Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for Difficult-to-Treat depression

Manji, Husseini K.; Quiróz, Jorge A.; Sporn, Jonathan; Payne, Jennifer L.; Denicoff, Kirk D.; Gray, N. A. B.; Zarate, Carlos A.; Charney, Dennis S.

doi:10.1016/s0006-3223(03)00117-3

Cited by 445 publications

(278 citation statements)

References 267 publications

(238 reference statements)

Supporting

Mentioning

259

Contrasting

Unclassified

Order By: Relevance

“…The mechanisms and genes underlying volume loss in the ACC have not yet been determined. Preclinical studies on the role and genetics of neurotrophic factors and the signaling cascade neurotrophic factor/MAP kinase/bcl-2 involved in the fine balance maintained between the levels and activities of cell survival and cell death factors (Manji et al, 2003b) may inform clinical studies associating ACC volume loss to genes.…”

Section: Functional Imagingmentioning

confidence: 99%

Discovering Endophenotypes for Major Depression

Hasler

Drevets

Manji

et al. 2004

Neuropsychopharmacol

Self Cite

1,022

739

View full text Add to dashboard Cite

The limited success of genetic studies of major depression has raised questions concerning the definition of genetically relevant phenotypes. This paper presents strategies to improve the phenotypic definition of major depression by proposing endophenotypes at two levels: First, dissecting the depressive phenotype into key components results in narrow definitions of putative psychopathological endophenotypes: mood bias toward negative emotions, impaired reward function, impaired learning and memory, neurovegetative signs, impaired diurnal variation, impaired executive cognitive function, psychomotor change, and increased stress sensitivity. A review of the recent literature on neurobiological and genetic findings associated with these components is given. Second, the most consistent heritable biological markers of major depression are proposed as biological endophenotypes for genetic studies: REM sleep abnormalities, functional and structural brain abnormalities, dysfunctions in serotonergic, catecholaminergic, hypothalamic-pituitary-adrenocortical axis, and CRH systems, and intracellular signal transduction endophenotypes. The associations among the psychopathological and biological endophenotypes are discussed with respect to specificity, temporal stability, heritability, familiality, and clinical and biological plausibility. Finally, the case is made for the development of a new classification system in order to reduce the heterogeneity of depression representing a major impediment to elucidating the genetic and neurobiological basis of this common, severe, and often life-threatening illness.

show abstract

Section: Functional Imagingmentioning

confidence: 99%

Discovering Endophenotypes for Major Depression

Hasler

Drevets

Manji

et al. 2004

Neuropsychopharmacol

Self Cite

1,022

739

View full text Add to dashboard Cite

show abstract

“…The elucidation of endogenous mechanisms underlying resilience to chronic stress should shed light on developing the therapeutic strategies for major depression (Zhu et al, 2017). Although a few of molecules are presumably involved in major depression versus resilience (Bergstrom, Jayatissa, Thykjaer, & Wiborg, 2007; Christensen, Bisgaard, & Wiborg, 2011; Friedman et al, 2014; Manji et al, 2003; Vialou et al, 2010; Wang, Perova, Arenkiel, & Li, 2014). However, comprehensive molecular profiles in specific brain areas remain to be systemically figured in terms of resilience and susceptibility to chronic stress for major depression.…”

Section: Introductionmentioning

confidence: 99%

microRNA and mRNA profiles in nucleus accumbens underlying depression versus resilience in response to chronic stress

Song

Sun

et al. 2018

American J of Med Genetics Pt B

View full text Add to dashboard Cite

Major depression in negative mood is presumably induced by chronic stress with lack of reward. However, most individuals who experience chronic stress demonstrate resilience. Molecular mechanisms underlying stress‐ induced depression versus resilience remain unknown, which are investigated in brain reward circuits. Mice were treated by chronic unpredictable mild stress (CUMS) for 4 weeks. The tests of sucrose preference, Y‐maze, and forced swimming were used to identify depression‐like emotion behavior or resilience. High‐throughput sequencing was used to analyze mRNA and miRNA quantity in the nucleus accumbens (NAc) harvested from the mice in the groups of control, CUMS‐induced depression (CUMS‐MDD), and CUMS‐resistance to identify molecular profiles of CUMS‐MDD versus CUMS‐resilience. In data analyses and comparison among three groups, 1.5‐fold ratio in reads per kilo‐base per million reads (RPKM) was set to judge involvements of mRNA and miRNA in CUMS, MDD, or resilience. The downregulations of serotonergic/dopaminergic synapses, MAPK/calcium signaling pathways, and morphine addiction as well as the upregulations of cAMP/PI3K‐Akt signaling pathways and amino acid metabolism are associated with CUMS‐MDD. The downregulations of chemokine signaling pathway, synaptic vesicle cycle, and nicotine addiction as well as the upregulations of calcium signaling pathway and tyrosine metabolism are associated with CUMS‐resilience. The impairments of serotonergic/dopaminergic synapses and PI3K‐Akt/MAPK signaling pathways in the NAc are associated with depression. The upregulation of these entities is associated with resilience. Consistent results from analyzing mRNA/miRNA and using different methods validate our finding and conclusion.

show abstract

“…One of the main theories is based on the notion that the neurochemical background of depression involves an impairment of central noradrenergic transmission with a concomitant decrease of the norepinephrine (NE) concentration in the synaptic gap. The noradrenergic hypothesis in depression is supported by the fact that drugs that deplete central nervous system (CNS) monoamines (eg reserpine) can produce depression, and that many antidepressants increase synaptic NE availability by inhibition of the reuptake of NE (Manji et al, 2003;Vetulani and Nalepa, 2000). There is also considerable evidence for alterations in growth hormone response to the noradrenergic agonist clonidine in depression (Schatzberg and Schildkraut, 1995;Siever et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Effect of Antidepressant Drugs in Mice Lacking the Norepinephrine Transporter

Dziedzicka-Wasylewska

Faron-Górecka

Kuśmider

et al. 2006

Neuropsychopharmacol

View full text Add to dashboard Cite

One of the main theories concerning the mechanism of action of antidepressant drugs (ADs) is based on the notion that the neurochemical background of depression involves an impairment of central noradrenergic transmission with a concomitant decrease of the norepinephrine (NE) in the synaptic gap. Many ADs increase synaptic NE availability by inhibition of the reuptake of NE. Using mice lacking NE transporter (NET À/À ) we examined their baseline phenotype as well as the response in the forced swim test (FST) and in the tail suspension test (TST) upon treatment with ADs that display different pharmacological profiles. In both tests, the NET À/À mice behaved like wild-type (WT) mice acutely treated with ADs. Autoradiographic studies showed decreased binding of the b-adrenergic ligand [ 3 H]CGP12177 in the cerebral cortex of NET À/À mice, indicating the changes at the level of b-adrenergic receptors similar to those obtained with ADs treatment. The binding of [ 3 H]prazosin to a 1 -adrenergic receptors in the cerebral cortex of NET À/À mice was also decreased, most probably as an adaptive response to the sustained elevation of extracellular NE levels observed in these mice. A pronounced NET knockout-induced shortening of the immobility time in the TST (by ca 50%) compared to WT mice was not reduced any further by NET-inhibiting ADs such as reboxetine, desipramine, and imipramine. Citalopram, which is devoid of affinity for the NET, exerted a significant reduction of immobility time in the NET À/À mice. In the FST, reboxetine, desipramine, imipramine, and citalopram administered acutely did not reduce any further the immobility time shortened by NET knockout itself (ca 25%); however, antidepressant-like action of repeatedly (7 days) administered desipramine was observed in NET À/À mice, indicating that the chronic presence of this drug may also affect other neurochemical targets involved in the behavioral reactions monitored by this test. From the present study, it may be concluded that mice lacking the NET may represent a good model of some aspects of depression-resistant behavior, paralleled with alterations in the expression of adrenergic receptors, which result as an adaptation to elevated levels of extracellular NE.

show abstract

Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for Difficult-to-Treat depression

Cited by 445 publications

References 267 publications

Discovering Endophenotypes for Major Depression

Discovering Endophenotypes for Major Depression

microRNA and mRNA profiles in nucleus accumbens underlying depression versus resilience in response to chronic stress

Effect of Antidepressant Drugs in Mice Lacking the Norepinephrine Transporter

Contact Info

Product

Resources

About