Small Increases To Employer Premiums Could Shift Millions Of People To The Exchanges And Add Billions To Federal Outlays
2013; 32 (9): 1531-1537
The Affordable Care Act will expand insurance coverage to more than twenty-five million Americans, partly through subsidized private insurance available from newly created health insurance exchanges for people with incomes of 133-400 percent of the federal poverty level. The act will alter the financial incentive structure for employers and influence their decisions on whether or not to offer their employees coverage. These decisions, in turn, will affect federal outlays and revenues through several mechanisms. We model the sensitivity of federal costs for the insurance exchange coverage provision of the Affordable Care Act using the nationally representative Medical Expenditure Panel Survey data set. We assess revenues and subsidy outlays for premiums and cost sharing for individuals purchasing private insurance through exchanges. Our findings show that changing theoretical premium contribution levels by just $100 could induce 2.25 million individuals to transition to exchanges and increase federal outlays by $6.7 billion. Policy makers and analysts should pay especially careful attention to participation rates as the act's implementation continues.
View details for DOI 10.1377/hlthaff.2013.0522
View details for Web of Science ID 000324681500004
View details for PubMedID 24019356
Targeting the BH3-interacting domain death agonist to develop mechanistically unique antidepressants
2012; 17 (8): 770-780
The BH3-interacting domain death agonist (Bid) is a pro-apoptotic member of the B-cell lymphoma-2 (Bcl-2) protein family. Previous studies have shown that stress reduces levels of Bcl-2 in brain regions implicated in the pathophysiology of mood disorders, whereas antidepressants and mood stabilizers increase Bcl-2 levels. The Bcl-2 protein family has an essential role in cellular resilience as well as synaptic and neuronal plasticity and may influence mood and affective behaviors. This study inhibited Bid in mice using two pharmacological antagonists (BI-11A7 and BI-2A7); the selective serotonin reuptake inhibitor citalopram was used as a positive control. These agents were studied in several well-known rodent models of depression-the forced swim test (FST), the tail suspension test (TST), and the learned helplessness (LH) paradigm-as well as in the female urine sniffing test (FUST), a measure of sex-related reward-seeking behavior. Citalopram and BI-11A7 both significantly reduced immobility time in the FST and TST and attenuated escape latencies in mice that underwent the LH paradigm. In the FUST, both agents significantly improved duration of female urine sniffing in mice that had developed helplessness. LH induction increased the activation of apoptosis-inducing factor (AIF), a caspase-independent cell death constituent activated by Bid, and mitochondrial AIF expression was attenuated by chronic BI-11A7 infusion. Taken together, the results suggest that functional perturbation of apoptotic proteins such as Bid and, alternatively, enhancement of Bcl-2 function, is a putative strategy for developing novel therapeutics for mood disorders.
View details for DOI 10.1038/mp.2011.77
View details for Web of Science ID 000306760600002
View details for PubMedID 21727899
Acute D-serine treatment produces antidepressant-like effects in rodents
INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY
2012; 15 (8): 1135-1148
Research suggests that dysfunctional glutamatergic signalling may contribute to depression, a debilitating mood disorder affecting millions of individuals worldwide. Ketamine, a N-methyl-D-aspartate (NMDA) receptor antagonist, exerts rapid antidepressant effects in approximately 70% of patients. Glutamate evokes the release of D-serine from astrocytes and neurons, which then acts as a co-agonist and binds at the glycine site on the NR1 subunit of NMDA receptors. Several studies have implicated glial deficits as one of the underlying facets of the neurobiology of depression. The present study tested the hypothesis that D-serine modulates behaviours related to depression. The behavioural effects of a single, acute D-serine administration were examined in several rodent tests of antidepressant-like effects, including the forced swim test (FST), the female urine sniffing test (FUST) following serotonin depletion, and the learned helplessness (LH) paradigm. D-serine significantly reduced immobility in the FST without affecting general motor function. Both D-serine and ketamine significantly rescued sexual reward-seeking deficits caused by serotonin depletion in the FUST. Finally, D-serine reversed LH behaviour, as measured by escape latency, number of escapes, and percentage of mice developing LH. Mice lacking NR1 expression in forebrain excitatory neurons exhibited a depression-like phenotype in the same behavioural tests, and did not respond to D-serine treatment. These findings suggest that D-serine produces antidepressant-like effects and support the notion of complex glutamatergic dysfunction in depression. It is unclear whether D-serine has a convergent influence on downstream synaptic plasticity cascades that may yield a similar therapeutic profile to NMDA antagonists like ketamine.
View details for DOI 10.1017/S1461145711001386
View details for Web of Science ID 000307188000011
View details for PubMedID 21906419
The tyrosine phosphatase STEP: implications in schizophrenia and the molecular mechanism underlying antipsychotic medications
Glutamatergic signaling through N-methyl-D-aspartate receptors (NMDARs) is required for synaptic plasticity. Disruptions in glutamatergic signaling are proposed to contribute to the behavioral and cognitive deficits observed in schizophrenia (SZ). One possible source of compromised glutamatergic function in SZ is decreased surface expression of GluN2B-containing NMDARs. STEP(61) is a brain-enriched protein tyrosine phosphatase that dephosphorylates a regulatory tyrosine on GluN2B, thereby promoting its internalization. Here, we report that STEP(61) levels are significantly higher in the postmortem anterior cingulate cortex and dorsolateral prefrontal cortex of SZ patients, as well as in mice treated with the psychotomimetics MK-801 and phencyclidine (PCP). Accumulation of STEP(61) after MK-801 treatment is due to a disruption in the ubiquitin proteasome system that normally degrades STEP(61). STEP knockout mice are less sensitive to both the locomotor and cognitive effects of acute and chronic administration of PCP, supporting the functional relevance of increased STEP(61) levels in SZ. In addition, chronic treatment of mice with both typical and atypical antipsychotic medications results in a protein kinase A-mediated phosphorylation and inactivation of STEP(61) and, consequently, increased surface expression of GluN1/GluN2B receptors. Taken together, our findings suggest that STEP(61) accumulation may contribute to the pathophysiology of SZ. Moreover, we show a mechanistic link between neuroleptic treatment, STEP(61) inactivation and increased surface expression of NMDARs, consistent with the glutamate hypothesis of SZ.
View details for DOI 10.1038/tp.2012.63
View details for Web of Science ID 000306221300009
View details for PubMedID 22781170
The effects of chronic treatment with mood stabilizers on the rat hippocampal post-synaptic density proteome
JOURNAL OF NEUROCHEMISTRY
2011; 119 (3): 617-629
Bipolar disorder is a devastating illness that is marked by recurrent episodes of mania and depression. There is growing evidence that the disease is correlated with disruptions in synaptic plasticity cascades involved in cognition and mood regulation. Alleviating the symptoms of bipolar disorder involves chronic treatment with mood stabilizers like lithium or valproate. These two structurally dissimilar drugs are known to alter prominent signaling cascades in the hippocampus, but their effects on the post-synaptic density complex remain undefined. In this work, we utilized mass spectrometry for quantitative profiling of the rat hippocampal post-synaptic proteome to investigate the effects of chronic mood stabilizer treatment. Our data show that in response to chronic treatment of mood stabilizers there were not gross qualitative changes but rather subtle quantitative perturbations in post-synaptic density proteome linked to several key signaling pathways. Our data specifically support the changes in actin dynamics on valproate treatment. Using label-free quantification methods, we report that lithium and valproate significantly altered the abundance of 21 and 43 proteins, respectively. Seven proteins were affected similarly by both lithium and valproate: Ank3, glutamate receptor 3, dynein heavy chain 1, and four isoforms of the 14-3-3 family. Immunoblotting the same samples confirmed the changes in Ank3 and glutamate receptor 3 abundance. Our findings support the hypotheses that BPD is a synaptic disorder and that mood stabilizers modulate the protein signaling complex in the hippocampal post-synaptic density.
View details for DOI 10.1111/j.1471-4159.2011.07424.x
View details for Web of Science ID 000297019300017
View details for PubMedID 21838781
Bax inhibitor 1, a modulator of calcium homeostasis, confers affective resilience
2011; 1403: 19-27
The endoplasmic reticulum (ER) is a critical site for intracellular calcium storage as well as protein synthesis, folding, and trafficking. Disruption of these processes is gaining support for contributing to heritable vulnerability of certain diseases. Here, we investigated Bax inhibitor 1 (BI-1), an anti-apoptotic protein that primarily resides in the ER and associates with B-cell lymphoma 2 (Bcl-2) and Bcl-XL, as an affective resiliency factor through its modulation of calcium homeostasis. We found that transgenic (TG) mice with BI-1 reinforced expression, via the neuronal specific enolase promoter, showed protection against the learned helplessness (LH) paradigm, an animal model to test stress coping. TG mice were also protected against anhedonia following both serotonin and catecholamine depletion as measured in two different models, the female urine sniffing test and the saccharine preference test. In addition, we used primary mouse cortical cultures to explore the ability of BI-1 to influence calcium homeostasis under basal conditions and also following challenge with thapsigargin (THPS), an inhibitor of sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA) that disrupts calcium homeostasis. TG neurons showed decreased basal cytosolic calcium levels and decreased Ca(2+) cytosolic accumulation following challenge with THPS as compared to WT neuronal cultures. Together, these data suggest that BI-1, through its actions on calcium homeostasis, may confer affective resiliency in multiple animal models of depression and anhedonia.
View details for DOI 10.1016/j.brainres.2011.05.067
View details for Web of Science ID 000293156800003
View details for PubMedID 21718971
Lithium treatment attenuates muscarinic M-1 receptor dysfunction
2011; 13 (3): 238-249
Altered muscarinic acetylcholine receptor levels and receptor-coupled signaling processes have been reported in mood disorders. M(1) , one of five muscarinic receptor subtypes, couples to the phospholipase C/protein kinase C and extracellular signal-regulated kinase (ERK) pathways. Mood stabilizers regulate these pathways. MicroRNAs (miRNAs) are small noncoding RNAs that suppress translation in a sequence-selective manner. Lithium downregulates several miRNAs, including let-7b and let-7c. One predicted target of let-7b and let-7c is the M(1) receptor. We hypothesized that miRNAs regulate M(1) receptor translation, and that disrupted M(1) expression leads to aberrant behaviors and disrupted downstream signaling pathways that are rescued by lithium treatment.The effects of miRNAs and chronic treatment with mood stabilizers on M(1) levels were tested in primary cultures and in rat frontal cortex. Effects of M(1) ablation and chronic treatment with mood stabilizers on several signaling cascades and M(1) -modulated behaviors were examined in wild-type and M(1) knockout mice. Results:? Let-7b, but not let-7c, negatively regulated M(1) levels. Chronic treatment with lithium, but not valproate, increased M(1) levels in the rat cortex. M(1) knockout mice exhibit ERK pathway deficits and behavioral hyperactivity; chronic treatment with lithium attenuated these deficits and hyperactivity.Lithium treatment can affect M(1) receptor function through intracellular signaling enhancement and, in situations without M(1) ablation, concomitant receptor upregulation via mechanisms involving miRNAs. Muscarinic dysfunction may contribute to mood disorders, while M(1) receptors and the downstream ERK pathway may serve as potential therapeutic targets for alleviating manic symptoms such as psychomotor hyperactivity.
View details for DOI 10.1111/j.1399-5618.2011.00915.x
View details for Web of Science ID 000292666000003
View details for PubMedID 21676127
Cellular mechanisms underlying affective resiliency: The role of glucocorticoid receptor- and mitochondrially-mediated plasticity
2009; 1293: 76-84
Bipolar disorder (BPD) is a devastating psychiatric illness marked by recurrent episodes of mania and depression. While the underlying pathophysiology of BPD remains elusive, an abnormal hypothalamic-pituitary-adrenal (HPA) axis and dysfunctional glucocorticoid receptor (GR) signaling are considered hallmarks. This review will examine how targeting resiliency signaling cascades at the cellular level may serve as a mechanism to treat BPD. Here, cellular resiliency is defined as the ability of a cell to adapt to an insult or stressor. Such resiliency at the cellular level could confer resiliency at the systems level and, ultimately, help individuals to cope with stressors or recover from depressive or manic states. This review will focus on four molecular targets of mood stabilizers that are known to play integral roles in these cellular resiliency signaling pathways: (1) B-cell CLL/lymphoma 2 (Bcl-2), (2) Bcl-2-associated athanogene (BAG-1), (3) glucocorticoid receptors (GRs), and (4) 51 kDa FK506-binding protein (FKBP5). These targets have emerged from neurobiological and human genetic studies and employ mechanisms that modulate GR function or promote anti-apoptotic processes critical to affective resilience. Future research should focus on elucidating sustainable treatments that target resiliency factors-such as BAG-1 or FKBP5-which could ultimately be used to treat individuals suffering from BPD and prevent relapses in afflicted individuals. Further identification of resiliency and susceptibility factors will also be vital. Ultimately, these developments would allow for the treatment of susceptible individuals prior to the development of BPD.
View details for DOI 10.1016/j.brainres.2009.06.103
View details for Web of Science ID 000270865600008
View details for PubMedID 19595676
MicroRNAs in Mental Health: From Biological Underpinnings to Potential Therapies
2009; 11 (3): 173-182
Psychiatric illnesses are disabling disorders with poorly understood underlying pathophysiologies. However, it is becoming increasingly evident that these illnesses result from disruptions across whole cellular networks rather than any particular monoamine system. Recent evidence continues to support the hypothesis that these illnesses arise from impairments in cellular plasticity cascades, which lead to aberrant information processing in the circuits that regulate mood, cognition, and neurovegetative functions (sleep, appetite, energy, etc.). As a result, many have begun to consider future therapies that would be capable of affecting global changes in cellular plasticity to restore appropriate synaptic function and neuronal connectivity. MicroRNAs (miRNAs) are non-coding RNAs that can repress the gene translation of hundreds of their targets and are therefore well-positioned to target a multitude of cellular mechanisms. Here, we review some properties of miRNAs and show they are altered by stress, glucocorticoids, mood stabilizers, and in a particular psychiatric disorder, schizophrenia. While this field is still in its infancy, we consider their potential for regulating behavioral phenotypes and targeting key predicted signaling cascades that are implicated in psychiatric illness. Clearly, considerable research is required to better determine any therapeutic potential of targeting miRNAs; however, these agents may provide the next generation of effective therapies for psychiatric illnesses.
View details for DOI 10.1007/s12017-009-8070-5
View details for Web of Science ID 000270284500005
View details for PubMedID 19544012
Reverse translational strategies for developing animal models of bipolar disorder
DISEASE MODELS & MECHANISMS
2009; 2 (5-6): 238-245
Bipolar disorder (BD) affects a significant portion of the population of the world, yet there has been limited success in developing novel treatments for the disorder. One of the major reasons for this dearth is the absence of suitable animal models for BD. Traditionally, animal models of human phenomena have been evaluated based on similarity to the human syndrome, response to appropriately corresponding medications, and the degree to which a model supports a common mechanistic theory between the human disorder and the model itself. The following review emphasizes the use of 'reverse translation', drawing on patient-based findings to develop suitable animal models for BD. We highlight some examples of this strategy, emphasizing their construct validity as a starting point. These studies have produced informative models that have altered the expression of genes/pathways implicated in BD, including the point mutation D181A of mouse mitochondrial DNA polymerase (POLG), glutamate receptor 6 (GluR6), Clock, extracellular regulated kinase 1 (ERK1), glycogen synthase kinase-3beta (GSK-3beta), B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated athanogene (BAG-1). These studies demonstrate that this method is useful, viable and deserves attention in new efforts to generate animal models of BD.
View details for DOI 10.1242/dmm.001628
View details for Web of Science ID 000268455300010
View details for PubMedID 19407332
Animal models of suicide-trait-related behaviors
TRENDS IN PHARMACOLOGICAL SCIENCES
2009; 30 (4): 165-173
Although antidepressants are moderately effective in treating major depressive disorder (MDD), concerns have arisen that selective serotonin-reuptake inhibitors (SSRIs) are associated with suicidal thinking and behavior, especially in children, adolescents and young adults. Almost no experimental research in model systems has considered the mechanisms by which SSRIs might be associated with this potential side effect in some susceptible individuals. Suicide is a complex behavior and impossible to fully reproduce in an animal model. However, by investigating traits that show strong cross-species parallels in addition to associations with suicide in humans, animal models might elucidate the mechanisms by which SSRIs are associated with suicidal thinking and behavior. Traits linked with suicide in humans that can be successfully modeled in rodents include aggression, impulsivity, irritability and hopelessness/helplessness. Modeling these relevant traits in animals can help to clarify the impact of SSRIs on these traits, suggesting avenues for reducing suicide risk in this vulnerable population.
View details for DOI 10.1016/j.tips.2009.01.004
View details for Web of Science ID 000265331100001
View details for PubMedID 19269045
The neurotrophic and neuroprotective effects of psychotropic agents.
Dialogues in clinical neuroscience
2009; 11 (3): 333-348
Accumulating evidence suggests that psychotropic agents such as mood stabilizers, antidepressants, and antipsychotics realize their neurotrophic/neuroprotective effects by activating the mitogen activated protein kinase/extracellular signal-related kinase, PI3-kinase, and wingless/glycogen synthase kinase (GSK) 3 signaling pathways. These agents also upregulate the expression of trophic/protective molecules such as brain-derived neurotrophic factor, nerve growth factor, B-cell lymphoma 2, serine-threonine kinase, and Bcl-2 associated athanogene 1, and inactivate proapoptotic molecules such as GSK-3. They also promote neurogenesis and are protective in models of neurodegenerative diseases and ischemia. Most if not all, of this evidence was collected from animal studies that used clinically relevant treatment regimens. Furthermore, human imaging studies have found that these agents increase the volume and density of brain tissue, as well as levels of N-acetyl aspartate and glutamate in selected brain regions. Taken together, these data suggest that the neurotrophic/neuroprotective effects of these agents have broad therapeutic potential in the treatment; not only of mood disorders and schizophrenia, but also neurodegenerative diseases and ischemia.
View details for PubMedID 19877500