Human models as tools in the development of psychotropic drugs

Despite the growing means devoted to research and development (R α D) and refinements in the preclinical stages, the efficiency of central nervous system (CMS) drug development is disappointing. Many drugs reach patient studies with an erroneous therapeutic indication andlor in incorrect doses. Apart from the first clinical studies, which are conducted in healthy volunteers and focus only on safety, iolerability, and pharmacokinetics, drug development mostly relies on patient studies. Psychiatric disorders are characterized by heterogeneity and a high rate of comorbidity. It is becoming increasingly difficult to recruit patients for clinical trials and there are many confounding factors in this population, for example, those related to treatments. In order to keep patient exposure and financial expenditure to a minimum, it is important to avoid ill-designed and inconclusive studies. This risk could be minimized by gathering pharmacodynamic data earlier in development and considering that the goal of a phase 1 plan is to reach patient studies with clear ideas about the compound's pharmacodynamic profile, its efficacy in the putative indication (proof of concept), and pharmacokinetic/pharmacodynamic relationships, in addition to safety, tolerability, and pharmacokinetics. Human models in healthy volunteers may be useful tools for this purpose, but their use necessitates a global adaptation of the phase scheme, favoring pharmacodynamic assessments without neglecting safety. We are engaged in an R α D program aimed to adapt existing models and develop new paradigms suitable for early proof of concept substantiation.     

The therapeutic transnosological use of psychotropic drugs

The current clinical use of psychotropic drugs is transnosologically oriented. This is facilitated by the current classification of mental disorders (International Classification of Diseases, 10th Revision [ICD-10]) and is perhaps justified if depression and psychosis (taken here as examples) are considered as being complex syndromes with heterogeneous etiologies, but common pathogenesis, more than specific entities. However, this approach does not identify possible differences between specific psychiatric entities, which could in turn mask differences in therapeutic responses and, therefore, therapeutic outcome. This is compounded by the current disharmony between the nosological classification of diseases, drug development, clinical research, and therapeutic uses of psychotropic drugs. Functional pharmacology targeting abnormal behavioral traits could represent an avenue for future research and treatment.     

Sleep disturbances, psychiatric disorders, and psychotropic drugs

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 pathophysiological 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.     

The genetics of obsessive-compulsive disorder: a review

Obsessive-compulsive disorder (OCD) is a serious psychiatric disorder that affects approximately 2% of the populations of children and adults. Family aggregation studies have demonstrated that OCD is familial, and results from twin studies demonstrate that the familiality is due in part to genetic factors. Only three genome-wide linkage studies have been completed to date, with suggestive but not definitive results. In addition, over 80 candidate gene studies have been published. Most of these studies have focused on genes in the serotonergic and dopaminergic pathways. Unfortunately, none have achieved genome-wide significance, and, with the exception of the glutamate transporter gene, none have been replicated. Future research will require the collaboration of multidisciplinary teams of investigators to (i) achieve sufficiently large samples of individuals with OCD; (ii) apply the state-of-the-art laboratory techniques; and ( iii) perform the bioinformatic analyses essential to the identification of risk loci.     

Simultaneous EEG and fMRI: towards the characterization of structure and dynamics of brain networks

Progress in the understanding of normal and disturbed brain function is critically dependent on the methodological approach that is applied. Both electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) are extremely efficient methods for the assessment of human brain function. The specific appeal of the combination is related to the fact that both methods are complementary in terms of basic aspects: EEG is a direct measurement of neural mass activity and provides high temporal resolution. FMRI is an indirect measurement of neural activity and based on hemodynamic changes, and offers high spatial resolution. Both methods are very sensitive to changes of synaptic activity, suggesting that with simultaneous EEG and fMRI the same neural events can be characterized with both high temporal and spatial resolution. Since neural oscillations that can be assessed with EEG are a key mechanism for multi-site communication in the brain, EEG-fMRI can offer new insights into the connectivity mechanisms of brain networks.     

Contribution of sleep research to the development of new antidepressants

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 con-insomnia is currently considered to be a major health concern in industrialized countries.     

Sleep-wake mechanisms and drug discovery: sleep EEG as a tool for the development of CNS-acting drugs

Sleep laboratory investigations constitute a unique noninvasive tool to analyze brain functioning, Polysomnographic recordings, even in the very early phase of development in humans, are mandatory in a developmental plan of a new sleep-acting compound. Sleep is also an interesting tool for the development of other drugs acting on the central nervous system (CNS), Indeed, changes in sleep electroencephalographic (EEG) characteristics are a very sensitive indication of the objective central effects of psychoactive drugs, and these changes are specific to the way the drug acts on the brain neurotransmitter systems. Moreover, new compounds can be compared with reference drugs in terms of the sleep EEG profile they induce. For instance, cognitive enhancers involving cholinergic mechanism have been consistently demonstrated to increase rapid eye movement (REM) sleep pressure, and studying drug-induced slow wave sleep (SWS) alteration is a particularly useful tool for the development of CNS compounds acting at the 5-HT(2A/C) receptor, such as most atypical antipsychotics and some antidepressant drugs. The sleep EEG profile of antidepressants, and particularly their effects on REM sleep, are specific to their ability to enhance noradrenergic or serotonergic transmission, it is suggested that the effects of noradrenergic versus serotonergic reuptake inhibition could be disentangled using specific monoamine depletion tests and by studying drug effects on sleep microsiructure.     

Genetics of drug dependence

Drug-dependence disorders (we focus here on cocaine, opioid, and nicotine dependence) are genetically influenced. Risk genes have been located based primarily on genetic linkage studies, and identified primarily based on genetic association studies. In this article we review salient results from linkage, association, and genome-wide association study methodologies, and discuss future prospects for risk allele identification based on these, and on newer, methodologies. Although considerable progress has been made, it is likely that the application of more extensive sequencing than has previously been practical will be required to identify a fuller range of risk variants.     

The genetic epidemiology of personality disorders

Genetic epidemiologic studies indicate that all ten personality disorders (PDs) classified on the DSM-IV axis II are modestly to moderately heritable. Shared environmental and nonadditive genetic factors are of minor or no importance. No sex differences have been identified. Multivariate studies suggest that the extensive comorbidity between the PDs can be explained by three common genetic and environmental risk factors. The genetic factors do not reflect the DSM-IV cluster structure, but rather: i) broad vulnerability to PD pathology or negative emotionality; ii) high impulsivity/low agreeableness; and iii) introversion. Common genetic and environmental liability factors contribute to comorbidity between pairs or clusters of axis I and axis II disorders. Molecular genetic studies of PDs, mostly candidate gene association studies, indicate that genes linked to neurotransmitter pathways, especially in the serotonergic and dopaminergic systems, are involved. Future studies, using newer methods like genome-wide association, might take advantage of the use of endophenotypes.     

Biological predictors of pharmacological therapy in anxiety disorders

At least one third of patients with anxiety disorders do not adequately respond to available pharmacological treatment. The reason that some patients with anxiety disorders respond well, but others not, to the same classes of medication is not yet fully understood. It is suggested that several biological factors may influence treatment mechanisms in anxiety and therefore could be identified as possible biomarkers predicting treatment response. In this review, we look at current evidence exploring different types of treatment predictors, including neuroimaging, genetic factors, and blood-related measures, which could open up novel perspectives in clinical management of patients with anxiety disorders.     

Cognitive impairment as a risk factor for psychosis

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.     

Nature and nurture in neuropsychiatric genetics: where do we stand?

Both genetic and nongenetic risk factors, as well as interactions and correlations between them, are thought to contribute to the etiology of psychiatric and behavioral phenotypes. Genetic epidemiology consistently supports the involvement of genes in liability. Molecular genetic studies have been less successful in identifying liability genes, but recent progress suggests that a number of specific genes contributing to risk have been identified. Collectively, the results are complex and inconsistent, with a single common DNA variant in any gene influencing risk across human populations. Few specific genetic variants influencing risk have been unambiguously identified. Contemporary approaches, however, hold great promise to further elucidate liability genes and variants, as well as their potential inter-relationships with each other and with the environment. We will review the fields of genetic epidemiology and molecular genetics, providing examples from the literature to illustrate the key concepts emerging from this work.     

Attention deficit-hyperactivity disorder and early-onset bipolar disorder: two facets of one entity?

Early-onset bipolar disorder (BD) and attention-deficithyperactivity disorder (ADHD) have recently been the subject of highly controversial debate, due to theories regarding underlying pathophysiological processes and a clinical overlap of symptoms. Epidemiological data, clinical aspect, neuroimaging, neurochemical, and genetic studies suggest that there may be a possible relationship between biological factors and clinical characteristic in the development of symptoms. However, longitudinal data supporting the hypothesis of a diagnostic shift from BD to ADHD symptoms and vice versa are currently not available. These would be essential to enable further investigations into whether these two disorders possibly represent two different aspects of an underlying common psychopathophysioiogical entity.     

New findings in the genetics of major psychoses

Schizophrenia and bipolar disorder have a largely unknown pathophysiology and etiology, but they are highly heritable. Although linkage and association studies have identified a series of chromosomal regions likely to contain susceptibility genes, progress in identifying causative genes has been largely disappointing. However, rapid technological advances are beginning to lead to new insights. Systematic genome-wide association and follow-up studies have reported genome-wide significant association findings of common variants for schizophrenia and bipolar disorder. The risk conferred by individual variants is small, and some variants confer a risk for both disorders. In addition, recent studies have identified rare, large structural variants (copy number variants) that confer a greater risk for schizophrenia. This review summarizes recent developments in genetic research into schizophrenia and bipolar disorder, and discusses possible future directions in this field.     

Structure and function of complex brain networks

An increasing number of theoretical and empirical studies approach the function of the human brain from a network perspective. The analysis of brain networks is made feasible by the development of new imaging acquisition methods as well as new tools from graph theory and dynamical systems. This review surveys some of these methodological advances and summarizes recent findings on the architecture of structural and functional brain networks. Studies of the structural connectome reveal several modules or network communities that are interlinked by hub regions mediating communication processes between modules. Recent network analyses have shown that network hubs form a densely linked collective called a “rich club,” centrally positioned for attracting and dispersing signal traffic. In parallel, recordings of resting and task-evoked neural activity have revealed distinct resting-state networks that contribute to functions in distinct cognitive domains. Network methods are increasingly applied in a clinical context, and their promise for elucidating neural substrates of brain and mental disorders is discussed.     

Brain mechanisms of hallucinogens and entactogens

This review focuses on recent brain imaging and behavioral studies of sensory gating functions, which assess similarities between the effects of classic hallucinogens (eg, psilocybin), dissociative anesthetics (eg, ketamine), and entactogens (eg, 3,4-methylenedioxymethamphetamine [MDMA]) in humans. Serotonergic hallucinogens and psychotomimetic anesthetics produce overlapping psychotic syndromes associated with a marked activation of the prefrontal cortex (hyperfrontality) and other overlapping changes in temporoparietal, striatal, and thalamic regions, suggesting that both classes of drugs act upon a common final pathway. Together with the observation that both hallucinogens and N-methyl-oaspartate (NMDA) antagonists disrupt sensory gating in rats by acting on 5-hydroxytryptamine (serotonin) 5-HT(2) receptors located in cortico-striato-thalamic circuitry these findings suggest that disruption of cortico-subcortical processing leading to sensory overload of the cortex is a communality of these psychoses. In contrast to hallucinogens, the entactogen MDMA produces an emotional state of positive mood, concomitant with an activation of prefrontolimbiclparalimbic structures and a deactivation of amygdala and thalamus.     

Clinicians' predictions of patient response to psychotropic medications

Clinicians prescribe a medication when they assume that there is a reasonable probability of its success. There are many studies on the predictive value of social or clinical information, but these studies do not include the prognosis made by psychiatrists before treatment. These studies indicate that a small to moderate proportion of the total variance of outcome can be predicted from social or clinical information. It is peculiar that there are very few studies on the accuracy of psychiatrists' "bets" about the effects of psychotropic drugs when they use the clinical characteristics of patients as predictors, considering the practical relevance of predicting the outcome of a psychiatric treatment. The absence of studies on the accuracy of clinicians' bets or predictions in psychiatry is unfortunate.     

Anticonvulsant drugs in bipolar disorder

Although much progress has been made in successfully treating bipolar disorder, there is increasing awareness of the limitations of traditional treatment regimens such as lithium and neuroleptics. The large family of anticonvulsant drugs, however, appears to be capable of providing new treatment options, not only as medication of second choice in patients refractory to treatment, but often as a treatment standard with high efficacy and low incidence of side effects. Besides established mood stabilizers such as carbamazepine and valproate, new antiepileptic drugs are entering the field with promising initial results in the treatment of bipolar patients. Furthermore, bringing to light the mechanisms of action of anticonvulsants and the similarities between anticonvulsants effective in bipolar disorder may also deepen our understanding of the pathophysiological basis of the disorder.     

Diagnostic classification of psychiatric disorders and familial-genetic research

The validity of diagnostic definitions in psychiatry is directly related to the extent to which their etiology can be specified. However, since detailed knowledge of causal or susceptibility factors is lacking for most psychiatric disorders with a known or suspected familial-genetic origin, the current widely accepted classification systems largely fail to achieve this ideal. To illustrate this problem, this paper looks at the difficulties posed by the criteria for schizophrenia as laid down in the International Classification of Diseases, 10th revision (ICD-10) and the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R), and highlights the discrepancies between the majority of diagnostic boundaries and the various phenotype aggregation patterns observed in family studies. Progress in our understanding of psychiatric disorders requires to be firmly based on the findings of epidemiological studies as well as on a clear appreciation of the limitations of classification tools.     

Brain functional network connectivity based on a visual task: visual information processing-related brain regions are significantly activated in the task state

It is not clear whether the method used in functional brain-network related research can be applied to explore the feature binding mechanism of visual perception. In this study, we investigated feature binding of color and shape in visual perception. Functional magnetic resonance imaging data were collected from 38 healthy volunteers at rest and while performing a visual perception task to construct brain networks active during resting and task states. Results showed that brain regions involved in visual information processing were obviously activated during the task. The components were partitioned using a greedy algorithm, indicating the visual network existed during the resting state. Z-values in the vision-related brain regions were calculated, confirming the dynamic balance of the brain network. Connectivity between brain regions was determined, and the result showed that occipital and lingual gyri were stable brain regions in the visual system network, the parietal lobe played a very important role in the binding process of color features and shape features, and the fusiform and inferior temporal gyri were crucial for processing color and shape information. Experimental findings indicate that understanding visual feature binding and cognitive processes will help establish computational models of vision, improve image recognition technology, and provide a new theoretical mechanism for feature binding in visual perception.