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Alcohol works on the brain to produce its desired effects, e.g., sociability and intoxication, and hence the brain is an important organ for exploring subsequent harms. These come in many different forms such as the consequences of damage during intoxication, e.g., from falls and fights, damage from withdrawal, damage from the toxicity of alcohol and its metabolites and altered brain structure and function with implications for behavioral processes such as craving and addiction. On top of that are peripheral factors that compound brain damage such as poor diet, vitamin deficiencies leading to Wernicke-Korsakoff syndrome. Prenatal alcohol exposure can also have a profound impact on brain development and lead to irremediable changes of fetal alcohol syndrome. This chapter briefly reviews aspects of these with a particular focus on recent brain imaging results. Cardiovascular effects of alcohol that lead to brain pathology are not covered as they are dealt with elsewhere in the volume.

Near-death experiences (NDEs) are complex subjective experiences, which have been previously associated with the psychedelic experience and more specifically with the experience induced by the potent serotonergic, N,N-Dimethyltryptamine (DMT). Potential similarities between both subjective states have been noted previously, including the subjective feeling of transcending one’s body and entering an alternative realm, perceiving and communicating with sentient ‘entities’ and themes related to death and dying. In this within-subjects placebo-controled study we aimed to test the similarities between the DMT state and NDEs, by administering DMT and placebo to 13 healthy participants, who then completed a validated and widely used measure of NDEs. Results revealed significant increases in phenomenological features associated with the NDE, following DMT administration compared to placebo. Also, we found significant relationships between the NDE scores and DMT-induced ego-dissolution and mystical-type experiences, as well as a significant association between NDE scores and baseline trait ‘absorption’ and delusional ideation measured at baseline. Furthermore, we found a significant overlap in nearly all of the NDE phenomenological features when comparing DMT-induced NDEs with a matched group of ‘actual’ NDE experiencers. These results reveal a striking similarity between these states that warrants further investigation.

Responses to psychedelics are notoriously difficult to predict, yet significant work is currently underway to assess their therapeutic potential and the level of interest in psychedelics among the general public appears to be increasing. We aimed to collect prospective data in order to improve our ability to predict acute- and longer-term responses to psychedelics. Individuals who planned to take a psychedelic through their own initiative participated in an online survey (www.psychedelicsurvey.com). Traits and variables relating to set, setting and the acute psychedelic experience were measured at five different time points before and after the experience. Principle component and regression methods were used to analyse the data. Sample sizes for the five time points were N = 654, N = 535, N = 379, N = 315, and N = 212 respectively. Psychological well-being was increased 2 weeks after a psychedelic experience and remained at this level after 4 weeks. Higher ratings of a “mystical-type experience” had a positive effect on the change in well-being after a psychedelic experience, whereas the other acute psychedelic experience measures, i.e., “challenging experience” and “visual effects”, did not influence the change in well-being after the psychedelic experience. Having “clear intentions” for the experience was conducive to mystical-type experiences. Having a positive “set” as well as having the experience with intentions related to “recreation” were both found to decrease the likelihood of having a challenging experience. The baseline trait “absorption” and higher drug doses promoted all aspects of the acute experience, i.e., mystical-type and challenging experiences, as well as visual effects. When comparing the relative contribution of different types of variables in explaining the variance in the change in well-being, it seemed that baseline trait variables had the strongest effect on the change in well-being after a psychedelic experience. These results confirm the importance of extra-pharmacological factors in determining responses to a psychedelic. We view this study as an early step towards the development of empirical guidelines that can evolve and improve iteratively with the ultimate purpose of guiding crucial clinical decisions about whether, when, where and how to dose with a psychedelic, thus helping to mitigate risks while maximizing potential benefits in an evidence-based manner.

Brain disorders pose major challenges to medicine and treatment innovation. This is because their spectrum spans inflammatory, degenerative, traumatic/ischaemic, and neoplastic disease processes with a complex and often ill- understood aetiology. An improved genetic and genomic understanding of specific disease pathways offers new approaches to these challenges, but at present it is in its infancy. Here, we review different aspects of the challenges facing neuromedicine, give examples of where there are advances, and highlight challenges to be overcome. We see that some disorders such as Huntington's disease are the product of single gene mutations, whose discovery has been leading to the development of new targeted interventions. In the field of neurosurgery, the identification of a number of mutations allows an elaborated genetic analysis of brain tumours and opens the door to individualised therapies. Psychiatric disorders remain the area where progress is slow. Genetic analyses show that for major common disorders such as schizophrenia and depression there are no single gene alterations which offer options for targeted therapy development. However, new approaches are being developed to leverage genetic information to predict patients' responses to treatment. These recent developments hold promise for early diagnosis, follow-up with personalised treatments with adjusted therapeutic doses, predictable responses, reduced adverse drug reactions, and personal health planning. The scenario is promising but calls for increased support for curiosity-driven research into the mechanisms of normal brain functioning as well as challenging adaptations of health care and research infrastructures, encompassing legal frameworks for analysing large amounts of personal data, a flexible regulatory framework for correlating big data analyses in cooperative networks between academia and the drug development industry, and finally new strategies for brain banking in order to increase access to brain tissue samples. To make personalised medicine for brain disorders a reality, a joint effort between all relevant stakeholders - among which patients and patient organisations should play an important role - is required.

Anxiety disorders are common and often disabling. They fall into five main categories: panic disorder, social anxiety disorder, generalized anxiety disorder, obsessive-compulsive disorder and posttraumatic stress disorder, each of which have characteristic symptoms and cognitions. All anxiety disorders respond to drugs and psychological treatments. This review will focus on drug treatments. Recent research has emphasized the value of antidepressants especially the selective serotonin reuptake inhibitors, benzodiazepines, and related sedative-like compounds. The common co-existence of depression with all of the anxiety disorders means that the selective serotonin reuptake inhibitors are now generally considered to be the first-line treatments but the benzodiazepines have some utility especiaRy in promoting sleep and working acutely to reduce extreme distress.

BackgroundAlcohol misuse, as well as being a major form of psychiatric morbidity, is also commonly associated with other psychiatric disorders. A greater understanding of the brain mechanisms underlying the adverse effects of alcohol is now possible, thanks to significant research advances made over the past decade.AimsTo elucidate for psychiatrists the growing knowledge of the importance of specific neurotransmitter interactions in the effects of alcohol.MethodA survey of the literature, extracting current knowledge of interest to psychiatrists.ResultsThere is good evidence that the acute effects of alcohol are mediated through interactions with amino acid neurotransmitters plus parallel changes in amines such as noradrenaline, dopamine and serotonin. Neuroadaptive responses at amino acid receptors probably underlie significant components of the withdrawal syndrome and probably also contribute to neuronal death found in chronic alcoholism.ConclusionsAn understanding of the pharmacology of alcohol use may lead to greater ability to treat psychiatric consequences of alcoholism, and may also prevent some of the secondary psychiatric comorbidity and later brain damage.

Aims and methodThere is considerable confusion at present among clinicians as regards the appropriateness of prescribing off-licence. Because of the nature of the registration process it is likely that a considerable proportion of prescribing will always be off-licence. This paper seeks to clarify when it is appropriate to prescribe off-licence. We convened a workshop on behalf of the British Association for Psychopharmacology involving clinicians and regulators from a variety of countries to explore this issue both generally and for specific childhood and learning disability clinical situations. Recent statements from the defence unions and consumer groups were also scrutinised.ResultsAcross senior clinicians and regulators from a number of European countries and North America there is a consensus that prescribing off-licence is a necessary part of the art of medicine.Clinical implicationsCurrent advice to clinicians on the issue of off-licence prescribing can sometimes overemphasise the hazards and neglect the benefits that may stem from appropriate off-licence prescribing. Good prescribing involves specifying treatment goals and monitoring outcomes and it is more important to share this with the patient than it is to communicate the licensed status of the drug being prescribed.

The clonidine challenge test is a means of assessing alpha-2-adrenoceptor sen sitivity in man. We review studies which have used this test to investigate central alpha-2- adrenoceptor changes in psychiatric illness, and to determine receptor changes after adminis tration and withdrawal of psychotropic treatments. Patients with severe depression show evidence of reduced alpha-2-adrenoceptor sensitivity, especially a reduced growth hormone response to clonidine. This may delineate a subgroup of patients with severe depressive illness from those with milder depression, and may even provide a trait marker for some depressed patients. Patients with panic disorder show evidence of subsensitivity to some and supersensitivity to other clonidine-induced responses. Other disorders, although less well investigated, may have abnormal test responses which may provide additional information about their cause and treatment. Changes in response after drug treatment have provided important information on the mode of action of antidepressants, and have suggested that noradrenergic function is altered by a variety of different antidepressants.

1. Panic Disorder and Agoraphobia Historical Introduction 2. Diagnosis, Classification, Epidemiology and Comorbidity 3. Course, Prognosis, Disability and Costs 4. Causation and Mechanisms 5. Depression and Panic Disorder 6. Treatment

It is timely to review the relationship between the pharmaceutical industry and psychiatry, given the continuing move towards more evidence-based practice in medicine, as well as two recent government initiatives to improve the value of research in the National Health Service (NHS), especially research that is commercially driven.