The deficit syndrome in schizophrenia: implications for the treatment of negative symptoms.

Schizophrenia psychopathology clusters around several symptom domains. One of these domains is negative symptomatology. We have defined the deficit syndrome as a disease entity characterized by the presence of primary enduring negative symptoms. A focus on primary negative symptoms demonstrates that deficit and nondeficit schizophrenia subgroups differ on clinical features, associated neuroimaging findings, neuropsychological and neurological measures, pattern of risk factors, and pharmacological response profiles. In the present article we focus on the importance of the distinction between primary and secondary negative symptoms for pathophysiology research. The development and mechanistic understanding of anti-negative symptom drugs may be informative regarding pathophysiology of primary negative symptoms. Although new antipsychotics are effective for secondary negative symptoms they have shown no efficacy for the deficit syndrome and new mechanisms of drug action appear to be required to address this aspect of the disease syndrome. The loss of precious human experiences and the association with poor long-term functional outcome justifies a focused and dedicated effort to discover the causes and treatments of this distinctive aspect of schizophrenia.     

Problems in designing and recruiting to therapeutic trials in primary progressive multiple sclerosis

Patients with primary progressive multiple sclerosis have atypical clinical and magnetic resonance imaging (MRI) characteristics which present unique problems in designing and recruiting to therapeutic trials. The first randomised controlled therapeutic trial specifically for primary progressive multiple sclerosis is now underway. Although only an exploratory phase II study, it has provided further insight into difficulties in diagnosis, classification and choice of clinical and MRI outcome measures. Patients with primary progressive multiple sclerosis have a wide differential diagnosis and do not readily conform to the Poser criteria. They may therefore present diagnostic uncertainty, particularly as their classification often relies on a retrospective history. This was highlighted during the recruitment to this study of interferon-β_1a. Of the 138 patients referred with a definite diagnosis of primary progressive multiple sclerosis only 50 were enrolled in the study. Of the 88 patients not included, 50% either did not have primary progressive multiple sclerosis, or the diagnosis was not secure. Outcome measures pose particular problems. Clinically the focus must be on progression, and the measure should be both responsive and reliable. In relation to MRI, the currently recommended measures for therapeutic trials in relapsing/remitting and secondary progressive multiple sclerosis show little change in primary progressive multiple sclerosis, and therefore more pathologically specific MRI measures are required. Strict clinical guidelines and further developments in clinical and MRI measures are required to facilitate future therapeutic trials in primary progressive multiple sclerosis. Received: 24 June 1998 Received in revised form: 21 December 1998 Accepted: 30 December 1998     

Designing and interpreting the results of first-time-to-man studies

First human administration of a new chemical entity (NCE) constitutes a critical step in drug development. The primary objective of such a study is the assessment of the shortterm safety and tolerability of single and multiple doses of the NCE in healthy volunteers. Secondary objectives are to obtain preliminary data on the pharmacokinetics and pharmacodynamics using surrogate or biornarkers of the beneficial as well as the adverse effects of the drug. Interpretation of safety data should be cautious and mainly based on comparisons with placebo. A special focus should be made on the assessment of adverse events, liver enzymes, and cardiac repolarization. Well-designed, first-time-to-man studies should determine the safety of the NCE in humans and predict the dose range that may be used to safely and accurately conduct further clinical trials in the target patient population based on safety data (maximum tolerated dose), pharmacodynamics (minimum active dose, duration of action, and dosage regimen), and pharmacokinetics (dosage regimen).     

An ideal trial to test differential onset of antidepressant effect

Although various published clinical studies have suggested that some antidepressants may have a more rapid onset of therapeutic effect than others, none of these trials was adequately designed to measure differential time to onset of effect. Thus, existing data do not support claims that one drug reduces the symptoms of depression faster than another. In this article, we propose a study that would be ideal for measuring comparative onset of antidepressant effect. The key features of this ideal trial include (1) a prospective definition of early onset of action, (2) increased frequency of assessment, (3) a data-analytic approach capable of capturing the dynamic nature of symptomatic change, and (4) various strategies to minimize bias and heterogeneity of response.     

Clinical trials in AD: are current formats and outcome measures adequate?

Great strides have been made in the measurement of outcomes and treatment efficacy in clinical trials of Alzheimer disease (AD) drugs during the past 25 years. Several sensitive, reliable, and valid clinical outcome measures have been developed. The methodology, trial design, and outcome measures for demonstrating symptomatic benefits of an AD drug are now established. However, a greater challenge lies ahead. Major advances in fundamental knowledge about the pathophysiology of the disease and in animal models have transformed the focus of current efforts to developing and testing therapies that may actually slow disease progression, delay the onset of symptoms, and even ultimately prevent the disease. The long-duration trials that will likely be necessary to demonstrate an effect on disease progression will be costly and difficult. Proof-of-concept trials and subsequent long-term trials could gain power and efficiency from use of biologic markers of underlying disease severity, but currently available biologic markers are not ideal. A major barrier to such trials is their size and cost. One approach to reducing the cost would be to recruit "enriched" samples of subjects who are at greater risk of developing AD during the trial than the general, elderly population. The major effort required to screen and recruit large numbers of subjects for such trials also contributes to the cost. Probably the biggest problem currently is the enormous effort and cost of conducting periodic clinical evaluations to determine if subjects have declined or developed dementia. Research to develop more efficient assessment methods is clearly needed. Data acquisition over the Internet is potentially efficient and attractive and may become practical as Internet accessibility increases.     

A Perspective on the Primary Care of Patients With Behavior, Mood, and Thought Disturbances: Clinical Applications of Olanzapine

Primary care practitioners are in an ideal position to initiate treatment for patients with behavior, mood, and thought disturbances. It is believed that early identification and treatment of these symptomatic features of primary or secondary central nervous system disorders may significantly reduce morbidity and benefit the patient, his/her family, and involved caregivers, including the primary care physician. A broad list of central nervous system-active medications are utilized by family physicians to treat patients who exhibit symptoms of agitation, altered mood, and disordered thought. Some medications have demonstrated superiority over placebo or active medicines in reported clinical trials. This article is a brief overview of the safety and efficacy from reported studies of the use of medications frequently used to treat symptoms related to behavior, mood, and thought disturbances, with a specific focus on the clinical applicability of olanzapine.     

Adjunctive therapies for HIV-1 associated neurologic disease

In the past decade we have seen a milder phenotype and decreased incidence of HIV-1 associated dementia (HAD), largely due to the widespread use of combination chemotherapy to reduce viral burden. However, the prevalence of neurologic disease in people living with HIV-1 has actually increased, raising significant concerns that new therapeutic strategies, directed at restoring neuronal and glial homeostasis and signaling in the central nervous system (CNS), as opposed to directly interfering with the life cycle of HIV-1, must be developed. In this review, we focus briefly on previous Phase 1 clinical trials for adjunctive (i.e., chemotherapeutic agents that do not have a primary antiretroviral mechanism of action) therapy in patients with HAD, followed by an overview of key molecular events in the neuropathogenesis of HAD, and then discuss in more detail our rationale for investigating the effects of therapeutic agents that restore impaired mitochondrial bioenergetics in the CNS. Specifically, we focus on agents that either work in part through K-ATP channels, present in both mitochondria and plasma membranes, and agents that work to weakly uncouple the respiratory capacity of the electron transport chain in mitochondria from ATP production. We propose these agents may be complementary to currently available antiretroviral agents and may significantly improve the capacity of CNS infected with HIV-1 to meet increased bioenergetic demands involved in normal synaptic communication.     

缺血性卒中病因分型发展

准确的缺血性卒中病因分型与病理生理、临床特征、疗效评估和预后相关。卒中目前存在数种病因分型系统,根据分类方式可分为表型分类系统及成因分类系统。前者主要根据检查结果可将一位卒中患者归为多个并列的病因,如动脉粥样硬化、小血管病、心源性和其他原因(atherothrombosis,small vessel disease,cardiac causes,and other uncommon causes,ASCO)分型;后者则把检查结果与临床表现相结合,经过分析做出一个最可能的病因,如急性卒中治疗低分子肝素试验(Trial of Org 10 172 in Acute Stroke Treatment,TOAST)分型、病因分类系统(causative classification system,CCS)。每种分型都有自身的优点及局限性。理想的分型系统应当有效、一致性高、易操作、基于证据及能够结合最新的研究成果。     

Evidence based migraine prophylactic drug therapy

Prophylactic drug therapy is a major component of overall migraine management. However, because we do not know how currently used prophylactic drugs exert their beneficial effects in migraine, their use is based primarily on clinical trials. In general, prophylactic drugs are indicated when patients have three or more attacks a month and symptomatic medication use alone is not satisfactory. The choice of drug must be individualized, and is influenced by contraindications, potential side effects, the need to treat associated symptoms like tension-type headache and insomnia, and drug cost. Whether an individual patient will respond to a given drug cannot be predicted, but there are varying degrees of scientific evidence supporting the use of each prophylactic drug in migraine. This evidence is best for metoprolol, divalproex, amitriptyline, atenolol, flunarizine and naproxen. Based on placebo-controlled crossover studies, it would appear that at least some prophylactic drugs exert the greater part of their prophylactic effects very quickly, and that these also disappear very quickly once the drug is stopped. This may not apply to all prophylactic drugs and more research is needed. More well designed clinical trials are needed to guide our use of migraine prophylactic drugs. Although clinical experience is useful, placebo responses and variations in the migraine tendency over time can make interpretation of this experience difficult. Major advances will likely only occur once the pathogenesis of migraine and the mode of action of the prophylactic drugs is better understood.     

Pediatric stroke: Opportunities and challenges in planning clinical trials

A conference entitled "Towards the establishment of clinical trials in pediatric and newborn stroke" assembled stroke animal model researchers, pediatric stroke researchers, adult stroke trialists, and members of the Food and Drug Administration and National Institute of Neurological Disorders and Stroke to focus on the obstacles and opportunities for conducting randomized trials in pediatric stroke. The need for good prospective clinical data in newborn and pediatric stroke in regard to outcome and recurrence risk was stressed. For clinical trials, there should be a scientific rationale. Preclinical data should be as promising and as complete as possible. Adult data should be explored, both positive and negative. For medication trials, reasonable safety and bioavailability data for the agent in question should be available. Commitment of researchers, collaboration with colleagues in primary care, emergency rooms, and intensive care units, and most importantly the willingness to participate of children and their families will all be crucial. Most children with cancer in the United States are enrolled in clinical trials and have an outcome superior to the adult patient with cancer, who is less likely to be enrolled in a trial. We should strive for enrollment and outcome results in pediatric stroke similar to those found in pediatric oncology trials.     

Antidepressants and their onset of action: a major clinical, methodological and pronostical issue

Although antidepressant medications are effective in about 50-70% of patients with major depressive disorder (MDD), they have a delayed onset of therapeutic effect. This latency is one of the current major limitations of these medications, in that it prolongs the impairments associated with depression, leaves patients vulnerable to an increased risk of suicide, increases the likelihood that a patient will prematurely discontinue therapy, and increases medical costs associated with severe depression. It is becoming increasingly clear that differences may exist between antidepressants and some evidence suggests that some antidepressant agents may begin to work faster than others. Escitalopram, duloxetine, venlafaxine, and mirtazapine have shown statistically significant differences in some measures of antidepressant action within the first two weeks of treatment, both in placebo-controlled trials and in head-to-head comparisons with other antidepressants. Results of the current review should be regarded with certain important limitations in mind. First, differences in times to onset of antidepressant response have been shown in clinical efficacy studies not specifically designed to detect differences in onset of action (post-hoc analysis). Second, results observed in 'pure' clinical trial samples should not be directly generalized to the real clinical practice since it has been proven in clinical settings that less than one in seven depressed patients would be eligible to participate in antidepressant clinical trials. For instance, depressed patients who are suicidal or who score higher than 30 on the 17-item HAM-D are excluded from antidepressant clinical trials. Third, caution is warranted when applying these findings to clinical populations with more severe depressions with respect to the fact that among clinical populations, severity of depression coincides with comorbidity, including such psychiatric disorders as anxiety disorders, personality disorders and substance abuse. In addition, the magnitudes of the size-effects of antidepressants versus placebo are clearly higher in severely depressed patients. Fourth, specific items on depression rating scales may induce greater antidepressant/placebo differences. For instance, the 17-item HAM-D contains three questions pertaining to sleep. It questions the fact that earlier onset may appear not only via a specific antidepressant effect but also via a non-specific effect on anxiety, sleep, physical pain or other accessory symptoms. Thus, current data do not clearly support claims that one drug reduces the symptoms of depression faster than another, though the existing literature suggests that escitalopram displays some superiority in terms of rapidity of action. Given the potential benefits of early-acting antidepressant treatments, the possibility of superior speed of onset of escitalopram presented here merits further study in adequately designed, prospective clinical trials. A definitive demonstration of early onset of action awaits the results of appropriately designed and powered clinical studies, which may include (1) a prospective definition of early onset of action, (2) more focused assessments of core emotional symptoms and cognitive deficits of depression by using specific and sensitive tools, (3) a data-analytic approach capable of capturing the dynamic nature of symptomatic change (for example, survival analysis), and (4) strategies to minimize biases and heterogeneity of response.     

Management of treatment-resistant depression

Given the limitations of evidence for treatment options that are consistently effective for TRD and the possibility that TRD is in fact a form of depression that has a low probability of resolving, how can clinicians help patients with TRD? Perhaps the most important conceptual shift that needs to take place before treatment can be helpful is to accept TRD as a chronic illness, an illness similar to many others, one that can be effectively managed but that is not, at our present level of knowledge, likely to be cured. An undue focus on remission or even a 50% diminution of symptoms sets unrealistic goals for both patients and therapists and may lead to overtreatment and demoralization. The focus should be less on eliminating depressive symptoms and more on making sense of and learning to function better in spite of them. It is important to acknowledge the difficult nature of the depressive illness, to remove blame from the patient and clinician for not achieving remission, to set realistic expectations, and to help promote better psychosocial functioning even in the face of persisting symptoms. The critical element when implementing such an approach is a judicious balance between maintaining hope for improvement without setting unrealistic expectations. It is important to reemphasize that following a disease management model with acceptance of the reality of a chronic illness is not nihilistic and does not mean the abandonment of hope for improvement. The first step in treating a patient with TRD is to perform a comprehensive assessment of the patient’s past and current treatment history to ensure that evidence-based treatment trials have in fact been undertaken, and if not, such treatment trials should be implemented. If the patient continues to have significant residual symptoms, it is important to determine the impact is of these symptoms on the patient’s quality of life and ability to function. It is also important to evaluate the factors that may be contributing to the persistence of depressive symptoms such as comorbid personality disorders, somatic disorders, substance abuse, and work and interpersonal conflicts. The treatment of patients with TRD needs to move beyond attempts to modify symptoms without taking into consideration and attempting to modify the patient’s personality, coping skills, and social system. Further somatic treatment trials can be undertaken, if desired by the patient and therapist, as a small (5%–15%) percentage of patients may respond and further treatment trials, and this may engender hope. The risk with this approach is that patients and therapists may not work at disease management skills if they believe there may be a resolution of the depression if they could just find the right medication or intervention. Therapists may also feel pressured by patients, families, insurance companies, as well as their own sense of helplessness to escalate treatment in a more and more aggressive manner in an attempt to achieve an elusive remission. A disease management program can provide the therapist and patient with sufficient structure, skills, and goals to encourage ongoing treatment without resorting to unproven measures that may create more side effects and problems. It is particularly important to include the patient’s significant others in the reformulation of the patient’s problem and thereby learn how to manage the illness more effectively. Significant others and family members can be invaluable in providing support for dealing with the difficult process of acquiring a new skill set. Indeed, they spend significantly more time with the patient than does any therapist. Family members are likely to provide this kind of support only if they have been part of the assessment and treatment process. Patients with a wide range of chronic medical illnesses can and do learn to function effectively and to achieve a satisfying quality of life in spite of their illness. There is no reason to think that patients with TRD should not be able to achieve a similar level of illness management, functioning, and quality of life.     

Randomized controlled trials for schizophrenia: study designs targeted to distinct goals

Randomized controlled trials for antipsychotic drugs have a variety of design features suited to diverse purposes. Efficacy (or explanatory) trials seek to establish if a drug can reduce psychotic symptoms under ideal circumstances. To isolate drug effects, researchers enroll carefully selected patients. Specialized research personnel use rating scales of symptoms that are sensitive to drug effects as the study primary outcomes. Large simple trials (LSTs) are conducted at typical treatment settings with usual clinical personnel and enroll large numbers of participants so small but clinically important differences between treatment options can be detected. LSTs focus narrowly on clearly defined, patient-oriented outcomes. To some extent, practical trials can be conceptualized as hybrids of efficacy and large simple trials. Practical trials provide independent evidence to inform decision makers about the everyday effectiveness of clinically relevant alternative interventions. Practical trial researchers include a heterogeneous population of patients and collect data on a broad range of meaningful health outcomes at many types of practice settings intended to represent usual treatment. The designers of practical trials make trade-offs between internal validity, external validity, the breadth of issues addressed, and the ability to detect small differences. The different objectives of trials should be considered in the interpretation of the complete body of randomized evidence on antipsychotic drugs.     

Revised 2004 International Classification of Headache Disorders: new headache types

In 1988, the International Headache Society created a classification system that has become the standard for headache diagnosis and research. The International Classification of Headache Disorders galvanized the headache community and stimulated nosologic, epidemiologic, pathophysiologic, and genetic research. It also facilitated multinational clinical drug trials that have led to the basis of current treatment guidelines. While there have been criticisms, the classification received widespread support by headache societies around the globe. Fifteen years later, the International Headache Society released the revised and expanded International Classification of Headache Disorders second edition. The unprecedented and rapid advances in the field of headache led to the inclusion of many new primary and secondary headache disorders in the revised classification. Using illustrative cases, this review highlights 10 important new headache types that have been added to the second edition. It is important for neurologists to familiarize themselves with the diagnostic criteria for the frequently encountered primary headache disorders and to be able to access the classification (www.i-h-s.org) for the less commonly encountered or diagnostically challenging presentations of headache and facial pain.     

The National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project: schizophrenia trial design and protocol development

The National Institute of Mental Health initiated the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) program to evaluate the effectiveness of antipsychotic drugs in typical settings and populations so that the study results will be maximally useful in routine clinical situations. The CATIE schizophrenia trial blends features of efficacy studies and large, simple trials to create a pragmatic trial that will provide extensive information about antipsychotic drug effectiveness over at least 18 months. The protocol allows for subjects who receive a study drug that is not effective to receive subsequent treatments within the context of the study. Medication dosages are adjusted within a defined range according to clinical judgment. The primary outcome is all-cause treatment discontinuation because it represents an important clinical endpoint that reflects both clinician and patient judgments about efficacy and tolerability. Secondary outcomes include symptoms, side effects, neurocognitive functioning, and cost-effectiveness. Approximately 50 clinical sites across the United States are seeking to enroll a total of 1,500 persons with schizophrenia. Phase 1 is a double-blinded randomized clinical trial comparing treatment with the second generation antipsychotics olanzapine, quetiapine, risperidone, and ziprasidone to perphenazine, a midpotency first generation antipsychotic. If the initially assigned medication is not effective, subjects may choose one of the following phase 2 trials: (1) randomization to open-label clozapine or a double-blinded second generation drug that was available but not assigned in phase 1; or (2) double-blinded randomization to ziprasidone or another second generation drug that was available but not assigned in phase 1. If the phase 2 study drug is discontinued, subjects may enter phase 3, in which clinicians help subjects select an open-label treatment based on individuals' experiences in phases 1 and 2.     

Recent developments in the understanding and management of functional somatic symptoms in primary care

PURPOSE OF REVIEW: Medically unexplained or functional somatic symptoms are prevalent in primary care, but general practitioners commonly find them difficult to treat. We focus on the conceptual issues and treatment from a primary care perspective, although the field is difficult to review because of the inconsistency and multiplicity of terminology used by different authors and specialties. RECENT FINDINGS: The training of general practitioners in management techniques has been hampered by an obsolete theoretical framework and outdated diagnostic systems. Epidemiological studies, however, indicate that valid, empirically based diagnostic criteria for functional disorders may be developed. Management studies in primary care have shown disappointing effects on patient outcome, but a lot may be gained by making the training programmes more sophisticated. Recently, stepped care approaches have been introduced but they need scientific evaluation. SUMMARY: There is an immediate need for a common language and a theoretical framework of understanding of functional symptoms and disorders across medical specialties, clinically and scientifically. Any names that presuppose a mind-body dualism (such as somatization, medically unexplained) ought to be abolished. The overall ambition for treatment is to offer patients with functional somatic symptoms the same quality of professional healthcare as we offer any other patient.     

Optimizing the early phase development of new analgesics by human pain biomarkers

Human pain biomarkers are based on standardized acute activation of pain pathways/mechanisms and quantitative assessment of the evoked responses. This approach can be applied to healthy volunteers, to pain patients, and before and after pharmacological interventions to help understanding and profile the mode of action (proof-of-concept) of new and existing analgesic compounds. Standardized stimuli of different modalities can be applied to different tissues (multimodal and multi-tissue) for profiling analgesic compounds with respect to modulation of pain transduction, transmission, specific mechanisms and processing. This approach substantiates which specific compounds may work in particular clinical pain conditions. Human pain biomarkers can be translational and may bridge animal findings in clinical pain conditions, which in turn can provide new possibilities for designing more successful clinical trials. Biomarker based proof-of-concept drug studies in either volunteers or selected patient populations provide inexpensive, fast and reliable mechanism-based information about dose-efficacy relationships. This is important information in the early drug development phase and for designing large expensive clinical trials.     

Interferon-β treatment for multiple sclerosis

Multiple sclerosis (MS) is the leading nontraumatic cause of neurologic disability in young adults. Interferon-β, approved for use in 1993, was the first treatment to modify the course and prognosis of the disease and remains a mainstay of MS treatment. Numerous large-scale clinical trials in early, active patient populations have established the clinical efficacy of interferon-β in reducing relapses and delaying disability progression. Although its mechanism of action remains incompletely understood, a reduction in active lesions seen on magnetic resonance imaging implies primary anti-inflammatory properties, a mechanism supported by basic immunologic research. Variation in individual patient responsiveness to interferon-β may be due to disease variability or differential induction of interferon-stimulated genes. The magnitude of the therapeutic effect appears to be similar among products, but the optimal dose, route, and frequency of administration of the drug remain uncertain.