Current Pharmaceutical Design - Volume 10, Issue 18, 2004

Traumatic brain injury triggers a series of secondary or delayed damage known to exacerbate the initial injury and deficits. In recent years many therapeutic strategies have been proposed and studied in traumatic brain injury in order to inhibit these mechanisms and prevent further damage. Although experimental studies have demonstrated a beneficial effect of some of these neuroprotection approaches, no effective or beneficial drug treatment has successfully been introduced into clinical practice. The past decade in brain injury research has brought tremendous advances in our understanding of the physiopathological mechanisms of brain injury. This has resulted in the identification of several novel targets in neuroprotection. The present issue reviews the current status of research in this field. The issue begins with an article by Enriquez and Bullock [1] on the recent advances in the molecular and cellular mechanisms in the pathophysiology of severe head injuries. Ungerstedt and Rostami [2] give an overview of the microdialysis technique used to monitor the neurochemistry in neurointensive care. Some recent targets for neuroprotection are reviewed in the four subsequent comprehensive articles: Venero, Machado and Cano [3] present an overview of brain edema and the importance of aquaporins in its physiopathology; Alves, Daugherty and Rios [4] address arterial hyperoxia in severe head injury; Biegon [5] reviews the neuroprotective role of cannabinoids, and Armstead [6] assesses endothelins and their role in the posttraumatic vasospasm. Finally, Sahuquillo, Mena, Vilalta and Poca [7] discuss the role of moderate hypothermia in the management of severe traumatic brain injury. We would like to thank the journal for the opportunity to contribute with such an issue and the authors for making it possible.

The pathophysiological process following traumatic brain injury is extremely complex and not fully understood. Recent developments have further advanced our knowledge of the cellular and molecular mechanisms that cause this damage. The excitotoxic damage, alterations in calcium homeostasis and free radical induced damage are thought to be the key pathways in this process. It is believed that the final target of all these pathways is the mitochondria, through the alteration in the mitochondrial permeability transition pore. Moreover, the inflammatory response may be important in the exacerbation of secondary damage but its exact role is not very well known. Further advances in our understanding of the cellular and molecular mechanisms will be crucial in the design of new therapies that should improve the prognosis of the traumatic brain injury patients.

Microdialysis is a technique for sampling the chemistry of the interstitial fluid of tissues and organs in animal and man. It is minimally invasive and simple to perform in a clinical setting. Although microdialysis samples essentially all small molecular substances present in the interstitial fluid the use of microdialysis in neurointensive care has focused on markers of ischemia and cell damage. The lactate / pyruvate ratio is a well-known marker of changes in the redox state of cells caused by ischemia Glycerol is an integral component of cell membranes. Loss of energy due to ischemia eventually leads to an influx of calcium and a decomposition of cell membranes, which liberates glycerol into the interstitial fluid. Thus the lactate / pyruvate ratio and glycerol have become the most important markers of ischemia and cell membrane damage. While the primary insult at the site of the accident is beyond our control, secondary insults during intensive care should be avoided by all means. Therefore, the single most important finding from microdialysis studies is the dramatic difference in the vulnerability of the penumbra surrounding a lesion as compared to normal brain tissue allowing early detection of secondary insults after traumatic brain injury as well as the onset of vasospasm after subarachnoid hemorrhage.

Aquaporins (AQPs) are water channels that mediate the efficient movement of water across the membrane. Among different AQPs, AQP4 is the predominant water channel in the brain and is thought to play a significant role in the physiopathology of brain edema. Brain edema is a major clinical problem since it largely accounts for the cause of death in patients suffering from traumatic brain injury or cerebrovascular accidents. In this review, we have tried to summarize comprehensive information about the pathological events conducting to brain edema. In addition, we also have summarized active investigation in the field of AQPs and cerebral edema to find plausible explanations and to deduce potential future directions for the treatment of this clinical condition.

There is mounting evidence both from experimental and clinical studies that traumatic brain injury (TBI) is associated with a reduction of aerobic metabolism. This results from a variable combination of impaired substrate delivery and mitochondrial failure. Mitochondria, which are responsible for the production of 95% of cell adenosine triphosphate (ATP), may become compromised after TBI. On the other hand, in the very early period after the primary injury, oxygen delivery may be impaired due to arterial hypoxia and/or to a reduction of cerebral blood flow (CBF). As a consequence, 80-90% of patients who die of head injury show ischemia on histo-pathological examination of the brain tissue. In the absence of an appropriate treatment for TBI, these observations favored the hypothesis that manipulation of brain oxygen delivery could be a therapeutic tool to improve aerobic metabolism. Several strategies were developed, including the increase of cerebral perfusion pressure (CPP) using amines or the increase of arterial partial pressure of oxygen (PaO2) through hyperbaric oxygen (HBO) or normobaric hyperoxia. Several experimental and clinical studies, using normobaric hyperoxia, demonstrated an increase in brain tissue oxygen tension and a reduction of brain extracellular lactate levels, but there is no consensus about the biological meaning of these findings. For some authors, they translate an improvement of brain oxidative metabolism, while for others they represent only biological epiphenomena. The current review addresses the rational behind normobaric hyperoxia as a therapeutic application and discusses the experimental and clinical results achieved so far.

The name “Cannabinoid” applies to a large and diverse family of compounds including plant derived, synthetic and endogenously produced chemicals, some but not all of which are psychotropic. Cannabinoids of all classes have the ability to protect neurons from a variety of insults that are believed to underlie delayed neuronal death after traumatic brain injury (TBI), including excitotoxicity, calcium influx, free radical formation and neuroinflammation. The pathways and experimental models supporting a neuroprotective role for the various classes of cannabinoids are critically reviewed vis a vis their potential to support the development of a clinically viable neuroprotective agent for human TBI.

Increasing evidence implicates endothelin in the pathophysiological development of cerebral vasospasm. This review summarizes background topics such as the structures and biosynthesis of endothelins, the types of endothelin and their receptors, as well as their biological effects. Basic science and clinical observations supportive of the role of endothelins in the spasm associated with stroke and subarachnoid hemorrhage are presented. Similar basic science and clinical observations are presented regarding the role of endothelins in impaired cerebral hemodynamics following traumatic brain injury, cryogenic cortical lesion injury and fluid percussion brain injury. The role of age in the contribution of endothelin to impaired cerebral hemodynamics following fluid percussion brain injury is discussed. Finally, potential mechanisms for endothelin contributions to vasospasm following fluid percussion brain injury such as impaired K+ channel function are described.

Many drugs with proven efficacy in the preclinical stage have failed to show any benefit in improving the outcome of severe traumatic brain injury (TBI) when tested in controlled clinical trials. Hypothermia is still the most powerful neuroprotective method in experimental models of TBI. Its ability to influence the multiple biochemical cascades that are set in motion after TBI is quite unique. In experimental models hypothermia protects against mechanical neuronal and axonal injury and improves behavioral outcome. Encouraging results from phase II and III clinical trials of hypothermia in TBI reported in the 1990s generated great enthusiasm. However, enthusiasm faded in 2001 after the final report of the multicenter phase III trial in which the neuroprotective effects of moderate hypothermia in TBI were formally tested. This study found no significant effect on outcome in the hypothermia group, leading many clinicians to lose interest in this therapy. The present article reviews the historical background of the use of hypothermia, presents the rationale for using both immediate and deferred hypothermia, and summarizes both experimental and clinical evidence supporting its potential benefits in the management of severe TBI. New technologies using intravascular methods to induce fast hypothermia have recently become available. Cooling either through the intravenous or intra-arterial route is an exciting alternative with great potential. We argue that moderate hypothermia is still the most powerful neuroprotective candidate for severe TBI and that it merits further research and discussion. We also defend the need for further clinical trials to prove or refute its potential for treating high intracranial pressure refractory to first level therapeutic measures. The premature abandonment of hypothermia could close new avenues for improving the devastating effects of TBI.

Over 40 different antipsychotic medications have been introduced around the world, 21 of which are available in the United States. The conventional antipsychotic drugs introduced in late 50s have two major groups of disadvantages, efficacy and safety. All of the atypical antipsychotic agents have higher 5-HT2 blocking than D2 blocking. Atypical antipsychotic agents differ in their receptor action and side effect profile. Among them, clozapine has superior efficacy, and both clozapine and olanzapine have a higher propensity to cause weight gain and possibly diabetes. Quetiapine is difficult to use in acute psychotic states as a result of titration. Ziprasidone and aripiprazole are less sedating, and diabetes as well as weight gain have not been reported with their use. In an acute setting, antipsychotic monotherapy in therapeutic doses is the most useful. AAP drugs are preferred because of the lack of acute EPS symptoms. Intramuscular preparations of haloperidol and ziprasidone are sometimes required to treat acute patients. The goal in acute treatment is to prevent harm to self or others by decreasing excitatory symptoms. Continuing the antipsychotic medication treatment after the acute symptoms are controlled reduces the likelihood of a relapse. The neuroleptic medication should be continued indefinitely. The minimum amount antipsychotic drugs necessary to prevent a relapse should be used, based on clinical decision.

Recently there has been increased concern over the side effects of the atypical antipsychotic drugs, including diabetes, hyperlipidemia and obesity. The relationship between diabetes and antipsychotic drugs requires a careful analysis. Patients with schizophrenia are known to suffer from diabetes more often than the general population. In addition, a number of case reports indicate that the conventional antipsychotic as well as atypical antipsychotic drugs produce diabetes. Clozapine and olanzapine, in particular, have been implicated producing diabetes as well as diabetic ketoacidosis. Epidemiological surveys have supplemented the case reports, finding increased incidence of diabetes in patients treated with atypical antipsychotic agents, but these surveys have not yielded consistent results regarding the differential effects of the various atypical antipsychotic drugs. The mechanism by which antipsychotic agents produce diabetes is not elucidated. Weight gain and consequent alteration in triglycerides and cholesterol have been known to occur frequently with olanzapine and clozapine. The ensuing metabolic syndrome itself may cause insulin resistance and diabetes. In the absence of definitive scientific data on the differential effects of antipsychotic drugs in inducing diabetes, clinical prudence and careful monitoring of all patients on atypical antipsychotic drugs is necessary. Aripiprazole and ziprasidone have not been shown to increase weight or produce diabetes, but more information on the diabetogenic effects of ziprasidone and aripiprazole is needed. In order to assess the differential effects of atypical antipsychotic drugs in producing diabetes and the mechanisms by which they produce this reaction, further research is necessary.

The administration of more than one drug for a single medical condition is considered to be polypharmacy. There are many possible reasons for polypharmacy: (1) psychosis is a chronic disease that cannot be cured; (2) expectations to improve patients' quality of life beyond what drugs can actually do is high; (3) the lack of side effects and interactions can cause physicians to be more daring in terms of potential complications; (4) information from the Internet may cause patients and their families to demand medications; (5) the diluted mental health system allows legal guardians and other mental health professionals to force physicians to provide multiple drugs; (6) many new drugs are available; and (7) physicians are forced to shorten hospitalization days. The 1997 American Psychiatric Association Practice Research Network found that 17% of 146 patients with schizophrenia were treated concurrently with more than one antipsychotic medication. Polypharmacy may increase the risk of adverse effects, drug interactions, noncompliance, and medication errors. It is not wise to use polypharmacy only to prevent side effects and drug and interactions. Our attempts to reduce polypharmacy may fail, as academicians also propagate polypharmacy, and all of the algorithms indicate polypharmacy as an option, putting physicians in a legal and ethical bind. Techniques such as experimental ward, peer review, computer information feedback, and comparing different techniques may temporarily reduce polypharmacy but long-term outcome is not affected. Scientific data on the efficacy of polypharmacy is needed in order to sort out good and bad polypharmacy.

Antipsychotic drugs induce extrapyramidal symptoms such as dystonia, akathisia and parkinsonian symptoms early in treatment, and tardive dyskinesia later in treatment. With the advent of atypical antipsychotic drugs, the incidence of extrapyramidal symptoms has decreased, but the danger still exists. There are many reasons that extrapyramidal symptoms are still a problem. Most often, psychiatrists use doses higher than the recommended dose of atypical antipsychotic agents. For example, the use of 8 to 10 mg of risperidone, 30 to 40 mg of olanzapine, or 1200 to 1500 mg of quetiapine daily is not uncommon. In addition, combinations of both conventional and atypical antipsychotic drugs are used together in many instances. Extrapyramidal symptoms produce unnecessary suffering and add to the health burden; therefore, prompt recognition of these symptoms is necessary. If EPS occur, it is of paramount importance to start an antiparkinsonian agent immediately to provide relief to the patient. In high-risk patients, prophylactic antiparkinsonian therapy is indicated but routine prophylaxis with antiparkinsonian agents is harmful. As only a segment of patients may develop EPS, many patients receive prophylactic medication unnecessarily, and the side effects of antiparkinsonian drugs prescribed without clinical indication may add to the health burden of the patient. If prophylactic antiparkinsonian treatment is initiated, it should be discontinued at least two weeks after its initiation. The long term use of antiparkinsonian treatment is not therapeutically beneficial to the patient, and studies indicate that the gradual withdrawal of antiparkinsonian medication will not produce recurrence of EPS.

Approximately half of patients with schizophrenia have a lifetime diagnosis of substance abuse disorders. These dual diagnosis patients are more likely to have poorer outcomes, including more severe psychiatric symptoms with increased hospitalizations, higher utilization of services and frequent homelessness. Assessment and treatment of dually diagnosed patients has evolved over the last twenty years. To date, the strongest evidence for effective management of dual diagnosis patients has been utilization of integrated treatment services, which combines both mental health and substance abuse treatments concurrently. Strategies commonly used include a combination of pharmacological treatment, intensive case management, motivational interviewing, individual and group psychotherapy, and family participation. This chapter summarizes the treatment options available for this population.

Research in new treatments for schizophrenia continues. At the same time, increasing numbers of persons with schizophrenia receive their treatment almost exclusively in correctional settings. Though the literature continues to describe this phenomenon in clearer detail, many questions regarding the characteristics of these mentally disordered offenders and their unique treatment needs remain. Research targeting this growing subset of persons with schizophrenia is limited. Risk factors that lead the person with schizophrenia into the correctional system, and whether the offenders with schizophrenia actually differ from non-offenders in terms of their psychopharmacological needs are significant questions that remain unaddressed. Countertransference towards the offender remains a significant issue as well. Given the many limitations on research in this population, pharmacologic strategies for the offender population must be extrapolated from the non-offender population. Traditional depot neuroleptics continue to be underutilized in the treatment of this population. It is argued that both traditional and forthcoming atypical depot neuroleptics may be the best first line agents in this population.

Although medication is the treatment of choice for schizophrenia, most patients continue to experience exhibit residual symptoms despite compliance. Recent studies suggest that cognitive behavioral therapy (CBT) is useful in the treatment of schizophrenia and other psychotic disorders [1]. Results of previous studies suggest that patients treated with CBT, in conjunction with medication, exhibit decreased frequency and severity of delusions, hallucinations and negative symptoms. Finally, CBT has been shown to increase medication compliance in patients with schizophrenia and bipolar disorder. Speaking of the outcome data on CBT, Weiden was recently quoted as saying, “if this were a patented drug trial, you would have heard about [these findings]” [2]. Despite the empirical evidence supporting the use of CBT in patients with schizophrenia, this treatment is relatively unknown to the psychiatric community. This article will review the mechanisms and findings associated with CBT and schizophrenia, and suggest future directions for dissemination in the psychiatric community.

Schizophrenia is a maldevelopmental disorder of the brain that manifests in positive, negative, cognitive and affective symptoms. Currently, the mainstay of treatment involves pharmacotherapy. The limitations of antipsychotic treatment are that they can only control symptoms and cannot cure the illness, and 20% of patients do not respond, thus leading to the requirement of maintenance treatment. Patients that do respond continue to have disabling residual symptoms such as amotivation and isolation, maladaptive behavior, and impaired social functioning. These symptoms prevent patients from attaining educational, occupational, and social roles. Psychosocial interventions and models of quality of life in schizophrenia are based on the notion that increases in psychosocial functioning will be related to improvement in subjective experiences, such as self-esteem and satisfaction with life. The comparative effect of specific treatment methods and the additional benefits of multiple treatments need to be explored. Diversified techniques have also been employed, such as shaping, cognitive process therapy, mastery-oriented skill training, motivation and enhancement. Issues in designing psychosocial interventions and the role of various professionals in providing such interventions need to be carefully considered. Predictor variables and the indications for particular therapies in an individual need to be explored. Generalizability of the gains made by rehabilitation / recovery is also an important consideration. Patients in jail, chronic mental hospitals, private facilities, and the Veterans Administration system are all different in their ability to benefit, their motivations, and the severity of their psychopathology. Therefore, it is very difficult to generalize findings from one setting to another.