Use of 30-Hz Accelerated iTBS in Drug-Resistant Unipolar and Bipolar Depression in a Public Healthcare Setting: A Case Series

Background: Depressive episodes, especially when resistant to pharmacotherapy, are a hard challenge to face for clinicians and a leading cause of disability worldwide. Neuromodulation has emerged as a potential therapeutic option for treatment-resistant depression (TRD), in particular transcranial magnetic stimulation (TMS). In this article, we present a case series of six patients who received TMS with an accelerated intermittent theta-burst stimulation (iTBS) protocol in a public healthcare setting.Methods: We enrolled a total number of six participants, affected by a treatment-resistant depressive episode, in either Major Depressive Disorder (MDD) or Bipolar Disorder (BD). Patients underwent an accelerated iTBS protocol, targeted to the left dorsolateral prefrontal cortex (DLPFC), 3-week-long, with a total of 6 days of overall stimulation. On each stimulation day, the participants received 3 iTBS sessions, with a 15-min pause between them. Patients were assessed by the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Rating Scale for Anxiety (HAM-A), and the Mania Rating Scale (MRS). At baseline (T0), at the end of the second week (T1), and at the end of the cycle of stimulation (T2).Results: The rANOVA (repeated Analysis of Variance) statistics showed no significant effect of time on the rating scale scores, with a slight decrease in MADRS scores and a very slight increase in HAM-A and HAM-D scores. No manic symptoms emerged during the entire protocol.Conclusions: Although accelerated iTBS might be considered a less time-consuming strategy for TMS administration, useful in a public healthcare setting, our results in a real-word six-patient population with TRD did not show a significant effect. Further studies on wider samples are needed to fully elucidate the potential of accelerated iTBS protocols in treatment-resistant depression.

Atypical antipsychotic Lumateperone Beyond Schizophrenia: Seeking clarity in a time of Uncertainty

Lumateperone (ITI-007) is a serotonin 5HT2A tosylate salt with high affinity for dopamine D2 and D1 receptors and the serotonin transporter. It is unusual in that it controls serotonin, dopamine, and glutamate neurotransmission concurrently, all of which have been implicated in severe mental illness. Consider it a multi-targeted ligand and multifunctional modulator of the serotoninergic system with possible precognitive, antipsychotic, antidepressant, and anxiolytic properties. While lumateperone has been explored as a new agent for schizophrenia therapy, it also provides a unique therapeutic option for a range of other psychiatric and neurological diseases, including behavioural signs of dementia or Alzheimer's disease, sleep problems, and bipolar depression. Additionally, it had a better safety profile than placebo, with no significant extrapyramidal side effects, hyperprolactinemia, or changes in cardiometabolic or endocrine characteristics. Additional study is needed to validate and analyse lumateperone's effectiveness, as well as to identify prospective therapeutic targets. This article gives a comprehensive overview of the most notable results and potential future applications of this chemical in personalised medicine, particularly for neurodegenerative diseases.

Mitochondrial modulators in the treatment of bipolar depression: a systematic review and meta-analysis

Mitochondrial dysfunction has been implicated in the risk, pathophysiology, and progression of mood disorders, especially bipolar disorder (BD). Thus, the objective of this meta-analysis was to determine the overall antidepressant effect of mitochondrial modulators in the treatment of bipolar depression. Outcomes included improvement in depression scale scores, Young Mania Rating Scale (YMRS) and Clinical Global Impression-Severity Scale (CGI-S) score. Data from randomized controlled trials (RCTs) assessing the antidepressant effect of diverse mitochondrial modulators were pooled to determine standard mean differences (SMDs) compared with placebo.13 RCTs were identified for qualitative review. The overall effect size of mitochondrial modulators on depressive symptoms was −0.48 (95% CI: −0.83 to −0.14, p = 0.007, I2 = 75%), indicative of a statistically significant moderate antidepressant effect. In the subgroup analysis, NAC improved depressive symptoms compared with placebo (−0.88, 95% CI: −1.48 to −0.27, I2 = 81%). In addition, there was no statistical difference between mitochondrial modulators and placebo in YMRS. Although mitochondrial modulators were superior to placebo in CGI-S score (−0.44, 95% CI: −0.83 to −0.06, I2 = 71%), only EPA was superior to placebo in subgroup analysis. Overall, a moderate antidepressant effect was observed for mitochondrial modulators compared with placebo in the treatment of bipolar depression. The small number of studies, diversity of agents, and small sample sizes limited interpretation of the current analysis.

Longitudinal assessment of disability amongst patients of bipolar and unipolar depressive disorders presenting to a tertiary care center in North India

Objectives: To assess and compare the changes in disability scores associated with Bipolar Depression (BD) and Unipolar Depression (UD) over 1 year. Methods: A longitudinal study was taken up in adults diagnosed with unipolar or bipolar depressive disorder with current depressive episode. Diagnosis was made according to Schedule for Clinical Assessment in Neuropsychiatry. Severity scoring was done using Hamilton’s Depression (HAM-D) rating scale and Hamilton’s Anxiety (HAM-A) rating scale. Disability was assessed using Indian Disability Evaluation and Assessment Scale (IDEAS) and London handicap Scale (LHS) at baseline, 6 and 12 months. Results: Sixty participants were recruited (42 UD and 18 BD). No significant differences were seen in socio-demographic parameters, except higher education levels and males being overrepresented in UD. Significant differences at baseline were seen in HAM-D ( p = .001) and HAM-A ( p = .003) scores. The extent of disability was seen to correlate with severity of illness only in case of BD at baseline. No significant differences were seen in the IDEAS scores at baseline. IDEAS score improved at each follow-up assessment ( p < .001). LHS showed significant improvement over time in UD ( p < .001), but not BD ( p = .076). Percentage individuals meeting cut-off for benchmark disability (>40%) were comparable at baseline but were significantly more in the BD at 12-months ( p = .049). Conclusion and implications: Disability in psychiatry occurs equally amongst unipolar and bipolar depressive disorders and tends to improve over time, although the level of improvement may differ. It may not always correspond to severity of illness. These factors should be considered while certifying disability.

New Evidence of Gut Microbiota Involvement in the Neuropathogenesis of Bipolar Depression by TRANK1 Modulation: Joint Clinical and Animal Data

Tetratricopeptide repeat and ankyrin repeat containing 1 (TRANK1) is a robust risk gene of bipolar disorder (BD). However, little is known on the role of TRANK1 in the pathogenesis of BD and whether the gut microbiota is capable of regulating TRANK1 expression. In this study, we first investigated the serum mRNA level of TRANK1 in medication-free patients with a depressive episode of BD, then a mice model was constructed by fecal microbiota transplantation (FMT) to explore the effects of gut microbiota on brain TRANK1 expression and neuroinflammation, which was further verified by in vitro Lipopolysaccharide (LPS) treatment in BV-2 microglial cells and neurons. 22 patients with a depressive episode and 28 healthy individuals were recruited. Serum level of TRANK1 mRNA was higher in depressed patients than that of healthy controls. Mice harboring ‘BD microbiota’ following FMT presented depression-like phenotype. mRNA levels of inflammatory cytokines and TRANK1 were elevated in mice hippocampus and prefrontal cortex. In vitro, LPS treatment activated the secretion of pro-inflammatory factors in BV-2 cells, which was capable of upregulating the neuronal expression of TRANK1 mRNA. Moreover, primary cortical neurons transfected with plasmid Cytomegalovirus DNA (pcDNA3.1(+)) vector encoding human TRANK1 showed decreased dendritic spine density. Together, these findings add new evidence to the microbiota-gut-brain regulation in BD, indicating that microbiota is possibly involved in the neuropathogenesis of BD by modulating the expression of TRANK1.