Does risperidone have a place in the treatment of nonschizophrenic patients?

There is a now a substantial body of evidence that suggests the new antipsychotic agent, risperidone, may be safe and effective for treating psychotic, affective or behavioural symptoms associated with various disorders other than schizophrenia, schizophreniform disorder or schizo-affective disorder. These conditions include bipolar disorder, obsessive-compulsive disorder, Tourette's syndrome, dementia, Lewy body disease, mental retardation, Parkinson's disease, idiopathic segmental dystonia and organic catatonia. Although much of the data is anecdotal or in the form of open studies, there is now emerging a small number of well controlled investigations supporting efficacy for mania, dementia, behavioural disturbance in mental retardation and conduct disorder. Conventional antipsychotics have long been used, either in a primary capacity or as an adjunct to treat these disorders; however, they have limited benefit, pose significant risks of extrapyramidal side-effects, and may cause the potentially life-threatening neuroleptic malignant syndrome. In contrast, risperidone at the recommended low doses may be efficacious and pose reduced risk of motor side-effects. This article reviews the evidence that risperidone may be an effective new treatment for disorders other than schizophrenia.     

Anti-oxidant therapy: does it have a role in the treatment of human disease?

Free radical oxidative stress has been implicated in the pathogenesis of a variety of human diseases. Natural anti-oxidant defences have also been found to be defective in many of the same diseases. Many researchers have concluded that, if the imbalance between the oxidative stresses and anti-oxidant defence can be corrected by supplementing natural anti-oxidant defences, it may be possible to prevent or retard disease progression. Potential anti-oxidant therapies include natural anti-oxidant enzymes and vitamins or synthetic agents with anti-oxidant activity. Diseases where anti-oxidant therapy may be beneficial can be divided into those involving acute intervention, such as reperfusion injury or inflammation, and those involving chronic preventative therapy, such as atherosclerosis, carcinogenesis and diabetic vascular disease. The pharmaceutical considerations are different in each case. The principles guiding the development, use and assessment of anti-oxidant therapies are discussed in this review.     

Repetitive transcranial magnetic stimulation : does it have potential in the treatment of depression?

Transcranial magnetic stimulation (TMS) has become a major research tool in experimental clinical neurophysiology as a result of its potential to noninvasively and focally stimulate cortical brain regions. Currently, studies are being conducted to investigate whether repetitive TMS (rTMS)-mediated modulation of cortical function may also provide a therapeutic approach in neurological and psychiatric disorders. Preclinical findings have shown that prefrontal rTMS can modulate the function of fronto-limbic circuits, which is reversibly altered in major depression. rTMS has also been found to exert effects on neurotransmitter systems involved in the pathophysiology of major depression (e.g. stimulates subcortical dopamine release and acts on the hypothalamic pituitary adrenal axis, which is dysregulated in depression). To date, numerous open and controlled clinical trials with widely differing stimulation parameters have explored the antidepressant potential of rTMS. Though conducted with small sample sizes, the majority of the controlled trials demonstrated significant antidepressant effects of active rTMS compared with a sham condition. Effect sizes, however, varied from modest to substantial, and the patient selection focused on therapy-resistant cases. Moreover, the average treatment duration was approximately 2 weeks, which is short compared with other antidepressant interventions. Larger multicentre trials, which would be mandatory to demonstrate the antidepressant effectiveness of rTMS, have not been conducted to date.A putative future application of rTMS may be the treatment of patients who did not tolerate or did not respond to antidepressant pharmacotherapy before trying more invasive strategies such as electroconvulsive therapy and vagus nerve stimulation. Theoretically, rTMS may be also applied early in the course of disease in order to speed up and increase the effects of antidepressant pharmacotherapy. However, this application has not been a focus of clinical trials to date. Research efforts should be intensified to further investigate the effectiveness of rTMS as an antidepressant intervention and to test specific applications of the technique in the treatment of depressive episodes.     

How effective is alcoholism treatment in the United States?

OBJECTIVE: Following in the footsteps of several prior attempts, this review seeks a meaningful and data-based answer to the common question of how people fare, on average, after being treated for alcoholism (broadly defined as alcohol use disorders). METHOD: Findings from seven large multisite studies were combined to derive estimates of the average effectiveness of alcoholism treatment. To provide common outcome measures, conversion equations were used to compute variables not reported in the original studies. RESULTS: During the year after treatment, 1 in 4 clients remained continuously abstinent on average, and an additional 1 in 10 used alcohol moderately and without problems. During this period, mortality averaged less than 2%. The remaining clients, as a group, showed substantial improvement, abstaining on 3 days out of 4 and reducing their overall alcohol consumption by 87%, on average. Alcohol-related problems also decreased by 60%. CONCLUSIONS: About one third of clients remain asymptomatic during the year following a single treatment event. The remaining two thirds show, on average, large and significant decreases in drinking and related problems. This substantial level of improvement in "unremitted" clients tends to be overlooked when outcomes are dichotomized as successful or relapsed.     

What is the place of psychological treatments in mood disorders?

While psychotherapy has many applications for mood disorders, this paper focuses on those psychotherapies (cognitive behaviour therapy or CBT, and interpersonal psychotherapy or IPT) that have been manualized, extensively evaluated, and positioned as definitive therapies for unipolar depressive disorders. This paper suggests some reasons as to why their role and utility remain unclear. First, despite many randomized controlled efficacy studies, differentiation from other psychotherapies or control interventions appears to occur only when the actual control treatment possesses few therapeutic ingredients. Second, their testing as if they have universal application for non-specific diagnostic entities (e.g. major depression), in trials where there is a high rate of non-specific responsivity to intervention, has limited our capacity to identify the circumstances in which such treatments have specific benefits. Thus, many of the limitations to the knowledge base more reflect limitations reflecting the current evaluation of all antidepressant therapies rather than being unique to the psychotherapies. This paper argues for a change in the paradigms for evaluating the psychotherapies, and argues for a 'horses for courses' approach for conceptualizing the roles of the psychotherapies in managing mood disorders, rather than any model assuming their universal application.     

What aspects of treatment matter to the patient in the treatment of cocaine dependence?

Patient views of the helpful aspects of treatment were examined in the NIDA Collaborative Cocaine Treatment Study, a multi-site trial comparing four psychosocial treatments: individual cognitive therapy (CT), individual supportive expressive dynamic therapy (SE), individual drug counseling, and group drug counseling only, for the treatment of cocaine dependence. Factor analysis of the items of Helpful Aspects of Treatment measure suggested a general therapy factor, a group treatment/education factor, and a treatment structure factor. No differences were found among the four treatments on the ratings of helpfulness of these three factors, common factors, or drug intervention components. However, treatment specific cognitive therapy items (e.g. use of the cognitive model) and treatment structure differentiated individual CT from individual SE, and to a lesser extent from individual drug counseling. Ratings of helpfulness were significantly related to retention and alliance but were largely unrelated to changes in drug use or psychiatric outcomes.     

Perspective: does ranolazine have potential for the treatment of atrial fibrillation?

Atrial fibrillation is the most common arrhythmia seen in clinical practice, and novel pharmacological approaches for treatment are sought. Ranolazine (Ranexa; N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-[2-methoxyphenoxy]propyl)piperazin-1-yl]acetamide) is used clinically for the treatment of angina pectoris. Evidence is reviewed from both pre-clinical and clinical studies, which suggests that ranolazine also exhibits antiarrhythmic activity with growing evidence for atrio-selectivity. Further work is required in order to explore more fully the potential of ranolazine in the treatment of atrial fibrillation. In particular, investigation of ranolazine actions against atrial fibrillation in animal models that incorporate atrial fibrillation-related remodeling and data from carefully controlled trials in human atrial fibrillation would be of value.     

Do antivirals have any utility in the treatment of arthritis?

Viruses have been linked to arthritides by several pathways. Apart from the ability of different viral pathogens to cause arthritic symptoms directly, only some circumstantial evidence for the involvement of (retro)viruses in the pathogenesis of rheumatoid arthritis has been presented in recent years. Therefore, the question of whether antiviral agents can be used to treat arthritis has become of interest. However, the mechanisms by which exogenous retroviral infection as well as activation of endogenous retroviral sequences may potentially lead to the induction of rheumatoid arthritis is just beginning to emerge. Moreover, the hypothesis that persistent viral infection may account for some hitherto unclassified, chronic arthritides, still needs to be confirmed. Therefore, the use of antiviral agents in the treatment of arthritides has been limited to viral complications of anti-arthritic therapy and to some experimental approaches. In this review, we will focus on current concepts of viral involvement in arthritis and point to future directions in the use of antiviral agents for arthritis.     

What is new in the treatment of multiple sclerosis?

Multiple sclerosis (MS) is considered an autoimmune disease associated with immune activity directed against central nervous system antigens. Based on this concept, immunosuppression and immunomodualtion have been the mainstays of therapeutic strategies in MS. During the last decade new therapies have been shown to significantly improve MS disease course. The effective therapies have led to a better understanding of MS pathogenesis and further development of even more efficient therapeutic interventions. Recombinant interferon (IFN)beta represents the first breakthrough in MS therapy. Three large placebo-controlled, double-blind studies and several smaller studies have demonstrated the efficacy of different forms of IFNbeta administrated by either subcutaneous or intramuscular routes and at different doses in patients with active relapsing-remitting multiple sclerosis (RR-MS). The three IFNbeta drugs are IFNbeta-1b and two IFNbeta-1a preparations (Avonex and Rebif). Although each clinical trial had unique features and differences that make direct comparisons difficult, the aggregate results demonstrate a clear benefit of IFNbeta for decreasing relapses and probability of sustained clinical disability progression in patients with RR-MS. All forms of IFNbeta therapy had beneficial effects on the disease process measured by brain magnetic resonance imaging (MRI). IFNbeta-1a (Avonex) also showed benefit in slowing or preventing the development of MS related brain atrophy measured by MRI after 2 years of therapy. Glatiramer acetate, the acetate salt of a mixture synthetic polypeptides thought to mimic the myelin basic protein showed a significant positive results in reducing the relapse rate in patients with RR-MS. Follow up of these patients for approximately 3 years continued to show a beneficial effect on disease relapse rate. Recent MRI data supported the beneficial clinical results seen with glatiramer acetate in patients with RR-MS. Recent studies using intravenous immune globulin (IVIG) suggest that IVIG could be effective to some degree in patients with RR-MS. However, there is not enough evidence that IVIG is equivalent to IFNbeta or glatiramer acetate in the treatment of patients with RR-MS. There have also been recent therapeutical advances in secondary progressive MS (SP-MS). A recent large phase II, placebo-controlled study with IFNbeta-1b in patients with SP-MS convincingly documented that IFNbeta-1b slowed progression of the disease independent of the degree of the clinical disability at the time of treatment initiation and independent of presence of superimposed relapses. Mitoxantrone, an anthracenedione synthetic agent, was also shown to be effective as treatment for active SP-MS. It is well tolerated but the duration of treatment is limited by cumulative cardiotoxicity. There is a growing consensus that disease-modifying therapies should be initiated early in the course of the disease before irreversible clinical disability has developed. Different therapies should be considered and tailored based on patient condition. Combination therapies could be considered as a therapeutic option for patients that failed therapies with IFNbeta and/or glatiramer acetate. Currently, there are new ongoing studies testing safety and/or efficacy of different combination regimens (i.e. azathioprine with IFNbeta, IFNbeta with glatiramer acetate, or pulses of intravenous cyclophosphamide with IFNbeta). Determining the effect of different therapies on the course of the disease within large clinical studies appears easier than determining individual responsiveness. Therefore, standardised methods for evaluating individual patients receiving disease-modifying therapies and development of effective therapeutic algorithms are needed.     

Do beta-blockers have a role in the treatment of chronic heart failure?

There has been growing interest in and recognition of the role of beta-blockers in chronic heart failure (CHF). The mode of action is complex and several mechanisms have been proposed. The principal rationale for the use of beta-blockade is to counteract neurohormonal activation and its deleterious consequences in CHF. While the positive effect of this treatment on haemodynamics, exercise tolerance and quality of life, and a clear trend in favour of improved prognosis have been shown, there is still no concrete proof that beta-blockers reduce mortality in CHF. Several large-scale, prospective, randomised, placebo-controlled trials, designed to provide a definitive answer, are underway.     

Could nanoparticle systems have a role in the treatment of cerebral gliomas?

Malignant brain tumors are difficult to manage clinically and are associated with high rates of morbidity and mortality. Late diagnosis and the limitations of conventional therapies that may result from inefficient delivery of the therapeutic or contrast agent to brain tumors due to the blood-brain barrier and nonspecificity of the agents, are major reasons for this unsolved clinical problem. Nanotechnology involves the design, synthesis, and characterization of materials and devices that have a functional organization in at least one dimension on the nanometer scale. The nanoparticle has emerged as a potential vector for brain delivery, able to overcome the difficulties of modern strategies. Moreover, multifunctionality can be engineered into a single nanoplatform so that it can provide tumor-specific detection, treatment, and follow-up monitoring. This review reports the latest research in nanoparticle-based glioma treatment. FROM THE CLINICAL EDITOR: In recent years, nanoparticles have emerged as potential delivery vectors targeting brain tumors, including multifunctional NP-s allowing tumor-specific detection, treatment, and follow-up monitoring. This review summarizes the latest research in nanoparticle-based glioma treatment.     

Renaissance of NMDA receptor antagonists: do they have a role in the pharmacotherapy for alcoholism?

Long-term alcohol exposure leads to the development of alcohol dependence, which is possibly induced by changes in specific neurotransmitter functions. Accumulating evidence suggests that the N-methyl-D-aspartate (NMDA) type of ionotropic glutamate receptor is a particularly important site of action for ethanol. Ethanol potently and selectively inhibits NMDA receptors (NMDARs) and prolonged ethanol exposure produces a compensatory 'upregulation' of NMDAR functions. These changes are believed to underlie the development of ethanol tolerance and dependence as well as acute and delayed signs of withdrawal. Therefore, negative modulators of NMDARs may be useful agents for the pharmacotherapy of alcoholism. NMDAR antagonists attenuate not only the physical symptoms but also some affective and motivational components of alcohol withdrawal. Encouraging experimental results have been obtained with novel uncompetitive (memantine and neramexane (Merz & Co GmbH/Forest Laboratories Inc)), glycine site and NR2B subunit-selective NMDA antagonists (SSNAs). Recently emerged NR2B SSNAs (CP-101606 (Pfizer Inc), Co-101244 (Pfizer Inc/Purdue Neuroscience Corp/Senju Pharmaceutical Co Ltd), CI-1041 (Purdue Neuroscience Corp/Pfizer Inc) and indole-2-carboxamide derivatives) have demonstrated excellent in vitro potency against withdrawal-induced cytotoxicity. Although in vivo data are few, according to their in vitro efficacy and good tolerability, novel NMDA antagonists, especially the NR2B-selective antagonists, may offer a preferable alternative to the presently available pharmacotherapies for treating alcoholism.