Large-Scale Neuroimaging of Mental Illness.

Neuroimaging has provided important insights into the brain variations related to mental illness. Inconsistencies in prior studies, however, call for methods that lead to more replicable and generalizable brain markers that can reliably predict illness severity, treatment course, and prognosis. A paradigm shift is underway with large-scale international research teams actively pooling data and resources to drive consensus findings and test emerging methods aimed at achieving the goals of precision psychiatry. In parallel with large-scale psychiatric genomics studies, international consortia combining neuroimaging data are mapping the transdiagnostic brain signatures of mental illness on an unprecedented scale. This chapter discusses the major challenges, recent findings, and a roadmap for developing better neuroimaging-based tools and markers for mental illness.

IV low dose ketamine infusions for treatment resistant depression: Results from a five-year study at a free public clinic in an academic hospital.

Individuals with major depressive disorder and treatment resistant depression (MDD-TRD) have limited and sometimes poorly tolerated therapeutic options. Low dose ketamine has presented promising and potent antidepressant effects in this population. To support the existent literature, we conducted a longitudinal study examining five years of real-world clinical data on the use of IV low-dose ketamine alongside standard care for MDD-TRD outpatients. For this study we collected demographic information, clinical scale scores, side effects and dropout data. The data was analyzed using descriptive statistics, effect size using Cohen's D analysis, and multivariate ANOVA (MANOVA) to determine the impact of sociodemographic variables. 71 outpatients (50.28 years old, SD: 14.26; female 74.65%) were included in the analysis. The results showed a significant reduction in depressive symptoms and suicide ideation (SI) by treatment endpoint. 54.93% of patients responded to the treatment, 78.26% experienced transient and mild side effects, and 11.27% of dropped out of the treatment. Multivariate analysis showed that the demographic variables did not impact treatment effect or tolerability. The results of this study suggest that IV low dose ketamine treatment is effective, fast-acting, and well tolerated for the management of depressive symptoms and SI in patients with MDD-TRD in naturalistic clinical practice.

Association between peripheral biomarkers and clinical response to IV ketamine for unipolar treatment-resistant depression: An open label study.

BACKGROUND: Major Depression is the leading cause of disability worldwide. A cohort of patients do not respond adequately to available antidepressants, leading to treatment-resistant depression (TRD). We evaluated the antidepressant efficacy of an acute intravenous ketamine treatment (0.5 mg/kg) for patients with unipolar TRD, and measured peripheral blood-based biomarkers associated with response to treatment. METHODS: Fifteen adults diagnosed with TRD completed an open label study of ten infusions of subanesthetic ketamine over four weeks. Out of fifteen patients, blood was collected from eleven patients at three timepoints to analyze peripheral biomarkers in isolated plasma, including IL-6, IL-10, TNF-α, BDNF, and irisin. Irisin analysis was completed using an ELISA assay, and the remaining biomarkers were analyzed together simultaneously using a multiplex immunoassay. RESULTS: Repeated ketamine infusions produced a significant decrease in total average depressive symptoms (MADRS) at all timepoints. Improvements in depressive symptoms were significant at one week, and continued to significantly decrease until two weeks, where it was maintained. Ketamine was generally well tolerated, and we observed improvements in functional impairment, anhedonia, and psychiatric symptoms, with no increases in manic symptoms. Levels of BDNF throughout treatment inversely correlated to decreases in MADRS scores, and higher levels of baseline BDNF predicted mood responses at one- and four weeks. LIMITATIONS: The study was observational and uncontrolled, with a sample size of 15. Outpatients remained on their course of medications, unless they were pharmacological agents that have previously been identified to block ketamine's effects. CONCLUSIONS: Ketamine may be an efficacious and safe pharmacological option for the acute treatment of patients suffering from severe TRD. BDNF has the potential to function as a prognostic biomarker for predicting response to ketamine treatments.

The Mechanisms Behind Rapid Antidepressant Effects of Ketamine: A Systematic Review With a Focus on Molecular Neuroplasticity.

The mechanism of action underlying ketamine's rapid antidepressant effects in patients with depression, both suffering from major depressive disorder (MDD) and bipolar disorder (BD), including treatment resistant depression (TRD), remains unclear. Of the many speculated routes that ketamine may act through, restoring deficits in neuroplasticity may be the most parsimonious mechanism in both human patients and preclinical models of depression. Here, we conducted a literature search using PubMed for any reports of ketamine inducing neuroplasticity relevant to depression, to identify cellular and molecular events, relevant to neuroplasticity, immediately observed with rapid mood improvements in humans or antidepressant-like effects in animals. After screening reports using our inclusion/exclusion criteria, 139 publications with data from cell cultures, animal models, and patients with BD or MDD were included (registered on PROSPERO, ID: CRD42019123346). We found accumulating evidence to support that ketamine induces an increase in molecules involved in modulating neuroplasticity, and that these changes are paired with rapid antidepressant effects. Molecules or complexes of high interest include glutamate, AMPA receptors (AMPAR), mTOR, BDNF/TrkB, VGF, eEF2K, p70S6K, GSK-3, IGF2, Erk, and microRNAs. In summary, these studies suggest a robust relationship between improvements in mood, and ketamine-induced increases in molecular neuroplasticity, particularly regarding intracellular signaling molecules.

Subanesthetic ketamine infusions for suicide ideation in patients with bipolar and unipolar treatment refractory depression.

We evaluated the effects of repeated subanesthetic ketamine infusions on suicidal ideation (SI) in patients with major depression. 82 subjects with treatment-resistant unipolar and bipolar depression completed a two-site open-label case-series of repeated (up to four weeks) infusions of ketamine (0.5 mg/kg). Ketamine produced a significant reduction in SI as early as one hour (71.1%) and up to 1-week post-infusion (60.4%), accompanied by a reduction in overall depressive symptoms which were maintained until the 4th week. The observed anti-suicidal effect was independent of mood changes, as patients whose mood did not respond still exhibited significantly less SI than baseline.

Pharmacological treatment for insomnia in patients with major depressive disorder.

INTRODUCTION: Insomnia in Major Depressive Disorder (MDD) is highly prevalent and associated with increased suffering and functional impairment. Effective, evidence-based treatments for insomnia in MDD are an unmet need in clinical practice. AREAS COVERED: Herein, the authors provide a review of the clinical correlates, putative neurobiological mechanisms and treatment options for the management of insomnia in individuals with MDD. EXPERT OPINION: Sleep disturbances in MDD should be recognized as at least one of the following: (1) a domain of depressive psychopathology; (2) a consequence of rhythm disruptions; (3) a manifestation of comorbidities of sleep disturbances; (4) a manifestation of the influence of sex hormones in the brain in MDD; (5) a general medical comorbidity; and (6) a side effect of antidepressant medications. Assessment of insomnia in clinical practices is routinely performed with the use of non-structured interviews. Other methods such as standardized questionnaires and sleep diaries, along with complementary methods such as actigraphy and polysomnography are more scarcely applied. Smartphones and personal devices offer a promising strategy with the use of passive, long lasting, and ecologically valid assessments despite the lack of studies specifically targeting insomnia in individuals with MDD. New therapeutic approaches are essential, including novel targets such as orexins/hypocretins and the endocannabinoid system.