Showing papers by "Philip S. Wang published in 2010"

Developing constructs for psychopathology research: research domain criteria.

Abstract: There exists a divide between findings from integrative neuroscience and clinical research focused on mechanisms of psychopathology. Specifically, a clear correspondence does not emerge between clusters of complex clinical symptoms and dysregulated neurobiological systems, with many apparent redundancies. For instance, many mental disorders involve multiple disruptions in putative mechanistic factors (e.g., excessive fear, deficient impulse control), and different disrupted mechanisms appear to play major roles in many disorders. The Research Domain Criteria (RDoC) framework is a heuristic to facilitate the incorporation of behavioral neuroscience in the study of psychopathology. Such integration might be achieved by shifting the central research focus of the field away from clinical description to more squarely examine aberrant mechanisms. RDoC first aims to identify reliable and valid psychological and biological mechanisms and their disruptions, with an eventual goal of understanding how anomalies in these mechanisms drive psychiatric symptoms. This approach will require new methods to ascertain samples, relying on hypothesized psychopathological mechanisms to define experimental groups instead of traditional diagnostic categories. RDoC, by design, uncouples research efforts from clinically familiar categories to focus directly on fundamental mechanisms of psychopathology. RDoC proposes a matrix of domains and levels of analyses and invites the field to test and refine the framework. If RDoC is successful, the domains will ultimately relate to familiar psychopathologies in ways that promote new knowledge regarding etiology and more efficient development of new preventive and treatment interventions.

Rethinking Mental Illness

Abstract: IN THE FIRST 2010 ISSUE OF NATURE, THE EDITOR, PHILIP Campbell, suggested that the next 10-year period is likely to be the “decade for psychiatric disorders.” This was not a prediction of an epidemic, although mental illnesses are highly prevalent, nor a suggestion that new illnesses would emerge. The key point was that research on mental illness was, at long last, reaching an inflection point at which insights gained from genetics and neuroscience would transform the understanding of psychiatric illnesses. The insights are indeed coming fast and furious. In this Commentary, we suggest ways in which genomics and neuroscience can help reconceptualize disorders of the mind as disorders of the brain and thereby transform the practice of psychiatry. Compelling reasons to look for genes that confer risk for mental illness come from twin studies demonstrating high heritability for autism, schizophrenia, and bipolar disorder. Although there have been notable findings from linkage and genome-wide association studies, with candidate genes and specific alleles identified for each of the major mental disorders, those that have been replicated explain only a fraction of the heritability. Where is the missing genetic signal for mental illness? The discovery that large ( 1 megabase) structural or copy number variants, such as deletions and duplications, are 10fold more common in autism and schizophrenia is an important clue. Copy number variants are individually rare, sometimes restricted to a single family or developing de novo in an individual. Although “private mutations” are rare (reminiscent of Tolstoy’s dictum that “each unhappy family is unhappy in its own way”), they are in aggregate remarkably common, spread across vast expanses of the genome, and ultimately could explain more genetic risk than common variants. Although many of the genes implicated are involved in brain development, copy number variants do not appear to be specific for illnesses in the current diagnostic scheme. Within families, the same copy number variant may be associated with schizophrenia in one person, bipolar disorder in another, and attention-deficit/hyperactivity disorder in yet another. The genetics of mental illness may really be the genetics of brain development, with different outcomes possible, depending on the biological and environmental context. The same twin studies that point to high heritability also demonstrate the limits of genetics: environmental factors must be important for mental disorders. The advent of epigenomics, which can detect the molecular effects of experience, may provide a powerful approach for understanding the critical effects of early-life events and environment on adult patterns of behavior. Epigenomics can now map changes across the entire genome with unbiased, highthroughput technologies and point to the mechanisms by which experience confers enduring changes in gene expression and, ultimately, changes in brain activity and function. Epigenomic modifications that alter transcription may also be a mechanism for mental illness, even in the absence of common or rare structural variants. For instance, a rare copy number variant detected in autism deletes the oxytocin receptor gene. In many individuals with autism who do not have this deletion, epigenomic modifications appear to silence this gene. Genomics and epigenomics already point to diverse molecular pathways that confer risk of mental illness. What binds these diverse molecular mechanisms together to yield clusters of symptoms recognized as the syndromes of psychiatric disorders? Increasingly, clinical neuroscientists are identifying specific circuits for major aspects of illness. But just as the genetic variants do not map selectively onto current diagnostic categories, so, also, circuits seem to be associated with cognitive and behavioral functions, without a oneto-one correspondence to diagnosis. For instance, the neural basis of extinction learning, which was first mapped in the rat brain, appears to be conserved in the human brain, with key nodes including ventromedial prefrontal cortex, amygdala, and hippocampus. Rather than defining the biology of a single illness, extinction is an important feature of posttraumatic stress disorder, obsessive-compulsive disorder, and various phobias. Two noteworthy points are emerging from systems neuroscience. First, there seem to be emerging relationships between genetic variation and development of neural circuits that mediate complex cognition and behavior, from reward to emotion regulation. Second, the current diagnos-

Comparative Safety of Antidepressant Agents for Children and Adolescents Regarding Suicidal Acts

Abstract: OBJECTIVE: The objective of this study was to assess the risk of suicide attempts and suicides after initiation of antidepressant medication use by children and adolescents, for individual agents. METHODS: We conducted a 9-year cohort study by using population-wide data from British Columbia. We identified new users of antidepressants who were 10 to 18 years of age with a recorded diagnosis of depression. Study outcomes were hospitalization attributable to intentional self-harm and suicide death. RESULTS: Of 20 906 children who initiated antidepressant therapy, 16774 (80%) had no previous antidepressant use. During the first year of use, we observed 266 attempted and 3 completed suicides, which yielded an event rate of 27.04 suicidal acts per 1000 person-years (95% confidence interval [CI]: 23.9–30.5 suicidal acts per 1000 person-years). There were no meaningful differences in the rate ratios (RRs) comparing fluoxetine with citalopram (RR: 0.97 [95% CI: 0.54–1.76]), fluvoxamine (RR: 1.05 [95% CI: 0.46–2.43]), paroxetine (RR: 0.80 [95% CI: 0.47–1.37]), and sertraline (RR: 1.02 [95% CI: 0.56–1.84]). Tricyclic agents showed risks similar to those of selective serotonin reuptake inhibitors (RR: 0.92 [95% CI: 0.43–2.00]). CONCLUSION: Our finding of equal event rates among antidepressant agents supports the decision of the Food and Drug Administration to include all antidepressants in the black box warning regarding potentially increased suicidality risk for children and adolescents beginning use of antidepressants.

Variation in the Risk of Suicide Attempts and Completed Suicides by Antidepressant Agent in Adults: A Propensity Score–Adjusted Analysis of 9 Years' Data

Abstract: Context A US Food and Drug Administration advisory has warned that antidepressants may be associated with an increased risk of suicidal thoughts and behaviors in adolescents. This prompted a meta-analysis of trials in adults that found no overall increase in risk, but individual agents could not be studied. Objective To assess the risk of suicide and suicide attempts associated with individual antidepressant agents. Design Cohort study of incident users of antidepressant agents. Setting Population-based health care utilization data of all residents of British Columbia, Canada, aged 18 years and older between January 1, 1997, and December 31, 2005. Patients British Columbia residents who had antidepressant therapy initiated and had a recorded diagnosis of depression. Intervention Initiation of various antidepressant medications. Main Outcome Measures Combined suicide death or hospitalization due to self-harm. Results In a population of 287 543 adults aged 18 years and older with antidepressant therapy initiated, we observed outcome rates ranging from 4.41/1000 person-years to 9.09/1000 person-years. Most events occurred in the first 6 months after treatment initiation. After extensive propensity score adjustment, we found no clinically meaningful variation in the risk of suicide and suicide attempt between antidepressant agents compared with fluoxetine hydrochloride initiation: citalopram hydrobromide, hazard ratio = 1.00 (95% confidence interval, 0.63-1.57); fluvoxamine maleate, hazard ratio = 0.98 (95% confidence interval, 0.63-1.51); paroxetine hydrochloride, hazard ratio = 1.02 (95% confidence interval, 0.77-1.35); and sertraline hydrochloride, hazard ratio = 0.75 (95% confidence interval, 0.53-1.05). Compared with selective serotonin reuptake inhibitors as a drug class, other classes including serotonin-norepinephrine reuptake inhibitors, tricyclic agents, and other newer and atypical agents had a similar risk. Restriction to patients with no antidepressant use in the past 3 years further reduced apparent differences between groups. Conclusions Our finding of equal event rates across antidepressant agents supports the US Food and Drug Administration's decision to treat all antidepressants alike in their advisory. Treatment decisions should be based on efficacy, and clinicians should be vigilant in monitoring after initiating therapy with any antidepressant agent.

Identification of hospitalizations for intentional self-harm when E-codes are incompletely recorded

Abstract: CONTEXT: Suicidal behavior has gained attention as an adverse outcome of prescription drug use. Hospitalizations for intentional self-harm, including suicide, can be identified in administrative claims databases using external cause of injury codes (E-codes). However, rates of E-code completeness in US government and commercial claims databases are low due to issues with hospital billing software. OBJECTIVE: To develop an algorithm to identify intentional self-harm hospitalizations using recorded injury and psychiatric diagnosis codes in the absence of E-code reporting. METHODS: We sampled hospitalizations with an injury diagnosis (ICD-9 800-995) from two databases with high rates of E-coding completeness: 1999-2001 British Columbia, Canada data and the 2004 US Nationwide Inpatient Sample. Our gold standard for intentional self-harm was a diagnosis of E950-E958. We constructed algorithms to identify these hospitalizations using information on type of injury and presence of specific psychiatric diagnoses. RESULTS: The algorithm that identified intentional self-harm hospitalizations with high sensitivity and specificity was a diagnosis of poisoning, toxic effects, open wound to elbow, wrist, or forearm, or asphyxiation; plus a diagnosis of depression, mania, personality disorder, psychotic disorder, or adjustment reaction. This had a sensitivity of 63%, specificity of 99% and positive predictive value (PPV) of 86% in the Canadian database. Values in the US data were 74, 98, and 73%. PPV was highest (80%) in patients under 25 and lowest those over 65 (44%). CONCLUSIONS : The proposed algorithm may be useful for researchers attempting to study intentional self-harm in claims databases with incomplete E-code reporting, especially among younger populations. Copyright © 2010 John Wiley & Sons, Ltd. Language: en

Impact of drug cost sharing on service use and adverse clinical outcomes in elderly receiving antidepressants.

Abstract: Background Depression imposes enormous burdens on the elderly. Despite this, rates of initiation of and adherence to recommended pharmacotherapy are frequently low in this population. Although initiatives such as the Medicare Modernization Act (MMA) in have improved seniors' access to antidepressants, there are concerns that the patient cost-sharing incorporated in the MMA may have unintended consequences if it reduces essential drug use. Age-related pharmacokinetic and pharmacodynamic changes could make seniors particularly vulnerable to antidepressant regimens used inappropriately to save costs, increasing their risks of morbidity, hospitalizations, and nursing home placements. Two sequential large-scale “natural experiments” in British Columbia provide a unique opportunity to evaluate the effect of cost sharing on outcomes and mental health service use among seniors. In January 2002 the province introduced a $25 Canadian copay ($10 for low-income seniors). In May 2003 this copay policy was replaced by a second policy consisting of an income-based deductible, 25% coinsurance once the deductible was met, and full coverage once an out-of-pocket ceiling was met. The transition between the two policies is analogous to what many U.S. seniors experience when they transition from private insurance requiring copays to Medicare Part D requiring deductibles and coinsurance.

Toward Enough of the Best for All: Research to Transform the Efficacy, Quality, and Reach of Mental Health Care for Youth

Abstract: The articles in this special journal issue observe the same paradox about mental health services for children and adolescents expressed in this old joke about food. Taken together, they make the case that current mental health care for children and adolescents is of poor quality and questionable effectiveness, and, moreover, is delivered in inadequate doses to a only a fraction of the nation’s youth who need it. In order to address these shortcomings in quality, quantity, and effectiveness, the authors mainly agree to eschew traditional individual-level approaches to addressing mental health problems in favor of a public health approach. A public health approach would target the population, in contrast to individuals, with a range of consistently high-quality services to meet diverse needs and, thus, provide maximum mental health benefit for the greatest number of youth. A public health approach, and the requisite system alterations recommended in this journal, imply that change must occur at all levels, from Federal and State policies to mental health care agencies, treatment providers, and individual interventions. Foster and McCombs-Thornton (2010), for example, would target the economics of mental health care, given that financing and cost help to determine care quality and intensity by informing and influencing decisions about providing and using mental health services. Horwitz et al. (2010) propose policy levers be used to compel child welfare agencies to deliver evidence-based parent training programs. Stelk and Slaton (2010) assert that States must radically strengthen their mental health infrastructures if they are to support and withstand the process of transformational improvement. Kelleher and Atkins (2010) posit that transition from a clinician-patient model to a public health approach will require changes in organizational culture and capacity, including assimilation of new information technologies and accountability systems. Atkins et al. (2010) cite the emerging consensus to incorporate mental health services into schools as renewed motivation to find best models for integrating academic learning with emotional, mental, and behavioral health. Garland et al. (2010) focus on improving usual care and assert that to do so, providers and agencies need readily available feedback on treatment process, outcomes, and implementation of evidence-based strategies. Schoenwald et al. (2010) recommend rethinking of the child mental health workforce and distribution of labor. Taking aim at clinical practice, Alegria et al. (2010) argue that traditional clinical approaches to child mental health too often fail youth from diverse backgrounds by ignoring culture and context. Heflinger and Hinshaw (2010) exhort providers to The views expressed in this commentary do not necessarily represent the views of the NIMH, NIH, HHS, or the United States Government.