Prescription opioid use during pregnancy and risk for preterm birth or term low birthweight.

OBJECTIVE: Examine the relationship between prescription opioid analgesic use during pregnancy and preterm birth or term low birthweight. DESIGN, SETTING, AND PARTICIPANTS: We analyzed data from the National Birth Defects Prevention Study, a US multisite, population-based study, for births from 1997 to 2011. We defined exposure as self-reported prescription opioid use between one month before conception and the end of pregnancy, and we dichotomized opioid use duration by ≤7 days and >7 days. MAIN OUTCOME MEASURES: We examined the association between opioid use and preterm birth (defined as gestational age <37 weeks) and term low birthweight (defined as <2500 g at gestational age ≥37 weeks). RESULTS: Among 10,491 singleton mother/infant pairs, 470 (4.5 percent) reported opioid use. Among women reporting opioid use, 236 (50 percent) used opioids for > 7 days; codeine (170, 36 percent) and hydrocodone (163, 35 percent) were the most commonly reported opioids. Opioid use was associated with slightly increased risk for preterm birth [adjusted odds ratio, 1.4; 95 percent confidence interval, 1.0, 1.9], particularly with hydrocodone [1.6; 1.0, 2.6], meperidine [2.5; 1.2, 5.2], or morphine [3.0; 1.5, 6.1] use for any duration; however, opioid use was not significantly associated with term low birthweight. CONCLUSIONS: Preterm birth occurred more frequently among infants of women reporting prescription opioid use during pregnancy. However, we could not determine if these risks relate to the drug or to indications for use. Patients who use opioids during pregnancy should be counseled by their practitioners about this and other potential risks associated with opioid use in pregnancy.

An Elective Course in Lesbian, Gay, Bisexual, and Transgender Health and Practice Issues.

Objective. To design, implement and assess a lesbian, gay, bisexual, and transgender (LGBT) health and practice elective course for second- and third-year Doctor of Pharmacy (PharmD) students. Methods. The course focused on health promotion, health care barriers, disease prevention, and treatment throughout an LGBT person's lifespan. The course included topic discussions, reading assignments, various active-learning activities, an objective structured clinical examination (OSCE) with a transgender person, and guest speakers from the LGBT community. Five quizzes were administered during the course that were mapped to specific session learning objectives and course learning outcomes. Students completed an anonymous pre- and post-course survey on the seven course learning outcomes to assess their knowledge and skills regarding the health of LGBT people. Results. Students exhibited significant learning with improvement in the seven course learning outcomes. The two most improved course learning outcomes were the medications used for LGBT people and summarizing health care resources available to LGBT people. The content of student portfolios included general themes of discrimination, health care access problems, advocacy, inclusive pharmacy environments, and desire to be a better practitioner. More than 91% of the students actively engaged the guest speakers from the LGBT community. Student performance on quizzes and in the OSCE activity was excellent. The capstone presentations covered a variety of topics including LGBT in Islam. Conclusion. Students demonstrated knowledge of the unique health care issues among the LGBT community. This elective course provides a framework for other pharmacy programs to incorporate LGBT health topics into the curriculum and to engage with their local LGBT community.

The Evolving Role of Pharmacists in Transgender Health Care.

Pharmacists are increasingly part of a multifaceted team providing health care to members of the often marginalized transgender (TG) community. Some pharmacists, however, may feel unprepared to care for and interact with TG individuals. By providing comprehensive, respectful, and gender-affirming support, improving physical pharmacy environments with policies and procedures, pharmacists can be trustworthy providers for TG patients. This review focuses primarily on the health issues of TG persons and the pharmacist's role in promoting health, identifying barriers to health care, and providing health care resources for TG persons. The evolution of psychiatric diagnostic criteria, access to health care, and inclusion of TG, lesbian, gay, and bisexual topics in the educational curriculum are presented. Cultural competency and diversity training that addresses gender identity and sexual orientation issues should be important interdisciplinary and interprofessional activities for all health care professional education programs. Pharmacists play a key role in the health care needs of TG persons that include appropriate laboratory monitoring, complex pharmacotherapeutic challenges, and providing unbiased gender-affirming interactions. The pharmacy's physical environment, staff training, and policies and procedures can offer unique services to TG persons.

Correction to: Long-Acting Injectable Second-Generation Antipsychotics: An Update and Comparison Between Agents.

1. In Page 244, under General Pharmacokinetic Principles, Column 1-the following sentence should come after reference 21.

Long-Acting Injectable Second-Generation Antipsychotics: An Update and Comparison Between Agents.

Schizophrenia is a chronic medical condition with periods of remission and relapses over a patient's lifetime. Antipsychotic medications represent the mainstay of treatment for this disease. Long-acting injectable (LAI) formulations of antipsychotics are an attractive alternative to their oral counterparts, as they enhance patient adherence. A number of second-generation antipsychotics (SGAs) are available in LAI formulations. These include paliperidone, aripiprazole, olanzapine, and risperidone. This article reviews the most recently developed and approved of these formulations-aripiprazole monohydrate, aripiprazole lauroxil, and paliperidone palmitate. While all were initially available as once-monthly formulations, a paliperidone palmitate 3-monthly injection formulation has been approved and is the first LAI agent to extend the dosing administration beyond the typical monthly time period. In addition, aripiprazole lauroxil every 6-week and 8-week administration preparations have been developed. LAI preparations of the SGAs have all demonstrated superiority over placebo and are comparable to their oral counterparts in terms of safety and tolerability, if injection site reactions are not taken into account. First-generation antipsychotic LAI preparations (e.g., haloperidol decanoate) have recently been compared with SGA LAI agents, and both formulations demonstrated comparable efficacy with the expected adverse events seen with each drug. Despite their availability, barriers to the use of LAIs remain. Education of both patients and clinicians on the use of LAI formulations and the continued development of these agents are important steps in ensuring these medications are available to the patients they would be most likely to benefit.

Unique collaboration between a private college of pharmacy and a private academic health system.

Advanced experiential education represents the culmination of a pharmacy student's training, where students can apply the knowledge they have learned in the classroom to real patients. Unfortunately, opportunities for students to provide the direct patient care recommended by pharmacy organizations and accrediting bodies are lacking. Additionally, academic health systems that can provide these experiences for students are experiencing hardships that have stalled the expansion of postgraduate training programs and services. Formal cooperation between unaffiliated colleges of pharmacies and academic health systems has the potential to increase the number of experiential students completing rotations in an academic environment, expand postgraduate education training programs, enhance the development of resident educators, increase research and scholarly opportunities, and expand clinical pharmacy services. This article describes the formation of a unique joint initiative between a private academic health system without a college of pharmacy and a private college of pharmacy without a hospital. The successful cultivation of the relationship has resulted in professional growth at both institutions and can be implemented at other sites around the country to synergize the efforts of academic health systems and colleges of pharmacy.

Diagnosis and treatment of bipolar disorders in adults: a review of the evidence on pharmacologic treatments.

BACKGROUND: Patients with bipolar disorder are exceptionally challenging to manage because of the dynamic, chronic, and fluctuating nature of their disease. Typically, the symptoms of bipolar disorder first appear in adolescence or early adulthood, and are repeated over the patient's lifetime, expressed as unpredictable recurrences of hypomanic/manic or depressive episodes. The lifetime prevalence of bipolar disorder in adults is reported to be approximately 4%, and its management was estimated to cost the US healthcare system in 2009 $150 billion in combined direct and indirect costs. OBJECTIVE: To review the published literature and describe the personal and societal burdens associated with bipolar disorder, the impact of delays in accurate diagnosis, and the evidence for the clinical effectiveness of available pharmacologic therapies. METHODS: The studies in this comprehensive review were selected for inclusion based on clinical relevance, importance, and robustness of data related to diagnosis and treatment of bipolar disorder. The search terms that were initially used on MEDLINE/PubMed and Google Scholar were restricted to 1994 through 2014 and included "bipolar disorder," "mania," "bipolar depression," "mood stabilizer," "atypical antipsychotics," and "antidepressants." High-quality, recent reviews of major relevant topics were included to supplement the primary studies. DISCUSSION: Substantial challenges facing patients with bipolar disorder, in addition to their severe mood symptoms, include frequent incidence of psychiatric (eg, anxiety disorders, alcohol or drug dependence) and general medical comorbidities (eg, diabetes, cardiovascular disease, obesity, migraine, and hepatitis C virus infection). It has been reported that more than 75% of patients take their medication less than 75% of the time, and the rate of suicide (0.4%) among patients with bipolar disorder is more than 20 times greater than in the general US population. Mood stabilizers are the cornerstone of treatment of bipolar disorder, but atypical antipsychotics are broadly as effective; however, differences in efficacy exist between individual agents in the treatment of the various phases of bipolar disorder, including treatment of acute mania or acute depression symptoms, and in the prevention of relapse. CONCLUSION: The challenges involved in managing bipolar disorder over a patient's lifetime are the result of the dynamic, chronic, and fluctuating nature of this disease. Diligent selection of a treatment that takes into account its efficacy in the various phases of the disorder, along with the safety profile identified in clinical trials and in the real world can help ameliorate the impact of this devastating condition.

Clinically significant drug interactions with atypical antipsychotics.

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.

Lack of a pharmacokinetic drug-drug interaction with venlafaxine extended-release/indinavir and desvenlafaxine extended-release/indinavir.

PURPOSE: To assess the effects of venlafaxine extended-release (XR) capsules and desvenlafaxine extended-release (XR) tablets upon indinavir pharmacokinetic properties when co-administrated to healthy volunteers. METHODS: This was an open-label, two-period, fixed-dose study conducted at the clinical research unit located on a university campus. Twenty-four healthy volunteers enrolled in the study (mean age 28.3 ± 8.0 years). Each subject received a single dose of indinavir 800 mg on day 1. Subsequently, subjects were then randomly assigned to either the venlafaxine XR group (N = 12) or the desvenlafaxine XR group (N = 12). Starting on day 2, venlafaxine XR was dosed at 37.5 mg/day for 4 days and increased to 75 mg/day for 6 days. Desvenlafaxine XR was dosed at 50 mg/day for 10 days. On day 12, indivanvir 800 mg was co-administered to both the venlafaxine XR and the desvenlafaxine XR groups. The pharmacokinetics of indinavir were determined both before and at the end of antidepressant dosing. Plasma indinavir, venlafaxine, and desvenlafaxine concentrations were assayed by high-performance liquid chromatography with ultra-violet (UV) detection. Indinavir pharmacokinetic parameters were calculated by noncompartmental analysis using validated computer software. RESULTS: Venlafaxine XR and desvenlafaxine XR did not produce any significant changes in indinavir disposition. Both antidepressants were well tolerated by the subjects with only minor adverse side effects. CONCLUSIONS: No pharmacokinetic drug-drug interaction was demonstrated between venlafaxine XR and indinavir or between desvenlafaxine XR and indinvair. The lack of interaction could be due to the venlafaxine and desvenlafaxine extended-release formulation.

Advanced strategies for treatment of Parkinson's disease: the role of early treatment.

Parkinson's disease (PD) is associated with significant patient disability and costs to the healthcare system. It is questioned whether early treatment may improve outcomes and delay disability. Early treatment relies on early diagnosis, which can be difficult to achieve because the diagnosis of PD is based on motor symptoms, is clinical in nature, and is complicated by potential presentation of nonmotor symptoms prior to motor symptoms. Economic analyses demonstrate that treatments other than levodopa may be cost-effective. The lack of correlation between Unified PD Rating Scale (UPDRS) outcomes and imaging studies of dopamine uptake may reflect the inappropriate selection of study end points, since activities of daily living scores may be more applicable than motor function scores. Levodopa, the standard therapy for motor control of PD and one of the most effective options, is associated with complications (a wearing-off effect) when used long term. Other therapies, including dopamine agonists and monoamine oxidase type-B (MAO-B) inhibitors, may limit the rate of dyskinesia relative to levodopa-based regimens. It appears that early treatment with the MAO-B inhibitor rasagiline (1 mg), as compared with late treatment, delays the onset of worsened UPDRS score, especially the nonmotor activities of daily living subscore.

Maternal treatment with opioid analgesics and risk for birth defects.

OBJECTIVE: We examined whether maternal opioid treatment between 1 month before pregnancy and the first trimester was associated with birth defects. STUDY DESIGN: The National Birth Defects Prevention Study (1997 through 2005) is an ongoing population-based case-control study. We estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIS) for birth defects categories with at least 200 case infants or at least 4 exposed case infants. RESULTS: Therapeutic opioid use was reported by 2.6% of 17,449 case mothers and 2.0% of 6701 control mothers. Treatment was statistically significantly associated with conoventricular septal defects (OR, 2.7; 95% CI, 1.1-6.3), atrioventricular septal defects (OR, 2.0; 95% CI, 1.2-3.6), hypoplastic left heart syndrome (OR, 2.4; 95% CI, 1.4-4.1), spina bifida (OR, 2.0; 95% CI, 1.3-3.2), or gastroschisis (OR, 1.8; 95% CI, 1.1-2.9) in infants. CONCLUSION: Consistent with some previous investigations, our study shows an association between early pregnancy maternal opioid analgesic treatment and certain birth defects. This information should be considered by women and their physicians who are making treatment decisions during pregnancy.

Antidepressant agents for the treatment of chronic pain and depression.

Depression and painful somatic symptoms commonly occur together. Depression and chronic pain can have devastating effects on a patient's health, productivity, and overall quality of life. When moderate-to-severe pain exists, it can impair patient function while making treatment more difficult or resistant, with increased severity in depressive symptoms and worse outcomes. A variety of chronic pain syndromes exist, including diabetic neuropathy. A high prevalence of patients with chronic pain display depressive symptoms. Treatment for these conditions relies on pharmacologic therapy coupled with diligent, periodic assessments of changes in symptom severity. The link between pain and depression lies in the central and peripheral nervous systems. The brain stem serves as an important connection between the higher brain centers and the spinal cord. In the brain stem, the neurotransmitters serotonin and norepinephrine modulate pain transmission through ascending and descending neural pathways. Both serotonin and norepinephrine are also key neurotransmitters involved with the pathophysiology of depression. Tricyclic antidepressants are effective treatments for pain and depression; selective serotonin reuptake inhibitors provide less benefit. Duloxetine and venlafaxine, which are serotonin and norepinephrine reuptake inhibitors, were shown in clinical trials to alleviate pain and depressive symptoms. Diabetic neuropathy and other chronic pain syndromes were also shown to benefit from duloxetine and venlafaxine. Antidepressants remain fundamental therapeutic agents for depression and anxiety disorders. Their extended use into chronic pain, depression with physical pain, physical pain with or without depression, and other potential medical conditions should be recognized.

Endogenous histamine and cortisol levels in subjects with different histamine N-methyltransferase C314T genotypes : a pilot study.

BACKGROUND: Histamine N-methyltransferase (HNMT) catalyzes the methylation of histamine and plays an important role in histamine biotransformation in bronchial epithelium. Enzymatic activity of HNMT has been shown to be regulated by genetic factors, including polymorphisms in the HNMT gene. In this pilot study we determined endogenous levels of histamine and cortisol in plasma and whole blood samples from subjects with different genotypes for the HNMT C314T polymorphism, and investigated whether these parameters differed between individuals with the HNMT CC genotype and those with the CT genotype. METHODS: Blood samples were collected from 48 unrelated volunteers (36 males, 12 females), aged 21-40 years, who participated in the study. PCR-restriction fragment length polymorphism analysis was used to determine HNMT C314T genotypes. Erythrocyte HNMT activity was determined as well as plasma and whole blood levels of histamine and cortisol. Two-group comparisons of the various parameters were analyzed by Blocked Wilcoxon test and Wilcoxon Rank Sum test as appropriate. RESULTS: Thirty-seven subjects (24 Caucasians, three African Americans, one Middle Eastern, five Indians, three Chinese, and one Filipino) were found to have the homozygous CC genotype. Ten subjects (eight Caucasians, one Middle Eastern, and one Chinese) were heterozygous and one individual (Pakistani) was homozygous for the variant 314T allele. The frequency of HNMT CT heterozygotes in the small Caucasian cohort was 0.125. Median enzyme activity was significantly lower in subjects with the heterozygous CT genotype than in those with the homozygous CC genotype (485 vs 631 U/mL of red blood cells; p=0.023). A broad range of histamine levels in plasma and whole blood was observed for all subjects. Whereas the median plasma histamine level was found to be higher in heterozygotes for the wild-type 314C allele than homozygotes (3.32 vs 2.30 nmol/L; p=0.021), there was no difference between the two groups in histamine levels in whole blood. Cortisol levels were similar between individuals with the homozygous CC genotype and those with the heterozygous CT genotype. CONCLUSION: Wide variability of plasma and whole-blood histamine levels was observed in subjects with different HNMT C314T genotypes. Endogenous levels of histamine are likely to be affected by various genes and polymorphisms.

Reduced methylprednisolone clearance causing prolonged pharmacodynamics in a healthy subject was not associated with CYP3A5*3 allele or a change in diet composition.

The influence of diet and genetics was investigated in a healthy white person who had distinctly low methylprednisolone clearance. Pharmacokinetic and pharmacodynamic parameter values were similar on 2 occasions during the consumption of a low-carbohydrate diet and a Weight Watchers diet, indicating that the decreased clearance was unlikely attributable to a change in diet composition. Although the subject was found to be homozygous for CYP3A5*3, genetic findings were not significant for a number of other CYP3A4 and CYP3A5 allelic variants. Because of the high prevalence of CYP3A5*3/*3 in whites and because 5 of 7 white control subjects are also homozygous for CYP3A5*3, this genotype cannot fully explain the reduced metabolism of the drug. Other genetic or contributing factors might have been involved. New polymerase chain reaction-based genotyping methods for functionally defective CYP3A5*6, *8, *9, and *10 alleles were developed in this study. These assays will be useful for CYP3A5 genotype analysis in future clinical studies.

Lack of pharmacokinetic interaction between lamotrigine and olanzapine in healthy volunteers.

STUDY OBJECTIVE: To investigate the potential drug-drug interaction between lamotrigine, an antiepileptic agent used to treat bipolar disorders, and olanzapine, an atypical antipsychotic drug also used to treat bipolar disorders, both of which are metabolized by the uridine diphosphate glucuronosyltransferase system. DESIGN: Prospective cohort study. SETTING: University center for clinical research. SUBJECTS: Fourteen nonsmoking, healthy volunteers. INTERVENTION: Subjects received lamotrigine 25 mg/day for 5 days, then 50 mg/day for 10 days to achieve steady-state concentrations. On day 15, blood samples were obtained before and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours after the dose. Lamotrigine 50 mg/day was then given for an additional 3 days. On the next day, lamotrigine 50 mg and olanzapine 5 mg were coadministered. Blood samples were obtained at the same times as before and at 48, 72, and 96 hours after dosing. MEASUREMENTS AND MAIN RESULTS: Blood samples were assayed for lamotrigine and olanzapine concentrations by means of high-performance liquid chromatography. Olanzapine did not significantly affect lamotrigine disposition, as we observed no differences in the area under the concentration-time curve from 0-24 hours or in lamotrigine plasma concentrations at baseline or at 24 hours. For lamotrigine, the mean time to reach maximum concentration was significantly prolonged during olanzapine coadministration (mean +/- SD 1.9 +/- 1.3 vs 4.0 +/- 3.0 hrs, p = 0.025), possibly because of the anticholinergic properties associated with olanzapine. Mild sedation was the only adverse effect that occurred during lamotrigine and olanzapine coadministration. CONCLUSION: Lamotrigine and olanzapine can safely be combined in healthy volunteers at the low doses studied, without a clinically significant interaction. When prescribing high doses of olanzapine and lamotrigine for bipolar disorder, patients must be carefully monitored.

Altered methylprednisolone pharmacodynamics in healthy subjects with histamine N-methyltransferase C314T genetic polymorphism.

This study investigated the potential differences in methylprednisolone pharmacodynamics between healthy subjects with different histamine N-methyltransferase (HNMT) C314T genotypes. Six individuals with C/C genotype and 4 with C/T genotype were administered a single intravenous dose of methylprednisolone 0.6 mg/kg ideal body weight in a randomized 2-period manner. Methylprednisolone plasma concentrations were fitted with a 1-compartment model. Cortisol and whole blood histamine suppression were assessed by indirect response models, with circadian baseline cortisol analyzed by Fourier analysis. The area between the baseline and effect curve and the area under the effect versus time curve suppression ratio were used to characterize plasma histamine suppression. Methylprednisolone pharmacokinetics and plasma and whole blood histamine suppression were similar between the 2 genotype groups. Median nadir of cortisol and the 50% inhibitory concentration for cortisol were significantly higher in subjects with C/T genotype than those with C/C genotype (P=.031 and .033, respectively, Wilcoxon rank sum test). Subjects who are heterozygous for the T314 variant allele thus appeared less sensitive to the suppressive effects of methylprednisolone on cortisol secretion.

Implications for atypical antipsychotics in the treatment of schizophrenia: neurocognition effects and a neuroprotective hypothesis.

Cognitive impairment in schizophrenia occurs in the early phases of the disease and remains throughout its course. The basis for cognition lies in two main brain regions: the prefrontal cortex and hippocampus. Positron emission tomography, functional magnetic resonance imaging, and proton magnetic spectroscopy studies have shown that prefrontal cortex and hippocampus activity and cell density are lower in patients with schizophrenia than in healthy controls. Dopamine remains the fundamental neurotransmitter involved with schizophrenia. Catechol- O -methyltransferase accounts for about 60% of dopamine metabolism in the prefrontal cortex. Functional polymorphism for the catechol- O -methyltransferase genotypes has been identified in patients with schizophrenia. Those with the valine-valine genotype demonstrate rapid inactivation of dopamine, and performance in cognitive testing in patients is poorer with this allele than with other genotypes. N -methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate acid receptors are also strongly associated with cognitive impairment. Changes occur in apolipoproteins D and E, cholinesterase enzyme activity, neurotensin, and neural growth factors, leading to a possible neurodegenerative process and cognitive impairment in patients with schizophrenia. A fundamental link between psychosis and neurocognition probably arises from complex interactions between these systems at the intracellular secondary messenger system and with protein phosphorylation. Atypical antipsychotics evaluated in receptor models, cell cultures, and animal behavior paradigms indicate that these agents may provide neuroprotective effects. Clinical studies with atypical antipsychotics have consistently demonstrated improvement in cognitive symptoms, and such improvement appears to be correlated with improvement of negative symptoms. A neurodevelopmental model of cognitive impairment in schizophrenia aids in understanding why atypical antipsychotics improve cognitive symptoms.

Dose-dependent alternations in the pharmacokinetics of olanzapine during coadministration of fluvoxamine in patients with schizophrenia.

Olanzapine, an atypical antipsychotic agent, is a substrate of the cytochrome P4501A2 (CYP1A2) enzyme. Administration of a potent CYP1A2 inhibitor (eg, fluvoxamine) may alter the pharmacokinetics of olanzapine. This study investigated the pharmacokinetic interactions between olanzapine and fluvoxamine in patients with schizophrenia. Ten male smokers were administrated a single dose of olanzapine 10 mg at baseline, followed by 2 weeks of fluvoxamine 50 mg/day and another 2 weeks of fluvoxamine 100 mg/day. Olanzapine 10 mg was given at day 10 during each fluvoxamine treatment. After pretreatment with fluvoxamine, the area under the curve, maximal plasma concentration, and half-time of olanzapine were significantly increased by 30% to 55%, 12% to 64%, and 25% to 32%, respectively. Volume of distribution and apparent clearance were significantly reduced by 4% to 26% and 26% t O 38%, respectively, after administration of fluvoxamine. Increases in area under the plasma concentration-time curve from time 0 to infinity appear to be dose dependent. Presumably, altered olanzapine pharmacokinetics are attributed to the inhibition of CYP1A2. Patients treated with the combination of olanzapine and fluvoxamine should be monitored carefully.