Pharmacoeconomic and associated cost savings among women who were prescribed systemic conjugated estrogens therapy compared with those without menopausal therapy.

OBJECTIVE: To explore changes in healthcare costs among postmenopausal women in a commercial population who were prescribed conjugated estrogens for menopausal symptoms. METHODS: Using the MarketScan dataset from April 1, 2008 through September 30, 2012, postmenopausal women aged ≥45 years, who were prescribed conjugated estrogen tablets (Premarin), were identified. A comparative cohort of postmenopausal women with vasomotor symptoms without any menopause therapy was also identified. Women included were required to have continuous medical and pharmacy benefits for 6 months before and 12 months after index date, with baseline characteristics compared using chi-square and t tests. The 6 and 12-month change (difference in follow-up and baseline costs) in direct healthcare costs was calculated and a difference-in-differences model was used to compare the incremental change at 6 and 12 months in healthcare costs between the cohorts, adjusting for demographic and clinical characteristics. RESULTS: The study included 1,404 women who were prescribed conjugated estrogens, and 3,096 untreated women. Women prescribed conjugated estrogens were significantly younger (52 vs 54 years; P < 0.0001) and had a lower Charlson comorbidity index score (0.29 vs 0.41; P < 0.001) compared with the untreated women. After adjusting for baseline characteristics, women treated with conjugated estrogens showed a greater difference in the change in total healthcare costs (-$1,601 vs -$503; P = 0.044), including inpatient stay costs (-$1,431 vs -$28; P < 0.0001), between the baseline and follow-up periods compared with untreated women. CONCLUSIONS: Women who were prescribed oral conjugated estrogens had a significantly greater reduction in healthcare costs after treatment initiation compared with untreated postmenopausal women.

Antidepressant drug-drug interaction profile update.

Drug-drug interactions continue to be underappreciated and misunderstood by most clinicians. Although life-threatening drug interactions are rare, serious clinical consequences, including altered drug response, poor tolerability with reduced medication adherence, and increased costs for care tied to the increased complexity of therapy, are fairly commonplace. Drug interactions may be further complicated by genetic differences in metabolic capacity. Patients who routinely require long-term treatment for depression have an increased likelihood of experiencing a drug-drug interaction since they will take over-the-counter and prescription medications for intercurrent and/or co-morbid illness. Antidepressants can be the object of drug interactions when their metabolic pathways are affected by other substances, or they can precipitate interactions by inhibiting enzyme pathways. Clinicians can improve the short- and long-term outcomes of patients with a depressive disorder by considering the possibility of drug-drug interactions both before prescribing a specific antidepressant and while monitoring for response, adverse effects and patient compliance.

Treatment with medications affecting dopaminergic and serotonergic mechanisms: effects on fluency and anxiety in persons who stutter.

UNLABELLED: Medications with dopamine antagonist properties, such as haloperidol, and those with serotonin reuptake inhibitor properties, such as clomipramine, have been shown to improve fluency. To examine the degree to which each of these two pharmacological mechanisms might independently affect fluency, a selective serotonin reuptake inhibitor, paroxetine, and a selective dopamine (D-2) antagonist, pimozide, were evaluated. Both types of medications also affect mood and anxiety, factors that could influence fluency levels. Therefore, we also evaluated the medications' effects on generalized and speech-related anxiety and the relationships between changes in anxiety and changes in fluency in 11 subjects with a history of developmental stuttering. The randomized, double blind, placebo-controlled crossover study that was designed had to be terminated prior to completion due to severe side effects following withdrawal from paroxetine. Even with a reduced sample size (n=6), significant improvement in percent fluent speaking time (p=0.02) was found using a telephone task between baseline and pimozide (n=6), with average duration of dysfluencies significantly shorter (p=0.04) but no significant difference in the estimated number of dysfluencies per minute. This significant improvement was associated with non-significant increases in generalized anxiety, but non-significant decreases in speech-related anxiety. No significant differences were found in fluency between baseline and paroxetine (n=5). These preliminary results suggest that fluency improvement is more likely to be mediated by dopaminergic rather than serotonergic mechanisms. Due to its side effects, however, pimozide may be considered a risk for treatment of stuttering. EDUCATIONAL OBJECTIVES: As a result of reading this paper the reader will describe and explain: (1) how medications may affect fluency and the rationale for selecting medications for treatment trials; (2) the interrelationship between fluency and anxiety; and (3) factors important in developing clinical trials using medications.

Treatment of pain syndromes with venlafaxine.

Major depressive disorder (MDD) and anxiety disorders such as generalized anxiety disorder (GAD) are often accompanied by chronic painful symptoms. Examples of such symptoms are backache, headache, gastrointestinal pain, and joint pain. In addition, pain generally not associated with major depression or an anxiety disorder, such as peripheral neuropathic pain (e.g., diabetic neuropathy and postherpetic neuralgia), cancer pain, and fibromyalgia, can be challenging for primary care providers to treat. Antidepressants that block reuptake of both serotonin and norepinephrine, such as the tricyclic antidepressants (e.g., amitriptyline), have been used to treat pain syndromes in patients with or without comorbid MDD or GAD. Venlafaxine, a serotonin and norepinephrine reuptake inhibitor, has been safe and effective in animal models, healthy human volunteers, and patients for treatment of various pain syndromes. The use of venlafaxine for treatment of pain associated with MDD or GAD, neuropathic pain, headache, fibromyalgia, and postmastectomy pain syndrome is reviewed. Currently, no antidepressants, including venlafaxine, are approved for the treatment of chronic pain syndromes. Additional randomized, controlled trials are necessary to fully elucidate the role of venlafaxine in the treatment of chronic pain.

Clozapine pharmacokinetics in children and adolescents with childhood-onset schizophrenia.

Clozapine (CLZ) dose-related adverse effects may be more common in children than adults, perhaps reflecting developmental pharmacokinetic (PK) differences. However, no pediatric CLZ PK data are available. Accordingly, we studied CLZ and its metabolites, norclozapine (NOR), and clozapine-N-oxide (NOX) in six youth, ages 9-16 years, with childhood onset schizophrenia (COS). At the time of the PK study, mean CLZ dose was 200 mg (3.4 mg/kg). Serum was collected during week 6 on CLZ before and 0.5-8 h after a morning dose. Serum concentrations were assayed by liquid chromatography/UV-detection. Mean concentration, area-under-the-curve (AUC), and clearance were calculated. CLZ clearance averaged 1.7 L/kg-h. NOR concentrations (410) exceeded CLZ (289) and NOX (63 ng/ml) and AUC(0-8h) of NOR (3,356) > CLZ (2,359) > NOX (559 ng/ml-h) [53, 38, and 9% of total analytes, respectively]. In adults, NOR serum concentrations on average are 10-25% < CLZ, differing significantly from our sample. Dose normalized concentrations of CLZ (mg/kg-d) did not vary with age and were similar to reported adult values. Clinical improvement seen in 5/6 patients correlated with serum CLZ concentrations. In addition, clinical response and total number of side effects correlated with NOR concentrations. NOR (a neuropharmacologically active metabolite) and free CLZ may contribute to the effectiveness and adverse effects in youth.

Pharmacology of antidepressants: focus on nefazodone.

The past decade has witnessed the introduction of a diverse group of antidepressants from a variety of distinct chemical classes, each with their own specificity for neurochemical transmitters, receptors, and cytochrome P450 isozymes. This review focuses on nefazodone, a distinct antidepressant with efficacy for the treatment of depression with depression-related anxiety symptoms, an established tolerability profile, and a multimodal mechanism of action. Relevant pharmacologic and pharmacodynamic effects are summarized that support nefazodone as an attractive choice for both the short- and long-term treatment of depression.