Showing papers in "Dialogues in Clinical Neuroscience in 2005"

Environmental programming of stress responses through DNA methylation: life at the interface between a dynamic environment and a fixed genome.

Abstract: Early experience permanently alters behavior and physiology. These effects are, in part, mediated by sustained alterations in gene expression in selected brain regions. The critical question concerns the mechanism of these environmental “programming” effects. We examine this issue with an animal model that studies the consequences of variations in mother-infant interactions on the development of individual differences in behavioral and endocrine responses to stress in adulthood. Increased levels of pup licking/grooming by rat mothers in the first week of life alter DNA structure at a glucocorticoid receptor gene promoter in the hippocampus of the offspring. Differences in the DNA methylation pattern between the offspring of high- and low-lickinglgrooming mothers emerge over the first week of life; they are reversed with cross-fostering; they persist into adulthood; and they are associated with altered histone acetylation and transcription factor (nerve growth factor-induced clone A [NGFIA]) binding to the glucocorticoid receptor promoter. DNA methylation alters glucocorticoid receptor expression through modifications of chromatin structure. Pharmacological reversal of the effects on chromatin structure completely eliminates the effects of maternal care on glucocorticoid receptor expression and hypothalamic-pituitary-adrenal (HPA) responses to stress, thus suggesting a causal relation between the maternally induced, epigenetic modification of the glucocorticoid receptor gene and the effects on stress responses in the offspring. These findings demonstrate that the structural modifications of the DNA can be established through environmental programming and that, in spite of the inherent stability of this epigenomic marker, it is dynamic and potentially reversible.

Environmental risk factors for psychosis.

Abstract: Genetic factors are clearly important in the etiology of schizophrenia, but the environment in which an individual's genes find expression is also crucial to the development of the illness. In this review of environmental risk factors for schizophrenia, we consider risks operating prenatally and perinatally, during childhood, and then later in life prior to illness onset Some of these risk factors have been well documented, for example, early hazards causing fetal growth retardation or hypoxia, and hazards nearer the onset of illness like drug abuse and migration. Others are much less certain. The importance of interaction between genetic and environmental risk is, however, undoubtedly important and there is emerging evidence for this from a range of sources. As the etiology of schizophrenia is unraveled, the picture becomes more complex, but also more obviously relevant to the plight of the individual patient.

The use of neurophysiological endophenotypes to understand the genetic basis of schizophrenia.

Abstract: Specifying the complex genetic architecture of the "fuzzy" clinical phenotype of schizophrenia is an imposing problem. Utilizing metabolic, neurocognitive, and neurophysiological "intermediate" endophenotypic measures offers significant advantages from a statistical genetics standpoint. Endophenotypic measures are amenable to quantitative genetic analyses, conferring upon them a major methodological advantage compared with largely qualitative diagnoses using the Diagnostic and Statistical Manual of Mental Health, 4th Edition (DSM-IV). Endophenotypic deficits occur across the schizophrenia spectrum in schizophrenia patients, schizotypal patients, and clinically unaffected relatives of schizophrenia patients. Neurophysiological measures, such as P50 event-related suppression and the prepulse inhibition (PPI) of the startle response, are endophenotypes that can be conceptualized as being impaired because of a single genetic abnormality in the functional cascade of DNA to RNA to protein. The "endophenotype approach" is also being used to understand other medical disorders, such as colon cancer, hemochromatosis, and hypertension, where there is interplay between genetically conferred vulnerability and nongenetic stressors. The power and utility of utilizing endophenotypes to understand the genetics of schizophrenia is discussed in detail in this article.

Sleep and psychiatry.

Abstract: Psychiatric disorders constitute 15.4% of the disease burden in established market economies. Many psychiatric disorders are associated with sleep disturbances, and the relationship is often bidirectional. This paper reviews the prevalence of various psychiatric disorders, their clinical presentation, and their association with sleep disorders. Among the psychiatric disorders reviewed are affective disorders, psychosis, anxiety disorders (including post-traumatic stress disorder), substance abuse disorders, eating disorders, and attention deficit/hyperactivity disorders. The spectrum of associated sleep disorders includes insomnia, hypersomnia, nocturnal panic, sleep paralysis, hypnagogic hallucinations, restless legs/periodic limb movements of sleep, obstructive sleep apnea, and parasomnias. The effects on sleep of various psychotropic medications utilized to treat the above psychiatric disorders are summarized.

Alcoholism: the dissection for endophenotypes

Abstract: Alcohol dependence (alcoholism) is a complex disorder attributed to the interaction of genetic and environmental factors that form a collage of "disease" predisposition, which is not identical for every alcohol-dependent individual. There is considerable evidence to demonstrate that genetic predisposition accounts for roughly half the risk in the development of alcohol dependence. Both family and population studies have identified a number of genomic regions with suggestive links to alcoholism, yet there have been relatively few definitive findings with regard to genetic determinants of alcoholism. This ambiguity can be attributed to a multitude of complications of studying complex mental disorders, such as clinical heterogeneity, polygenic determinants, reduced penetrance, and epistatic effects. Complex mental disorders are clinical manifestations described by combinations of various signs and symptoms. One approach to overcoming the ambiguity in studying the association between genetic risk factors and disease is to dissect the complex, heterogeneous disorder by using intermediate phenotypes--or endophenotypes--to generate more homogeneous diagnostic groupings than an all-encompassing definition, such as the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-derived term "alcohol dependence" or the commonly used term "alcoholism." The advantage of using endophenotypes is that the number of influential factors that contribute to these characteristics should be fewer and more easily identified than the number of factors affecting the heterogeneous entity of alcohol dependence (alcoholism). A variety of alcohol-related characteristics have been investigated in epidemiological, clinical, and basic research as potential endophenotypes of alcohol dependence. These include phenotypes related to alcohol metabolism, physiological and endocrine measures, neural imaging, electrophysiology, personality, drinking behavior, and responses to alcohol and alcohol-derived cues. This review summarizes the current literature, focused on human data, of promising endophenotypes for dissecting alcoholism.

Intermediate phenotypes in schizophrenia: a selective review.

Abstract: Studies aiming to identify susceptibility genes for schizophrenia and other complex psychiatric disorders are faced with the confounds of subjective clinical criteria, commonly occurring phenocopies, significant between-subject variability of candidate traits, and the likelihood of allelic and locus heterogeneity that has been shown to define the genetics of other complex human brain and somatic disorders. Additionally, research aimed at identification of the molecular origins of schizophrenia must also deal with the confounding nature of the human brain. Unlike organs with a few common cellular phenotypes, transcriptomes, and proteomes, individual neurons are often distinct from one another in all of these respects. In this review, we present recent work testing the assumption that studies of genetic susceptibility in complex polygenic disorders such as schizophrenia might be enhanced by the identification of intermediate phenotypes related to more fundamental aspects of brain development and function. Progress in the identification of meaningful intermediate phenotypes in schizophrenia has been made possible by the advent of newer methods in cognitive neuroscience and neuroimaging, and the use of combined multimodal techniques.

The pharmacological management of depression

Abstract: Depressive disorders are common, recurrent, and chronic, and require treatment A review of the symptom picture and current drug targets demonstrates the need for accurate assessment of depression severity, including suicidality. The initial focus of treatment is rapid resolution of symptoms during an acute phase, followed by continuation. Maintenance treatment is indicated if the risk of recurrence is high. The range of available medications is considerable and the benefit/risk ratio is acceptable. Depression is diagnosable across the life span and treatable at every age (although recent disagreement has arisen with regard to young patients). Comorbidity, both psychiatric and medical, need to be assessed, as does the possible presence of two subtypes of depression (psychotic and bipolar) often requiring different interventions. It is expected that the next generation of antidepressants would be associated with more specific disease and outcome biomarkers.

Genetic bases for endophenotypes in psychiatric disorders.

Abstract: This article reviews the concept of an endophenotype, with particular reference to heritability as well as diagnostic specificity. An endophenotype need not be heritable, for example, the possible influence of in utero viral infections for schizophrenia. However, heritability is a useful characteristic for a potential endophenotype, as it can be studied in relation to a plausible candidate gene. It should be noted that the traditional methods of demonstrating heritability eg, twin studies, can be supplemented with DNA sequence studies, suggesting heritability. Endophenotypes need not be specific to a given nosological class of psychiatric disorders, as these classes do not reflect biological categories. Evidence for two useful schizophrenia endophenotypes, the P50 abnormalities and cognitive deficits, is summarized.

Toward a world consensus on prevention of schizophrenia.

Abstract: Screening for preschizophrenia in the general population with the aim of preventing transition to full-blown illness is an epidemiological impossibility because a rare disease cannot be predicted. The lack of specificity resulting in abundance of false-positives can be remedied in part by using much more restrictive screening criteria that combine several indicators of risk for transition to schizophrenia. Raising the specificity (reducing the false-positives), however, can only be done at the expense of sensitivity (increasing the false-negatives). The most commonly used strategy to raise specificity is the sample enrichment strategy. This involves the creation of samples enriched with schizophrenia risk by selectively filtering at-risk people out over a range of consecutive referral processes starting in the general population, through to general practioners, mental health services, and the early detection clinic. However, improvements in specificity obtained by the sample enrichment strategy should not be attributed to the use of some predictive instrument that supposedly identifies high-risk individuals. The epidemiologically and ethically most viable way for screening and early detection is to selectively increase the permeability of the filters on the pathway to mental health care. This will occasion samples of help-seekers enriched with schizophrenia risk at the level of mental health services (thus reducing false-positives), while at the same time making an attempt to "attract" as many detectable schizophrenia prodromes as possible through the filters along the pathway to mental health care (thus reducing false-negatives). Early psychosis research has yielded some useful suggestions in that it is becoming increasingly clear that it is not just psychosis itself, but rather the clinical context of the psychotic experience that determines risk for transition to schizophrenia. Thus, risk for transition to full-blown psychotic disorder is to a large degree determined by size of psychosis "load," comorbid distress and depression, cannabis use, cognitive ability, and subjective reports of impairment and coping. Making a diagnosis of psychotic disorder is not an exact science: it involves an arbitrary cutoff imposed on dimensional variation of psychopathology and need for care over time. Gaining insight into the cognitive and biological factors that drive the dimensional variation, including therapeutic interventions, is arguably more useful than sterile dichotomous prediction models.

The AGNP-TDM Expert Group Consensus Guidelines: focus on therapeutic monitoring of antidepressants.

Abstract: Therapeutic drug monitoring (TDM) of psychotropic drugs such as antidepressants has been widely introduced for optimization of pharmacotherapy in psychiatric patients The interdisciplinary TDM group of the Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) has worked out consensus guidelines with the aim of providing psychiatrists and TDM laboratories with a tool to optimize the use of TDM Five research-based levels of recommendation were defined with regard to routine monitoring of drug plasma concentrations: (i) strongly recommended; (ii) recommended; (iii) useful; (iv) probably useful; and (v) not recommended In addition, a list of indications that justify the use of TDM is presented, eg, control of compliance, lack of clinical response or adverse effects at recommended doses, drug interactions, pharmacovigilance programs, presence of a genetic particularity concerning drug metabolism, and children, adolescents, and elderly patients For some drugs, studies on therapeutic ranges are lacking, but target ranges for clinically relevant plasma concentrations are presented for most drugs, based on pharmacokinetic studies reported in the literature For many antidepressants, a thorough analysis of the literature on studies dealing with the plasma concentration-clinical effectiveness relationship allowed inclusion of therapeutic ranges of plasma concentrations In addition, recommendations are made with regard to the combination of pharmacogenetic (phenotyping or genotyping) tests with TDM Finally, practical instructions are given for the laboratory practitioners and the treating physicians how to use TDM: preparation of TDM, drug analysis, reporting and interpretation of results, and adequate use of information for patient treatment TDM is a complex process that needs optimal interdisciplinary coordination of a procedure implicating patients, treating physicians, clinical pharmacologists, and clinical laboratory specialists These consensus guidelines should be helpful for optimizing TDM of antidepressants

Cognitive impairment as a risk factor for psychosis.

Abstract: Since the time of Kraepelin and Bleuler, it has been recognized that schizophrenia is associated with a profound and persistent cognitive impairment. This paper reviews the major clinical and epidemiological studies of cognitive functioning in schizophrenia and other psychotic disorders, and presents several possible models to explain the association between cognitive impairment and psychosis. Cognitive impairment is present in the majority of patients with schizophrenia, and, in some, it is already evident in the premorbid stages of the disorder. This cognitive impairment is not secondary to psychotic symptoms, negative symptoms, or socioeconomic status. Cognitive impairment can also be observed in nonpsychotic family members of psychotic patients. On the basis of this evidence, it has been proposed that abnormal cognitive functioning can be considered as a possible causal risk factor for psychosis. Recent studies assessing the relationship between genetic background, cognition, brain function, and schizophrenia are presented here as an outline for future research.

Interpreting the association between cannabis use and increased risk for schizophrenia.

Abstract: Recent longitudinal studies from Sweden, the Netherlands, New Zealand, and Israel report that cannabis use during childhood and adolescence doubles the risk of later appearance of psychosis or schizophrenia, These data have been interpreted as indicating that cannabis has a causal effect along the pathway to psychosis. In this paper, we will offer an alternative explanation of these data. Recent investigations of patients with schizophrenia found increased density of cannabinoid receptors in the dorsolateral prefrontal cortex and the anterior cingulate cortex. Others reported higher levels of endogenous cannabinoids in the blood and cerebrospinal fluid of patients; these findings were independent of possible cannabis use. Several genetic studies have reported an association between genes encoding the cannabinoid receptor and schizophrenia. Thus, an alternative explanation of the association between cannabis use and schizophrenia might be that pathology of the cannabinoid system in schizophrenia patients is associated with both increased rates of cannabis use and increased risk for schizophrenia, without cannabis being a causal factor for schizophrenia.

Endophenotypes in the personality disorders

Abstract: 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 impulsiwity 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 psychoticlike 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.

Early biomarkers of psychosis.

Abstract: Biological traits that are predictive of the later development of psychosis have not yet been identified. The complex, multidetermined nature of schizophrenia and other psychoses makes it unlikely that any single biomarker will be both sensitive and specific enough to unambiguously identify individuals who will later become psychotic. However, current genetic research has begun to identify genes associated with schizophrenia, some of which have phenotypes that appear early in life. While these phenotypes have low predictive power for identifying individuals who will become psychotic, they do serve as biomarkers for pathophysiological processes that can become the targets of prevention strategies. Examples are given from work on the role of the alpha(T)nicotinic receptor and its gene CHRNA7 on chromosome 15 in the neurobiology and genetic transmission of schizophrenia.

Psychiatric aspects of organic sleep disorders.

Abstract: In recent years, a number of studies have attempted to characterize psychological disturbances related to various sleep disorders. The objective of this type of research is to investigate the possibility that psychopathology may represent an etiological factor, a complication, and/or a target for treatment. In addition, disordered sleep can present itself in a complex and atypical fashion in which the primary sleep-related component may not be immediately apparent. This article reviews the evidence for a relationship between organic sleep disorders and psychiatric morbidity. Generally, it can be concluded that organic sleep disorders have a profound negative impact on most domains of health-related quality of life. Results for the sleep disorders that have been studied (narcolepsy idiopathic hypersomnia, sleep apnea/hypopnea syndrome, restless legs syndrome, periodic limb movement disorder, and circadian sleep disorders) show strong evidence for an association with mood disorders. After treatment, depression scores may or may not improve to the level of population norms, suggesting that this relationship is more complex than one of mere cause and effect.

Dose-response relationship of recent antidepressants in the short-term treatment of depression.

Abstract: Antidepressant drugs are widely recommended for the treatment of depressive disorders, and finding the “right dose for the right patient” is an important issue Whatever antidepressant is prescribed, a proportion of adult patients with major depression fail to respond satisfactorily to adequate first-line treatment A frequent strategy for patients with insufficient response to an initial antidepressant dose is to increase the dose This review is about this strategy ie, the possible benefits of prescribing higher doses of recent antidepressants The results show that a flat dose-response curve is a class phenomenon for selective serotonin reuptake inhibitors (SSRIs), according to randomized, controlled, fixed-dose clinical trials For the serotonin and noradrenaline reuptake inhibitors (SNRIs), the strategy of dose increase may be relevant for venlafaxine, in order to increase the number of responders Thus, the subgroup of patients for whom high doses of SSRIs could be useful remains to be defined

The possible contribution of neuronal nicotinic acetylcholine receptors in depression.

Abstract: Although tobacco use and smoking were introduced long ago, it was only recently that the nicotine contained in the tobacco leaves was recognized as an addictive substance acting on the central nervous system (CNS). However, even prior to this recognition, several studies have reported an association between smoking and psychiatric disorders. One of the many observations was that cessation is accompanied by a marked increase in the probability of major depression. In parallel with the discovery of the neuronal nicotinic acetylcholine receptors and their extensive expression in the CNS, this association sheds new light on the influence of cholinergic transmission in depression. In this article, we examine the various modes of action of nicotine in the CNS and discuss the mechanisms by which this alkaloid can prevent or precipitate mood disorders, and the possibility of discovering new therapeutic avenues for the treatment of depression.

Pharmacogenomics in depression and antidepressants

Abstract: Genetic factors are believe y a major role in the variation of treatment response and the incidence of adverse effects to medication. The aim of pharmacogenetics is to elucidate this variability according to hereditary differences. Considering current hypotheses for the mechanisms of action of antidepressants, most investigations to date have concentrated on mutations in genes coding either for the pathways in the serotonergic and noradrenergic systems or for drug-metabolizing enzymes. Recent studies shifted the emphasis on the mains mechanism of drug action from changes in neurotransmitter concentration or receptor function toward long-lasting adaptive processes within the neurons. Although the results are controversial, many studies support the hypothesis that psychopharmacogenetics will help predict an individual's drug response, while minimizing the side effects. The inclusion of functional genomics, investigate the complex gene and/or protein expression in response to a given drug, may lead to the development of novel and safer drugs.

Neuroendocrine predictors of the evolution of depression

Abstract: Depression is both clinically and biologically a heterogeneous entity. Despite advances in psychopharmacology, a significant proportion of depressed patients either continue to have residual symptoms or do not respond to antidepressants. It has therefore become essential to determine parameters (or predictors) that would rationalize the therapeutic choice, taking into account not only the clinical features, but also the "biological state," which is a major determinant in the antidepressant response. Such predictors can derive from bioclinical correlates and, in this context, the neuroendocrine strategy appears particularly suited. Numerous studies have investigated neuroendocrine parameters--derived mainly from dynamic challenge tests--in order to (i) determine the predictive profiles of good clinical responders to given antidepressants; (ii) monitor the progression of markers in parallel with the clinical outcome; and (iii) evaluate "in vivo" in humans the mechanisms of action of antidepressant compounds (before, during, and after treatment). This article does not attempt to be exhaustive, but rather uses selected examples to illustrate the usefulness of the investigation of the adrenal and thyroid axes and the assessment of central serotonergic, noradrenergic, and dopaminergic systems by means of neuroendocrine tests. Given methodological constraints, most of these investigations--except for baseline hormone values and the dexamethasone suppression test--cannot be used routinely in psychiatry. Despite these limitations, the neuroendocrine strategy still offers new insights in biology and the treatment of depression. Its possible expansion depends mainly on the development of specific agonists or antagonists for better investigation of the receptors supposedly involved in the pathophysiology of depression. These investigations will help define more homogeneous subgroups from a bioclinical and therapeutic viewpoint.

Antidepressants and psychotherapy: a clinical research review.

Abstract: This review focuses on information concerning antidepressants and psychotherapy in the treatment of both acute and chronic forms of unipolar depression in the English language literature. In it, we address the use of combination therapy, both from the outset of treatment and in a variety of sequences, ie, we examine the potential advantages of adding a targeted psychotherapy to an incompletely effective pharmacotherapy and the potential advantages of adding pharmacotherapy to an incompletely effective psychotherapy. The number of research reports available to address these questions is small relative to their importance for clinical practice. There is a clear need for more information about the relative efficacy of pharmacotherapy-psychotherapy combinations or sequences versus either pharmacotherapy or psychotherapy provided as monotherapies.

Treating early psychosis: who, what, and when?

Abstract: Early intervention and prevention in schizophrenia is just over 10 years old. The assumption guiding this field is that intervention is likely to be most effective if it begins before psychosis sets in, ie, during the prodromal phase. Although a substantial number of prodromal treatment programs have been initiated around the world, three early programs have generated most of the intervention findings to date: Personal Assessment and Crisis Evaluation (PACE) in Australia, and the Prevention through Risk Identification, Management, and Education (PRIME) and Recognition and Prevention (RAP) programs in the USA. The data suggest that early intervention leads to a reduction in prodromal symptoms and clinical distress. However, prevention of psychosis remains an unresolved question. Other issues include defining who should be treated, with what, and when. In addition, treatment targets associated with functional disability, such as early prodromal negative symptoms and risk factors, continue to emerge. Newly identified targets, in turn, suggest the need for a variety of novel interventions and treatment strategies.

Alteration of sleep microstructure in psychiatric disorders.

Abstract: Macrostructure describes the temporal organization of sleep based on successive epochs of conventional length, while microstructure, which is analyzed on the basis of the scoring of phasic events, provides additional important dynamic characteristics in the evaluation of both normal and pathological sleep processes. Relationships between sleep, sleep disorders, and psychiatric disorders are quite complex, and it clearly appears that both the macrostructure and the microstructure of sleep are valuable physiologically and clinically. Psychiatric patients often complain about their sleep, and they may show sleep abnormalities that increase with the severity of their illness. Changes in the occurrence and frequency of phasic events during sleep may be associated with specific psychiatric disorders, and may provide valuable information for both diagnosis and prognosis of these disorders.

Contribution of sleep research to the development of new antidepressants.

Abstract: Several sleep anomalies are known to accompany depression and other psychiatric disorders, and to be partially modified by drugs efficient on clinical symptoms. Many puzzling theoretical questions remain, even after 30 years of research, because these drugs do not act in a uniform way: some reduce slow-wave sleep while others increase it; some prolong rapid-eye movement sleep latency while others do not. The relationship between insomnia and depression is likely to be a close one, since a large majority of patients with depression suffer insomnia, and that insomnia can predate depression by a few years. However, questions remain here, too, since sleep deprivation is also an effective means to combat depression, and some patients present with hypersomnia rather than insomnia. This review details the action of all current classes of antidepressants on sleep. It examines the predictive value of baseline electronencephalographic sleep symptoms or early modifications due to treatment for eventual clinical efficiency. We will also discuss the two main theories on the relationship between sleep and depression. The action on sleep of all new drugs- and antidepressants in particular - is carefully examined during development, for insomnia is currently considered to be a major health concern in industrialized countries.

Behavioral and psychiatric consequences of sleep-wake schedule disorders.

Abstract: Circadian rhythm sleep disorders (CRSDs) arise when an individual's sleep-wake rhythm mismatches the environmental 24-h schedule. Physiological data and genetic studies in patients with CRSDs suggest that these disorders result from abnormal functioning of the circadian timing system. Diagnosis involves recognition of the characteristics of CRSDs, which can be achieved by clinical interview and actigraphic monitoring of rest-activity patterns. Bright-light therapy and melatonin administration have proved to be the most effective treatment modalities of CRSDs. In psychiatric practice, CRSDs can be encountered on various occasions. Some evidence indicates that a deviant sleep-wake schedule might be a predisposing factor to personality disorders. CRSDs can emerge as an iatrogenic effect of certain psychoactive drugs, such as haloperidol and fluvoxamine. It is not uncommon that the daytime functional difficulties that accompany CRSDs are misinterpreted as symptoms of psychopathology. Recognition and awareness of these disorders should prevent years of erroneous diagnosis and treatment in these patients.

The treatment of schizophrenia: from premorbid manifestations to the first episode of psychosis.

Abstract: To achieve the best therapeutic results in schizophrenia - like most other disorders - primary prevention is preferable to early and prompt treatment, which, in turn, is preferable to treatment of chronically established illness. Unfortunately, there currently exist no accurate makers that can provide information regarding the future course of illness and guide treatment in asymptomatic or mildly symptomatic individuals. Therefore, most treatment efforts are currently focused on patients who have already experienced their first psychotic episode. This paper reviews the efforts to identify accurate markers heralding psychotic illness, as well as treatment considerations in the early phase of the disease.

Sleep disturbances, psychiatric disorders, and psychotropic drugs

Abstract: Brain neurotransmitter dysfunctions involved in the pathophysiological processes of psychiatric disorders are likely to be reflected by concomitant alterations in sleep continuity and architecture. Since the corrective effects of psychotropic drugs on dysfunctional neurotransmission systems can be evidenced through polysomnographic recordings, one may consider sleep as a kind of “window” on the neurobiology of psychiatric disorders. During the last 10 years, major breakthroughs in our understanding of sleep-wake mechanisms have provided some indications on how psychotropic drugs could influence the sleep-wake cycle. In this review, recent inroads into the understanding of sleep regulatory neural mechanisms are introduced and discussed in terms of the effects of psychotropic drugs. The relationship between the patho-physiological process of a disease, its consequence on sleep, and the corrective effect of a psychotropic drug are exemplified by two psychopathological states: substance withdrawal and major depression. One may conclude that polysomnographic recordings are a unique noninvasive tool to analyze brain functioning, and are particularly well suited to evaluating the objective effects of new psychotropic drugs.

Ethology and the biological correlates of mood.

Abstract: The insights of ethology―the science of animal behavior from a biological and psychological point of view―were incorporated in the 1950s by the British developmental psychiatrist, John Bowlby, into his attachment theory which argued that a secure affective base in infancy was critical to the normal development of perception, cognition, learning, and emotion, in addition to that of physical parameters. The theory was illustrated by Harlow's pioneering experiments with baby monkeys: those raised with a wire-frame “mother” failed to thrive, compared with the more normal development of those deriving comfort contact from a terry-cloth surrogate. Modern neuroscience techniques have confirmed that the absence of sensory stimulation during periods of maximal synaptic expansion provides the substrate for a subsequent mood disorder, Ethology offers a novel “nature plus nurture” approach to the development of abnormal mood, as well as a target for treatment.

Neuroimaging the genetic effects of brain-derived neurotrophic factor on human hippocampus

Abstract: The genetic determinants of human brain function have long been elusive, but are now beginning to emerge. The conjunction of the sequencing of the human genome (ie, the discovery of all genes) with the development of new neuroimaging techniques has produced an astonishing leap forward in our ability to detect the effects of genes on neurobiological processes. This poster focuses on a prototypical study of the gene for brain-derived neurotrophic factor (BDNF), showing its role in human hippocampal function and memory.