The impact of neuroscience on society: cognitive enhancement in neuropsychiatric disorders and in healthy people.

In addition to causing distress and disability to the individual, neuropsychiatric disorders are also extremely expensive to society and governments. These disorders are both common and debilitating and impact on cognition, functionality and wellbeing. Cognitive enhancing drugs, such as cholinesterase inhibitors and methylphenidate, are used to treat cognitive dysfunction in Alzheimer's disease and attention deficit hyperactivity disorder, respectively. Other cognitive enhancers include specific computerized cognitive training and devices. An example of a novel form of cognitive enhancement using the technological advancement of a game on an iPad that also acts to increase motivation is presented. Cognitive enhancing drugs, such as methylphenidate and modafinil, which were developed as treatments, are increasingly being used by healthy people. Modafinil not only affects 'cold' cognition, but also improves 'hot' cognition, such as emotion recognition and task-related motivation. The lifestyle use of 'smart drugs' raises both safety concerns as well as ethical issues, including coercion and increasing disparity in society. As a society, we need to consider which forms of cognitive enhancement (e.g. pharmacological, exercise, lifelong learning) are acceptable and for which groups (e.g. military, doctors) under what conditions (e.g. war, shift work) and by what methods we would wish to improve and flourish.All cited psychopharmacological work from Professor Sahakian laboratory was funded by a Wellcome Trust Grant (089589/Z/09/Z) awarded to T.W. Robbins, B.J. Everitt, A.C. Roberts, J.W. Dalley, and B.J. Sahakian, and it was conducted at the Behavioural and Clinical Neuroscience Institute, which is supported by a joint award from the Medical Research Council and Wellcome Trust (G00001354). B.J. Sahakian receives funding from the Human Brain Project. We thank Janssen/J&J for funding the study on cognitive training in schizophrenia.This is the final version of the article. It first appeared from RSC via http://dx.doi.org/10.1098/rstb.2014.021

Brain neurokinin-1 receptors in depression and interactions with the serotonin system

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Brain neurokinin-1 receptors in depression and interactions with the serotonin system

Emerging evidence suggests neurokinin-1 receptors (NK1Rs) may be altered in depression and NK1R antagonists may have antidepressant properties. In addition, blockade or deletion of NK1Rs has been shown to increase neuronal firing in the dorsal raphe nucleus suggestive of an interaction with the serotonin (5-HT) system. Against this background, one main aim of this thesis was to investigate anatomical interactions in the rat brain between NK1Rs and the 5-HT system. The second main aim was to use the positron emission tomography (PET) radioligand [18F] SPA-RQ to study NK1Rs in vivo in normal human volunteers and in patients with depression. In the animal studies, immunofluorescence experiments found NK1Rs colocalised with 5-HT1A receptors to a high degree in many forebrain regions, in particular in the medial septum and hippocampus. Colocalisation was also present in the prefrontal cortex, frontal cortex and lateral/basolateral amygdala, but to a lesser degree. NK1Rs were found to mostly colocalise with 5-HT2A receptors in hippocampus only. Colocalisation between NK1Rs and 5-HT1A receptors was much greater than that between NK1Rs and 5-HT2A receptors. In separate experiments, using retrograde tracing combined with immunohistochemistry and light and electron microscopy, NK1Rs were found on the cell bodies of some of the neurons within the lateral habenula and locus coeruleus that project to the dorsal raphe nucleus, but were not found on the cell bodies of afferent neurons in the prefrontal cortex. In the human studies, a comparison of a reversible two-tissue, four rate constants compartment model using plasma input function was made with a transient equilibrium model for the in vivo quantification of NK1Rs in humans using the PET radioligand [18F]SPA-RQ. The regional brain uptake of [18F]SPA-RQ was found to be consistent with the known distribution of NK1Rs: highest in the striatum, moderate in cortex and thalamus and low in the cerebellum. Furthermore, using the transient equilibrium model and a simplified PET imaging protocol with [18F]SPA-RQ, there was no difference in binding potential in any of the brain regions studied between depressed patients, patients recovered from depression and controls. However, a negative correlation was found between age and binding potential for global and regional NK1Rs (in particular, anterior temporal lobe). Collectively these data provide evidence for an interaction between NK1Rs and the 5-HT system at both the presynaptic and postsynaptic levels. In addition, they confirm the utility of the PET radioligand [18F] SPA-RQ for studying NK1Rs in vivo in humans. However, they do not support the idea of altered NK1R numbers in depression

Brain neurokinin-1 receptors in depression and interactions with the serotonin system

Emerging evidence suggests neurokinin-1 receptors (NK1Rs) may be altered in depression and NK1R antagonists may have antidepressant properties. In addition, blockade or deletion of NK1Rs has been shown to increase neuronal firing in the dorsal raphe nucleus suggestive of an interaction with the serotonin (5-HT) system. Against this background, one main aim of this thesis was to investigate anatomical interactions in the rat brain between NK1Rs and the 5-HT system. The second main aim was to use the positron emission tomography (PET) radioligand [18F] SPA-RQ to study NK1Rs in vivo in normal human volunteers and in patients with depression. In the animal studies, immunofluorescence experiments found NK1Rs colocalised with 5-HT1A receptors to a high degree in many forebrain regions, in particular in the medial septum and hippocampus. Colocalisation was also present in the prefrontal cortex, frontal cortex and lateral/basolateral amygdala, but to a lesser degree. NK1Rs were found to mostly colocalise with 5-HT2A receptors in hippocampus only. Colocalisation between NK1Rs and 5-HT1A receptors was much greater than that between NK1Rs and 5-HT2A receptors. In separate experiments, using retrograde tracing combined with immunohistochemistry and light and electron microscopy, NK1Rs were found on the cell bodies of some of the neurons within the lateral habenula and locus coeruleus that project to the dorsal raphe nucleus, but were not found on the cell bodies of afferent neurons in the prefrontal cortex. In the human studies, a comparison of a reversible two-tissue, four rate constants compartment model using plasma input function was made with a transient equilibrium model for the in vivo quantification of NK1Rs in humans using the PET radioligand [18F]SPA-RQ. The regional brain uptake of [18F]SPA-RQ was found to be consistent with the known distribution of NK1Rs: highest in the striatum, moderate in cortex and thalamus and low in the cerebellum. Furthermore, using the transient equilibrium model and a simplified PET imaging protocol with [18F]SPA-RQ, there was no difference in binding potential in any of the brain regions studied between depressed patients, patients recovered from depression and controls. However, a negative correlation was found between age and binding potential for global and regional NK1Rs (in particular, anterior temporal lobe). Collectively these data provide evidence for an interaction between NK1Rs and the 5-HT system at both the presynaptic and postsynaptic levels. In addition, they confirm the utility of the PET radioligand [18F] SPA-RQ for studying NK1Rs in vivo in humans. However, they do not support the idea of altered NK1R numbers in depression. </p

The Effect of Clozapine on Self-reported Duration of Sleep and Its Interaction With 23 Other Medications: A 5-Year Naturalistic Study.

BACKGROUND: Sedation is a common and incapacitating clozapine adverse effect, but the factors associated with sedation and its pharmacological management remain poorly studied. METHODS: We conducted a retrospective cohort study based on deidentified electronic clinical records of clozapine-treated patients from the secondary mental health care provider for Cambridgeshire and Peterborough, United Kingdom. We first evaluated cross-sectionally the influence of clozapine dose, clozapine, and norclozapine plasma levels on self-reported hours slept, as a proxy for sedation, using bivariate correlation and then the longitudinal effect of changes in clozapine dose and other 23 medications using linear mixed effect models. We followed 241 clozapine-treated patients for 56 months on average, with 2237 face-to-face assessments in total. RESULTS: Patients slept for a mean of 9.35 h/d, with 46% reporting 10 h/d or more. Cross-sectionally, sleep duration did not correlate with clozapine dose (r = 0.14, P = 0.106), but with clozapine plasma levels (r = 0.38, P < 0.0001) and norclozapine plasma levels (r = 0.25, P = 0.005). Longitudinally, the final mixed-effects model revealed 4 pharmacological variables that had a significant impact on hours slept: clozapine, risperidone augmentation, and atenolol were associated with increased sleep, whereas aripiprazole augmentation was associated with decreased sleep. We found that 20 other psychotropic medications measured were not associated with changes in sleep when added to clozapine. Excess sleep is a clozapine level-dependent adverse effect. CONCLUSIONS: The impact of different augmentation strategies might help clinicians decide on the most adequate strategy, albeit further studies should confirm our results.This study has not received direct funding. Clinical Research Database (CRD) was supported by intramural grant by National Institute Health Research – Cambridge Biomedical Research Centre (NIHR-BRC-1215-20014); the views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care