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Background: Patients with major depressive disorder (MDD) can present with altered brain structure and deficits in cognitive function similar to those seen in aging. However, the interaction between age-related brain changes and brain development in MDD remains understudied. In a cohort of adolescents and adults with and without MDD, we assessed brain aging differences and associations through a newly developed tool that quantifies normative neurodevelopmental trajectories., Methods: A total of 304 participants with MDD and 236 control participants without depression were recruited and scanned from 3 studies under the Canadian Biomarker Integration Network for Depression. Volumetric data were used to generate brain centile scores, which were examined for 1) differences between participants with MDD and control participants; 2) differences between individuals with versus without severe childhood maltreatment; and 3) correlations with depressive symptom severity, neurocognitive assessment domains, and escitalopram treatment response., Results: Brain centiles were significantly lower in the MDD group than in the control group. Brain centile was also significantly correlated with working memory in the control group but not the MDD group. No significant associations were observed between depression severity or antidepressant treatment response and brain centiles. Likewise, childhood maltreatment history did not significantly affect brain centiles., Conclusions: Consistent with previous work on machine learning models that predict brain age, brain centile scores differed in people diagnosed with MDD, and MDD was associated with differential relationships between centile scores and working memory. The results support the notion of atypical development and aging in MDD, with implications for neurocognitive deficits associated with aging-related cognitive function., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Clinical studies of major depression (MD) generally focus on group effects, yet interindividual differences in brain function are increasingly recognized as important and may even impact effect sizes related to group effects. Here, we examine the magnitude of individual differences in relation to group differences that are commonly investigated (e.g., related to MD diagnosis and treatment response). Functional MRI data from 107 participants (63 female, 44 male) were collected at baseline, 2, and 8 weeks during which patients received pharmacotherapy (escitalopram, N  = 68) and controls ( N  = 39) received no intervention. The unique contributions of different sources of variation were examined by calculating how much variance in functional connectivity was shared across all participants and sessions, within/across groups (patients vs controls, responders vs nonresponders, female vs male participants), recording sessions, and individuals. Individual differences and common connectivity across groups, sessions, and participants contributed most to the explained variance (>95% across analyses). Group differences related to MD diagnosis, treatment response, and biological sex made significant but small contributions (0.3-1.2%). High individual variation was present in cognitive control and attention areas, while low individual variation characterized primary sensorimotor regions. Group differences were much smaller than individual differences in the context of MD and its treatment. These results could be linked to the variable findings and difficulty translating research on MD to clinical practice. Future research should examine brain features with low and high individual variation in relation to psychiatric symptoms and treatment trajectories to explore the clinical relevance of the individual differences identified here., Competing Interests: B.N.F. has received grant/research support from Alternative Funding Plan Innovations Award, Brain and Behavior Research Foundation, Canadian Institutes of Health Research, Hamilton Health Sciences Foundation, J. P. Bickell Foundation, Ontario Brain Institute, Ontario Mental Health Foundation, Society for Women's Health Research, Teresa Cascioli Charitable Foundation, Eli Lilly, and Pfizer and has received consultant and/or speaker fees from AstraZeneca, Bristol-Myers Squibb, Canadian Psychiatric Association, CANMAT, Daiichi Sankyo, Lundbeck, Pfizer, Servier, and Sunovion. R.M. has received consulting and speaking honoraria from AbbVie, Allergan, Janssen, KYE, Lundbeck, Otsuka, and Sunovion and research grants from CAN-BIND, CIHR, Janssen, Lallemand, Lundbeck, Nubiyota, OBI, and OMHF. S.P. has been a consultant to Takeda, Bristol Myers Squibb, Lundbeck; has had a research contract with Assurex; and has equity in Mensante. R.W.L. has received speaker and consultant honoraria or research funds from AstraZeneca, Brain Canada, Bristol-Myers Squibb, the Canadian Institutes of Health Research (CIHR), the Canadian Network for Mood and Anxiety Treatments, the Canadian Psychiatric Association, Eli Lilly, Janssen, Lundbeck, Lundbeck Institute, Medscape, Otsuka, Pfizer, Servier, St. Jude Medical, Takeda, the University Health Network Foundation, Vancouver Coastal Health Research Institute, Allergan, Asia-Pacific Economic Cooperation, BC Leading Edge Foundation, Healthy Minds Canada, Michael Smith Foundation for Health Research, MITACS, Myriad Neuroscience, Ontario Brain Institute, Otsuka, Unity Health, Viatris, and VGH-UBCH Foundation. S.H.K. has received honoraria or research funds from Abbott, Alkermes, Allergan, Boehringer Ingelheim, Brain Canada, CIHR, Janssen, Lundbeck, Lundbeck Institute, Ontario Brain Institute, Ontario Research Fund, Otsuka, Pfizer, Servier, Sunovion, and Sun Pharmaceutical and holds stock in Field Trip Health. D.J.M. has received consulting and speaking honoraria from Lundbeck and Genomind. C.S. has received consulting and speaking honoraria from Pfizer, Otsuka, Bayer, Eisai, and research grants from CAN-BIND, CIHR, OBI, and SEAMO. S.C.S. is a senior Scientific Advisor and shareholder in ADMdx, which receives NIH funding, and during the period of this research, he had research grants from Brain Canada, Canada Foundation for Innovation (CFI), Canadian Institutes of Health Research (CIHR), and the Ontario Brain Institute in Canada. Other authors declare no competing financial interests., (Copyright © 2024 van der Wijk et al.)

There is a growing interest in examining the wealth of data generated by fusing functional and structural imaging information sources. These approaches may have clinical utility in identifying disruptions in the brain networks that underlie major depressive disorder (MDD). We combined an existing software toolbox with a mathematically dense statistical method to produce a novel processing pipeline for the fast and easy implementation of data fusion analysis (FATCAT-awFC). The novel FATCAT-awFC pipeline was then utilized to identify connectivity (conventional functional, conventional structural and anatomically weighted functional connectivy) changes in MDD patients compared to healthy comparison participants (HC). Data were acquired from the Canadian Biomarker Integration Network for Depression (CAN-BIND-1) study. Large-scale resting-state networks were assessed. We found statistically significant anatomically-weighted functional connectivity (awFC) group differences in the default mode network and the ventral attention network, with a modest effect size (d < 0.4). Functional and structural connectivity seemed to overlap in significance between one region-pair within the default mode network. By combining structural and functional data, awFC served to heighten or reduce the magnitude of connectivity differences in various regions distinguishing MDD from HC. This method can help us more fully understand the interconnected nature of structural and functional connectivity as it relates to depression., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Repetitive transcranial magnetic stimulation (rTMS) is a first-line option for treatment-resistant depression (TRD), but prediction of treatment outcome remains a clinical challenge. The present study aimed to compare structural and functional covariance networks (SCNs and FCNs) between remitters and nonremitters. We determined the predictive capacities of SCNs and FCNs to discriminate the two groups. Fifty TRD patients underwent a course of rTMS to the left dorsolateral prefrontal cortex. They were categorized into remitters (n = 22) and nonremitters (n = 28) based on HDRS≤7 at the end of treatment. Baseline structural and functional magnetic imaging (sMRI and fMRI) of the patients and 42 healthy controls were collected. SCNs and FCNs were defined based on structural and functional covariance of gray mater volume (GMV) and fractional amplitude of low-frequency fluctuations (fALFF) from sMRI and fMRI, respectively. Structural/functional network integrity of these networks (default mode network [DMN], central executive network [CEN] and salience network [SN]) were compared between the three groups. In patients, associations between SCNs and FCNs with clinical improvements were studied using linear correlation analysis. Receiver-operating characteristic (ROC) analysis was conducted to confirm the utility of the SCNs and FCNs in classifying clinical sub-groups. Nonremitters exhibited lower structural integrity in CEN than remitters and controls. Higher structural integrity of CEN was related to clinical improvement (r = 0.423, p = .002), and structural integrity distinguished remitters and nonremitters with a fairly high accuracy (AUC = 0.71, p = .008). No group differences or correlation with clinical changes were found in FCNs. Results suggest the CEN may play a role mediating clinical improvement in rTMS for depression. Structural covariance networks may be features to consider in prediction of clinical improvement., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: The neurobiological underpinnings of bipolar I disorder are not yet understood. Previous structural neuroimaging studies of bipolar disorder have produced rather conflicting results. We hypothesise that clinical sub-phenotypes of bipolar I disorder defined by their psychotic symptoms, especially those with mood-incongruent psychotic features, may have more extensive structural brain abnormalities., Methods: We investigated structural brain alterations in patients with first-episode mania (n = 55) with mood-congruent (n = 16) and mood-incongruent (n = 32) psychotic features, as well as those without psychotic symptoms (n = 7), relative to healthy subjects (n = 56)., Results: Total intracranial volume was significantly reduced in patients with mood-incongruent psychosis compared to healthy subjects while cerebrospinal fluid (CSF) volume was significantly increased. Patients with mood-congruent psychosis showed significant reduction in total white matter volume and significant CSF volume increase. Patients with psychosis had significant volume reduction in anterior cingulate and medial prefrontal cortices. Relative to mood-congruent psychotic features, mood-incongruent psychotic features were associated with volume reduction in the left middle temporal gyrus, right inferior parietal gyrus, right fusiform gyrus, left middle orbitofrontal gyrus and cerebellum., Conclusions: While preliminary, our findings suggest that the presence and type of psychosis in first-episode mania may be phenotypic markers of underlying biological variants of bipolar disorder.

Background: Magnetic resonance imaging (MRI) studies have yielded inconsistent findings with regard to subcortical volumetric abnormalities in patients with bipolar I disorder. Duration of illness and long term medication intake could have confounded the findings., Method: Volumes of nine subcortical structures were compared between 63 patients who recently remitted from their first manic episode and 77 healthy volunteers. The volumetric segmentation was performed with the automated segmentation algorithm Freesurfer version 5.1., Results: There were no significant volumetric differences between the two groups in any of the structures examined including caudate, putamen, globus pallidum, nucleus accumbens, amygdala, thalamus, cerebellum, hippocampus and lateral ventricles (q > 0.05-false discovery rate corrected)., Limitations: All patients were on psychotropic medications at the time of scanning, which might have confounded the results. Sample size may not be large enough to detect small volumetric changes., Conclusions: Patients with bipolar I disorder do not appear to have any significant subcortical volumetric abnormalities during the early stage of the disease. Thus, early stage bipolar disorder may present an opportunity for intervention to arrest neuroprogression of the disease., (Copyright © 2017. Published by Elsevier B.V.)

Background: Parcellating brain regions into functionally homogeneous subdivisions is critical for understanding normal and abnormal brain functions., New Method: In this study, we developed a new sparse representation-based parcellation method for functional magnetic resonance imaging (fMRI) data, and applied the new method to investigate functional insular subdivisions in treatment-resistant major depressive disorder (MDD). Realistic simulations were implemented to demonstrate the feasibility of the method. Subsequently, the method was used to parcellate the insula in a sample of fifty-six MDD patients and thirty-six healthy volunteers (HVs). The optimal number of clusters was determined by an independent test-retest dataset. Finally, differences of the functional connectivity profiles of each insular subdivision between patients and HVs were inspected., Results: The results from both simulated and test-retest fMRI datasets demonstrated the feasibility of the proposed elastic net-based (EN) method. With the proposed method, the insula was parcellated into four subdivisions (dorsal anterior dAI; ventral anterior vAI; middle, MI and posterior, PI). Whereas patients showed hypo-connectivity between vAI and right medial temporal lobe, there were no functional volumetric differences in insular subdivisions between MDD patients and HVs., Comparison With Existing Method: Results from both simulated and real fMRI datasets showed that the proposed EN method achieved higher accuracy than least absolute shrinkage and selection operator-based (LASSO) method., Conclusions: These findings suggest that EN-based parcellation has the potential to be a useful addition to the parcellation techniques for fMRI data, and provide evidence of decreased functional connectivity without functional volumetric changes of the insula in treatment-resistant MDD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: Bipolar disorder (BD) is a common and highly disabling disease characterized by substantial cognitive and functional impairment. The exact neurobiological mechanisms underlying the expression of symptoms in this condition remain unknown but there is growing evidence that glutamate might play an important role. Using proton magnetic resonance spectroscopy (¹H-MRS), a number of studies have examined brain glutamate/glutamine levels in patients with bipolar disorder, but they have produced conflicting results. The objective of this paper was to conduct a systematic review and meta-analysis of the literature on brain glutamate/glutamine in BD as measured by ¹H-MRS., Methods: A Medline search for the period January 1980-April 2010 was conducted to identify published studies that used ¹H-MRS to measure glutamate + glutamine (Glx), the Glx/creatine (Cr) ratio, glutamate (Glu), or the Glu/Cr ratio in any brain region in adult or child/adolescent patients with BD and healthy subjects. A meta-analysis of the pooled data was conducted., Results: BD patients were found to have increased Glx compared to healthy subjects when all brain areas were combined. This finding remained true in medicated and non-medicated patients, and in frontal brain areas in adults. There was a non-significant trend (p = 0.09) for an increase in whole-brain Glx/Cr and Glu in patients compared with healthy subjects. No significant difference was found in Glu/Cr., Conclusions: The results of this meta-analysis suggest that brain Glx levels are elevated in BD patients and support the idea that glutamate might play an important role in the pathophysiology of BD., (© 2012 John Wiley and Sons A/S.)

Context: Decreased brain serotonin (5-hydroxytryptamine) levels are considered to mediate depressive relapse induced by the tryptophan depletion paradigm. However, in patients who recently achieved remission from a major depressive episode with antidepressant treatment, only about half become depressed following tryptophan depletion. We hypothesized that downregulation of brain serotonin(2) receptors might be a compensatory mechanism that prevents some patients from becoming depressed with tryptophan depletion., Objective: To assess, with use of positron emission tomography, whether brain serotonin(2) receptor downregulation occurs in patients with recently remitted depression who do not have depressive relapse, but not in those who become depressed, following tryptophan depletion., Design: Each patient underwent 2 fluorine 18-labeled- setoperone positron emission tomography scans, one following a tryptophan depletion session and another following a control session. The order of scanning was counterbalanced., Setting: Academic university hospital with imaging facilities., Participants: Seventeen patients in recent remission from a DSM-IV major depressive episode following treatment with selective serotonin reuptake inhibitors., Main Outcome Measures: Changes in brain serotonin(2) receptor binding., Results: Of the 17 patients, 8 (47%) became depressed during the tryptophan depletion session, and none developed depression during the control session. The depletion session was associated with a significant reduction in brain serotonin(2) receptor binding compared with the control session for all participants. A subgroup analysis revealed that the reduction in serotonin(2) receptor binding was significant only for the nondepressed group., Conclusion: Reduction in brain serotonin(2) receptors might be a potential compensatory mechanism to prevent tryptophan depletion-induced depressive relapse.

Background: Compared with normal-weight patients, obese patients with bipolar I disorder (BD) suffer more manic and depressive episodes and make more suicide attempts. In the general population, obesity is associated with reduced total brain volume (TBV) and gray matter volume (GMV), but the neurobiology of obesity in BD has not been investigated., Methods: We used magnetic resonance imaging to examine TBV, GMV, white matter volume (WMV), as well as frontal, parietal, occipital, and temporal lobe volumes, in 55 healthy subjects (17 overweight/obese and 38 normal weight) and 57 patients with BD following their first manic episode (20 overweight/obese and 37 normal weight)., Results: Linear regression analyses demonstrated that when other predictors of brain volume were accounted for, increased body mass index (BMI) in healthy subjects was significantly associated with decreased TBV and GMV. In contrast, increased BMI in patients with BD was significantly associated with decreased WMV and temporal lobe volume, areas of known vulnerability in early BD., Conclusions: This is the first published report to show a relationship between elevated BMI and reduced brain volumes in BD, or any psychiatric illness. Our results suggest that obesity is associated with unique neurobiological changes in BD. They further imply a possible biological mechanism underlying the association between obesity and a more severe illness course in BD., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Although 5-hydroxytryptamine (5-HT) has been implicated in mania, the precise alterations in the 5-HT system remain elusive., Aims: To assess brain 5-HT2 receptors in drug-free individuals experiencing a manic episode in comparison with healthy volunteers using positron emission tomography (PET)., Method: Participants (n = 10) with DSM-IV bipolar I disorder-manic episode and healthy controls (n = 10) underwent [18F]-setoperone scans. The differences in 5-HT2 receptor binding potential between the two groups were determined using statistical parametric mapping (SPM) analysis., Results: Age was a significant correlate with 5-HT2 receptor binding potential with a similar magnitude of correlation in both groups. The SPM analysis with age as a covariate showed that the individuals with current mania had significantly lower 5-HT2 receptor binding potential in frontal, temporal, parietal and occipital cortical regions, with changes more prominent in the right cortical regions compared with controls., Conclusions: This study suggests that brain 5-HT2 receptors are decreased in people with acute mania.

Objectives: Patients with bipolar disorder have changes in brain structures but it is unclear if these are present at disease onset and thus predispose subjects to develop the disorder, or whether they develop during the course of the disorder, either due to the effects of multiple episodes or as a consequence of treatment with psychotropic agents. Studies in first-episode (FE) manic patients have the potential to provide answers to these questions., Methods: Voxel-based morphometry (VBM) was used to assess magnetic resonance imaging scans of 15 FE manic patients and 15 matched healthy controls., Results: Using a priori defined statistical criteria, no significant differences in brain structures were noted between the two groups. However, there was approximately a 6% reduction in left anterior cingulate, left precuneus and right posterior cingulate volume in FE patients and these reductions were significant (p

Objective: To examine the effects of treatment with valproate on brain 5-HT2A receptors in acute manic patients using positron emission tomography (PET) and [18F]-setoperone., Methods: Patients with DSM-IV bipolar I disorder-manic episode were recruited. Patients were drug free or drug naïve at the time of baseline PET scan. All patients were treated with valproate and one patient received lithium in addition to valproate for 3-5 weeks following which they had a post-treatment PET scan. The effect of treatment on brain 5-HT2A receptor binding was determined using statistical parametric mapping (SPM) and region of interest (ROI) analyses. Of the 12 manic patients recruited, seven patients had both baseline and post-treatment PET scans., Results: All seven patients improved with treatment and were in remission at the time of the second PET scan. Both SPM and ROI analyses showed that treatment with mood stabilizers had no significant effect on brain 5-HT2A receptor binding in manic patients., Conclusion: This study suggests that changes in brain 5-HT2A receptors are not involved in the antimanic effects of mood stabilizers however, we cannot exclude the possibility of 5-HT2A receptor involvement in down-stream signaling pathways.

Objective: A previous study reported a higher than normal density of dopamine D(2) receptors in psychotic mania but not in nonpsychotic mania. The purpose of this study was to further examine D(2) receptor density in a larger sample of nonpsychotic manic patients by using positron emission tomography (PET) and [(11)C]raclopride., Method: Thirteen neuroleptic- and mood- stabilizer-naive patients with DSM-IV mania without psychotic features and 14 healthy comparison subjects underwent [(11)C]raclopride PET scans. Of the 13 patients, 10 were treated with divalproex sodium monotherapy. PET scans were repeated 2-6 weeks after commencement of divalproex sodium. D(2) receptor binding potential was calculated by using a ratio method with the cerebellum as the reference region., Results: The [(11)C]raclopride D(2) binding potential was not significantly different in manic patients than in the comparison subjects in the striatum. Treatment with divalproex sodium had no significant effect on the [(11)C]raclopride D(2) binding potential in manic patients. There was no correlation between the D(2) binding potential and manic symptoms before or after treatment., Conclusions: These results suggest that D(2) receptor density is not altered in nonpsychotic mania and that divalproex sodium treatment does not affect D(2) receptor availability.

Background: The mechanism by which rapid tryptophan depletion (RTD) paradigm induces depressive relapse in recently remitted patients with depression is unknown., Aims: To determine the effects of RTD on brain 5-HT(2) receptors using positron emission tomography (PET) and (18)F-labelled setoperone., Method: Ten healthy women under went two PET scans. Each scan was done 5 h after the ingestion of either a balanced or a tryptophan-deficient amino acid mixture, and the two test sessions were separated by at least 5 days., Results: The RTD decreased plasma free tryptophan levels significantly but it had no significant effects on mood. Subjects showed a significant decrease in brain 5-HT(2) receptor binding in various cortical regions following the RTD session., Conclusions: When taken with the evidence that antidepressant treatment is associated with a decrease in brain 5-HT(2) receptors, these findings suggest that a decrease in 5-HT(2) binding following RTD might be an adaptive response that provides protection against depressive symptoms.

Background: Postmortem and brain imaging studies that measured brain serotinin(2) (5-HT(2)) receptors in major depression reported an increase, decrease, and no change compared with controls. In this study, we assessed brain 5-HT(2) receptors in 20 depressed patients (mean +/- SD age, 40.1 +/- 9.5 years; range, 22-60 years) and 20 healthy controls similar in age (37.2 +/- 12.6 years; range, 19-59 years) using positron emission tomography and setoperone labeled with fluorine 18 ([(18)F]setoperone)., Methods: Patients with DSM-IV major depression and healthy controls underwent scanning with [(18)F]setoperone. All study subjects were drug free for at least 2 weeks. The 5-HT(2) binding images were created using region-to-cerebellum ratios. The differences in 5-HT(2) receptor binding potential between the two groups were determined with statistical parametric mapping software and region of interest analysis., Results: There was a significant negative correlation between 5-HT(2) receptor binding potential and age in both patients and controls, and the magnitude of this correlation was similar in both groups. Both statistical parametric mapping and region of interest analyses showed that, compared with healthy controls, depressed patients had significantly lower 5-HT(2) receptor binding potential in frontal, temporal, parietal, and occipital cortical regions. Statistical parametric mapping analysis showed that the mean decrease in 5-HT(2) receptor binding potential for the entire cluster in these regions was 22%, and it ranged from 22% to 27% for local maxima within the clusters of significant voxels., Conclusion: This study suggests that brain 5-HT(2) receptors are decreased in patients with major depression.

Background: The neuroreceptor changes involved in therapeutic efficacy of various antidepressants remain unclear. Preclinical studies have shown that long-term administration of various antidepressants causes down-regulation of brain serotonin 2 (5-HT2) receptors in rodents, but it is unknown if similar changes occur following antidepressant treatment in depressed patients. Our purpose, therefore, was to assess the effects of treatment with desipramine hydrochloride on brain 5-HT2 receptors in depressed patients using positron emission tomography (PET) and fluorine-18 (18F)-labeled setoperone., Methods: Eleven patients who met DSM-IV criteria for major depression as determined by a structured clinical interview for DSM-III-R diagnosis and suitable for treatment with desipramine were recruited. Ten patients underwent a PET scan before and another after 3 to 4 weeks of treatment with desipramine., Results: Eight of the 10 patients responded to desipramine treatment as indicated by more than 50% decrease in Hamilton Depression Rating Scale scores. Depressed patients showed a significant decrease in 5-HT2 receptor binding as measured by setoperone binding in frontal, temporal, parietal, and occipital cortical regions following desipramine treatment. The decrease in 5-HT2 receptor binding was observed bilaterally and was particularly prominent in frontal cortex., Conclusions: Depressed patients showed a significant reduction in available 5-HT2 receptors in the brain following desipramine treatment, but it is unknown if this change in 5-HT2 receptors is due to clinical improvement or an effect of desipramine that is unrelated to clinical status.