Historical and cultural aspects of man's relationship with addictive drugs

Our taste for addictive psychoactive substances is attested to in the earliest human records. Historically, psychoactive substances have been used by (i) priests in religious ceremonies (eg, amanita muscaria); (ii) healers for medicinal purposes (eg, opium); or (iii) the general population in a socially approved way (eg, alcohol, nicotine, and caffeine). Our forebears refined more potent compounds and devised faster routes of administration, which contributed to abuse. Pathological use was described as early as classical Antiquity. The issue of loss of control of the substance, heralding today's concept of addiction, was already being discussed in the 17th century. The complex etiology of addiction is reflected in the frequent pendulum swings between opposing attitudes on issues that are still currently being debated, such as: is addiction a sin or a disease; should treatment be moral or medical; is addiction caused by the substance; the individual's vulnerability and psychology, or social factors; should substances be regulated or freely available.     

Neuroplasticity in mood disorders

Neuroimaging and neuropathological studies of major depressive disorder (MDD) and bipolar disorder (BD) have identified abnormalities of brain structure in areas of the prefrontal cortex, amygdala, striatum, hippocampus, parahippocampal gyrus, and raphe nucleus. These structural imaging abnormalities persist across illness episodes, and preliminary evidence suggests they may in some cases arise prior to the onset of depressive episodes in subjects at high familial risk for MDD. In other cases, the magnitude of abnormality is reportedly correlated with time spent depressed. Postmortem histopathological studies of these regions have shown abnormal reductions of synaptic markers and glial cells, and, in rare cases, reductions in neurons in MDD and BD. Many of the regions affected by these structural abnormalities show increased glucose metabolism during depressive episodes. Because the glucose metabolic signal is dominated by glutamatergic transmission, these data support other evidence that excitatory amino acid transmission is elevated in limbic-cortical-striatal-pallidal-thalamic circuits during depression. Some of the subject samples in which these metabolic abnormalities have been demonstrated were also shown to manifest abnormally elevated stressed plasma cortisol levels. The co-occurrence of increased glutamatergic transmission and Cortisol hypersecretion raises the possibility that the gray matter volumetric reductions in these depressed subjects are partly accounted for by processes homologous to the dendritic atrophy induced by chronic stress in adult rodents, which depends upon interactions between elevated glucocorticoid secretion and N-meihyl-D-aspartate (NMDA)-glutamate receptor stimulation. Some mood-stabilizing and antidepressant drugs that exert neurotrophic effects in rodents appear to reverse or attenuate the gray matter volume abnormalities in humans with mood disorders. These neurotrophic effects may be integrally related to the therapeutic effects of such agents, because the regions affected by structural abnormalities in mood disorders are known to play major roles in modulating the endocrine, autonomic, behavioral, and emotional experiential responses to stressors.     

Pharmacogenetic aspects of addictive behaviors

Addictions are illnesses of complex causation, including inheritance and a role for gene/environment interactions. Functional alleles influencing pharmacodynamic (tissue response) and pharmacokinetic (absorption, distribution, and metabolism) play a role, but these interact with diverse environmental factors including early life stress, underage drug exposure, availability of addictive agents, and response to clinical interventions including pharmacotherapies. Identification of genetic factors in addiction thus plays an important role in the understanding of processes of addiction and origins of differential vulnerabilities and treatment responses.     

The effectiveness of anticonvulsants in psychiatric disorders

Anticonvulsant drugs are widely used in psychiatric indications. These include mainly alcohol and benzodiazepine withdrawal syndromes, panic and anxiety disorders, dementia, schizophrenia, affective disorders, bipolar affective disorders in particular, and, to some extent, personality disorders. A further area in which neurology and psychiatry overlap is pain conditions, in which some anticonvulsants, and also typical psychiatric medications such as antidepressants, are helpful. From the beginning of their psychiatric use, anticonvulsants have also been used to ameliorate specific symptoms of psychiatric disorders independently of their causality and underlying illness, eg, aggression, and, more recently, cognitive impairment, as seen in affective disorders and schizophrenia. With new anticonvulsants currently under development, it is likely that their use in psychiatry will further increase, and that psychiatrists need to learn about their differential efficacy and safety profiles to the same extent as do neurologists.     

NMDA receptors and fear extinction: implications for cognitive behavioral therapy

Based primarily on studies that employ Pavlovian fear conditioning, extinction of conditioned fear has been found to be mediated by N-methyi-D-aspartate (NMDA) receptors in the amygdala and medial prefrontal cortex. This led to the discovery that an NMDA partial agonist, D-cycloserine, could facilitate fear extinction when given systemically or locally into the amygdala. Because many forms of cognitive behavioral therapy depend on fear extinction, this led to the successful use of D-cycloserine as an adjunct to psychotherapy in patients with so-called simple phobias (fear of heights), social phobia, obsessive-compulsive behavior, and panic disorder. Data in support of these conclusions are reviewed, along with some of the possible limitations of D-cycloserine as an adjunct to psychotherapy.     

Alcohol, nicotine, caffeine, and mental disorders

Alcohol, nicotine, and caffeine are the most widely consumed psychotropic drugs worldwide. They are largely consumed by normal individuals, but their use is even more frequent in psychiatric patients, Thus, patients with schizophrenia tend to abuse all three substances. The interrelationships between depression and alcohol are complex. These drugs can all create dependence, as understood in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Alcohol abuse is clearly deleterious to the brain, provoking acute and chronic mental disorders, ranging from intoxication with impairment of cognition, to delirium tremens, halluosis, and dementia. In contrast, the main health consequences of nicotine, notably cancer and cardiovascular disases, lie outside the realm of psychiatry However, the mes of nicotine dependence and motivation to smoke or quit are of concern to psychiatrists.     

Assessment and treatment of mood disorders in the context of substance abuse

Recognition and management of mood symptoms in individuals using alcohol and/or other drugs represent a daily challenge for clinicians in both inpatient and outpatient treatment settings. Diagnosis of underlying mood disorders in the context of ongoing substance abuse requires careful collection of psychiatric history, and is often critical for optimal treatment planning and outcomes. Failure to recognize major depression or bipolar disorders in these patients can result in increased relapse rates, recurrence of mood episodes, and elevated risk of completed suicide. Over the past decade, epidemiologic research has clarified the prevalence of comorbid mood disorders in substance-dependent individuals, overturning previous assumptions that depression in these patients is simply an artifact of intoxication and/or withdrawal, therefore requiring no treatment. However, our understanding of the bidirectional relationships between mood and substance use disorders in terms of their course(s) of illness and prognoses remains limited. Like-wise, strikingly little treatment research exists to guide clinical decision making in co-occurring mood and substance use disorders, given their high prevalence and public health burden. Here we overview what is known and the salient gaps of knowledge where data might enhance diagnosis and treatment of these complicated patients.     

Opioids, dopamine, stress, and the addictions

The articulated goals of Dialogues in Clinical Neuroscience are to serve as "an interface between clinical neuropsychiatry and the neurosciences by providing state-of-the-art information and original insights into relevant clinical, biological, and therapeutic aspects." My laboratory the Laboratory of the Biology of Addictive Diseases at The Rockefeller University, has for years been focused on "bidirectional translational research," that is, learning by careful observations and study in patient populations with the disorders under study, in this case primarily specific addictive diseases, and then using that knowledge to create improved animal models or other laboratory-based research paradigms, while, at the same time, taking research findings made at the bench into the clinic as promptly as that is appropriate and feasible. In this invited review, therefore, the focus will be on perspectives of our Laboratory of the Biology of Addictive Diseases and related National Institutes of Health/National Institute on Drug Abuse research Center, including laboratory-based molecular neurobiological research, research using several animal models designed to mimic human patterns of drug abuse and addiction, as well as basic clinical research, intertwined with treatment-related research.     

The value of assessing cognitive function in drug development

This paper reviews the value and utility of measuring cognitive function in the development of new medicines by reference to the most widely used automated system in clinical research. Evidence is presented from phase 1 to 3 of the nature and quality of the information that can be obtained by applying the Cognitive Drug Research computerized assessment system to ongoing clinical trials. Valuable evidence can be obtained even in the first trial in which a novel compound is administered to man. One application of such testing is to ensure that novel compounds are relatively free from cognition-impairing properties, particularly in relation to competitor products. Another is to ensure that unwanted interactions with alcohol and other medications do not occur, or, if they do, to put them in context. In many patient populations, cognitive dysfunction occurs as a result of the disease process, and newer medicines which can treat the symptoms of the disease without further impairing function can often reveal benefits as the disease-induced cognitive dysfunction is reduced. Another major application is to identify benefits for compounds designed to enhance cognitive function. Such effects can be sought in typical phase 1 trials, or a scopolamine model of the core deficits of Alzheimer's disease can be used to screen potential antidernentia drugs. Ultimately, of course, such effects can be demonstrated using properly validated and highly sensitive automated procedures in the target populations. The data presented demonstrate that the concept of independently assessing a variety of cognitive functions is crucial in helping differentiate drugs, types of dementia, and different illnesses. Such information offers a unique insight into how the alterations to various cognitive functions will manifest themselves in everyday behavior. This reveals a major limitation of scales that yield a single score, because such limited information does not permit anything but a quantitative interpretation; and the concept of "more" cognitive function or "less" is manifestly inappropriate for something as complex and diverse as the interplay between cognitive function and human behavior. Finally, the next generations of cognitive testing are described. Testing via the telephone has just been introduced and will have dramatic effects on the logistics of conducting cognitive testing in large patient trials. Testing via the Internet is not far off either, and will come fully into play as the proportion of homes connected to the Internet increases in Europe and North America. There are no sound reasons for not wishing to include cognitive function testing in the development protocol of any novel medicine.     

Partial remission,residual symptoms,and relapse in depression

Partial remission from depression, with residual symptoms, is an important problem in depression. This paper reviews the frequency and features of this outcome, and its association with relapse. Residual symptoms occur in many depressed patients after acute treatment. They span the typical symptoms of depression, except those characteristic of severe disorders. Other persistent abnormalities include social dysfunction, dysfunctional attitudes, hypothalamic-pituitary-adrenal axis overactivity, shortened REM sleep latency, and mood lowering after tryptophan depletion. Associations of some of these with residual symptoms are not clear. There is growing evidence for similar residual symptoms in bipolar disorder, particularly bipolar depression. The most important consequence of residual symptoms is a much-increased risk of relapse, particularly in the first year. Residual symptoms are a strong indication for vigorous and longer than usual continuation of antidepressant treatment, in order to prevent relapse. There is good evidence for the use of cognitive therapy as an adjunct.     

Neuroimaging in anxiety disorders

Over the last few years, neuroimaging techniques have contributed greatly to the identification of the structural and functional neuroanatomy of anxiety disorders. The amygdala seems to be a crucial structure for fear and anxiety, and has consistently been found to be activated in anxiety-provoking situations. Apart from the amygdala, the insula and anterior cinguiate cortex seem to be critical, and ail three have been referred to as the "fear network." In the present article, we review the main findings from three major lines of research. First, we examine human models of anxiety disorders, including fear conditioning studies and investigations of experimentally induced panic attacks. Then we turn to research in patients with anxiety disorders and take a dose look at post-traumatic stress disorder and obsessive-compulsive disorder. Finally, we review neuroimaging studies investigating neural correlates of successful treatment of anxiety, focusing on exposure-based therapy and several pharmacological treatment options, as well as combinations of both.     

Epidemiology of mental disorders in children and adolescents

This article provides a review of the magnitude of mental disorders in children and adolescents from recent community surveys across the world. Although there is substantial variation in the results depending upon the methodological characteristics of the studies, the findings converge in demonstrating that approximately one fourth of youth experience a mental disorder during the past year, and about one third across their lifetimes. Anxiety disorders are the most frequent conditions in children, followed by behavior disorders, mood disorders, and substance use disorders. Fewer than half of youth with current mental disorders receive mental health specialty treatment. However, those with the most severe disorders tend to receive mental health services. Current issues that are now being identified in the field of child psychiatric epidemiology include: refinement of classification and assessment, inclusion of young children in epidemiologic surveys, integration of child and adult psychiatric epidemiology, and evaluation of both mental and physical disorders in children.     

Constructive memory: past and future

Human memory is not a literal reproduction of the past, but instead relies on constructive processes that are sometimes prone to error and distortion. Understanding of constructive memory has accelerated during recent years as a result of research that has linked together its cognitive and neural bases. This article focuses on three aspects of constructive memory that have been the target of recent research: (i) the idea that certain kinds of memory distortions reflect the operation of adaptive cognitive processes that contribute to the efficient functioning of memory; (ii) the role of a constructive memory system in imagining or simulating possible future events; and (iii) differences between true and false memories that have been revealed by functional neuroimaging techniques. The article delineates the theoretical implications of relevant research, and also considers some clinical and applied implications.     

Neural systems underlying approach and avoidance in anxiety disorders

Approach-avoidance conflict is an important psychological concept that has been used extensively to better understand cognition and emotion. This review focuses on neural systems involved in approach, avoidance, and conflict decision making, and how these systems overlap with implicated neural substrates of anxiety disorders. In particular, the role of amygdala, insula, ventral striatal, and prefrontal regions are discussed with respect to approach and avoidance behaviors. Three specific hypotheses underlying the dysfunction in anxiety disorders are proposed, including: (i) over-representation of avoidance valuation related to limbic overactivation; (ii) under- or over-representation of approach valuation related to attenuated or exaggerated striatal activation respectively; and (iii) insufficient integration and arbitration of approach and avoidance valuations related to attenuated orbitofrontal cortex activation. These dysfunctions can be examined experimentally using versions of existing decision-making paradigms, but may also require new translational and innovative approaches to probe approach-avoidance conflict and related neural systems in anxiety disorders.     

Endophenotypes in the personality disorders

The identification of endophenotypes in the personality disorders may provide a basis for the identification of underlying genotypes that influence the traits and dimensions of the personality disorders, as well as susceptibility to major psychiatric illnesses. Clinical dimensions of personality disorders that lend themselves to the study of corresponding endophenotypes include affective instability, impulsivity, aggression, emotional information processing, cognitive disorganization, social deficits, and psychosis. For example, the propensity to aggression can be evaluated by psychometric measures, interview, laboratory paradigms, neurochemical imaging, and pharmacological studies. These suggest that aggression is a measurable trait that may be related to reduced serotonergic activity. Hyperresponsiveness of amygdala and other limbic structures may be related to affective instability, while structural and functional brain alterations underlie the cognitive disorganization in psychotic-like symptoms of schizotypal personality disorder. Thus, an endophenotypic approach not only provides clues to underlying candidate genes contributing to these behavioral dimensions, but may also point the way to a better understanding of pathophysiological mechanisms.     

Treatment of affective disorders in cardiac disease

Patients with cardiovascular disease (CVD) commonly have syndromal major depression, and depression has been associated with an increased risk of morbidity and mortality. Prevalence of depression is between 17% and 47% in CVD patients. Pharmacologic and psychotherapeutic interventions have long been studied, and in general are safe and somewhat efficacious in decreasing depressive symptoms in patients with CVD. The impact on cardiac outcomes remains unclear. The evidence from randomized controlled clinical trials indicates that antidepressants, especially selective serotonin uptake inhibitors, are overwhelmingly safe, and likely to be effective in the treatment of depression in patients with CVD. This review describes the prevalence of depression in patients with CVD, the physiological links between depression and CVD, the treatment options for affective disorders, and the clinical trials that demonstrate efficacy and safety of antidepressant medications and psychotherapy in this patient population. Great progress has been made in understanding potential mediators between major depressive disorder and CVD—both health behaviors and shared biological risks such as inflammation.     

Mental disorders in primary care

Current estimates indicate that 50% of the population experience at least one mental disorder in their lifetime and that at least 25% have suffered a mental disorder in the past year. recognition, diagnosis, treatment, and referral depend overwhelmingly on general practitioners, at least one third of whose consultations have a direct and explicit psychological component. Yet despite this intensive familiarization with the presentation of mental pathology, and the appropriateness of the primary care setting to its management, even the most recent surveys indicate that performance is best described by the rule of diminishing halves: only half the patients with a thresh-old disorder are recognized; only half of those recognized are treated; and only half of those treated are effectively treated. There is no single solution to this problem, only multiple solutions, which must be aimed, consistently and simultaneously, at the patient, practitioner, practice, and research levels.     

Role of DNA methylation and the DNA methyltransferases in learning and memory

Dynamic regulation of chromatin structure in postmitotic neurons plays an important role in learning and memory. Methylation of cytosine nucleotides has historically been considered the strongest and least modifiable of epigenetic marks. Accumulating recent data suggest that rapid and dynamic methylation and demethylation of specific genes in the brain may play a fundamental role in learning, memory formation, and behavioral plasticity. The current review focuses on the emergence of data that support the role of DNA methylation and demethylation, and its molecular mediators in memory formation.