Showing papers in "Dialogues in Clinical Neuroscience in 2004"

Biology of Parkinson's disease: pathogenesis and pathophysiology of a multisystem neurodegenerative disorder.

Abstract: Parkinson's disease (PD) is the second most common movement disorder. The characteristic motor impairments - bradykinesia, rigidity, and resting tremor - result from degenerative loss of midbrain dopamine (DA) neurons in the substantia nigra, and are responsive to symptomatic treatment with dopaminergic medications and functional neurosurgery. PD is also the second most common neurodegenerative disorder. Viewed from this perspective, PD is a disorder of multiple functional systems, not simply the motor system, and of multiple neurotransmitter systems, not merely that of DA. The characteristic pathology - intraneuronal Lewy body inclusions and reduced numbers of surviving neurons - is similar in each of the targeted neuron groups, suggesting a common neurodegenerative process. Pathological and experimental studies indicate that oxidative stress, proteolytic stress, and inflammation figure prominently in the pathogenesis of PD. Yet, whether any of these mechanisms plays a causal role in human PD is unknown, because to date we have no proven neuroprotective therapies that slow or reverse disease progression in patients with PD. We are beginning to understand the pathophysiology of motor dysfunction in PD, but its etiopathogenesis as a neurodegenerative disorder remains poorly understood.

Mild cognitive impairment: an epidemiological perspective

Abstract: Mild cognitive impairment (MCI) refers to cognitive impairment that is assumed to be due to pathological central nervous system processes, but which interacts with normal aging-related changes. Epidemiological studies conducted in the general population have been able to examine more heterogeneous forms of this disorder than clinical studies, and have also been able to provide early estimations of population incidence and prevalence. Large differences in case identification procedures and sampling methods have led to considerable divergence in the rates of prevalence reported, which ranged from 1% to 29%. Suggested improvements in the definition of MCI have led to an upward adjustment of prevalence rates in most studies, giving between 5% and 29%. Incidence is estimated as 8 to 58 new cases per thousand persons per year, and the probability of conversion from MCI to dementia is estimated at around 15%. The principal risk factors that have been identified so far for MCI using regression models applied to general population data are age, education, race, medicated hypertension, infarcts, white matter lesions, depression, and apolipoprotein E4 (AP0E-4J allele. An etiological model derived from these studies indicates possible intervention points for future therapeutic strategies at the level of both clinical intervention and environmental exposure. There is, however, a clear need for epidemiological studies that take into account a broader range of risk factors than those studied to date, which have focused principally on known risk factors for dementia.

Texture analysis methodologies for magnetic resonance imaging.

Abstract: Methods for the analysis of digital-image texture are reviewed. The functions of MaZda, a computer program for quantitative texture analysis developed within the framework of the European COST (Cooperation in the Field of Scientific and Technical Research) B11 program, are introduced. Examples of texture analysis in magnetic resonance images are discussed.

Neural plasticity: consequences of stress and actions of antidepressant treatment

Abstract: Neural plasticity is emerging as a fundamental and critical mechanism of neuronal function, which allows the brain to receive information and make the appropriate adaptive responses to subsequent related stimuli. Elucidation of the molecular and cellular mechanisms underlying neural plasticity is a major goal of neuroscience research, and significant advances have been made in recent years. These mechanisms include regulation of signal transduction and gene expression, and also structural alterations of neuronal spines and processes, and even the birth of new neurons in the adult brain. Altered plasticity could thereby contribute to psychiatric and neurological disorders. This article revievi/s the literature demonstrating altered plasticity in response to stress, and evidence that chronic antidepressant treatment can reverse or block the effects, and even induce neural piasiicity-iike responses. Continued elucidation of the mechanisms underlying neural plasticity will lead to novel drug targets that could prove to be effective and rapidly acting therapeutic interventions.

Postmortem studies in Parkinson's disease.

Abstract: No animal model to date perfectly replicates Parkinson's disease (PD) etiopathogenesis, and the anatomical organization of the nigrostriatal system differs considerably between species. Human postmortem material therefore remains the gold standard for both formulating hypotheses for subsequent testing in in vitro and in vivo PD models and verifying hypotheses derived from experimental PD models with regard to their validity in the human disease. This article focuses on recent and relevant fields in which human postmortem work has generated significant impact in our understanding of PD. These fields include Lewy body formation, regional vulnerability of dopaminergic neurons, oxidative/nitrative cellular stress, inflammation, apoptosis, infectious and environmental agents, and nondopaminergic lesions.

Neuroplasticity in mood disorders.

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

Cellular abnormalities in depression: evidence from postmortem brain tissue.

Abstract: During the past two decades, in vivo neuroimaging studies have permitted significant insights into the general location of dysfunctional brain regions in depression. In parallel and often intersecting ways, neuroanatomical, pharmacological, and biochemical studies of postmortem brain tissue are permitting new insights into the pathophysiology of depression. In addition to long-recognized neurochemical abnormalities in depression, novel studies at the microscopic level support the contention that mood disorders are associated with abnormalities in cell morphology and distribution. In the past 6 years, cell-counting studies have identified changes in the density and size of both neurons and glia in a number of frontolimbic brain regions, including dorsolateral prefrontal, orbitofrontal, and anterior cingulate cortex, and the amygdala and hippocampus. Convergence of cellular changes at the microscopic level with neuroimaging changes detected in vivo provides a compelling integration of clinical and basic research for disentangling the pathophysiology of depression. The ultimate integration of these two research approaches will occur with premortem longitudinal clinical studies on well-characterized patients linked to postmortem studies of the same subjects.

Mild cognitive impairment : historical development and summary of research

Abstract: This review article broadly traces the historical development, diagnostic criteria, clinical and neuropathological characteristics, and treatment strategies related to mild cognitive impairment (MCI), The concept of MCI is considered in the context of other terms that have been developed to characterize the elderly with varying degrees of cognitive impairment Criteria based on clinical global scale ratings, cognitive test performance, and performance on other domains of functioning are discussed. Approaches employing clinical, neuropsychological, neuroimaging, biological, and molecular genetic methodology used in the validation of MCI are considered, including results from cross-sectional, longitudinal, and postmortem investigations. Results of recent drug treatment studies of MCI and related methodological issues are also addressed.

Structural plasticity of the adult brain: how animal models help us understand brain changes in depression and systemic disorders related to depression.

Abstract: The brain interprets experiences and translates them into behavioral and physiological responses. Stressful events are those which are threatening or, at the very least, unexpected and surprising, and the physiological and behavioral responses are intended to promote adaptation via a process called "allostasis. " Chemical mediators of allostasis include cortisol and adrenalin from the adrenal glands, other hormones, and neurotransmitters, the parasympathetic and sympathetic nervous systems, and cytokines and chemokines from the immune system. Two brain structures, the amygdala and hippocampus, play key roles in interpreting what is stressful and determining appropriate responses. The hippocampus, a key structure for memories of events and contexts, expresses receptors that enable it to respond to glucocorticoid hormones in the blood, it undergoes atrophy in a number of psychiatric disorders; it also responds to stressors with changes in excitability, decreased dendritic branching, and reduction in number of neurons in the dentate gyrus. The amygdala, which is important for "emotional memories, " becomes hyperactive in posttraumatic stress disorder and depressive illness, in animal models of stress, there is evidence for growth and hypertrophy of nerve cells in the amygdala. Changes in the brain after acute and chronic stressors mirror the pattern seen in the metabolic, cardiovascular, and immune systems, that is, short-term adaptation (allostasis) followed by long-term damage (allostatic load), eg, atherosclerosis, fat deposition obesity, bone demineralization, and impaired immune function. Allostatic load of this kind is seen in major depressive illness and may also be expressed in other chronic anxiety and mood disorders.

Structural plasticity of the adult brain

Abstract: The adult brain has long been considered stable and unchanging, except for the inevitable decline that occurs with aqinq This view is now being challenged with clear evidence that structural changes occur in the brain throughout life, including the generation of new neurons and other brain cells, and connections between and among neurons What is as remarkable is that the changes that occur in the adult brain are influenced by the behaviors an individual engages in, as well as the environment in which an individual lives, works, and plays Learning how behavior and environment regulate brain structure and function will lead to strategies to live more effective lives and perhaps protect from, or repair, brain damage and brain disease

Mild cognitive impairment: animal models

Abstract: Mild cognitive impairment (MCI) is an aspect of cognitive aging that is considered to be a transitional state between normal aging and the dementia into which it may convert. Appropriate animal models are necessary in order to understand the pathogenic mechanisms of MCI and develop drugs for its treatment. In this review, we identify the features that should characterize an animal model of MCI, namely old age, subtle memory impairment, mild neuropathological changes, and changes in the cholinergic system, and the age at which these features can be detected in laboratory animals. These features should occur in aging animals with normal motor activity and feeding behavior. The animal models may be middle-aged rats and mice, rats with brain ischemia, transgenic mice overexpressing amyloid precursor protein and presenilin 1 (tested at an early stage), or aging monkeys. Memory deficits can be detected by selecting appropriately difficult behavioral tasks, and the deficits can be associated with neuropathological alterations. The reviewed literature demonstrates that, under certain conditions, these animal species can be considered to be MCI models, and that cognitive impairment in these models responds to drug treatment.

Treatment-refractory schizophrenia.

Abstract: Between one-third and one-half of the individuals who meet diagnostic criteria for schizophrenia remain actively ill despite optimal pharmacological treatment These individuals tend to progressively deteriorate in terms of social and vocational functioning despite major public and private investments in their rehabilitation For patients who do not respond to the first prescribed antipsychotic drug, current clinical practice is to switch to a second and a third drug, and eventually to clozapine, the only antipsychotic drug proven to be effective in treatment-refractory schizophrenia (TRS) Occasionally, two antipsychotics are given concomitantly or psychotropic drugs are added to antipsychotic drugs; however, very few empirical data exist to support this practice Although there are many exceptions, patients who do not benefit from the first prescribed drug will not benefit from any pharmacological intervention Therefore, efforts are under way to determine the reason for lack of response to available treatments and devise novel, more effective treatments To be successful these efforts must result in a more specific definition of TRS, as well as in a better understanding of the illness pathophysiology and the mechanism of action of the drugs

Differing response to antipsychotic therapy in schizophrenia: pharmacogenomic aspects

Abstract: Treatment-resistance in schizophrenia remains a public health problem: about 20% to 30% of patients do not respond to antipsychotic therapy. Clozapine has been shown to be effective in about one-third of patients, but the medical risks and weekly blood tests limit its broad application. While the heterogeneity of the disease and the duration of untreated psychosis are important, pharmacogenomic aspects must also be considered. Pharmacogenomic investigations offer the opportunity to individualize antipsychotic therapy according to the growing knowledge of the function and effect of the genetic polymorphisms that affect the pharmacokinetics and pharmacodynamics of antipsychotics. On the pharmacokinetic level, polymorphic phase I and II drug-metabolizing enzymes and transport proteins affect drug concentration at the target structure. The cytochrome P450 enzymes, N-acetyltransferase, and multidrug resistance protein (MDR1) particularly influence this parameter. Genetic alterations affecting drug pharmacodynamic properties have an impact on therapeutic outcome that is generally independent of the applied dosage regimen. A combined analysis of genetic polymorphisms in the dopaminergic and serotonergic receptors, neurotransmitter transporters, and other target structures involved in psychiatric disorders is already a powerful predictor of therapeutic outcome. An understanding of other factors influencing gene expression and protein production will facilitate individualized therapy in the future.

Drug treatment of Parkinson's disease.

Abstract: Parkinson's disease (PD) is a common neurodegenerative disease. While its cause remains elusive, much progress has been made regarding its treatment. Available drugs have a good symptomatic effect, but none has yet been shown to slow the progression of the disease in humans. The most efficacious drug is levodopa, but it remains unclear whether the symptomatic benefit is associated with neurotoxic effects and long-term deterioration. The long-term problem associated with levodopa is the appearance of dyskinesias, which is significantly delayed among patients treated with dopamine agonists as initial therapy. Less clear is the role of other drugs in PD, such as monoamine oxidase inhibitors (MAOIs), including selegiline and rasagiline, the putative N-meihyl-o-aspartaie (NMDA) receptor antagonists amantadine and memantine, and the muscarinic receptor blockers. All these may be used as initial therapy and delay the use of dopaminergic drugs, or can be added later to reduce specific symptoms (tremor or dyskinesias). Advanced PD is frequently associated with cognitive decline. To some extent, this can be helped by treatment with cholinesterase inhibitors such as rivastigmine. Similarly, hallucinations and delusions affect PD patients in the advanced stages of their disease. The use of classical neuroleptic drugs in these patients is contraindicated because of their extrapyramidal effects, but atypical drugs, and particularly clozapine, are very helpful. The big void in the therapy of PD lies in the more advanced stages. Several motor symptoms, like postural instability, dysphagia, and dysphonia, as well as dyskinesias, are poorly controlled by existing drugs. New therapies should also be developed against autonomic symptoms, particularly constipation.

Stem cell therapy for Parkinson's disease.

Abstract: Transplantation of human fetal dopamine (DA) neurons to patients with Parkinson's disease (PD) has given proof of the principle that new neurons can survive for at least a decade, and then functionally integrate and provide significant symptomatic relief. Unfortunately, the ethical, technical, and practical limitations of using fetal DA neurons as the source for cell transplantation in PD, in combination with the development of unwanted grafting-related side effects, have put a halt to the spread of this treatment into clinical practice. Hopefully, recent advances in the fields of stem cell biology and adult neurogenesis research will lead totamen in new exciting ways to better understand and control the biological parameters necessary for achieving safe and successful neuronal replacement in PD patients.

CSF tau and β-amyloid as biomarkers for mild cognitive impairment.

Abstract: Early diagnosis of Alzheimer s disease (AD) is relevant in order to initiate symptomatic treatment with antidementia drugs. This will be of greater significance if the drugs aimed at slowing down the degenerative process (secondary prevention) prove to affect AD pathology and are clinically effective, such as γ-secretase inhibitors. However, there is currently no clinical assessment to differentiate the patients with mild cognitive impairment (MCI) who will progress to AD from those with a benign form of memory impairment that is part of the normal aging process. Thus, there is great clinical need for diagnostic and predictive biomarkers, as well as biomarkers for classification purposes, to identify incipient AD in MCI subjects. The most promising cerebrospinal fluid (CSF) biomarker candidates are total tau protein (T-tau), phosphorylated tau protein (P-tau), and the 42-andno acid form offi-amyloid (Aβ42), which may, if used in the right clinical context, prove to have sufficient diagnostic accuracy and predictive power to resolve this diagnostic challenge.

Sex-dependent modulation of treatment response.

Abstract: The response to a psychotropic medication reflects characteristics of both the medication and the substrate, ie, the individual receiving the medication. Sex is an individual characteristic that influences all elements of the pharmacokinetic process - absorption, distribution, metabolism, and elimination. The effects of sex on these components of the pharmacokinetic process often counterbalance one another to yield minimal or varying sexual differences in blood levels achieved. However, sex also appears to influence pharmacodynamics, the tissue response to a given level of medication. Consideration by the practitioner of sex as a possible contributing factor to treatment nonresponse will enhance the efficacy and precision of clinical interventions.

Pharmacotherapy of mild cognitive impairment.

Abstract: Amnestic mild cognitive impairment (MCI) can be considered as a state with a high risk of developing Alzheimer's disease within 5 years, or as a prodromal stage of this condition. Randomized clinical trials comparing the acetylcholinesterase inhibitor donepezil with placebo have shown some symptomatic benefit on (i) cognition in one short-term (6-month) study; and (ii)conversion to dementia in one long-term (3-year) study, but not for the full duration of the study, except in subjects with the apolipoprotein E4 (APOE-4) mutation, in whoom the benefit was sustained throughout the 3 years. Results from studies on galantamine are still being analyzed; and a rivastigmine study will close in the fall of 2004. It is premature to recommend that acetylcholinesterase inhibitors be used systematically in amnestic MCI. However, important lessons have been learned from studies in this prodromal stage of AD, allowing the testing of hypotheses for disease modification.

Cellular consequences of stress and depression.

Abstract: Stress is known to activate distinct neuronal circuits in the brain and induce multiple changes on the cellular level, including alterations in neuronal structures. On the basis of clinical observations that stress often precipitates a depressive disease, chronic psychosocial stress serves as an experimental model to evaluate the cellular and molecular alterations associated with the consequences of major depression. Antidepressants are presently believed to exert their primary biochemical effects by readjusting aberrant intrasynaptic concentrations of neurotransmitters, such as serotonin or noradrenaline, suggesting that imbalances viihin the monoaminergic systems contribute to the disorder (monoaminergic hypothesis of depression). Here, we reviev the results that comprise our understanding of stressful experience on cellular processes, with particular focus on the monoaminergic systems and structural changes within brain target areas of monoaminergic neurons.

Problems in texture analysis with magnetic resonance imaging.

Abstract: Since its introduction in the 1930s, magnetic resonance imaging (MRI) has become recognized as a powerful in vivo diagnostic tool. The objective of this article is to discuss developments in quantitative MRI - and particularly texture analysis - that maximize diagnostic information, A fundamental part of the work involves careful study of the optimal MRI data collection strategies for texture analysis. This is critical, because different centers may vary their measuring sequences and acquisition protocols for clinical reasons, and may be reluctant to vary these for texture investigation. Different measuring techniques, such as spin echo, gradient echo, and echo planar, and different measuring parameters produce totally different patterns in texture. Careful investigation of the dependence of all these variables using texture phantoms (test objects) will help understand how MRI image texture is formed from tissue structures. Therefore, it is essential to design and test reliable and accurate test objects for a detailed assessment of texture analysis methods in MRI, The main feature of these test objects is their ability to simulate tissue-like textures with tissue-like MR relaxation properties. Long-term stability is also vital, as is uniformity of the overall texture. Another aspect is to examine the test objects under a whole range of MRI measuring sequences and imaging conditions using different scanners to determine their stability and utility.

Behavioral disturbances in Parkinson's disease.

Abstract: Treatment of Parkinson's disease (PD) is complex and often involves addressing behavioral changes in addition to the movement disorder. Patients with PD are susceptible to any psychiatric condition seen in the general population; some disorders, such as depression and anxiety, may result from PD-related neuropathological changes. Medicationrelated hallucinations are seen in many PD patients who are treated with dopaminergic agents for motor symptoms. Cognitive impairment is also seen and can be multifactorial. Treatment of behavioral symptoms in PD can greatly improve patients“ overall function and quality of life. As surgical interventions to treat motor symptoms, such as deep brain stimulation of the subthalamic nucleus of the substantia nigra, become more prevalent, the behavioral effects of these procedures must also be addressed,

Treatment goals: response and nonresponse

Abstract: Psychiatric symptomatology is often subjective, but it can be partly made more objective for the purposes of evaluation. Esquirol was the first modern psychiatrist to stress the need for a scientific approach to treatment evaluation. The kinetics of treatment is complex because different components of the clinical picture improve at a different pace. Assessment of treatment requires prior definition of end point, response, and nonresponse. Response is influenced by several factors, such as placebo effect, diagnostic category and subtypes, and patient heterogeneity. Treatment response may be predicted from clinical and biological parameters. This article lists the main causes of nonresponse, and suggests how to remedy them.

Cellular plasticity and resilience and the pathophysiology of severe mood disorders.

Abstract: Recent advances in the identification of the neural circuits, neurochemicals, and signal transduction mechanisms involved in the pathophysiology and treatment of mood disorders have led to much progress toward understanding the roles of genetic factors and psychosocial stressors. The monoaminergic neurotransmitter systems have received the most attention, partly because of the observation that effective antidepressant drugs exert their primary biochemical effects by regulating intrasynaptic concentrations of serotonin and norepinephrine. Furthermore, the monoaminergic systems are extensively distributed throughout the network of limbic, striatal, and prefrontal cortical neuronal circuits thought to support the behavioral and visceral manifestations of mood disorders. Increasing numbers of neuroimaging, neuropathological, and biochemical studies indicate impairments in cellular plasticity and resilience in patients who suffer from severe, recurrent mood disorders. In this paper, we describe studies identifying possible structural, functional, and cellular abnormalities associated with depressive disorders, which are potentially the cellular underpinnings of these diseases. We suggest that drugs designed to enhance cellular plasticity and resilience, and attenuate the activity of maladaptive stress-responsive systems, may be useful for the treatment of severe mood disorders.

Regulation of cellular plasticity and resilience by mood stabilizers: the role of AMPA receptor trafficking.

Abstract: There is increasing evidence from a variety of sources that severe mood disorders are associated with regional reductions in brain volume, as well as reductions in the number, size, and density of glia and neurons in discrete brain areas. Although the precise pathophysiology underlying these morphometric changes remains to be fully elucidated, the data suggest that severe mood disorders are associated with impairments of structural plasticity and cellular resilience. In this context, it is noteworthy that a growing body of data suggests that the glutamaiergic system (which is known to play a major role in neuronal plasticity and cellular resilience) may be involved in the pathophysiology and treatment of mood disorders. Glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) GluR1 receptor trafficking plays a critical role in regulating various forms of neural plasticity. It is thus noteworthy that recent studies have shown that structurally dissimilar mood stabilizers lithium and valproate regulate GluR1 receptor subunit trafficking and localization at synapses. These studies suggest that regulation of glutamatergically mediated synaptic plasticity may play a role in the treatment of mood disorders, and raises the possibility that agents more directly affecting synaptic GluR1 represent novel therapies for these devastating illnesses.

Texture analysis of the brain: from animal models to human applications

Abstract: Magnetic resonance imaging (MRI) is widely used to image brain in vivo both in studies in animal models and for human diagnosis. A large part of the value of MRI is due to the fact that soft tissue contrast is enhanced by the substantial variation in the T1 and T2 relaxation times between tissues. It may be possible to use an alternative approach, which does not rely on the absolute measurement of relaxation times. Generally speaking, textures are complex visual patterns composed of entities, or subpatterns, that have characteristic brightness, color, slope, size, etc. Thus, texture can be regarded as a similarity grouping in an image. The properties of the local subpattern give rise to the perceived lightness, uniformity, density, roughness, regularity, linearity, frequency, phase, directionality, coarseness, randomness, fineness, smoothness, and granulation. The purpose here is to illustrate how texture analysis can be used in animal models and in human clinical applications, as well as in the search for further pharmacological applications in humans. Thus, this article summarzes three different MRI studies in (i) rats, using the lipocarpine epileptic rat model as an animal model; (ii) patients with Alzheimer's disease; and (iii) patients with schizophrenia.

Current perspectives in the management of treatment-resistant depression

Abstract: Depressive disorders are a leading cause of disability worldwide and greatly impact morbidity, health care utilization, and medical costs. Major depression that does not resolve with adequate antidepressant treatment is termed treatment-resistant depression (TRD), There is no universally accepted definition of TRD and several criteria have been suggested to define it. Multiple factors can contribute to treatment resistance, including unrecognized comorbid medical or psychiatric illness, the use of concomitant medications, noncompliance, and psychosocial stressors. TRD is associated with extensive use of depression-related and general medical services, and poses a substantial economic burden. Current approaches to its management include the use of antidepressant strategies, such as increasing the dose of the antidepressant, augmentation strategies, combination strategies, and switching strategies, electroconvulsive therapy, and cognitive behavioral therapy. Although no definite algorithm exists for treating TRD, research in this area has advanced considerably in recent years. One approach to this is a clinical trial called STAR*D (Sequenced Treatment Alternatives to Relieve Depression). This has the potential to increase our understanding about the diagnostic and therapeutic aspects of TRD, to substantially reduce disability, and to enhance the quality of life in individuals with this condition.

Poor response to treatment: beyond medication.

Abstract: In psychiatry, one of the main factors contributing to poor response to pharmacological treatment is adherence. Noncompliance with maintenance treatments for chronic illnesses such as schizophrenia and affective disorders can exceed 50%, Poor adherence can be due to drug-related factors (tolerance, complexity of prescription, side effects, or cost), patient-related variables (illness symptoms, comorbidity, insight capacity, belief system, or sociocultural environment), and physician-related factors (communication or psychoeducational style). Psychosocial treatments must be used in conjunction with medication during the maintenance phase to improve adherence to treatment and to achieve - through the management of psychological variables - better social, work, and family functioning. This article reviews the concepts of adherence and noncompliance, and their impact on maintenance treatments, as well as the effect of dealing with psychosocial factors in psychiatric treatment.

The future of genetic testing for drug response.

Abstract: The effect of variation in genes coding for drug targets and for the enzymes involved in drug metabolism has highlighted the genetic component of drug response. Drug response can be likened to a complex, multifactorial genetic trait, and the study of its genetic variation, termed pharmacogenetics, is analogous to the study of complex genetic disease in terms of the questions posed and the analytical possibilities. Just as DNA variants are associated with specific disease predispositions, so will they be associated with individual response to certain drugs. The testing for drug response is following the same route as the genetic testing for inherited disorders, and has reached the stage where genome-wide analysis, as opposed to the analysis of single genes, is a reality. In this article, we will discuss some of the technical advances that facilitate such analyses, leading to faster and more extensive diagnostic capabilities.

Genetic variation and pharmacogenomics: concepts, facts, and challenges.

Abstract: The analysis of genetic variation in candidate genes is an issue of central importance in pharmacogenomics. The specific approaches taken will have a critical impact on the successful identification of disease genes, the molecular correlates of drug response, and the establishment of meaningful relationships between genetic variants and phenotypes of biomedical and pharmaceutical importance in general. Against a historical background, this article distinguishes different approaches to candidate gene analysis, reflecting different stages in human genome research. Only recently has it become feasible to analyze genetic variation systematically at the ultimate level of resolution, ie, the DNA sequence. In this context, the importance of haplotype-based approaches to candidate gene analysis has at last been recognized; the determination of the specific combinations of variants for each of the two sequences of a gene defined as a haplotype is essential. An up-to-date summary of such maximum resolution data on the amount, nature, and structure of genetic variation in candidate genes will be given. These data demonstrate abundant gene sequence and haplotype diversity. Numerous individually different forms of a gene may exist. This presents major challenges to the analysis of relationships between genetic variation, gene function, and phenotype. First solutions seem within reach. The implications of naturally occurring variation for pharmacogenomics and “personalized” medicine are now evident. Future approaches to the identification, evaluation, and prioritization of drug targets, the optimization of clinical trials, and the development of efficient therapies must be based on in-depth knowledge of candidate gene variation as an essential prerequisite.

Clinicians' predictions of patient response to psychotropic medications.

Abstract: 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.