A Double-Blind, Placebo-Controlled Randomized Trial of Vilazodone in the Treatment of Posttraumatic Stress Disorder and Comorbid Depression.

OBJECTIVE: To determine the efficacy, safety, and tolerability of vilazodone in the treatment of posttraumatic stress disorder (PTSD) with comorbid mild-to-moderate depression. METHODS: A 12-week randomized, double-blind, placebo-controlled trial was conducted in adult outpatients who met DSM-IV criteria for PTSD with comorbid depression between February 2013 and September 2015. Participants were randomly assigned to receive vilazodone 40 mg/d or placebo, and outcome measures were obtained at scheduled visits. Primary outcome measures included change in PTSD symptoms from baseline to end of study as indexed by the Clinician-Administered PTSD Scale (CAPS) and PTSD Symptom Scale-Self-Report (PSS-SR). Secondary outcome measures of anxiety, depression, and impairment were obtained, as well as biomarker assessment at baseline and end of study. RESULTS: A total of 59 patients were randomly assigned to receive vilazodone (n = 29) or placebo (n = 30). Of those who were randomized, there were 25 completers in the vilazodone group and 22 completers in the placebo group. No significant differences were observed between the groups on any of the primary or secondary outcome measures. Vilazodone was generally well tolerated with few differences in the rate of adverse events between groups. CONCLUSIONS: Treatment with vilazodone 40 mg/d did not improve symptoms of PTSD and comorbid depression. Further investigation of the biological mechanisms underlying PTSD may lead to identification of improved therapeutic targets. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01715519.

Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial.

IMPORTANCE: Less than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant. OBJECTIVE: To determine the relative effectiveness and safety of 3 common alternate treatments for MDD. DESIGN, SETTING, AND PARTICIPANTS: From December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks. INTERVENTIONS: Switch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase). MAIN OUTCOMES AND MEASURES: The primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects. RESULTS: Among 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain. CONCLUSIONS AND RELEVANCE: Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01421342.

Dried blood spot testing: a novel approach for the therapeutic drug monitoring of ziprasidone-treated patients.

BACKGROUND: A novel analytical approach, based on dried blood spot (DBS) testing, has been developed, validated and applied for the first time to the analysis of ziprasidone (ZPR) for the therapeutic drug monitoring (TDM) of schizophrenic patients. DBS represent a more feasible but reliable matrix, alternative to blood and plasma. METHODS: The assays were carried out using an HPLC method with native fluorescence. Blood drops were applied to DBS cards and dried by microwaves, an internal standard solution was added to the DBS and 5-mm punches were cut out for analysis. ZPR was extracted from DBS with methanol, giving good extraction yields, precision and selectivity results. RESULTS: The method was applied with satisfactory results to DBS samples from psychiatric patients to determine ZPR levels for therapy optimization. CONCLUSION: This innovative methodology provides reliable and significant TDM information, with important advantages over classical blood sampling in terms of collection, storage and processing.

CYP2D6 genotype in relation to perphenazine concentration and pituitary pharmacodynamic tissue sensitivity in Asians: CYP2D6-serotonin-dopamine crosstalk revisited.

OBJECTIVES: Hyperprolactinemia is a common side effect of first-generation antipsychotics mediated by antagonism of dopaminergic neurotransmission in the pituitary. Most first-generation antipsychotics are metabolized by CYP2D6 in the liver. Further, CYP2D6 is expressed in the human brain as a 5-methoxyindolethylamine O-demethylase potentially contributing to regeneration of serotonin from 5-methoxytryptamine. As dopaminergic neurotransmission is subject to regulation by serotonin, CYP2D6 may exert a nuanced (serotonergic) influence on dopaminergic tone in the pituitary. CYP2D6*10 is an allele associated with reduced enzyme function and occurs in high frequency (about 50%) in Asians. We prospectively evaluated significance of CYP2D6 genetic variation for prolactin response to perphenazine (a model first-generation antipsychotic) in Asians. METHODS: A single oral dose of perphenazine (0.1 mg/kg) or placebo was administered to 22 medication-free nonsmoker healthy male Chinese-Canadian volunteers, following a double-blind within-subject randomized design. Blood samples were drawn at baseline and 2, 3, 4, 5 and 6 h after drug administration. RESULTS: In volunteers with CYP2D6*10/CYP2D6*10 genotype, the mean area under curve (AUC0-6) for perphenazine concentration was 2.9-fold higher than those who carry the CYP2D6*1 allele (P<0.01). Notably, volunteers homozygous for CYP2D6*10 exhibited a significant reduction (66%) in mean pharmacodynamic tissue sensitivity as measured by the (prolactin-AUC0-6/perphenazine-AUC0-6) ratio (P=0.02). CONCLUSIONS: CYP2D6 genotype is a significant contributor to perphenazine concentration in Chinese-Canadians. Importantly, prolactin response, when normalized per unit perphenazine concentration, appears to be blunted in volunteers homozygous for CYP2D6*10. We suggest that CYP2D6 genetic variation may potentially influence pharmacodynamic tissue sensitivity in the pituitary, presumably through disposition of an endogenous substrate (e.g. 5-methoxytryptamine).

Second-generation antipsychotic exposure and metabolic-related disorders in patients with schizophrenia: an observational pharmacoepidemiology study from 1988 to 2002.

Patients with schizophrenia are at increased risk for cardiovascular disease as a consequence of lifestyle habits, impaired access to health care, and, increasingly, due to metabolic side effects ostensibly attributed to second-generation antipsychotics (SGAs). There is little evidence, however, on the extent and temporal patterns of SGA-associated metabolic side effects. We longitudinally examined the differential prevalence rates of obesity, diabetes mellitus, and diabetic ketoacidosis among inpatients with schizophrenia compared with control inpatients without schizophrenia. The data were derived from the National Inpatient Sample, the largest all-payer inpatient care database in the United States consisting of 5 to 8 million inpatient hospital stays per year sampled to approximate a 20% sample of community hospitals from 1988 to 2002. Overlaid on these observations was the market penetration data for SGAs. In 1988, the net difference from controls in obesity prevalence among inpatients with schizophrenia was +4.7%; by 2002, this difference had widened to +14.7%. Similarly, a significant increase in net prevalence of diabetes mellitus and diabetic ketoacidosis was observed from 1988 to 2002 among schizophrenic inpatients. In conclusion, after the introduction of SGAs, patients with schizophrenia in the United States have experienced a striking net increase in the prevalence of obesity and diabetes mellitus. This is likely to significantly add to an already elevated risk for cardiovascular disease in this population. Further investigations are urgently required so that health policy can be appropriately amended for preventive measures.

Simultaneous determination of fluvoxamine isomers and quetiapine in human plasma by means of high-performance liquid chromatography.

An original HPLC-UV method has been developed for the simultaneous determination of the atypical antipsychotic quetiapine and the geometric isomers of the second-generation antidepressant fluvoxamine. The analytes were separated on a reversed-phase C8 column (150 mm x 4.6mm i.d., 5 microm) using a mobile phase composed of acetonitrile (30%) and a 10.5mM, pH 3.5 phosphate buffer containing 0.12% triethylamine (70%). The flow rate was 1.2 mL min(-1) and the detection wavelength was 245 nm. Sample pretreatment was carried out by an original solid-phase extraction procedure using mixed-mode cation exchange (DSC-MCAX) cartridges; only 300 microL of plasma were needed for one analysis. Citalopram was used as the internal standard. The method was validated in terms of linearity, extraction yield, precision and accuracy. Good linearity was obtained in plasma over the 5.0-160.0 ng mL(-1) concentration range for each fluvoxamine isomer and over the 2.5-400.0 ng mL(-1) concentration range for quetiapine. Extraction yield values were always higher than 93%, with precision (expressed as relative standard deviation values) better than 4.0%. The method was successfully applied to human plasma samples drawn from patients undergoing polypharmacy with the two drugs. Satisfactory accuracy values were obtained, with mean recovery higher than 94%.

Pharmacogenetics for off-patent antipsychotics: reframing the risk for tardive dyskinesia and access to essential medicines.

First-generation antipsychotics (FGAs) induce tardive dyskinesia, a debilitating involuntary hyperkinetic movement disorder, in 20-50% of individuals with a psychotic illness during chronic treatment. There is presently no curative treatment or definitive predictive test for tardive dyskinesia. The authors note that the three antipsychotic drugs enlisted in the most recent (14th) World Health Organization Model List of Essential Medicines--chlorpromazine, fluphenazine and haloperidol--belong to the FGA therapeutic class. In this regard, the need to choose between the competing objectives of ensuring global access to affordable and efficacious medicines, such as FGAs, and the formidable long-term risk for tardive dyskinesia, may create an ethical conundrum. Pharmacogenetics has thus far been conceptually framed as a tool to individualize therapy with new drugs under patent protection. However, the authors suggest that pharmacogenetics may also improve access to pharmacotherapy through the reintroduction of affordable second-line generic drugs or FGAs with suboptimal safety, as first-line therapy, in targeted subpopulations in whom they present a lower risk for tardive dyskinesia. To impact positively on global public health and distributive justice, a directory complementary to the essential medicines library--one that enlists the 'essential biomarkers' required for optimal pharmacotherapy--may benefit patients who do not have adequate access to new antipsychotic medications. This review discusses pharmacogenetic associations of tardive dyskinesia that are in part supported by meta-analyses and the oxidative stress-neuronal degeneration hypothesis.

Low-dose fluvoxamine as an adjunct to reduce olanzapine therapeutic dose requirements: a prospective dose-adjusted drug interaction strategy.

Despite the advances in antipsychotic pharmacotherapy over the past decade, many atypical antipsychotic agents are not readily accessible by patients with major psychosis or in developing countries where the acquisition costs may be prohibitive. Olanzapine is an efficacious and widely prescribed atypical antipsychotic agent. In theory, olanzapine therapeutic dose requirement may be reduced during concurrent treatment with inhibitors of drug metabolism. In vitro studies suggest that smoking-inducible cytochrome P450 (CYP) 1A2 contributes to formation of the metabolite 4'-N-desmethylolanzapine. The present prospective study tested the hypothesis that olanzapine steady-state doses can be significantly decreased by coadministration of a low subclinical dose of fluvoxamine, a potent inhibitor of cytochrome P450 1A2. The study design followed a targeted "at-risk" population approach with a focus on smokers who were likely to exhibit increased cytochrome P450 1A2 expression. Patients with stable psychotic illness (N = 10 men, all smokers) and receiving chronic olanzapine treatment were evaluated for steady-state plasma concentrations of olanzapine and 4'-N-desmethylolanzapine. Subsequently, olanzapine dose was reduced from 17.5 +/- 4.2 mg/d (mean +/- SD) to 13.0 +/- 3.3 mg/d, and a nontherapeutic dose of fluvoxamine (25 mg/d, PO) was added to regimen. Patients were reevaluated at 2, 4, and 6 weeks during olanzapine-fluvoxamine cotreatment. There was no significant change in olanzapine plasma concentration, antipsychotic response, or metabolic indices (eg, serum glucose and lipids) after dose reduction in the presence of fluvoxamine (P > 0.05). 4'-N-desmethylolanzapine/olanzapine metabolic ratio decreased from 0.45 +/- 0.20 at baseline to 0.25 +/- 0.11 at week 6, suggesting inhibition of the cytochrome P450 1A2-mediated olanzapine 4'-N-demethylation by fluvoxamine (P < 0.05). In conclusion, this prospective pilot study suggests that a 26% reduction in olanzapine therapeutic dose requirement may be achieved by coadministration of a nontherapeutic oral dose of fluvoxamine.

Pharmacogenomic-guided rational therapeutic drug monitoring: conceptual framework and application platforms for atypical antipsychotics.

Atypical antipsychotic agents such as aripiprazole, clozapine, olanzapine, quetiapine and ziprasidone offer many advantages over conventional neuroleptics. These agents reduce negative symptoms of schizophrenia, are effective in treatment refractory cases, and have a markedly lower incidence of extrapyramidal symptoms and tardive dyskinesia. However, there is considerable patient-to-patient variability in therapeutic dose requirements of atypical antipsychotics and the propensity for side effects. Hence, the initial excitement since the introduction of atypical antipsychotics in late 1980s is now shifting towards a focus on individualization of pharmacotherapy and elucidation of the mechanistic basis of interindividual variability in drug response with use of pharmacokinetic and pharmacodynamic biomarkers. Pharmacogenomics, introduced in late 1990s, is the study of variability in drug response using information from the entire genome of a given individual patient. Both pharmacogenomics and conventional therapeutic drug monitoring (TDM) share the similar goal of improving pharmacotherapy through better explanation of individual variability in drug response. Hence, pharmacogenomic biomarkers offer a unique opportunity to complement and expand the scope of traditional TDM in clinical psychopharmacology. Importantly, pharmacogenomics enables the investigation of factors distal to drug exposure in the plasma compartment (e.g. drug targets at the biophase), thereby providing a more complete portrayal of sources of variability in psychotropic drug response. We discuss (1). the definitions for biomarkers and surrogate endpoints in the context of pharmacogenomics, (2). genetic variations in isozyme-specific atypical antipsychotic metabolism in vivo, (3). selected examples of pharmacogenomic variability in pertinent drug targets and, (4). the anticipated roadmap from implementation of pharmacogenomics to changes in healthcare and therapeutic policy. In addition, a conceptual framework that outlines the theoretical advantages of pharmacogenomics-guided TDM is presented using recent clinical applications as precedence.