‍Mitochondrial Dysfunction in Bipolar Disorder: Insights From Patient-Derived Cerebral Organoids
Dana El Soufi of the University of Toronto reported “BD-derived cerebral organoids exhibited significantly higher ROS (reactive oxygen species) and circulating cell-free mitochondrial DNA (ccf-mtDNA) levels than controls, indicating increased oxidative stress and mitochondrial inflammation. JC-1 fluorescence was elevated in BD organoids, indicating reduced mitochondrial membrane potential, a marker of mitochondrial dysfunction. Additionally, BD organoids showed a pronounced increase in NLRP3 inflammasome activation and over 50% reduction in ATP levels, underscoring mitochondrial inefficiency and heightened inflammatory sensitivity in BD.

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Elevated C-reactive Protein is Associated With Suicide Attempts in Youth With Bipolar Disorder
Mikaela Dimick of the Centre for Addiction and Mental Health reported “CRP levels differed across groups (F3,250=6.39, p<0.001). In post-hoc analyses, CRP levels were significantly higher in the BD-SA group compared to HC (p<0.001)” as well as all other bipolar groups.  “Given the wide availability and low cost of CRP testing, findings from this study have (important) potential clinical implications.”

Cognitive Improvement and Prefrontal Network Interactions in Individuals With Remitted Bipolar Disorder After Transcranial Infrared Laser Stimulation (TILS)
Francisco Gonzalez-Lima of The University of Texas at Austin reported “Cognitive test results showed that in people with remitted BD, TILS was effective at improving performance in trail-making (p<0.01) and 2-back (p<0.001) tasks. TILS enhanced speed and accuracy in both tasks reflecting improved cognitive flexibility, working memory, and attentional control.  They concluded “Repeated TILS may be a safe and effective non-invasive intervention to improve cognition in people with remitted BD.”

Interactions Between Lipid Metabolism and Inflammation: Impact on Depression Severity and Symptoms of Anhedonia and Fatigue

HoLim Lee of Emory University School of Medicine reported seventy-four trauma-exposed Black women that “Compared to those with low lipids and low inflammation, those with high lipids and high inflammation had greater depression severity ( p<0.001), anhedonia ( p=0.023), and fatigue (p=0.012)….

Conclusions: Findings demonstrate an interaction between inflammation and lipid metabolism in association with depressive symptoms and support an immunometabolic phenotype.”

Pramipexole in Works in Treatment Resistant Depression:

Michael Browning of the University of Oxford reported “Participants were randomised to 48 weeks of either pramipexole or placebo augmentation, with doses titrated up to 2.5mg daily… By week 12 these scores had reduced by a mean 6.4 in the pramipexole group and 2.4 in the placebo group (… p<0.0001). All other secondary efficacy outcomes were significant in favour of pramipexole, up to final assessment at week 48. Significantly more people in the pramipexole group discontinued treatment due to side effects (15 (20%) vs. 4 (5.3%), p=0.01)”. They concluded “Pramipexole augmentation was effective at reducing symptoms of depression across the course of a year. The effect size was large, comparing favourably to that reported for other common interventions for TRD.”

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Higher Intensity of Mystical Experience Following Magnesium-Ibogaine is Associated With Larger Decreases in PTSD Severity
Randi Brown of Stanford University/VA Palo Alto Health Care System reported that “Higher MEQ (Mystical Experience Questionnaire) scores following magnesium-ibogaine were associated with larger decreases in PTSD severity from baseline to (immediate and one month) post-treatment timepoints.”  

PSD-95 is a Marker of Lithium Response in Bipolar Disorder Patient-Derived Glutamatergic Neurons 

Johansen Amin of the University of California - San Diego reported on “BD patients participated in a multi-center, 12-week lithium monotherapy trial… Donors provided skin biopsies for fibroblasts that were subsequently used to generate induced pluripotent stem cells (iPSCs)…. the expression of synapsin I (SYN1) and PSD-95 is reduced in BD neurons compared to controls at baseline…. However, lithium increased PSD-95 expression, a post synaptic marker, selectively in neurons from lithium-responders and not in neurons from lithium non-responders, leading to group differences in the colocalization of SYN1 and PSD-95…. We conclude that synaptic protein markers are associated with BD pathology and correction of post-synaptic protein expression may be an important mechanism underlying lithium response.”

Gray and White Matter Alterations in Bipolar Disorder: A global Voxel-Based Morphometry Analysis in 5,511 Individuals

Shane Pracar of the Institute of Psychiatry, King's College reported on “3D T1-weighted brain MRI scans, for 2,126 individuals with BD and 3,385 HC, spanning 39 international cohorts…. The VBM analysis revealed widespread patterns of lower gray matter volume in BD individuals vs HC, in a cluster encompassing the cerebral cortex and the thalamus (peak Hedges’ g=0.24). BD individuals vs HC had smaller white matter volume in the splenium of the corpus callosum (g=0.29). BD individuals taking lithium showed greater thalamic volume (g=0.14) and a region of greater white matter volume (g=0.11) than those not taking lithium….Lithium use was associated with greater gray and white matter volumes, aligning with prior ENIGMA-BD studies.”

Ketamine-Assisted Mindfulness-Based Cognitive Therapy (MBCT) for Treatment-Resistant Depression

Arushi Badola of The Ohio State University reported on “Patients with TRD (that) are recruited from OSU clinics, and undergo a psychiatric assessment, then engaged in an 8-week MBCT program including weekly, 2-hour group sessions and daily home mindfulness practices, with a ketamine infusion (0.5 mg/kg) administered between weeks 2 and 3…. These participants demonstrated a significant acute response to ketamine, with reduced depression symptoms… which was sustained six weeks after infusion (week 8, p=0.01)…. The findings are consistent with our hypothesis that ketamine may enhance the effects of MBCT, supporting the feasibility of combining IV ketamine with MBCT for extended antidepressant effects and improved treatment outcomes.”

Saint Neuromodulation System to Treat Major Depressive Disorder in Adolescents

Brandon Bentzley of Magnus Medical Inc., Burlingame, CA reported “Thirteen participants, aged 18-21 years (4 male, 9 female), completed (a five day course of aiTBS) treatment. Participants had a mean (SD) MADRS score of 19.9(6.1) at baseline indicating moderate depression. Following treatment, 69.2% of participants met criteria for remission (MADRS ≤10 or CGI-I ≤2 within 1 week following treatment)… These preliminary findings indicate that a 5-day course of SAINT can provide rapid and significant improvements in depression (and suicidal) symptoms in an adolescent population warranting larger clinical trials. “

Association of Adverse Childhood Experiences With Depression Symptom Reduction Following Ketamine Infusions  in a Large, Naturalistic Sample

Raquel Kosted of The University of Texas at Austin Dell Medical School reported on 566 patients who received 2 to 6 ketamine infusions and were assessed with the PHQ-9 and the Adverse Childhood Experiences (ACE) scale. “PHQ-9 scores improved significantly over time (time: p<.001), with decelerating rates of improvement (quadratic time: p<.001)… Notably, greater ACE exposure was associated with larger magnitude of symptom improvement (time*ACE: p=.03). .. Ketamine therapy is associated with similar rapid-acting, antidepressant effects across ages, genders, and with/without psychotherapy. Enhanced magnitude of symptom reduction for those with greater ACE exposure suggests a potentially unique and targeted benefit of ketamine over conventional antidepressants.”

Role of Voltage-Gated Calcium Channels in Vulnerable Pyramidal Neurons in Primate Dorsolateral Prefrontal Cortex: Elucidating the Role of Cav3.1 and Cav1.2 in Higher-Order Cognition

Dibyadeep Datta of Yale University School of Medicine reported that “Physiological recordings revealed an inverted-U dose-response, where high level channel blockade reduced firing, indicating that T-type channels are needed for working memory-related persistent neuronal firing. However, low dose channel blockade enhanced firing, indicating that excessive Cav3.1 reduces firing, similar to excessive Cav1.2 opening of SK potassium channels….These data help to explain why either loss- or gain-of-function mutations in T-type-calcium-channel-Cav3.1 (CACNA1G) or L-type-calcium-channel Cav1.2 (CACNA1C) would abrogate layer III DLPFC pyramidal cells, impair DLPFC cognitive function and be linked to increased risk of schizophrenia and related disorders” including bipolar disorder and depression that are strongly associated with the CACNA1C variant. 

Editors Note: The dihydropyridine calcium channel blocker directly inhibits the CACNA1C variant and has lithium-like effects in mania and depression and also has some positive effects on cognition.  It is a good add-on to those who cannot tolerate high enough doses of lithium to be effects.  Nimodipine also has good effects in inhibiting ultra-rapid and ultradian cycling.

Resilient Transcriptomic Networks in the Nucleus Accumbens
following Chronic Social Defeat Stress (CSDS) in Mice

Trevonn Gyles of the Icahn School of Medicine At Mount Sinai reported that “approximately 40% of genes upregulated in the NAc of resilient mice overlapped between sexes. WGCNA identified convergent gene modules with one pair showing a 25% overlap—the highest across sexes. Within these modules, GPRIN1 and STX1A emerged as key driver genes positively correlated with resilience. Overexpression of these genes in male mice using viral manipulation induced pro-resilient effects.

Dynamics of AMPA receptors in the habenula underlie the efficacy of ketamine in treatment-resistant depression

Waki Nakajima of the Department of Physiology, Yokohama City University reported on “Thirty-four patients with TRD underwent PET-scans using [11C]K-2, PET tracer for AMPARs. They were administered with saline(n=17) or ketamine(n=17) twice a week for two weeks and performed 2nd-PET scan at 1 month after the first-scan… AMPARs density of the fronto-parietal cortices may regulate depressive symptoms as ketamine alters AMPARs distribution patterns along with the change in the illness severity. Moreover, [11C]K-2 could serve as a promising tool for predicting ketamine response in patients with TRD.

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