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.