MRI predictors of pharmacotherapy response in major depressive disorder

Gerlach, Andrew R.; Karim, Helmet T.; Peciña, Marta; Ajilore, Olusola; Taylor, Warren D.; Butters, Meryl A.; Andreescu, Carmen

doi:10.1016/j.nicl.2022.103157

Cited by 27 publications

(14 citation statements)

References 164 publications

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“…We also showed that in vivo the Th17 and Treg relative frequencies play key roles in myelin maintenance and regeneration, with higher Th17 associated with higher fractional anisotropy in the core WM skeleton of the brain (Poletti et al, 2017). WM integrity predicts antidepressant response both in MDD and in BD (Bollettini et al, 2015; Gerlach et al, 2022). Rapid antidepressant response associates with a rapid improvement in WM integrity (Melloni et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Low-dose interleukin 2 antidepressant potentiation in unipolar and bipolar depression: Safety, efficacy, and immunological biomarkers

Poletti,

Zanardi,

Mandelli

et al. 2023

Preprint

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Immune-inflammatory mechanisms are promising targets for antidepressant pharmacology. Based on reported immune cell abnormalities, we defined an antidepressant potentiation treatment with add-on low-dose interleukin 2 (IL-2), a T-cell growth factor of proven anti-inflammatory efficacy in autoimmune conditions, increasing thymic production of naive CD4+ T cells, and possibly correcting the partial T cell defect observed in mood disorders. We performed a single-center, randomised, double-blind, placebo-controlled phase II trial evaluating the safety, clinical efficacy and biological responses of low-dose IL-2 in depressed patients with MDD or BD. 36 consecutively recruited inpatients at the Mood Disorder Unit were randomised in a 2:1 ratio to receive either aldesleukin (12 MDD and 12 BD) or placebo (6 MDD and 6 BD). Active treatment significantly potentiated antidepressant response to ongoing SSRI/SNRI treatment in both diagnostic groups, and expanded the population of Treg, Th2, and Naive CD4+/CD8+ immune cell counts. Changes in cell counts were rapidly induced in the first five days of treatment, and predicted the later improvement of depression severity. No serious adverse effect was observed. This is the first RCT evidence supporting the hypothesis that treatment to strengthen the T cell system could be a successful way to correct the immuno-inflammatory abnormalities associated with mood disorders, and potentiate antidepressant response.

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Section: Discussionmentioning

confidence: 99%

Low-dose interleukin 2 antidepressant potentiation in unipolar and bipolar depression: Safety, efficacy, and immunological biomarkers

Poletti,

Zanardi,

Mandelli

et al. 2023

Preprint

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“…The CCN is primarily involved in top-down executive functions [ 48 ]. Substantial evidence suggests CCN integrity differentiates healthy controls from depressed individuals [ 42 ] and influences treatment response [ 49 ]. The CCN may be especially relevant in LLD characterized by executive dysfunction [ 50 , 51 ], where aberrant functional connectivity of the CCN (particularly the dorsolateral prefrontal cortex [DLPFC] hub), is associated with executive deficits [ 52 ].…”

Section: Neural Network Implicated In Depressionmentioning

confidence: 99%

“…Individuals with persistent depressive symptoms similarly exhibit greater increases in WMH volume over time [ 163 ]. Greater vascular burden may be associated with poorer response to pharmacological and nonpharmacological treatments [ 158 , 164 – 166 ], although this relationship for medication response is somewhat weak [ 49 , 78 ]. The higher vascular burden is further associated with greater disability [ 167 ], gait and other motor deficits [ 168 ], and frailty [ 169 ].…”

Section: Factors Contributing To Depression Vulnerabilitymentioning

confidence: 99%

Biological factors influencing depression in later life: role of aging processes and treatment implications

Szymkowicz,

Gerlach,

Homiack

et al. 2023

Transl Psychiatry

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Late-life depression occurring in older adults is common, recurrent, and malignant. It is characterized by affective symptoms, but also cognitive decline, medical comorbidity, and physical disability. This behavioral and cognitive presentation results from altered function of discrete functional brain networks and circuits. A wide range of factors across the lifespan contributes to fragility and vulnerability of those networks to dysfunction. In many cases, these factors occur earlier in life and contribute to adolescent or earlier adulthood depressive episodes, where the onset was related to adverse childhood events, maladaptive personality traits, reproductive events, or other factors. Other individuals exhibit a later-life onset characterized by medical comorbidity, pro-inflammatory processes, cerebrovascular disease, or developing neurodegenerative processes. These later-life processes may not only lead to vulnerability to the affective symptoms, but also contribute to the comorbid cognitive and physical symptoms. Importantly, repeated depressive episodes themselves may accelerate the aging process by shifting allostatic processes to dysfunctional states and increasing allostatic load through the hypothalamic–pituitary–adrenal axis and inflammatory processes. Over time, this may accelerate the path of biological aging, leading to greater brain atrophy, cognitive decline, and the development of physical decline and frailty. It is unclear whether successful treatment of depression and avoidance of recurrent episodes would shift biological aging processes back towards a more normative trajectory. However, current antidepressant treatments exhibit good efficacy for older adults, including pharmacotherapy, neuromodulation, and psychotherapy, with recent work in these areas providing new guidance on optimal treatment approaches. Moreover, there is a host of nonpharmacological treatment approaches being examined that take advantage of resiliency factors and decrease vulnerability to depression. Thus, while late-life depression is a recurrent yet highly heterogeneous disorder, better phenotypic characterization provides opportunities to better utilize a range of nonspecific and targeted interventions that can promote recovery, resilience, and maintenance of remission.

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“…Directly complementary human studies to investigate the effects of antipressant changes on the brain cannot yet be pursued as no direct in vivo measurement of plasticity or dendritic spine density in humans is possible 20 . However, structural changes in volumetric magnetic resonance imaging (MRI) have been found to be partially explained by increases in dendritic spine density 21 and also clinically useful to investigate brain changes in response to antidepressants 22 .…”

Section: Introductionmentioning

confidence: 99%

Hippocampal volume changes after (R,S)-ketamine administration in patients with major depressive disorder and healthy volunteers

Evans,

Graves,

Nugent

et al. 2024

Sci Rep

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The hippocampus and amygdala have been implicated in the pathophysiology and treatment of major depressive disorder (MDD). Preclinical models suggest that stress-related changes in these regions can be reversed by antidepressants, including ketamine. Clinical studies have identified reduced volumes in MDD that are thought to be potentiated by early life stress and worsened by repeated depressive episodes. This study used 3T and 7T structural magnetic resonance imaging data to examine longitudinal changes in hippocampal and amygdalar subfield volumes associated with ketamine treatment. Data were drawn from a previous double-blind, placebo-controlled, crossover trial of healthy volunteers (HVs) unmedicated individuals with treatment-resistant depression (TRD) (3T: 18 HV, 26 TRD, 7T: 17 HV, 30 TRD) who were scanned at baseline and twice following either a 40 min IV ketamine (0.5 mg/kg) or saline infusion (acute: 1–2 days, interim: 9–10 days post infusion). No baseline differences were noted between the two groups. At 10 days post-infusion, a slight increase was observed between ketamine and placebo scans in whole left amygdalar volume in individuals with TRD. No other differences were found between individuals with TRD and HVs at either field strength. These findings shed light on the timing of ketamine’s effects on cortical structures.

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MRI predictors of pharmacotherapy response in major depressive disorder

Cited by 27 publications

References 164 publications

Low-dose interleukin 2 antidepressant potentiation in unipolar and bipolar depression: Safety, efficacy, and immunological biomarkers

Low-dose interleukin 2 antidepressant potentiation in unipolar and bipolar depression: Safety, efficacy, and immunological biomarkers

Biological factors influencing depression in later life: role of aging processes and treatment implications

Hippocampal volume changes after (R,S)-ketamine administration in patients with major depressive disorder and healthy volunteers

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