Onset before age 15 Duration of disorder, months Duration of medications, months Follow-up period, months HCV, mm3 Right Left nHCV, mm3 Right Left Total intracranial volume, mm3 Serum BDNF Serum NGF
Healthy comparison group (n = 23)
p
16.37±1.326
16.30±1.105
0.752
12/18 15 17 31±16.3 23.7±15.1 30±10.3
12/11
0.416
13 – –
2,987.5±297.6 2,921.4±374.7
3,067.0±432.6 2,961.9±363.8
0.542 0.590
2.2±0.2 2.1±0.2 11,305±113.0 1,734.5±899.2 29.0±10.9
2.2±0.2 2.2±0.3 13,521±124.1 2,000.0±1,160.4 25.8±12.8
0.720 0.858 0.914 0.604 0.095
Mean ± SD; χ2 (demographic variables), Mann-Whitney U (continuous variables).
Table 2. BDNF/NGF levels and HCVs of the lithium-treated and VPA-treated groups
Characteristics HCV, mm3 Right Left nHCV, mm3 Right Left Total intracranial volume, mm3 Serum BDNF Serum NGF
Lithium-treated (n = 11)
Other group (n = 19)
p
VPA-treated (n = 16)
Other group (n = 14)
p
3,102.4±385.7 2,918.5±405.2
2,920.96±217.3 2,923.08±367.3
0.237 0.753
2,941.4±208.5 2,955.4±375.6
3,040.2±376.5 2,882.5±383.7
0.430 0.747
2.2±0.2 2.1±0.2 13,677±114 1,472.8±861.6 31.5±10.0
2.1±0.2 2.1±0.3 13,489±114 1,886.0±907.8 27.5±11.4
0.232 0.703 0.832 0.071 0.144
2.2±0.2 2.2±0.3 13,416±111 1,807.7±912.5 30.9±11.1
2.2±0.2 2.1±0.2 13,719±116 1,650.9±910.4 26.8±10.7
0.697 0.313 0.448 0.373 0.989
Mean ± SD; Mann-Whitney U (continuous variables).
Demographics, Neurotrophic Factors and HCV Characteristics The demographic and other characteristics of the 30 bipolar subjects and 23 healthy comparison subjects are presented in table 1. These groups did not differ in terms of demographic variables, HCVs, nHCVs or BDNF or NGF serum levels. Univariate ANOVA with gender as a cofactor revealed that the HCV (right: F = 0.47, d.f. = 1, HCVs and Neuroprogression in Adolescents with Bipolar Disorder
p = 0.5; left: F = 2.63, d.f. = 1, p = 0.1) and nHCV (right: F = 0.079, d.f. = 1, p = 0.8; left: F = 1.3, d.f. = 1, p = 0.2) in each hemisphere did not differ significantly among the groups. Effects of Medications on Results The lithium-treated and VPA-treated groups did not differ in terms of HCVs, nHCVs or BDNF or NGF serum levels when compared to the other treatment groups. The results of this analysis are presented in table 2. Neuropsychobiology 2015;71:140–148 DOI: 10.1159/000375311
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Results
2.75
Right nHCVs
2.50
2.25
2.00
1.75 R2 linear = 0.192 0.000
1.000 2.000 3.000 4.000 Total duration of disorder (years)
5.000
Fig. 1. Correlations between the right nHCVs (×10–3 mm3) and
2.75
Lithium-nontreated group
Scale 3.0 2.5 2.0 1.5 1.0
Spearman’s r: 142, p: 0.5
Color version available online
total duration in the BP group.
Left nHCVs
2.50
2.25
2.00
1.75 R2 linear = 0.016 10.00
15.00
20.00 25.00 30.00 Follow-up period (months)
35.00
40.00
Fig. 2. Correlations between the right nHCVs (×10–3 mm3) and
total duration in the lithium-nontreated group.
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Bivariate Correlations The Kolmogorov-Smirnov test was conducted to evaluate the data on quantitative variables. According to the results of the Kolmogorov-Smirnov tests, no difference from a normal distribution was noted for BDNF levels (p = 0.4), NGF levels (p = 0.3), left nHCVs (p = 0.7), or right nHCVs (p = 0.5). There was a positive correlation between NGF and BDNF levels in the patient group (r = 0.405, p = 0.027). There were also positive correlations between the duration of medications and the NGF (r = 0.486, p = 0.006) and BDNF levels (r = 0.479, p = 0.007) in the patient group. There were negative correlations between the right nHCVs and the durations of the disorder (r = –0.43, p = 0.015; fig. 1) and medications (r = –0.43, p = 0.016). Further, a positive correlation was noted between the follow-up period and left nHCVs (r = 0.40, p = 0.02) in the BP group. In terms of treatment groups different from lithiumnontreated group (fig. 3), there was a positive correlation between the follow-up period and left nHCVs in the lithium-treated BP group (Spearman’s r = 0.76, p = 0.006; fig. 2). A negative correlation between the right nHCV and the duration of the disorder was noted in the VPA-treated group (Spearman’s r = –0.597, p = 0.001).
Discussion
The main finding of this study was a lack of significant difference between the right and left HCVs and serum levels of NGF and BDNF when comparing patients with BP with the healthy controls. We aimed to evaluate the long-term effects of the disorder, of age and treatment on hippocampal losses, as well as any potential relationship among the consequences of these effects, neurotrophins and brain plasticity. Although our study was not a prospective or longitudinal study, we followed all of our patients before and after the research process in a naturalistic way. For this reason, we had a good level of knowledge and data regarding the progression of our subjects’ illnesses. To the best of our knowledge, this is the first study to report such a relationship in adolescents with BP. To evaluate the relationships among structural changes, neurotrophins and the long-term effects of the disorder, we conducted a bivariate correlational analysis and found a positive correlation between the NGF and BDNF serum levels, as well as between both serum levels and the duration of the medication. We found a negative correlaInal-Emiroglu/Resmi/Karabay/Guleryuz/ Baykara/Cevher/Akay
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r: –0.43, p: 0.015
Color version available online
BP group
HCVs and Neuroprogression in Adolescents with Bipolar Disorder
Neuropsychobiology 2015;71:140–148 DOI: 10.1159/000375311
2.75
Left nHCVs
2.50
Scale 4.0 3.5 3.0 2.5 2.0 1.5 1.0
Spearman’s r: 0.76, p: 0.006
2.25
2.00
1.75 R2 linear = 0.741 0.00
10.00
20.00 30.00 40.00 Follow-up period (months)
50.00
Fig. 3. Correlations between the right nHCVs (×10–3 mm3) and
total duration in the lithium-treated group.
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Color version available online
tion between the right HCVs and the durations of the disorder and medications. In addition to this correlation, we found a positive relationship between the follow-up period and left nHCVs in the patient and lithium-treated groups. The hippocampal findings in youths with BP have been somewhat contradictory. Decreased HCV may be more prominent in cases of pediatric as opposed to adult BP [9, 11, 15, 32, 33]. On the other hand, some studies found no structural differences for HCVs in youths with BP, similar to our results [12–14]. However, even though we did not find any differences in terms of decreased HCVs and nHCVs between BP and healthy groups, we did find a decrease in the volume of right nHCVs over the course of illness and medication duration. Although the mechanism underlying the observed structural abnormalities is not sufficiently understood, the HC is one of the regions of the brain that is most vulnerable to neuronal loss. In fact, the HC may be one of the earliest structures to be negatively impacted by the disorder [34]. A recent study using three-dimensional modeling found significant volume reductions in HCV among
youths with BP and alterations in the volumetric changes associated with age [15]. Nevertheless, the findings of cross-sectional structural MRI studies in children and youths have been controversial. Whereas some studies have identified HCV decreases in young patients with BP [9–11], others found no differences in global HCV between children with BP and controls [12–14]. Our results suggest that youths with BP may exhibit a later development of the HC structures with continued decreases over time with a longer exposure to the illness. It seems difficult to establish a connection with the general findings of decreased volume, although this challenge may be related to alterations in the timing of normal hippocampal development in youths with BP. Furthermore, it remains possible that there are heterogeneous alterations in HCVs over time; future research should explore the reasons behind this possibility. Although illness-related changes in children and adolescents with BP are often interpreted as evidence of neurodevelopmental abnormalities, the role of the underlying neurophysiological progression related to recurrent affective episodes has not been sufficiently investigated as a reason for potential alterations in the neurodevelopmental trajectories or in other progressive changes by evaluating the correlations of structural measurements with age or with measures of illness burden and treatment (e.g., duration of illness and medication). Furthermore, we tested the associations among these biological variables and such clinical measures as the duration of the disorder, age at onset and treatment. There are positive correlations between the duration of the medications and both the NGF and BDNF levels in a patient group. Limited studies and results exist regarding BDNF and NGF in the pathophysiology of children and adolescents with BP. One previous study on youths with BP found that the BDNF mRNA levels in the lymphocytes and BDNF protein levels in the platelets of drug-free subjects were significantly lower compared to those of normal control subjects and that long-term treatment with mood-stabilizing drugs significantly increased the levels of BDNF mRNA in subjects with BP [35]. Our study indicated that long-term exposure to lithium and VPA may lead to greater increases in the BDNF and NGF levels of youths with early-onset BP. Recently, it has been shown that chronic treatment with either mood stabilizers, such as lithium, or VPA increases BDNF immunoreactivity in rat frontal cortices, potentially enhancing the synaptic plasticity related to BDNF [36, 37]. Furthermore, a considerable amount of evidence suggests that aberrations in the regulation of
Lithium-treated group
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mates from our preliminary findings [24]. We followed these patients for a long time in a naturalistic manner. However, for more reliable results, further longitudinal follow-up studies are needed with large enough sample sizes to sort out developmental and medication influences on the brain structures over time in the BP population. Since all BP patients are in a euthymic state, this study also attempted to determine the state-trait plasticity of HC. Even though we had a good level of knowledge regarding the follow-up of our BP patients, the main limitation of the current study is its cross-sectional design as adolescent brains are developing and it would be difficult to differentiate the impact of an illness or of psychiatric medications on a developing brain. In addition, larger sample sizes are needed to produce more reliable results, according to power analysis. All observed correlations between two or more variables may not represent causality and there may be unexplained variance due to variables not included in the analysis. Different durations of exposure to lithium and VPA, in addition to the effects of polypharmacy from using several atypical antipsychotics, may have led to heterogeneous effects on the brain structures. Additionally, the 1.5-tesla scanner is not powerful enough for hippocampal imaging compared to 3- and 7-tesla scanners in terms of resolution. Further research is needed to determine the structural correlates associated with clinical, treatment or functional differences in early-onset BP.
Acknowledgments The authors acknowledge Dr. Ellen Leibenluft for her invaluable editorial contributions and Drs. Hulya Ellidokuz and Ahmet Topuzoglu for their invaluable help during statistical analyses. The manuscript was edited by American Journal Experts (AJE) editing services in terms of language and grammatical rules. However, the authors are entirely responsible for the scientific content of the article. This study was supported by the Dokuz Eylül University Foundation of Scientific Research Projects (BAP) and was partly supported by the Research Support Award 2008 of the International Society for Bipolar Disorders-affiliated Society for Bipolar Disorders-Turkey.
Disclosure Statement Drs. Inal-Emiroglu, Resmi, Karabay, Guleryuz, Baykara, and Cevher have no potential conflict of interest. Dr. Akay is a member of the scientific council of Janssen Cilag and Lilly drug companies in Turkey.
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neurotrophic signaling play a role in the pathophysiology of BP and certainly appear to be relevant targets for the action of mood stabilizers. These data raise the possibility that early intervention to prevent certain atrophic changes via neurotrophic factors, such as BDNF and NGF, could have major beneficial effects on the course and trajectory of BP. The available data suggest that lithium or VPA might have utility in the treatment of degenerative disorders. Although such drugs would certainly not ‘cure’ these illnesses, any impact that they might have on slowing down disease progression should prove worthwhile [16]. In our cases, psychotropic agents (atypical antipsychotics) and mood stabilizers (lithium and VPA) were potentially found to act via NGF and BDNF as neurotrophic factors, compensating for the destructive effects of this disorder. On the other hand, although both BDNF and NGF serum levels were increased in the course of illness along with medication usage, these increases could not prevent the loss in the right HCVs over time. Inversely, in all BP groups and the lithium-treated group, there was a relationship between increased left HCVs and the follow-up period that could reflect the positive effects of treatment and, especially, of lithium treatment. The neuroprotective effects of lithium have been well documented in experimental animal models [38, 39], and several neuroimaging studies have reported findings suggestive of similar effects of lithium in humans [40–44]. A recent meta-analysis found significantly smaller bilateral HCVs in nontreated lithium patients with BP compared to healthy controls and lithium-treated patients with BP [45]. Another study investigated the effects of lithium, anticonvulsants and antipsychotics on brain structure in BP, finding gray matter in the subgenual anterior cingulate gyrus on the right (extending into the hypothalamus) and in the postcentral gyrus. The HC/amygdala complex and the insula on the left were greater in BP patients on lithium treatment when compared to all other treatment groups [46]. In our study, we found a decreased right HCV when the duration of the illness and medication usage were increasing, but we did not see the same results in the lithium-treated group and healthy groups, similar to previous studies. These findings support a neuroprotective role for lithium against early-onset BP. The child- and adolescent-onset BP group has the advantage of being able to reflect the early neurodevelopmental period of the illness as well as the fact that longterm effects, including medication effects, have not yet to be seen. To fully investigate these effects, we increased our sample size in order to increase the precision of our esti-
References
HCVs and Neuroprogression in Adolescents with Bipolar Disorder
14
15
16
17
18
19 20 21
22
23
24
van MS, Ryan ND, Birmaher B, Soares JC: Cross-sectional study of abnormal amygdala development in adolescents and young adults with bipolar disorder. Biol Psychiatry 2004; 56:399–405. Dickstein DP, Milham MP, Nugent AC, Drevets WC, Charney DS, Pine DS, Leibenluft E: Frontotemporal alterations in pediatric bipolar disorder: results of a voxel-based morphometry study. Arch Gen Psychiatry 2005; 62:734–741. Bearden CE, Soares JC, Klunder AD, Nicoletti M, Dierschke N, Hayashi KM, Narr KL, Brambilla P, Sass RB, Axelson D, Ryan N, Birmaher B, Thompson PM: Three-dimensional mapping of hippocampal anatomy in adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 2008;47:515– 525. Shaltiel G, Chen G, Manji HK: Neurotrophic signaling cascades in the pathophysiology and treatment of bipolar disorder. Curr Opin Pharmacol 2007;7:22–26. Suzuki F, Junier MP, Guilhem D, Sorensen JC, Onteniente B: Morphogenetic effect of kainite on adult hippocampal neurons associated with a prolonged expression of brain-derived neurotrophic factor. Neurosciences 1995;64:665–674. Altar CA, Dugich-Djordjevic M, Armanini M, Bakhit C: Medial-to-lateral gradient of neostriatal NGF receptors: relationship to cholinergic neurons and NGF like immunoreactivity. J Neurosci 1991;11:828–836. Duman RS, Monteggia LM: A neurotrophic model for stress-related mood disorders Biol Psychiatry 2006;59:1116–1127. Groves JO: Is it time to reassess the BDNF hypothesis of depression? Mol Psychiatry 2007; 12:1079–1088. Jornada LK, Moretti M, Valvassori SS, Ferreira CL, Padilha PT, Arent CO, Fries GR, Kapczinski F, Quevedo J: Effects of mood stabilizers on hippocampus and amygdala BDNF levels in an animal model of mania induced by ouabain. J Psychiatr Res 2010; 44: 506–510. Katoh-Semba R, Wakako R, Komori T, Shigemi H, Miyazaki N, Ito H, Kumagai T, Tsuzuki M, Shigemi K, Yoshida F, Nakayama A: Age-related changes in BDNF protein levels in human serum: differences between autism cases and normal controls. Int J Dev Neurosci 2007;25:367–372. Perovic M, Tesic V, Djordjevic AM, Smiljanic K, Loncarevic-Vasiljkovic N, Ruzdijic S, Kanazir S: BDNF transcripts, proBDNF and proNGF, in the cortex and hippocampus throughout the life span of the rat. Age 2013; 35:2057–2070. Baykara B, Inal-Emiroglu N, Karabay N, Çakmakçı H, Cevher N, Şentürk Pilan B, Alşen S: Increased HCVs in lithium treated adolescents with bipolar disorders: a structural MRI study. J Affect Disord 2012;138:433–439.
25 Gökler B, Ünal F, Pehlivantürk B, ÇengelKültür E, Akdemir D, Taner Y: Reliability and validity of schedule for affective disorders and schizophrenia for school age children present and lifetime version – Turkish version (KSADS-PL-T). Çocuk ve Gençlik Ruh Saglıgı Dergisi 2004;11:109–116. 26 Inal-Emiroglu FN, Baykara B, Miral S: A case series of Turkish children and adolescents with bipolar spectrum disorder: a naturalistic clinical phenomenological follow-up. Minerva Pediatr 2008;60:51–57. 27 Robbins DR, Alessi NE, Colfer MV, Yanchyshyn GW: Use of the Hamilton Rating Scale for Depression and the Carroll Self-Rating Scale in adolescents. Psychiatry Res 1985; 14:123–129. 28 Yee AM, Algorta GP, Youngstrom EA, Findling RL, Birmaher B, Fristad MA; The Lams Group: Unfiltered administration of the YMRS and CDRS-R in a clinical sample of children. J Clin Child Adolesc Psychol 2014;2:1–16. 29 Lukasiewicz M, Gerard S, Besnard A, Falissard B, Perrin E, Sapin H, Tohen M, Reed C, Azorin JM; Emblem Study Group: Young Mania Rating Scale: how to interpret the numbers? Determination of a severity threshold and of the minimal clinically significant difference in the EMBLEM cohort. Int J Methods Psychiatr Res 2013;22:46–58. 30 Konrad C, Ukas T, Nebel C, Arolt V, Toga AW, Narr KL: Defining the human hippocampus in cerebral magnetic resonance images – an overview of current segmentation protocols. Neuroimage 2009;47:1185–1195. 31 Lang UE, Hellweg R, Seifert F, Schubert F, Gallinat J: Correlation between serum brainderived neurotrophic factor level and an in vivo marker of cortical integrity. Biol Psychiatry 2007;62:530–535. 32 Frazier JA, Ahn MS, DeJong S, Bent EK, Breeze JL, Giuliano AJ: Magnetic resonance imaging studies in early-onset bipolar disorder: a critical review. Harv Rev Psychiatry 2005;13:125–140. 33 MacMaster FP, Carrey N, Langevin LM, Jaworska N, Crawford S: Disorder-specific volumetric brain difference in adolescent major depressive disorder and bipolar depression. Brain Imaging Behav 2014;8:119–127. 34 Sapolsky RM: The possibility of neurotoxicity in the hippocampus in major depression: a primer on neuron death. Biol Psychiatry 2000;48:755–765. 35 Pandey GN, Hooriyah SR, Yogesh D, Pavuluri MN: Brain-derived neurotrophic factor gene expression in pediatric bipolar disorder: effects of treatment and clinical response. J Am Acad Child Adolesc Psychiatry 2008; 9: 1077–1085. 36 Einat H, Yuan P, Gould TD, Li J, Du J, Zhang L, Manji HK, Chen G: The role of the extracellular signal-regulated kinase signaling pathway in mood modulation. J Neurosci 2003;23: 7311–7316.
Neuropsychobiology 2015;71:140–148 DOI: 10.1159/000375311
147
Downloaded by: Gazi Üniversitesi 194.27.18.18 - 5/4/2015 6:13:47 PM
1 Axelson D, Birmaher B, Strober M, Gill MK, Valeri S, Chiappetta L, Ryan N, Leonard H, Hunt J, Iyengar S, Bridge J, Keller M: Phenomenology of children and adolescents with bipolar spectrum disorders. Arch Gen Psychiatry 2006;63:1139–1148. 2 Birmaher B, Axelson D, Goldstein B, Strober M, Gill MK, Hunt J, Houck P, Ha W, Iyengar S, Kim E, Yen S, Hower H, Esposito-Smythers C, Goldstein T, Ryan N, Keller M: Four-year longitudinal course of children and adolescents with bipolar spectrum disorders: the Course and Outcome of Bipolar Youth (COBY) study. Am J Psychiatry 2009; 166: 795–804. 3 Schneider MR, DelBello MP, McNamara RK, Strakowski SM, Adler CM: Neuroprogression in bipolar disorder. Bipolar Disord 2012; 14: 356–374. 4 Kronmüller KT, Schröder J, Köhler S, Götz B, Victor D, Unger J, Giesel F, Magnotta V, Mundt C, Essig M, Pantel J: Hippocampal volume in first episode and recurrent depression. Psychiatry Res 2009;174:62–66. 5 Soares JC, Mann JJ: The anatomy of mood disorders – review of structural neuroimaging studies. Biol Psychiatry 1997;41:86–106. 6 Goldstein BI, Birmaher B: Prevalence, clinical presentation and differential diagnosis of pediatric bipolar disorder. Isr J Psychiatry Relat Sci 2012;49:3–14. 7 Brambilla P, Glahn DC, Balestrieri M, Soares JC: Magnetic resonance findings in bipolar disorder. Psychiatr Clin North Am 2005; 28: 443–467. 8 McDonald C, Zanelli J, Rabe-Hesketh S, Ellison-Wright I, Sham P, Kalidindi S, Murray RM, Kennedy N: Meta-analysis of magnetic resonance imaging brain morphometry studies in bipolar disorder. Biol Psychiatry 2004; 56:411–417. 9 Blumberg HP, Kaufman J, Martin A, Whiteman R, Zhang JH, Gore JC, Charney DS, Krystal JH, Peterson BS: Amygdala and HCVs in adolescents and adults with bipolar disorder. Arch Gen Psychiatry 2003; 60: 1201–1208. 10 Brambilla P, Hatch JP, Soares JC: Limbic changes identified by imaging in bipolar patients. Curr Psychiatry Rep 2008;10:505–509. 11 Frazier JA, Chiu S, Breeze JL, Makris N, Lange N, Kennedy DN, Herbert MR, Bent EK, Koneru K, Dieterich ME, Hodge SM, Rauch SL, Grant PE, Cohen BM, Seidman LJ, Caviness VS, Biederman J: Structural brain magnetic resonance imaging of limbic and thalamic volumes in pediatric bipolar disorder. Am J Psychiatry 2005;162:1256–1265. 12 Chang K, Karchemskiy A, Barnea-Goraly N, Garrett A, Simeonova DI, Reiss A: Reduced amygdalar gray matter volume in familial pediatric bipolar disorder. J Am Acad Child Adolesc Psychiatry 2005;44:565–573. 13 Chen BK, Sassi R, Axelson D, Hatch JP, Sanches M, Nicoletti M, Brambilla P, Kesha-
148
McDonald C: Structural magnetic resonance imaging in bipolar disorder: an international collaborative mega-analysis of individual adult patient data. Biol Psychiatry 2011; 69: 326–335. 41 Moore GJ, Bebchuk JM, Wilds IB, Chen G, Manji HK: Lithium-induced increase in human brain gray matter. Lancet 2000; 356: 1241–1242. 42 Moore GJ, Bebchuk JM, Hasanat K, Chen G, Seraji-Bozorgzad N, Wilds IB, Faulk MW, Koch S, Glitz DA, Jolkovsky L, Manji HK: Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2’s neurotrophic effects? Biol Psychiatry 2000;48:1–8. 43 Sassi RB, Nicoletti M, Brambilla P, Mallinger AG, Frank E, Kupfer DJ, Keshavan MS, Soares JC: Increased gray matter volume in lithium-
Neuropsychobiology 2015;71:140–148 DOI: 10.1159/000375311
treated bipolar disorder patients. Neurosci Lett 2002;329:243–245. 44 Yucel K, McKinnon MC, Taylor VH, Macdonald K, Alda M, Young LT, MacQueen GM: Bilateral hippocampal increases after longterm lithium treatment in patients with bipolar disorder: a longitudinal MRI study. Psychopharmacology (Berl) 2007;195:357–367. 45 Hajek T, Kopecek M, Höschl C, Alda M: Smaller hippocampal volumes in patients with bipolar disorder are masked by exposure to lithium: a meta-analysis. J Psychiatry Neurosci 2012;37:333–343. 46 Germana C, Kempton MJ, Sarnicola A, Christodoulou T, Haldane M, Hadjulis M, Girardi P, Tatarelli R, Frangou S: The effects of lithium and anticonvulsants on brain structure in bipolar disorder. Acta Psychiatr Scand 2010;122:481–487.
Inal-Emiroglu/Resmi/Karabay/Guleryuz/ Baykara/Cevher/Akay
Downloaded by: Gazi Üniversitesi 194.27.18.18 - 5/4/2015 6:13:47 PM
37 Fukumoto T, Morinobu S, Okamoto Y, Kagaya A, Yamawaki S: Chronic lithium treatment increases the expression of brain-derived neurotrophic factor in the rat brain. Psychopharmacology (Berl) 2001;158:100–106. 38 Gould TD, Picchini AM, Einat H, Manji HK: Targeting glycogen synthase kinase-3 in the CNS: implications for the development of new treatments for mood disorders. Curr Drug Targets 2006;7:1399–1409. 39 Zarate CA Jr, Singh J, Manji HK: Cellular plasticity cascades: targets for the development of novel therapeutics for bipolar disorder. Biol Psychiatry 2006;59:1006–1020. 40 Hallahan B, Newell J, Soares JC, Brambilla P, Strakowski SM, Fleck DE, Kieseppä T, Altshuler LL, Fornito A, Malhi GS, McIntosh AM, Yurgelun-Todd D, Labar KS, Sharma V, MacQueen GM, Murray RM,
