Anxiety Disorders: Manji HK

Khairova RA, Machado-Vieira R, Du J, Manji HK. · Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. · Int J Neuropsychopharmacol. · Pubmed #19224657 No free full text.

Abstract: A growing body of data suggests that hyperactivation of the immune system has been implicated in the pathophysiology of major depressive disorder (MDD). Several pro-inflammatory cytokines, such as tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) have been found to be significantly increased in patients with MDD. This review focuses on these two cytokines based on multiple lines of evidence from genetic, animal behaviour, and clinical studies showing that altered levels of serum TNF-alpha and IL-1 are associated with increased risk of depression, cognitive impairments, and reduced responsiveness to treatment. In addition, recent findings have shown that centrally expressed TNF-alpha and IL-1 play a dual role in the regulation of synaptic plasticity. In this paper, we review and critically appraise the mechanisms by which cytokines regulate synaptic and neural plasticity, and their implications for the pathophysiology and treatment of MDD. Finally, we discuss the therapeutic potential of anti-inflammatory-based approaches for treating patients with severe mood disorders. This is a promising field for increasing our understanding of the mechanistic interaction between the immune system, synaptic plasticity, and antidepressants, and for the ultimate development of novel and improved therapeutics for severe mood disorders.

Zarate CA, Manji HK. · Mark O Hatfield CRC, Bethesda, Maryland 20892, USA. · Expert Opin Drug Metab Toxicol. · Pubmed #18721116 links to  free full text

Abstract: BACKGROUND: The glutamate system seems to be an important contributor to the pathophysiology of mood and anxiety disorders. Thus, glutamatergic modulators are reasonable candidate drugs to test in patients with mood and anxiety disorders. Riluzole, a neuroprotective agent with anticonvulsant properties approved for the treatment of amyotrophic lateral sclerosis (ALS) is one such agent. OBJECTIVE: To assess the potential risks and benefits of riluzole treatment in psychiatric patients. METHODS: A PubMed search was performed using the keywords 'riluzole', 'inhibitor of glutamate release' and 'glutamatergic modulator' to identify all clinical studies and case reports involving riluzole in psychiatric patients. RESULTS/CONCLUSION: Riluzole's side effect profile is favorable and preliminary results regarding riluzole for the treatment of severe mood, anxiety and impulsive disorders are encouraging.

Zarate CA, Manji HK. · Laboratory of Molecular Pathophysiology and Experimental Therapeutics, Mood and Anxiety Disorders Research Program, National Institute of Mental Health, Bethesda, MD, USA. · Mt Sinai J Med. · Pubmed #18704977 No free full text.

Abstract: Current pharmacotherapy for bipolar disorder is generally unsatisfactory for a large number of patients. Even with adequate modern bipolar pharmacological therapies, many afflicted individuals continue to have persistent mood episode relapses, residual symptoms, functional impairment, and psychosocial disability. Creating novel therapeutics for bipolar disorder is urgently needed. Promising drug targets and compounds for bipolar disorder worthy of further study include both systems and intracellular pathways and targets. Specifically, the purinergic system, the dynorphin opioid neuropeptide system, the cholinergic system (muscarinic and nicotinic systems), the melatonin and serotonin [5-hydroxytryptamine receptor 2C] system, the glutamatergic system, and the hypothalamic-pituitary adrenal axis have all been implicated. Intracellular pathways and targets worthy of further study include glycogen synthase kinase-3 protein, protein kinase C, and the arachidonic acid cascade.

Machado-Vieira R, Salvadore G, Luckenbaugh DA, Manji HK, Zarate CA. · Mood and Anxiety Disorders Program, National Institute of Mental Health, Department of Health and Human Services, Bethesda, MD 20892-1282, USA. · J Clin Psychiatry. · Pubmed #18435563 links to  free full text

Abstract: OBJECTIVE: Current therapeutics of depression are similar in their time to antidepressant action and often take weeks to months to achieve response and remission, which commonly results in considerable morbidity and disruption in personal, professional, family, and social life, as well as risk for suicidal behavior. Thus, treatment strategies presenting a rapid improvement of depressive symptoms--within hours or even a few days--and whose effects are sustained would have an enormous impact on public health. This article reviews the published data related to different aspects of rapid improvement of depressive symptoms. DATA SOURCES: Literature for this review was obtained through a search of the MEDLINE database (1966-2007) using the following keywords and phrases: rapid response, antidepressant, time to, glutamate, sleep, therapeutics, latency, and depression. The data obtained were organized according to the following topics: clinical relevance and time course of antidepressant action, interventions showing evidence of rapid response and its potential neurobiological basis, and new technologies for better understanding rapid anti-depressant actions. DATA SYNTHESIS: A limited number of prospective studies evaluating rapid antidepressant actions have been conducted. Currently, only a few interventions have been shown to produce antidepressant response in hours or a few days. The neurobiological basis of these rapid antidepressant actions is only now being deciphered. CONCLUSIONS: Certain experimental treatments can produce antidepressant response in a much shorter period of time than existing medications. Understanding the molecular basis of these experimental interventions is likely to lead to the development of improved therapeutics rather than simply furthering our knowledge of current standard antidepressants.

Catapano LA, Manji HK. · Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, NIH, HHS, Bethesda, MD, USA. · Drug Discov Today. · Pubmed #18405841 No free full text.

Abstract: Bipolar disorder is one of the most severely debilitating of all medical illnesses, and is increasingly recognized as a major public health problem. For many patients with bipolar disorder, current pharmacotherapy is insufficient. Exciting recent data suggest that regulation of signaling molecules may be involved in the pathophysiology of the disorder, and in the mechanisms of action of mood stabilizers and antidepressants. Through our developing understanding of the biochemical targets of effective medications, several potential targets for new therapies have emerged. This short review will focus on two of the most promising such targets: glycogen synthase-3 and protein kinase C.

Zarate CA, Manji HK. · Laboratory of Molecular Pathophysiology and Experimental Therapeutics, Mood and Anxiety Disorders Research Program, National Institute of Mental Health/NIH, 10 Center Drive, Bethesda, MD 20892, USA. · Exp Neurol. · Pubmed #18291371 links to  free full text

This publication has no abstract.

Mathew SJ, Manji HK, Charney DS. · Mood and Anxiety Disorders Program, Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA. · Neuropsychopharmacology. · Pubmed #18172433 links to  free full text

Abstract: Monoaminergic-based drugs remain the primary focus of pharmaceutical industry drug discovery efforts for mood disorders, despite serious limitations regarding their ability to achieve remission. The quest for novel therapies for unipolar depression and bipolar disorder has generally centered on two complementary approaches: (1) understanding the presumed therapeutically relevant biochemical targets of currently available medications, and using that knowledge to design new drugs directed at both direct biochemical targets and downstream targets that are regulated by chronic drug administration; and (2) developing pathophysiological models of the illness to design therapeutics to attenuate or prevent those pathological processes. This review describes several promising drugs and drug targets for mood disorders using one or both of these approaches. Agents interacting with non-catecholamine neurotransmitter systems with particular promise for unipolar and bipolar depression include excitatory amino acid neurotransmitter modulators (eg, riluzole, N-methyl-D-aspartate antagonists, and AMPA receptor potentiators) and neuropeptide antagonists (targeting corticotropin releasing factor-1 and neurokinin receptors). Potential antidepressant and mood-stabilizing agents targeting common intracellular pathways of known monoaminergic agents and lithium/mood stabilizers are also reviewed, such as neurotrophic factors, extracellular receptor-coupled kinase (ERK) mitogen-activated protein (MAP) kinase and the bcl-2 family of proteins, and inhibitors of phosphodiesterase, glycogen synthase kinase-3, and protein kinase C. A major thrust of drug discovery in mood disorders will continue efforts to identify agents with rapid and sustained onsets of action (such as intravenous administration of ketamine), as well as identify drugs used routinely in non-psychiatric diseases for their antidepressant and mood-stabilizing properties.

Schloesser RJ, Huang J, Klein PS, Manji HK. · Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, NIH, Bethesda, MD 20892, USA. · Neuropsychopharmacology. · Pubmed #17912251 links to  free full text

Abstract: Bipolar disorder (BPD) is characterized by recurrent episodes of disturbed affect including mania and depression as well as changes in psychovegetative function, cognitive performance, and general health. A growing body of data suggests that BPD arises from abnormalities in synaptic and neuronal plasticity cascades, leading to aberrant information processing in critical synapses and circuits. Thus, these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters. In addition, commonly used mood-stabilizing drugs that are effective in treating BPD have been shown to target intracellular signaling pathways that control synaptic plasticity and cellular resilience. In this article we draw on clinical, preclinical, neuroimaging, and post-mortem data to discuss the neurobiology of BPD within a conceptual framework while highlighting the role of neuroplasticity in the pathophysiology and treatment of this disorder.

Chuang DM, Manji HK. · Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1363, USA. · Biol Psychiatry. · Pubmed #17572175 links to  free full text

This publication has no abstract.

Gould TD, Dow ER, O'Donnell KC, Chen G, Manji HK. · Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, NIH, HHS, Bethesda, Maryland 20892-3711, USA. · CNS Neurol Disord Drug Targets. · Pubmed #17511616 No free full text.

Abstract: Regulation of complex signaling pathways plays a critical role in higher-order brain functions including the regulation of mood, cognition, appetite, sexual arousal, sleep patterns, and weight, all of which are altered in mood disorders, suggesting the involvement of signaling pathways in mood disorder pathogenesis and pathophysiology. Most existing medications used to treat mood disorders take many weeks to exert their full clinical effects, a fact which implicates changes in gene and protein expression, as well as neuroplasticity, in their mechanism of action. Modulation of signaling pathways has many downstream effects on gene expression and protein function, causing changes in synaptic function, plasticity, and response to various inputs such as neurohormones. The Wnt signaling pathway has recently been linked to the therapeutically relevant actions of available treatments of mood disorders. We provide a brief introduction to signaling cascades and their potential roles in mood disorder pathophysiology and treatment. Subsequently, we describe the Wnt signaling pathway, and glycogen synthase kinase-3 (GSK-3) and beta-catenin specifically, discussing studies that have implicated these proteins as relevant to the pathophysiology and treatment of mood disorders. Future directions, aimed at understanding mood disorders and developing more efficacious treatments, are also discussed.

Schloesser RJ, Chen G, Manji HK. · Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Research Program National Institute of Mental Health, Bethesda, Maryland 20892, USA. · Int Rev Neurobiol. · Pubmed #17178474 No free full text.

This publication has no abstract.

Catapano LA, Manji HK. · Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, NIH, HHS, Bethesda, MD 20892, USA. · Biochim Biophys Acta. · Pubmed #17078926 links to  free full text

Abstract: Although the molecular mechanisms underlying psychiatric illnesses such as depression, bipolar disorder and schizophrenia remain incompletely understood, there is increasing clinical, pharmacologic, and genetic evidence that G protein-coupled receptors (GPCRs) play critical roles in these disorders and their treatments. This perspectives paper reviews and synthesizes the available data. Dysfunction of multiple neurotransmitter and neuropeptide GPCRs in frontal cortex and limbic-related regions, such as the hippocampus, hypothalamus and brainstem, likely underlies the complex clinical picture that includes cognitive, perceptual, affective and motoric symptoms. The future development of novel agents targeting GPCR signaling cascades remains an exciting prospect for patients refractory to existing therapeutics.

Shaltiel G, Chen G, Manji HK. · Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-4405, USA. · Curr Opin Pharmacol. · Pubmed #17055337 No free full text.

Abstract: Increasing evidence suggests that bipolar disorder (BPD) is associated with regional brain volumetric reductions, accompanied by cellular atrophy and/or loss. Considerable data suggest that the protypical drugs for BPD--lithium and valproate--when administered in therapeutically relevant paradigms regulate neurotrophic signaling cascades. Notably, brain-derived neurotrophic factor, the extracellular signal-regulated kinase pathway, the glycogen synthase kinase-3-mediated pathway and Bcl-2 are major targets for mood stabilizers. Further data suggest that agents which directly target neurotrophic signaling cascades may have considerable utility for the treatment of this devastating illness.

Chen G, Manji HK. · Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Research Program, National Institute of Mental Health, National Institute of Health, Bethesda, Maryland 20892-3711, USA. · Curr Opin Psychiatry. · Pubmed #16612219 No free full text.

Abstract: PURPOSE OF REVIEW: There exists a growing appreciation that, though not classical neurodegenerative disorders, severe mood disorders are associated with regional impairments of structural plasticity and cellular resilience. Exciting recent data suggest that synaptic plasticity probably is involved in mechanisms of actions of mood stabilizers and antidepressants. Notably, the extracellular signal-regulated kinase pathway is a critical 'plasticity pathway' in the brain. The present review summarizes neurobiological, pharmacological, and behavioral data on the role of the extracellular signal-regulated kinase pathway in regulating some of the symptoms of bipolar disorder and as a therapeutically relevant target for mood stabilizers. RECENT FINDINGS: The extracellular signal-regulated kinase pathway is known to mediate neurotrophic actions and synaptic plasticity. Treatment with lithium and valproate activates the extracellular signal-regulated kinase pathway in cultured cells and in prefrontal cortex and hippocampus. In addition, lithium or valproate treatment promotes neurogenesis, neurite growth, and cell survival. The extracellular signal-regulated kinase pathway is also targeted by antipsychotics. Modulation of the central nervous system extracellular signal-regulated kinase pathway induces animal behavioral alterations reminiscent of manic symptoms; these complex behaviors probably depend on the effects of extracellular signal-regulated kinase on discrete brain regions and the presence of other interacting molecules. SUMMARY: The extracellular signal-regulated kinase pathway may represent a novel target for the development of improved therapeutics for bipolar disorder.

Zarate CA, Singh J, Manji HK. · Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Research Program, National Institute of Mental Health, Bethesda, Maryland, USA. · Biol Psychiatry. · Pubmed #16487491 No free full text.

Abstract: For a number of patients with bipolar disorder, current pharmacotherapy is generally insufficient. Despite adequate treatment, patients continue to have recurrent mood episodes, residual symptoms, functional impairment, psychosocial disability, and significant medical and psychiatric comorbidity. Drug development for bipolar disorder may occur through one of two approaches: the first is by understanding the therapeutically relevant biochemical targets of currently effective medications. Two promising direct targets of lithium and valproate are glycogen synthase kinase-3 and histone deacetylase. The second path results from our understanding that severe mood disorders, although not classical neurodegenerative disorders, are associated with regional impairments of structural plasticity and cellular resilience. This suggests that effective treatments will need to provide both trophic and neurochemical support, which serves to enhance and maintain normal synaptic connectivity, thereby allowing the chemical signal to reinstate the optimal functioning of critical circuits necessary for normal affective functioning. For many refractory patients, drugs mimicking "traditional" strategies, which directly or indirectly alter monoaminergic levels, may be of limited benefit. Newer "plasticity enhancing" strategies that may have utility in the treatment of mood disorders include inhibitors of glutamate release, N-methyl-D-aspartate antagonists, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid potentiators, cyclic adenosine monophosphate phosphodiesterase inhibitors, and glucocorticoid receptor antagonists.

Hasler G, Drevets WC, Gould TD, Gottesman II, Manji HK. · Mood and Anxiety Disorders Program, National Institute of Mental Health, Bethesda, Maryland, USA. · Biol Psychiatry. · Pubmed #16406007 No free full text.

Abstract: Research aimed at elucidating the underlying neurobiology and genetics of bipolar disorder, and factors associated with treatment response, have been limited by a heterogeneous clinical phenotype and lack of knowledge about its underlying diathesis. We used a survey of clinical, epidemiological, neurobiological, and genetic studies to select and evaluate candidate endophenotypes for bipolar disorder. Numerous findings regarding brain function, brain structure, and response to pharmacological challenge in bipolar patients and their relatives deserve further investigation. Candidate brain function endophenotypes include attention deficits, deficits in verbal learning and memory, cognitive deficits after tryptophan depletion, circadian rhythm instability, and dysmodulation of motivation and reward. We selected reduced anterior cingulate volume and early-onset white matter abnormalities as candidate brain structure endophenotypes. Symptom provocation endophenotypes might be based on bipolar patients' sensitivity to sleep deprivation, psychostimulants, and cholinergic drugs. Phenotypic heterogeneity is a major impediment to the elucidation of the neurobiology and genetics of bipolar disorder. We present a strategy constructed to improve the phenotypic definition of bipolar disorder by elucidating candidate endophenotypes. Studies to evaluate candidate endophenotypes with respect to specificity, heritability, temporal stability, and prevalence in unaffected relatives are encouraged.

Quiroz JA, Gould TD, Manji HK. · Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, NIH, Bethesda, Maryland 20892, USA. · Mol Interv. · Pubmed #15471909 links to  free full text

Abstract: Bipolar affective disorder is a common, severe, chronic, and often life-threatening illness, associated with other medical and psychiatric conditions (i.e., co-morbidity). The treatment of this devastating disorder was revolutionized by the discovery of lithium's antimanic effects over fifty years ago. Recent molecular and cellular biological studies have identified a number of unexpected targets for this monovalent cation, notably glycogen synthase kinase-3 and neurotrophic signaling cascades. These findings are leading to a reconceptualization of the biological underpinnings of bipolar disorder and are resulting in considerable interest in utilizing lithium for the treatment of certain neurodegenerative disorders. We review recent insights into lithium's actions including its direct inhibitory actions on inositol monophosphatase, inositol polyphosphate 1-phosphatase, glycogen synthase kinase-3, fructose 1,6-bisphosphatase, bisphosphate nucleotidase, and phosphoglucomutase enzymes. We also discuss lithium's intracellular downstream targets including adenylate cyclase, the phosphoinositol cascade (and its effect on protein kinase C), arachidonic acid metabolism, and effects on neurotrophic cascades. Many of the new insights of lithium's actions may lead to the strategic development of improved therapeutics for the treatment of bipolar disorder.

Hasler G, Drevets WC, Manji HK, Charney DS. · Mood and Anxiety Disorders Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, USA. · Neuropsychopharmacology. · Pubmed #15213704 links to  free full text

Abstract: 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.

Du J, Szabo ST, Gray NA, Manji HK. · Laboratory of Molecular Pathophysiology, National Institute of Mental Health, Bethesda, MD 20892, USA. · Int J Neuropsychopharmacol. · Pubmed #15154976 No free full text.

This publication has no abstract.

Charney DS, Manji HK. · Mood and Anxiety Disorders Research Program, National Institute of Mental Health, 15K North Drive, Room 101, MSC 2670, Bethesda, MD 20892-2670, USA. · Sci STKE. · Pubmed #15039492 No free full text.

Abstract: Major depression is a common, severe, chronic, and often life-threatening illness. There is a growing appreciation that, far from being a disease with purely psychological manifestations, major depression is a systemic disease with deleterious effects on multiple organ systems. Stressful life events have a substantial causal association with depression, and there is now compelling evidence that even early life stress constitutes a major risk factor for the subsequent development of depression. The emerging evidence suggests that the combination of genetics, early life stress, and ongoing stress may ultimately determine individual responsiveness to stress and the vulnerability to psychiatric disorders, such as depression. It is likely that genetic factors and life stress contribute not only to neurochemical alterations, but also to the impairments of cellular plasticity and resilience observed in depression. Recent preclinical and clinical studies have shown that signaling pathways involved in regulating cell plasticity and resilience are long-term targets for the actions of antidepressant agents. Agents capable of reversing the hypothesized impairments of cellular resilience, reductions in brain volume, and cell death or atrophy in depression have the potential of becoming new therapeutic classes of antidepressant drugs. Novel cellular targets include agents targeting neurotrophic pathways, glucocorticoid signaling, phosphodiesterase activity, and glutamatergic throughput. The future development of treatments that more directly target molecules in critical CNS (central nervous system) signaling pathways that regulate cellular plasticity thus hold promise as novel, improved long-term treatments for major depression.

Zarate CA, Du J, Quiroz J, Gray NA, Denicoff KD, Singh J, Charney DS, Manji HK. · Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, Bethesda, Maryland 20892, USA. · Ann N Y Acad Sci. · Pubmed #14684452 No free full text.

Abstract: There is increasing evidence from a variety of sources that mood disorders are associated with regional reductions in brain volume, as well as reductions in the number, size, and density of glia and neurons in discrete brain areas. Although the precise pathophysiology underlying these morphometric changes remains to be fully elucidated, the data suggest that severe mood disorders are associated with impairments of structural plasticity and cellular resilience. In this context, it is noteworthy that a growing body of data suggests that the glutamatergic system--which is known to play a major role in neuronal plasticity and cellular resilience--may be involved in the pathophysiology and treatment of mood disorders. Preclinical studies have shown that the glutamatergic system represents targets (often indirect) for the actions of antidepressants and mood stabilizers. There are a number of glutamatergic "plasticity enhancing" strategies that may be of considerable utility in the treatment of mood disorders. Among the most immediate ones are NMDA antagonists, inhibitors of glutamate-release agents, and AMPA potentiators; this research progress holds much promise for the development of novel therapeutics for the treatment of severe, refractory mood disorders.

Manji HK, Gottesman II, Gould TD. · Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, NIMH, Bethesda, MD 20892, USA. · Sci STKE. · Pubmed #14600293 No free full text.

Abstract: Although psychiatric diseases are among the most common and destructive of all human illnesses, the molecular and cellular mechanisms underlying their complex origins remain to be elucidated. Dysfunction of critical intracellular signaling pathways is very likely to be involved. This conclusion is based on a number of observations, including the short- and long-term cellular effects of psychiatric drugs; the critical role signaling pathways play in neurotransmitter, neuropeptide, and neurohormone communication; and the fact that signaling pathways are principle regulators of the diverse array of behavioral symptoms experienced by patients. The genomics era has brought to psychiatry an abundance of genetic linkage and candidate gene findings. The difficult task--now under way--is to discern the functional relevance of these results. Recent evidence suggests the involvement of the ubiquitous protein phosphatase 2B (calcineurin), a critical regulator of many signal transduction pathways, as a schizophrenia susceptibility gene. It is likely that genetic findings in severe psychiatric disorders will continue to implicate direct and indirect modulation of critical intracellular signaling pathways.

Holmes MK, Erickson K, Luckenbaugh DA, Drevets WC, Bain EE, Cannon DM, Snow J, Sahakian BJ, Manji HK, Zarate CA. · Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. · Bipolar Disord. · Pubmed #19032712 No free full text.

Abstract: OBJECTIVE: Neuropsychological studies of bipolar disorder reveal deficits in a variety of domains, including affective processing, memory, and sustained attention. These findings are difficult to interpret due to the potential confounding effects of mood-stabilizing medications. The present study aims to compare the cognitive performance of medicated and unmedicated subjects with bipolar depression to healthy control subjects. METHOD: Unmedicated subjects with bipolar depression (UBD, n = 32), subjects with bipolar depression on therapeutic doses of lithium or valproic acid (MBD, n = 33), and healthy control subjects (HC, n = 52) performed neuropsychological tasks measuring affective processing, visual memory, and sustained attention. Performance measures were covaried with age and mood ratings, where applicable. RESULTS: With regard to affective processing, the MBD group exhibited greater response latency than the UBD and HC groups. For the same task, the MBD group made more omission errors during the happy condition than in the sad condition. On a task of sustained attention, the MBD group made more errors than the HC group. There were no significant group differences on measures of visual memory. CONCLUSIONS: Deficits in affective processing were found in the medicated group, while unmedicated subjects appear to be unaffected. In particular, the MBD group made more errors during happy conditions, indicating a potential attentional bias in subjects with bipolar depression on mood-stabilizing medications. The present study also implicates impairment in sustained attention for medicated subjects with bipolar disorder, particularly those with the type II variety.

Zarate CA, Payne JL, Singh J, Quiroz JA, Luckenbaugh DA, Denicoff KD, Charney DS, Manji HK. · Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institute of Health, Department of Human and Health Services, Bethesda, Maryland, USA. · Biol Psychiatry. · Pubmed #15219473 No free full text.

Abstract: BACKGROUND: The original serotonergic and noradrenergic hypotheses do not fully account for the neurobiology of depression or mechanism of action of effective antidepressants. Research implicates a potential role of the dopaminergic system in the pathophysiology of bipolar disorder. The current study was undertaken as a proof of the concept that dopamine agonists will be effective in patients with bipolar II depression. METHODS: In a double-blind, placebo-controlled study, 21 patients with DSM-IV bipolar II disorder, depressive phase on therapeutic levels of lithium or valproate were randomly assigned to treatment with pramipexole (n = 10) or placebo (n = 11) for 6 weeks. Primary efficacy was assessed by the Montgomery-Asberg Depression Rating Scale. RESULTS: All subjects except for one in each group completed the study. The analysis of variance for total Montgomery-Asberg Depression Rating Scale scores showed a significant treatment effect. A therapeutic response (>50% decrease in Montgomery-Asberg Depression Rating Scale from baseline) occurred in 60% of patients taking pramipexole and 9% taking placebo (p =.02). One subject on pramipexole and two on placebo developed hypomanic symptoms. CONCLUSIONS: The dopamine agonist pramipexole was found to have significant antidepressant effects in patients with bipolar II depression.

Zarate CA, Payne JL, Quiroz J, Sporn J, Denicoff KK, Luckenbaugh D, Charney DS, Manji HK. · Laboratory of Molecular Pathophysiology and Experimental Therapeutics and the Pathophysiology Branch, Mood and Anxiety Disorders Program, NIMH, Department of Health and Human Services, NIH, Bethesda, MD 20892, USA. · Am J Psychiatry. · Pubmed #14702270 links to  free full text

Abstract: OBJECTIVE: This study was conducted to determine the efficacy and safety of riluzole, a glutamate-modulating agent, in patients with recurrent major depression. METHOD: After a 1-week drug-free period, subjects 18 years or older with a diagnosis of recurrent major depression and a Montgomery-Asberg Depression Rating Scale score > or = 20 received riluzole monotherapy (100-200 mg/day) openly for 6 weeks. RESULTS: Nineteen treatment-resistant depressed patients, 53% of whom were classified as having stage 2 treatment resistance or greater, received riluzole at a mean dose of 169 mg/day. Significant improvement occurred during weeks 3 through 6 for all patients and weeks 2 through 6 for completers. CONCLUSIONS: Although preliminary, these results indicate that riluzole may have antidepressant properties in some patients.