Steven C. Stoner

Asenapine: A Clinical Review of a Second-Generation Antipsychotic

BACKGROUND Schizophrenia and bipolar disorder are both prevalent types of psychiatric illness in the United States. As second-generation antipsychotics have become a more viable first-line treatment option, their use has been associated with a new era of adverse events (AEs), most notably metabolic and cardiovascular concerns. Although treatment options for schizophrenia and bipolar disorder have arguably improved, there continues to be a need for medications that achieve and maintain desired efficacy with minimal AEs. OBJECTIVES This article serves as a comprehensive review of the pharmacologic profile of the second-generation antipsychotic asenapine, as well as a review of its efficacy and safety profiles based on the findings from clinical trials in schizophrenia and bipolar disorder. METHODS Searches of Ovid MEDLINE, EMBASE, and IDIS were conducted (January 1996 to November 2011) to identify clinical studies and other primary literature sources with the following search terms: asenapine, bipolar disorder, antipsychotic, psychosis, dopamine, and schizophrenia. Only studies of asenapine and placebo and/or active-comparator arms were included. RESULTS The literature search yielded 67 unique articles, including review articles, which were excluded. The efficacy of asenapine was reported in 3 clinical studies in patients with schizophrenia, 1 each in acute and long-term settings, measured as significant changes in Positive and Negative Syndrome Scale scores over 6 and 52 weeks. Asenapine also had reported efficacy in the prevention of relapse in schizophrenia during a 26-week extension study. In addition, efficacy of asenapine was reported in 2 studies in acute mania as well as extension phases of both 9 and 40 weeks, as determined by significant changes in Young Mania Rating Scale scores. The most commonly reported AEs in these studies were somnolence (13%-24%), extrapyramidal symptoms (EPS) (7%-12%), and dizziness (11%). CONCLUSIONS The findings from multiple studies have suggested that asenapine is efficacious in the acute treatment of schizophrenia. Asenapine has reported long-term efficacy for this indication and the potential to reduce the incidence of relapse. Asenapine efficacy was also reported in the treatment of acute manic or mixed states associated with bipolar I disorder. Asenapine had an acceptable safety profile across the different disease states studied, although it was not devoid of metabolic and EPS-related AEs.

Anticholinergic Drug Abuse and Misuse

SummaryAbuse of the centrally acting anticholinergic agents is a phenomenon occasionally reported in the medical literature. Anticholinergics, most often used in psychiatry to treat antipsychotic-induced extrapyramidal symptoms, are also used by some patients for their mood altering and psychedelic effects. The changes in sensorium can range from mild euphoria and increased sociability to hallucinations and toxic psychosis.In this article, we have reviewed 110 cases of reported anticholinergic abuse and identified 3 distinct groups of abusers: (i) those individuals who have no valid medical need for the medication and consume it only for its mind-altering effects; (ii) those with a valid indication for the use of anticholinergics who also abuse the agents for their mind-altering effects; and (iii) those who have an appropriate medical indication for the agents and appear to be using anticholinergics to relieve chronic or subclinical extrapyramidal symptoms, depression or negative schizophrenic symptoms. True abusers (i.e. those individuals in the first 2 groups) can be recognised because they feign extrapyramidal symptoms, repeatedly ‘lose’ their medications or request unnecessary dose increases.In order to reduce the risk of abuse, exposure to anticholinergics should be minimised in patients at risk. Patients who are reluctant to have their anticholinergics discontinued should be carefully evaluated to identify potential risks and benefits of continued use before prolonged therapy is instituted. Anticholinergics should not be abruptly discontinued, but instead tapered over a 2-week period in patients receiving high doses or long term treatment.

Historical Review of Carbamazepine for the Treatment of Bipolar Disorder

The management of bipolar disorder has seen significant evolution in terms of the number of treatment options now approved for both the acutely manic phase and the maintenance stages of the illness. In addition, new formulations of traditional agents are available for clinicians to use in their treatment approach. One such example is carbamazepine, which has approval by the United States Food and Drug Administration for the treatment of acute and mixed mania in an extended‐release formulation that uses a three‐bead delivery system. Although the parent compound has been available for decades, its approval for bipolar disorder is recent despite numerous clinical trials that have supported its use in both the acute and maintenance phases of bipolar disorder. Advantages of the new formulation include less fluctuation in plasma concentration and, in general, improved tolerability. However, issues remain with regard to cytochrome P450 drug‐related interactions and the need for therapeutic drug monitoring (e.g., drug concentrations, epoxide metabolite concentrations, hematology, and liver function tests) as part of the treatment and monitoring process. We review the current body of literature describing the use of carbamazepine in bipolar disorder during both the acute and maintenance phases of the disorder, including trials of both monotherapy and combination therapy, as well as findings from trials that included patients with rapid cycling and mixed episodes.

A program to convert patients from trade-name to generic clozapine

In spring 2000, the Missouri Department of Mental Health mandated that its psychiatric inpatient facilities convert patients from trade‐name to generic clozapine. The pharmacy department at our facility was encouraged to develop a conversion program to oversee and assess the efficacy and tolerability of the change. A protocol to monitor the conversion of patients to generic clozapine hospitalwide was developed. The primary objective was to determine whether therapeutic response and level of tolerability were the same with generic versus trade‐name clozapine. The secondary objective was to determine whether changes in monitoring white blood cell and absolute neutrophil counts were necessary after conversion. Our results showed that most patients did not experience changes greater than a mean of 5 points in their scores on the Brief Psychiatric Rating Scale (BPRS). However, a statistically significant difference was seen in 22 patients who had a mean reduction or an increase of less than 5 points (p=0.0139) in BPRS scores compared with two patients who had a mean increase greater than 5 points. Assessment of percentage change in BPRS scores indicated that 14 (58%) converted patients had a 1–50% decrease in mean BPRS scores, and 10 (42%) had a 1–40% increase. However, of those with a mean BPRS increase, five (50%) had an increase of 10% or less. Our clozapine conversion program resulted in the successful conversion of all 24 patients.

Community pharmacy patient perceptions of a pharmacy-initiated mobile technology app to improve adherence.

To determine patient perceptions of using a demonstration application (app) of mobile technology to improve medication adherence and to identify desired features to assist in the management of medications.

Delayed-Onset Neutropenia with Divalproex Sodium

Objective: To report the development of neutropenia in a patient after almost 8 years of being stabilized on delayed-release divalproex sodium (DVPX). Case Summary: A 45-year-old man had been maintained on DVPX for nearly 8 years, with serum valproic acid concentrations of 85-120 mg/L and normal white blood cell (WBC) counts and absolute neutrophil counts (ANCs). Five months prior to the development of neutropenia (defined as ANC <1800 cells/μL), the patients DVPX dosage was decreased by 250 mg to 1250 mg every morning and 1500 mg every evening. After 2 months of that regimen, the DVPX dosage was increased back to 1500 mg twice daily. Three months alter that increase, the patients WBC count dropped to 3.7 × 103/μL and ANC was 1199 cells/μL Although the ANC was below 1800 cells/μL, he showed no physical manifestations consistent with neutropenia. DVPX was discontinued, and 2 weeks later the patients WBC count was 7.2 x 103/μL and ANC was 2290 cells/μL. Discussion: Although a complete blood cell count with differential is a commonly accepted form of therapeutic drug monitoring with DVPX, the monitoring is considered most necessary to identify dose-retated thrombocytopenia. However, neutropenia has been rarely associated with the use of DVPX and could contribute to the development of different types of infection, including those of a bacterial, viral, or fungal origin. Although neutropenia is generally mild in severity, potentially severe DVPX-associated neutropenia can occur any time during the course of therapy, although it is most common within the first few months of treatment. In this case, DVPX was the probable cause of the neutropenia, according to the Naranjo probability scale. However, this case of neutropenia is atypical with respect to the timeframe in which it developed and was identified. Although the documented laboratory findings suggest neutropenia, the patient did not experience any clinical complications as a result. The late onset of the patients neutropenia is unlike other cases that have been documented in the literature. Conclusions: Hematologic therapeutic drug monitoring continues to be clinically important regardless of whether the patient is early in therapy or even years later in the course. In this patient, continued regular therapeutic drug monitoring identified a suspected drug-related complication and the medication was able to be discontinued without the development of clinical complications.

Augmentation of Aripiprazole with Low‐Dose Clozapine

An issue under much clinical debate is whether treatment with two antipsychotic agents simultaneously is advantageous for optimizing response in patients whose previous monotherapy with antipsychotic agents has failed. Minimal evidence supports treatment with multiple antipsychotics, even when the agents have different mechanisms of action. The standard of care for treating schizophrenia is to first use monotherapy of adequate dosage and duration, including a trial of clozapine before adding a second agent. We report the case of a 32‐year‐old man whose monotherapy with various antipsychotic agents failed. During attempted conversion from aripiprazole to clozapine, the patient experienced a significant reduction in psychiatric features. Despite this improvement, the patient became resistant to the clozapine titration schedule due to complaints of sedation. Aripiprazole combined with low‐dose clozapine as maintenance therapy resulted in a positive clinical outcome despite a clozapine serum level that is generally considered subtherapeutic. This case emphasizes the importance of making interventions based on individual patient response.

Agitation Associated with Aripiprazole Initiation

Aripiprazole is a novel antipsychotic with a mechanism of action different from those of traditional first‐ and second‐generation antipsychotics. We describe three patients with long histories of treatment for schizophrenia or schizoaffective disorder in whom conversion to aripiprazole was being attempted. After they started aripiprazole, their psychosis, agitation, anxiety, or aggression worsened. Although the cause of the increased agitation was unclear, it may have been related to long‐term use of dopamine‐blocking antipsychotics and resultant upregulation of postsynaptic dopamine receptors. The mechanism of partial dopamine agonism observed with aripiprazole may increase dopaminergic activity and worsen positive dopamine‐associated symptoms, such as paranoia, agitation, and aggression. The treatment of schizophrenia is often a clinical challenge, particularly when patients have a long history of noncompliance and poor response. Clinicians face difficult decisions in finding an effective and well‐tolerated regimen. These cases magnify some of the challenges and provide insight into the clinical implications of converting to therapies with different pharmacodynamic effects.

Community pharmacy transition of care services and rural hospital readmissions: A case study

OBJECTIVES To explore community pharmacist involvement in the transition of care (TOC) process for patients discharged with acute myocardial infarction (AMI), heart failure (HF), pneumonia, chronic obstructive pulmonary disease (COPD), or elective total hip or knee arthroplasty (THA/TKA). SETTING Patients discharged from a 60-bed acute care hospital located in rural Missouri were seen by a community pharmacist in 2 independent community pharmacy locations. PRACTICE INNOVATION Patients admitted with 1 of the 5 qualifying conditions and identifying the participating pharmacy as their primary pharmacy spoke with a community pharmacist within 72 hours of discharge to complete a comprehensive medication review. A follow-up telephone call occurred 7 days after the encounter to evaluate for drug-related problems, adherence, and key information recalled from the previous visit. A final telephone call occurred on the 30th day after discharge to assess for hospital readmissions and emergency department (ED) visits. EVALUATION Number of patients readmitted or visiting the ED within 30 days after discharge. RESULTS Of the 9 patients completing the study, none were readmitted or visited the ED within 30 days after discharge. All of the participants were satisfied with the care and education provided by pharmacists. The majority of patients recalled points related to specific medication education topics. Based on the adherence tool, 8 of the 9 study participants had at least 1 barrier to medication access or adherence that could lead to post-discharge medication-related problems. CONCLUSION Community pharmacist involvement in the TOC process may help to prevent readmissions for patients with AMI, HF, pneumonia, COPD, and elective THA/TKA. Patients are overall satisfied with community pharmacist involvement as they move from inpatient care to home. In addition, there are multiple barriers affecting access and adherence to medication therapy while at home, providing opportunities for pharmacist intervention and assistance.

An Exploratory Retrospective Evaluation of Ropinirole-Associated Psychotic Symptoms in an Outpatient Population Treated for Restless Legs Syndrome or Parkinson's Disease

Background: Traditional treatment approaches for the management of restless legs syndrome (RLS) and Parkinsons disease (PD) include the use of medications that either directly or indirectly increase dopamine levels. In turn, a potential adverse event that could be expected is the development or exacerbation of psychiatric-related symptoms. Objective: To evaluate and describe the incidence of psychosis and associated behavioral features in patients taking ropinirole for RLS or PD. Methods: Patients were identified from a computerized database search of outpatients being treated with ropinirole for 1 of 2 medical conditions: PD or RLS. Data were collected in a retrospective manner from 95 patients who were tracked over the course of their therapy to determine whether psychosis or associated behavioral symptoms developed as a result and whether an intervention was needed to adjust ropinirole dosing or if additional medications had to be added to control features associated with psychosis. Results: A total of 284 patients being treated for RLS or PD were identified; of this group, 95 patients were identified as being treated for PD or RLS with ropinirole. Of the 95 patients being treated with ropinirole, 13 developed psychotic features that required therapeutic intervention with either the use of an antipsychotic or dose adjustment of ropinirole. PD patients included in this study were numerically more likely to develop psychotic features compared with RLS patients; however, the difference was not statistically significant (p = 0.122). The results do suggest that this risk is increased when ropinirole is used as part of a dual therapy approach with dopamine agonists in the treatment of either PD or RLS (p = 0.003). Discussion: Dopamine agonists have long been used as preferred treatment in the management of PD and RLS. When treating either PD or RLS in the psychiatric population, the concern arises that increased activity at dopamine receptors may induce or exacerbate psychiatric features. A potential clinical concern with the use of ropinirole is the potential for patients to develop psychiatric features, although there are few data available to demonstrate whether stimulation of targeted individual dopamine receptors is linked to the development or exacerbation of psychotic features. It is also undetermined whether concurrent antipsychotic treatment provides any protective benefit against psychosis, especially in patients already being treated for psychotic symptoms. Conclusions: Our findings suggest that ropinirole may play a role in inducing or exacerbating psychosis and its associated features, although a number of confounding variables prevent the determination of a clear association and suggest that further investigation is warranted in controlled clinical trials.