Current Research on Medications used in the Treatment of Schizophrenia Essay Example

Current Research on Medications used in the Treatment of Schizophrenia Paper The introduction of drugs to the treatment of schizophrenia heralded the modern era of psychopharmacology. The French anesthesiologist Hans Labroit was the first to note the antipsychotic effects of chlorpromazine while utilizing the drug as a preanesthetic medication. Medications have long been the primary component of effective treatment for schizophrenia (Denckner, 2001). Conventional antipsychotics have been in use since the 1950s. However, these medications have a number of unpleasant side effects. The use of the new generation of schizophrenia medications, generally known as atypical or novel antipsychotics, has increased dramatically over the past decade. The first medication in this series was clozapine, which, because of the higher risk of agranulocytosis, found limited application in routine clinical practice. In 1989, the Food and Drug Administration (FDA) approved clozapine, the first of a new class of antipsychotic medications. Although clozapine can cause agranulocytosis, a potentially fatal blood disorder that is reversible if the medication is stopped, it has far fewer of the extrapyramidal side effects typically associated with conventional antipsychotics (hence the term atypical). Atypical agents introduced in more recent years, such as risperidone, olanzapine, and quetiapine, have not been associated with an increased risk of this side effect and were shown in clinical trials to be at least as efficacious as conventional antipsychotics for schizophrenia and other psychotic disorders (Remington and Chong 1999; Worrel et al. We will write a custom essay sample on Current Research on Medications used in the Treatment of Schizophrenia specifically for you for only $16.38 $13.9/page Order now We will write a custom essay sample on Current Research on Medications used in the Treatment of Schizophrenia specifically for you FOR ONLY $16.38 $13.9/page Hire Writer We will write a custom essay sample on Current Research on Medications used in the Treatment of Schizophrenia specifically for you FOR ONLY $16.38 $13.9/page Hire Writer 2000). Randomized clinical trials have also shown that patients treated with these medications have fewer extrapyramidal symptoms and, as a result, have better adherence, fewer gaps in treatment, and fewer rehospitalizations (Rosenheck et al. 2000). The use of these new medications increased quickly after their approval by the FDA. By 1999, 58. 8% of all patients with schizophrenia who received an antipsychotic in the Department of Veterans Affairs (VA) were prescribed an atypical medication (Seeman et al. , 1996), and the proportion had increased to 64. 4% by 2000 (Wong et al. , 2005). However, little is known about the process by which these medications are adopted, i. e. , whether there is a simple switch to a new medication or a more complex process of trial and error. Literature Review The history of antipsychotic drug development is closely linked to the dopamine (DA) hypothesis of schizophrenia. This hypothesis postulates that schizophrenia is associated with a disorder in DA neurotransmission based on several observations: 1. Dopamine agonists, such as d-amphetamine, bromocriptine, and l-DOPA can exacerbate symptoms in schizophrenic patients and can produce psychotic symptoms in non-schizophrenic persons. 2. All currently used antipsychotic drugs share the common property of D2 dopamine receptor blockade both in vivo and in vitro. 3. A correlation exists between D2 dopamine blocking potential and clinical antipsychotic efficacy (Creese et al. , 2006). An increase in D2 dopamine receptors in the drug-naive schizophrenic brain has been reported but this finding has not been replicated (Wong et al. , 2005). In contrast, it has been shown that the D2 dopamine receptor and its gene are reported to be normal in schizophrenia and the antipsychotic drugs can only control symptoms and cannot cure the disease. While this hypothesis provided a rationale for the development of new drugs, there are still many unresolved problems. Not all schizophrenic symptoms can be explained by excess of dopamine. The positive symptoms of schizophrenia are related to a hyperdopaminergic state in the mesolimbic and mesocortical areas (Crow, 2005), and the negative symptoms to a hypodopaminergic state in the medial prefrontal cortical area (Merriam et al. , 2000). Therefore, a dopamine blocking agent cannot logically be the most suitable drug to improve both the positive and negative dimensions of schizophrenia. Current Pharmacological Treatment of Schizophrenic Patients Clinical Goals of Treatment Antipsychotic therapy focuses on four primary symptom domains in schizophrenia – positive symptoms, negative symptoms, cognitive impairments, and disturbance of mood and affect (Tandon et al. , 2005). Positive symptoms are prominent during acute exacerbations of illness, and often precipitate hospital admission. Negative symptoms include both primary and secondary components, due to either the illness itself or due to other factors such as depression, environmental deprivation, or parkinsonian side effects of antipsychotic medications (Miller et al. , 2000). Although they rarely precipitate hospitalization, they frequently worsen during acute psychotic episodes, and typically do not fully resolve after the episode. Negative symptoms are moderately associated with functional impairments between acute episodes of illness. Cognitive symptoms include deficits in all four major areas of neuropsychological function – memory, attention, language, and executive function. Although cognitive functions often show significant premorbid impairment, there is evidence that they continue to decline after the onset of illness, especially during acute episodes of illness. These symptoms are largely due to the underlying pathology of schizophrenia, but are also worsened by secondary factors, such as depression or pharmacologic treatment. Cognitive symptoms are highly correlated with lifetime functional impairment in schizophrenic patients (Bilder, 2007). Mood and affective symptoms common in schizophrenia include depression, anxiety, agitation, and behavioral dyscontrol. These symptoms contribute to subjective distress, functional impairment, and hospitalization, and are appropriate targets for pharmacologic intervention. The remarkable heterogeneity of schizophrenia is attributable in part to the relative contributions of each of these domains of pathology to individual cases of the disorder. Furthermore, the quality and severity of each type of symptom varies over the course of illness in the individual patient, creating a unique mosaic of symptoms over time. Antipsychotic treatment has usually been focused on positive symptoms, which respond most dramatically to pharmacologic interventions. Modest symptom improvement in other domains typically follows reduction in psychosis. There are two major reasons to focus more intently on negative, cognitive, and mood symptoms. First, they are highly correlated with patients’ functional status and quality of life. Second, because they are difficult to treat once they occur, it is critical to avoid the progression of these symptoms, which is usually associated with acute episodes of illness. Thus, prevention of acute episodes benefits the patient not only by avoidance of hospital admission, but also by minimization of the functional deterioration associated with progression of negative and cognitive symptoms. General Principles Antipsychotic medications have been the mainstay of the pharmacologic treatment of schizophrenia. AAP drugs show levels of antipsychotic efficacy comparable with the conventional agents, but are somewhat more effective in the treatment of negative, cognitive, and mood symptoms, and they carry a greatly reduced risk of EPS and TD (Meltzer, 1993). Clozapine is unique in its antipsychotic efficacy, effective treating 30% to 50% of patients who do not respond to other medications (Kane et al. , 1998). Because of its associated risk for agranulocytosis, seizures, hypotension diabetes and weight gain, clozapine is not considered a first-line agent, and is reserved for treatment-refractory cases. In treating a schizophrenic patient, two factors – the temporal and dimensional – need to be considered. Temporal factors include emergency, acute, chronic and rehabilitation treatments and dimensional factors include the positive, negative, cognitive and mood target symptoms. Acute Treatment Acute patients generally enter treatment through the emergency room and, if needed, may get admitted into the psychiatric ward of a hospital. The removal of the patient from the stressful environment, if any, is itself positive. In an acute setting, antipsychotic monotherapy is the most useful line of treatment, and AAP drugs are preferred because of the lack of acute EPS. Antipsychotic drugs are used in therapeutic doses and in most instances, use of high doses is not needed. There is no evidence that schizophrenic patients respond to any one specific medication and the response depends on the individual. Intramuscular preparations are sometimes required to treat acute patients; both haloperidol and ziprasidone are available in intramuscular formulation. Occasionally, lorazepam intramuscularly either alone or with haloperidol is administered to decrease agitation (Salzman, 1988). The goal in acute treatment is to prevent harm to self or others by decreasing excitatory symptoms. When to Expect improvement Positive symptoms improve first. Of the positive symptoms, psychomotor excitement improves in a day or two and sometimes in a few hours. Akathisia and dystonia also occurs most often with in the first 48 hours to a week, and patients need to watched carefully during this period. Hallucinations and delusions take about 3 months to improve and, in some instances, may continue unabated. Thought disorders improve gradually. There is variability in how an individual patient responds. Adjunct medications, increase in antipsychotic medication dose, addition of another antipsychotic drug, or changing the antipsychotic agent within a month is unwise. Maintenance Treatment Continuing antipsychotic medication treatment after acute symptoms are controlled reduces the likelihood of a relapse (Davis, 1995). The antipsychotic medication should be continued indefinitely. Depot injections decrease relapse rates better than oral medications and are indicated in certain circumstances. Tardive dyskinesia is a major risk with CAP drugs, occurring in about 5% of the haloperidol treated patients per year. In older patients, in one year 27 % of patients develop tardive dyskinesia (Jeste Caligiuri, 1993). It is the risk of tardive dyskinesia which is partly responsible for the popularity of AAP drugs as the first choice for treatment. Dose of the medication is an unsettled issue. With regard to antidepressant therapy, the dose that helped a person to improve is the same dose used as maintenance dose. With antipsychotic drugs, there is a need to use the minimum amount necessary to prevent relapses. What the minimum dose is, is a clinical decision. The maintenance antipsychotic treatment has to be flexible to suit the individual needs with a positive risk-benefit ratio. Discussion The introduction of chlorpromazine a half century ago clearly revolutionized the treatment of schizophrenia and other psychotic disorders. Unfortunately, neither this drug nor other typical antipsychotic medications are uniformly or optimally effective in the treatment of individuals with schizophrenia. These agents do not reduce psychotic symptoms in all patients and have limited efficacy against other clinical features of the illness (e. g. , negative symptoms and cognitive deficits). In addition, the different side effects associated with these medications have both contributed to problems with compliance and introduced additional sources of morbidity. The availability of atypical agents, such as clozapine, olanzapine, and risperidone, promised advantages in both efficacy and tolerance but raised very important questions, such as, 1) Which antipsychotic medication used is best for a given profile of symptoms of schizophrenia? and 2) just how much advantage in treatment efficacy, especially for negative symptoms, do the current atypical medications actually provide? Clear answers to these questions have been difficult to obtain from the existing literature because the available studies evaluated only a subset of the medications of interest, used different experimental designs and outcome measures that hinder comparisons across studies, and examined primarily acutely ill subjects, making it difficult to determine whether clinical improvement reflected reductions in not only secondary but also primary negative symptoms. In addition, a number of the comparative studies that have been published were developed and sponsored by the pharmaceutical companies whose medications were being evaluated, raising concerns about potential sources of bias in experimental design or interpretation of outcomes. The study by Papanikolaou and colleagues provides compelling new data that address these important issues. These investigators recruited 157 inpatients who had a diagnosis of chronic schizophrenia or schizoaffective disorder and a history of suboptimal treatment response to adequate duration and doses of one or more typical antipsychotics. The patients were randomly assigned to receive clozapine, olanzapine, risperidone, or haloperidol in a 14-week, double blind trial. Total Positive and Negative Syndrome Scale scores were significantly improved for all three patient groups treated with atypical agents but were unchanged for the haloperidol treated group. This finding would be expected for individuals who were selected for study because 1) they had not responded adequately to previous treatment with typical antipsychotics and 2) they had not failed previously to respond to treatment with atypical agents. When compared with haloperidol treatment (with conservative corrections for the performance of multiple statistical tests), only clozapine and olanzapine demonstrated statistically significant improvement in negative symptoms. In addition, none of the three atypical antipsychotics produced a statistically significant improvement in positive symptoms or general psychopathology compared with haloperidol. In considering the significance of these findings, several aspects of this study are worthy of note. First, the importance of such double-blind direct comparisons of therapeutic agents is rivaled by the difficulties involved in conducting such studies. For example, achieving the optimal dose for each agent can be a major challenge; as noted by the authors, the dose of risperidone was probably too high, presenting one limitation to the study. In addition to the complexity involved and time required to conduct these types of studies, the staged introduction of new medications produces problems in making direct comparisons across medications. In the study by Papanikolaou et al. , the comparison of haloperidol, clozapine, and risperidone was designed and implemented when olanzapine became available commercially. To enhance the relevance of their study to clinical practice, the investigators subsequently added an olanzapine treatment arm. However, the later addition of olanzapine-treated subjects meant that assignment to treatment with olanzapine was not completely random with the other three medications, creating the possibility of a cohort effect. This raises the question of whether subjects who entered the study later, and received olanzapine, were somehow different from the subjects who entered the study earlier, and received the other drugs, in a way that would account for any differential response (or lack thereof) to a given treatment. The authors have thoughtfully addressed this question and provide reasonable arguments for the absence of such a cohort effect, but they acknowledge that the possibility cannot be completely excluded. Second, the study was supported by a grant from the National Institute of Mental Health (NIMH), contributions of medications from four pharmaceutical corporations, and supplemental funding for the olanzapine arm (equal to about 18% of the total cost of the project) from Eli Lilly and Company, the manufacturer of olanzapine. This arrangement, a realistic compromise that made possible the direct comparison of four drugs, nonetheless raises concerns about potential bias, given that olanzapine proved to be more effective than other drugs on some measures. However, in contrast to investigations that are initiated and controlled by industry, the authors had complete independence in the design, conduct, analysis, and interpretation of the study. In some ways, this study may represent a model approach for the support of clinical trials; that is, the study was designed and conducted by independent investigators, principally funded by the federal government, and supplemented by contributions from, but without undue influence by, the pharmaceutical industry. Indeed, such government/private collaborations for investigator-initiated research have been encouraged by NIMH. Third, despite achieving statistical significance, the differences in efficacy across the medications examined in this study were, as noted by the authors, modest and their clinical significance limited. Thus, the disappointingly small added value of atypical antipsychotics in this patient population clearly underscores the need for the identification of more effective treatments. In this regard, the study by Leucht et al. (1999) in this months Journal provides an informative lesson. These authors conducted a meta-analysis of amisulpride, an atypical atypical antipsychotic that has been used clinically in France for the past decade. Leucht et al. found that amisulpride was superior to typical antipsychotics in improving global symptoms and negative symptoms in acutely ill patients with schizophrenia and more effective than placebo (but not than typical antipsychotics) in patients with predominantly negative symptoms. However, as in the study by Papanikolaou et al. , the additional improvement provided by amisulpride was relatively small. For example, the mean effect size was 0. 11 in acutely ill patients, indicating 11 percentage points more improvement in Brief Psychiatric Rating Scale total score with amisulpride than with typical antipsychotic medications. In addition to clarifying the clinical efficacy of amisulpride, the findings of Leucht and colleagues are informative regarding the pharmacological basis for the atypicality of antipsychotic medications. Although it shares the clinical properties (e. g. , reduced extrapyramidal symptoms at therapeutic doses) that characterize other atypical agents, amisulpride is unusual in that it lacks the combination of activity at dopamine D2 and serotonin 5-HT2 receptors that has been proposed to account for the efficacy and side effect profile of atypical antipsychotics (1). In contrast, amisulpride is a highly selective antagonist of dopamine D2/D3 receptors. Thus, the superiority of amisulpride in terms of clinical response and reduced extrapyramidal symptoms suggests that activity at the serotonin 5-HT2 receptor is not required for atypicality. As a consequence, these findings may indirectly support the hypothesis of Seeman and Kapur (1996) that fast dissociation from the dopamine D2 receptor accounts for the distinctive features of atypical antipsychotic medications. Conclusion The findings of both studies may further enhance the ability of clinicians to make informed, evidence-based decisions regarding the antipsychotic medication that is most likely to be effective in individual patients. 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