0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Meta-analysis |

Meta-analysis, Database, and Meta-regression of 98 Structural Imaging Studies in Bipolar Disorder FREE

Matthew J. Kempton, MSci, MSc, PhD; John R. Geddes, MD, FRCPsych; Ulrich Ettinger, BSc, MSc, PhD, CPsychol; Steven C. R. Williams, BSc, PhD; Paul M. Grasby, MBBS, MD, FRCP, MRCPsych, FMedSci
[+] Author Affiliations

Author Affiliations: Centre for Neuroimaging Sciences (Drs Kempton and Ettinger and Prof Williams) and Section of Neurobiology of Psychosis (Dr Kempton), Institute of Psychiatry, King's College London and Medical Research Council Clinical Sciences Centre, Imperial College, Hammersmith Hospital (Prof Grasby), London, and Department of Psychiatry, University of Oxford, Oxford (Prof Geddes), England.


Arch Gen Psychiatry. 2008;65(9):1017-1032. doi:10.1001/archpsyc.65.9.1017.
Text Size: A A A
Published online

Context  Despite 25 years of structural imaging in bipolar disorder, brain regions affected in the disorder are ill defined.

Objectives  To use meta-analytical techniques to investigate structural brain changes in bipolar disorder and to assess the effect of medication use and demographic and clinical variables.

Data Sources  The MEDLINE, EMBASE, and PsycINFO databases were searched from 1980-2007 for studies using magnetic resonance imaging or x-ray computed tomography to compare brain structure in patients with bipolar disorder and controls.

Study Selection  We identified 1471 unique publications from which 141 studies were included in a database and 98 were selected for meta-analysis.

Data Extraction  Twenty-six demographic and clinical variables were extracted from each study where available. For the meta-analysis, mean structure size and standard deviation were extracted for continuous variables, and numbers of patients and controls with an abnormality were extracted for binary variables.

Data Synthesis  Bipolar disorder was associated with lateral ventricle enlargement (effect size = 0.39; 95% confidence interval, 0.24-0.55; P = 8×10−7) and increased rates of deep white matter hyperintensities (odds ratio = 2.49; 95% confidence interval, 1.64-3.79; P = 2×10−5) but not periventricular hyperintensities. Gray matter volume increased among patients when the proportion of patients using lithium increased (P = .004). Calculations from this meta-analysis show current imaging studies (which typically examine 8 regions) have a 34% chance of making a type I error. Type II errors are also appreciable (for example, 70% when measuring the lateral ventricular volume in a typical study involving 25 patients and 33 controls).

Conclusions  The meta-analyses revealed robust but regionally nonspecific changes of brain structure in bipolar disorder. Individual studies will remain underpowered unless sample size is increased or improvements in phenotypic selection and imaging methods are made to reduce within-study heterogeneity. The provision of online databases, as illustrated herein, may facilitate a more refined design and analysis of structural imaging data sets in bipolar disorder.

Figures in this Article

Despite 25 years of structural neuroimaging of patients with bipolar disorder, including more than 7000 magnetic resonance imaging (MRI) scans, there remains considerable debate over the sensitivity and specificity of structural brain changes in bipolar disorder. Studies continue to report conflicting findings, such as both significantly larger or smaller volumes of the amygdala,1,2 hippocampus,3,4 and thalamus3,5 among patients with bipolar disorder. Meta-analyses are beginning to reveal consistent abnormalities in bipolar disorder, such as increased rates of hyperintensities6,7 and perhaps lateral ventricular enlargement.8,9 Studies may be contradictory because of between-study heterogeneity in the patient and control groups in terms of medication use10,11 and demographic12,13 and clinical variables14,15 and because individual studies may suffer from high rates of type I and type II errors. There is good evidence to suggest medication may affect brain structure; cross-sectional studies1618 and a longitudinal study19 have suggested lithium increases gray matter volume, possibly through its neurotrophic effects,20 and typical neuroleptic medication may be associated with striatal enlargement.21,22 In addition, type I and II errors are prevalent because of the large number of measures made in individual studies and small sample sizes, respectively. Finally, although effect sizes may be calculated from individual studies, there is little published information from meta-analyses on the pooled Cohen effect sizes of structural differences between patients with bipolar disorder and controls, making it difficult to accurately calculate a priori the number of participants necessary to show a significant group difference.

In the present meta-analysis, we directly address these problems while extending the scope and methods of previous meta-analyses. The number of studies included is approximately 4 times the largest previous meta-analysis9 in bipolar disorder. We have maximized the number of brain regions analyzed by comprehensively listing all brain structures reported in 3 or more studies. In addition, we used meta-regression techniques to investigate the effect of medication use and clinical and demographic variables, which had not been attempted previously. We present the results as Cohen effect sizes (with a correction for small sample sizes), enabling researchers to calculate subject numbers required for future studies to be sufficiently powered. In addition, we present a small supplementary meta-analysis comparing patients with bipolar disorder to patients with schizophrenia (when included as a subgroup in a bipolar study) to evaluate the diagnostic specificity of our findings. Finally, we provide an online database of structural imaging results in bipolar disorder, listing 26 clinical and demographic variables, where available, from 141 studies.

The study was divided into 2 parts, the construction of a database of 141 studies investigating structural abnormalities in bipolar disorder and a meta-analysis comparing patients with bipolar disorder to controls from a subgroup of 98 studies in the database. A smaller, supplementary meta-analysis compared brain structure between patients with bipolar disorder and schizophrenia from a subgroup of 23 studies.

DATABASE STUDY SELECTION

The inclusion criteria for the database required peer-reviewed studies that made a structural brain measure using x-ray computed tomography (CT) or MRI in patients with bipolar disorder and a control group. We excluded case studies, reviews, publications without standard diagnostic criteria, studies combining patients with bipolar disorder and major depressive disorder, duplicate publications, and investigations using voxel-based morphometry, which cannot be included in a traditional meta-analysis. The MEDLINE, EMBASE, and PsycINFO databases were searched up to October 2007 using relevant expanded subject headings and free text searches; detailed search terms are available from the authors on request. A total of 1471 unique publications were examined. One hundred forty-one publications fulfilled the inclusion criteria and were included in the database.

DATA RECORDED IN THE DATABASE

The following were recorded from each study where available: number of patients with bipolar disorder and controls, mean (SD) age, number of females in the patient and control groups, diagnostic classification system (eg, DSM-IV), and number of patients with bipolar I and bipolar II disorder. Patients with bipolar disorder were assumed to have bipolar I disorder if described as having mania or psychosis. For current medication use within the bipolar group, we recorded the number of patients who were described as being drug free, using mood stabilizers, or taking lithium, anticonvulsants, sodium valproate, carbamazepine, antipsychotics, antidepressants, or benzodiazepines. In addition, the number of patients previously treated with electroconvulsive therapy was recorded if available. For each study, we recorded all structures or abnormalities measured, the number of separate measurements made, if the measurement was MRI or CT based, the field strength of the MRI scanner, and slice thickness.

DATABASE STATISTICAL ANALYSIS

Because the majority of variables in the database were not normally distributed, correlations were assessed in SPSS 15.0 (SPSS Inc, Chicago, Illinois) using the Spearman ρ. Power calculations were carried out using GPOWER 2.0.23

IDENTIFICATION OF BRAIN REGIONS/ABNORMALITIES TO BE INCLUDED IN THE META-ANALYSIS

To ensure no bias in selecting brain regions/abnormalities for the meta-analysis, we recorded every structure or abnormality investigated in the 141 studies. As with previous meta-analyses, exact anatomical definitions of individual structures varied across studies. For a given structure, some studies reported left and right measurements separately, while others reported the total combined measure. In this meta-analysis, the left, right, and total measurements were treated as separate measures. To ensure the meta-analysis was sufficiently powered, brain region measures were included if there were 3 or more studies reporting a mean and standard deviation in both the control and patient groups (continuous measures), and abnormalities were included if there were 3 or more studies reporting the number of patients and controls with the abnormality (binary measure). After this process, 47 regions or abnormalities from a total of 98 studies were selected for the bipolar vs control meta-analysis and 12 regions/abnormalities from 23 studies were selected for the bipolar vs schizophrenia meta-analysis. Eight studies using CT measures of total lateral ventricle volume were included in the meta-analyses; all other brain structures were imaged using MRI.

META-ANALYSIS

The meta-analyses were performed in STATA 9.2 (StataCorp, College Station, Texas) using the METAN command. For continuous outcome measures (eg, volume of a brain region), Hedges g was used, which is Cohen effect size with a correction for bias from small sample sizes.24 This metric is commonly used in meta-analyses and is representative of the difference in structural measurement between the control and patient distribution. However, we also show percentage difference effect size to aid biological interpretation of the data.9 While the majority of studies report absolute volume measures, some studies report volumes as ratios of the entire brain or cross-sectional area measures. All such measurements have been included in the meta-analysis. However, as combining measures may increase heterogeneity, an additional analysis was carried out with volume measures only (see “Sensitivity Analysis” subsection).

For binary outcome measures (eg, number of patients and controls with deep white matter hyperintensities), the odds ratio was used. Outcome measures from each study were rechecked on a separate occasion by the same investigator (M.J.K.) to ensure accuracy. In addition, no inconsistencies were found when a second investigator (U.E.) verified a random sample of 50 sets of outcome measures.

COMBINING STUDY ESTIMATES

A separate meta-analysis was performed for each brain region/abnormality. Where 2 or more studies reported similar patient or control demographics, we contacted the authors directly to verify there was not a significant overlap in the sample. Outcome measures were combined using a random-effects, inverse-weighted variance model (DerSimonian and Laird method).25 Because the bipolar vs control meta-analysis examined a large number of regions, type I errors should be considered, and thus, results that pass Bonferroni correction for multiple comparisons are indicated.

PATIENT SUBGROUPS

A minority of imaging studies presented measures from patient subgroups rather than a combined patient group. In such cases, we entered the subgroups into the meta-analysis as if they were separate studies, with the number of subjects in the control group being divided by the number of patient subgroups. Where studies reported males and females separately, we entered the results as if they were from 2 separate studies, a technique adopted by a previous meta-analysis.26

ASSESSING BETWEEN-STUDY HETEROGENEITY

To test for between-study heterogeneity, the Cochran Q test statistic was used, and where P < .10, the studies were concluded to be heterogeneous.27 The I2 statistic (equal to the percentage of total variation across studies due to heterogeneity) was used to aid interpretability of between-study heterogeneity.28

PUBLICATION BIAS

Publication bias was investigated for regions where the pooled effect size revealed a significant group difference and where at least 5 studies were included in the meta-analysis. Although publication bias may be assessed by visually inspecting a funnel plot, we used the Egger regression test, which is a more quantitative method of assessing publication bias.29 Evidence of bias is indicated if the intercept of a regression line of effect size/standard error against 1/standard error significantly deviates from zero.

META-REGRESSION OF CLINICAL VARIABLES AND STUDY QUALITY

The effects of clinical variables and study quality were assessed using a random-effects meta-regression implemented using the METAREG command in STATA 9.2. The default option using residual maximum likelihood was selected. To avoid type I errors, demographic and clinical variables were chosen based on key clinical questions and the availability of the variables reported in studies.30 For structures where there was a significant difference between patients with bipolar disorder and controls, we investigated whether effect size was modulated by study quality. Study quality was scored in 6 key areas by 2 independent investigators (M.J.K. and U.E.), with disputes resolved by consensus. One point was given for each of the following categories: age matching (not stated/significant difference = 0, matched = 1), sex matching (not stated/significant difference = 0, matched = 1), control subjects had no psychiatric illness (not stated = 0, no psychiatric illness = 1), same CT/MRI scanner and sequence used for each subject (different scanner or sequence = 0, same scanner and sequence = 1), good reliability of measures (intraclass correlation coefficient/κ <0.8/not stated = 0, intraclass correlation coefficient/κ ≥0.8 = 1), and small slice thickness (≥4 mm = 0, >1.5 mm and <4 mm = 0.5, and ≤1.5 mm = 1).

SENSITIVITY ANALYSIS

To test how robust the results were to variations in meta-analysis inputs, we examined the effect of the following: (1) percentage difference in the patient mean volume compared with the control mean volume as an outcome measure for continuous data (the calculation of this effect size and the effect size variance has been described in more detail in previous meta-analytical studies)9,26; (2) excluding studies with patients with bipolar II disorder; and (3) excluding studies reporting continuous data as area, length, or ratios rather than absolute volume.

Demographic and clinical data from the database are reported, followed by results from the meta-analyses.

DATABASE

One hundred forty-one studies, including 3509 patients with bipolar disorder and 4687 controls, were entered into the database (Table 1). Table 2 summarizes the variables recorded. Bipolar disorder was defined using DSM-IV (69 studies), DSM-III-R (38 studies), DSM-III (22 studies), Research Diagnostic Criteria (11 studies), and International Statistical Classification of Diseases, 10th Revision (1 study). For image acquisition, 125 studies used MRI and 16 studies used CT imaging. Among MRI studies, 78% used a field strength of 1.5 T, 18% used lower field strength, and 3% used higher field strength. The mean (SD) slice thickness was 9.3 (1.0) mm in CT studies and 3.5 (2.5) mm in MRI studies. The Bipolar Disorder Neuroimaging Database (BiND) is freely available athttp://www.bipolardatabase.org.

Table Graphic Jump LocationTable 1. List of Studies Included in the Databasea
Table Graphic Jump LocationTable 2. Patient and Control Demographic and Clinical Data Recorded in the Database
TRENDS IN STUDY VARIABLES OVER TIME

Studies did not recruit a larger number of subjects over time (R = −0.10; P = .22) (Figure 1), although the number of studies per year increased (R = 0.79; P < .001) (Figure 2). The mean age of participants decreased during the review period (patients, R = −0.34; P < .001; controls, R = −0.34; P < .001), with recent studies recruiting adolescent patients. In addition, studies recorded increasing numbers of demographic variables over time (R = 0.50; P < .001).

Place holder to copy figure label and caption
Figure 1.

Total number of subjects (patients + controls) per study over time.

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

Number of bipolar structural imaging studies per year.

Graphic Jump Location
IMPLICATIONS FOR TYPE I ERRORS IN INDIVIDUAL STUDIES

The mean number of regions or abnormalities measured per study was 8, and there was a negative correlation between the number of measures made and the total number of subjects included in each study (R = −0.23; P = .007).

DIFFERENT REGIONS/ ABNORMALITIES MEASURED

From the 141 studies, 377 different regions or abnormalities were measured. Only 47 were analyzed by 3 or more studies and hence were included in the bipolar vs control meta-analysis. Twelve structures were also measured in patients with schizophrenia in 3 or more studies, and these were included in the bipolar vs schizophrenia meta-analysis.

META-ANALYSIS COMPARING PATIENTS WITH BIPOLAR DISORDER TO CONTROL SUBJECTS

Patients with bipolar disorder showed increased volumes of the total lateral ventricles, right lateral ventricle, and third ventricle and decreased cross-sectional area of the corpus callosum (Table 3) (Figure 3). Hyperintensities, deep white matter hyperintensities, subcortical gray matter hyperintensities, and hyperintensities in the left hemisphere, right hemisphere, and frontal and parietal lobe were more frequently observed in patients with bipolar disorder (Table 4) (Figure 4). Analysis of the occipital and temporal lobes was not possible because of low numbers of hyperintensities reported in these regions. Increased total lateral ventricular volume, hyperintensities, deep white matter hyperintensities, and hyperintensities in the right hemisphere remained significant after Bonferroni correction.

Place holder to copy figure label and caption
Figure 3.

Continuous variables from the bipolar-control meta-analysis. Effect size is shown for each structure with 95% confidence intervals. The effect size is positive when the structure is larger in patients with bipolar disorder compared to controls and negative when the structure is smaller in patients with bipolar disorder. Red bars represent significant differences, and blue bars are nonsignificant differences. n Indicates the number of studies included in each meta-analysis. The values at the top of the figure indicate the number of required patients for a future study to be sufficiently powered, assuming within-study heterogeneity is similar to studies included in the meta-analysis.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Binary variables from the bipolar-control meta-analysis. Odds ratios are shown for each type of hyperintensity with 95% confidence intervals. An odds ratio greater than 1 means the hyperintensity is more common in patients with bipolar disorder than controls. Red bars represent significant differences, and blue bars are nonsignificant differences. n Indicates the number of studies included in each meta-analysis.

Graphic Jump Location
Table Graphic Jump LocationTable 3. Meta-analysis of Continuous Data Comparing Patients With Bipolar Disorder to Controlsa
Table Graphic Jump LocationTable 4. Meta-analysis of Binary Data Comparing Patients With Bipolar Disorder to Controlsa
PUBLICATION BIAS

Of the 13 affected regions/abnormalities, 10 were reported by enough studies to perform a publication bias test. There was evidence of significant publication bias for the combined hyperintensities category and hyperintensities in the right hemisphere (Table 3 and Table 4).

META-REGRESSION AND INVESTIGATION OF HETEROGENEITY

Nineteen of the 47 brain regions/abnormalities examined showed significant between-study heterogeneity, justifying the use of a random-effects model to combine the effect sizes. The following meta-regression analysis investigated possible sources of this heterogeneity. To investigate whether lateral ventricle expansion may be present at the beginning of the illness or may progress with time, we examined the effect of duration of illness and age on the difference in total lateral ventricular volume between patients and controls. No effect of mean patient age (n = 15 studies; P = .66) or duration of illness (n = 11 studies; P = .36) was detected. Because hyperintensities have reportedly been increased in older patients with depression and patients with a late age at onset,157,158 we investigated the effects of these variables on the difference in incidence rates of deep white matter lesions between patients with bipolar disorder and controls. However, there was no significant effect of age (n = 13 studies; P = .60) or age at onset (n = 8; P = .42). The proportion of patients using lithium in a given study had no observable effect on the incidence of deep white matter hyperintensities in patients compared with controls (n = 4 studies; P = .46). Because lithium has been reported to increase gray matter volume,19 we performed a meta-regression investigating whether the number of patients taking lithium modulated the effect size of patient and control differences in total gray matter. Gray matter volume increased among patients compared with controls when the proportion of patients using lithium increased (n = 8 studies; P = .004). Amygdala volume change was especially heterogeneous between studies; however, this heterogeneity was not explained by differences in patient sex or age (data not shown). There was no significant effect of study quality score for any of the structures differing between patients with bipolar disorder and controls (P > .15 in all cases).

Older studies measured the lateral ventricles using CT imaging, rather than MRI, and/or reported lateral ventricle to brain ratio (VBR) rather than a volume measure. To assess if these measures affected the results, we combined 9 MRI studies measuring the lateral ventricle, giving an effect size of 0.26 (95% confidence interval [CI], 0.07 to 0.45; P = .007), and compared this with 8 CT studies that gave a combined effect size of 0.52 (95% CI, 0.28 to 0.76; P < .001). When combining 10 studies reporting a VBR measure, we obtained an effect size of 0.44 (95% CI, 0.20 to 0.68; P < .001), while 6 studies reporting a volume measure gave an effect size of 0.28 (95% CI, 0.06 to 0.49; P = .0082).

The results of the sensitivity analysis are shown in Table 5.

Table Graphic Jump LocationTable 5. Sensitivity of the Results to Different Analysis Methods
META-ANALYSIS COMPARING PATIENTS WITH BIPOLAR DISORDER TO PATIENTS WITH SCHIZOPHRENIA

The left lateral ventricle and third ventricle were smaller in patients with bipolar disorder compared to patients with schizophrenia (Table 6). Both the left and right hippocampus were larger in patients with bipolar disorder compared with patients with schizophrenia, although there was evidence of publication bias for these measures.

Table Graphic Jump LocationTable 6. Meta-analysis of Continuous Data and Binary Data Comparing Patients With Bipolar Disorder With Patients With Schizophreniaa
SUMMARY OF STRUCTURAL CHANGES IN BIPOLAR DISORDER

Patients with bipolar disorder had lateral ventricular enlargement (+17%) and increased rates of deep white matter hyperintensities (2.5 times more likely in patients than controls) but did not have increased rates of periventricular hyperintensities. From the meta-regression analysis, there was no evidence that age, age at onset, or use of lithium affected rates of deep white matter hyperintensities or that duration of illness increased ventricular enlargement. However, lithium use was associated with increased total gray matter volume. Meta-regression is statistically low powered and may be prone to type II errors; in addition, associations found at the level of multiple studies may not exist at the individual-patient level.159 Despite this, the association of lithium use with increased gray matter volume has been reported in a number of individual studies,16,18,19 supporting our finding.

Given the size of the meta-analysis, the relatively small number of significant findings is perhaps surprising. There may be genuinely limited structural change in bipolar disorder, or between-study heterogeneity may have obscured other differences. A large number of factors may affect between-study heterogeneity, and some parameters, such as variations in brain region definitions and scanner sequences, are difficult to examine with meta-regression techniques. In this sense, meta-analyses are limited and well-controlled imaging studies with very large sample sizes may provide more definitive answers.

BIOLOGICAL IMPLICATIONS OF MAIN FINDINGS

Ventricular enlargement has been extensively documented in schizophrenia,26 although it is not clear if the expansion is due to diffuse or focal gray/white matter volume reduction. Although the neuropathological mechanism for this change is not known, the volume loss may be due in part to smaller neuronal cell bodies and fewer dendritic spines and dendritic arborizations on pyramidal neurones reportedly found in patients with schizophrenia.160 In bipolar disorder, ventricular expansion and corresponding reduction in brain volume may be linked to the reduced population of glial cells and neuronal density observed in this condition.161 It is not clear if ventricular enlargement occurs before, during, or after illness onset, although our meta-regression suggests enlargement does not progress with illness duration and so may be present near the beginning of the illness.

Increased rates of hyperintensities are not specific to bipolar disorder, being associated with major depressive disorder, normal aging, dementia, cardiovascular disease, and elevated diastolic blood pressure.162 Postmortem studies of subjects with depression using in vitro MRI have reported that hyperintensities represent dilated perivascular spaces, oligemic demyelination, and ischemic demyelination.163

INDIVIDUAL STUDIES HAVE HIGH RATES OF TYPE I AND TYPE II ERRORS

To provide sufficient statistical power, studies that measured a large number of regions would also need to recruit a large number of subjects. Indeed, if there were a consensus for the expected effect size for differences in cerebral structures between patients with bipolar disorder and control subjects, and a consensus for controlling multiple comparisons, one would expect to see a positive correlation between the number of subjects in a study and the number of measurements made. In contrast, there was a significant negative correlation, suggesting there is no consensus in one or both of these issues.

Typically, 8 regions were investigated per study, giving the probability of a type I error as 0.34 (calculation from Bonferroni equation), unless a correction for multiple comparisons is made. This estimate is an upper boundary for false-positive error rates, assuming regional brain measures are independent. Studies are not only at risk for type I errors; for example, if a study measured the volume of the lateral ventricles, which was associated with one of the largest effect sizes in the meta-analysis (effect size = 0.39), and recruited the mean number of patients and controls per study calculated from the database (25 and 33 respectively), the study would have a 70% chance of making a type II error. If the effect size for lateral ventricle dilation is calculated from MRI studies only, a representative study has an 84% chance of making a type II error. Hence, a typical structural imaging study is underpowered to detect one of the largest effect sizes found in the meta-analysis. To combat these problems, studies will need to recruit larger numbers of patients and controls and have a consistent way of dealing with multiple comparisons.

Despite the aforementioned problems, recruitment size has not changed during the last 25 years and studies remain underpowered. It is possible type I errors have actually misled researchers into believing that 20 to 30 patients and controls is a sufficient sample size because previous studies have “obtained results” with these numbers of participants. For a future study to be sufficiently powered, the required number of subjects may be readily calculated from the effect sizes given in Table 3. For example, for a study to be sufficiently powered to detect a difference in lateral ventricle volume, 105 patients and 105 controls would be required (power = 0.8; α = .05, 2-tailed t test). The power calculations and effect sizes are based on studies included in the meta-analysis, and the prediction of required sample sizes for future studies assumes within-study heterogeneity will remain constant. However, if future studies were to minimize within-study heterogeneity through refined phenotype selection and improved imaging methods, the effect sizes may increase, leading to smaller required sample sizes. In addition, where a structure strongly correlates with age and brain volume, the required number of subjects may also be smaller because using these variables as nuisance covariates will increase the power of the analysis. Small studies are still important but should perhaps be cautious in their conclusions and combine their result with previous studies and report an “updated effect size.”

COMPARISON WITH PREVIOUSLY PUBLISHED META-ANALYSES

Our study was in good agreement with previous meta-analyses of brain structure in bipolar disorder. Previously reported odds ratios of increased rates of hyperintensities among patients with bipolar disorder were 3.296 and 3.3,7 which are in close agreement with the odds ratio of 3.04 calculated in this study. We extended these findings by performing meta-analyses on the location and subtype of hyperintensities. Compared with a previous meta-analysis of patients with affective disorder,8 we found a similar effect size for increased total lateral ventricular volume among patients with bipolar disorder (d = 0.42 and d = 0.39, respectively). Our results also concur with a previous meta-analysis showing right lateral ventricle enlargement in bipolar disorder.9

In our study, patients with schizophrenia compared to bipolar disorder showed enlargement of the left lateral ventricle and third ventricle and decreased hippocampal volume. However, relatively few brain structures were included because of the small number of studies directly comparing these diagnostic groups. For a more comprehensive comparison, we compared our bipolar-control meta-analysis with a previous meta-analysis by Wright et al26 comparing patients with schizophrenia with controls (Figure 5). This comparison supports our own findings as well as suggests that patients with schizophrenia show increased volume of the total and right lateral ventricle, reduced volume of the amygdala, and perhaps increased volume of the globus pallidus compared to patients with bipolar disorder. For cortical structures, both our meta-analysis and the Wright et al meta-analysis pooled studies that measured gray matter volume alone with studies that combined gray and white matter. Combining such studies may dilute the effect of regional reductions in cortical gray matter, an example being superior temporal lobe volumes in schizophrenia, where reviews by Shenton et al164 and McCarley et al165 have highlighted that gray matter reductions are obscured when gray and white matter are analyzed together. However, when we separated studies based on this criterion, results in our meta-analysis did not change (data not shown). Two meta-analyses of hippocampus volume in major depressive disorder166,167 report a volumetric reduction, which contrasts with our null finding in bipolar disorder. The possible neuroprotective effects of lithium use may have masked the reduction in hippocampal volume in bipolar disorder.19,168 To test this hypothesis, we performed a meta-regression of the proportion of patients using lithium on the effect size of total hippocampal volume. The effect was close to significant (n = 4 studies; P = .051); as the number of patients using lithium increased, the volume of the hippocampus compared with controls also increased, supporting our hypothesis. Individual structural imaging studies in bipolar disorder that have directly investigated correlations between lithium use and hippocampus volume are equivocal, with 4 studies reporting that lithium use was associated with hippocampus enlargement,4,148,155,156 while 2 reported no effect.108,116

Place holder to copy figure label and caption
Figure 5.

Comparison of our meta-analysis (A) and the meta-analysis of patients with schizophrenia by Wright et al26 (B). Only regions investigated by both studies are shown. Computed tomographic studies have been excluded from our analysis, and effect sizes are calculated from percentage increase or decrease in structure size compared with the control group to match the methods used by Wright et al; as such, the significance of results may vary from Figure 3 (see also “Sensitivity Analysis” subsection in the text). Red bars represent significant differences, and blue bars are nonsignificant differences.

Graphic Jump Location

A meta-analysis involving more studies may have increased power to detect significant differences; however, studies included may be more heterogeneous, increasing the variance and hence reducing the chance of detecting a significant difference. The rationale used for the present meta-analysis was that the advantage of including more studies outweighed the disadvantage from increased heterogeneity due to different types of measurement. Where the number of studies was large enough, we attempted subanalyses, such as volume and ratio measures of lateral ventricle volume, to reduce heterogeneity and give further specificity to the findings and also attempted to account for study heterogeneity by implementing a meta-regression analysis. Lateral ventricular volume measured using CT was associated with a larger effect size than MRI studies. This may be because older CT studies were less stringent in controlling for possible confounds, such as alcohol and drug abuse/dependence, which are relatively common in bipolar disorder169 and are associated with brain volume change.170 Computed tomographic studies were also more likely to report the VBR measure; because this measurement reduces variance due to brain volume, it may be more sensitive to ventricular dilation in bipolar disorder compared with absolute volume measures.

The results database and meta-analysis are publicly available on the Internet for the purpose of allowing researchers to verify the methods used, aiding upcoming studies and reviews, and enabling further meta-analyses. Customized meta-regressions may be carried out on the data by individual researchers interested in the effect of various combinations of demographic and clinical variables on a region of interest (eg, the effect of age and sex on temporal lobe volume in bipolar disorder).

In conclusion, there are robust but limited changes in brain structure in bipolar disorder and evidence that lithium medication increases gray matter volume. Without refinements in phenotypic selection and imaging methods or increased sample size, type I and type II errors will remain appreciable. Future studies would benefit by providing comprehensive patient clinical data as well as continuing to provide raw structural measures to facilitate future meta-analyses. The publicly available results database and meta-analysis from this article may prove to be a useful resource for planning future structural imaging studies.

Correspondence: Matthew J. Kempton, MSci, MSc, PhD, Centre for Neuroimaging Sciences, PO89, Institute of Psychiatry, DeCrespigny Park, London SE5 8AF, England (matthew.kempton@iop.kcl.ac.uk).

Submitted for Publication: July 2, 2007; final revision received March 31, 2008; accepted March 31, 2008.

Author Contributions: Dr Kempton had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Disclosure: None reported.

Funding/Support: Dr Kempton was supported by a Medical Research Council studentship and was funded in part by the National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at King's College London, Institute of Psychiatry, and South London and Maudsley NHS Foundation Trust. Dr Ettinger is funded by an NIHR Personal Award.

Disclaimer: The views expressed in this publication are those of the authors and not necessarily those of the National Health Service, NIHR, or Department of Health.

Additional Contributions: We thank S. Landau, PhD, of the Department of Biostatistics at the Institute of Psychiatry for a helpful discussion regarding the meta-analysis methods.

Chang  KKarchemskiy  ABarnea-Goraly  NGarrett  ASimeonova  DIReiss  A Reduced amygdalar gray matter volume in familial pediatric bipolar disorder. J Am Acad Child Adolesc Psychiatry 2005;44 (6) 565- 573
PubMed
Altshuler  LLBartzokis  GGrieder  TCurran  JJimenez  TLeight  KWilkins  JGerner  RMintz  J An MRI study of temporal lobe structures in men with bipolar disorder or schizophrenia. Biol Psychiatry 2000;48 (2) 147- 162
PubMed
Frazier  JAChiu  SBreeze  JLMakris  NLange  NKennedy  DNHerbert  MRBent  EKKoneru  VKDieterich  MEHodge  SMRauch  SLGrant  PECohen  BMSeidman  LJCaviness  VSBiederman  J Structural brain magnetic resonance imaging of limbic and thalamic volumes in pediatric bipolar disorder. Am J Psychiatry 2005;162 (7) 1256- 1265
PubMed
Beyer  JLKuchibhatla  MPayne  MEMoo-Young  MCassidy  FMacfall  JKrishnan  KR Hippocampal volume measurement in older adults with bipolar disorder. Am J Geriatr Psychiatry 2004;12 (6) 613- 620
PubMed
Dupont  RMJernigan  TLHeindel  WButters  NShafer  KWilson  THesselink  JGillin  JC Magnetic resonance imaging and mood disorders: localization of white matter and other subcortical abnormalities. Arch Gen Psychiatry 1995;52 (9) 747- 755
PubMed
Altshuler  LLCurran  JGHauser  PMintz  JDenicoff  KPost  R T2 hyperintensities in bipolar disorder: magnetic resonance imaging comparison and literature meta-analysis. Am J Psychiatry 1995;152 (8) 1139- 1144
PubMed
Videbech  P MRI findings in patients with affective disorder: a meta-analysis. Acta Psychiatr Scand 1997;96 (3) 157- 168
PubMed
Elkis  HFriedman  LWise  AMeltzer  HY Meta-analyses of studies of ventricular enlargement and cortical sulcal prominence in mood disorders: comparisons with controls or patients with schizophrenia. Arch Gen Psychiatry 1995;52 (9) 735- 746
PubMed
McDonald  CZanelli  JRabe-Hesketh  SEllison-Wright  ISham  PKalidindi  SMurray  RMKennedy  N Meta-analysis of magnetic resonance imaging brain morphometry studies in bipolar disorder. Biol Psychiatry 2004;56 (6) 411- 417
PubMed
Gulseren  SGurcan  MGulseren  LGelal  FErol  A T2 hyperintensities in bipolar patients and their healthy siblings. Arch Med Res 2006;37 (1) 79- 85
PubMed
López-Larson  MPDelBello  MPZimmerman  MESchwiers  MLStrakowski  SM Regional prefrontal gray and white matter abnormalities in bipolar disorder. Biol Psychiatry 2002;52 (2) 93- 100
PubMed
de Asis  JMGreenwald  BSAlexopoulos  GSKiosses  DNAshtari  MHeo  MYoung  RC Frontal signal hyperintensities in mania in old age. Am J Geriatr Psychiatry 2006;14 (7) 598- 604
PubMed
Kaur  SSassi  RBAxelson  DNicoletti  MBrambilla  PMonkul  ESHatch  JPKeshavan  MSRyan  NBirmaher  BSoares  JC Cingulate cortex anatomical abnormalities in children and adolescents with bipolar disorder. Am J Psychiatry 2005;162 (9) 1637- 1643
PubMed
Haznedar  MMRoversi  FPallanti  SBaldini-Rossi  NSchnur  DBLicalzi  EMTang  CHof  PRHollander  EBuchsbaum  MS Fronto-thalamo-striatal gray and white matter volumes and anisotropy of their connections in bipolar spectrum illnesses. Biol Psychiatry 2005;57 (7) 733- 742
PubMed
Zimmerman  MEDelBello  MPGetz  GEShear  PKStrakowski  SM Anterior cingulate subregion volumes and executive function in bipolar disorder. Bipolar Disord 2006;8 (3) 281- 288
PubMed
Sassi  RBNicoletti  MBrambilla  PMallinger  AGFrank  EKupfer  DJKeshavan  MSSoares  JC Increased gray matter volume in lithium-treated bipolar disorder patients. Neurosci Lett 2002;329 (2) 243- 245
PubMed
Kieseppä  Tvan Erp  TGHaukka  JPartonen  TCannon  TDPoutanen  VPKaprio  JLonnqvist  J Reduced left hemispheric white matter volume in twins with bipolar I disorder. Biol Psychiatry 2003;54 (9) 896- 905
PubMed
Bearden  CEThompson  PMDalwani  MHayashi  KMLee  ADNicoletti  MTrakhtenbroit  MGlahn  DCBrambilla  PSassi  RBMallinger  AGFrank  EKupfer  DJSoares  JC Greater cortical gray matter density in lithium-treated patients with bipolar disorder. Biol Psychiatry 2007;62 (1) 7- 16
PubMed
Moore  GJBebchuk  JMWilds  IBChen  GManji  HK Lithium-induced increase in human brain grey matter [published correction appears in Lancet. 2000;356(9247):2104]. Lancet 2000;356 (9237) 1241- 1242
PubMed
Fukumoto  TMorinobu  SOkamoto  YKagaya  AYamawaki  S Chronic lithium treatment increases the expression of brain-derived neurotrophic factor in the rat brain. Psychopharmacology (Berl) 2001;158 (1) 100- 106
PubMed
Chakos  MHLieberman  JABilder  RMBorenstein  MLerner  GBogerts  BWu  HKinon  BAshtari  M Increase in caudate nuclei volumes of first-episode schizophrenic patients taking antipsychotic drugs. Am J Psychiatry 1994;151 (10) 1430- 1436
PubMed
Keshavan  MSBagwell  WWHaas  GLSweeney  JASchooler  NRPettegrew  JW Changes in caudate volume with neuroleptic treatment. Lancet 1994;344 (8934) 1434
PubMed
 GPOWER: A priori, post-hoc, and compromise power analyses for MS-DOS [computer program]. Version 2.0. Bonn, Germany Bonn University Dept of Psychology1992;
Hedges  LVOlkin  I Statistical Methods for Meta-analysis.  Orlando, FL Academic Press1985;
DerSimonian  RLaird  N Meta-analysis in clinical trials. Control Clin Trials 1986;7 (3) 177- 188
PubMed
Wright  ICRabe-Hesketh  SWoodruff  PWDavid  ASMurray  RMBullmore  ET Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry 2000;157 (1) 16- 25
PubMed
Sutton  AJ Methods for Meta-analysis in Medical Research.  Chichester, NY Wiley2000;
Higgins  JPThompson  SGDeeks  JJAltman  DG Measuring inconsistency in meta-analyses. BMJ 2003;327 (7414) 557- 560
PubMed
Egger  MDavey Smith  GSchneider  MMinder  C Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315 (7109) 629- 634
PubMed
Thompson  SGHiggins  JP How should meta-regression analyses be undertaken and interpreted? Stat Med 2002;21 (11) 1559- 1573
PubMed
Nasrallah  HAJacoby  CGMcCalley-Whitters  M Cerebellar atrophy in schizophrenia and mania. Lancet 1981;1 (8229) 1102
PubMed
Lippmann  SManshadi  MBaldwin  HDrasin  GRice  JAlrajeh  S Cerebellar vermis dimensions on computerized tomographic scans of schizophrenic and bipolar patients. Am J Psychiatry 1982;139 (5) 667- 668
PubMed
Nasrallah  HAMcCalley-Whitters  MJacoby  CG Cerebral ventricular enlargement in young manic males: a controlled CT study. J Affect Disord 1982;4 (1) 15- 19
PubMed
Nasrallah  HAMcCalley-Whitters  MJacoby  CG Cortical atrophy in schizophrenia and mania: a comparative CT study. J Clin Psychiatry 1982;43 (11) 439- 441
PubMed
Rangel-Guerra  RAPerez-Payan  HMinkoff  LTodd  LE Nuclear magnetic resonance in bipolar affective disorders. AJNR Am J Neuroradiol 1983;4 (3) 229- 231
PubMed
Pearlson  GDGarbacz  DJTompkins  RHAhn  HSGutterman  DFVeroff  AEDePaulo  JR Clinical correlates of lateral ventricular enlargement in bipolar affective disorder. Am J Psychiatry 1984;141 (2) 253- 256
PubMed
Lippmann  SManshadi  MBaldwin  HDrasin  GWagemaker  HRice  JAlrajeh  S Cerebral CAT scan imaging in schizophrenic and bipolar patients. J Ky Med Assoc 1985;83 (1) 13- 15
PubMed
Pearlson  GDGarbacz  DJMoberg  PJAhn  HSDePaulo  JR Symptomatic, familial, perinatal, and social correlates of computerized axial tomography (CAT) changes in schizophrenics and bipolars. J Nerv Ment Dis 1985;173 (1) 42- 50
PubMed
Dewan  MJHaldipur  CVLane  EDonnelly  MPBoucher  MMajor  LF Normal cerebral asymmetry in bipolar patients. Biol Psychiatry 1987;22 (9) 1058- 1066
PubMed
Dupont  RMJernigan  TLGillin  JCButters  NDelis  DCHesselink  JR Subcortical signal hyperintensities in bipolar patients detected by MRI. Psychiatry Res 1987;21 (4) 357- 358
PubMed
Yates  WRJacoby  CGAndreasen  NC Cerebellar atrophy in schizophrenia and affective disorder. Am J Psychiatry 1987;144 (4) 465- 467
PubMed
Dewan  MJHaldipur  CVBoucher  MMajor  LF Is CT ventriculomegaly related to hypercortisolemia? Acta Psychiatr Scand 1988;77 (2) 230- 231
PubMed
Dewan  MJHaldipur  CVLane  EEIspahani  ABoucher  MFMajor  LF Bipolar affective disorder, I: comprehensive quantitative computed tomography. Acta Psychiatr Scand 1988;77 (6) 670- 676
PubMed
Iacono  WGSmith  GNMoreau  MBeiser  MFleming  JALin  TYFlak  B Ventricular and sulcal size at the onset of psychosis. Am J Psychiatry 1988;145 (7) 820- 824
PubMed
Hauser  PDauphinais  IDBerrettini  WDeLisi  LEGelernter  JPost  RM Corpus callosum dimensions measured by magnetic resonance imaging in bipolar affective disorder and schizophrenia. Biol Psychiatry 1989;26 (7) 659- 668
PubMed
Johnstone  ECOwens  DGCrow  TJFrith  CDAlexandropolis  KBydder  GColter  N Temporal lobe structure as determined by nuclear magnetic resonance in schizophrenia and bipolar affective disorder. J Neurol Neurosurg Psychiatry 1989;52 (6) 736- 741
PubMed
Andreasen  NCSwayze  V  IIFlaum  MAlliger  RCohen  G Ventricular abnormalities in affective disorder: clinical and demographic correlates. Am J Psychiatry 1990;147 (7) 893- 900
PubMed
Coffman  JABornstein  RAOlson  SCSchwarzkopf  SBNasrallah  HA Cognitive impairment and cerebral structure by MRI in bipolar disorder. Biol Psychiatry 1990;27 (11) 1188- 1196
PubMed
Dolan  RJPoynton  AMBridges  PKTrimble  MR Altered magnetic resonance white-matter T1 values in patients with affective disorder. Br J Psychiatry 1990;157107- 110
PubMed
Dupont  RMJernigan  TLButters  NDelis  DHesselink  JRHeindel  WGillin  JC Subcortical abnormalities detected in bipolar affective disorder using magnetic resonance imaging: clinical and neuropsychological significance. Arch Gen Psychiatry 1990;47 (1) 55- 59
PubMed
Harvey  IWilliams  MToone  BKLewis  SWTurner  SWMcGuffin  P The ventricular-brain ratio (VBR) in functional psychoses: the relationship of lateral ventricular and total intracranial area. Psychol Med 1990;20 (1) 55- 62
PubMed
Swayze  VW  IIAndreasen  NCAlliger  RJEhrhardt  JCYuh  WT Structural brain abnormalities in bipolar affective disorder: ventricular enlargement and focal signal hyperintensities. Arch Gen Psychiatry 1990;47 (11) 1054- 1059
PubMed
Altshuler  LLConrad  AHauser  PLi  XMGuze  BHDenikoff  KTourtellotte  WPost  R Reduction of temporal lobe volume in bipolar disorder: a preliminary report of magnetic resonance imaging. Arch Gen Psychiatry 1991;48 (5) 482- 483
PubMed
Figiel  GSKrishnan  KRRao  VPDoraiswamy  MEllinwood  EH  JrNemeroff  CBEvans  DBoyko  O Subcortical hyperintensities on brain magnetic resonance imaging: a comparison of normal and bipolar subjects. J Neuropsychiatry Clin Neurosci 1991;3 (1) 18- 22
PubMed
Lewine  RRRisch  SCRisby  EStipetic  MJewart  RDEccard  MCaudle  JPollard  W Lateral ventricle-brain ratio and balance between CSF HVA and 5-HIAA in schizophrenia. Am J Psychiatry 1991;148 (9) 1189- 1194
PubMed
McDonald  WMKrishnan  KRDoraiswamy  PMBlazer  DG Occurrence of subcortical hyperintensities in elderly subjects with mania. Psychiatry Res 1991;40 (4) 211- 220
PubMed
Brown  FWLewine  RJHudgins  PARisch  SC White matter hyperintensity signals in psychiatric and nonpsychiatric subjects. Am J Psychiatry 1992;149 (5) 620- 625
PubMed
Risch  SCLewine  RJKalin  NHJewart  RDRisby  EDCaudle  JMStipetic  MTurner  JEccard  MBPollard  WE Limbic-hypothalamic-pituitary-adrenal axis activity and ventricular-to-brain ratio studies in affective illness and schizophrenia. Neuropsychopharmacology 1992;6 (2) 95- 100
PubMed
Swayze  VW  IIAndreasen  NCAlliger  RJYuh  WTEhrhardt  JC Subcortical and temporal structures in affective disorder and schizophrenia: a magnetic resonance imaging study. Biol Psychiatry 1992;31 (3) 221- 240
PubMed
Strakowski  SMWoods  BTTohen  MWilson  DRDouglass  AWStoll  AL MRI subcortical signal hyperintensities in mania at first hospitalization. Biol Psychiatry 1993;33 (3) 204- 206
PubMed
Strakowski  SMWilson  DRTohen  MWoods  BTDouglass  AWStoll  AL Structural brain abnormalities in first-episode mania. Biol Psychiatry 1993;33 (8-9) 602- 609
PubMed
Aylward  EHRoberts-Twillie  JVBarta  PEKumar  AJHarris  GJGeer  MPeyser  CEPearlson  GD Basal ganglia volumes and white matter hyperintensities in patients with bipolar disorder. Am J Psychiatry 1994;151 (5) 687- 693
PubMed
Bullmore  EBrammer  MHarvey  IPersaud  RMurray  RRon  M Fractal analysis of the boundary between white matter and cerebral cortex in magnetic resonance images: a controlled study of schizophrenic and manic-depressive patients. Psychol Med 1994;24 (3) 771- 781
PubMed
Harvey  IPersaud  RRon  MABaker  GMurray  RM Volumetric MRI measurements in bipolars compared with schizophrenics and healthy controls. Psychol Med 1994;24 (3) 689- 699
PubMed
Kato  TShioiri  TMurashita  JHamakawa  HInubushi  TTakahashi  S Phosphorus-31 magnetic resonance spectroscopy and ventricular enlargement in bipolar disorder. Psychiatry Res 1994;55 (1) 41- 50
PubMed
Schlaepfer  TEHarris  GJTien  AYPeng  LWLee  SFederman  EBChase  GABarta  PEPearlson  GD Decreased regional cortical gray matter volume in schizophrenia. Am J Psychiatry 1994;151 (6) 842- 848
PubMed
Botteron  KNVannier  MWGeller  BTodd  RDLee  BC Preliminary study of magnetic resonance imaging characteristics in 8- to 16-year-olds with mania. J Am Acad Child Adolesc Psychiatry 1995;34 (6) 742- 749
PubMed
Dupont  RMButters  NSchafer  KWilson  THesselink  JGillin  JC Diagnostic specificity of focal white matter abnormalities in bipolar and unipolar mood disorder. Biol Psychiatry 1995;38 (7) 482- 486
PubMed
Lewine  RRHudgins  PBrown  FCaudle  JRisch  SC Differences in qualitative brain morphology findings in schizophrenia, major depression, bipolar disorder, and normal volunteers. Schizophr Res 1995;15 (3) 253- 259
PubMed
Ohaeri  JUAdeyinka  AOEnyidah  SNOsuntokun  BO Schizophrenic and manic brains in Nigerians: computerised tomography findings. Br J Psychiatry 1995;166 (4) 496- 500
PubMed
Woods  BTYurgelun-Todd  DMikulis  DPillay  SS Age-related MRI abnormalities in bipolar illness: a clinical study. Biol Psychiatry 1995;38 (12) 846- 847
PubMed
Shioiri  TOshitani  YKato  TMurashita  JHamakawa  HInubushi  TNagata  TTakahashi  S Prevalence of cavum septum pellucidum detected by MRI in patients with bipolar disorder, major depression and schizophrenia. Psychol Med 1996;26 (2) 431- 434
PubMed
Drevets  WCPrice  JLSimpson  JR  JrTodd  RDReich  TVannier  MRaichle  ME Subgenual prefrontal cortex abnormalities in mood disorders. Nature 1997;386 (6627) 824- 827
PubMed
Pearlson  GDBarta  PEPowers  REMenon  RRRichards  SSAylward  EHFederman  EBChase  GAPetty  RGTien  AY Ziskind-Somerfeld Research Award 1996: medial and superior temporal gyral volumes and cerebral asymmetry in schizophrenia versus bipolar disorder. Biol Psychiatry 1997;41 (1) 1- 14
PubMed
Persaud  RRussow  HHarvey  ILewis  SWRon  MMurray  RMdu Boulay  G Focal signal hyperintensities in schizophrenia. Schizophr Res 1997;27 (1) 55- 64
PubMed
Zipursky  RBSeeman  MVBury  ALangevin  RWortzman  GKatz  R Deficits in gray matter volume are present in schizophrenia but not bipolar disorder. Schizophr Res 1997;26 (2-3) 85- 92
PubMed
Altshuler  LLBartzokis  GGrieder  TCurran  JMintz  J Amygdala enlargement in bipolar disorder and hippocampal reduction in schizophrenia: an MRI study demonstrating neuroanatomic specificity. Arch Gen Psychiatry 1998;55 (7) 663- 664
PubMed
Roy  PDZipursky  RBSaint-Cyr  JABury  ALangevin  RSeeman  MV Temporal horn enlargement is present in schizophrenia and bipolar disorder. Biol Psychiatry 1998;44 (6) 418- 422
PubMed
Bilder  RMWu  HBogerts  BAshtari  MRobinson  DWoerner  MLieberman  JADegreef  G Cerebral volume asymmetries in schizophrenia and mood disorders: a quantitative magnetic resonance imaging study. Int J Psychophysiol 1999;34 (3) 197- 205
PubMed
Dasari  MFriedman  LJesberger  JStuve  TAFindling  RLSwales  TPSchulz  SC A magnetic resonance imaging study of thalamic area in adolescent patients with either schizophrenia or bipolar disorder as compared to healthy controls. Psychiatry Res 1999;91 (3) 155- 162
PubMed
DelBello  MPStrakowski  SMZimmerman  MEHawkins  JMSax  KW MRI analysis of the cerebellum in bipolar disorder: a pilot study. Neuropsychopharmacology 1999;21 (1) 63- 68
PubMed
Friedman  LFindling  RLKenny  JTSwales  TPStuve  TAJesberger  JALewin  JSSchulz  SC An MRI study of adolescent patients with either schizophrenia or bipolar disorder as compared to healthy control subjects. Biol Psychiatry 1999;46 (1) 78- 88
PubMed
Lim  KORosenbloom  MJFaustman  WOSullivan  EVPfefferbaum  A Cortical gray matter deficit in patients with bipolar disorder. Schizophr Res 1999;40 (3) 219- 227
PubMed
McDonald  WMTupler  LAMarsteller  FAFigiel  GSDiSouza  SNemeroff  CBKrishnan  KR Hyperintense lesions on magnetic resonance images in bipolar disorder. Biol Psychiatry 1999;45 (8) 965- 971
PubMed
Sax  KWStrakowski  SMZimmerman  MEDelBello  MPKeck  PE  JrHawkins  JM Frontosubcortical neuroanatomy and the continuous performance test in mania. Am J Psychiatry 1999;156 (1) 139- 141
PubMed
Strakowski  SMDelBello  MPSax  KWZimmerman  MEShear  PKHawkins  JMLarson  ER Brain magnetic resonance imaging of structural abnormalities in bipolar disorder. Arch Gen Psychiatry 1999;56 (3) 254- 260
PubMed
Young  RCNambudiri  DEJain  Hde Asis  JMAlexopoulos  GS Brain computed tomography in geriatric manic disorder. Biol Psychiatry 1999;45 (8) 1063- 1065
PubMed
Hauser  PMatochik  JAltshuler  LLDenicoff  KDConrad  ALi  XPost  RM MRI-based measurements of temporal lobe and ventricular structures in patients with bipolar I and bipolar II disorders. J Affect Disord 2000;60 (1) 25- 32
PubMed
Hirayasu  YMcCarley  RWSalisbury  DFTanaka  SKwon  JSFrumin  MSnyderman  DYurgelun-Todd  DKikinis  RJolesz  FAShenton  ME Planum temporale and Heschl gyrus volume reduction in schizophrenia: a magnetic resonance imaging study of first-episode patients. Arch Gen Psychiatry 2000;57 (7) 692- 699
PubMed
Krabbendam  LHonig  AWiersma  JVuurman  EFHofman  PADerix  MMNolen  WAJolles  J Cognitive dysfunctions and white matter lesions in patients with bipolar disorder in remission. Acta Psychiatr Scand 2000;101 (4) 274- 280
PubMed
Rabins  PVAylward  EHolroyd  SPearlson  G MRI findings differentiate between late-onset schizophrenia and late-life mood disorder. Int J Geriatr Psychiatry 2000;15 (10) 954- 960
PubMed
Brambilla  PHarenski  KNicoletti  MAMallinger  AGFrank  EKupfer  DJKeshavan  MSSoares  JC Anatomical MRI study of basal ganglia in bipolar disorder patients. Psychiatry Res 2001;106 (2) 65- 80
PubMed
Brambilla  PHarenski  KNicoletti  MMallinger  AGFrank  EKupfer  DJKeshavan  MSSoares  JC MRI study of posterior fossa structures and brain ventricles in bipolar patients. J Psychiatr Res 2001;35 (6) 313- 322
PubMed
Brambilla  PHarenski  KNicoletti  MMallinger  AGFrank  EKupfer  DJKeshavan  MSSoares  JC Differential effects of age on brain gray matter in bipolar patients and healthy individuals. Neuropsychobiology 2001;43 (4) 242- 247
PubMed
Caetano  SCSassi  RBrambilla  PHarenski  KNicoletti  MMallinger  AGFrank  EKupfer  DJKeshavan  MSSoares  JC MRI study of thalamic volumes in bipolar and unipolar patients and healthy individuals. Psychiatry Res 2001;108 (3) 161- 168
PubMed
McIntosh  AMForrester  ALawrie  SMByrne  MHarper  AKestelman  JNBest  JJJohnstone  ECOwens  DG A factor model of the functional psychoses and the relationship of factors to clinical variables and brain morphology. Psychol Med 2001;31 (1) 159- 171
PubMed
Moore  PBShepherd  DJEccleston  DMacmillan  ICGoswami  UMcAllister  VLFerrier  IN Cerebral white matter lesions in bipolar affective disorder: relationship to outcome. Br J Psychiatry 2001;178172- 176
PubMed
Moore  PBEl-Badri  SMCousins  DShepherd  DJYoung  AHMcAllister  VLFerrier  IN White matter lesions and season of birth of patients with bipolar affective disorder. Am J Psychiatry 2001;158 (9) 1521- 1524
PubMed
Noga  JTVladar  KTorrey  EF A volumetric magnetic resonance imaging study of monozygotic twins discordant for bipolar disorder. Psychiatry Res 2001;106 (1) 25- 34
PubMed
Sassi  RBNicoletti  MBrambilla  PHarenski  KMallinger  AGFrank  EKupfer  DJKeshavan  MSSoares  JC Decreased pituitary volume in patients with bipolar disorder. Biol Psychiatry 2001;50 (4) 271- 280
PubMed
Brambilla  PNicoletti  MAHarenski  KSassi  RBMallinger  AGFrank  EKupfer  DJKeshavan  MSSoares  JC Anatomical MRI study of subgenual prefrontal cortex in bipolar and unipolar subjects. Neuropsychopharmacology 2002;27 (5) 792- 799
PubMed
Getz  GEDelBello  MPFleck  DEZimmerman  MESchwiers  MLStrakowski  SM Neuroanatomic characterization of schizoaffective disorder using MRI: a pilot study. Schizophr Res 2002;55 (1-2) 55- 59
PubMed
Lyoo  IKLee  HKJung  JHNoam  GGRenshaw  PF White matter hyperintensities on magnetic resonance imaging of the brain in children with psychiatric disorders. Compr Psychiatry 2002;43 (5) 361- 368
PubMed
Pillai  JJFriedman  LStuve  TATrinidad  SJesberger  JALewin  JSFindling  RLSwales  TPSchulz  SC Increased presence of white matter hyperintensities in adolescent patients with bipolar disorder. Psychiatry Res 2002;114 (1) 51- 56
PubMed
Strakowski  SMDelBello  MPZimmerman  MEGetz  GEMills  NPRet  JShear  PAdler  CM Ventricular and periventricular structural volumes in first- versus multiple-episode bipolar disorder. Am J Psychiatry 2002;159 (11) 1841- 1847
PubMed
Bertolino  AFrye  MCallicott  JHMattay  VSRakow  RShelton-Repella  JPost  RWeinberger  DR Neuronal pathology in the hippocampal area of patients with bipolar disorder: a study with proton magnetic resonance spectroscopic imaging. Biol Psychiatry 2003;53 (10) 906- 913
PubMed
Blumberg  HPKaufman  JMartin  AWhiteman  RZhang  JHGore  JCCharney  DSKrystal  JHPeterson  BS Amygdala and hippocampal volumes in adolescents and adults with bipolar disorder. Arch Gen Psychiatry 2003;60 (12) 1201- 1208
PubMed
Brambilla  PHarenski  KNicoletti  MSassi  RBMallinger  AGFrank  EKupfer  DJKeshavan  MSSoares  JC MRI investigation of temporal lobe structures in bipolar patients. J Psychiatr Res 2003;37 (4) 287- 295
PubMed
Brambilla  PNicoletti  MASassi  RBMallinger  AGFrank  EKupfer  DJKeshavan  MSSoares  JC Magnetic resonance imaging study of corpus callosum abnormalities in patients with bipolar disorder. Biol Psychiatry 2003;54 (11) 1294- 1297
PubMed
Sassi  RBBrambilla  PNicoletti  MMallinger  AGFrank  EKupfer  DJKeshavan  MSSoares  JC White matter hyperintensities in bipolar and unipolar patients with relatively mild-to-moderate illness severity. J Affect Disord 2003;77 (3) 237- 245
PubMed
Sharma  VMenon  RCarr  TJDensmore  MMazmanian  DWilliamson  PC An MRI study of subgenual prefrontal cortex in patients with familial and non-familial bipolar I disorder. J Affect Disord 2003;77 (2) 167- 171
PubMed
Silverstone  TMcPherson  HLi  QDoyle  T Deep white matter hyperintensities in patients with bipolar depression, unipolar depression and age-matched control subjects. Bipolar Disord 2003;5 (1) 53- 57
PubMed
Ahn  KHLyoo  IKLee  HKSong  ICOh  JSHwang  JKwon  JKim  MJKim  MRenshaw  PF White matter hyperintensities in subjects with bipolar disorder. Psychiatry Clin Neurosci 2004;58 (5) 516- 521
PubMed
Beyer  JLKuchibhatla  MPayne  MMoo-Young  MCassidy  FMacFall  JKrishnan  KR Caudate volume measurement in older adults with bipolar disorder. Int J Geriatr Psychiatry 2004;19 (2) 109- 114
PubMed
Brambilla  PNicoletti  MSassi  RBMallinger  AGFrank  EKeshavan  MSSoares  JC Corpus callosum signal intensity in patients with bipolar and unipolar disorder. J Neurol Neurosurg Psychiatry 2004;75 (2) 221- 225
PubMed
Chen  BKSassi  RAxelson  DHatch  JPSanches  MNicoletti  MBrambilla  PKeshavan  MSRyan  NDBirmaher  BSoares  JC Cross-sectional study of abnormal amygdala development in adolescents and young adults with bipolar disorder. Biol Psychiatry 2004;56 (6) 399- 405
PubMed
Chen  HHNicoletti  MAHatch  JPSassi  RBAxelson  DBrambilla  PMonkul  ESKeshavan  MSRyan  NDBirmaher  BSoares  JC Abnormal left superior temporal gyrus volumes in children and adolescents with bipolar disorder: a magnetic resonance imaging study. Neurosci Lett 2004;363 (1) 65- 68
PubMed
Chen  HHNicoletti  MSanches  MHatch  JPSassi  RBAxelson  DBrambilla  PKeshavan  MSRyan  NBirmaher  BSoares  JC Normal pituitary volumes in children and adolescents with bipolar disorder: a magnetic resonance imaging study. Depress Anxiety 2004;20 (4) 182- 186
PubMed
Connor  SENg  VMcDonald  CSchulze  KMorgan  KDazzan  PMurray  RM A study of hippocampal shape anomaly in schizophrenia and in families multiply affected by schizophrenia or bipolar disorder. Neuroradiology 2004;46 (7) 523- 534
PubMed
Davis  KAKwon  ACardenas  VADeicken  RF Decreased cortical gray and cerebral white matter in male patients with familial bipolar I disorder. J Affect Disord 2004;82 (3) 475- 485
PubMed
DelBello  MPZimmerman  MEMills  NPGetz  GEStrakowski  SM Magnetic resonance imaging analysis of amygdala and other subcortical brain regions in adolescents with bipolar disorder. Bipolar Disord 2004;6 (1) 43- 52
PubMed
Hirashima  FParow  AMStoll  ALDemopulos  CMDamico  KERohan  MLEskesen  JGZuo  CSCohen  BMRenshaw  PF Omega-3 fatty acid treatment and T(2) whole brain relaxation times in bipolar disorder. Am J Psychiatry 2004;161 (10) 1922- 1924
PubMed
Sassi  RBBrambilla  PHatch  JPNicoletti  MAMallinger  AGFrank  EKupfer  DJKeshavan  MSSoares  JC Reduced left anterior cingulate volumes in untreated bipolar patients. Biol Psychiatry 2004;56 (7) 467- 475
PubMed
Supprian  TReiche  WSchmitz  BGrunwald  IBackens  MHofmann  EGeorg  TFalkai  PReith  W MRI of the brainstem in patients with major depression, bipolar affective disorder and normal controls. Psychiatry Res 2004;131 (3) 269- 276
PubMed
Blumberg  HPFredericks  CWang  FKalmar  JHSpencer  LPapademetris  XPittman  BMartin  APeterson  BSFulbright  RKKrystal  JH Preliminary evidence for persistent abnormalities in amygdala volumes in adolescents and young adults with bipolar disorder. Bipolar Disord 2005;7 (6) 570- 576
PubMed
Chang  KBarnea-Goraly  NKarchemskiy  ASimeonova  DIBarnes  PKetter  TReiss  AL Cortical magnetic resonance imaging findings in familial pediatric bipolar disorder. Biol Psychiatry 2005;58 (3) 197- 203
PubMed
Frazier  JABreeze  JLMakris  NGiuliano  ASHerbert  MRSeidman  LBiederman  JHodge  SMDieterich  MEGerstein  EDKennedy  DNRauch  SLCohen  BMCaviness  VS Cortical gray matter differences identified by structural magnetic resonance imaging in pediatric bipolar disorder. Bipolar Disord 2005;7 (6) 555- 569
PubMed
Mills  NPDelbello  MPAdler  CMStrakowski  SM MRI analysis of cerebellar vermal abnormalities in bipolar disorder. Am J Psychiatry 2005;162 (8) 1530- 1532
PubMed
Pariante  CMDazzan  PDanese  AMorgan  KDBrudaglio  FMorgan  CFearon  POrr  KHutchinson  GPantelis  CVelakoulis  DJones  PBLeff  JMurray  RM Increased pituitary volume in antipsychotic-free and antipsychotic-treated patients of the AEsop first-onset psychosis study. Neuropsychopharmacology 2005;30 (10) 1923- 1931
PubMed
Sanches  MSassi  RBAxelson  DNicoletti  MBrambilla  PHatch  JPKeshavan  MSRyan  NDBirmaher  BSoares  JC Subgenual prefrontal cortex of child and adolescent bipolar patients: a morphometric magnetic resonance imaging study. Psychiatry Res 2005;138 (1) 43- 49
PubMed
Sanches  MRoberts  RLSassi  RBAxelson  DNicoletti  MBrambilla  PHatch  JPKeshavan  MSRyan  NDBirmaher  BSoares  JC Developmental abnormalities in striatum in young bipolar patients: a preliminary study. Bipolar Disord 2005;7 (2) 153- 158
PubMed
Strasser  HCLilyestrom  JAshby  ERHoneycutt  NASchretlen  DJPulver  AEHopkins  RODepaulo  JRPotash  JBSchweizer  BYates  KOKurian  EBarta  PEPearlson  GD Hippocampal and ventricular volumes in psychotic and nonpsychotic bipolar patients compared with schizophrenia patients and community control subjects: a pilot study. Biol Psychiatry 2005;57 (6) 633- 639
PubMed
Atmaca  MYildirim  HOzdemir  HPoyraz  AKTezcan  EOgur  E Hippocampal 1H MRS in first-episode bipolar I patients. Prog Neuropsychopharmacol Biol Psychiatry 2006;30 (7) 1235- 1239
PubMed
Blumberg  HPKrystal  JHBansal  RMartin  ADziura  JDurkin  KMartin  LGerard  ECharney  DSPeterson  BS Age, rapid-cycling, and pharmacotherapy effects on ventral prefrontal cortex in bipolar disorder: a cross-sectional study. Biol Psychiatry 2006;59 (7) 611- 618
PubMed
Coyle  TRKochunov  PPatel  RDNery  FGLancaster  JLMangin  JFRiviere  DPillow  DRDavis  GJNicoletti  MASerap Monkul  EFox  PTSoares  JC Cortical sulci and bipolar disorder. Neuroreport 2006;17 (16) 1739- 1742
PubMed
El-Badri  SMCousins  DAParker  SAshton  HCMcAllister  VLFerrier  INMoore  PB Magnetic resonance imaging abnormalities in young euthymic patients with bipolar affective disorder. Br J Psychiatry 2006;18981- 82
PubMed
Hwang  JLyoo  IKDager  SRFriedman  SDOh  JSLee  JYKim  SJDunner  DLRenshaw  PF Basal ganglia shape alterations in bipolar disorder. Am J Psychiatry 2006;163 (2) 276- 285
PubMed
McDonald  CMarshall  NSham  PCBullmore  ETSchulze  KChapple  BBramon  EFilbey  FQuraishi  SWalshe  MMurray  RM Regional brain morphometry in patients with schizophrenia or bipolar disorder and their unaffected relatives. Am J Psychiatry 2006;163 (3) 478- 487
PubMed
Monkul  ESNicoletti  MASpence  DSassi  RBAxelson  DBrambilla  PHatch  JPKeshavan  MRyan  NBirmaher  BSoares  JC MRI study of thalamus volumes in juvenile patients with bipolar disorder. Depress Anxiety 2006;23 (6) 347- 352
PubMed
Pardo  PJGeorgopoulos  APKenny  JTStuve  TAFindling  RLSchulz  SC Classification of adolescent psychotic disorders using linear discriminant analysis. Schizophr Res 2006;87 (1-3) 297- 306
PubMed
Velakoulis  DWood  SJWong  MTMcGorry  PDYung  APhillips  LSmith  DBrewer  WProffitt  TDesmond  PPantelis  C Hippocampal and amygdala volumes according to psychosis stage and diagnosis: a magnetic resonance imaging study of chronic schizophrenia, first-episode psychosis, and ultra-high-risk individuals. Arch Gen Psychiatry 2006;63 (2) 139- 149
PubMed
Voelbel  GTBates  MEBuckman  JFPandina  GHendren  RL Caudate nucleus volume and cognitive performance: are they related in childhood psychopathology? Biol Psychiatry 2006;60 (9) 942- 950
PubMed
Yasar  ASMonkul  ESSassi  RBAxelson  DBrambilla  PNicoletti  MAHatch  JPKeshavan  MRyan  NBirmaher  BSoares  JC MRI study of corpus callosum in children and adolescents with bipolar disorder. Psychiatry Res 2006;146 (1) 83- 85
PubMed
Ahn  MSBreeze  JLMakris  NKennedy  DNHodge  SMHerbert  MRSeidman  LJBiederman  JCaviness  VSFrazier  JA Anatomic brain magnetic resonance imaging of the basal ganglia in pediatric bipolar disorder. J Affect Disord 2007;104 (1-3) 147- 154
PubMed
Atmaca  MYildirim  HOzdemir  HOgur  ETezcan  E Hippocampal 1H MRS in patients with bipolar disorder taking valproate versus valproate plus quetiapine. Psychol Med 2007;37 (1) 121- 129
PubMed
Atmaca  MOzdemir  HYildirim  H Corpus callosum areas in first-episode patients with bipolar disorder. Psychol Med 2007;37 (5) 699- 704
PubMed
Atmaca  MOzdemir  HCetinkaya  SParmaksiz  SBelli  HPoyraz  AKTezcan  EOgur  E Cingulate gyrus volumetry in drug free bipolar patients and patients treated with valproate or valproate and quetiapine. J Psychiatr Res 2007;41 (10) 821- 827
PubMed
Bearden  CEThompson  PMDutton  RAFrey  BNPeluso  MANicoletti  MDierschke  NHayashi  KMKlunder  ADGlahn  DCBrambilla  PSassi  RBMallinger  AGSoares  JC Three-dimensional mapping of hippocampal anatomy in unmedicated and lithium-treated patients with bipolar disorder [published online ahead of print August 8, 2007]. Neuropsychopharmacology 2008;33 (6) 1229- 123810.1038/sj.npp.1301507
PubMed
Chiu  SWidjaja  FBates  MEVoelbel  GTPandina  GMarble  JBlank  JADay  JBrule  NHendren  RL Anterior cingulate volume in pediatric bipolar disorder and autism [published online ahead of print June 13, 2007]. J Affect Disord 2008;105 (1-3) 93- 99
PubMed10.1016/j.jad.2007.04.019
Kim  MJLyoo  IKDager  SRFriedman  SDChey  JHwang  JLee  YJDunner  DLRenshaw  PF The occurrence of cavum septi pellucidi enlargement is increased in bipolar disorder patients. Bipolar Disord 2007;9 (3) 274- 280
PubMed
Molina  VSanchez  JSanz  JReig  SBenito  CLeal  ISarramea  FRebolledo  RPalomo  TDesco  M Dorsolateral prefrontal N-acetyl-aspartate concentration in male patients with chronic schizophrenia and with chronic bipolar disorder. Eur Psychiatry 2007;22 (8) 505- 512
PubMed
Najt  PNicoletti  MChen  HHHatch  JPCaetano  SCSassi  RBAxelson  DBrambilla  PKeshavan  MSRyan  NDBirmaher  BSoares  JC Anatomical measurements of the orbitofrontal cortex in child and adolescent patients with bipolar disorder. Neurosci Lett 2007;413 (3) 183- 186
PubMed
Rosso  IMKillgore  WDCintron  CMGruber  SATohen  MYurgelun-Todd  DA Reduced amygdala volumes in first-episode bipolar disorder and correlation with cerebral white matter. Biol Psychiatry 2007;61 (6) 743- 749
PubMed
Salisbury  DFKuroki  NKasai  KShenton  MEMcCarley  RW Progressive and interrelated functional and structural evidence of post-onset brain reduction in schizophrenia. Arch Gen Psychiatry 2007;64 (5) 521- 529
PubMed
Yucel  KTaylor  VHMcKinnon  MCMacdonald  KAlda  MYoung  LTMacQueen  GM Bilateral hippocampal volume increase in patients with bipolar disorder and short-term lithium treatment [published online ahead of print April 4, 2007]. Neuropsychopharmacology 2008;33 (2) 361- 367
PubMed10.1038/sj.npp.1301405
Yucel  KMcKinnon  MCTaylor  VHMacdonald  KAlda  MYoung  LTMacQueen  GM Bilateral hippocampal volume increases after long-term lithium treatment in patients with bipolar disorder: a longitudinal MRI study. Psychopharmacology (Berl) 2007;195 (3) 357- 367
PubMed
Baldwin  RC Is vascular depression a distinct sub-type of depressive disorder? A review of causal evidence. Int J Geriatr Psychiatry 2005;20 (1) 1- 11
PubMed
de Groot  JCde Leeuw  FEOudkerk  MHofman  AJolles  JBreteler  MM Cerebral white matter lesions and depressive symptoms in elderly adults. Arch Gen Psychiatry 2000;57 (11) 1071- 1076
PubMed
Berlin  JASantanna  JSchmid  CHSzczech  LAFeldman  HI Individual patient- versus group-level data meta-regressions for the investigation of treatment effect modifiers: ecological bias rears its ugly head. Stat Med 2002;21 (3) 371- 387
PubMed
Harrison  PJWeinberger  DR Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2005;10 (1) 40- 68
PubMed
Harrison  PJ The neuropathology of primary mood disorder. Brain 2002;125 (pt 7) 1428- 1449
PubMed
Gootjes  LTeipel  SJZebuhr  YSchwarz  RLeinsinger  GScheltens  PMoller  HJHampel  H Regional distribution of white matter hyperintensities in vascular dementia, Alzheimer's disease and healthy aging. Dement Geriatr Cogn Disord 2004;18 (2) 180- 188
PubMed
Thomas  AJPerry  RBarber  RKalaria  RNO'Brien  JT Pathologies and pathological mechanisms for white matter hyperintensities in depression. Ann N Y Acad Sci 2002;977333- 339
PubMed
Shenton  MEDickey  CCFrumin  MMcCarley  RW A review of MRI findings in schizophrenia. Schizophr Res 2001;49 (1-2) 1- 52
PubMed
McCarley  RWWible  CGFrumin  MHirayasu  YLevitt  JJFischer  IAShenton  ME MRI anatomy of schizophrenia. Biol Psychiatry 1999;45 (9) 1099- 1119
PubMed
Campbell  SMarriott  MNahmias  CMacQueen  GM Lower hippocampal volume in patients suffering from depression: a meta-analysis. Am J Psychiatry 2004;161 (4) 598- 607
PubMed
Videbech  PRavnkilde  B Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatry 2004;161 (11) 1957- 1966
PubMed
Jiang  HGuo  WLiang  XRao  Y Both the establishment and the maintenance of neuronal polarity require active mechanisms: critical roles of GSK-3beta and its upstream regulators. Cell 2005;120 (1) 123- 135
PubMed
Regier  DAFarmer  MERae  DSLocke  BZKeith  SJJudd  LLGoodwin  FK Comorbidity of mental disorders with alcohol and other drug abuse: results from the Epidemiologic Catchment Area (ECA) Study. JAMA 1990;264 (19) 2511- 2518
PubMed
Rosenbloom  MSullivan  EVPfefferbaum  A Using magnetic resonance imaging and diffusion tensor imaging to assess brain damage in alcoholics. Alcohol Res Health 2003;27 (2) 146- 152
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Total number of subjects (patients + controls) per study over time.

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

Number of bipolar structural imaging studies per year.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Continuous variables from the bipolar-control meta-analysis. Effect size is shown for each structure with 95% confidence intervals. The effect size is positive when the structure is larger in patients with bipolar disorder compared to controls and negative when the structure is smaller in patients with bipolar disorder. Red bars represent significant differences, and blue bars are nonsignificant differences. n Indicates the number of studies included in each meta-analysis. The values at the top of the figure indicate the number of required patients for a future study to be sufficiently powered, assuming within-study heterogeneity is similar to studies included in the meta-analysis.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Binary variables from the bipolar-control meta-analysis. Odds ratios are shown for each type of hyperintensity with 95% confidence intervals. An odds ratio greater than 1 means the hyperintensity is more common in patients with bipolar disorder than controls. Red bars represent significant differences, and blue bars are nonsignificant differences. n Indicates the number of studies included in each meta-analysis.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 5.

Comparison of our meta-analysis (A) and the meta-analysis of patients with schizophrenia by Wright et al26 (B). Only regions investigated by both studies are shown. Computed tomographic studies have been excluded from our analysis, and effect sizes are calculated from percentage increase or decrease in structure size compared with the control group to match the methods used by Wright et al; as such, the significance of results may vary from Figure 3 (see also “Sensitivity Analysis” subsection in the text). Red bars represent significant differences, and blue bars are nonsignificant differences.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. List of Studies Included in the Databasea
Table Graphic Jump LocationTable 2. Patient and Control Demographic and Clinical Data Recorded in the Database
Table Graphic Jump LocationTable 3. Meta-analysis of Continuous Data Comparing Patients With Bipolar Disorder to Controlsa
Table Graphic Jump LocationTable 4. Meta-analysis of Binary Data Comparing Patients With Bipolar Disorder to Controlsa
Table Graphic Jump LocationTable 5. Sensitivity of the Results to Different Analysis Methods
Table Graphic Jump LocationTable 6. Meta-analysis of Continuous Data and Binary Data Comparing Patients With Bipolar Disorder With Patients With Schizophreniaa

References

Chang  KKarchemskiy  ABarnea-Goraly  NGarrett  ASimeonova  DIReiss  A Reduced amygdalar gray matter volume in familial pediatric bipolar disorder. J Am Acad Child Adolesc Psychiatry 2005;44 (6) 565- 573
PubMed
Altshuler  LLBartzokis  GGrieder  TCurran  JJimenez  TLeight  KWilkins  JGerner  RMintz  J An MRI study of temporal lobe structures in men with bipolar disorder or schizophrenia. Biol Psychiatry 2000;48 (2) 147- 162
PubMed
Frazier  JAChiu  SBreeze  JLMakris  NLange  NKennedy  DNHerbert  MRBent  EKKoneru  VKDieterich  MEHodge  SMRauch  SLGrant  PECohen  BMSeidman  LJCaviness  VSBiederman  J Structural brain magnetic resonance imaging of limbic and thalamic volumes in pediatric bipolar disorder. Am J Psychiatry 2005;162 (7) 1256- 1265
PubMed
Beyer  JLKuchibhatla  MPayne  MEMoo-Young  MCassidy  FMacfall  JKrishnan  KR Hippocampal volume measurement in older adults with bipolar disorder. Am J Geriatr Psychiatry 2004;12 (6) 613- 620
PubMed
Dupont  RMJernigan  TLHeindel  WButters  NShafer  KWilson  THesselink  JGillin  JC Magnetic resonance imaging and mood disorders: localization of white matter and other subcortical abnormalities. Arch Gen Psychiatry 1995;52 (9) 747- 755
PubMed
Altshuler  LLCurran  JGHauser  PMintz  JDenicoff  KPost  R T2 hyperintensities in bipolar disorder: magnetic resonance imaging comparison and literature meta-analysis. Am J Psychiatry 1995;152 (8) 1139- 1144
PubMed
Videbech  P MRI findings in patients with affective disorder: a meta-analysis. Acta Psychiatr Scand 1997;96 (3) 157- 168
PubMed
Elkis  HFriedman  LWise  AMeltzer  HY Meta-analyses of studies of ventricular enlargement and cortical sulcal prominence in mood disorders: comparisons with controls or patients with schizophrenia. Arch Gen Psychiatry 1995;52 (9) 735- 746
PubMed
McDonald  CZanelli  JRabe-Hesketh  SEllison-Wright  ISham  PKalidindi  SMurray  RMKennedy  N Meta-analysis of magnetic resonance imaging brain morphometry studies in bipolar disorder. Biol Psychiatry 2004;56 (6) 411- 417
PubMed
Gulseren  SGurcan  MGulseren  LGelal  FErol  A T2 hyperintensities in bipolar patients and their healthy siblings. Arch Med Res 2006;37 (1) 79- 85
PubMed
López-Larson  MPDelBello  MPZimmerman  MESchwiers  MLStrakowski  SM Regional prefrontal gray and white matter abnormalities in bipolar disorder. Biol Psychiatry 2002;52 (2) 93- 100
PubMed
de Asis  JMGreenwald  BSAlexopoulos  GSKiosses  DNAshtari  MHeo  MYoung  RC Frontal signal hyperintensities in mania in old age. Am J Geriatr Psychiatry 2006;14 (7) 598- 604
PubMed
Kaur  SSassi  RBAxelson  DNicoletti  MBrambilla  PMonkul  ESHatch  JPKeshavan  MSRyan  NBirmaher  BSoares  JC Cingulate cortex anatomical abnormalities in children and adolescents with bipolar disorder. Am J Psychiatry 2005;162 (9) 1637- 1643
PubMed
Haznedar  MMRoversi  FPallanti  SBaldini-Rossi  NSchnur  DBLicalzi  EMTang  CHof  PRHollander  EBuchsbaum  MS Fronto-thalamo-striatal gray and white matter volumes and anisotropy of their connections in bipolar spectrum illnesses. Biol Psychiatry 2005;57 (7) 733- 742
PubMed
Zimmerman  MEDelBello  MPGetz  GEShear  PKStrakowski  SM Anterior cingulate subregion volumes and executive function in bipolar disorder. Bipolar Disord 2006;8 (3) 281- 288
PubMed
Sassi  RBNicoletti  MBrambilla  PMallinger  AGFrank  EKupfer  DJKeshavan  MSSoares  JC Increased gray matter volume in lithium-treated bipolar disorder patients. Neurosci Lett 2002;329 (2) 243- 245
PubMed
Kieseppä  Tvan Erp  TGHaukka  JPartonen  TCannon  TDPoutanen  VPKaprio  JLonnqvist  J Reduced left hemispheric white matter volume in twins with bipolar I disorder. Biol Psychiatry 2003;54 (9) 896- 905
PubMed
Bearden  CEThompson  PMDalwani  MHayashi  KMLee  ADNicoletti  MTrakhtenbroit  MGlahn  DCBrambilla  PSassi  RBMallinger  AGFrank  EKupfer  DJSoares  JC Greater cortical gray matter density in lithium-treated patients with bipolar disorder. Biol Psychiatry 2007;62 (1) 7- 16
PubMed
Moore  GJBebchuk  JMWilds  IBChen  GManji  HK Lithium-induced increase in human brain grey matter [published correction appears in Lancet. 2000;356(9247):2104]. Lancet 2000;356 (9237) 1241- 1242
PubMed
Fukumoto  TMorinobu  SOkamoto  YKagaya  AYamawaki  S Chronic lithium treatment increases the expression of brain-derived neurotrophic factor in the rat brain. Psychopharmacology (Berl) 2001;158 (1) 100- 106
PubMed
Chakos  MHLieberman  JABilder  RMBorenstein  MLerner  GBogerts  BWu  HKinon  BAshtari  M Increase in caudate nuclei volumes of first-episode schizophrenic patients taking antipsychotic drugs. Am J Psychiatry 1994;151 (10) 1430- 1436
PubMed
Keshavan  MSBagwell  WWHaas  GLSweeney  JASchooler  NRPettegrew  JW Changes in caudate volume with neuroleptic treatment. Lancet 1994;344 (8934) 1434
PubMed
 GPOWER: A priori, post-hoc, and compromise power analyses for MS-DOS [computer program]. Version 2.0. Bonn, Germany Bonn University Dept of Psychology1992;
Hedges  LVOlkin  I Statistical Methods for Meta-analysis.  Orlando, FL Academic Press1985;
DerSimonian  RLaird  N Meta-analysis in clinical trials. Control Clin Trials 1986;7 (3) 177- 188
PubMed
Wright  ICRabe-Hesketh  SWoodruff  PWDavid  ASMurray  RMBullmore  ET Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry 2000;157 (1) 16- 25
PubMed
Sutton  AJ Methods for Meta-analysis in Medical Research.  Chichester, NY Wiley2000;
Higgins  JPThompson  SGDeeks  JJAltman  DG Measuring inconsistency in meta-analyses. BMJ 2003;327 (7414) 557- 560
PubMed
Egger  MDavey Smith  GSchneider  MMinder  C Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315 (7109) 629- 634
PubMed
Thompson  SGHiggins  JP How should meta-regression analyses be undertaken and interpreted? Stat Med 2002;21 (11) 1559- 1573
PubMed
Nasrallah  HAJacoby  CGMcCalley-Whitters  M Cerebellar atrophy in schizophrenia and mania. Lancet 1981;1 (8229) 1102
PubMed
Lippmann  SManshadi  MBaldwin  HDrasin  GRice  JAlrajeh  S Cerebellar vermis dimensions on computerized tomographic scans of schizophrenic and bipolar patients. Am J Psychiatry 1982;139 (5) 667- 668
PubMed
Nasrallah  HAMcCalley-Whitters  MJacoby  CG Cerebral ventricular enlargement in young manic males: a controlled CT study. J Affect Disord 1982;4 (1) 15- 19
PubMed
Nasrallah  HAMcCalley-Whitters  MJacoby  CG Cortical atrophy in schizophrenia and mania: a comparative CT study. J Clin Psychiatry 1982;43 (11) 439- 441
PubMed
Rangel-Guerra  RAPerez-Payan  HMinkoff  LTodd  LE Nuclear magnetic resonance in bipolar affective disorders. AJNR Am J Neuroradiol 1983;4 (3) 229- 231
PubMed
Pearlson  GDGarbacz  DJTompkins  RHAhn  HSGutterman  DFVeroff  AEDePaulo  JR Clinical correlates of lateral ventricular enlargement in bipolar affective disorder. Am J Psychiatry 1984;141 (2) 253- 256
PubMed
Lippmann  SManshadi  MBaldwin  HDrasin  GWagemaker  HRice  JAlrajeh  S Cerebral CAT scan imaging in schizophrenic and bipolar patients. J Ky Med Assoc 1985;83 (1) 13- 15
PubMed
Pearlson  GDGarbacz  DJMoberg  PJAhn  HSDePaulo  JR Symptomatic, familial, perinatal, and social correlates of computerized axial tomography (CAT) changes in schizophrenics and bipolars. J Nerv Ment Dis 1985;173 (1) 42- 50
PubMed
Dewan  MJHaldipur  CVLane  EDonnelly  MPBoucher  MMajor  LF Normal cerebral asymmetry in bipolar patients. Biol Psychiatry 1987;22 (9) 1058- 1066
PubMed
Dupont  RMJernigan  TLGillin  JCButters  NDelis  DCHesselink  JR Subcortical signal hyperintensities in bipolar patients detected by MRI. Psychiatry Res 1987;21 (4) 357- 358
PubMed
Yates  WRJacoby  CGAndreasen  NC Cerebellar atrophy in schizophrenia and affective disorder. Am J Psychiatry 1987;144 (4) 465- 467
PubMed
Dewan  MJHaldipur  CVBoucher  MMajor  LF Is CT ventriculomegaly related to hypercortisolemia? Acta Psychiatr Scand 1988;77 (2) 230- 231
PubMed
Dewan  MJHaldipur  CVLane  EEIspahani  ABoucher  MFMajor  LF Bipolar affective disorder, I: comprehensive quantitative computed tomography. Acta Psychiatr Scand 1988;77 (6) 670- 676
PubMed
Iacono  WGSmith  GNMoreau  MBeiser  MFleming  JALin  TYFlak  B Ventricular and sulcal size at the onset of psychosis. Am J Psychiatry 1988;145 (7) 820- 824
PubMed
Hauser  PDauphinais  IDBerrettini  WDeLisi  LEGelernter  JPost  RM Corpus callosum dimensions measured by magnetic resonance imaging in bipolar affective disorder and schizophrenia. Biol Psychiatry 1989;26 (7) 659- 668
PubMed
Johnstone  ECOwens  DGCrow  TJFrith  CDAlexandropolis  KBydder  GColter  N Temporal lobe structure as determined by nuclear magnetic resonance in schizophrenia and bipolar affective disorder. J Neurol Neurosurg Psychiatry 1989;52 (6) 736- 741
PubMed
Andreasen  NCSwayze  V  IIFlaum  MAlliger  RCohen  G Ventricular abnormalities in affective disorder: clinical and demographic correlates. Am J Psychiatry 1990;147 (7) 893- 900
PubMed
Coffman  JABornstein  RAOlson  SCSchwarzkopf  SBNasrallah  HA Cognitive impairment and cerebral structure by MRI in bipolar disorder. Biol Psychiatry 1990;27 (11) 1188- 1196
PubMed
Dolan  RJPoynton  AMBridges  PKTrimble  MR Altered magnetic resonance white-matter T1 values in patients with affective disorder. Br J Psychiatry 1990;157107- 110
PubMed
Dupont  RMJernigan  TLButters  NDelis  DHesselink  JRHeindel  WGillin  JC Subcortical abnormalities detected in bipolar affective disorder using magnetic resonance imaging: clinical and neuropsychological significance. Arch Gen Psychiatry 1990;47 (1) 55- 59
PubMed
Harvey  IWilliams  MToone  BKLewis  SWTurner  SWMcGuffin  P The ventricular-brain ratio (VBR) in functional psychoses: the relationship of lateral ventricular and total intracranial area. Psychol Med 1990;20 (1) 55- 62
PubMed
Swayze  VW  IIAndreasen  NCAlliger  RJEhrhardt  JCYuh  WT Structural brain abnormalities in bipolar affective disorder: ventricular enlargement and focal signal hyperintensities. Arch Gen Psychiatry 1990;47 (11) 1054- 1059
PubMed
Altshuler  LLConrad  AHauser  PLi  XMGuze  BHDenikoff  KTourtellotte  WPost  R Reduction of temporal lobe volume in bipolar disorder: a preliminary report of magnetic resonance imaging. Arch Gen Psychiatry 1991;48 (5) 482- 483
PubMed
Figiel  GSKrishnan  KRRao  VPDoraiswamy  MEllinwood  EH  JrNemeroff  CBEvans  DBoyko  O Subcortical hyperintensities on brain magnetic resonance imaging: a comparison of normal and bipolar subjects. J Neuropsychiatry Clin Neurosci 1991;3 (1) 18- 22
PubMed
Lewine  RRRisch  SCRisby  EStipetic  MJewart  RDEccard  MCaudle  JPollard  W Lateral ventricle-brain ratio and balance between CSF HVA and 5-HIAA in schizophrenia. Am J Psychiatry 1991;148 (9) 1189- 1194
PubMed
McDonald  WMKrishnan  KRDoraiswamy  PMBlazer  DG Occurrence of subcortical hyperintensities in elderly subjects with mania. Psychiatry Res 1991;40 (4) 211- 220
PubMed
Brown  FWLewine  RJHudgins  PARisch  SC White matter hyperintensity signals in psychiatric and nonpsychiatric subjects. Am J Psychiatry 1992;149 (5) 620- 625
PubMed
Risch  SCLewine  RJKalin  NHJewart  RDRisby  EDCaudle  JMStipetic  MTurner  JEccard  MBPollard  WE Limbic-hypothalamic-pituitary-adrenal axis activity and ventricular-to-brain ratio studies in affective illness and schizophrenia. Neuropsychopharmacology 1992;6 (2) 95- 100
PubMed
Swayze  VW  IIAndreasen  NCAlliger  RJYuh  WTEhrhardt  JC Subcortical and temporal structures in affective disorder and schizophrenia: a magnetic resonance imaging study. Biol Psychiatry 1992;31 (3) 221- 240
PubMed
Strakowski  SMWoods  BTTohen  MWilson  DRDouglass  AWStoll  AL MRI subcortical signal hyperintensities in mania at first hospitalization. Biol Psychiatry 1993;33 (3) 204- 206
PubMed
Strakowski  SMWilson  DRTohen  MWoods  BTDouglass  AWStoll  AL Structural brain abnormalities in first-episode mania. Biol Psychiatry 1993;33 (8-9) 602- 609
PubMed
Aylward  EHRoberts-Twillie  JVBarta  PEKumar  AJHarris  GJGeer  MPeyser  CEPearlson  GD Basal ganglia volumes and white matter hyperintensities in patients with bipolar disorder. Am J Psychiatry 1994;151 (5) 687- 693
PubMed
Bullmore  EBrammer  MHarvey  IPersaud  RMurray  RRon  M Fractal analysis of the boundary between white matter and cerebral cortex in magnetic resonance images: a controlled study of schizophrenic and manic-depressive patients. Psychol Med 1994;24 (3) 771- 781
PubMed
Harvey  IPersaud  RRon  MABaker  GMurray  RM Volumetric MRI measurements in bipolars compared with schizophrenics and healthy controls. Psychol Med 1994;24 (3) 689- 699
PubMed
Kato  TShioiri  TMurashita  JHamakawa  HInubushi  TTakahashi  S Phosphorus-31 magnetic resonance spectroscopy and ventricular enlargement in bipolar disorder. Psychiatry Res 1994;55 (1) 41- 50
PubMed
Schlaepfer  TEHarris  GJTien  AYPeng  LWLee  SFederman  EBChase  GABarta  PEPearlson  GD Decreased regional cortical gray matter volume in schizophrenia. Am J Psychiatry 1994;151 (6) 842- 848
PubMed
Botteron  KNVannier  MWGeller  BTodd  RDLee  BC Preliminary study of magnetic resonance imaging characteristics in 8- to 16-year-olds with mania. J Am Acad Child Adolesc Psychiatry 1995;34 (6) 742- 749
PubMed
Dupont  RMButters  NSchafer  KWilson  THesselink  JGillin  JC Diagnostic specificity of focal white matter abnormalities in bipolar and unipolar mood disorder. Biol Psychiatry 1995;38 (7) 482- 486
PubMed
Lewine  RRHudgins  PBrown  FCaudle  JRisch  SC Differences in qualitative brain morphology findings in schizophrenia, major depression, bipolar disorder, and normal volunteers. Schizophr Res 1995;15 (3) 253- 259
PubMed
Ohaeri  JUAdeyinka  AOEnyidah  SNOsuntokun  BO Schizophrenic and manic brains in Nigerians: computerised tomography findings. Br J Psychiatry 1995;166 (4) 496- 500
PubMed
Woods  BTYurgelun-Todd  DMikulis  DPillay  SS Age-related MRI abnormalities in bipolar illness: a clinical study. Biol Psychiatry 1995;38 (12) 846- 847
PubMed
Shioiri  TOshitani  YKato  TMurashita  JHamakawa  HInubushi  TNagata  TTakahashi  S Prevalence of cavum septum pellucidum detected by MRI in patients with bipolar disorder, major depression and schizophrenia. Psychol Med 1996;26 (2) 431- 434
PubMed
Drevets  WCPrice  JLSimpson  JR  JrTodd  RDReich  TVannier  MRaichle  ME Subgenual prefrontal cortex abnormalities in mood disorders. Nature 1997;386 (6627) 824- 827
PubMed
Pearlson  GDBarta  PEPowers  REMenon  RRRichards  SSAylward  EHFederman  EBChase  GAPetty  RGTien  AY Ziskind-Somerfeld Research Award 1996: medial and superior temporal gyral volumes and cerebral asymmetry in schizophrenia versus bipolar disorder. Biol Psychiatry 1997;41 (1) 1- 14
PubMed
Persaud  RRussow  HHarvey  ILewis  SWRon  MMurray  RMdu Boulay  G Focal signal hyperintensities in schizophrenia. Schizophr Res 1997;27 (1) 55- 64
PubMed
Zipursky  RBSeeman  MVBury  ALangevin  RWortzman  GKatz  R Deficits in gray matter volume are present in schizophrenia but not bipolar disorder. Schizophr Res 1997;26 (2-3) 85- 92
PubMed
Altshuler  LLBartzokis  GGrieder  TCurran  JMintz  J Amygdala enlargement in bipolar disorder and hippocampal reduction in schizophrenia: an MRI study demonstrating neuroanatomic specificity. Arch Gen Psychiatry 1998;55 (7) 663- 664
PubMed
Roy  PDZipursky  RBSaint-Cyr  JABury  ALangevin  RSeeman  MV Temporal horn enlargement is present in schizophrenia and bipolar disorder. Biol Psychiatry 1998;44 (6) 418- 422
PubMed
Bilder  RMWu  HBogerts  BAshtari  MRobinson  DWoerner  MLieberman  JADegreef  G Cerebral volume asymmetries in schizophrenia and mood disorders: a quantitative magnetic resonance imaging study. Int J Psychophysiol 1999;34 (3) 197- 205
PubMed
Dasari  MFriedman  LJesberger  JStuve  TAFindling  RLSwales  TPSchulz  SC A magnetic resonance imaging study of thalamic area in adolescent patients with either schizophrenia or bipolar disorder as compared to healthy controls. Psychiatry Res 1999;91 (3) 155- 162
PubMed
DelBello  MPStrakowski  SMZimmerman  MEHawkins  JMSax  KW MRI analysis of the cerebellum in bipolar disorder: a pilot study. Neuropsychopharmacology 1999;21 (1) 63- 68
PubMed
Friedman  LFindling  RLKenny  JTSwales  TPStuve  TAJesberger  JALewin  JSSchulz  SC An MRI study of adolescent patients with either schizophrenia or bipolar disorder as compared to healthy control subjects. Biol Psychiatry 1999;46 (1) 78- 88
PubMed
Lim  KORosenbloom  MJFaustman  WOSullivan  EVPfefferbaum  A Cortical gray matter deficit in patients with bipolar disorder. Schizophr Res 1999;40 (3) 219- 227
PubMed
McDonald  WMTupler  LAMarsteller  FAFigiel  GSDiSouza  SNemeroff  CBKrishnan  KR Hyperintense lesions on magnetic resonance images in bipolar disorder. Biol Psychiatry 1999;45 (8) 965- 971
PubMed
Sax  KWStrakowski  SMZimmerman  MEDelBello  MPKeck  PE  JrHawkins  JM Frontosubcortical neuroanatomy and the continuous performance test in mania. Am J Psychiatry 1999;156 (1) 139- 141
PubMed
Strakowski  SMDelBello  MPSax  KWZimmerman  MEShear  PKHawkins  JMLarson  ER Brain magnetic resonance imaging of structural abnormalities in bipolar disorder. Arch Gen Psychiatry 1999;56 (3) 254- 260
PubMed
Young  RCNambudiri  DEJain  Hde Asis  JMAlexopoulos  GS Brain computed tomography in geriatric manic disorder. Biol Psychiatry 1999;45 (8) 1063- 1065
PubMed
Hauser  PMatochik  JAltshuler  LLDenicoff  KDConrad  ALi  XPost  RM MRI-based measurements of temporal lobe and ventricular structures in patients with bipolar I and bipolar II disorders. J Affect Disord 2000;60 (1) 25- 32
PubMed
Hirayasu  YMcCarley  RWSalisbury  DFTanaka  SKwon  JSFrumin  MSnyderman  DYurgelun-Todd  DKikinis  RJolesz  FAShenton  ME Planum temporale and Heschl gyrus volume reduction in schizophrenia: a magnetic resonance imaging study of first-episode patients. Arch Gen Psychiatry 2000;57 (7) 692- 699
PubMed
Krabbendam  LHonig  AWiersma  JVuurman  EFHofman  PADerix  MMNolen  WAJolles  J Cognitive dysfunctions and white matter lesions in patients with bipolar disorder in remission. Acta Psychiatr Scand 2000;101 (4) 274- 280
PubMed
Rabins  PVAylward  EHolroyd  SPearlson  G MRI findings differentiate between late-onset schizophrenia and late-life mood disorder. Int J Geriatr Psychiatry 2000;15 (10) 954- 960
PubMed
Brambilla  PHarenski  KNicoletti  MAMallinger  AGFrank  EKupfer  DJKeshavan  MSSoares  JC Anatomical MRI study of basal ganglia in bipolar disorder patients. Psychiatry Res 2001;106 (2) 65- 80
PubMed
Brambilla  PHarenski  KNicoletti  MMallinger  AGFrank  EKupfer  DJKeshavan  MSSoares  JC MRI study of posterior fossa structures and brain ventricles in bipolar patients. J Psychiatr Res 2001;35 (6) 313- 322
PubMed
Brambilla  PHarenski  KNicoletti  MMallinger  AGFrank  EKupfer  DJKeshavan  MSSoares  JC Differential effects of age on brain gray matter in bipolar patients and healthy individuals. Neuropsychobiology 2001;43 (4) 242- 247
PubMed
Caetano  SCSassi  RBrambilla  PHarenski  KNicoletti  MMallinger  AGFrank  EKupfer  DJKeshavan  MSSoares  JC MRI study of thalamic volumes in bipolar and unipolar patients and healthy individuals. Psychiatry Res 2001;108 (3) 161- 168
PubMed
McIntosh  AMForrester  ALawrie  SMByrne  MHarper  AKestelman  JNBest  JJJohnstone  ECOwens  DG A factor model of the functional psychoses and the relationship of factors to clinical variables and brain morphology. Psychol Med 2001;31 (1) 159- 171
PubMed
Moore  PBShepherd  DJEccleston  DMacmillan  ICGoswami  UMcAllister  VLFerrier  IN Cerebral white matter lesions in bipolar affective disorder: relationship to outcome. Br J Psychiatry 2001;178172- 176
PubMed
Moore  PBEl-Badri  SMCousins  DShepherd  DJYoung  AHMcAllister  VLFerrier  IN White matter lesions and season of birth of patients with bipolar affective disorder. Am J Psychiatry 2001;158 (9) 1521- 1524
PubMed
Noga  JTVladar  KTorrey  EF A volumetric magnetic resonance imaging study of monozygotic twins discordant for bipolar disorder. Psychiatry Res 2001;106 (1) 25- 34
PubMed
Sassi  RBNicoletti  MBrambilla  PHarenski  KMallinger  AGFrank  EKupfer  DJKeshavan  MSSoares  JC Decreased pituitary volume in patients with bipolar disorder. Biol Psychiatry 2001;50 (4) 271- 280
PubMed
Brambilla  PNicoletti  MAHarenski  KSassi  RBMallinger  AGFrank  EKupfer  DJKeshavan  MSSoares  JC Anatomical MRI study of subgenual prefrontal cortex in bipolar and unipolar subjects. Neuropsychopharmacology 2002;27 (5) 792- 799
PubMed
Getz  GEDelBello  MPFleck  DEZimmerman  MESchwiers  MLStrakowski  SM Neuroanatomic characterization of schizoaffective disorder using MRI: a pilot study. Schizophr Res 2002;55 (1-2) 55- 59
PubMed
Lyoo  IKLee  HKJung  JHNoam  GGRenshaw  PF White matter hyperintensities on magnetic resonance imaging of the brain in children with psychiatric disorders. Compr Psychiatry 2002;43 (5) 361- 368
PubMed
Pillai  JJFriedman  LStuve  TATrinidad  SJesberger  JALewin  JSFindling  RLSwales  TPSchulz  SC Increased presence of white matter hyperintensities in adolescent patients with bipolar disorder. Psychiatry Res 2002;114 (1) 51- 56
PubMed
Strakowski  SMDelBello  MPZimmerman  MEGetz  GEMills  NPRet  JShear  PAdler  CM Ventricular and periventricular structural volumes in first- versus multiple-episode bipolar disorder. Am J Psychiatry 2002;159 (11) 1841- 1847
PubMed
Bertolino  AFrye  MCallicott  JHMattay  VSRakow  RShelton-Repella  JPost  RWeinberger  DR Neuronal pathology in the hippocampal area of patients with bipolar disorder: a study with proton magnetic resonance spectroscopic imaging. Biol Psychiatry 2003;53 (10) 906- 913
PubMed
Blumberg  HPKaufman  JMartin  AWhiteman  RZhang  JHGore  JCCharney  DSKrystal  JHPeterson  BS Amygdala and hippocampal volumes in adolescents and adults with bipolar disorder. Arch Gen Psychiatry 2003;60 (12) 1201- 1208
PubMed
Brambilla  PHarenski  KNicoletti  MSassi  RBMallinger  AGFrank  EKupfer  DJKeshavan  MSSoares  JC MRI investigation of temporal lobe structures in bipolar patients. J Psychiatr Res 2003;37 (4) 287- 295
PubMed
Brambilla  PNicoletti  MASassi  RBMallinger  AGFrank  EKupfer  DJKeshavan  MSSoares  JC Magnetic resonance imaging study of corpus callosum abnormalities in patients with bipolar disorder. Biol Psychiatry 2003;54 (11) 1294- 1297
PubMed
Sassi  RBBrambilla  PNicoletti  MMallinger  AGFrank  EKupfer  DJKeshavan  MSSoares  JC White matter hyperintensities in bipolar and unipolar patients with relatively mild-to-moderate illness severity. J Affect Disord 2003;77 (3) 237- 245
PubMed
Sharma  VMenon  RCarr  TJDensmore  MMazmanian  DWilliamson  PC An MRI study of subgenual prefrontal cortex in patients with familial and non-familial bipolar I disorder. J Affect Disord 2003;77 (2) 167- 171
PubMed
Silverstone  TMcPherson  HLi  QDoyle  T Deep white matter hyperintensities in patients with bipolar depression, unipolar depression and age-matched control subjects. Bipolar Disord 2003;5 (1) 53- 57
PubMed
Ahn  KHLyoo  IKLee  HKSong  ICOh  JSHwang  JKwon  JKim  MJKim  MRenshaw  PF White matter hyperintensities in subjects with bipolar disorder. Psychiatry Clin Neurosci 2004;58 (5) 516- 521
PubMed
Beyer  JLKuchibhatla  MPayne  MMoo-Young  MCassidy  FMacFall  JKrishnan  KR Caudate volume measurement in older adults with bipolar disorder. Int J Geriatr Psychiatry 2004;19 (2) 109- 114
PubMed
Brambilla  PNicoletti  MSassi  RBMallinger  AGFrank  EKeshavan  MSSoares  JC Corpus callosum signal intensity in patients with bipolar and unipolar disorder. J Neurol Neurosurg Psychiatry 2004;75 (2) 221- 225
PubMed
Chen  BKSassi  RAxelson  DHatch  JPSanches  MNicoletti  MBrambilla  PKeshavan  MSRyan  NDBirmaher  BSoares  JC Cross-sectional study of abnormal amygdala development in adolescents and young adults with bipolar disorder. Biol Psychiatry 2004;56 (6) 399- 405
PubMed
Chen  HHNicoletti  MAHatch  JPSassi  RBAxelson  DBrambilla  PMonkul  ESKeshavan  MSRyan  NDBirmaher  BSoares  JC Abnormal left superior temporal gyrus volumes in children and adolescents with bipolar disorder: a magnetic resonance imaging study. Neurosci Lett 2004;363 (1) 65- 68
PubMed
Chen  HHNicoletti  MSanches  MHatch  JPSassi  RBAxelson  DBrambilla  PKeshavan  MSRyan  NBirmaher  BSoares  JC Normal pituitary volumes in children and adolescents with bipolar disorder: a magnetic resonance imaging study. Depress Anxiety 2004;20 (4) 182- 186
PubMed
Connor  SENg  VMcDonald  CSchulze  KMorgan  KDazzan  PMurray  RM A study of hippocampal shape anomaly in schizophrenia and in families multiply affected by schizophrenia or bipolar disorder. Neuroradiology 2004;46 (7) 523- 534
PubMed
Davis  KAKwon  ACardenas  VADeicken  RF Decreased cortical gray and cerebral white matter in male patients with familial bipolar I disorder. J Affect Disord 2004;82 (3) 475- 485
PubMed
DelBello  MPZimmerman  MEMills  NPGetz  GEStrakowski  SM Magnetic resonance imaging analysis of amygdala and other subcortical brain regions in adolescents with bipolar disorder. Bipolar Disord 2004;6 (1) 43- 52
PubMed
Hirashima  FParow  AMStoll  ALDemopulos  CMDamico  KERohan  MLEskesen  JGZuo  CSCohen  BMRenshaw  PF Omega-3 fatty acid treatment and T(2) whole brain relaxation times in bipolar disorder. Am J Psychiatry 2004;161 (10) 1922- 1924
PubMed
Sassi  RBBrambilla  PHatch  JPNicoletti  MAMallinger  AGFrank  EKupfer  DJKeshavan  MSSoares  JC Reduced left anterior cingulate volumes in untreated bipolar patients. Biol Psychiatry 2004;56 (7) 467- 475
PubMed
Supprian  TReiche  WSchmitz  BGrunwald  IBackens  MHofmann  EGeorg  TFalkai  PReith  W MRI of the brainstem in patients with major depression, bipolar affective disorder and normal controls. Psychiatry Res 2004;131 (3) 269- 276
PubMed
Blumberg  HPFredericks  CWang  FKalmar  JHSpencer  LPapademetris  XPittman  BMartin  APeterson  BSFulbright  RKKrystal  JH Preliminary evidence for persistent abnormalities in amygdala volumes in adolescents and young adults with bipolar disorder. Bipolar Disord 2005;7 (6) 570- 576
PubMed
Chang  KBarnea-Goraly  NKarchemskiy  ASimeonova  DIBarnes  PKetter  TReiss  AL Cortical magnetic resonance imaging findings in familial pediatric bipolar disorder. Biol Psychiatry 2005;58 (3) 197- 203
PubMed
Frazier  JABreeze  JLMakris  NGiuliano  ASHerbert  MRSeidman  LBiederman  JHodge  SMDieterich  MEGerstein  EDKennedy  DNRauch  SLCohen  BMCaviness  VS Cortical gray matter differences identified by structural magnetic resonance imaging in pediatric bipolar disorder. Bipolar Disord 2005;7 (6) 555- 569
PubMed
Mills  NPDelbello  MPAdler  CMStrakowski  SM MRI analysis of cerebellar vermal abnormalities in bipolar disorder. Am J Psychiatry 2005;162 (8) 1530- 1532
PubMed
Pariante  CMDazzan  PDanese  AMorgan  KDBrudaglio  FMorgan  CFearon  POrr  KHutchinson  GPantelis  CVelakoulis  DJones  PBLeff  JMurray  RM Increased pituitary volume in antipsychotic-free and antipsychotic-treated patients of the AEsop first-onset psychosis study. Neuropsychopharmacology 2005;30 (10) 1923- 1931
PubMed
Sanches  MSassi  RBAxelson  DNicoletti  MBrambilla  PHatch  JPKeshavan  MSRyan  NDBirmaher  BSoares  JC Subgenual prefrontal cortex of child and adolescent bipolar patients: a morphometric magnetic resonance imaging study. Psychiatry Res 2005;138 (1) 43- 49
PubMed
Sanches  MRoberts  RLSassi  RBAxelson  DNicoletti  MBrambilla  PHatch  JPKeshavan  MSRyan  NDBirmaher  BSoares  JC Developmental abnormalities in striatum in young bipolar patients: a preliminary study. Bipolar Disord 2005;7 (2) 153- 158
PubMed
Strasser  HCLilyestrom  JAshby  ERHoneycutt  NASchretlen  DJPulver  AEHopkins  RODepaulo  JRPotash  JBSchweizer  BYates  KOKurian  EBarta  PEPearlson  GD Hippocampal and ventricular volumes in psychotic and nonpsychotic bipolar patients compared with schizophrenia patients and community control subjects: a pilot study. Biol Psychiatry 2005;57 (6) 633- 639
PubMed
Atmaca  MYildirim  HOzdemir  HPoyraz  AKTezcan  EOgur  E Hippocampal 1H MRS in first-episode bipolar I patients. Prog Neuropsychopharmacol Biol Psychiatry 2006;30 (7) 1235- 1239
PubMed
Blumberg  HPKrystal  JHBansal  RMartin  ADziura  JDurkin  KMartin  LGerard  ECharney  DSPeterson  BS Age, rapid-cycling, and pharmacotherapy effects on ventral prefrontal cortex in bipolar disorder: a cross-sectional study. Biol Psychiatry 2006;59 (7) 611- 618
PubMed
Coyle  TRKochunov  PPatel  RDNery  FGLancaster  JLMangin  JFRiviere  DPillow  DRDavis  GJNicoletti  MASerap Monkul  EFox  PTSoares  JC Cortical sulci and bipolar disorder. Neuroreport 2006;17 (16) 1739- 1742
PubMed
El-Badri  SMCousins  DAParker  SAshton  HCMcAllister  VLFerrier  INMoore  PB Magnetic resonance imaging abnormalities in young euthymic patients with bipolar affective disorder. Br J Psychiatry 2006;18981- 82
PubMed
Hwang  JLyoo  IKDager  SRFriedman  SDOh  JSLee  JYKim  SJDunner  DLRenshaw  PF Basal ganglia shape alterations in bipolar disorder. Am J Psychiatry 2006;163 (2) 276- 285
PubMed
McDonald  CMarshall  NSham  PCBullmore  ETSchulze  KChapple  BBramon  EFilbey  FQuraishi  SWalshe  MMurray  RM Regional brain morphometry in patients with schizophrenia or bipolar disorder and their unaffected relatives. Am J Psychiatry 2006;163 (3) 478- 487
PubMed
Monkul  ESNicoletti  MASpence  DSassi  RBAxelson  DBrambilla  PHatch  JPKeshavan  MRyan  NBirmaher  BSoares  JC MRI study of thalamus volumes in juvenile patients with bipolar disorder. Depress Anxiety 2006;23 (6) 347- 352
PubMed
Pardo  PJGeorgopoulos  APKenny  JTStuve  TAFindling  RLSchulz  SC Classification of adolescent psychotic disorders using linear discriminant analysis. Schizophr Res 2006;87 (1-3) 297- 306
PubMed
Velakoulis  DWood  SJWong  MTMcGorry  PDYung  APhillips  LSmith  DBrewer  WProffitt  TDesmond  PPantelis  C Hippocampal and amygdala volumes according to psychosis stage and diagnosis: a magnetic resonance imaging study of chronic schizophrenia, first-episode psychosis, and ultra-high-risk individuals. Arch Gen Psychiatry 2006;63 (2) 139- 149
PubMed
Voelbel  GTBates  MEBuckman  JFPandina  GHendren  RL Caudate nucleus volume and cognitive performance: are they related in childhood psychopathology? Biol Psychiatry 2006;60 (9) 942- 950
PubMed
Yasar  ASMonkul  ESSassi  RBAxelson  DBrambilla  PNicoletti  MAHatch  JPKeshavan  MRyan  NBirmaher  BSoares  JC MRI study of corpus callosum in children and adolescents with bipolar disorder. Psychiatry Res 2006;146 (1) 83- 85
PubMed
Ahn  MSBreeze  JLMakris  NKennedy  DNHodge  SMHerbert  MRSeidman  LJBiederman  JCaviness  VSFrazier  JA Anatomic brain magnetic resonance imaging of the basal ganglia in pediatric bipolar disorder. J Affect Disord 2007;104 (1-3) 147- 154
PubMed
Atmaca  MYildirim  HOzdemir  HOgur  ETezcan  E Hippocampal 1H MRS in patients with bipolar disorder taking valproate versus valproate plus quetiapine. Psychol Med 2007;37 (1) 121- 129
PubMed
Atmaca  MOzdemir  HYildirim  H Corpus callosum areas in first-episode patients with bipolar disorder. Psychol Med 2007;37 (5) 699- 704
PubMed
Atmaca  MOzdemir  HCetinkaya  SParmaksiz  SBelli  HPoyraz  AKTezcan  EOgur  E Cingulate gyrus volumetry in drug free bipolar patients and patients treated with valproate or valproate and quetiapine. J Psychiatr Res 2007;41 (10) 821- 827
PubMed
Bearden  CEThompson  PMDutton  RAFrey  BNPeluso  MANicoletti  MDierschke  NHayashi  KMKlunder  ADGlahn  DCBrambilla  PSassi  RBMallinger  AGSoares  JC Three-dimensional mapping of hippocampal anatomy in unmedicated and lithium-treated patients with bipolar disorder [published online ahead of print August 8, 2007]. Neuropsychopharmacology 2008;33 (6) 1229- 123810.1038/sj.npp.1301507
PubMed
Chiu  SWidjaja  FBates  MEVoelbel  GTPandina  GMarble  JBlank  JADay  JBrule  NHendren  RL Anterior cingulate volume in pediatric bipolar disorder and autism [published online ahead of print June 13, 2007]. J Affect Disord 2008;105 (1-3) 93- 99
PubMed10.1016/j.jad.2007.04.019
Kim  MJLyoo  IKDager  SRFriedman  SDChey  JHwang  JLee  YJDunner  DLRenshaw  PF The occurrence of cavum septi pellucidi enlargement is increased in bipolar disorder patients. Bipolar Disord 2007;9 (3) 274- 280
PubMed
Molina  VSanchez  JSanz  JReig  SBenito  CLeal  ISarramea  FRebolledo  RPalomo  TDesco  M Dorsolateral prefrontal N-acetyl-aspartate concentration in male patients with chronic schizophrenia and with chronic bipolar disorder. Eur Psychiatry 2007;22 (8) 505- 512
PubMed
Najt  PNicoletti  MChen  HHHatch  JPCaetano  SCSassi  RBAxelson  DBrambilla  PKeshavan  MSRyan  NDBirmaher  BSoares  JC Anatomical measurements of the orbitofrontal cortex in child and adolescent patients with bipolar disorder. Neurosci Lett 2007;413 (3) 183- 186
PubMed
Rosso  IMKillgore  WDCintron  CMGruber  SATohen  MYurgelun-Todd  DA Reduced amygdala volumes in first-episode bipolar disorder and correlation with cerebral white matter. Biol Psychiatry 2007;61 (6) 743- 749
PubMed
Salisbury  DFKuroki  NKasai  KShenton  MEMcCarley  RW Progressive and interrelated functional and structural evidence of post-onset brain reduction in schizophrenia. Arch Gen Psychiatry 2007;64 (5) 521- 529
PubMed
Yucel  KTaylor  VHMcKinnon  MCMacdonald  KAlda  MYoung  LTMacQueen  GM Bilateral hippocampal volume increase in patients with bipolar disorder and short-term lithium treatment [published online ahead of print April 4, 2007]. Neuropsychopharmacology 2008;33 (2) 361- 367
PubMed10.1038/sj.npp.1301405
Yucel  KMcKinnon  MCTaylor  VHMacdonald  KAlda  MYoung  LTMacQueen  GM Bilateral hippocampal volume increases after long-term lithium treatment in patients with bipolar disorder: a longitudinal MRI study. Psychopharmacology (Berl) 2007;195 (3) 357- 367
PubMed
Baldwin  RC Is vascular depression a distinct sub-type of depressive disorder? A review of causal evidence. Int J Geriatr Psychiatry 2005;20 (1) 1- 11
PubMed
de Groot  JCde Leeuw  FEOudkerk  MHofman  AJolles  JBreteler  MM Cerebral white matter lesions and depressive symptoms in elderly adults. Arch Gen Psychiatry 2000;57 (11) 1071- 1076
PubMed
Berlin  JASantanna  JSchmid  CHSzczech  LAFeldman  HI Individual patient- versus group-level data meta-regressions for the investigation of treatment effect modifiers: ecological bias rears its ugly head. Stat Med 2002;21 (3) 371- 387
PubMed
Harrison  PJWeinberger  DR Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2005;10 (1) 40- 68
PubMed
Harrison  PJ The neuropathology of primary mood disorder. Brain 2002;125 (pt 7) 1428- 1449
PubMed
Gootjes  LTeipel  SJZebuhr  YSchwarz  RLeinsinger  GScheltens  PMoller  HJHampel  H Regional distribution of white matter hyperintensities in vascular dementia, Alzheimer's disease and healthy aging. Dement Geriatr Cogn Disord 2004;18 (2) 180- 188
PubMed
Thomas  AJPerry  RBarber  RKalaria  RNO'Brien  JT Pathologies and pathological mechanisms for white matter hyperintensities in depression. Ann N Y Acad Sci 2002;977333- 339
PubMed
Shenton  MEDickey  CCFrumin  MMcCarley  RW A review of MRI findings in schizophrenia. Schizophr Res 2001;49 (1-2) 1- 52
PubMed
McCarley  RWWible  CGFrumin  MHirayasu  YLevitt  JJFischer  IAShenton  ME MRI anatomy of schizophrenia. Biol Psychiatry 1999;45 (9) 1099- 1119
PubMed
Campbell  SMarriott  MNahmias  CMacQueen  GM Lower hippocampal volume in patients suffering from depression: a meta-analysis. Am J Psychiatry 2004;161 (4) 598- 607
PubMed
Videbech  PRavnkilde  B Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatry 2004;161 (11) 1957- 1966
PubMed
Jiang  HGuo  WLiang  XRao  Y Both the establishment and the maintenance of neuronal polarity require active mechanisms: critical roles of GSK-3beta and its upstream regulators. Cell 2005;120 (1) 123- 135
PubMed
Regier  DAFarmer  MERae  DSLocke  BZKeith  SJJudd  LLGoodwin  FK Comorbidity of mental disorders with alcohol and other drug abuse: results from the Epidemiologic Catchment Area (ECA) Study. JAMA 1990;264 (19) 2511- 2518
PubMed
Rosenbloom  MSullivan  EVPfefferbaum  A Using magnetic resonance imaging and diffusion tensor imaging to assess brain damage in alcoholics. Alcohol Res Health 2003;27 (2) 146- 152
PubMed

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.