William Klugh Kennedy

Long-acting injectable antipsychotics (LAIs) are a pharmacotherapeutic option to help clinicians individualize schizophrenia treatment. LAIs have been available since the 1960s, starting with fluphenazine and later haloperidol; however, second-generation antipsychotics were not available in the United States until 2007 (1), (2) and more are in development (Box). (3), (4) Box Long-acting injectable antipsychotics in development Aripiprazole microsphere long-acting injectable (LAI) is a phase III investigational drug that at press time was being reviewed by the FDA. This formulation appears to be similar to risperidone LAI. The active antipsychotic differs in side effect profile and pharmacokinetics. Because the pharmaceutical science of microsphere construction allows many variations, it is not possible to determine the strengths and weaknesses of aripiprazole LAI compared with risperidone LAI microspheres at this time. The dosing intervals currently under investigation are 14 and 28 days. (3) Iloperidone crystalline LAI is a phase II-III investigational drug. FDA registration documents and early publication and presentation data report that iloperidone LAI will be a crystalline salt structure pharmaceutically similar to paliperidone and olanzapine LAI formulations, (4) The dosing interval under investigation is 28 days. [ILLUSTRATION OMITTED] Up to one-half of patients with schizophrenia do not adhere to their medications. (5) LAI use may mitigate relapse in acute schizophrenia that is caused by poor adherence to oral medications. LAIs may have a lower risk of dose-related adverse effects because of lower peak antipsychotic plasma levels and less variation between peak and trough plasma levels. LAIs may decrease the financial burden of schizophrenia and increase individual quality of life because patients spend fewer days hospitalized due to acute exacerbations. (6) Some widely used schizophrenia treatment algorithms, such as the Harvard Schizophrenia Algorithm, neglect LAIs. Also, LAIs have not been well studied for maintenance treatment of bipolar disorder (BD) even though nonadherence is a substantial problem in these patients. Patients, families, and legal guardians may choose LAI antipsychotics over oral formulations to decrease the frequency and severity of psychotic relapse or for convenience because patients who receive LAIs do not need to take a medication every day Understanding the similarities and differences among LAIs (7) and potential interpatient variability of each LAI allows prescribers to tailor the dosing regimen to the patient more safely and efficiently (Table, page 42). (1), (8-11) All LAI antipsychotic formulations rely on absorption pharmacokinetics (PK) rather than elimination PK, which generally is true for sustained-release oral formulations as well. Absorption half-life duration and absorption half-life variability are key concepts in LAI dosing. Table Characteristics of long-acting injectable antipsychotics Antipsychotic Oral Formulation Absorption Time elimination half-life between half-life injections Fluphenazine 1 day Decanoate in 14 days 7to21 days organic oil Haloperidol 1 day Decanoate in 21 days 28 days organic oil Olanzapine 1.5 day Pamoate 30 days 14 to 28 crystalline days Risperidone 1 day Microspheres 5 days 14 days Paliperidone 1 day Palmitate 45 day 28 day crystalline Antipsychotic relevant Overlapping Loading PK/PD taper dose variability necessary? possible? (a) Fluphenazine + + + Yes No Haloperidol +/- No Yes Olanzapine + + Maybe No Risperidone + + Yes No Paliperidone + No Yes (a) More + indicates greater variability among patients PD: pharmacodynamics; PK: pharmacokinetics Source: References 1,8-11 Clinical pearls Before prescribing an LAI, check that your patient has no known contraindications to the active drug or delivery method. …

American Journal of Health-System Pharmacy Society Logo Skip to main page content. HOME; CURRENT ISSUE; PAST ISSUES; SUPPLEMENTS; REPRINTS; ALERTS. KEYWORDS GO. Advanced Search ». Advertisement: Articles: RM Huggins,; WK Kennedy,; MJ Melroy,; and DG Tollerton. Cardiac arrest from succinylcholine-induced hyperkalemia Am J Health Syst Pharm April 1, 2003 60:694-697. Full Text (PDF). Add to CiteULike CiteULike; Add to Connotea Connotea; Add to Delicious Delicious; ...

Predefined error opportunity categories were used as a surrogate for medication errors to assess the impact of computerized prescriber order entry (CPOE) on the potential for error in the prescribing and order entry phases of the medication-use process. This study was performed in a neonatal intensive care unit at a 535-bed tertiary care center. Pre- and post-CPOE implementation incidence of error opportunity was compared by evaluating 500 orders before and after implementation using 18 predefined criteria. A total of 14 913 opportunities for error (OE) existed in our sample of 1000 medication orders. The number of orders with zero OE improved from 42% (n = 209) to 98% (n = 480; P < .0001), in the pre- and postgroups, respectively. The odds ratio with 95% confidence interval was 0.058 (0.036-0.094) in favor of CPOE. The implementation of CPOE was associated with a reduction in OEs in the prescribing phase or order entry phase of the medication-use process.

Atypical antipsychotics [also known as second-generation antipsychotics (SGAs)] have become a mainstay therapeutic treatment intervention for patients with schizophrenia, bipolar disorders and other psychotic conditions. These agents are commonly used with other medications—most notably, antidepressants and antiepileptic drugs. Drug interactions can take place by various pharmacokinetic, pharmacodynamic and pharmaceutical mechanisms. The pharmacokinetic profile of each SGA, especially with phase I and phase II metabolism, can allow for potentially significant drug interactions. Pharmacodynamic interactions arise when agents have comparable receptor site activity, which can lead to additive or competitive effects without alterations in measured plasma drug concentrations. Additionally, the role of drug transporters in drug interactions continues to evolve and may effect both pharmacokinetic and pharmacodynamic interactions. Pharmaceutical interactions occur when physical incompatibilities take place between agents prior to drug absorption. Approximate therapeutic plasma concentration ranges have been suggested for a number of SGAs. Drug interactions that markedly increase or decrease the concentrations of these agents beyond their ranges can lead to adverse events or diminished clinical efficacy. Most clinically significant drug interactions with SGAs occur via the cytochrome P450 (CYP) system. Many but not all drug interactions with SGAs are identified during drug discovery and pre-clinical development by employing a series of standardized in vitro and in vivo studies with known CYP inducers and inhibitors. Later therapeutic drug monitoring programmes, clinical studies and case reports offer methods to identify additional clinically significant drug interactions. Some commonly co-administered drugs with a significant potential for drug–drug interactions with selected SGAs include some SSRIs. Antiepileptic mood stabilizers such as carbamazepine and valproate, as well as other antiepileptic drugs such as phenobarbital and phenytoin, may decrease plasma SGA concentrations. Some anti-infective agents such as protease inhibitors and fluoroquinolones are of concern as well. Two additional important factors that influence drug interactions with SGAs are dose and time dependence. Smoking is very common among psychiatric patients and can induce CYP1A2 enzymes, thereby lowering expected plasma levels of certain SGAs. It is recommended that ziprasidone and lurasidone are taken with food to promote drug absorption, otherwise their bioavailability can be reduced. Clinicians must be aware of the variety of factors that can increase the likelihood of clinically significant drug interactions with SGAs, and must carefully monitor patients to maximize treatment efficacy while minimizing adverse events.

Alcohol abuse and dependence are major causes of morbidity and mortality and come with a high societal cost. The illness is notoriously difficult to treat and relapse is a common occurrence. Acamprosate represents an effective addition to the treatment options available for alcohol dependence with a novel mechanism of action. We review the published acamprosate literature focusing on major and recent comparative clinical trials and meta-analyses. We included all studies found in National Library of Medicine's PubMed database searching on Mesh term: acamprosate excluded animal studies excluding non-English publications, and focusing on efficacy/effectiveness studies. Additionally, we discuss background information on alcohol dependence and acamprosate's putative mechanism of action. Safety and tolerability data are also presented. The reader will gain a better understanding of the role of acamprosate in the treatment of alcohol dependence and find a useful synopsis of the more recently published literature evaluating acamprosate's effectiveness based on what are not always identically defined primary study outcomes. Acamprosate is safe and effective in the maintenance of abstinence from alcohol use/abuse and is most commonly used in combination with nonpharmacologic therapeutic modalities. The effect size ranged from 1.3 to 2 for most of the studies included in this review.

To determine the prevalence of and factors associated with the off-label use of antidepressant, anticonvulsant, and antipsychotic medications. A retrospective analysis of Georgia Medicaid recipients was conducted. Recipients prescribed antidepressant, anticonvulsant, or antipsychotic medications were identified. Logistic regression analysis was used to identify factors associated with off-label use. A total of 46,976 (75.42%) antidepressant recipients, 38,497 (80.12%) anticonvulsant recipients, and 21,252 (63.62%) antipsychotic recipients received at least 1 of these medications off-label in 2001. The likelihood of receiving off-label medications increased remarkably with advancing age (>or= 65 vs. < 65 years: antidepressant: OR = 5.15, 95% CI = 4.76 to 5.56; anticonvulsant: OR = 4.54, 95% CI = 4.16 to 4.96; antipsychotic: OR = 5.21, 95% CI = 4.82 to 5.63). Although receiving new anticonvulsants launched after 1993 was the strongest predictor (OR = 7.63, 95% CI = 7.07 to 8.23) of receiving off-label anticonvulsant medications, exposure to newer antidepressants and antipsychotics did not confer a higher chance of receiving off-label medications (selective serotonin reuptake inhibitors vs. tricyclic antidepressants: OR = 0.43, 95% CI = 0.40 to 0.45; atypical vs. conventional antipsychotics: OR = 0.76, 95% CI = 0.72 to 0.80). The off-label use of antidepressant, anticonvulsant, and antipsychotic medications is highly prevalent. Further research to study the effects of off-label use among this high risk subpopulation may be an important step toward defining the scope of and potential for such use.

A case of acute dystonia related to rivastigmine use is reported. A 61-year-old Caucasian woman who had suffered from bipolar II disorder with rapid cycling for over 30 years was admitted to an inpatient psychiatry unit. In addition to bipolar II disorder, the patient had been previously diagnosed with early-stage Alzheimer's disease, posttraumatic stress disorder, and various anxiety disorders. During the current hospitalization, she was taking clonazepam, dextroamphetamine, lamotrigine, lansoprazole, levothyroxine, memantine, quetiapine, risperidone, rivastigmine, tranylcypromine, trazodone, and zolpidem. Soon after hospital admission, she began to complain of a tightening in her chest. A review of her records revealed similar complaints during previous hospitalizations. Rivastigmine was discontinued due to concerns of interactions with her antipsychotic regimen. Although these symptoms were previously attributed to anxiety, they appeared worse during this hospitalization. During these events she would be witnessed lying in bed in a supine position with her head canted posteriorly. Benztropine was given to help determine if she was having a dystonic reaction. Within 30 minutes, her chest discomfort began to resolve, and her symptoms resolved completely over the next 48 hours. Three days later, rivastigmine was restarted by the attending psychiatrist because of concerns about the patient's memory, and the dystonia-like symptoms returned within 2 hours of her morning dose. Rivastigmine was discontinued, and benztropine was given and then discontinued, with no return of symptoms for the remainder of her two-week hospitalization. A patient with bipolar II disorder and mild-to-moderate Alzheimer's disease developed dystonia, possibly caused by rivastigmine. However, the patient was taking various other medications that could have lowered the threshold for extrapyramidal syndromes.

Prescribing adjunctive mood stabilizers to manage schizophrenia is prevalent, despite the lack of substantial evidence to support the long-term use of this treatment regimen. The objective of this study was to assess the impact of using adjunctive mood stabilizers on antipsychotic utilization, total health expenditures, inpatient hospitalizations, long-term care stays, and emergency room (ER) visits for patients with schizophrenia. Georgia Medicaid claims from 1999 through 2001 were analyzed to identify recipients diagnosed with schizophrenia (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM]: 295. XX). The treatment groups consisted of subjects who received combination therapy of mood stabilizers and antipsychotics (including both atypical and typical medications), while the comparison group consisted of subjects who were on antipsychotic medications without exposure to the mood stabilizers under investigation. Four treatment groups (valproate, lithium, carbamazepine, and combination mood stabilizer therapy) were formed based on the mood stabilizers patient received. Differences in annual health care use and expenditures were estimated between propensity score matched treatment and comparison groups controlling for comorbidity, prior utilization, demographic, and health provider specialty. During the 1-year observation period, subjects in treatment groups filled an average of 200-days supply of adjunctive mood stabilizers. These adjunctive mood stabilizer recipients had significantly longer antipsychotic treatment durations than the subjects who did not have exposure to mood stabilizers (valproate + antipsychotic vs. antipsychotic only, net difference: 56.47 days, p < 0.0001; lithium + antipsychotic vs. antipsychotic only, net difference: 90.25 days, p < 0.0001; carbamazepine + antipsychotic vs. antipsychotic only, net difference: 41.27 days, p = 0.0439; multiple mood stabilizers + antipsychotic vs. antipsychotic only, net difference: 83.14 days, p < 0.0001). The intensive pharmacotherapy associated with treatment groups resulted in $900-$1300 higher pharmacy costs than the comparison groups (valproate + antipsychotic vs. antipsychotic only, net difference: $1218.43, p < 0.0001; lithium + antipsychotic vs. antipsychotic only, net difference:…

A case of clozapine-induced leukopenia successfully treated with lithium is reported. A 55-year-old man with paranoid schizophrenia who had been stable on clozapine for more than 10 years was admitted to an inpatient behavioral health unit with leukopenia associated with clozapine use. This patient's history was significant for four previous hospitalizations for psychiatric issues, none of which occurred while he was using clozapine. On admission, the patient's clozapine was discontinued and he was started on olanzapine. On hospital day 4, his white blood cell (WBC) count had risen to 3400/mm(3) and clozapine was resumed due to increasing auditory hallucinations and suicidal ideation. On hospital day 5, his WBC count decreased to 2900/mm(3) and clozapine was again stopped. The patient was given lithium carbonate 300 mg at bedtime, and olanzapine was discontinued. The next day, clozapine was restarted at 12.5 mg daily at bedtime. On hospital day 11, his WBC count had risen to 5400/mm(3). The patient was discharged on clozapine 25 mg at bedtime, with a WBC count of 3400/mm(3). The patient has not been rehospitalized and has not had significant changes in his WBC count or absolute neutrophil count (ANC) for more than 14 months. A 55-year-old man with schizophrenia developed clozapine- induced leukopenia after more than 10 years of treatment. Lithium was used to stimulate leukocyte production, and clozapine was restarted successfully. The patient was maintained on clozapine and lithium without significant changes in his WBC count or ANC.

Discussion. Alternatives to varenicline's being the cause of the patient's symptoms include (1) nonadherence to drug therapy (the patient asserted that she had been taking her medications as directed and nothing suggested otherwise),(2) illicit drug use (she reported abstinence from illicit drugs and alcohol; a urine drug screen was positive for cannabis, but she was discharged before the results were known and was unavailable to respond), and (3) nicotine withdrawal (the timing of the symptoms went beyond that expected if ...