Matthew A. Fuller

Comparative Study of the Development of Diabetes Mellitus in Patients Taking Risperidone and Olanzapine

Objectives. A growing body of literature suggests that certain atypical antipsychotics, especially olanzapine and clozapine, may induce glucoregulatory dysfunction. We assessed the differences in risk of developing diabetes mellitus during treatment with olanzapine and risperidone by using patients treated with haloperidol and fluphenazine as control subjects in whom we would not expect to see an increased risk.

Long-Acting Injectable Risperidone

OBJECTIVE To review the pharmacology, pharmacokinetics, clinical efficacy, and safety profile of long-acting (LA) risperidone for the treatment of schizophrenia. DATA SOURCES Information was selected from PubMed (1965–July 2004). Applicable scientific posters were also used. STUDY SELECTION AND DATA EXTRACTION All published information on risperidone LA was considered. Material providing a comprehensive description was considered. DATA SYNTHESIS Risperidone LA is the first long-acting, injectable atypical antipsychotic. It is dosed at 25–50 mg every 2 weeks. Adverse effects are similar to those seen with oral risperidone. A short-term study showed that risperidone LA is better than placebo in reducing the signs and symptoms of schizophrenia, and a long-term trial showed that stable schizophrenic patients can be switched from either oral or other injectable antipsychotic medications to risperidone LA. CONCLUSIONS Risperidone LA is efficacious and safe in the treatment of schizophrenia.

Pharmacokinetics of Quetiapine in Elderly Patients with Selected Psychotic Disorders

ObjectiveTo assess the pharmacokinetics and tolerability of quetiapine in elderly patients with selected psychotic disorders.Study designThis was a multicentre, open-label, 27-day, rising multiple-dose trial. Descriptive statistics summarised plasma quetiapine concentrations and pharmacokinetic parameters by trial day. A two-way analysis of variance was used to evaluate all pharmacokinetic parameters, and 90% confidence intervals of the mean differences were calculated.MethodsAntipsychotic drugs taken prior to the study period were discontinued on day 1. Quetiapine treatment began on day 3. Doses were increased stepwise, starting at 25mg three times daily and reaching 250mg three times daily by day 21. Patients: Twelve patients (age 63–85 years) with schizophrenia, schizoaffective disorder or bipolar disorder.Main outcome measures and resultsKey assessments included quetiapine plasma concentrations, and neurological and safety evaluations. Under steady-state conditions, the 100 and 250mg doses of quetiapine were not significantly different in terms of dose-normalised area under the plasma concentration-time curve within an 8-hour dose administration interval, or in dose-normalised minimum plasma concentration (Cmin) at the end of a dose administration interval. The morning Cmin values for the seven discrete dose amounts evaluated also increased linearly with dose. The apparent oral clearance, volume of distribution and half-life did not change as a function of dose. There were no serious adverse events. The most common adverse events were postural hypotension (n = 6), dizziness (n = 5) and somnolence (n = 4).ConclusionsWhile quetiapine was well tolerated at doses up to 250mg three times daily, the potential for reduced clearance, as well as the adverse effects of postural hypotension and dizziness, indicated that quetiapine should be introduced at lower doses and titrated at a relatively slower rate in patients ≥65 years.

Discontinuation of clozapine: a 15-year naturalistic retrospective study of 320 patients.

Clozapine is underutilized in the management of treatment‐resistant schizophrenia. To understand contributing factors, we analyzed the frequency and causes of clozapine discontinuations that occurred over a 15‐year period in a clinical setting.

Clozapine reduces water-drinking behavior in schizophrenic patients with polydipsia.

Disordered water balance, or polydipsia, is an underassessed and underreported phenomenon present in the severely psychiatrically disabled population. Prevalence rates for polydipsia range from 6.2 to 20%. We followed up five male patients (mean age 43) with chronic schizophrenia who met the Kane criteria for being treatment nonresponders and who, in addition, had marked polydipsia. Three patients had previously received medical care for hyponatremia and had to be placed on fluid restriction when admitted to the hospital. All patients exhibited polydipsia despite high doses of typical antipsychotic drugs. Each patient was treated openly with clozapine (range 450-800 mg/day) for at least 6 months. In each case, there was a decline in the Brief Psychiatric Rating Scale score (preclozapine mean, 63; postclozapine mean, 46), and a marked reduction in fluid-seeking behavior. All fluid restrictions could be lifted, and the patients were discharged from the hospital. During a mean follow-up period of 17 months, during which patients were evaluated weekly, polydipsic behavior that required intervention had not been noted. We conclude that clozapine may be a highly effective treatment for polydipsia in patients with treatment-refractory schizophrenia. Future studies may aim to delineate neurobiologic mechanisms.

Sertraline and Psychotic Symptoms: A Case Series

Sertraline and other SSRIs have a relatively favorable side-effect profile and are widely prescribed. We report the emergence of psychotic symptoms during treatment with sertraline in four patients. Three of these patients had a history of psychotic illness and were on antipsychotic medication, when sertraline was added. The psychotic symptoms emerged within 3 days-7 weeks of starting sertraline and resolved on its discontinuation. We wish to alert clinicians to the possibility that sertraline may provoke or exacerbate positive psychotic symptoms, particularly in patients on neuroleptics, with a previous history of psychosis.

Selegiline in Treatment of Behavioral and Cognitive Symptoms of Alzheimer Disease

OBJECTIVE: To evaluate the effects of selegiline on behavioral and cognitive symptoms of patients with Alzheimer disease. DATA SOURCES: An English-language MEDLINE search (1982–1995) was used to identify the review articles and human clinical trials discussed in this article. STUDY SELECTION: Double- and single-blind and open-label trials were reviewed. Studies were also reviewed if selegiline was evaluated comparatively with other agents. Review articles were used for background information. DATA EXTRACTION: Data were evaluated from human studies. Studies were critiqued on the basis of design, methodology, duration, sample size, and the degree to which neuropsychological tests used in each study were compared. DATA SYNTHESIS: Selegiline is a selective, irreversible inhibitor of monoamine oxidase type B. Eight of 11 controlled trials showed selegiline had a positive effect on cognition (e.g., word fluency, delayed recall, total recall). Two of 5 controlled trials evaluating selegilines effect on behavior (e.g., anxiety, tension, excitement, depression) showed a positive effect. CONCLUSIONS: The role of selegiline remains to be determined by large well-controlled, long-term clinical trials. Selegiline may be a useful agent in managing behavioral and cognitive symptomatology associated with Alzheimer disease. Given that the management of Alzheimer disease is symptomatic and no standard treatment exists, selegiline should be considered among the various options.

Lurasidone: An Atypical Antipsychotic for Schizophrenia

OBJECTIVE: To provide a clinical overview of the antipsychotic lurasidone. DATA SOURCES: Articles were identified by searching the MEDLINE, PubMed, Cochrane Library, and EBSCO databases (through February 2012) using the key word lurasidone. The manufacturer provided information on unpublished Phase 2 and 3 trials. The Clinicaltrials.gov database was reviewed for the status of ongoing and upcoming trials. STUDY SELECTION AND DATA EXTRACTION: All clinical trials lasting longer than 3 weeks and published in the English language were selected for review. Additional documentation, including the product dossier, package insert, and poster presentations supplied by the publisher, was also evaluated. DATA SYNTHESIS: Lurasidone hydrochloride is an atypical antipsychotic that is approved for the treatment of schizophrenia. It is under investigation for treatment of bipolar I disorder. It should be administered with food, is pregnancy category B, is contraindicated for coadministration with strong CYP3A4 inducers and inhibitors, and requires dose adjustments with certain medications and in renal and hepatic impairment. Like other atypical antipsychotics, lurasidone possesses dopamine D2 and serotonin 5-HT2A antagonism but exhibits little affinity for histamine H1, α1-adrenergic, or cholinergic M1 receptors. Additionally, it is a potent 5-HT7 antagonist, which may impact depression and cognition. Phase 3 trial results revealed that 40-80 mg administered once daily resulted in statistically significant improvements in schizophrenia symptomatology compared with placebo. Lurasidones rate of metabolic adverse events is low relative to other atypical antipsychotics; however, this is offset by dose-dependent increases in somnolence, akathisia, and parkinsonism. CONCLUSIONS: Lurasidone has shown efficacy when compared to placebo in acute schizophrenia. Full characterization of the adverse effect profile and cognitive and affective benefits requires publication of trials with longer durations.

Nefazodone therapy in patients with treatment-resistant or treatment-intolerant depression and high psychiatric comorbidity

Given the potentially severe functional impairment, morbidity, and high costs associated with refractory depression, it is important to explore all treatment options that may benefit patients with this disorder. This is a retrospective, uncontrolled analysis of our experience with nefazodone therapy in treatment-resistant and treatment-intolerant depression. Potential candidates for nefazodone therapy were referred by their treating psychiatrist. Documentation of failure to respond to previous antidepressant therapy, a diagnosis of clinical depression according to criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and completion of a Beck Depression Inventory (BDI) were required before initiation of nefazodone. A follow-up BDI was obtained after > or =4 weeks of nefazodone therapy. A Clinical Global Inventory (CGI) score was obtained retrospectively based on documentation of target symptoms in the clinical record of the last clinic visit. The study group consisted of 20 patients with treatment-resistant or treatment-intolerant major depression who received nefazodone therapy. The mean (+/- SD) age of the group was 48.1+/-9.4 years. The mean number of previously failed antidepressant trials was 1.9+/-0.6. Psychiatric comorbidity in this group was substantial, with posttraumatic stress disorder (PTSD) found in 11 (55%) patients, substance abuse in 3 (15%) patients, and personality disorder found in 2 (10%) patients. After treatment with nefazodone, 11 of 20 patients (55%) were rated on the CGI as much or very much improved. In addition, 9 patients (45%) had >20% improvement on BDI, 3 patients (15%) had 10% to 20% improvement, and 6 patients (30%) had <10% change. Two patients (10%) discontinued nefazodone therapy due to adverse effects. Analysis of our experience with nefazodone therapy in a population with treatment-resistant depression and a high degree of psychiatric comorbidity suggests that approximately 50% of patients may have substantial response to treatment, with a smaller proportion having a more modest clinical response. While receiving nefazodone therapy, most patients continued to take concurrently prescribed psychotropic medications, primarily anxiolytics or other antidepressants. Of interest was the positive drug response among a subgroup of individuals with depression and chronic, severe PTSD. Larger, controlled studies are needed to determine whether these preliminary observations are confirmed.

Dalfampridine: A Medication to Improve Walking in Patients with Multiple Sclerosis

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of dalfampridine. DATA SOURCES: A search of PubMed (1966-March 2012) was conducted using the words dalfampridine and Ampyra. Bibliographies of retrieved articles were reviewed to identify additional references. STUDY SELECTION AND DATA EXTRACTION: All identified studies published in English involving the efficacy and safety of dalfampridine were reviewed. DATA SYNTHESIS: Dalfampridine (Ampyra) is a broad-spectrum potassium channel blocker that is indicated as a treatment to improve walking in patients with multiple sclerosis (MS). Dalfampridine is the only medication approved for this indication. Efficacy has been demonstrated in 2 Phase 3 trials involving patients with MS. Dalfampridine 10 mg twice daily improved walking, as shown by a higher proportion of timed walk responders in the dalfampridine-treated group (42.9% and 35%) versus the placebo-treated group (9.3% and 8%) during the 2 studies (p < 0.001). The maximum recommended dose of dalfampridine is 10 mg twice daily; higher doses are associated with an increased risk of seizures. At doses greater than 10 mg twice daily, the frequency of other adverse reactions and discontinuations was greater and showed no additional benefit. The average wholesale price of a 10-mg dalfampridine tablet is