Husseini K Manji

Janssen Research & Development, LLC, Раритан, New Jersey, United States

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Publications (357)2468.56 Total impact

  • No preview · Article · Dec 2015 · Neuron
  • Vaibhav A. Narayan · Husseini K. Manji
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    ABSTRACT: What could be the benefits of moving the treatment paradigm for serious neuropsychiatric disorders towards earlier intervention, and what is needed to achieve this?
    No preview · Article · Nov 2015 · Nature Reviews Drug Discovery
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    ABSTRACT: Background: The purpose of this study was to assess the efficacy and safety and to explore the dose response of esketamine intravenous (IV) infusion in patients with treatment-resistant depression (TRD). Methods: This multicenter, randomized, placebo-controlled trial was conducted in 30 patients with TRD. Patients were randomly assigned 1:1:1 to receive an IV infusion of .20 mg/kg or .40 mg/kg esketamine or placebo over 40 minutes on day 1. The primary end point was change in Montgomery-Åsberg Depression Rating Scale total score from day 1 (baseline) to day 2. Nonresponders who received placebo on day 1 were randomly assigned again 1:1 to IV esketamine .20 mg/kg or .40 mg/kg on day 4. Secondary efficacy and safety measures were also evaluated. Results: Of the enrolled patients, 97% (29 of 30) completed the study. The least squares mean changes (SE) from baseline to day 2 in Montgomery-Åsberg Depression Rating Scale total score for the esketamine .20 mg/kg and .40 mg/kg dose groups were -16.8 (3.00) and -16.9 (2.61), respectively, and showed significant improvement (one-sided p = .001 for both groups) compared with placebo (-3.8 [2.97]). Esketamine showed a rapid (within 2 hours) and robust antidepressant effect. Treatment-emergent adverse events were dose dependent. The most common treatment-emergent adverse events were headache, nausea, and dissociation; the last-mentioned was transient and did not persist beyond 4 hours from the start of the esketamine infusion. Conclusions: A rapid onset of robust antidepressant effects was observed in patients with TRD after a 40-min IV infusion of either .20 mg/kg or .40 mg/kg of esketamine. The lower dose may allow for better tolerability while maintaining efficacy.
    Full-text · Article · Nov 2015 · Biological Psychiatry
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    ABSTRACT: Mood disorders are among the most common medical conditions and cause amongst the greatest disease burden. Currently approved antidepressants target monoamine pathways; these medicines take many weeks to relieve symptoms, and most patients do not have sustained responses. This review will highlight recent advances in translational science identifying dysfunctional biochemical processes and neuronal circuits associated with mood disorders. We will also summarize strategies for targeting these pathways and for enhancing synaptic plasticity to develop most effective and rapidly acting antidepressant therapies.
    No preview · Article · Oct 2015 · Neuroscience & Biobehavioral Reviews
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    ABSTRACT: Neurogenesis continues throughout life in the hippocampal dentate gyrus. Chronic treatment with monoaminergic antidepressant drugs stimulates hippocampal neurogenesis, and new neurons are required for some antidepressant-like behaviors. Electroconvulsive seizures (ECS), a laboratory model of electroconvulsive therapy (ECT), robustly stimulate hippocampal neurogenesis. ECS requires newborn neurons to improve behavioral deficits in a mouse neuroendocrine model of depression. We utilized immunohistochemistry for doublecortin (DCX), a marker of migrating neuroblasts, to assess the impact of Sham or ECS treatments (1 treatment per day, 7 treatments over 15 days) on hippocampal neurogenesis in animals receiving 6 weeks of either vehicle or chronic corticosterone (CORT) treatment in the drinking water. We conducted tests of anxiety- and depressive-like behavior to investigate the ability of ECS to reverse CORT-induced behavioral deficits. We also determined whether adult neurons are required for the effects of ECS. For these studies we utilized a pharmacogenetic model (hGFAPtk) to conditionally ablate adult born neurons. We then evaluated behavioral indices of depression after Sham or ECS treatments in CORT-treated wild-type animals and CORT-treated animals lacking neurogenesis. ECS is able to rescue CORT-induced behavioral deficits in indices of anxiety- and depressive-like behavior. ECS increases both the number and dendritic complexity of adult-born migrating neuroblasts. The ability of ECS to promote antidepressant-like behavior is blocked in mice lacking adult neurogenesis. ECS ameliorates a number of anxiety- and depressive-like behaviors caused by chronic exposure to CORT. ECS requires intact hippocampal neurogenesis for its efficacy in these behavioral indices. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Jun 2015 · Brain Stimulation

  • No preview · Article · Oct 2014 · European Neuropsychopharmacology
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    ABSTRACT: Background: Genetic contributions to major depressive disorder (MDD) are thought to result from multiple genes interacting with each other. Different procedures have been proposed to detect such interactions. Which approach is best for explaining the risk of developing disease is unclear. Results: Although none of the interaction survived correction for multiple comparisons, the results provide important information for future genetic interaction studies in complex disorders. Among the 0.5% most significant observations, none had been reported previously for risk to MDD. Within this group of interactions, less than 0.03% would have been detectable based on main effect approach or an a priori algorithm. We evaluated correlations among the three different models and conclude that all three algorithms detected the same interactions to a low degree. Although the top interactions had a surprisingly large effect size for MDD (e.g. additive dominant model Puncorrected = 9.10E-9 with attributable proportion (AP) value = 0.58 and multiplicative recessive model with Puncorrected = 6.95E-5 with odds ratio (OR estimated from β3) value = 4.99) the area under the curve (AUC) estimates were low (< 0.54). Moreover, the population attributable fraction (PAF) estimates were also low (< 0.15). Conclusions: We conclude that the top interactions on their own did not explain much of the genetic variance of MDD. The different statistical interaction methods we used in the present study did not identify the same pairs of interacting markers. Genetic interaction studies may uncover previously unsuspected effects that could provide novel insights into MDD risk, but much larger sample sizes are needed before this strategy can be powerfully applied.
    Full-text · Article · Sep 2014 · BioData Mining
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    Husseini K Manji · Thomas W Insel · Vaibhav A Narayan

    Preview · Article · Aug 2014 · Nature Reviews Drug Discovery
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    ABSTRACT: Introduction: Bipolar disorder (BPD) is a severe illness with few treatments available. Understanding BPD pathophysiology and identifying potential relevant targets could prove useful for developing new treatments. Remarkably, subtle impairments of mitochondrial function may play an important role in BPD pathophysiology. Areas covered: This article focuses on human studies and reviews evidence of mitochondrial dysfunction in BPD as a promising target for the development of new, improved treatments. Mitochondria are crucial for energy production, generated mainly through the electron transport chain (ETC) and play an important role in regulating apoptosis and calcium (Ca²⁺) signaling as well as synaptic plasticity. Mitochondria move throughout the neurons to provide energy for intracellular signaling. Studies showed polymorphisms of mitochondria-related genes as risk factors for BPD. Postmortem studies in BPD also show decreased ETC activity/expression and increased nitrosative and oxidative stress (OxS) in patient brains. BPD has been also associated with increased OxS, Ca²⁺ dysregulation and increased proapoptotic signaling in peripheral blood. Neuroimaging studies consistently show decreased energy levels and pH in brains of BPD patients. Expert opinion: Targeting mitochondrial function, and their role in energy metabolism, synaptic plasticity and cell survival, may be an important avenue for development of new mood-stabilizing agents.
    Full-text · Article · Jul 2014 · Expert Opinion on Therapeutic Targets
  • Guang Chen · Ioline D Henter · Husseini K Manji

    No preview · Article · Jul 2014 · Biological Psychiatry
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    Ming Ren · Vania Cao · Yizhou Ye · Husseini K Manji · Kuan Hong Wang
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    ABSTRACT: The brain encodes information about past experience in specific populations of neurons that communicate with one another by firing action potentials. Studies of experience-dependent neural plasticity have largely focused on individual synaptic changes in response to neuronal input. Indicative of the neuronal output transmitted to downstream neurons, persistent firing patterns are affected by prior experience in selective neuronal populations. However, little is known about the molecular and cellular mechanisms by which experience-related persistent firing patterns are regulated in specific neuronal populations. Using frontal cortical slices prepared from transgenic mice carrying a fluorescent reporter of Arc gene expression, this study investigates how behavioral experience and the activity-regulated Arc gene affect patterns of neuronal firing. We found that motor training increases Arc expression in subsets of excitatory neurons. Those neurons exhibit persistent firing in contrast to Arc-negative neurons from the same mice or neurons from the untrained mice. Furthermore, in mice carrying genetic deletion of Arc, the frontal cortical circuitry is still in place to initiate experience-dependent gene expression, but the level of persistent firing thereafter is diminished. Finally, our results showed that the emergence of persistent activity is associated with Arc-dependent changes in the function of NMDA-type glutamate receptors, rather than changes in AMPA-type receptors or membrane excitability. Our findings therefore reveal an Arc-dependent molecular pathway by which gene-experience interaction regulates the emergence of persistent firing patterns in specific neuronal populations.
    Preview · Article · May 2014 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    ABSTRACT: The prediction of treatment response in many neuropsychiatric disorders would be facilitated by easily accessible biomarkers. Using flow cytometry, we herein demonstrate correlations between early reductions of p11 levels in Natural Killer (NK) cells and monocytes and antidepressant response to citalopram in patients with major depressive disorder (MDD).
    Preview · Article · Mar 2014 · Molecular Psychiatry
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    ABSTRACT: Abnormal serotonin type 1A (5-HT1A) receptor function and binding have been implicated in the pathophysiology of mood disorders. Preclinical studies have consistently shown that stress decreases the gene expression of 5-HT1A receptors in experimental animals, and that the associated increase in hormone secretion plays a crucial role in mediating this effect. Chronic administration of the mood stabilizers lithium and divalproex (valproate semisodium) reduces glucocorticoid signaling and function in the hippocampus. Lithium has further been shown to enhance 5-HT1A receptor function. To assess whether these effects translate to human subject with bipolar disorder (BD), positron emission tomography (PET) and [18F]trans-4-fluoro-N-(2-[4-(2-methoxyphenyl) piperazino]-ethyl)-N-(2-pyridyl) cyclohexanecarboxamide ([(18)F]FCWAY) were used to acquire PET images of 5-HT1A receptor binding in 10 subjects with BD, before and after treatment with lithium or divalproex. Mean 5-HT1A binding potential (BPP) significantly increased following mood stabilizer treatment, most prominently in the mesiotemporal cortex (hippocampus plus amygdala). When mood state was also controlled for, treatment was associated with increases in BPP in widespread cortical areas. These preliminary findings are consistent with the hypothesis that these mood stabilizers enhance 5-HT1A receptor expression in BD, which may underscore an important component of these agents' mechanism of action.
    No preview · Article · Aug 2013 · Journal of Psychopharmacology
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    K Martinowich · D V Jimenez · C A Zarate · H K Manji
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    ABSTRACT: Available treatments for depression have significant limitations, including low response rates and substantial lag times for response. Reports of rapid antidepressant effects of a number of compounds, including the glutamate N-methyl-D-aspartate receptor antagonist ketamine, have spurred renewed translational neuroscience efforts aimed at elucidating the molecular and cellular mechanisms of action that result in rapid therapeutic response. This perspective provides an overview of recent advances utilizing compounds with rapid-acting antidepressant effects, discusses potential mechanism of action and provides a framework for future research directions aimed at developing safe, efficacious antidepressants that achieve satisfactory remission not only by working rapidly but also by providing a sustained response.Molecular Psychiatry advance online publication, 21 May 2013; doi:10.1038/mp.2013.55.
    Full-text · Article · May 2013 · Molecular Psychiatry
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    ABSTRACT: Background: Multiple lines of evidence support a role for the glutamatergic system in the pathophysiology of major depressive disorder (MDD). Ketamine, an N-methyl-D-aspartate antagonist, rapidly improves depressive symptoms in individuals with treatment-resistant depression. The neural mechanisms underlying this effect remain unknown. Methods: In this preliminary study, 20 unmedicated participants with treatment-resistant MDD underwent positron emission tomography to measure regional cerebral glucose metabolism at baseline and following ketamine infusion (single dose of .5mg/kg intravenous over 40minutes). Metabolic data were compared between conditions using a combination of region-of-interest and voxelwise analyses, and differences were correlated with the associated antidepressant response. Results: Whole-brain metabolism did not change significantly following ketamine. Regional metabolism decreased significantly under ketamine in the habenula, insula, and ventrolateral and dorsolateral prefrontal cortices of the right hemisphere. Metabolism increased postketamine in bilateral occipital, right sensorimotor, left parahippocampal, and left inferior parietal cortices. Improvement in depression ratings correlated directly with change in metabolism in right superior and middle temporal gyri. Conversely, clinical improvement correlated inversely with metabolic changes in right parahippocampal gyrus and temporoparietal cortex. Conclusions: Although preliminary, these results indicate that treatment-resistant MDD subjects showed decreased metabolism in the right habenula and the extended medial and orbital prefrontal networks in association with rapid antidepressant response to ketamine. Conversely, metabolism increased in sensory association cortices, conceivably related to the illusory phenomena sometimes experienced with ketamine. Further studies are needed to elucidate how these functional anatomical changes relate to the molecular mechanisms underlying ketamine's rapid antidepressant effects.
    No preview · Article · Mar 2013 · Biological psychiatry
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    ABSTRACT: Following their birth in the adult hippocampal dentate gyrus, newborn progenitor cells migrate into the granule cell layer where they differentiate, mature, and functionally integrate into existing circuitry. The hypothesis that adult hippocampal neurogenesis is physiologically important has gained traction, but the precise role of newborn neurons in hippocampal function remains unclear. We investigated whether loss of new neurons impacts dendrite morphology and glutamate levels in area CA3 of the hippocampus by utilizing a human GFAP promoter-driven thymidine kinase genetic mouse model to conditionally suppress adult neurogenesis. We found that chronic ablation of new neurons induces remodeling in CA3 pyramidal cells and increases stress-induced release of the neurotransmitter glutamate. The ability of persistent impairment of adult neurogenesis to influence hippocampal dendrite morphology and excitatory amino acid neurotransmission has important implications for elucidating newborn neuron function, and in particular, understanding the role of these cells in stress-related excitoxicity.
    Full-text · Article · Mar 2013 · Brain Structure and Function
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    ABSTRACT: The time has come to move beyond product-focused 'magic bullet' therapeutic development strategies towards models that can also incorporate devices, tools and services to provide integrated health-care solutions.
    No preview · Article · Feb 2013 · Nature Reviews Drug Discovery
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    Dataset: JCP,2010b

    Full-text · Dataset · Feb 2013
  • J.John Mann · Dianne Currier · Jorge A. Quiroz · Husseini K. Manji
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    ABSTRACT: The most common mood disorder diagnoses are major depressive disorder (MDD); dysthymia, a less severe but more chronic form of depression akin to a mood trait; and bipolar disorder (BD), characterized by both depressive epi­sodes and episodes of mania and hypomania. The recurrent episodes or chronicity of the disorders suggests long-term alterations in neurobiological function, while the variability of symptomatic expression between episodes implies that the specific manifes­tation of an episode of a mood disorder is sensitive to state-dependent factors. Therefore, the pathophysiology of mood disorders should reflect both a common trait-dependent com­ponent and a more variable state-dependent component. Studies of serotonin function in major depression suggest both hypofunction and accompanying compensatory altera­tions to increase serotonergic activity. Multiple neurotransmitters have been implicated in the pathophysiology of mood disorders, and more recent research using brain imaging has examined the structure and function­ing of neural networks associated with mood regulation and mood disorders.
    No preview · Chapter · Dec 2012
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    ABSTRACT: Targeted metabolomics provides an approach to quantify metabolites involved in specific molecular pathways. We applied an electrochemistry-based, targeted metabolomics platform to define changes in tryptophan, tyrosine, purine and related pathways in the depressed and remitted phases of major depressive disorder (MDD). Biochemical profiles in the cerebrospinal fluid of unmedicated depressed (n514; dMDD) or remitted MDD subjects (n514; rMDD) were compared against those in healthy controls (n518; HC). The rMDD group showed differences in tryptophan and tyrosine metabolism relative to the other groups. The rMDD group also had higher methionine levels and larger methionine-to-glutathione ratios than the other groups, implicating methylation and oxidative stress pathways. The dMDD sample showed nonsignificant differences in the same direction in several of the metabolic branches assessed. The reductions in metabolites associated with tryptophan and tyrosine pathways in rMDD may relate to the vulnerability this population shows for developing depressive symptoms under tryptophan or catecholamine depletion.
    Full-text · Article · Sep 2012 · Scientific Reports

Publication Stats

26k Citations
2,468.56 Total Impact Points


  • 2012-2015
    • Janssen Research & Development, LLC
      Раритан, New Jersey, United States
  • 1990-2014
    • National Institute of Mental Health (NIMH)
      • • Experimental Therapeutics and Pathophysiology
      • • Laboratory of Molecular Pathophysiology
      • • Section on Pharmacology
      베서스다, Maryland, United States
  • 2009-2012
    • Johnson & Johnson
      Нью-Брансуик, New Jersey, United States
    • University of Zurich
      Zürich, Zurich, Switzerland
    • Penn State Hershey Medical Center and Penn State College of Medicine
      Hershey, Pennsylvania, United States
    • University of Wuerzburg
      Würzburg, Bavaria, Germany
  • 2002-2009
    • National Institutes of Health
      • • Branch of Mood and Anxiety Disorders
      • • Laboratory of Molecular Physiology
      베서스다, Maryland, United States
    • Harvard Medical School
      • Department of Psychiatry
      Boston, Massachusetts, United States
  • 2008
    • Missouri Institute of Mental Heath
      Maryland, United States
    • Columbia University
      • College of Physicians and Surgeons
      New York, New York, United States
    • State University of New York Press
      New York, New York, United States
  • 2007-2008
    • Karolinska Institutet
      • Department of Neuroscience
      Solna, Stockholm, Sweden
    • U.S. Department of Health and Human Services
      Washington, Washington, D.C., United States
    • University of Tartu
      • Department of Psychiatry (ARPS)
      Dorpat, Tartu, Estonia
  • 2006-2007
    • University of Minnesota Duluth
      • • College of Pharmacy
      • • Department of Pharmacy Practice and Pharmaceutical Sciences
      Duluth, Minnesota, United States
  • 2004
    • Dokuz Eylul University
      • Department of Psychiatry
      İzmir, Izmir, Turkey
    • Northern Inyo Hospital
      BIH, California, United States
  • 2003
    • National Heart, Lung, and Blood Institute
      Maryland, United States
  • 1995-2003
    • Wayne State University
      • Department of Psychiatry and Behavioral Neurosciences
      Detroit, Michigan, United States
  • 1998
    • Detroit Medical Center
      Detroit, Michigan, United States