Journal of Clinical Psychopharmacology

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Journal of Clinical Psychopharmacology: Monthly Highlights

Each post will summarize and discuss the implications of the articles in the most recent issue of JCP. The findings of original research studies will not be disclosed on this blog; discussion will be limited to research question and study design.

Wednesday, March 1, 2017

We welcome the unofficial beginning of spring with a preview of our April 2017 issue!

Activating and Sedating Adverse Effects of Second-Generation Antipsychotics in the Treatment of Schizophrenia and Major Depressive Disorder: Absolute Risk Increase and Number Needed to Harm

Leslie Citrome, MD, MPH

This analysis compiled data from U.S. Food and Drug Administration (FDA) package inserts in order to quantify rates of activating and sedating adverse effects of second-generation antipsychotics. Akathisia, restlessness, anxiety, and insomnia were the principal activating effects studied, while somnolence and fatigue were the major sedating effects. The author reports the incidence of activating and sedating adverse effects associated with each of 12 commonly used second-generation antipsychotics. The outcomes of greatest interest were the rates of somnolence and akathisia for each antipsychotic. The author discusses the degree of heterogeneity among the side effect profiles of individual agents, as well as the propensity for certain agents to cause both activating and sedating effects.  

Predictors of Nonhospitalization and Functional Response in Clozapine Treatment: A Nationwide, Population-Based Cohort Study

Ole Köhler-Forsberg, MSc; Henriette T. Horsdal, MSc, PhD; Sophie E. Legge, MSc, PhD; et al.


This prospective cohort study aimed to identify predictors for favorable therapeutic response to clozapine. The authors identified patients prescribed clozapine for treatment-refractory schizophrenia who received a Global Assessment of Functioning (GAF) score within 30 days of the first prescription (n=502). At a follow-up duration of two years, the authors conducted a second GAF assessment and determined whether patients had been re-hospitalized during the study period. The authors stratified patients according to re-hospitalization (yes/no) as well as degree of GAF improvement at follow-up (no improvement, moderate improvement, or substantial improvement). The primary outcomes were the relative risk ratios for non-hospitalization and GAF improvement according to patient-specific factors such as time since diagnosis, length of prior hospitalization, work status, and educational level.


The Effect of Glycopyrrolate on Nocturnal Sialorrhea in Patients Using Clozapine:  A Randomized, Crossover, Double-Blind, Placebo-Controlled Trial

Wai Hong Man, PharmD, MSc; Jantine C.A. Colen-de Koning, PharmD, MSc; Peter F.J. Schulte, MD, PhD, et al.


For unknown reasons, up to 90% of patients prescribed clozapine experience nighttime sialorrhea, which can lead to poor sleep quality and increased risk for aspiration. The purpose of this randomized, controlled trial was to evaluate the efficacy of glycopyrrolate, an anticholinergic agent with minimal central nervous system activity, for the treatment of clozapine-associated nighttime sialorrhea. Patients treated stably with clozapine (n=32) received either placebo or 1mg of glycopyrrolate at bedtime during the 6-day double-blind phase, followed by 2mg of glycopyrrolate at bedtime during the 6-day open-label phase. The primary outcome was subjective improvement of sialorrhea based upon Patient Global Impression of Improvement (PGI-I) score.

Atypical Antipsychotics and the Risk of Falls and Fractures Among Older Adults: an Emulation Analysis and an Evaluation of Additional Confounding Control Strategies

Darmendra Ramcharran, PhD; Hong Qiu, MD, PhD; Martijn J. Schuemie, PhD; Patrick B. Ryan, PhD


An increased risk for falls and fractures has been reported in older adults newly treated with atypical antipsychotics, though it is not fully clear whether antipsychotics themselves cause this increased risk. In this retrospective case-control study, the authors analyzed Medicare claims data regarding patients aged >65 who had received a new atypical antipsychotic prescription within 90 days of the index date (n= 147,166). Age-matched controls (n=1,477,150) were not prescribed an antipsychotic. The authors report the odds ratio for fracture or fall requiring hospitalization among cases compared to controls, both before and after statistical adjustment for psychiatric diagnosis and medical co-morbidities.


5-HT6 Receptor Antagonist as an Adjunct Treatment Targeting Residual Symptoms in Patients With Schizophrenia: Unexpected Sex-Related Effects (Double-Blind Placebo-Controlled Trial)

Margarita Morozova, MD, PhD; Denis Burminskiy, MD; George Rupchev, PhD; et al.


The selective 5-HT6 receptor antagonist AVN-211 is currently under investigation as an adjunct therapy for schizophrenia. In this randomized, double-blind, placebo-controlled trial, the authors investigated the efficacy of AVN-211 add-on therapy for residual psychotic symptoms in patients with schizophrenia. Patients with a stable antipsychotic medication regimen for at least 3 months (n=80) were randomized to receive 4-8mg of AVN-211 or placebo as additional treatment. The primary outcome was the change in Positive and Negative Symptom Scale (PANSS) score after 6 weeks. The authors highlight gender differences regarding the observed efficacy of AVN-211.


Guarding the Gate: Remote Structured Assessments to Enhance Enrollment Precision in Depression Trials

Marlene P. Freeman, MD; James Pooley, BA; Martina J. Flynn, BA; et al.


The authors report the results of a novel protocol for subject enrollment in their investigational drug trials for major depressive disorder (MDD) and treatment-resistant depression (TRD). Specifically, the authors examine the impact of administration of a secondary screening tool, the SAFER Interview, to patients previously deemed eligible for participation at study sites. In 9 previous trials assessing investigational therapies for MDD and TRD, in which the authors were the principal investigators, the authors report the proportion of potential subjects whose status changed from eligible to ineligible after administration of the SAFER Interview. The authors discuss the most common reasons for exclusion among these subjects, as well as the role of tools such as the SAFER Interview in obtaining an optimal study population for future clinical trials.


Efficacy of Desvenlafaxine Compared With Placebo in Major Depressive Disorder Patients by Age Group and Severity of Depression at Baseline

Daniel Mosca, MD; Min Zhang, MS; Rita Prieto, MD; Matthieu Boucher, PhD


In this pooled post hoc analysis of 9 randomized, controlled trials, the authors assessed the statistical effects of age and illness severity upon the efficacy of desvenlafaxine for major depressive disorder. Patients were stratified into 4 categories based upon age (18-40y; 40-55y; 55-65y; and >65y) and 3 categories based upon baseline HAM-D17 rating scale score (<18; 18-25; and >25). In all trials, the primary outcomes were changes in HAM-D(17) and MADRS scores. The authors discuss whether their results identify patient populations most likely to benefit from desvenlafaxine therapy.


Comparison of the Efficacy and Safety of Aripiprazole Versus Bupropion Augmentation in Patients With Major Depressive Disorder Unresponsive to Selective Serotonin Reuptake Inhibitors: A Randomized, Prospective, Open-Label Study

Eun-Jin Cheon, MD, PhD; Kwang-Hun Lee, MD, PhD; Young-Woo Park, MD, PhD; et al.


Aripiprazole and buproprion both affect the dopaminergic system and have demonstrated efficacy in patients with major depressive disorder refractory to SSRI monotherapy. In this randomized, open-label trial, the authors sought a direct safety and efficacy comparison between aripiprazole and bupropion in patients with major depressive disorder and an inadequate response to SSRI treatment. Participants (n=107) were randomized to receive aripiprazole (minimum 2 mg/day) or bupropion (minimum 150 mg/day) for 6 weeks in addition to their existing SSRI regimen. The primary efficacy outcome was change in MADRS score at the conclusion of the study period. The primary safety outcome was the overall incidence of adverse events during the study period.


Clinical Outcomes of Concomitant Use of Warfarin and Selective Serotonin Reuptake Inhibitors: A Multidatabase Observational Cohort Study

Yaa-Hui Dong, PhD; Katsiaryna Bykov, MS, PharmD; Niteesh K. Choudhry, MD, PhD; et al.


Patients taking warfarin together with an SSRI may have an increased risk of serious bleeding compared to patients taking either drug alone. SSRIs have known anti-platelet effects, but it has also been proposed that some SSRIs may raise plasma concentrations of warfarin via CYP450 inhibition. In this prospective cohort study, the authors identified patients treated with both warfarin and an SSRI (n=52,129) in order to determine whether CYP450 inhibition by SSRIs contributes to an increased bleeding risk in these patients. One group comprised patients taking CYP2C9 inhibitors (fluoxetine and fluvoxamine), while the second group comprised patients taking any other SSRI. The primary outcomes were the incidence of bleeding events and all-cause mortality during the 180 days following the index date.


Short-Term Effects of Methylphenidate on Math Productivity in Children with Attention-Deficit/Hyperactivity Disorder Are Mediated by Symptom Improvements: Evidence from a Placebo-Controlled Trial

Anne Fleur Kortekaas-Rijlaarsdam, MSc; Marjolein Luman, PhD; Edmund Sonuga-Barke, PhD; et al.      


In this randomized, controlled trial, the authors aimed to characterize the effects of methylphenidate on academic performance in children with attention-deficit hyperactivity disorder (ADHD). The authors also sought to establish whether any positive effects were related to or independent of overall ADHD symptom improvement. Patients with ADHD (n=63; mean age 10.49) and typically developing children (n=67; mean age 10.16) received extended-release methylphenidate (minimum dose 10mg) for 7 days followed by placebo for a 7-day "washout" period. The primary outcomes were parent- and teacher-rated ADHD symptom severity, as well as math, reading, and spelling performance as measured by subject-specific standardized tests. The authors address the subject areas in which methylphenidate produced the greatest and least improvement, as well as whether academic performance changed similarly between ADHD patients and controls.


Effect of Methylphenidate on Emotional Dysregulation in Children With Attention-Deficit/Hyperactivity Disorder + Oppositional Defiant Disorder / Conduct Disorder

Ayse Kutlu, MD; Ulku Akyol Ardic, MD; Eyup Sabri Ercan, MD


This prospective, open-label study assessed the efficacy of methylphenidate for the treatment of emotional dysregulation in children with comorbid ADHD and oppositional-defiant disorder (ODD). Patients (n=118; mean age approximately 9 years) were assessed at baseline with the Conners Parent Rating Scale, Turgay DSM-IV-S, Parental Acceptance and Rejection Questionnaire, and Childhood Depression Inventory, which measured behaviors characteristic of the syndrome of emotional dysregulation. Treatment consisted of immediate-release methylphenidate (up to 60 mg/day) for 12 months; for 11 of the 12 months, parents of patients also participated in a structured training program. All rating scales were re-administered at the conclusion of the study period; these score changes constituted the primary outcomes. The authors discuss the degree to which observed improvement in emotional dysregulation was independent of ADHD and/or ODD symptom improvement.


Lymphocyte Phospho-Ser-GSK-3 / Total GSK-3 Protein Levels Ratio is Not Affected by Chronic Lithium or Valproate Treatment in Euthymic Patients with Bipolar Disorder

Abed N. Azab, PhD; Ella Vainer, PhD; Galila Agam, PhD; Yuly Bersudsky, MD, PhD


The precise mechanism by which mood stabilizers ameliorate symptoms of bipolar disorder is unknown; however, inhibition of glycogen synthase kinase 3 (GSK3), which has been observed in vitro with lithium, has been proposed as a key molecular effect of mood stabilizers. This biochemical analysis aimed to determine whether the mood stabilizers lithium and valproate produced in vivo inhibition of GSK3 in patients with bipolar disorder. The authors obtained fresh lymphocytes from patients with bipolar disorder treated with either lithium or valproate (n=47); the ratio of phosphorylated GSK3 to total GSK3 was used to quantify GSK3 inhibition. Samples were also obtained from controls (n=32). Based upon their results, the authors discuss the plausibility of GSK3 inhibition as a therapeutic mechanism.


High Incidence and Prevalence of Drug-Related Movement Disorders in Young Patients with Psychotic Disorders

Thierry Q. Mentzel, MSc; Ritsaert Lieverse, MD, PhD; Oswald Bloemen, MD, PhD; et al.


This prospective, naturalistic cohort study aimed to characterize the prevalence and incidence of movement disorders in relatively young patients receiving long-term antipsychotic therapy. 94% of the study sample (n=828 total) was younger than age 40; the mean age was 27. Patients were assessed at baseline and 3-year follow-up for the presence of Parkinsonism, akathisia, dystonia, and tardive dyskinesia. The authors also determined the prevalence of persistent movement disorders, defined as a movement disorder present both at baseline and follow-up. The statistical effects of antipsychotic dose and symptom severity upon likelihood of developing a movement disorder are also presented.


Differential Risk of Peptic Ulcer Among Users of Antidepressants Combined with Nonsteroidal Anti-Inflammatory Drugs

Ju-Young Shin, PhD; Inmyung Song, PhD; Jin-Ho Lee, MD, PhD; et al.


Use of nonsteroidal anti-inflammatory drugs (NSAIDs) is a major risk factor for the development of peptic ulcer disease. Some antidepressants, particularly SSRIs, are also thought to carry an increased risk. In this retrospective cohort study, the authors aimed to determine the risks of peptic ulcer disease associated with different classes of antidepressants, as well as whether concomitant use of antidepressants and NSAIDs conferred an additive risk of peptic ulcers. The authors matched patients who took antidepressants alone (n=384,425) to patients who took antidepressants plus NSAIDs (n=384,425) during the four-year period of interest. The first primary outcome was the hazard ratio for peptic ulcer development in the antidepressant plus NSAID group compared to the antidepressant alone group. The second primary outcome was the hazard ratio for peptic ulcer development associated with individual classes of antidepressants (SSRI, SNRI, tricyclic, and MAOI) when taken in combination with NSAIDs compared to when taken alone.


Memantine as an Adjuvant Treatment for Obsessive-Compulsive Symptoms in Manic Phase of Bipolar Disorder: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Ali Sahraian, MD; Leila Razehgian Jahromi, MD; Ahmad Ghanizadeh, MD; Arash Mowla, MD


This randomized, controlled trial evaluated the efficacy of the NMDA receptor antagonist memantine for the treatment of obsessive-compulsive symptoms during the manic phase of bipolar disorder. Patients with active bipolar disorder and obsessive-compulsive symptoms (n=38) were randomized to receive either memantine (minimum 5 mg/day) or placebo in addition to a regimen of lithium (800-825 mg/day), olanzapine (7.5 mg/day), and clonazepam ((0.5-0.75 mg/day). The primary outcome was change in Yale Brown Obsessive Compulsive Scale score at the conclusion of the 16-week study period.


Sunday, January 1, 2017

Happy New Year! The Journal of Clinical Psychopharmacology wishes you a healthy and prosperous 2017. We are delighted to preview the February 2017 issue.

The Relationship Between Early Haloperidol Response and Associated Extrapyramidal Side Effects

            Sean A. Rasmussen, PhD; Patricia I. Rosebush, MD; Michael F. Mazurek, MD

While schizophrenic patients with a positive early response to antipsychotic medication are known to have better long-term outcomes, it is not known whether such patients also experience more extrapyramidal side effects. In this naturalistic, observational study, the authors identified 136 patients treated for first-episode psychosis with haloperidol. At week 2 of treatment, medication response was assessed using the Brief Psychiatric Rating Scale, Hamilton Depression Rating Scale, and Hamilton Anxiety Rating Scale. Patients were also evaluated for the presence of dystonia, parkinsonism, dyskinesia, and akathisia. The authors determined whether greater symptom improvement was statistically associated with a higher incidence of movement disorders.

Time to Discontinuation of Second-Generation Antipsychotics Versus Haloperidol and Sulpiride in People With Schizophrenia: A Naturalistic, Comparative Study

            Hung-Yu Chan, MD, PhD; Yi-Ju Pan, MD, PhD; Jiahn-Jyh Chen, MD; Chiung-Hsu Chen, MD

 Antipsychotic side effects and subsequent medication changes and/or non-adherence represent major barriers to the treatment of schizophrenia. In this retrospective study, the authors identified individuals with schizophrenia (n=918) treated either with haloperidol or sulpiride (first-generation antipsychotics) or with a second-generation antipsychotic on an outpatient basis. The primary outcome was treatment duration, until such time as medication was discontinued for at least 28 days. The authors report the average treatment time for first- and second-generation antipsychotics and discuss possible reasons for the difference between groups.

Unaltered Dopamine Transporter Availability in Drug-Naïve Patients With Schizophrenia After 6 Months of Antipsychotic Treatment: A Naturalistic Study

            Wei Hung Chang, MD; Kao Chin Chen, MD, PhD; I Hui Lee, MD; et al.

Although the roles of several neurotransmitter systems in schizophrenia have been investigated, the "dopamine hypothesis" remains the predominant neurobiological model of schizophrenia. In this prospective study, patients with new-onset schizophrenia (n=24) were treated with either first-or second-generation antipsychotics based upon providers' judgment. At baseline and after 6 months of treatment, single photon-emission CT (SPECT) imaging was used to assess dopamine transporter (DAT) density. The primary outcome was the average difference in DAT density between baseline and 6-month follow-up. As secondary outcomes, the authors measured whether SPECT findings differed between patients treated with first- and second-generation antipsychotics, as well as whether DAT changes correlated with clinical symptom changes.

Sex Differences in the Effect of Atomoxetine on the QT Interval in Adult Patients With Attention-Deficit Hyperactivity Disorder

            Yutaro Suzuki, MD, PhD; Misuzu Tajiri, MD; Atsunori Sugimoto, MD, PhD; et al.

It is currently unclear whether atomoxetine significantly affects the QT interval in adults. In this prospective study, patients with attention-deficit hyperactivity disorder (n=41) were treated with atomoxetine (40, 80, or 120mg) daily for two weeks. Electrocardiographic measurements were obtained before and after treatment. The primary outcome was average change in QT interval during treatment, as well as whether any such change was dose-dependent.

Comparative Risk of Ventricular Arrhythmia and Sudden Cardiac Death Across Antidepressants in Patients With Depressive Disorders

            Chi-Shin Wu, MD, PhD; Yu-Ting Tsai, MS; Chao A. Hsiung, PhD; Hui-Ju Tsai, MPH, PhD

Antidepressants, particularly older agents, may carry a small risk of cardio-toxicity, but it is unclear to what extent this hazard should influence prescribing. In this prospective cohort study, the authors determined the incidence of ventricular arrhythmia and sudden cardiac death among a cohort of antidepressant users. Subjects (n=793,460) were stratified by antidepressant class including, but not limited to, SSRI, SNRI, and tricyclic antidepressants. The primary outcome was the incidence of ventricular arrhythmia and/or sudden cardiac death among patients treated with each class of antidepressant.

 Increased Brain Lactate During Depressive Episodes and Reversal Effects by Lithium Monotherapy in Drug-Naïve Bipolar Disorder

            Rodrigo Machado-Vieira, MD, PhD; Marcus V. Zanetti, MD, PhD; Maria C. Otaduy, PhD; et al.

Recent evidence has suggested that mitochondrial dysfunction is involved in the pathophysiology of bipolar disorder. It has also been hypothesized that lithium, the mechanism of which is not fully understood, may restore normal neuronal oxidative metabolism. In this prospective study, brain lactate levels in patients with recent-onset bipolar disorder and current depressive symptoms were quantified with 1H-MRS imaging. Bipolar disorder patients (n=20) were matched to healthy controls and received 6 weeks of daily open-label treatment with lithium. 1H-MRS was conducted at baseline and again following treatment. The primary outcomes were differences in brain lactate levels between patients and controls, as well as changes in lactate levels following lithium treatment.

Adjunctive Brexpiprazole as a Novel Effective Strategy for Treating Major Depressive Disorder: A Systematic Review and Meta-Analysis

            Seoyoung Yoon, MD; Sang Won Jeon, MD; Young-Hoon Ko, MD, PhD; et al.

Brexpiprazole is a relatively new atypical antipsychotic; it is similar in mechanism to the D2 partial agonist aripiprazole but has less activity at this receptor. The authors conducted a meta-analysis of randomized, controlled trials evaluating the efficacy of brexpiprazole as augmentation therapy for major depressive disorder. The authors also discuss the rates of discontinuation due to adverse effects in the trials studied.

 Effect of Rivastigmine Augmentation in Treatment of Male Patients with Combat-Related Chronic Posttraumatic Stress Disorder: A Randomized Controlled Trial

            Amir Rezaei Ardani, MD; Golkoo Hosseini, MD, MSED; Mohammad Reza Fayyazi Bordbar, MD; et al.

Posttraumatic stress disorder is managed with a variety of pharmacologic agents, but available treatments have relatively low effectiveness. In this randomized, controlled trial, the authors assessed the efficacy of rivastigmine, an acetylcholinesterase inhibitor, as a treatment for post-traumatic stress disorder refractory to first-line therapy. Subjects (n=36) had a diagnosis of post-traumatic stress disorder and had not responded adequately to 4 weeks of treatment with citalopram plus valproic acid. In addition to their current therapy, subjects were randomly assigned to receive rivastigmine, placebo, or no additional drug. The primary outcomes were average PTSD Checklist — Military Version (PCL-M) and Spitzer Quality of Life Index scores at weeks 2,4,8, and 12 of treatment.

Cognitive Impairment and Tramadol Dependence

            Medhat M. Bassiony, MD, MSc, MBBCh; Usama M. Youssef, MD, MSc, MBBCh; Mervat S. Hassan, MD, MSc, MBBCh; et al.

Despite its low potency as a mu opioid receptor agonist, tramadol exhibits significant abuse potential. In this retrospective case-control study, the authors aimed to characterize the prevalence of cognitive impairment among patients with a history of tramadol dependence. Cases (n=100) were either dependent upon tramadol alone (n=24) or dependent upon tramadol in addition to other substances (n=76). The primary outcome was the odds ratio for cognitive impairment, as measured by the Montreal Cognitive Assessment (MoCA), among tramadol-dependent subjects compared to age- and education-matched controls.  ​

A Validation Study of the International Consensus Diagnostic Criteria for Neuroleptic Malignant Syndrome

            Ronald J. Gurrera, MD; Gino Mortillaro, MD; Varadaraj Velamoor, MD, FRCP (C); Stanley N. Caroff, MD

 Neuroleptic malignant syndrome requires immediate identification, but, until recently, there has been no internationally validated set of diagnostic criteria. In this review, the authors compared the sensitivity and specificity of recently published International Expert Consensus (IEC) guidelines with the current diagnostic reference standard. The authors analyzed telephone reports of neuroleptic malignant syndrome to the Malignant Hyperthermia Association of the United States (n=221). The primary outcome was the degree of agreement between IEC guidelines and the current standard DSM-IV-TR guidelines.

































Thursday, November 10, 2016

An early "Happy Holidays" from the JCP Blog! We hope you enjoy the wide variety of outstanding contributions to our latest issue.

Pharmacokinetic Drug-Drug Interactions of Mood Stabilizers and Risperidone in Patients Under Combined Treatment

George Schoretsanitis, MD; Ekkehard Haen, MD, PhD; Gerhard Gründer, MD; et al.

Risperidone is metabolized principally by CYP2D6 but also by CYP3A4. Both carbamazepine and valproate are extensively metabolized by the CYP450 system; notably, carbamazepine is a clinically important inducer of CYP3A4. Therefore, significant drug-drug interactions are possible between risperidone and mood-stabilizing agents, although these interactions have not been studied. In this retrospective case-control study, the authors investigated whether the pharmacokinetics of risperidone are significantly affected by concomitant use of carbamazepine and/or valproate. From a therapeutic drug-monitoring database, the authors identified 852 patients receiving risperidone alone, 153 patients receiving risperidone plus valproate, and 21 patients receiving risperidone plus carbamazepine. The average daily dose of risperidone was not significantly different among the groups. The primary outcome was median plasma concentration of risperidone and 9-hydroxyrisperidone (the main metabolite of risperidone) in each group.

Quetiapine Extended Release Open-Label Treatment Associated Changes in Amygdala Activation in Anxious Depression: an fMRI Study

Murat Altinay, MD; Harish Karne, MS; Erik Beall, PhD; and Amit Anand, MD

fMRI studies have demonstrated that patients with major depressive disorder often have distinctive changes in amygdala activity. Successful treatment with SSRI antidepressants has been shown to reverse these changes. However, it is unclear whether atypical antipsychotics, which are common second-line treatments for major depression, have similar effects upon the function of the amygdala This prospective study analyzed fMRI data from healthy (n=15) and depressed (n=15) subjects before and after treatment with extended-release quetiapine. The primary outcomes were changes in task-induced amygdala activation and resting amygdala-cortex connectivity after eight weeks of open-label therapy.

Peony-Glycyrrhiza Decoction for Antipsychotic-Related Hyperprolactinemia in Women With Schizophrenia: A Randomized Controlled Trial

Sui Cheung Man, BS; Xian-Bin Li, MD; Huai-Hai Wang, MD; et al.

Hyperprolactinemia is relatively common in patients receiving antipsychotics and is often difficult to treat. In this randomized, double-blind, placebo-controlled trial, the authors evaluated the efficacy of an herbal preparation (peony-glycyrrhiza) in the treatment of antipsychotic-induced hyperprolactinemia. Female subjects with schizophrenia and symptomatic hyperprolactinemia (n=99) were randomized to receive peony-glycyrrhiza or placebo for 16 weeks. The primary outcome was change in Prolactin-Related Adverse Event Questionnaire score at the conclusion of the study period. The authors discuss potential mechanistic and clinical differences between peony-glycyrrhiza and traditional treatments for hyperprolactinemia (e.g., bromocriptine).

Antipsychotic Response Worsens with Postmenopausal Duration in Women with Schizophrenia

Alexandre Gonzalez-Rodriguez, MD; Rosa Catalan, MD, PhD; Rafael Penades, PhD; et al.

Some evidence suggests that females with schizophrenia respond more robustly to antipsychotic treatment than males. Therefore, it has been hypothesized that lower estrogen levels are associated with increased severity of schizophrenia. In this prospective cohort study, the authors investigated whether greater duration since menopause was associated with a decreased likelihood of antipsychotic response. Participants (n=60) were postmenopausal women with schizophrenia who required a change in antipsychotic therapy due to lack of efficacy. Participants were followed for twelve weeks, during which time antipsychotic treatment was adjusted non-systematically according to clinical judgment. At the conclusion of the study period, participants were classified as responders or non-responders based upon change in Positive and Negative Syndrome Scale (PANSS) score. The primary outcome was average duration since menopause in the responder and non-responder groups.

Prevalence of Vitamin D Deficiency in Adult Outpatients with Bipolar Disorder or Schizophrenia

Remco Boerman, MANP, CNS; Dan Cohen, PhD; Peter F.J. Schulte, PhD; and Annet Nugter, PhD

Vitamin D deficiency has been associated with increased prevalence of a number of psychiatric and neurocognitive diseases. In this cross-sectional study, the authors examined whether patients with schizophrenia or bipolar disorder have a higher prevalence of Vitamin D deficiency than controls. Vitamin D levels were obtained from 320 Dutch patients with schizophrenia, bipolar disorder, and schizoaffective disorder. Each patient was categorized as having a deficient, insufficient, sufficient, or optimum Vitamin D level. The prevalence of Vitamin D deficiency in the study group was compared to the Dutch population prevalence of Vitamin D deficiency (primary outcome). The authors also compared the average absolute vitamin D level in the study population to the Dutch population mean (secondary outcome).

Incidence of Antipsychotic-Associated Side Effects: Impact of Clinician Versus Patient Ratings and Change Versus Absolute Scores

Hiroyoshi Takeuchi, MD, PhD; Gagan Fervaha, BSc; and Gary Remington, MD, PhD, FRCPC

Because of the high incidence of antipsychotic side effects, small changes in the sensitivity of side effect detection may have significant population-level implications.  In this retrospective analysis of a randomized, controlled trial (the CATIE study; n=1460), the authors aimed to determine whether patient-centered or clinician-centered rating scales could detect antipsychotic side effects with greater sensitivity. In the original trial, 18 separate side effects were assessed concurrently with subjective and objective rating scales. The first primary outcome was the difference between subjective and objective detection rates for each side effect. The authors also examined the change in sensitivity when scores took the patient's pre-treatment baseline into account.

Agomelatine for the Treatment of Major Depressive Episodes in Schizophrenia-Spectrum Disorders: An Open-Prospective Proof-of-Concept Study

Susanne Englisch, MD; Hanna Sophie Jung; Antje Lewien, MD; et al.

Depression is a common negative symptom of schizophrenia and contributes significantly to morbidity and mortality among schizophrenic patients. Agomelatine, a novel antidepressant with action at melatonin and serotonin receptors, has demonstrated non-inferior safety and efficacy relative to other antidepressants in the treatment of unipolar depression. In this prospective, open-label study, the authors aimed to establish the efficacy of agomelatine for depressive symptoms of schizophrenia. Participants (n=27) had a diagnosis of schizophrenia, stable and well-controlled psychotic symptoms, and a score of at least 8 on the Calgary Depression Scale for Schizophrenia (CDSS) or at least 18 on the Hamilton Depression Scale (HAMD). Participants received 25 mg of agomelatine daily for 12 weeks, which was increased to 50 mg if deemed appropriate. The primary outcome was average change in CDSS and HAMD scores at the conclusion of the study period.

Evaluation of the Relationship Between Pharmacokinetics and the Safety of Aripiprazole and its Cardiovascular Effects

Carmen Belmonte, MSc; Dolores Ochoa, MD, PhD; Manuel Roman, MLT; et al.

In this prospective study, the authors characterized gender differences in the pharmacokinetics, cardiovascular effects, and adverse effects of aripiprazole. Participants were healthy volunteers (n=157) who received a single, 10mg oral dose of aripiprazole. The authors calculated several pharmacokinetic parameters (including AUC and half-life) and measured blood pressure, heart rate, and QTc interval at 0.5, 2, 4, 6, and 8 hours post-dose. The incidence of adverse reactions, principally GI disturbances, was also recorded for males and females. The authors discuss whether gender differences were observed in the pharmacokinetic properties, cardiovascular effects, and/or adverse reaction rates of oral aripiprazole. The possibility of an association between pharmacokinetic and clinical gender differences is also addressed.

Metabolic Abnormalities Related to Treatment with Selective Serotonin Reuptake Inhibitors in Patients with Schizophrenia or Bipolar Disorder

Katrine Kveli Fjukstad, MD; Anne Engum, MD, PhD; Stian Lydersen, PhD; et al.

Among individuals with schizophrenia and bipolar disorder, metabolic abnormalities are common. It is not clear whether these abnormalities are fully attributable to antipsychotic side effects or partly to unknown features of the underlying illnesses. Unlike antipsychotics, SSRI antidepressants are generally thought to have few metabolic effects. This retrospective case-control study assessed whether SSRIs are associated with unanticipated metabolic disturbances in patients with schizophrenia and bipolar disorder. The authors identified 280 patients with schizophrenia and bipolar disorder treated with an SSRI and 1201 patients with the same diagnoses not treated with an SSRI. The primary outcome was the average difference in total cholesterol between SSRI-treated patients and controls. Secondary outcomes included differences in serum glucose and BMI.

Prescribing Practice in Inpatients Versus Outpatients with Schizophrenia Initiating Treatment with Second-Generation Antipsychotics: A Naturalistic Follow-Up Study

Monika Edlinger, MD; Maria A. Rettenbacher,MD; Georg Kemmler, PhD; et al.

In this naturalistic prospective study, the authors examined whether patients with treatment-resistant schizophrenia were more likely to be switched to a typical or atypical antipsychotic based upon clinical setting (inpatient versus outpatient). Additionally, the authors studied whether inpatients or outpatients were more likely to receive benzodiazepines as adjunctive therapy. Subjects (n=137) had schizophrenia and had failed at least one antipsychotic. The primary outcome was the proportion of inpatients and outpatients prescribed an atypical antipsychotic and/or benzodiazepine as second-line treatment. The authors discuss factors that may predispose clinicians to prescribe typical or atypical agents in different environments of care.   

Efficacy and Safety of Adjunctive Aripiprazole in Schizophrenia: Meta-Analysis of Randomized Controlled Trials

Wei Zhang, MD; Ying-Jun Zheng, MD; Xian-Bin Li, MD; et al.

Because of its unique pharmacodynamic profile, aripiprazole may be desirable for combined use with other antipsychotics in the treatment of schizophrenia. The authors conducted a meta-analysis of 38 randomized, controlled trials comparing the safety and efficacy of antipsychotic monotherapy to that of combined treatment with aripiprazole. The primary outcomes were changes in PANSS score (efficacy) and body weight (safety) in the combined treatment and monotherapy groups.

Subjective Versus Objective Weight Gain During Acute Treatment with Second-Generation Antipsychotics in Schizophrenia and Bipolar Disorder

Keming Gao, MD, PhD; Fang Fang, MD, MS; Zuowei Wang, MD, PhD; and Joseph R. Calabrese, MD

An earlier contribution [see Takeuchi et al. in this issue] studied the sensitivity of patient- and clinician-centered reporting of antipsychotic side effects. This retrospective analysis of randomized, controlled trials addresses a similar question with a focus upon the side effect of weight gain. The authors included 52 trials that measured both self-reported and objective (>7% body weight) weight gain associated with atypical antipsychotic treatment. The primary outcome was the overall number needed to harm (NNH) according to both self-reported and objective measures. A separate NNH was calculated for 11 individual atypical agents. The authors discuss the extent to which their results are consistent with previous literature regarding antipsychotic-associated weight gain.

Sex Differences in Body Mass Index and Obesity in Chinese Patients with Chronic Schizophrenia

 Qiongzhen Li, MD, PhD; Dachuan Chen, MD; Tiebang Liu, MD, PhD; et al.

Relatively little is known about gender differences in the likelihood of weight gain associated with antipsychotic treatment. In this cross-sectional study, the authors collected body weight and BMI data, as well as PANSS scores, from inpatients with schizophrenia (n= 206). The authors report the prevalence of obesity among males and females, as well as the association between PANSS score and BMI. Of note, the prevalence of active antipsychotic treatment was significantly different between males and females and was not 100% in either group. The authors discuss possible reasons for this difference as well as non-pharmacologic factors underlying observed rates of obesity.

Time to First Discontinuation, Adherence and Persistence in New Users of Second-Generation Antipsychotics

Henry C. Ndukwe, MSc and Prasad S. Nishtala, PhD

 Current guidelines recommend that atypical antipsychotics should not be used for more than 12 weeks to treat behavioral and psychological symptoms of dementia. However, actual prescribing of antipsychotics in elderly patients may be highly variable among clinicians and institutions. In this prospective cohort study, the authors assessed temporal patterns of antipsychotic use in the elderly. Subjects (n=30,297) were first-time antipsychotic users aged 65 or older receiving medication doses considered sub-therapeutic for schizophrenia. The cohort was followed until permanent medication discontinuation or death occurred. The primary outcomes were average time to medication discontinuation, medication adherence (as measured by variable medication possession ratio), and medication persistence (proportion of patients who required two or more separate courses of treatment).

Pain Relief in Depressive Disorders: A Meta-Analysis of the Effects of Antidepressants

Stefan Gebhardt, MD; Monika Heinzel-Gutenbrenner, PhD; and Udo König, MSc

Pain is a prevalent symptom among depressed patients. However, in the setting of depressive disorders, the comparative efficacy of different antidepressant classes against pain is uncertain. In this meta-analysis of 19 randomized, controlled trials, the authors evaluated the efficacy of SSRI, SNRI, tricyclic, and mixed-mechanism antidepressants in the treatment of pain associated with depression. In the trials studied, the principal measure of pain improvement was change in Brief Pain Inventory score. The authors report overall effect sizes for each antidepressant class. The authors also discuss the possible mechanisms underlying the observed effects. While some antidepressants are thought to have primary analgesic effects, the authors also address the hypothesis that observed improvements in pain resulted directly from amelioration of depressed mood.

 Anterior Cingulate Glutamate is Reduced by Acamprosate Treatment in Patients with Alcohol Dependence

 Mark A. Frye, MD; David J. Hinton, BA; Victor M. Karpyak, MD, PhD; et al.

Acamprosate is an effective pharmacologic treatment for alcohol dependence; although its mechanism is not fully understood, it is thought to modulate glutamatergic neurotransmission. In this prospective study, the authors tested the hypothesis that acamprosate treatment would reverse excessive glutamatergic transmission in the anterior cingulate cortex of alcohol dependent-patients. Of 13 patients recruited, 9 received four weeks of acamprosate and 4 did not; assignment was non-random and was based upon a clinical assessment. In each patient, non-invasive Proton MRS imaging was used to quantify cortical glutamate levels at baseline and at the end of the study period. Pre-treatment imaging studies of the 13 patients were compared to those of 16 healthy controls. The authors primarily discuss follow-up imaging results in alcohol-dependent patients treated with acamprosate compared to untreated patients.

Dihydroxyphenylglycol as a Biomarker of Norepinephrine Transporter Inhibition by Atomoxetine: Human Model to Assess Central and Peripheral Effects of Dosing

Peter R. Bieck, MD, PhD; Mark Leibowitz, MD; D. Richard Lachno, DPhil; et al. ​

In this exploratory study, the authors aimed to establish the validity of 3,4-dihydroxyphenylglycol (DHPG) as a biomarker for norepinephrine transporter function. Healthy subjects (n=12) were treated with atomoxetine, an inhibitor of the norepinephrine transporter, for 18 days. The primary outcome was the change in DHPG in plasma, urine, and CSF over the study period. The authors discuss the feasibility of measuring central and/or peripheral effects of norepinephrine reuptake inhibitors using DHPG.








Wednesday, October 19, 2016

The October 2016 issue is here! We are excited to preview eight original contributions this month. We hope that these summaries will help readers select items of interest.


How Hyperprolactinemia Affects Sexual Function in Patients Under Antipsychotic Treatment

            Elena Rubio-Abadal, PhD; Nuria Del Cacho, MD; Gerard Saenz-Navarrette, MD; et al.

Hyperprolactinemia and sexual dysfunction are well-known and often distressing adverse effects of antipsychotic treatment. In particular, the precise mechanism of antipsychotic-associated sexual dysfunction remains unknown; the extent to which hyperprolactinemia may contribute is unclear.  

In this cross-sectional study, the authors investigated the relationship between hyperprolactinemia and sexual dysfunction in antipsychotic-treated patients. Participants (n=101) had a diagnosis of a psychotic spectrum disorder and were receiving a stable dose of any antipsychotic medication. The authors report the prevalence of hyperprolactinemia and the mean prolactin level in patients with and without self-reported sexual dysfunction. The association between absolute prolactin level and self-reported sexual functioning is also discussed.

Treatment Patterns and Antipsychotic Medication Adherence Among Commercially Insured Patients With Schizoaffective Disorder in the United States

            Kruti Joshi, MPH; Jay Lin, PhD; Melissa Lingohr-Smith, PhD; et al.

Patients with schizoaffective disorder present a unique clinical challenge due to their overlapping psychotic and depressive symptoms.

The authors hypothesized that these patients are likely to receive inadequate treatment and/or demonstrate poor medication adherence. Participants in this prospective cohort study (n=2713) had a diagnosis of schizoaffective disorder with 12 months of continuous prescription drug coverage. The authors report the prevalence of psychotropic prescribing by class, as well as the prevalence of polypharmacy, at 12-month follow-up. The authors also describe rates of medication adherence, as measured by the proportion of patients with a medication possession ratio >80% at follow-up.

Omega-3 Fatty Acids, Depressive Symptoms, and Cognitive Performance in Patients With Coronary Artery Disease: Analyses From a Randomized, Double-Blind, Placebo-Controlled Trial

            Graham Mazereeuw, PhD; Nathan Herrmann, MD; Paul I. Oh, MD; et al.

Evidence suggests that omega-3 fatty acids are effective in the treatment of depression and mild cognitive dysfunction. They may also be cardio-protective and, therefore, could substantially benefit patients with co-existing psychiatric and cardiovascular disease.

In this randomized, double-blind, placebo-controlled trial, the authors hypothesized that omega-3 treatment would improve depressive and cognitive symptoms in patients with coronary artery disease relative to placebo. Participants (n=92) had clinically stable coronary artery disease and met diagnostic criteria for depression. Participants received either EPA/DHA or placebo daily for 12 weeks. The primary outcome was change in Hamilton Depression Rating Scale (HAM-D) scores over the study period. Exploratory measures of cognitive function included changes in California Verbal Learning Test and Digital Symbol Substitution Test scores.

Antidepressant Medication Treatment and Risk of Death

            Kara Zivin, PhD; H. Myra Kim, ScD; Matheos Yosef, PhD; et al.

The authors hypothesized that antidepressant treatment is associated with an increased risk of all-cause mortality among depressed veterans compared to no treatment. In this case-control study, subjects (n=720,821) had a diagnosis of depression and received treatment at a VA facility during a 90-day index period. Cases were stratified by antidepressant class (SSRI, TCA, and atypical). The primary outcome was relative risk of all-cause mortality at 1 year after index date.

The Validity of the Different Versions of the Hamilton Depression Scale in Separating Remission Rates of Placebo and Antidepressants in Clinical Trials of Major Depression

            Phillip Raphael Kyle, MSc; Ole Michael Lemming, MSc; Nina Timmerby, MD; et al.

In clinical trials evaluating therapies for major depression, high placebo-response rates often significantly complicate assessments of drug efficacy.  The HAM-D rating scale is commonly used in such trials, although 6-question, 17-question, and 21-question versions of this scale are sometimes used interchangeably.

The authors aimed to determine which version of the HAM-D is most sensitive in detecting differences between placebo and treatment. Participants in a published randomized, controlled trial comparing duloxetine and vortioxetine to placebo comprised the study population. Each participant's Clinical Global Impression of Severity score was converted to a HAM-D(6), HAM-D(17), and HAM-D(21) score. For each rating instrument, the primary outcome was the effect size of vortioxetine/duloxetine compared to placebo.

A Phase 2 Randomized Dose-Finding Study With Esmirtazapine in Patients With Primary Insomnia

            Frank Ruwe, MSc; Pieta Ijzerman-Boon, PhD; Thomas Roth, PhD; et al.

Mirtazapine, an atypical antidepressant, is frequently prescribed "off-label" as a sedative-hypnotic. The purified enantiomer esmirtazapine differs from racemic mirtazapine in its pharmacokinetic and pharmacodynamic profiles; it is a more potent H(1) receptor antagonist with a shorter elimination half-life. This compound is also under investigation as a hypnotic.

The authors report the results of a randomized, double-blind, placebo-controlled, crossover, multicenter study evaluating the efficacy of esmirtazapine relative to placebo in patients with primary insomnia. Participants (n=60) demonstrated polysomnogram findings consistent with primary insomnia for two consecutive nights. Each participant received eight nights of treatment with esmirtazapine as well as a five-day placebo washout. Primary outcomes were awake time and latency to persistent sleep (measured by polysomnogram), as well as participant assessment of sleep quality.

 Associations Between Personality Traits and Adherence to Antidepressants Assessed Through Self-Report, Electronic Monitoring, and Pharmacy Dispensing Data: A Pilot Study

           Hans Wouters, PhD; Darya Amin, MSc; Katja Taxis, PhD; et al.

Medication non-adherence is prevalent and clinically significant among patients taking antidepressants.

This novel prospective cohort study examined the association between individual personality traits and antidepressant adherence. Participants (n=137) were receiving any individual antidepressant for any indication. Participants completed a self-assessment questionnaire for "Big Five" traits: Extraversion, Neuroticism, Conscientiousness, Agreeableness, and Openness. Medication adherence was subsequently assessed both subjectively, using a questionnaire, and objectively, using electronic monitoring of pharmacy records. The authors discuss how the presence of any personality trait(s) affected the degree of medication adherence.

Risk of Extrapyramidal Adverse Events with Aripiprazole

Unlike other atypical antipsychotics, aripiprazole is a D(2) receptor partial agonist rather than a full antagonist, a property that is thought to confer a substantially lower risk of extrapyramidal side effects. However, case reports of extrapyramidal reactions associated with aripiprazole have been published.

This retrospective case-control study examined the odds ratio of extrapyramidal side effects in patients treated with aripiprazole compared to controls and patients treated with risperidone. The total number of subjects was 6,110,723; subjects with a diagnosis of schizophrenia were excluded. The authors also discuss possible predisposing factors for extrapyramidal reactions associated with aripiprazole.


Friday, September 9, 2016

We are delighted to announce the launch of the Journal of Clinical Psychopharmacology blog! We recognize the ever-increasing need for a scientific presence in the digital and social media spaces, and we are excited for this opportunity to make our content more accessible to a wider readership.

For each subsequent issue of JCP, this blog will feature brief summaries of all original research contributions. The design and potential implications of each original study will be reviewed. We hope that these sneak-previews will help readers identify articles of particular interest.

Stay tuned for the next issue.