Metabolic effects of treatment with atypical antipsychotics.
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Adolescent↗
Biomedical subjects
John M Kane
Publications and source records attributed to John M Kane.
Tardive dyskinesia rates with atypical antipsychotics in adults: prevalence and incidence.
Both conventional and atypical antipsychotics cause an up-regulation of dopamine-2 receptors and have been associated with tardive dyskinesia. Studies of adult and elderly subjects have shown a greater incidence of tardive dyskinesia among patients who were administered conventional antipsychotic drugs than those given atypical antipsychotic drugs. This article will review studies of the prevalence and incidence of tardive dyskinesia in patients taking antipsychotic agents.
Adult↗
Sex differences in frontal lobe white matter microstructure: a DTI study.
There is evidence that the brains of men and women are structurally different, but there are few data regarding possible sex differences in white matter microstructure. Using diffusion tensor imaging we assessed fractional anisotropy (FA) in the frontal lobe white matter on contiguous 5 mm slices in nine healthy male and 11 healthy female adults. Overall, women had higher FA in the left frontal lobe compared to men and a leftward asymmetry of FA in contrast to men, who showed no hemispheric asymmetry. Among women, greater leftward asymmetry of frontal lobe FA correlated significantly with better verbal comprehension and memory functioning. Our findings may be indicative of increased directional coherence and/or density of left hemisphere white matter fibers and a leftward asymmetry of this structural integrity among women compared to men.
Adult↗
Impairments in perceptual competency and maintenance on a visual delayed match-to-sample test in first-episode schizophrenia.
BACKGROUND: Deficits in working memory (WM) have been reported in patients with schizophrenia, but WM is a complex construct dependent on several subprocesses, including input representation (perceptual competency) and holding stimuli on-line (maintenance). A visual delayed match-to-sample task (DMST) was developed to isolate perceptual competency from maintenance during delays. It was hypothesized that patients in the first episode of schizophrenia would exhibit dissociable deficits in both WM domains. METHODS: Performance on the DMST was assessed in 57 patients in the first episode of schizophrenia or schizoaffective disorder and 22 healthy comparison subjects. In phase 1 of the DMST, a complex visual stimulus (target) was followed immediately by a forced choice between 2 test stimuli, and item difficulty (differences between the test stimuli) was titrated until each subject achieved a consistent accuracy (80%-90%) in this no-delay condition. In phase 2, a delay of 4 or 8 seconds with a mask of randomly illuminated pixels was introduced between target and test stimuli; test stimuli were fixed in difficulty level based on phase 1 titration. Main outcome measures were mean item difficulty attained in the no-delay condition and mean accuracy in matching after delay. RESULTS: Compared with controls, patients attained a lower level of difficulty in the no-delay condition (P =.001) and significantly lower accuracy with delay (P =.002). CONCLUSIONS: Deficits in both domains of WM suggest abnormality in the posterior and prefrontal cortexes. These deficits can be observed in a task involving complex visual pattern stimuli using only a brief delay and are present even in unmedicated patients in the first episode of illness.
Adult↗
Controversies in the surgical management of rectal cancer.
At the present time, standard therapy for potentially curable rectal cancer consists of transabdominal surgical resection and adjuvant chemoradiation for American Joint Committee on Cancer stage II/III disease. Controversial issues include the use of local excision as opposed to formal resection and total mesorectal excision (TME) alone without adjuvant therapy. Although early stage tumors are the ideal potential candidates for local excision, clinical staging with endoscopic ultrasound is extremely variable in accurately predicting T and N stage. In addition, even low-grade or T1 tumors are associated with a 7% to 14% chance of nodal metastatic disease. Overall, the risk for local recurrence is higher after local excision but may be reduced by adjuvant therapy. Salvage rates for recurrent disease range from 21% to 91%. In regard to TME, local recurrence rates are an impressive 0% to 12% without adjuvant radiation. However, the addition of radiation therapy may further reduce these already low rates, especially in higher-risk groups. The results of 2 large European studies show acceptable complication rates and the applicability of this technique to a diverse patient population.
Digestive System Surgical Procedures↗
Treatment models and designs for intervention research during the psychotic prodrome.
Recently, interventions for the psychotic prodrome have gained considerable interest. The goal of early interventions for prepsychotic, but symptomatic, individuals is to reduce disability and impairment by ameliorating subpsychotic symptoms and, potentially, preventing the progression into a full-blown psychotic disorder. However, several central questions regarding early interventions for the psychotic prodrome require clarification: Is it possible to prevent or to delay the onset of a psychotic disorder by intervening in the prodromal state? Is it possible to alter the natural course of the illness; i.e., to reduce subsequent symptom severity, relapse rates, treatment refractoriness, and/or functional disability, by treating subsyndromal symptoms? What is the relationship between treatment response of prodromal symptoms or specific symptom clusters and the prevention of disease progression or improvement of functional outcome? In the context of these questions, different treatment models and trial designs are presented, focusing on patient selection, target symptoms, interventions, control conditions, outcome measures, trial duration, and exit strategies, as well as statistical and ethical considerations. Finally, the methodology of completed and ongoing intervention trials in putative prodromal populations is discussed.
Clinical Trials as Topic↗
Lithium treatment of acute mania in adolescents: a large open trial.
OBJECTIVE: To examine initial response to treatment in a large sample of acutely manic bipolar I adolescents and to examine potential predictors of nonresponse, such as the presence of prominent depressive features, psychosis, or psychiatric comorbidity. METHOD: Adolescents, 12 to 18 years of age, with an acute manic episode were treated with open lithium. Response was defined as a decline in Young Mania Rating Scale total score of >or=33% and a rating of "much improved" or "very much improved" on the Clinical Global Impressions Improvement item at week 4. Remission of mania was defined as a Young Mania Rating Scale score of <or=6. Axis I diagnoses were assessed using the Lifetime Schedule for Affective Disorders and Schizophrenia for Adolescents. RESULTS: Of 100 subjects, 63 met response criteria and 26 achieved remission of manic symptoms at the week 4 assessment. Prominent depressive features, age at first mood episode, severity of mania, and comorbidity with attention-deficit/hyperactivity disorder did not distinguish responders from nonresponders. When treated with adjunctive antipsychotic medication, subjects with psychotic features at baseline responded as well as subjects without psychosis. CONCLUSIONS: In this largest systematic treatment trial of acutely manic adolescents to date, lithium appears effective for acute stabilization of symptoms. Controlled treatment studies in adolescents with acute mania are needed.
Acute Disease↗
Early prediction of antipsychotic response in schizophrenia.
OBJECTIVE: The authors' goal was to examine the predictive value of early symptom changes indicating response to antipsychotic medication in schizophrenia. METHOD: One hundred thirty-one acutely ill patients with schizophrenia received 4 weeks of fluphenazine treatment. Brief Psychiatric Rating Scale (BPRS) ratings were obtained at baseline and weekly. The authors examined the relationship between changes in BPRS total score and each factor score following 1 week of treatment and ultimate response status, defined as a reduction of 20% or more in total BPRS score. RESULTS: None of the patients who [corrected] displayed an improvement of less than 20% in total [corrected] BPRS score and only 5% [corrected] of the [corrected] patients who displayed a reduction of less than 20% in BPRS thought disturbance [corrected] score after 4 weeks of treatment had been classified as responders at 1 week (i.e., 100% and 95% specificity) [corrected] CONCLUSIONS: These data suggest that patients with minimal improvement in positive symptoms during the first week of treatment with a typical antipsychotic are unlikely to respond to a 4-week trial. These data require confirmation and extension to studies with second-generation antipsychotics.
Adolescent↗
Smaller anterior hippocampal formation volume in antipsychotic-naive patients with first-episode schizophrenia.
OBJECTIVE: The authors investigated volumetric alterations of the anterior hippocampal formation in patients experiencing a first episode of schizophrenia relative to healthy comparison subjects. METHOD: From contiguous 1.5-mm coronal magnetic resonance images, the hippocampal formation was divided into posterior and anterior segments, and the anterior hippocampal formation was separated from the amygdala. Volumes of the posterior and anterior hippocampal formation and amygdala were computed in 46 (31 male and 15 female) patients experiencing a first episode of schizophrenia and in 34 (21 male and 13 female) healthy comparison subjects. Twenty-four patients were antipsychotic naive at the time of the scan. RESULTS: Patients had significantly reduced total (right plus left) anterior hippocampal formation volume relative to healthy comparison subjects but did not differ in volumes of either the posterior hippocampal formation or amygdala. Similar findings were obtained when analyses were restricted to the antipsychotic-naive subgroup of patients. CONCLUSIONS: These findings suggest that volumetric abnormalities of the hippocampus-amygdala complex may be specific to the anterior hippocampal formation in patients experiencing a first episode of schizophrenia and are consistent with hypotheses regarding abnormal frontolimbic connectivity playing a role in the pathophysiology of the disorder.
Acute Disease↗
Long-acting injectable risperidone: efficacy and safety of the first long-acting atypical antipsychotic.
OBJECTIVE: The authors assessed the efficacy and safety of the first long-acting atypical antipsychotic (long-acting injectable risperidone) in patients with schizophrenia. METHOD: In a 12-week, multicenter, double-blind, randomized study, patients received intramuscular injections every 2 weeks of placebo or long-acting risperidone (25 mg, 50 mg, or 75 mg). The primary measure of efficacy was the change in total score on the Positive and Negative Syndrome Scale. RESULTS: Of the 554 patients who were enrolled, 400 entered the double-blind study, and 370 received at least one postbaseline assessment. Mean changes in score of -6.2, -8.5, and -7.4 on the Positive and Negative Syndrome Scale were seen at endpoint for the 25-, 50-, and 75-mg risperidone groups, respectively; all three change scores were significantly different from that seen with placebo (+2.6). Improvements in positive and negative symptoms were also significantly greater in patients receiving risperidone. Long-acting risperidone was well tolerated. Adverse events related to extrapyramidal symptoms were spontaneously reported by 13% of patients receiving placebo and 10% of patients in the 25-mg risperidone group, with higher rates in the 50-mg and 75-mg groups. Severity of extrapyramidal symptoms was mild at baseline and throughout the trial in each treatment group. Mean weight changes were small in the 25-, 50-, and 75-mg risperidone groups (0.5 kg, 1.2 kg, and 1.9 kg, respectively). Injection site pain was rated as low by the patients, consistent with the investigators' pain ratings. CONCLUSIONS: Long-acting injectable risperidone was efficacious and well tolerated and provides both clinicians and patients with a new mode of treatment that can improve the outcome of long-term therapy.
Adolescent↗
Relapse prevention in schizophrenia with new-generation antipsychotics: a systematic review and exploratory meta-analysis of randomized, controlled trials.
OBJECTIVE: The authors performed a systematic review and meta-analysis of studies of the potential of new-generation antipsychotic drugs to improve adherence and decrease relapse rates in patients with schizophrenia. METHOD: Randomized, controlled trials comparing new-generation antipsychotic drugs with placebo and/or conventional antipsychotics were identified. Data on relapse, general treatment failure, and dropout due to adverse events were extracted and combined in a meta-analysis. RESULTS: Because few trials were available for each individual drug, the effects of new-generation antipsychotic drugs as a group were analyzed. The analysis of six placebo comparisons, involving a total of 983 patients, clearly demonstrated that new-generation antipsychotic drugs are effective for relapse prevention. Eleven studies with a total of 2,032 patients provided comparative data on relapse/treatment failure for new-generation and conventional antipsychotics. The analysis revealed that rates of relapse and overall treatment failure were modestly but significantly lower with the newer drugs. Whether this advantage was partly mediated by improved adherence to treatment remains unclear. No significant superiority in terms of fewer dropouts due to adverse events was found for the newer drugs. Furthermore, a number of methodological problems were identified. CONCLUSIONS: Overall, the currently available data suggest that new-generation antipsychotics have the potential to reduce relapse rates. Methodological issues to be addressed in future trials include the choice of comparator, use of appropriate doses, application of clinically relevant relapse criteria, monitoring of adherence, and minimization of dropouts.
Antipsychotic Agents↗
Clozapine as a first treatment for schizophrenia.
OBJECTIVE: The authors' goal was to explore whether clozapine given as the first antipsychotic treatment favorably affects the course of schizophrenia. METHOD: Thirty-four inpatients experiencing their first episode of schizophrenia or schizoaffective disorder were treated first with clozapine and then followed for up to 4 years. In a previous study, the authors followed patients experiencing their first episode of schizophrenia or schizoaffective disorder who were given fluphenazine as the first treatment. In the current study and the previous study, response criteria required sustained remission of positive symptoms. RESULTS: Nineteen of the 34 subjects met response criteria while taking clozapine. The median time to treatment response was 11 weeks (range=2-13). Using survival analysis, the authors determined that the cumulative response rate for the 34 patients was 66.4% at the end of 13 weeks, which is comparable to the response rate to fluphenazine in the previous study. All responses to clozapine occurred by 13 weeks. Eight (42%) of the clozapine responders discontinued clozapine before 6 months, and only six (32%) remained on clozapine for all of their time in the study. CONCLUSIONS: The authors found no benefit for clozapine over conventional antipsychotics for acute treatment of the first episode of schizophrenia or schizoaffective disorder. Long-term benefits could not be studied because of the high rate of early discontinuation of clozapine treatment.
Adolescent↗
An integrated analysis of acute treatment-emergent extrapyramidal syndrome in patients with schizophrenia during olanzapine clinical trials: comparisons with placebo, haloperidol, risperidone, or clozapine.
BACKGROUND: The frequency and severity of extrapyramidal syndrome (EPS) were evaluated in patients with DSM-III or DSM-IV schizophrenia in the acute phase (- 8 weeks) of randomized, double-blind, controlled trials from the integrated olanzapine clinical trial database. METHOD: This retrospective analysis included 23 clinical trials and 4611 patients from November 11, 1991, through July 31, 2001. Incidences of dystonic, parkinsonian, and akathisia events were compared using treatment-emergent adverse-event data. Categorical analyses of Simpson-Angus Scale and Barnes Akathisia Scale (BAS) scores, use of anticholinergic medications, and baseline-to-endpoint changes in Simpson-Angus Scale and BAS scores were compared. RESULTS: A significantly smaller percentage of olanzapine-treated patients experienced dystonic events than did haloperidol- (p <.001) or risperidone-treated patients (p =.047). A significantly greater percentage of haloperidol-treated patients experienced parkinsonian (p <.001) and akathisia (p <.001) events than did olanzapine-treated patients. Categorical analysis of Simpson-Angus Scale scores showed significantly more haloperidol- (p <.001) or risperidone-treated patients (p =.004) developed parkinsonism than did olanzapine-treated patients. Olanzapine-treated patients experienced significantly greater reductions in Simpson-Angus Scale scores than did haloperidol- (p <.001), risperidone- (p <.001), or clozapine-treated (p =.032) patients. Categorical analysis of BAS scores showed significantly more haloperidol-treated patients experienced treatment-emergent akathisia versus olanzapine-treated patients (p <.001). Significantly greater reductions in BAS scores were experienced during olanzapine treatment versus placebo (p =.007), haloperidol (p <.001), and risperidone (p =.004) treatments. A significantly smaller percentage of olanzapine-treated patients received anticholinergic medications compared with that of haloperidol- (p <.001) or risperidone-treated patients (p =.018). Compared with that in olanzapine-treated patients, the duration of anticholinergic cotreatment was significantly longer among haloperidol- (p <.001) or risperidone-treated patients (p =.040) and significantly shorter among clozapine-treated patients (p =.021). CONCLUSION: This analysis of available data from olanzapine clinical trials lends additional support to olanzapine's favorable EPS profile.
Acute Disease↗
Partial compliance and patient consequences in schizophrenia: our patients can do better.
OBJECTIVE: The primary objective of this review is to evaluate the strategies used to improve patient compliance with antipsychotic medication in the treatment of schizophrenia. DATA SOURCES: An electronic literature search of relevant studies using MEDLINE and the Cochrane Library (January 1974-December 2002) was performed using the search terms adherence, antipsychotic, atypical, compliance, conventional, and schizophrenia. STUDY SELECTION: English-language and non-English-language articles, references from bibliographies of reviews, original research articles, and other articles of interest were reviewed. DATA EXTRACTION: Data quality was determined by publication in the peer-reviewed literature and the most important information was identified. DATA SYNTHESIS: Atypical antipsychotics are associated with an improved side-effect profile and reduced risk of relapse compared with the older agents. Additional benefit may be provided by long-acting injectable formulations as they provide the confidence of continuous medication coverage. CONCLUSIONS: Successful treatment of patients with schizophrenia requires acknowledgment that partial compliance will present a major barrier to achieving maximum outcomes. Ideally, all patients suspected of partial compliance should be considered suitable for treatment with a long-acting injectable atypical antipsychotic.
Antipsychotic Agents↗
The expert consensus guideline series. Optimizing pharmacologic treatment of psychotic disorders. Introduction: methods, commentary, and summary.
OBJECTIVES: A growing number of atypical antipsychotics are available for clinicians to choose from in the treatment of psychotic disorders. However, a number of important questions concerning medication selection, dosing and dose equivalence, and the management of inadequate response, compliance problems, and relapse have not been adequately addressed by clinical trials. To aid clinical decision-making, a consensus survey of expert opinion on the pharmacologic treatment of psychotic disorders was undertaken to address questions not definitively answered in the research literature. METHOD: Based on a literature review, a written survey was developed with 60 questions and 994 options. Approximately half of the options were scored using a modified version of the RAND 9-point scale for rating the appropriateness of medical decisions. For the other options, the experts were asked to write in answers (e.g., average doses) or check a box to indicate their preferred answer. The survey was sent to 50 national experts on the pharmacologic treatment of psychotic disorders, 47 (94%) of whom completed it. In analyzing the responses to items rated on the 9-point scale, consensus on each option was defined as a non random distribution of scores by chi-square "goodness-of-fit"test. We assigned a categorical rank (first line/preferred choice,second line/alternate choice, third line/usually inappropriate) to each option based on the 95% confidence interval around the mean rating. Guideline tables indicating preferred treatment strategies were then developed for key clinical situations. RESULTS: The expert panel reached consensus on 88% of the options rated on the 9-point scale. The experts overwhelmingly endorsed the atypical antipsychotics for the treatment of psychotic disorders. Risperidone was the top choice for first-episode and multi-episode patients, with the other newer atypicals rated first line or high second line depending on the clinical situation. Clozapine and a long-acting injectable atypical (when available)were other high second line options for multi-episode patients. The expert's dosing recommendations agreed closely with the package inserts for the drugs, and their estimates of dose equivalence among the antipsychotics followed a linear pattern. The experts considered 3-6 weeks an adequate antipsychotic trial, but would wait a little longer (4-10 weeks) before making a major change in treatment regimen if there is a partial response. The experts recommended trying to improve response by increasing the dose of atypical and depot antipsychotics before switching to a different agent; there was less agreement about increasing the dose of conventional antipsychotics before switching, probably because of concern about side effects at higher doses. If it is decided to switch because of inadequate response, risperidone was the expert's first choice to switch to, no matter what drug was initially tried. Although there was some disparity in the expert's recommendations concerning how many agents to try before switching to clozapine, the expert's responses suggest that switching to clozapine should be Clozapine was also the antipsychotic of choice for patients with suicidal behavior. When switching oral antipsychotics,the experts considered cross-titration the preferred strategy. When switching to an injectable antipsychotic, the experts stressed the importance of continuing the oral antipsychotic until therapeutic levels of the injectable agent are achieved. The experts considered psychosocial interventions the first choice strategy for partially compliant patients, with pharmacologic interventions the first choice for patients with clear evidence of noncompliance. However, because it can be difficult to distinguish partially compliant from noncompliant patients, the editors recommended combining psychosocial and pharmacologic interventions to improve compliance whenever possible. When patients relapse because of compliance problems or if there is any doubt about compliance, the experts recommended the use of a long-acting injectable antipsychotic and would select an injectable atypical when this option becomes available. The experts would also consider using an injectable atypical antipsychotic (when available) in many clinical situations that do not involve compliance problems. The experts stressed the importance of monitoring for health problems-especially obesity, diabetes, cardiovascular problems,HIV risk behaviors, medical complications of substance abuse, heavy smoking and its effects, hypertension, and amenorrhea-in patients being treated with antipsychotics. Although many patients are prescribed adjunctive treatments,multiple antipsychotics, and combinations of different classes of drugs (e.g., antipsychotics plus mood stabilizers or antidepressants) in an effort to enhance response, the experts gave little support to any of these strategies, with the exception of antidepressants for patients with dysphoria/depression, antidepressants or ECT for patients with suicidal behavior, and mood stabilizers for patients with aggression/violence. When asked about indicators of remission and recovery, the experts considered acute improvement in psychotic symptoms the most important indicator of remission, whereas they considered more sustained improvement in multiple outcome domains (e.g., occupational/educational functioning, peer relationships,independent living) important in assessing recovery. CONCLUSIONS: The experts reached a high level of consensus on many of the key treatment questions in the survey. Within the limits of expert opinion and with the expectation that future research data will take precedence, these guidelines provide direction for addressing common clinical dilemmas that arise in the pharmacologic treatment of psychotic disorders. They can be used to inform clinicians and educate patients regarding the relative merits of a variety of interventions. Clinicians should keep in mind that no guidelines can address the complexities involved in the care of each individual patient and that sound clinical judgment based on clinical experience should be used in applying these recommendations.
Antipsychotic Agents↗
Strategies for improving compliance in treatment of schizophrenia by using a long-acting formulation of an antipsychotic: clinical studies.
Despite evidence showing the importance of continuous medication in preventing relapse in patients with schizophrenia and the harmful consequences that relapse can have, clinical efforts often focus on hospital-based treatment or treatment of acute exacerbations of schizophrenia rather than on ensuring appropriate and effective relapse prevention. Inadequate compliance with antipsychotic treatment further deters from the goal of long-term management of schizophrenia; however, appropriate use of injectable, long-acting antipsychotic medications--especially atypical antipsychotics--has the potential to increase compliance and thus improve the long-term prognosis of patients with schizophrenia. A long-acting formulation of the atypical antipsychotic risperidone has undergone large-scale clinical testing, during which it showed significant improvement on measures of disease severity while maintaining an acceptable side effect profile.
Adult↗
Clinical guidelines: Dosing and switching strategies for long-acting risperidone.
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Antipsychotic Agents↗
Introduction. Ziprasidone in schizophrenia: from acute treatment to long-term management.
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Acute Disease↗