Induced pluripotent stem cells: a new tool to confront the challenge of neuropsychiatric disorders

Studies in the area of human brain development are critical as research on neurological and psychiatric disorders has advanced, revealing the origins of pathophysiology to be in the earliest developmental stages. Only with a more precise understanding of the genes and environments that influence the brain in these early stages can we address questions about the pathology, diagnosis, prevention and treatment of neuropsychiatric disorders of developmental origin, like autism, schizophrenia, and Tourette syndrome. A new approach for studying early developmental events is the use of induced pluripotent stem cells (iPSCs). These are cells with wide potential, similar to that of embryonic stem cells, derived from mature somatic cells. We review the protocols used to create iPSCs, including the most efficient and reliable reprogramming strategies available to date for generating iPSCs. In addition, we discuss how this new tool can be applied to neuropsychiatric research. The use of iPSCs can advance our understanding of how genes and gene products are dynamically involved in the formation of unique features of the human brain, and how aberrant genetic variation may interfere with its typical formation. The iPSC technology, if properly applied, can also address basic questions about neural differentiation such as how stem cells can be guided into general and specific neurodevelopmental pathways. Current work in neuropsychiatry with iPSCs derived from patients has focused on disorders with specific genetics deficits and those with less-defined origins; it has revealed previously unknown aspects of pathology and potential pharmacological interventions. These exciting advances based on the use of iPSCs hold promise for improving early diagnosis and, possibly, treatment of psychiatric disorders. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.     

Psychiatric aspects of phosphodiesterases: An overview

Phosphodiesterases (PDE) are exciting new targets in medical sciences. These enzymes are some of the key mediators of cellular functions in the body and hence are attractive sites for drug-induced modulations. With the finding that Tofisopam, a new anxiolytic, inhibits PDEs, the authors were inspired to look into the role of PDE and drugs acting on them in psychiatry. Hence, the review was undertaken. We found several research materials available highlighting the role of PDE in cellular functions and the possible newer etiological mechanisms of neuropsychiatric illnesses such as schizophrenia, depression/anxiety disorders, and cognitive dysfunction involving PDEs. We also found that there are many molecules acting on PDEs, which have the potential to alter the way we treat mental illnesses today. This article is intended to provide an in-depth look at these enzymes so that more cost-effective therapeutic molecules may be synthesized and marketed in India for managing mental illnesses.KEY WORDS: Affective disorders, anxiety, cognition, phosphodiesterase, phosphodiesterase inhibitor, schizophrenia     

Cognitive Training for Impaired Neural Systems in Neuropsychiatric Illness

Neuropsychiatric illnesses are associated with dysfunction in distributed prefrontal neural systems that underlie perception, cognition, social interactions, emotion regulation, and motivation. The high degree of learning-dependent plasticity in these networks—combined with the availability of advanced computerized technology—suggests that we should be able to engineer very specific training programs that drive meaningful and enduring improvements in impaired neural systems relevant to neuropsychiatric illness. However, cognitive training approaches for mental and addictive disorders must take into account possible inherent limitations in the underlying brain ‘learning machinery'' due to pathophysiology, must grapple with the presence of complex overlearned maladaptive patterns of neural functioning, and must find a way to ally with developmental and psychosocial factors that influence response to illness and to treatment. In this review, we briefly examine the current state of knowledge from studies of cognitive remediation in psychiatry and we highlight open questions. We then present a systems neuroscience rationale for successful cognitive training for neuropsychiatric illnesses, one that emphasizes the distributed nature of neural assemblies that support cognitive and affective processing, as well as their plasticity. It is based on the notion that, during successful learning, the brain represents the relevant perceptual and cognitive/affective inputs and action outputs with disproportionately larger and more coordinated populations of neurons that are distributed (and that are interacting) across multiple levels of processing and throughout multiple brain regions. This approach allows us to address limitations found in earlier research and to introduce important principles for the design and evaluation of the next generation of cognitive training for impaired neural systems. We summarize work to date using such neuroscience-informed methods and indicate some of the exciting future directions of this field.     

Biological markers in schizophrenia: An update

Biological markers are quantitative measures that allow clinicians to diagnose and assess the disease process, monitor response to treatment and may, to some extent, assist with prognostic assessments (1). Biological markers can modify the way clinicians approach, treat and care for patients. This has significant diagnostic and treatment-related implications, especially for chronic disabling disorders with complex etiopathogenesis, such as schizophrenia. Years of research have yielded a variety of relatively consistent findings in different domains including neuroanatomy, functional and molecular neuroimaging, neurophysiology, genetics and biochemistry. These attributes can complement clinical findings with improved diagnostic validity, and to some extent, assist the clinician in early initiation of efficacious treatment and predicting prognosis. On the contrary, many of these potential biological markers may require expensive testing and enhanced technological expertise. Considering the issues with sensitivity and specificity and an overlap with other neuropsychiatric disorders, their role in routine clinical care continues to be ambiguous.     

Prenatal stress: Role in psychotic and depressive diseases

Rationale  

The birth of neurons, their migration to appropriate positions in the brain, and their establishment of the proper synaptic contacts happen predominately during the prenatal period. Environmental stressors during gestation can exert a major impact on brain development and thereby contribute to the pathogenesis of neuropsychiatric illnesses, such as depression and psychotic disorders including schizophrenia.     

Nicotinic receptor mechanisms and cognition in normal states and neuropsychiatric disorders

Cigarette smoking rates in the American population are approximately 23%, whereas rates of smoking in clinical and population studies of individuals with neuropsychiatric disorders are typically two- to four-fold higher. Studies conducted in a variety of neuropsychiatric populations [e.g. attention-deficit hyperactivity disorder (ADHD), Alzheimer's disease, schizophrenia] have collectively suggested that nicotine may be efficacious in remediating selected cognitive deficits associated with these disorders, thus providing a framework for understanding the specific vulnerability of these patients to smoking initiation and maintenance. However, the specific gain in cognitive performance produced by nicotine administration in healthy subjects with normal cognitive function is less clear. This article reviews our current understanding of central nicotinic acetylcholine receptor (nAChRs) systems in normal and neuropsychiatric disease states and, specifically, their role with respect to cognitive dysfunction and clinical symptoms in several specific neuropsychiatric populations, including ADHD, Alzheimer's disease, Parkinson's disease, Tourette's Disorder, schizophrenia and affective disorders. The potential benefits of nicotinic agents for therapeutic use in neuropsychiatric disorders is discussed, as well as directions for further research in this area.     

Effect of rivastigmine in the treatment of behavioral disturbances associated with dementia: review of neuropsychiatric impairment in Alzheimer's disease

ABSTRACT

Cognitive decline is conventionally regarded as the defining clinical symptom of Alzheimer's disease (AD), but behavioral and neuropsychiatric symptoms are also present throughout the course of the disease. In fact, behavioral symptoms may appear before cognitive decline is diagnosed. The presence of these symptoms may predict an increasing need for community-based services or even nursing home placement. The characteristic behavioral and neuropsychiatric symptoms associated with AD may be related to the same pathophysiology that underlies the cognitive abnormalities. AD is characterized by a loss of cholinergic neurons as well as by the presence of neurofibrillary tangles (NFTs) and senile plaques in brain regions with cholinergic deficits, resulting in a deficiency in acetylcholine (ACh) in areas of the brain that modulate cognition, behavior, and emotion. Cholinesterase inhibitors are thought to augment or maximize the concentration of ACh in the synaptic cleft. Rivastigmine is a dual inhibitor of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), enzymes involved in hydrolysis of ACh. Literature searches using MEDLINE and EMBASE databases were performed to identify studies of rivastigmine (through August 2005) that assessed neuropsychiatric aspects of AD. Rivastigmine has been demonstrated to be safe and effective in stabilizing or improving the cognitive symptoms of AD in 3 large, well-controlled, randomized clinical trials, which also demonstrated that rivastigmine improves overall global functioning. Smaller studies and meta-analyses of pooled data from the 3 large trials have suggested that rivastigmine may improve the behavioral and neuropsychiatric symptoms associated with AD.     

Ethics and neuropsychiatric genetics: a review of major issues

Advances in neuropsychiatric genetics hold great hopes for improved prevention, diagnosis and treatment. However, the power of genetic testing to identify individuals at increased risk for disorders and to convey information about relatives creates a set of complex ethical issues. Public attitudes are inevitably affected by the shadow of eugenics, with its history of distorting scientific findings to serve socio-political ends. Nonetheless, the growing availability of genetic tests means that more patients will seek genetic information and physicians must manage the process of informed consent to allow meaningful decisions. Patients should be helped to understand the often-limited predictive power of current knowledge, potential psychological impact, risks of stigma and discrimination and possible implications for family members. Decisions for predictive testing of children raise additional concerns, including distortions of family dynamics and negative effects on children's self-image; testing is best deferred until adulthood unless preventive interventions exist. Pharmacogenomic testing, part of personalized medicine, may bring collateral susceptibility information for which patients should be prepared. The implications of genetic findings for families raise the question of whether physicians have duties to inform family members of implications for their health. Finally, participation in research in neuropsychiatric genetics evokes a broad range of ethical concerns, including the contentious issue of the extent to which results should be returned to individual subjects. As genetic science becomes more widely applied, the public will become more sophisticated and will be likely to demand a greater role in determining social policy on these issues.     

Stress and hippocampal abnormalities in psychiatric disorders.

The hippocampus plays a main role in regulating stress response in humans, but is itself highly sensitive to neurotoxic effects of repeated stressful episodes. Hippocampal atrophy related to experimental stress has been reported in laboratory studies in animals. Several controlled brain imaging studies have also shown hippocampal abnormalities in psychiatric disorders, including posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and borderline personality disorder (BPD). This paper reviews the physiological role of the hippocampus in stress circuitry and the effects of stress on cognitive functions mediated by the hippocampus. We also review brain imaging studies investigating hippocampus in PTSD, MDD, and BPD. This literature suggests that individuals with PTSD, MDD, and BPD may suffer hippocampal atrophy as a result of stressors associated with these disorders. Prospective, longitudinal studies will be needed in high-risk offspring and first-episode subjects to explore the relationship between stress and hippocampal atrophy in these neuropsychiatric illnesses.     

Immunological aetiology of major psychiatric disorders: evidence and therapeutic implications

Historically, immunological research in psychiatry was based on empirical findings and early epidemiological studies indicating a possible relationship between psychiatric symptoms and acute infectious diseases. However, aetiopathological explanations for psychiatric disorders are no longer closely related to acute infection. Nevertheless, immune hypotheses have been discussed in schizophrenia, affective disorders and infantile autism in the last decades.Although the variability between the results of the epidemiological studies conducted to date is strikingly high, there is still some evidence that the immune system might play a role in the aetiopathogenesis of these three psychiatric diseases, at least in subgroups of patients. In anxiety disorders immunological research is still very much in its infancy, and the few and inconsistent data of immune changes in these patients are believed to reflect the influence of short- or long-term stress exposure. Nevertheless, there are also some hints raising the possibility that autoimmune mechanisms could interrupt neurotransmission, which would be of significance in certain patients with anxiety and panic disorders. Drug and alcohol (ethanol) dependence are not believed to be primarily influenced by an immunological aetiology. On the other hand, immune reactions due to different drugs of abuse and alcohol may directly or indirectly influence the course of concomitant somatic diseases. In different organic brain disorders the underlying somatic disease is defined as a primary immune or autoimmune disorder, for instance HIV infection or systemic lupus erythematosus (SLE). For other neurodegenerative disorders, such as Alzheimer's disease, immunoaetiopathological mechanisms are supported by experimental and clinical studies. Treatment strategies based on immune mechanisms have been investigated in patients with schizophrenia and affective disorders. Furthermore, some antipsychotics and most antidepressants are known to have direct or indirect effects on the immune system. Different immunotherapies have been used in autism, including transfer factor, pentoxifylline, intravenous immunoglobulins and corticosteroids. Immunosuppressive and/or immunomodulating agents are well established methods for treating the neuropsychiatric sequelae of immune or autoimmune disorders, for example AIDS and SLE. Therapeutic approaches in Alzheimer's disease also apply immunological methods such as strategies of active/passive immunisation and NSAIDs.Considering the comprehensive interactive network between mind and body, future research should focus on approaches linking targets of the different involved systems.     

Effect of rivastigmine in the treatment of behavioral disturbances associated with dementia: review of neuropsychiatric impairment in Alzheimer's disease

Cognitive decline is conventionally regarded as the defining clinical symptom of Alzheimer's disease (AD), but behavioral and neuropsychiatric symptoms are also present throughout the course of the disease. In fact, behavioral symptoms may appear before cognitive decline is diagnosed. The presence of these symptoms may predict an increasing need for community-based services or even nursing home placement. The characteristic behavioral and neuropsychiatric symptoms associated with AD may be related to the same pathophysiology that underlies the cognitive abnormalities. AD is characterized by a loss of cholinergic neurons as well as by the presence of neurofibrillary tangles (NFTs) and senile plaques in brain regions with cholinergic deficits, resulting in a deficiency in acetylcholine (ACh) in areas of the brain that modulate cognition, behavior, and emotion. Cholinesterase inhibitors are thought to augment or maximize the concentration of ACh in the synaptic cleft. Rivastigmine is a dual inhibitor of both acetylcholin esterase (AChE) and butyrylcholinesterase (BuChE), enzymes involved in hydrolysis of ACh. Literature searches using MEDLINE and EMBASE databases were performed to identify studies of rivastigmine (through August 2005) that assessed neuropsychiatric aspects of AD. Rivastigmine has been demonstrated to be safe and effective in stabilizing or improving the cognitive symptoms of AD in 3 large, well-controlled, randomized clinical trials, which also demonstrated that rivastig mine improves overall global functioning. Smaller studies and meta-analyses of pooled data from the 3 large trials have suggested that rivastigmine may improve the behavioral and neuropsychiatric symptoms associated with AD.     

Radiopharmaceuticals in neurological and psychiatric disorders

The development of functional brain nuclear medicine techniques and their application in the investigation of neuropsychiatric disorders, have contributed significantly in the illumination of the underlying pathophysiological processes of these disorders. Furthermore, Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) brain studies provide information in early diagnosis, differential diagnosis, development of new drugs, and monitoring the response to therapeutic management. SPECT and PET brain imaging require the use of radiopharmaceuticals that cross the intact Blood Brain Barrier (BBB). Such radiotracers have been used in regional Cerebral Blood Flow (rCBF) SPECT and PET imaging and brain metabolism imaging with PET; these are well established methods in the diagnosis and management of various cerebral vascular diseases (e.g. stroke, dementia, epilepsy). Advances in radiotracer chemistry have resulted in the development of molecular imaging which represents the molecular and cellular processes of neuropsychiatric diseases. SPECT and PET molecular imaging has become available for the study of acetylcholinergic, dopaminergic and serotonergic systems, as well as for benzodiazepine and opioid receptors, with promising results. More studies are needed to validate the role of molecular imaging in the clinical practice of neuropsychiatric disorders.     

IFN-induced depression: a role for NSAIDs

Interferon-alpha (IFN) is widely used for the treatment of viral illnesses and other chronic diseases, though its usefulness is hampered by a problematic side-effect profile. In particular, IFN-alpha induces neuropsychiatric and neurotoxic side effects, including depression, anxiety, insomnia, lethargy, confusion, and psychosis. Of particular interest, a number of patients develop full psychiatric syndromes, particularly depressive disorders. Recent evidence suggests that conventional antidepressants (especially selective serotonin reuptake inhibitors) are effective in preventing or reducing IFN-induced side-effects, but even these compounds are not 100% effective in preventing these symptoms. As such, alternative treatments must be considered. Non-steroidal anti-inflammatory drugs (NSAIDs) are known to counteract a number of IFN-induced side effects, including cytokine activation, stress hormone release, and neurochemical alterations (reduced 5-HT [serotonin]). NSAIDs are widely recommended for various aspects of flu-like symptoms or sickness behaviors in humans, including those induced specifically by IFN. In addition, NSAIDs appear to be effective in treating premenstrual dysphoric disorder. These data indirectly specify a role for NSAIDs in syndromes with a prominent depression component. Drawing from an extensive pre-clinical and clinical research base, we hypothesize that pretreatment with NSAIDs will not only reduce the incidence of flu-like symptoms, but also prove effective for the prevention or reduction of IFN-induced depression.     

Nitric oxide as a physiopathological factor in neuropsychiatric disorders

The dominant research subject on schizophrenia, mood disorders, autism and other central nervous system diseases has been related to neurotransmitter system abnormalities. For example, the dopamine hypothesis states that schizophrenia is the result of dopaminergic hyperactivity. The therapeutic approach has also been directed towards finding agents which will modulate or regulate these neurotransmitter systems at any step. There is substantial and mounting evidence that subtle abnormalities of reactive oxygen species (ROS) and nitric oxide (NO) may underlie a wide range of neuropsychiatric disorders. NO has chemical properties that make it uniquely suitable as an intracellular and intercellular messenger. It is produced by the activity of nitric oxide synthases which are present in peripheral tissues and in neurons. On the other hand, NO is known to be an oxygen radical in the central and peripheral nervous systems. NO has been implicated in a number of physiological functions such as noradrenaline and dopamine releases, memory and learning and certain pathologies such as schizophrenia, bipolar disorder and major depression. Evidence has been considered here for the proposal that an abnormality of NO metabolism may be a contributory factor in some neuropsychiatric disorders. The direct evidence for NO abnormalities in schizophrenia and other psychiatric disorders remains relatively limited to date, although there are some clinical and experimental studies. The suggestion that NO and other ROS may play a role in some neuropsychiatric disorders clearly has important implications for new treatment possibilities. The primary objective of the present review was to summarize and critically evaluate the current knowledge regarding a potential contribution of NO to the neuropathophysiology of schizophrenia as well as other neuropsychiatric disorders.     

Combining genetic and genomic approaches to study mood disorders

Recent technological advances in genetic manipulations and DNA microarrays are profoundly altering the landscape of biological research, offering opportunities to investigate biological questions that were only dreamed of a few years ago. With this revolution comes the hope of being able to tackle some of the more arduous challenges that the central nervous system has presented to the research community. Specifically, a major goal in the study of neuropsychiatric disorders has been to identify underlying mechanisms of brain dysfunction with the expectation that these insights may allow a better diagnosis, prevention and effective treatments for these disorders. For the most part, treatments of these disorders have relied on serendipitous discovery of pharmacological entities with therapeutic efficacy, while the causes of the disorders have remained unknown. The serotonin system, and the serotonin_1A (5-HT_1A) receptor in particular, have been under intense investigation, mostly due to the fact that serotonergic drugs that directly or indirectly affect the 5-HT_1A receptor, are effective therapeutic agents in treating patients with various neuropsychiatric disorders, including anxiety and depression. Genetic deletion of the receptor in mouse results in increased anxiety, thus supporting an active role for this receptor in mood regulation. However, the analysis of genetic deletion experiments can be confounded by hidden developmental roles of the missing receptor, by adaptive compensatory mechanisms, as well by the fact that the genes or gene products that are responsible for the cellular and molecular aspects of the phenotype may be several steps removed from the genetic intervention. Here, we present a combined methodological approach of tissue specific and conditional genetic manipulations, with large-scale search for altered gene expression, as an experimental framework to investigate the role of genes with complex functions and/or complex expression patterns. The 5-HT_1A receptor is used as a model of gene product with complex functions and distributions, and as a prototypical system to which these new genetic approaches are currently being applied.     

The ethics of elective psychopharmacology

Pharmacological cognitive enhancers (PCEs) are used to improve cognitive functions, such as attention, learning, memory and planning in patients with impairments in cognition resulting from traumatic brain injury (TBI) or from neuropsychiatric disorders such as Alzheimer's disease (AD), mild cognitive impairment, schizophrenia, and attention deficit hyperactivity disorder (ADHD). Moreover, PCEs have been shown to improve cognition in healthy volunteers with no psychiatric disorders. This article describes the rationale behind the need for their use in neuropsychiatric patients and illustrates how PCEs can ameliorate cognitive impairments, improve quality of life and wellbeing, and therefore reduce the economic burden associated with these disorders. We also describe evidence that PCEs are being used as cognitive enhancers by healthy people. Crucially, as the lifestyle use of these drugs becomes very popular in the healthy population, a final aim is to present an overview of the current and future neuroethical considerations of enhancing the healthy brain. As information regarding their actual use, benefits and harms in various healthy populations is currently lacking, we propose research that aims to obtain relevant empirical data, monitor the short- and long-term effectiveness and side-effects, and initiate accurate surveys to determine current patterns and quantity of usage of PCE drugs by healthy people. Furthermore, in order to instigate a dialogue between neuroethics and neuropsychopharmacology, we urge scientists to explore and communicate the social and ethical implications of their research to the public. Finally, we discuss and highlight other means of enhancing cognition in both patients and healthy adults, including education and physical exercise.     

Metabotropic and ionotropic glutamate receptors as neurobiological targets in anxiety and stress-related disorders: focus on pharmacology and preclinical translational models

Anxiety disorders are amongst the most common and disabling of psychiatric illnesses and have severe health and socio-economic implications. Despite the availability of a number of treatment options there is still a strong medical need for novel and improved pharmacological approaches in treating these disorders. New developments at the forefront of preclinical research have begun to identify the therapeutic potential of molecular entities integral to the biological response to adversity, particularly molecules and processes that may pre-determine vulnerability or resilience, and those that may act to switch off or “unlearn” a response to an aversive event. The glutamate system is an interesting target in this respect, especially given the impact anxiety disorders have on neuroplasticity, cognition and affective function. These areas of research demonstrate expanding and improved evidence-based options for treating disorders where stress in various guises plays an important etiological role. The current review will discuss how these pathways are involved in fear circuitry of the brain and compare the strength of therapeutic rationale as well as progress towards pharmacological validation of the glutamate pathway towards the treatment of anxiety disorders, with a particular focus on metabotropic and ionotropic glutamate receptors. Specific reference to their anxiolytic actions and efficacy in translational disease models of posttraumatic stress disorder, obsessive-compulsive disorder, panic disorder and phobia will be made. In addition, the availability of ligands necessary to assist clinical proof of concept studies will be discussed.     

Development of radioligands for imaging of brain norepinephrine transporters in vivo with positron emission tomography

In the central nervous system (CNS) and in the periphery, specific proteins (transporters) are responsible for the regulation of the synaptic concentrations of the major monoamine neurotransmitters, noradrenaline (NE), serotonin (5-HT) and dopamine (DA). Several reports have shown that the expression of these transporters within the CNS may be altered in patients with certain neurodegenerative or neuropsychiatric disorders. Therefore, in the CNS the monoamine transporters are major targets for existing and developmental drugs. The best known drugs targeting these transporters are the selective 5-HT reuptake inhibitors (SSRIs) (e.g. citalopram, Celexa) that are most frequently used in the treatment of clinical depression. Selective NE reuptake inhibitors (NRIs) have also found use for the treatment of depression and other conditions such as attention deficit hyperactivity (ADHD) disorder. Given that the NE transporter (NET) is also a binding site for cocaine and drugs of abuse, there is a great need for a probe to assess the densities of NET in vivo by brain imaging with either positron emission tomography (PET) or single photon emission tomography (SPET). PET in particular has the potential to measure NET densities quantitatively and with high resolution in the human brain in vivo. The quality of a PET image depends crucially on the radioligand used in the emission measurement. Commonly used radionuclides in PET radioligands are carbon 11 (t(1/2) = 20.4 min) and fluorine-18 (t(1/2) = 109.8 min). This review specifically summarizes the present status of the development of (11)C- or (18)F-labeled ligands as tools for imaging NET in brain with PET in support of neuropsychiatric clinical research and drug development.     

Modafinil: a review of neurochemical actions and effects on cognition.

Modafinil (2-[(Diphenylmethyl) sulfinyl] acetamide, Provigil) is an FDA-approved medication with wake-promoting properties. Pre-clinical studies of modafinil suggest a complex profile of neurochemical and behavioral effects, distinct from those of amphetamine. In addition, modafinil shows initial promise for a variety of off-label indications in psychiatry, including treatment-resistant depression, attention-deficit/hyperactivity disorder, and schizophrenia. Cognitive dysfunction may be a particularly important emerging treatment target for modafinil, across these and other neuropsychiatric disorders. We aimed to comprehensively review the empirical literature on neurochemical actions of modafinil, and effects on cognition in animal models, healthy adult humans, and clinical populations. We searched PubMed with the search term 'modafinil' and reviewed all English-language articles for neurochemical, neurophysiological, cognitive, or information-processing experimental measures. We additionally summarized the pharmacokinetic profile of modafinil and clinical efficacy in psychiatric patients. Modafinil exhibits robust effects on catecholamines, serotonin, glutamate, gamma amino-butyric acid, orexin, and histamine systems in the brain. Many of these effects may be secondary to catecholamine effects, with some selectivity for cortical over subcortical sites of action. In addition, modafinil (at well-tolerated doses) improves function in several cognitive domains, including working memory and episodic memory, and other processes dependent on prefrontal cortex and cognitive control. These effects are observed in rodents, healthy adults, and across several psychiatric disorders. Furthermore, modafinil appears to be well-tolerated, with a low rate of adverse events and a low liability to abuse. Modafinil has a number of neurochemical actions in the brain, which may be related to primary effects on catecholaminergic systems. These effects are in general advantageous for cognitive processes. Overall, modafinil is an excellent candidate agent for remediation of cognitive dysfunction in neuropsychiatric disorders.