Pathways to new drug discovery in neuropsychiatry

There is currently a crisis in drug discovery for neuropsychiatric disorders, with a profound, yet unexpected drought in new drug development across the spectrum. In this commentary, the sources of this dilemma and potential avenues to redress the issue are explored. These include a critical review of diagnostic issues and of selection of participants for clinical trials, and the mechanisms for identifying new drugs and new drug targets. Historically, the vast majority of agents have been discovered serendipitously or have been modifications of existing agents. Serendipitous discoveries, based on astute clinical observation or data mining, remain a valid option, as is illustrated by the suggestion in the paper by Wahlqvist and colleagues that treatment with sulfonylurea and metformin reduces the risk of affective disorder. However, the identification of agents targeting disorder-related biomarkers is currently proving particularly fruitful. There is considerable hope for genetics as a purist, pathophysiologically valid pathway to drug discovery; however, it is unclear whether the science is ready to meet this promise. Fruitful paradigms will require a break from the orthodoxy, and creativity and risk may well be the fingerprints of success

Genetic inhibition of neurotransmission reveals role of glutamatergic input to dopamine neurons in high-effort behavior

Midbrain dopamine neurons are crucial for many behavioral and cognitive functions. As the major excitatory input, glutamatergic afferents are important for control of the activity and plasticity of dopamine neurons. However, the role of glutamatergic input as a whole onto dopamine neurons remains unclear. Here we developed a mouse line in which glutamatergic inputs onto dopamine neurons are specifically impaired, and utilized this genetic model to directly test the role of glutamatergic inputs in dopamine-related functions. We found that while motor coordination and reward learning were largely unchanged, these animals showed prominent deficits in effort-related behavioral tasks. These results provide genetic evidence that glutamatergic transmission onto dopaminergic neurons underlies incentive motivation, a willingness to exert high levels of effort to obtain reinforcers, and have important implications for understanding the normal function of the midbrain dopamine system.Fil: Hutchison, M. A.. National Institutes of Health; Estados UnidosFil: Gu, X.. National Institutes of Health; Estados UnidosFil: Adrover, Martín Federico. National Institutes of Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Lee, M. R.. National Institutes of Health; Estados UnidosFil: Hnasko, T. S.. University of California at San Diego; Estados UnidosFil: Alvarez, V. A.. National Institutes of Health; Estados UnidosFil: Lu, W.. National Institutes of Health; Estados Unido

Evaluation of Quantitative EEG by Classification and Regression Trees to Characterize Responders to Antidepressant and Placebo Treatment

The study objective was to evaluate the usefulness of Classification and Regression Trees (CART), to classify clinical responders to antidepressant and placebo treatment, utilizing symptom severity and quantitative EEG (QEEG) data. Patients included 51 adults with unipolar depression who completed treatment trials using either fluoxetine, venlafaxine or placebo. Hamilton Depression Rating Scale (HAM-D) and single electrodes data were recorded at baseline, 2, 7, 14, 28 and 56 days. Patients were classified as medication and placebo responders or non-responders. CART analysis of HAM-D scores showed that patients with HAM-D scores lower than 13 by day 7 were more likely to be treatment responders to fluoxetine or venlafaxine compared to non-responders (p=0.001). Youden’s index γ revealed that CART models using QEEG measures were more accurate than HAM-D-based models. For patients given fluoxetine, patients with a decrease at day 2 in θ cordance at AF2 were classified by CART as treatment responders (p=0.02). For those receiving venlafaxine, CART identified a decrease in δ absolute power at day 7 at the PO2 region as characterizing treatment responders (p=0.01). Using all patients receiving medication, CART identified a decrease in δ absolute power at day 2 in the FP1 region as characteristic of nonresponse to medication (p=0.003). Optimal trees from the QEEG CART analysis primarily utilized cordance values, but also incorporated some δ absolute power values. The results of our study suggest that CART may be a useful method for identifying potential outcome predictors in the treatment of major depression

The Effects of Cocaine on Different Redox Forms of Cysteine and Homocysteine, and on Labile, Reduced Sulfur in the Rat Plasma Following Active versus Passive Drug Injections

Received: 28 November 2012 / Revised: 19 April 2013 / Accepted: 6 May 2013 / Published online: 16 May 2013 The Author(s) 2013. This article is published with open access at Springerlink.comThe aim of the present studies was to evaluate cocaine-induced changes in the concentrations of different redox forms of cysteine (Cys) and homocysteine (Hcy), and products of anaerobic Cys metabolism, i.e., labile, reduced sulfur (LS) in the rat plasma. The above-mentioned parameters were determined after i.p. acute and subchronic cocaine treatment as well as following i.v. cocaine self-administration using the yoked procedure. Additionally, Cys, Hcy, and LS levels were measured during the 10-day extinction training in rats that underwent i.v. cocaine administration. Acute i.p. cocaine treatment increased the total and protein-bound Hcy contents, decreased LS, and did not change the concentrations of Cys fractions in the rat plasma. In turn, subchronic i.p. cocaine administration significantly increased free Hcy and lowered the total and protein-bound Cys concentrations while LS level was unchanged. Cocaine self-administration enhanced the total and protein-bound Hcy levels, decreased LS content, and did not affect the Cys fractions. On the other hand, yoked cocaine infusions did not alter the concentration of Hcy fractions while decreased the total and protein-bound Cys and LS content. This extinction training resulted in the lack of changes in the examined parameters in rats with a history of cocaine self-administration while in the yoked cocaine group an increase in the plasma free Cys fraction and LS was seen. Our results demonstrate for the first time that cocaine does evoke significant changes in homeostasis of thiol amino acids Cys and Hcy, and in some products of anaerobic Cys metabolism, which are dependent on the way of cocaine administration

Should Research Ethics Encourage the Production of Cost-Effective Interventions?

This project considers whether and how research ethics can contribute to the provision of cost-effective medical interventions. Clinical research ethics represents an underexplored context for the promotion of cost-effectiveness. In particular, although scholars have recently argued that research on less-expensive, less-effective interventions can be ethical, there has been little or no discussion of whether ethical considerations justify curtailing research on more expensive, more effective interventions. Yet considering cost-effectiveness at the research stage can help ensure that scarce resources such as tissue samples or limited subject popula- tions are employed where they do the most good; can support parallel efforts by providers and insurers to promote cost-effectiveness; and can ensure that research has social value and benefits subjects. I discuss and rebut potential objections to the consideration of cost-effectiveness in research, including the difficulty of predicting effectiveness and cost at the research stage, concerns about limitations in cost-effectiveness analysis, and worries about overly limiting researchers’ freedom. I then consider the advantages and disadvantages of having certain participants in the research enterprise, including IRBs, advisory committees, sponsors, investigators, and subjects, consider cost-effectiveness. The project concludes by qualifiedly endorsing the consideration of cost-effectiveness at the research stage. While incorporating cost-effectiveness considerations into the ethical evaluation of human subjects research will not on its own ensure that the health care system realizes cost-effectiveness goals, doing so nonetheless represents an important part of a broader effort to control rising medical costs

A Randomized Community-based Intervention Trial Comparing Faith Community Nurse Referrals to Telephone-Assisted Physician Appointments for Health Fair Participants with Elevated Blood Pressure

To measure the effect of faith community nurse referrals versus telephone-assisted physician appointments on blood pressure control among persons with elevated blood pressure at health fairs. Randomized community-based intervention trial conducted from October 2006 to October 2007 of 100 adults who had an average blood pressure reading equal to or above a systolic of 140 mm Hg or a diastolic of 90 mm Hg obtained at a faith community nurse-led church health event. Participants were randomized to either referral to a faith community nurse or to a telephone-assisted physician appointment. The average enrollment systolic blood pressure (SBP) was 149 ± 14 mm Hg, diastolic blood pressure (DBP) was 87 ± 11 mm Hg, 57% were uninsured and 25% were undiagnosed at the time of enrollment. The follow-up rate was 85% at 4 months. Patients in the faith community nurse referral arm had a 7 ± 15 mm Hg drop in SBP versus a 14 ± 15 mm Hg drop in the telephone-assisted physician appointment arm (p = 0.04). Twenty-seven percent of the patients in the faith community nurse referral arm had medication intensification compared to 32% in the telephone-assisted physician appointment arm (p = 0.98). Church health fairs conducted in low-income, multiethnic communities can identify many people with elevated blood pressure. Facilitating physician appointments for people with elevated blood pressure identified at health fairs confers a greater decrease in SBP than referral to a faith community nurse at four months

A Pair of Dopamine Neurons Target the D1-Like Dopamine Receptor DopR in the Central Complex to Promote Ethanol-Stimulated Locomotion in Drosophila

Dopamine is a mediator of the stimulant properties of drugs of abuse, including ethanol, in mammals and in the fruit fly Drosophila. The neural substrates for the stimulant actions of ethanol in flies are not known. We show that a subset of dopamine neurons and their targets, through the action of the D1-like dopamine receptor DopR, promote locomotor activation in response to acute ethanol exposure. A bilateral pair of dopaminergic neurons in the fly brain mediates the enhanced locomotor activity induced by ethanol exposure, and promotes locomotion when directly activated. These neurons project to the central complex ellipsoid body, a structure implicated in regulating motor behaviors. Ellipsoid body neurons are required for ethanol-induced locomotor activity and they express DopR. Elimination of DopR blunts the locomotor activating effects of ethanol, and this behavior can be restored by selective expression of DopR in the ellipsoid body. These data tie the activity of defined dopamine neurons to D1-like DopR-expressing neurons to form a neural circuit that governs acute responding to ethanol

Public understandings of addiction: where do neurobiological explanations fit?

Developments in the field of neuroscience, according to its proponents, offer the prospect of an enhanced understanding and treatment of addicted persons. Consequently, its advocates consider that improving public understanding of addiction neuroscience is a desirable aim. Those critical of neuroscientific approaches, however, charge that it is a totalising, reductive perspective–one that ignores other known causes in favour of neurobiological explanations. Sociologist Nikolas Rose has argued that neuroscience, and its associated technologies, are coming to dominate cultural models to the extent that 'we' increasingly understand ourselves as 'neurochemical selves'. Drawing on 55 qualitative interviews conducted with members of the Australian public residing in the Greater Brisbane area, we challenge both the 'expectational discourses' of neuroscientists and the criticisms of its detractors. Members of the public accepted multiple perspectives on the causes of addiction, including some elements of neurobiological explanations. Their discussions of addiction drew upon a broad range of philosophical, sociological, anthropological, psychological and neurobiological vocabularies, suggesting that they synthesised newer technical understandings, such as that offered by neuroscience, with older ones. Holding conceptual models that acknowledge the complexity of addiction aetiology into which new information is incorporated suggests that the impact of neuroscientific discourse in directing the public's beliefs about addiction is likely to be more limited than proponents or opponents of neuroscience expect