Showing papers in "Dialogues in Clinical Neuroscience in 2006"

The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress.

Abstract: Animals respond to stress by activating a wide array of behavioral and physiological responses that are collectively referred to as the stress response. Corticotropin-releasing factor (CRF) plays a central role in the stress response by regulating the hypothalamic-pituitary-adrenal (HPA) axis. In response to stress, CRF initiates a cascade of events that culminate in the release of glucocorticoids from the adrenal cortex. As a result of the great number of physiological and behavioral effects exerted by glucocorticoids, several mechanisms have evolved to control HPA axis activation and integrate the stress response. Glucocorticoid feedback inhibition plays a prominent role in regulating the magnitude and duration of glucocorticoid release. In addition to glucocorticoid feedback, the HPA axis is regulated at the level of the hypothalamus by a diverse group of afferent projections from limbic, mid-brain, and brain stem nuclei. The stress response is also mediated in part by brain stem noradrenergic neurons, sympathetic andrenornedullary circuits, and parasympathetic systems. In summary, the aim of this review is to discuss the role of the HPA axis in the integration of adaptive responses to stress. We also identify and briefly describe the major neuronal and endocrine systems that contribute to the regulation of the HPA axis and the maintenance of homeostasis in the face of aversive stimuli.

Protective and damaging effects of stress mediators: central role of the brain.

Abstract: The mind involves the whole body, and two-way communication between the brain and the cardiovascular, immune, and other systems via neural and endocrine mechanisms Stress is a condition of the mind-body interaction, and a factor in the expression of disease that differs among individuals It is not just the dramatic stressful events that exact their toll, but rather the many events of daily life that elevate and sustain activities of physiological systems and cause sleep deprivation, overeating, and other health-damaging behaviors, producing the feeling of being “stressed out” Over time, this results in wear and tear on the body, which is called “allostatic load,” and it reflects not only the impact of life experiences but also of genetic load, individual lifestyle habits reflecting items such as diet, exercise, and substance abuse, and developmental experiences that set life-long patterns of behavior and physiological reactivity Hormones associated with stress and allostatic load protect the body in the short run and promote adaptation by the process known as allostasis, but in the long run allostatic load causes changes in the body that can lead to disease The brain is the key organ of stress, allostasis, and allostatic load, because it determines what is threatening and therefore stressful, and also determines the physiological and behavioral responses Brain regions such as the hippocampus, amygdala, and prefrontal cortex respond to acute and chronic stress by undergoing structural remodeling, which alters behavioral and physiological responses Translational studies in humans with structural and functional imaging reveal smaller hippocampal volume in stress-related conditions, such as mild cognitive impairment in aging and prolonged major depressive illness, as well as in individuals with low self-esteem Alterations in amygdala and prefrontal cortex are also reported Besides Pharmaceuticals, approaches to alleviate chronic stress and reduce allostatic load and the incidence of diseases of modern life include lifestyle change, and policies of government and business that would improve the ability of individuals to reduce their own chronic stress burden

Traumatic stress: effects on the brain.

Abstract: Brain areas implicated in the stress response include the amygdala, hippocampus, and prefrontal cortex. Traumatic stress can be associated with lasting changes in these brain areas. Traumatic stress is associated with increased cortisol and norepinephrine responses to subsequent stressors. Antidepressants have effects on the hippocampus that counteract the effects of stress. Findings from animal studies have been extended to patients with post-traumatic stress disorder (PTSD) showing smaller hippocampal and anterior cingulate volumes, increased amygdala function, and decreased medial prefrontal/anterior cingulate function. In addition, patients with PTSD show increased cortisol and norepinephrine responses to stress. Treatments that are efficacious for PTSD show a promotion of neurogenesis in animal studies, as well as promotion of memory and increased hippocampal volume in PTSD.

A review of emotion deficits in schizophrenia.

Abstract: Emotion deficits in schizophrenia have been described since the time of Kraepelin. However, no comprehensive review of clinical emotion studies has ever been conducted. In this work, studies that used diagnostic criteria and were published in English were selected from an extensive PubMed search. Fifty-five studies on emotion expression repeatedly showed that individuals with schizophrenia (IWSs) display fewer overt expressions than nonpatient comparison subjects (NCSs) in verbal, facial, and acoustic channels. No clear differences were found between IWSs and depressed subjects. Sixty-nine studies examined emotion experience in schizophrenia. IWSs report higher anhedonia, and they tend to show more negative emotions in real-life event studies. In evocative studies, they report a similar degree of pleasantness and a similar or higher degree of unpleasantness. From 110 studies, it can be concluded that emotion recognition is impaired in schizophrenia in all channels. These deficits in social perception are correlated with neurocognitive deficits and some social skills. IWSs show dysfunction in the three domains of emotion expression, emotion experience, and emotion recognition, and these dysfunctions appear to be independent of each other across domains. These deficits in basic emotion processing may be linked to psychopathology and functional outcomes.

Somatic symptoms in depression.

Abstract: Both painful and nonpainful somatic symptoms essentially characterize clinical states of depressive mood. So far, this well-established psychopathological knowledge has been appreciated only insufficiently by the official diagnostic systerms of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV TR) and the ICD-10 Classification of Mental and Behavioral Disorders. Clinical Descriptions and Diagnostic Guidelines (ICD-10). From a perspective of primary care services, this unmet diagnostic need is deplorable, as the main mode of presenting a depression is by reporting somatic symptoms. This somatic form of presentation, however, significantly contributes to low rates of recognition in primary care. A diagnostic challenge may be seen in the differentiation of a depression with prevailing somatic symptoms from anxiety, somatoform disorders, and medical conditions. When somatic symptoms, particularly painful physical conditions, accompany the already debilitating psychiatric and behavioral symptoms of depression, the course of the illness may be more severe, implying a higher risk of early relapse, chronicity, suicide, or mortality due to other natural causes, the economic burden increases considerably the functional status may be hampered heavily, and health-related quality of life may be lowered dramatically. The neurobiological underpinnings of somatic symptoms in depression may guide more promising treatment approaches.

The role of serendipity in drug discovery.

Abstract: Serendipity is one of the many factors that may contribute to drug discovery. It has played a role in the discovery of prototype psychotropic drugs that led to modern pharmacological treatment in psychiatry. It has also played a role in the discovery of several drugs that have had an impact on the development of psychiatry, “Serendipity” in drug discovery implies the finding of one thing while looking for something else. This was the case in six of the twelve serendipitous discoveries reviewed in this paper, ie, aniline purple, penicillin, lysergic acid diethylamide, meprobamate, chlorpromazine, and imipramine, in the case of three drugs, ie, potassium bromide, chloral hydrate, and lithium, the discovery was serendipitous because an utterly false rationale led to correct empirical results; and in case of two others, ie, iproniazid and sildenafil, because valuable indications were found for these drugs which were not initially those sought. The discovery of one of the twelve drugs, chlordiazepoxide, was sheer luck.

Behavioral control, the medial prefrontal cortex, and resilience

Abstract: The degree of control that an organism has over a stressor potently modulates the impact of the stressor, with uncontrollable stressors producing a constellation of outcomes that do not occur if the stressor is behaviorally controllable. It has generally been assumed that this occurs because uncontrollability actively potentiates the effects of stressors. Here it will be suggested that in addition, or instead, the presence of control actively inhibits the impact of stressors. At least in part this occurs because (i) the presence of control is detected by regions of the ventral medial prefrontal cortex (mPFCv); and (ii) detection of control activates mPFCv output to stress-responsive brain stem and limbic structures that actively inhibit stress-induced activation of these structures, Furthermore, an initial experience with control over stress alters the mPFCv response to subsequent stressors so that mPFCv output is activated even if the subsequent stressor is uncontrollable, thereby making the organism resilient. The general implications of these results for understanding resilience in the face of adversity are discussed.

Depression and sleep: pathophysiology and treatment

Abstract: This review examines the relationship between sleep and depression. Most depressive disorders are characterized by subjective sleep disturbances, and the regulation of sleep is intricately linked to the same mechanisms that are implicated in the pathophysiology of depression. After briefly reviewing the physiology and topography of normal sleep, the disturbances revealed in studies of sleep in depression using polysomnographic recordings and neuroimaging assessments are discussed. Next, treatment implications of the disturbances are reviewed at both clinical and neurobiologic levels. Most antidepressant medications suppress rapid eye movement (REM) sleep, although this effect is neither necessary nor sufficient for clinical efficacy. Effects on patients' difficulties initiating and maintaining sleep are more specific to particular types of antidepressants. Ideally, an effective antidepressant will result in normalization of disturbed sleep in concert with resolution of the depressive syndrome, although few interventions actually restore decreased slow-wave sleep. Antidepressants that block central histamine 1 and serotonin 2 tend to have stronger effects on sleep maintenance, but are also prone to elicit complaints of daytime sedation. Adjunctive treatment with sedative hypnotic medications--primarily potent, shorter-acting benzodiazepine and gamma-aminobutyric acid (GABA A)-selective compounds such as zolpidem--are often used to treat associated insomnia more rapidly. Cognitive behavioral therapy and other nonpharmacologic strategies are also helpful.

Substance abuse in patients with schizophrenia

Abstract: The comorbidity of schizophrenia and substance abuse has attracted increasing attention in the past years, with multiple potential links, including genetic vulnerability, neurobiological aspects, side effects of medications, and psychosocial factors being under discussion. The link between the use of substances and the development of psychoses is demonstrated by the high prevalence of substance abuse in schizophrenia. Apart from alcohol misuse, substances commonly abused in this patient group include nicotine, cocaine, and cannabis. In particular, heavy cannabis abuse has been reported to be a stressor eliciting relapse in schizophrenic patients. In general, substance use in psychosis is associated with poorer outcomes, including increased psychotic symptoms and poorer treatment compliance. Since both disorders have been observed to be closely interdependent, a particular treatment for schizophrenic patients with comorbidity of substance abuse is needed in order to provide more effective care. In this article, we discuss various potential modes of interaction and interdependence, and the possibility of embarking on new therapeutic paths for treating this particular population.

A dopaminergic deficit hypothesis of schizophrenia: the path to discovery

Abstract: In contrast to the conventional view of dopamine involvement in schizophrenia, which posits hyperactive dopaminergic transmission, we propose that for unknown developmental and/or biochemical reasons, a primary defect occurs in efficient, tight dopaminergic synaptic transmission, triggering feedback activation and receptor upregulation, and resulting in the well-characterized increase in dopaminergic tone. This hypothesis is driven by suggestive evidence for subpopulations of dopamine D2 receptors delivering contrasting forms of dopaminergic transmission: synaptic receptors, responsible for basic dopaminergic function and subject to effective feedback control, and poorly controlled extrasynaptic receptors partly responsible for the positive symptoms of psychosis. Since the primary defect is dopamine deficiency, we term this theory the dopaminergic deficit hypothesis of schizophrenia. It is currently informing clinical studies with novel partial dopamine antagonists (dopamine stabilizers) such as ACR16, which preferentially target extrasynaptic receptors while leaving synaptic transmission and basic dopamine function intact.

Membrane transporter proteins: a challenge for CNS drug development.

Abstract: Drug transporters are membrane proteins present in various tissues such as the lymphocytes, intestine, liver, kidney, testis, placenta, and central nervous system. These transporters play a significant role in drug absorption and distribution to organic systems, particularly if the organs are protected by blood-organ barriers, such as the blood-brain barrier or the maternal-fetal barrier. In contrast to neurotransmitters and receptor-coupled transporters or other modes of interneuronal transmission, drug transporters are not directly involved in specific neuronal functions, but provide global protection to the central nervous system. The lack of capillary fenestration, the low pinocytic activity and the tight junctions between brain capillary and choroid plexus endothelial cells represent further gatekeepers limiting the entrance of endogenous and exogenous compounds into the central nervous system. Drug transport is a result of the concerted action of efflux and influx pumps (transporters) located both in the basolateral and apical membranes of brain capillary and choroid plexus endothelial cells. By regulating efflux and influx of endogenous or exogenous substances, the blood-brain barrier and, to a lesser extent the blood-cerebrospinal barrier in the ventricles, represents the main interface between the central nervous system and the blood, i.e., the rest of the body. As drug distribution to organs is dependent on the affinity of a substrate for a specific transport system, membrane transporter proteins are increasingly recognized as a key determinant of drug disposition. Many drug transporters are members of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter superfamily or the solute-linked carrier (SLC) class. The multidrug resistance protein MDR1 (ABCB1), also called P-glycoprotein, the multidrug resistance-associated proteins MRP1 (ABCC1) and MRP2 (ABCC2), and the breast cancer-resistance protein BCRP (ABCG2) are ATP-dependent efflux transporters expressed in the blood-brain barrier They belong to the superfamily of ABC transporters, which export drugs from the intracellular to the extracellular milieu. Members of the SLC class of solute carriers include, for example, organic ion transporting peptides, organic cation transporters, and organic ion transporters. They are ATP-independent polypeptides principally expressed at the basolateral membrane of brain capillary and choroid plexus endothelial cells that also mediate drug transport through central nervous system barriers.

Depression and associated physical diseases and symptoms.

Abstract: Depression can occur in association with virtually all the other psychiatric and physical diagnoses. Physical illness increases the risk of developing severe depressive illness. There are two broadly different mechanisms. The most obvious has a psychological or cognitive mechanism. Thus, the illness may provide the life event or chronic difficulty that triggers a depressive episode in a vulnerable Individual. Secondly more specific associations appear to exist between depression and particular physical disorders. These may turn out to be of particular etiological interest. The best examples are probably stroke and cardiovascular disease. Finally major depression, but especially minor depression, dysthymia, and depressive symptoms merge with other manifestations of human distress with which patients present to their doctors, Such somatic presentations test the conventional distinction between physical and mental disorder, and are a perennial source of controversy.

Rating scales in depression: limitations and pitfalls

Abstract: Since the introduction of antidepressants to psychopharmacology in the 1960s, the Hamilton Depression Rating Scale (HAM-D) has been the most frequently used rating scale for depression. When used as a scale for prediction of outcome with antidepressants, the HAM-D, by its total score, has obtained limited use analogous to the Diagnostic and Statistical Manual of Mental Disorders. 4th ed (DSM-IV) diagnosis of major depression. Most research has been devoted to the use of the HAM-D to discriminate between placebo and active drugs or to show dose-response relationship in patients with major depression. An improvement in the total HAM-D score during a drug trial does not, however, in itself qualify the drug as an antidepressant, because the total score is not a sufficient statistic. The problem of statistical versus clinical significance when analyzing placebo-controlled trials, including dose-response relationship, is outlined, with the recommendation to use effect size statistics.

Are cross-species measures of sensorimotor gating useful for the discovery of procognitive cotreatments for schizophrenia?

Abstract: Prepulse inhibition of startle (PPI), a measure of sensorimotor gating used to identify antipsychotics, is reduced in schizophrenia patients and in rodents treated with dopamine agonists or glutamate antagonists. The National institute of Menial Health (NIMH)-funded Measurement And Treatment Research to improve Cognition in Schizophrenia (MATRICS) program has initiated a new era in the development of procognitive cotreatments in schizophrenia, independently of treating positive symptoms. Although PPI is not a cognitive process per se, such abnormalities in attention may be predictive of or lead to cognitive deficits. Since first-generation antipsychotics block PPI deficits induced by dopamine agonists, this model cannot identify cognitive enhancers for use as cotreatments with antipsychotics, PPI deficits caused by glutamate antagonists, like the exacerbation of symptoms they produce in patients, are insensitive to dopamine antagonists, but reduced by clozapine. Similarly, both PPI and cognitive deficits in schizophrenia patients are insensitive to firstgeneration antipsychotics, but attenuated by clozapine. Hence, treatment-induced reversals of glutamate antagonist effects on PPI may provide animal and human models to identify treatments of cognitive deficits in patients already treated with existing antipsychotics.

Hypothalamic-pituitary-adrenal axis modulation of GABAergic neuroactive steroids influences ethanol sensitivity and drinking behavior.

Abstract: Activation of the hypothalamic-pituitary-adrenal (HPA) axis leads to elevations in γ-aminobutyric acid (GABA)-ergic neuroactive steroids that enhance GABA neurotransmission and restore homeostasis following stress. This regulation of the HPA axis maintains healthy brain function and protects against neuropsychiatrie disease. Ethanol sensitivity is influenced by elevations in neuroactive steroids that enhance the GABAergic effects of ethanol, and mayprevent excessive drinking in rodents and humans. Low ethanol sensitivity is associated with greater alcohol consumption and increased risk ofalcoholism. Indeed, ethanol-dependent rats show blunted neurosteroid responses to ethanol admin­istration that may contribute to ethanol tolerance and the propensity to drink greater amounts of ethanol. The review presents evidence to support the hypothesis that neurosteroids contribute to ethanol actions and prevent excessive drinking, while the lack of neurosteroid responses to ethanol may underlie innate or chronic tolerance and increased risk of excessive drinking. Neurosteroids may have therapeutic use in alcohol withdrawal or for relapse prevention.

Genetics of stress response and stress-related disorders.

Abstract: The major findings regarding the genetics of stress response and stress-related disorders are: (i) variations in genes involved in the sympathetic system or in the hypothalamic-pituitary-adrenocortical axis are associated with altered stress responses; (ii) genes related to the renin-angiotensin-aldosterone system or inflammation/immune response show associations with cardiovascular disorders; (iii) genes involved in monoaminergic neurotransmitter systems are associated with bipolar disorder and unipolar depression. The vast majority of these association studies followed a conventional hypothesis-driven approach, restricting the gene selection to established candidates. This very conservative approach retarded our understanding of the complex interplay between genetic factors, stress response, and stress-related disorders. Chip-based whole-genome technologies will open up access to new unbiased and statistically efficient approaches that will help to identify new candidate genes, which should be thoroughly validated in clinical and preclinical confirmatory studies. This, together with the use of new text--and information-mining tools, will bring us closer to integrating all the findings into sophisticated models delineating the pathways from genes to stress response and stress-related disorders.

Understanding structural brain changes in schizophrenia.

Abstract: Schizophrenia is a chronic progressive disorder that has at its origin structural brain changes in both white and gray matter. It is likely that these changes begin prior to the onset of clinical symptoms in cortical regions, particularly those concerned with language processing. Later, they can be detected by progressive ventricular enlargement. Current magnetic resonance imaging (MRI) technology can provide a valuable tool for detecting early changes in cortical atrophy and anomalous language processing, which may be predictive of who will develop schizophrenia.

The NIMH-MATRICS project for developing cognition-enhancing agents for schizophrenia.

Abstract: The US National Institute of Mental Health supported an initiative to facilitate the development of pharmacological agents for enhancing neurocognition in patients with schizophrenia. This has been accomplished through a consensus-building process that has included representatives from academia, the pharmaceutical industry, and government. The group has addressed obstacles to drug development that include (i) the lack of a well-accepted instrument for measuring neurocognition in clinical trials; (ii) the lack of a consensus on the best molecular target or targets for drug development; (iii) the lack of a consensus regarding the optimal trial design for either comedication that improves cognition when added to an antipsychotic or a broad spectrum agent that improves cognition and treats psychosis; and (iv) the approaches of regulatory agencies such as the US Food and Drug Administration to approving and labeling a new agent.

Experimental models of stress

Abstract: Illustrating the complexity of the stress response and its multifaceted manifestations is the leading idea of this overview of experimental paradigms used for stress induction in laboratory animals. The description of key features of models based on naturalistic stressors, pharmacological challenges, and genomic manipulations is complemented by comprehensive analysis of physiological, behavioral, neurochemical, and endocrine changes and their appropriateness as outcome readouts. Particular attention has been paid to the role of sex and age as determinants of the dynamics of the stress response. Possible translational applications of stress-inducing paradigms as models of disease are briefly sketched.

Various forms of depression.

Abstract: The current subtyping of depression is based on the Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision (DSM-IV-TR) categorical division of bipolar and depressive disorders. Current evidence, however, supports a dimensional approach to depression, as a continuum/spectrum of overlapping disorders, ranging from bipolar I depression to major depressive disorder. Types of depression which have recently been the focus of most research will be reviewed: bipolar II depression, mixed depression, agitated depression, atypical depression, melancholic depression, recurrent brief depression, minor depressive disorder, seasonal depression, and dysthymic disorder. Most research has focused on bipolar II depression, mixed depression (defined by depression and superimposed manic/hypomanic symptoms), and atypical depression. Mixed depression, by its combination of opposite polarity symptoms, has been found to be common by systematic probing for co-occurring manic/hypomanic symptoms. Mixed depression is a treatment challenge for clinicians, because antidepressants alone (ie, not protected by mood-stabilizing agents) may worsen its manic/hypomanic symptoms, such as irritability and psychomotor agitation, which the Food and Drug Administration (FDA) has listed as possible precursors to suicidality.

Experimental animal models for the simulation of depression and anxiety

Abstract: An impressive number of animal models to assess depression and anxiety are available today. However, the relationship between these models and the clinical syndromes of depression and anxiety is not always clear. Since human anxiety disorders represent a multifactorial phenomenon frequently comorbid with major depression and/or other psychiatric problems, the chance of creating animal models which consistently reflect the human situation is quite poor. When using experimental models to understand homologies between animal and human behavior, we have to consider the context in which an animal is investigated, and both the functional significance and relevance of the behavioral parameters that are quantified. Moreover, gender and interindividual and interspecies variabilities in behavioral responses to the test situation and in the sensitivity to pharmacological treatments are potential sources for confounding results. In the past, these aspects have been often neglected in preclinical approaches to behavioral pharmacology and psychopharmacology. A pragmatic approach of combined preclinical and clinical efforts is necessary to imitate one or more aspects relevant to pathological anxiety disorders and depression. The resulting models may identify central nervous processes regulating defined behavioral output, with the potential to develop more effective treatments.

Schizophrenia in late life: emerging issues

Abstract: Schizophrenia in late life is emerging as a major public health concern worldwide. We discuss several areas of research and clinical care that are particularly pertinent to older persons with schizophrenia, including the public health challenge and the cost of care. We then discuss clinical issues relevant to late-life schizophrenia (course of illness and cognition), medical care and comorbidity in older psychiatric patients (general and illness-related), and treatment concerns related to the use of atypical antipsychotics in older persons with psychosis (efficacy and side effects). Clinical care for this ever-increasing segment of our population requires special consideration of the unique characteristics of older persons with schizophrenia.

Nonpharmacological, somatic treatments of depression: electroconvulsive therapy and novel brain stimulation modalities

Abstract: Until recently, a review of nonpharmacological, somatic treatments of psychiatric disorders would have included only electroconvulsive therapy (ECT). This situation is now changing very substantially Although ECT remains the only modality in widespread clinical use, several new techniques are under investigation. Their principal indication in the psychiatric context is the treatment of major depression, but other applications are also being studied. All the novel treatments involve brain stimulation, which is achieved by different technological methods. The treatment closest to the threshold of clinical acceptability is transcranial magnetic stimulation (TMS). Although TMS is safe and relatively easy to administer, its efficacy has still to be definitively established. Other modalities, at various stages of research development, include magnetic seizure therapy (MST), deep brain stimulation (DBS), and vagus nerve stimulation (VNS). We briefly review the development and technical aspects of these treatments, their potential role in the treatment of major depression, adverse effects, and putative mechanism of action. As the only one of these treatment modalities that is in widespread clinical use, more extended consideration is given to ECT. Although more than half a century has elapsed since ECT was first introduced, it remains the most effective treatment for major depression, with efficacy in patients refractory to antidepressant drugs and an acceptable safety profile. Although they hold considerable promise, the novel brain stimulation techniques reviewed here will be need to be further developed before they achieve clinical acceptability.

Angst and the amygdala

Abstract: Fear is an adaptation to danger, but excessive fear underlies diverse forms of mental anguish and pathology. One neural site linked to a sense of adversity is the amygdala, and one neuropeptide, corticotropin-releasing hormone (CRH), is localized within the central nucleus of the amygdala. Glucocorticoids enhance the production of CRH in this region of the brain, resulting in increased attention to external events and, when sustained for longer periods of time, perhaps contributing to anxious depression.

Changes in the immune system in depression and dementia: causal or coincidental effects?

Abstract: Epidemiological studies show that there is a correlation between chronic depression and the likelihood of demential in later life There is evidence that inflammatory changes in the brain are pathological features of both depression and dementia This suggests that an increase in inflammation-induced apoptosis, together with a reductin in the synthesis of neurotrophic factors caused by a rise in brain glucocorticoids, may play a role in the pathology of these disorders A reduction in the neuroprotective components of the kynurenine pathway, such as kynurenic acid, and an increase in the neurodegenerative components, 3-hydroxykynurenine and quinolinic acid, contribute to the pathological changes Such changes are postulated t cause neuronal damage, and thereby predispose chronically depressed patients to demential

Treatments in depression.

Abstract: Major depression is believed to be a multifactorial disorder involving predisposing temperament and personality traits, exposure to traumatic and stressful life events, and biological susceptibility. Depression, both unipolar and bipolar, is a “phasic” disease. Stressful life events are known to trigger depressive episodes, while their influence seems to decrease over the course of the illness. This suggests that depression is associated with progressive stress response abnormalities, possibly linked to impairments of structural plasticity and cellular resilience. It therefore appears crucial to adequately treat depression in the early stages of the illness, in order to prevent morphological and functional abnormalities. While evidence suggests that a severely depressed patient needs antidepressant drug therapy and that a non-severely depressed patient may benefit from other approaches (ie, “nonbiological”), little research has been done on the effectiveness of different treatments for depression. The assertion that the clinical efficacy of antidepressants is comparable between the classes and within the classes of those medications may be true from a statistical viewpoint, but is of limited value in practice. The antidepressant drugs may produce differences in therapeutic response and tolerability. Among the possible predictors of outcome in depression treatment, those derived from clinical assessment, neuroendocrine investigations, polysomnographic sleep parameters, genetic variables, and brain imaging techniques have been extensively studied. This article also reviews therapeutic strategies used when initial treatment fails, and describes briefly new concepts in antidepressant therapies such as the regulation of disturbances in circadian rhythms. The treatment of depressive illness does not stop with treatment of acute episodes, and has to be envisaged as a continuous therapeutic intervention, of which we are still not able to determine the optimal duration of treatment and the moment that it should be ceased.

Pharmacogenetics of antipsychotic therapy: pivotal research issues and the prospects for clinical implementation.

Abstract: The core hypothesis underlying pharmacogenetics is that genetic factors play a significant role in the well-recognized differences between individuals in response to medication and susceptibility to adverse effects. If these genetic factors can be identified and understood, they may serve as predictors to guide clinicians in tailoring medication to the individual patient. Recent developments in the field of antipsychotic drug treatment suggest that pharmacogenetics could play an important role, permitting the use of first-generation antipsychotics (FGAs) for patients in whom the use of second-generation antipsychotics (SGAs) is limited by efficacy considerations or adverse effects, in this paper, key issues that need to be taken into consideration in designing and interpreting pharmacogenetic studies of antipsychotic drugs are discussed against the background of data emanaling from studies on the genetics of tardive dyskinesia (TD), an important adverse effect of FGAs. The issues considered include the advantages and potential pitfalls of case-control association studies of pharmacogenetic traits, the role of demographic factors such as age and gender, additive effects of genes, and gene-gene and gene-environment interaction. The prospects for implementation of pharmacogenetic testing in the clinic are considered in the context of a preliminary model that has been tested for prediction of susceptibility to TD.

Functional genomics in postmortem human brain: Abnormalities in a DISC1 molecular pathway in schizophrenia

Abstract: The disrupted in schizophrenia 1 (DISC1) gene has been identified as a schizophrenia susceptibility gene based on linkage and single nucleotide polymorphism (SNP) association studies and clinical data, suggesting that risk SNPs impact on hippocampal structure and function. We hypothesized that altered expression of DISC1 andlor its molecular partners (nuclear distribution element-like [NUDEL], fasciculation and elongation protein zeta-1 [FEZ1], and lissencephaly 1 [L1S1 ]) may underlie its pathogenic role in schizophrenia and explain its genetic association. We examined the expression of DISC1 and its binding partners in the hippocampus and dorsolateral prefrontal cortex of postmortem human brains of schizophrenic patients and controls. We found no difference in the expression of DISC1 mRNA in schizophrenia, and no association with previously identified risk SNPs, However, the expression of NUDEL, FEZ1, and LIS1 vas significantly reduced in tissue from schizophrenic subjects, and the expression of each showed association with high-risk DISC1 polymorphisms. These data suggest involvement of genetically linked abnormalities in the DISC1 molecular pathway in the pathophysiology of schizophrenia.

ADHD in adolescence and adulthood, with a special focus on the dopamine transporter and nicotine.

Abstract: The persistence of attention deficit hyperactivity disorder (ADHD) into adolescence and adulthood has now been accepted as a clinical entity. The rate of prevalence among adults is assumed to be from 2% to 4%. With increasing age, a symptom change has to be considered; disturbance of attention becomes more prominent, whereas hyperactivity often diminishes or changes to inactivity. Neuroimaging studies show a high striatal dopamine transporter (DAT) availability in most adults with ADHD; this can be reduced by stimulants. Nicotine seems to have a stimulant-like action on the DAT. In most adults with ADHD, therapy has to be multimodal, combining psychotherapy and medication. Methylphenidate is the first-line drug in adult ADHD; further options are amphetamine and noradrenaline reuptake inhibitors. Nonresponders to methylphenidate seem to have no elevated DAT availability prior to therapy. Combination with other psychiatric disorders occurs frequently in adults with ADHD; in these patients additional pharmacological treatment with special regard to the comorbid disease is recommended.

The impact of subjective well-being under neuroleptic treatment on compliance and remission.

Abstract: The patients' perspective of antipsychotic treatment was largely neglected for a long period. It has only been during the last 10 years, with the development of atypical antipsychotics, that scientific interest in this issue has markedly increased. Numerous studies have shown that the majority of schizophrenic patients are able to fill out a self-rating scale in a meaningful way, and several self-report scales with sufficient internal consistency and good construct validity have been developed. The effects of antipsychotic treatment on psychopathology and on subjective well-being (SW) are not strongly related; the perspectives of the patient and his/her psychiatrist markedly differ. Recent research indicates that SW/quality of life, much more improved by atypical than by typical antipsychotics, has a strong impact on compliance, as well as on the chance of achieving remission. The data strongly suggest that a systematic evaluation of the patient's perspective of antipsychotic treatment is meaningful and necessary to increase compliance, functional outcome, and long-term prognosis.