A multiattribute decision model for bipolar disorder: identification of preferred mood-stabilizing medications.

OBJECTIVE: To develop a multiattribute decision model (MADM) to aid in the selection of preferred medications for the treatment of bipolar disorder. STUDY DESIGN: Data were obtained via a self-administered online survey among psychiatric pharmacist specialists. These survey data were used to construct a MADM based on multiattribute utility technology. METHODS: Anticonvulsant mood stabilizers, atypical antipsychotics, olanzapine-fluoxetine combination, and lithium carbonate were evaluated using a MADM. Attributes included in the model were effectiveness, safety and tolerability, cost, monitoring burden, and dosing frequency. A survey instrument was developed to score the relative importance of each attribute and the factor scores for each medication. Four iterations of the model were performed to ascertain the medication with the highest total utility score when the effectiveness factors were weighted to consider the following: overall effectiveness, effectiveness in acute mania, effectiveness in acute bipolar depression, and effectiveness in maintenance treatment. Sensitivity analyses were performed to evaluate the stability of the MADM results. RESULTS: When overall effectiveness, effectiveness in acute mania, or effectiveness in maintenance treatment was considered, lithium carbonate had the highest total utility score. When effectiveness in acute bipolar depression was considered, lamotrigine had the highest total utility score. When considering only atypical antipsychotics, aripiprazole was associated with the highest total utility score for all iterations of the MADM. CONCLUSION: The use of a MADM may be a beneficial tool to assist in making formulary or preferred therapeutic agent decisions.

Successful use of topiramate in a patient with severe postherpetic neuralgia.

OBJECTIVE: To describe the case of a patient with postherpetic neuralgia (PHN) who had a marked response to topiramate despite failure of several previous therapies. CASE SUMMARY: A 79-year-old white male with multiple medical comorbidities developed severe trigeminal territory PHN requiring treatment with opiates to maintain adequate pain relief. Topiramate was initiated after the patient failed treatment with 4 other antiepileptic medications due to various adverse events. After 3 months of topiramate therapy, with dosages up to 50 mg twice daily, PHN pain had decreased to the point that the patient was able to discontinue the use of opiates entirely. At time of writing, he continued to be maintained on topiramate 50 mg twice daily with good pain relief and no reported adverse effects. DISCUSSION: Topiramate exhibits a number of actions that may contribute to the relief of neuropathic pain, including modulation of voltage-gated sodium and calcium channels, potentiation of gamma-aminobutyric acid inhibition, and blockade of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainite glutamate receptors. Current evidence-based recommendations consider topiramate to be a third-line agent for the treatment of neuropathic pain based on studies of its use in painful diabetic neuropathy and chronic lumbar radicular pain. A comprehensive search of MEDLINE (1950-August 2008) using the terms postherpetic neuralgia, neuralgia, and topiramate revealed only one previously published case report evaluating the use of topiramate specifically for treatment of PHN. CONCLUSIONS: While it is impossible to determine whether pain relief in this case was due to treatment with topiramate as opposed to spontaneous resolution of pain over time, this additional case report suggests that topiramate may be a useful treatment option for patients with PHN who have not responded to or are intolerant of other interventions. Further studies are needed to determine whether topiramate should receive a stronger recommendation for the treatment of PHN.

Paliperidone extended-release tablets for the acute and maintenance treatment of schizophrenia.

BACKGROUND: Paliperidone, which is available in extended-release (ER) tablets, was approved by the US Food and Drug Administration in 2007 for the acute and maintenance treatment of schizophrenia. It is the seventh second-generation antipsychotic (SGA) to be introduced to the US market. Paliperidone is the major active metabolite of risperidone, an established anti-psychotic agent. OBJECTIVE: This article reviews the available literature on the pharmacodynamics, pharmacokinetics, clinical efficacy, and tolerability of paliperidone. METHODS: A comprehensive search of MEDLINE using the terms paliperidone, 9-hydroxy-risperidone, and Invega was performed for the years 1950 through December 2007. Articles that discussed the efficacy and tolerability of 9-hydroxy-risperidone formed as a metabolite of risperidone were excluded; all others were included. Abstracts and posters presented at recent national and international scientific meetings were also included in the review. RESULTS: At therapeutic doses (3-12 mg), paliperidone ER follows linear pharmacokinetics. Like that of its parent drug, paliperidone's mechanism of action is thought to be through antagonistic actions at dopamine D(2) and serotonin-2A receptors. In vivo studies suggest that the cytochrome P450 enzyme system plays a minimal role in paliperidone metabolism, with none of the metabolites accounting for >10% of a dose. The majority (59%) of paliperidone is eliminated through the kidneys as unchanged drug. The results of three 6-week, randomized, double-blind, parallel-group trials indicated the efficacy of paliperidone ER compared with placebo in the treatment of acute exacerbations of schizophrenia, with response rates ranging from 39.8% to 61.0% for paliperidone ER, compared with 18.3% to 34.0% for placebo. During a 52-week, double-blind, relapse-prevention trial, the time to 25% of patients experiencing a recurrence was 83 days for paliperidone ER, compared with 23 days for placebo. The proportions of patients in the 6-week trials who reported at least 1 extrapyramidal symptom-related adverse event were 13%, 10%, 25%, 26%, and 24% for paliperidone ER 3, 6, 9, 12, and 15 mg/d, respectively; the pooled incidence rate was not statistically different from that with placebo (11%). Headache and insomnia were the most common adverse events in patients treated with paliperidone ER in the 6-week trials (pooled data: 11%-18% and 4%-14%, respectively). In the relapse-prevention trial, the incidence of prolactin-related adverse events was 4% for paliperidone ER and 0% for placebo. CONCLUSIONS: Current evidence supports the efficacy and tolerability of paliperidone ER in the acute and long-term treatment of schizophrenia. Randomized, head-to-head comparisons with other SGAs, particularly risperidone, are needed to define the role of paliperidone ER in the treatment of schizophrenia.

Schizophrenia: multi-attribute utility theory approach to selection of atypical antipsychotics.

BACKGROUND: Current guidelines/algorithms recommend atypical antipsychotics as first-line agents for the treatment of schizophrenia. Because there are extensive healthcare costs associated with the treatment of schizophrenia, many institutions and health systems are faced with making restrictive formulary decisions regarding the use of atypical antipsychotics. Often, medication acquisition costs are the driving force behind formulary decisions, while other treatment factors are not considered. OBJECTIVE: To apply a multi-attribute utility theory (MAUT) analysis to aid in the selection of a preferred agent among the atypical antipsychotics for the treatment of schizophrenia. METHODS: Five atypical antipsychotics (risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole) were selected as the alternative agents to be included in the MAUT analysis. The attributes identified for inclusion in the analysis were efficacy, adverse effects, cost, and adherence, with relative weights of 35%, 35%, 20%, and 10%, respectively. For each agent, attribute scores were calculated, weighted, and then summed to generate a total utility score. The agent with the highest total utility score was considered the preferred agent. RESULTS: Aripiprazole, with a total utility score of 75.8, was the alternative agent with the highest total utility score in this model. This was followed by ziprasidone, risperidone, and quetiapine, with total utility scores of 71.8, 69.0, and 65.9, respectively. Olanzapine received the lowest total utility score. A sensitivity analysis was performed and failed to displace aripiprazole as the agent with the highest total utility score. CONCLUSIONS: This model suggests that aripiprazole should be considered a preferred agent for the treatment of schizophrenia unless found to be otherwise inappropriate.

Atomoxetine versus stimulants for treatment of attention deficit/hyperactivity disorder.

OBJECTIVE: To identify, review, and analyze studies comparing atomoxetine with psychostimulants with the intent of determining the role of atomoxetine in the pharmacologic management of attention deficit/hyperactivity disorder (ADHD). DATA SOURCES: Primary, review, and meta-analysis articles were identified by a MEDLINE search (1966-December 2005). MeSH headings used in the search include: attention deficit/hyperactivity disorder, ADHD, atomoxetine, stimulants, psychostimulants, methylphenidate, and amphetamine salts. Relevant data presented at professional meetings that we attended were also identified. STUDY SELECTION AND EXTRACTION: All clinical studies comparing atomoxetine with psychostimulants, regardless of study design, were evaluated. Relevant efficacy and safety data from these studies were included in the discussion. DATA SYNTHESIS: At time of writing, 5 head-to-head trials had compared psychostimulants and atomoxetine in the treatment of ADHD. No significant difference between atomoxetine and methylphenidate immediate-release were found on the ADHD Rating Scale total score. Osmotic oral release system (OROS) methylphenidate showed significantly greater improvement at weeks 1 and 2, and significantly more patients treated with OROS methylphenidate were classified as responders. Patients on both atomoxetine and mixed amphetamine salts extended-release (MAS XR) showed significant improvements at endpoint over baseline; however, Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) scores were significantly better with MAS XR. Tolerability was similar between atomoxetine and stimulant medications. CONCLUSIONS: Based on available evidence, psychostimulants are regarded as first-line pharmacologic treatment for children and adolescents with ADHD, as the efficacy and safety of these agents have been well established based on clinical trials and extensive naturalistic use. Adverse effects in some patients and abuse potential have led to the search for new treatments. Atomoxetine represents an alternative treatment for ADHD and is unlikely to be associated with abuse; however, long-term safety data are needed to further establish its place in therapy.

Duloxetine hydrochloride: a new dual-acting medication for the treatment of major depressive disorder.

BACKGROUND: Duloxetine hydrochloride has recently been approved by the US Food and Drug Administration for the treatment of major depressive disorder (MDD). Duloxetine is a potent inhibitor of serotonin and norepinephrine reuptake, with weak effects on dopamine reuptake. OBJECTIVE: This article reviews the literature on duloxetine with regard to its pharmacodynamics, pharmacokinetics, clinical efficacy, and tolerability. METHODS: A comprehensive search of MEDLINE was performed using the terms duloxetine, Cymbalta, and major depressive disorder, with no restriction on year. The Eli Lilly and Company clinical trial registry, and abstracts and posters from recent American Psychiatric Association meetings were also reviewed. RESULTS: Duloxetine exhibits linear, dose-dependent pharmacokinetics across the approved oral dosage range of 40 to 60 mg/d. No dose adjustment appears to be needed based on age. Duloxetine has shown efficacy in reducing depressive symptoms compared with placebo, and duloxetine recipients have shown significant improvements in global functioning compared with placebo (both, P < 0.05). Response and remission rates have been comparable to or greater than those seen with fluoxetine or paroxetine. Duloxetine is generally well tolerated, with nausea, dry mouth, and fatigue being the most common treatment-emergent adverse effects. Cardiovascular adverse effects do not appear to result in sustained blood pressure elevations, QTc-interval prolongation, or other electrocardiographic changes. CONCLUSIONS: Based on the available evidence, duloxetine is a well-tolerated and effective treatment for MDD in adults. Randomized head-to-head comparisons against established antidepressants are needed to determine the relative safety and efficacy of duloxetine.

Clinicians' adherence to an algorithm for pharmacotherapy of depression in the Texas public mental health sector.

This study evaluated clinicians' adherence to the major depressive disorder algorithm of the Texas Implementation of Medication Algorithms (TIMA) as a component of usual care in the Texas public mental health system. Data were collected from two Texas Department of Mental Health and Mental Retardation centers between April and December 2000. Clinician adherence measures included documentation of outcome measures, prescribing patterns (correct medications, therapeutic dosing, dosage increases, and appropriate medication changes), and visit frequency. Clinicians had consistently high adherence to appropriate drug regimens, at appropriate dosages. Variability in attempts to increase dosages when warranted, visit frequency, and documentation of patient outcome measures between clinicians were seen. The results suggest that implementation of medication algorithms is possible in the public mental health sector.

Sudden late onset of clozapine-induced agranulocytosis.

OBJECTIVE: To report a patient who suddenly developed agranulocytosis after long-term clozapine therapy. CASE SUMMARY: A 41-year-old white man suddenly developed agranulocytosis after 89 months of nearly continuous clozapine therapy. During this time, which included the addition of risperidone to the treatment regimen, his white blood cell (WBC) and granulocyte counts remained stable. One week after having stable hematologic counts, the patient suddenly developed agranulocytosis. WBC and granulocyte counts returned to baseline shortly after discontinuation of all medications and administration of sargramostim. DISCUSSION: The main factor limiting the use of clozapine as a first-line agent in mentally ill patients is the risk of agranulocytosis. Although the greatest risk of developing this adverse reaction is during the initial 6-month exposure, clozapine-induced agranulocytosis continues to pose a risk after years of exposure. Current product labeling requires weekly WBC and granulocyte monitoring for the first 6 months of treatment with clozapine, which may be decreased to biweekly monitoring after 6 months. Based on the sudden and late onset of agranulocytosis in our patient, clinicians may consider opting for weekly monitoring of hematologic function for patients on long-term clozapine therapy. The likelihood that clozapine was the cause of the agranulocytosis was rated possible according to the Naranjo probability scale. CONCLUSIONS: Clinicians must remain vigilant to trends in WBC and granulocyte counts and may wish to consider weekly hematologic monitoring regardless of duration of clozapine therapy. Patient and treatment system compliance with the registries' protocol regarding WBC monitoring is instrumental in reducing morbidity and mortality rates associated with clozapine use.