The genetics of severe depression.

Genome-wide association studies (GWASs) of major depressive disorder (MDD) have recently achieved extremely large sample sizes and yielded substantial numbers of genome-wide significant loci. Because of the approach to ascertainment and assessment in many of these studies, some of these loci appear to be associated with dysphoria rather than with MDD, potentially decreasing the clinical relevance of the findings. An alternative approach to MDD GWAS is to focus on the most severe forms of MDD, with the hope that this will enrich for loci of larger effect, rendering their identification plausible, and providing potentially more clinically actionable findings. Here we review the genetics of severe depression by using clinical markers of severity including: age of onset, recurrence, degree of impairment, and treatment with ECT. There is evidence for increased family-based and Single Nucleotide Polymorphism (SNP)-based estimates of heritability in recurrent and early-onset illness as well as severe functional impariment. GWAS have been performed looking at severe forms of MDD and a few genome-wide loci have been identified. Several whole exome sequencing studies have also been performed, identifying associated rare variants. Although these findings have not yet been rigorously replicated, the elevated heritability seen in severe MDD phenotypes suggests the value of pursuing additional genome-wide interrogation of samples from this population. The challenge now is generating a cohort of adequate size with consistent phenotyping that will allow for careful and robust classifications and distinctions to be made. We are currently pursuing such a strategy in our 50-site worldwide Gen-ECT-ics consortium.

Ketamine vs Electroconvulsive Therapy for Treatment-Resistant Depression: A Secondary Analysis of a Randomized Clinical Trial.

Importance: The ELEKT-D: Electroconvulsive Therapy (ECT) vs Ketamine in Patients With Treatment Resistant Depression (TRD) (ELEKT-D) trial demonstrated noninferiority of intravenous ketamine vs ECT for nonpsychotic TRD. Clinical features that can guide selection of ketamine vs ECT may inform shared decision-making for patients with TRD. Objective: To evaluate whether selected clinical features were associated with differential improvement with ketamine vs ECT. Design, Setting, and Participants: This secondary analysis of an open-label noninferiority randomized clinical trial was a multicenter study conducted at 5 US academic medical centers from April 7, 2017, to November 11, 2022. Analyses for this study, which were not prespecified in the trial protocol, were conducted from May 10 to Oct 31, 2023. The study cohort included patients with TRD, aged 21 to 75 years, who were in a current nonpsychotic depressive episode of at least moderate severity and were referred for ECT by their clinicians. Exposures: Eligible participants were randomized 1:1 to receive either 6 infusions of ketamine or 9 treatments with ECT over 3 weeks. Main Outcomes and Measures: Association between baseline factors (including 16-item Quick Inventory of Depressive Symptomatology Self-Report [QIDS-SR16], Montgomery-Asberg Depression Rating Scale [MADRS], premorbid intelligence, cognitive function, history of attempted suicide, and inpatient vs outpatient status) and treatment response were assessed with repeated measures mixed-effects model analyses. Results: Among the 365 participants included in this study (mean [SD] age, 46.0 [14.5] years; 191 [52.3%] female), 195 were randomized to the ketamine group and 170 to the ECT group. In repeated measures mixed-effects models using depression levels over 3 weeks and after false discovery rate adjustment, participants with a baseline QIDS-SR16 score of 20 or less (-7.7 vs -5.6 points) and those starting treatment as outpatients (-8.4 vs -6.2 points) reported greater reduction in the QIDS-SR16 with ketamine vs ECT. Conversely, those with a baseline QIDS-SR16 score of more than 20 (ie, very severe depression) and starting treatment as inpatients reported greater reduction in the QIDS-SR16 earlier in course of treatment (-8.4 vs -6.7 points) with ECT, but scores were similar in both groups at the end-of-treatment visit (-9.0 vs -9.9 points). In the ECT group only, participants with higher scores on measures of premorbid intelligence (-14.0 vs -11.2 points) and with a comorbid posttraumatic stress disorder diagnosis (-16.6 vs -12.0 points) reported greater reduction in the MADRS score. Those with impaired memory recall had greater reduction in MADRS during the second week of treatment (-13.4 vs -9.6 points), but the levels of MADRS were similar to those with unimpaired recall at the end-of-treatment visit (-14.3 vs -12.2 points). Other results were not significant after false discovery rate adjustment. Conclusions and Relevance: In this secondary analysis of the ELEKT-D randomized clinical trial of ECT vs ketamine, greater improvement in depression was observed with intravenous ketamine among outpatients with nonpsychotic TRD who had moderately severe or severe depression, suggesting that these patients may consider ketamine over ECT for TRD.

Transgender women's perspectives on mental health care related to vaginoplasty for gender affirmation.

PURPOSE: This study aimed to describe patient experiences and attitudes about the role of the mental health professional as it relates to pursuing gender affirmation surgery. METHODS: This was a mixed-models study with semi-structured interviews. Participants who presented for gender affirming vaginoplasty and had completed pre-surgical requirements but had not yet had the procedure were invited to participate in the study. Semi-structured phone interviews were conducted from November 2019 and December 2020 until saturation of themes was achieved at a sample size of 14. Interviews were then transcribed verbatim and coded by theme. Qualitative analysis was performed using a grounded theory approach. RESULTS: Almost half of the patients did not identify any barriers to obtaining mental health care, but a majority brought up concerns for less advantaged peers, with less access to resources. Some patients also felt that there was benefit to be obtained from the mental health care required before going through with surgery, while others felt the requirements were discriminatory. Finally, a large proportion of our participants reported concerns with the role of mental health care and the requirements set forth by the World Professional Association for Transgender Health (WPATH), and patients gave suggestions for future improvements including decreasing barriers to care while rethinking how guidelines impact patients. CONCLUSION: There are many competing goals to balance when it comes to the guidelines for gender affirmation surgery, and patients had differing and complex relationships with mental health care and the pre-surgical process.

Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression.

BACKGROUND: Electroconvulsive therapy (ECT) and subanesthetic intravenous ketamine are both currently used for treatment-resistant major depression, but the comparative effectiveness of the two treatments remains uncertain. METHODS: We conducted an open-label, randomized, noninferiority trial involving patients referred to ECT clinics for treatment-resistant major depression. Patients with treatment-resistant major depression without psychosis were recruited and assigned in a 1:1 ratio to receive ketamine or ECT. During an initial 3-week treatment phase, patients received either ECT three times per week or ketamine (0.5 mg per kilogram of body weight over 40 minutes) twice per week. The primary outcome was a response to treatment (i.e., a decrease of ≥50% from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report; scores range from 0 to 27, with higher scores indicating greater depression). The noninferiority margin was -10 percentage points. Secondary outcomes included scores on memory tests and patient-reported quality of life. After the initial treatment phase, the patients who had a response were followed over a 6-month period. RESULTS: A total of 403 patients underwent randomization at five clinical sites; 200 patients were assigned to the ketamine group and 203 to the ECT group. After 38 patients had withdrawn before initiation of the assigned treatment, ketamine was administered to 195 patients and ECT to 170 patients. A total of 55.4% of the patients in the ketamine group and 41.2% of those in the ECT group had a response (difference, 14.2 percentage points; 95% confidence interval, 3.9 to 24.2; P<0.001 for the noninferiority of ketamine to ECT). ECT appeared to be associated with a decrease in memory recall after 3 weeks of treatment (mean [±SE] decrease in the T-score for delayed recall on the Hopkins Verbal Learning Test-Revised, -0.9±1.1 in the ketamine group vs. -9.7±1.2 in the ECT group; scores range from -300 to 200, with higher scores indicating better function) with gradual recovery during follow-up. Improvement in patient-reported quality-of-life was similar in the two trial groups. ECT was associated with musculoskeletal adverse effects, whereas ketamine was associated with dissociation. CONCLUSIONS: Ketamine was noninferior to ECT as therapy for treatment-resistant major depression without psychosis. (Funded by the Patient-Centered Outcomes Research Institute; ELEKT-D ClinicalTrials.gov number, NCT03113968.).

Differences in network properties of the structural connectome in bipolar and unipolar depression.

BACKGROUND: Differentiation between Bipolar Disorder Depression (BDD) and Unipolar Major Depressive Disorder (MDD) is critical to clinical practice. This study investigated machine learning classification of BDD and MDD using graph properties of Diffusion-weighted Imaging (DWI)-based structural connectome. METHODS: This study included a large number of medication-free (N =229) subjects: 60 BDD, 95 MDD, and 74 Healthy Control (HC) subjects. DWI probabilistic tractography was performed to create Fractional Anisotropy (FA) and Total Streamline (TS)-based structural connectivity matrices. Global and nodal graph properties were computed from these matrices and tested for group differences. Next, using identified graph properties, machine learning classification (MLC) between BDD, MDD, MDD with risk factors for developing BD (MDD+), and MDD without risk factors for developing BD (MDD-) was conducted. RESULTS: Communicability Efficiency of the left superior frontal gyrus (SFG) was significantly higher in BDD vs. MDD. In particular, Communicability Efficiency using TS-based connectivity in the left SFG as well as FA-based connectivity in the right middle anterior cingulate area was higher in the BDD vs. MDD- group. There were no significant differences in graph properties between BDD and MDD+. Direct comparison between MDD+ and MDD- showed differences in Eigenvector Centrality (TS-based connectivity) of the left middle frontal sulcus. Acceptable Area Under Curve (AUC) for classification were seen between the BDD and MDD- groups, and between the MDD+ and MDD- groups, using the differing graph properties. CONCLUSION: Graph properties of DWI-based connectivity can discriminate between BDD and MDD subjects without risk factors for BD.

Resting-state functional connectivity graph-properties correlate with bipolar disorder-risk in young medication-free depressed subjects: Bipolar-risk Resting State Functional Connectivity in Major Depression.

BACKGROUND: Major Depressive Disorder (MDD) is frequently associated with risk factors for the development of Bipolar Disorder (BD). Using graph theory, we investigated brain network properties associated with BD risk factors in young MDD subjects. METHODS: Resting-state fMRI was acquired from a large cohort (N= 104) of medication-free currently depressed participants (25 BD depression (BDD), 79 MDD). Lifetime mania symptom count (LMSC), current Young Mania Rating Scale (YMRS) score, and family history of mood disorders (FHMD) were examined as BD risk factors. Functional connectivity matrices from 280 regions of interests (ROIs) were first entered into the Network Based Statistic (NBS) toolbox to identify connections that varied with each risk factor. Next, within the correlated network for each risk factor, global and nodal graph properties for the top five linked nodes were calculated. Last, using identified graph properties, machine learning classification (MLC) between BDD, MDD with BD risk factors (MDD+), and without BD risk factors (MDD-) was conducted. RESULTS: LMSC positively correlated with left lateral orbitofrontal cortex (LOFC) Communication Efficiency and with left middle temporal Eigenvector Centrality. Current YMRS score positively correlated with right amygdala Communication Efficiency and Closeness Centrality. FHMD positively correlated with right insula Eigenvector Centrality. Acceptable MLC accuracy was seen between BDD and MDD- using middle temporal Eigenvector Centrality, whereas moderate accuracy was seen between MDD+ and MDD- using OFC Communication Efficiency. LIMITATION: Although participants were medication-free, they were not medication-naïve. CONCLUSION: Functional connectome graph properties may serve as BD vulnerability biomarkers in young individuals with MDD.

Left Dorsolateral Prefrontal Cortex Glx/tCr Predicts Efficacy of High Frequency 4- to 6-Week rTMS Treatment and Is Associated With Symptom Improvement in Adults With Major Depressive Disorder: Findings From a Pilot Study.

About 20-40% of estimated 121 million patients with major depressive disorder (MDD) are not adequately responsive to medication treatment. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive, non-convulsive neuromodulation/neurostimulation method, has gained popularity in treatment of MDD. Because of the high cost involved in rTMS therapy, ability to predict the therapy effectiveness is both clinically and cost wise significant. This study seeks an imaging biomarker to predict efficacy of rTMS treatment using a standard high frequency 10-Hz 4- to 6-week protocol in adult population. Given the significance of excitatory and inhibitory neurotransmitters glutamate (Glu) and gamma aminobutyric acid (GABA) in the pathophysiology of MDD, and the involvement of the site of rTMS application, left dorsolateral prefrontal cortex (lDLPFC), in MDD, we explored lDLPFC Glx (Glu + glutamine) and GABA levels, measured by single voxel magnetic resonance spectroscopy (MRS) with total creatine (tCr; sum of creatine and phosphocreatine) as reference, as possible biomarkers of rTMS response prediction. Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) MRS data from 7 patients (40-74 y) were used in the study; 6 of these patients were scanned before and after 6 weeks of rTMS therapy. Findings from this study show inverse correlation between pretreatment lDLPFC Glx/tCr and (i) posttreatment depression score and (ii) change in depression score, suggesting higher Glx/tCr as a predictor of treatment efficacy. In addition association was observed between changes in depression scores and changes in Glx/tCr ratio. The preliminary findings did not show any such association between GABA/tCr and depression score.

Neuroimaging correlates of emotional response-inhibition discriminate between young depressed adults with and without sub-threshold bipolar symptoms (Emotional Response-inhibition in Young Depressed Adults).

BACKGROUND: Many subjects with major depression (MDD) exhibit subthreshold mania symptoms (MDD+). This study investigated, for the first time, using emotional inhibition tasks, whether the neural organization of MDD+ subjects is more similar to bipolar depression (BDD) or to MDD subjects without subthreshold bipolar symptoms (MDD-). METHOD: This study included 118 medication-free young adults (15 - 30 yrs.): 20 BDD, 28 MDD+, 41 MDD- and 29 HC subjects. Participants underwent fMRI during emotional and non-emotional Go/No-go tasks during which they responded for Go stimuli and inhibited response for happy, fear, and non-emotional (gender) faces No-go stimuli. Univariate linear mixed-effects (LME) analysis for group effects and multivariate Gaussian Process Classifier (GPC) analyses were conducted. RESULTS: MDD- group compared to both the BDD and MDD+ groups, exhibited significantly lower activation in parietal, temporal and frontal regions (cluster-wise corrected p <0.05) for emotional inhibition conditions vs. non-emotional condition. GPC classification of emotional (happy + fear) vs. non-emotional response-inhibition activation pattern showed good discrimination between BDD and MDD- subjects (AUC: 0.70; balanced accuracy: 70% (corrected p = 0.018)) as well as between MDD+ and MDD- subjects (AUC: 0.72; balanced accuracy: 67% (corrected p = 0.045)) but less efficient discrimination between BDD and MDD+ groups (AUC: 0.68; balanced accuracy: 61% (corrected p = 0.273)). Notably, classification of the MDD- group was weighted for left amygdala activation pattern. LIMITATIONS: Results also need to be tested in a different independent dataset. CONCLUSION: Using an fMRI emotional Go-Nogo task, MDD- subjects can be discriminated from BDD and MDD+ subjects.

The NEO-FFI domain of openness to experience moderates ketamine response in treatment resistant depression.

BACKGROUND: There are many putative mechanisms by which ketamine has its effect and many unanswered questions about risks and benefits of long-term ketamine therapy. A research imperative is the identification of predictors of response to intravenous ketamine, especially a sustained response to maintenance ketamine. Temperament is an inherited aspect of personality and is a predictive factor for outcome in treatment resistant depressed (TRD) patients. METHODS: We analyzed which domains of personality impacted initial and sustained ketamine response. Utilizing the Neuroticism Extraversion Openness Five Factor Inventory (NEO-FFI) on 125 participants with TRD, we tested (1) whether the degree of neuroticism predicted initial and/or sustained response to ketamine; and (2) whether extraversion, agreeableness, openness to experience, and conscientiousness had an impact on response. RESULTS: Our findings confirmed previous literature that elevated neuroticism, low conscientiousness, and low extraversion was the pattern of our TRD population regardless of response. Openness was the only factor to significantly predict sustained treatment outcome. LIMITATIONS: Our findings are limited by the lack of placebo control, small sample size, non- standardized infusion intervals, polypharmacy rather than ketamine monotherapy, a select TRD population in that they had all failed ECT, and a primarily Caucasian population. CONCLUSIONS: Our registry adds to the literature that factors making up temperament may have predictive value in regard to treatment response, specifically the outcome for TRD patients receiving long-term ketamine infusion therapy. If confirmed, assessing for Openness could reduce inappropriate exposure to ketamine with its attendant unknown long-term risks.

Neuroimaging gender dysphoria: a novel psychobiological model.

Gender identity development is complex and involves several key processes. Transgender people experience incongruence between their biological and identified gender. This incongruence can cause significant impairment in overall functioning and lead to gender dysphoria (GD). The pathophysiology of GD is complex and is poorly understood. A PubMed search based on predetermined eligibility criteria was conducted to review neuropsychiatric articles focused on neurological, biological and neuroimaging aspects of gender development, transgender identity and GD. The information obtained from the literature was then used to formulize a GD model. Distinct gray matter volume and brain activation and connectivity differences were found in individuals with GD compared to controls, suggesting a neurobiological basis of GD; which leads to the concept of brain gender. Individuals with GD encounter a recurrent conflict between their brain gender and the societal feedback; which causes recurrent and ongoing cognitive dissonance, finally leading to GD and functional connectivity and activation changes in the transgender brain. GD has neurobiological basis, but it is closely associated with the individuals' interaction with the external world, their self-perception and the feedback received in return. We propose a novel model where the development of GD includes cognitive dissonance, involving anterior cingulate cortex and ventral striatum as the key brain structures. This model can be used to generate testable hypotheses using behavioral and neuroimaging techniques to understand the neuropsychobiology of GD.

Mental Health Diagnoses Among Transgender Patients in the Clinical Setting: An All-Payer Electronic Health Record Study.

We performed a cross-sectional analysis of the prevalence of psychiatric diagnoses among transgender patients in clinical care using an all-payer electronic health record database. Of 10,270 transgender patients identified, 58% (n=5940) had at least one psychiatric diagnosis compared with 13.6% (n=7,311,780) in the control patient population (p<0.0005). Transgender patients had a statistically significant increase in prevalence for all psychiatric diagnoses queried, with major depressive disorder and generalized anxiety disorder being the most common diagnoses (31% and 12%, respectively). Utilizing an all-payer database, although not without limitations, enables assessment of mental health and substance use diagnoses in this otherwise small population.

The Role of the Ethicist in an Interdisciplinary Transgender Health Care Team.

Unique ethical issues arise in the provision of gender-affirming care to transgender and gender diverse people. One of the distinctive trends in transgender health care has been the development of interdisciplinary specialty teams with expertise in gender-affirming care. Clinical ethicists can play an important role on these teams in helping gender variant patients and gender-affirming providers navigate complex ethical issues, creating opportunities for enhancing patient experience, and easing provider moral uncertainty. Many opportunities exist for clinical ethicists to lend their skills to this area of clinical care. It is important for interdisciplinary transgender health care teams and other health care professionals providing transgender-specific care to understand the ethical issues involved in such care, the ways in which ethics expertise can be a resource, and the benefits and drawbacks of integrating a clinical ethicist into their team.

Administration of Sub-anesthetic Dose of Ketamine and Electroconvulsive Treatment on Alternate Week Days in Patients with Treatment Resistant Depression: A Double Blind Placebo Controlled Trial.

Introduction and Background: Patients with depression who fail to respond to at least two antidepressants in their current episode are considered to have Treatment Resistant Depression (TRD). ECT is an effective treatment of TRD but cognitive side effects limit its use. Ketamine elicits a rapid antidepressant response in sub-anesthetic repeated doses. ECT and ketamine may be modulating the glutamate system, therefore when administered in an interleaved fashion, they could have a synergistic effect. Methods: 15 TRD patients were recruited and 12 were included in the analysis. Patients were randomly assigned to an ECT + iv. ketamine or ECT + iv. placebo (midazolam). At baseline and before each infusion, depression severity scales were administered. At baseline, halfway through and at the end of the study, cognitive tests were administered. Results: There was no difference between the ketamine and placebo arms, per change in 17-item Hamilton Depression Scores (HAM-D), Young Mania Rating Scores or cognitive tests. Per HAMD scores, 3 ECT +ketamine subjects (42%) showed early remission (HAMD < 8) and maintained euthymia for 3 additional visits. None of the ECT +midazolam subjects (0%) achieved early remission. This difference showed a trend level significance (Chi square P-Value = 0.0910). Conclusion: The results of the study were limited due to the small sample size. However, a trend level difference in rates of early remission was seen, suggesting that ketamine + ECT may lead to a faster symptom relief. A larger sample size is needed for statistical confirmation.

Effects of Repeated Intravenous Ketamine in Treatment-Resistant Geriatric Depression: A Case Series.

PURPOSE: There is an immediate need for more sustainable, effective therapies for treatment-resistant depression in patients who do not respond to traditional psychopharmacology. The aim of this study was to determine the efficacy and safety of intravenous ketamine infusions on the elderly population by using a case series of 6 geriatric patients with treatment-resistant depression. METHODS: Eligible patients aged 65 to 82 were given a subanesthetic ketamine hydrochloride dose of 0.5 mg/kg delivered intravenously over 40 minutes twice weekly for an acute series. If patients reported a 50% decrease in depression symptoms after the acute series of 2 to 4 infusions, they would be moved to a maintenance series of infusions, which would occur every 2 to 6 weeks on an individual basis. RESULTS: Of the 6 patients given ketamine, 1 failed to respond to the acute treatment phase, 4 responded to the acute infusion phase but failed to sustain a response after a range of 8 to 22 maintenance infusions, and 1 responded to the infusions but relapsed into alcohol use; therefore, treatment was discontinued. CONCLUSIONS: The relative safety of intravenous ketamine in the elderly was demonstrated by the mild, transient adverse effects seen by this patient group. The geriatric population is unable to maintain an antidepressant response to intravenous ketamine over time, signifying that ketamine has low efficacy for the elderly.

ELEctroconvulsive therapy (ECT) vs. Ketamine in patients with Treatment-resistant Depression: The ELEKT-D study protocol.

Major depressive disorder (MDD) is the most common mental illness and the leading cause of disability worldwide. Electroconvulsive therapy (ECT) is the most effective treatment for MDD and the gold-standard therapy for treatment-resistant depression (TRD), yet it remains underutilized due to factors such as limited availability, stigma, and concerns about cognitive side effects. Ketamine has emerged as the first rapid-acting antidepressant and shows robust short-term efficacy in clinical trials, but there are concerns about its long-term safety and efficacy. While response rates are similar between ECT and ketamine in clinical trials, these treatments have never been compared head-to-head in a sufficiently large, well-powered randomized study. Here we describe the study protocol for ELEctroconvulsive therapy (ECT) vs. Ketamine in patients with Treatment-resistant Depression (ELEKT-D), a non-inferiority, comparative effectiveness trial. Patients with TRD seeking clinical treatment are randomized (1:1) to receive ECT (thrice weekly) or intravenous ketamine (twice weekly) for 3-5 weeks. The primary outcome is the proportion of responders in each group at the end of study visit, as measured by a patient-reported outcome measure (Quick Inventory of Depressive Symptomatology-Self Report). The study is powered such that the non-inferiority margin allows for ketamine to retain 90% of the ECT treatment effect, with a projected sample size of 400 patients (200 per group). Secondary outcomes include remission rates, depression severity, cognitive functioning, quality of life, adverse events, and tolerability. The results of the ELEKT-D study will have important implications for patient choice, clinical practice, and health insurance policies.

Sub-threshold bipolar disorder in medication-free young subjects with major depression: Clinical characteristics and antidepressant treatment response.

BACKGROUND: This study, for the first time, compared illness and antidepressant response characteristics of young subjects with major depression (MDD) at low (LRMDD) or high-risk (HRMDD) for developing bipolar disorder with characteristics of young bipolar (BPD) subjects and healthy controls (HC). METHODS: One hundred and six young (15-30 yr), medication-free subjects MDD subjects (HRMDD, N = 51; LRMDD, N = 55) were compared with 32 BPD (Type I: 14; Type II: 18) as well as 49 HC subjects. Baseline illness characteristics and frequency of comorbid conditions were examined using Analysis of Variance and Cochran-Armitage trend test. Additionally, in MDD subjects, the effect of open-label antidepressant treatment for up to 24 months with periodic assessments was compared between HRMDD and LRMDD groups for treatment response, remission and (hypo)mania switch while controlling for attrition. RESULTS: Significant gradation from LRMDD to HRMDD to BPD groups was found for increasing occurrence of alcohol dependence (p = 0.006), comorbid PTSD (p = 0.006), borderline personality traits (p = 0.001), and occurrence of melancholic features (p < 0.005). Antidepressant treatment response was similar between the two groups except that for the 12-month period HRMDD showed a trend for a lower response. Switch to (hypo)mania was infrequent in both groups though the HRMDD showed a higher occurrence of spikes in (hypo)mania symptoms (>25% increase in YMRS scores)(p = 0.04). CONCLUSION: Findings of the study indicate that a substantial proportion of young MDD subjects share BPD illness characteristics. These HRMDD subjects, if treated with antidepressants, need to be monitored for development of BPD. TRIAL REGISTRATION: NCT01811147.

Lithium monotherapy associated clinical improvement effects on amygdala-ventromedial prefrontal cortex resting state connectivity in bipolar disorder.

BACKGROUND: This study, for the first time, investigated lithium monotherapy associated effects on amygdala- ventromedial prefrontal cortex (vMPFC) resting-state functional connectivity and correlation with clinical improvement in bipolar disorder (BP) METHODS: Thirty-six medication-free subjects - 24 BP (12 hypomanic BPM) and 12 depressed (BPD)) and 12 closely matched healthy controls (HC), were included. BP subjects were treated with lithium and scanned at baseline, after 2 weeks and 8 weeks. HC were scanned at same time points but were not treated. The effect of lithium was studied for the BP group as a whole using two way (group, time) ANOVA while regressing out effects of state. Next, correlation between changes in amygdala-vMPFC resting-state connectivity and clinical global impression (CGI) of severity and improvement scale scores for overall BP illness was calculated. An exploratory analysis was also conducted for the BPD and BPM subgroups separately. RESULTS: Group by time interaction revealed that lithium monotherapy in patients was associated with increase in amygdala-medial OFC connectivity after 8 weeks of treatment (p = 0.05 (cluster-wise corrected)) compared to repeat testing in healthy controls. Increased amygdala-vMPFC connectivity correlated with clinical improvement at week 2 and week 8 as measured with the CGI-I scale. LIMITATIONS: The results pertain to open-label treatment and do not account for non-treatment related improvement effects. Only functional connectivity was measured which does not give information regarding one regions effect on the other. CONCLUSIONS: Lithium monotherapy in BP is associated with modulation of amygdala-vMPFC connectivity which correlates with state-independent global clinical improvement.

Quetiapine Extended Release Open-Label Treatment Associated Changes in Amygdala Activation and Connectivity in Anxious Depression: An fMRI Study.

BACKGROUND: This study investigated extended release quetiapine (quetiapine XR) associated changes in functional MRI (fMRI) measures of task-induced amygdalar activation and resting state connectivity in anxious unipolar major depressive disorder (AMDD). METHODS: Anxious unipolar major depressive disorder patients (n = 15) (17-item Hamilton Depression Rating Scale (HAM-D) >18 and Hamilton Anxiety Scale (HAM-A) >18) and closely matched healthy control (HC) subjects were compared at baseline for task induced amygdala activation and resting state connectivity on fMRI. Subsequently, AMDD patients were treated for 8 weeks with open-label quetiapine XR. Weekly HAM-D and HAM-A ratings were obtained, and the fMRI scan was repeated at weeks 2 and 8. Changes in fMRI measures were calculated using repeated-measures analysis of variance and correlation with decrease in HAM-D and HAM-A scores was examined. RESULTS: At baseline, AMDD compared with HC exhibited increased task-induced left amygdalar activation (P = 0.05 clusterwise corrected) and decreased resting state amygdala-cortical and amygdala-pons connectivity (P < 0.05 clusterwise corrected). Quetiapine XR treatment was associated with significant decrease in HAM-D (df = 1,28; female [F] = 39; P = 0.001) and HAM-A scores (df = 1,28; F = 55; P = 0.001). The AMDD group showed increased amygdala-cortical connectivity (P < 0.05 [clusterwise corrected]) at week 2, which was maintained at week 8. At week 8, additional areas showed increased connectivity including insula and putamen. At 8 weeks, decrease in HAM-D scores correlated with increase in amygdala-mid cingulate and amygdala-cuneus connectivity (P = 0.05 [clusterwise corrected]). Decrease in HAM-A scores correlated with increase in amygdala-cuneus and parietal cortex connectivity (P = 0.05 [clusterwise corrected]). LIMITATIONS: Small sample-size, open-label single-arm design, HC only tested at baseline, focused only on amygdala. CONCLUSIONS: Quetiapine XR effects in the treatment of AMDD are associated with modulation of amygdala connectivity.

Resting State Brain Network Disturbances Related to Hypomania and Depression in Medication-Free Bipolar Disorder.

Research on resting functional brain networks in bipolar disorder (BP) has been unable to differentiate between disturbances related to mania or depression, which is necessary to understand the mechanisms leading to each state. Past research has also been unable to elucidate the impact of BP-related network disturbances on the organizational properties of the brain (eg, communication efficiency). Thus, the present work sought to isolate network disturbances related to BP, fractionate these into components associated with manic and depressive symptoms, and characterize the impact of disturbances on network function. Graph theory was used to analyze resting functional magnetic resonance imaging data from 60 medication-free patients meeting the criteria for BP and either a current hypomanic (n=30) or depressed (n=30) episode and 30 closely age/sex-matched healthy controls. Correction for multiple comparisons was carried out. Compared with controls, BP patients evidenced hyperconnectivity in a network involving right amygdala. Fractionation revealed that (hypo)manic symptoms were associated with hyperconnectivity in an overlapping network and disruptions in the brain's 'small-world' network organization. Depressive symptoms predicted hyperconnectivity in a network involving orbitofrontal cortex along with a less resilient global network organization. Findings provide deeper insight into the differential pathophysiological processes associated with hypomania and depression, along with the particular impact these differential processes have on network function.

Differential Resting-State Functional Connectivity of Striatal Subregions in Bipolar Depression and Hypomania.

Bipolar disorder (BP) is characterized by periods of depression (BPD) and (hypo)mania (BPM), but the underlying state-related brain circuit abnormalities are not fully understood. Striatal functional activation and connectivity abnormalities have been noted in BP, but consistent findings have not been reported. To further elucidate striatal abnormalities in different BP states, this study investigated differences in resting-state functional connectivity of six striatal subregions in BPD, BPM, and healthy control (HC) subjects. Ninety medication-free subjects (30 BPD, 30 BPM, and 30 HC), closely matched for age and gender, were scanned using 3T functional magnetic resonance imaging (fMRI) acquired at resting state. Correlations of low-frequency blood oxygen level dependent signal fluctuations for six previously described striatal subregions were used to obtain connectivity maps of each subregion. Using a factorial design, main effects for differences between groups were obtained and post hoc pairwise group comparisons performed. BPD showed increased connectivity of the dorsal caudal putamen with somatosensory areas such as the insula and temporal gyrus. BPM group showed unique increased connectivity between left dorsal caudate and midbrain regions, as well as increased connectivity between ventral striatum inferior and thalamus. In addition, both BPD and BPM exhibited widespread functional connectivity abnormalities between striatal subregions and frontal cortices, limbic regions, and midbrain structures. In summary, BPD exhibited connectivity abnormalities of associative and somatosensory subregions of the putamen, while BPM exhibited connectivity abnormalities of associative and limbic caudate. Most other striatal subregion connectivity abnormalities were common to both groups and may be trait related.