Matthew Macaluso

Randomized proof of concept trial of GLYX-13, an N-methyl-D-aspartate receptor glycine site partial agonist, in major depressive disorder nonresponsive to a previous antidepressant agent.

BACKGROUNDnApproximately 45% of patients with major depressive disorder (MDD) do not remit when treated with biogenic amine antidepressants. Consequently, there is a significant need for antidepressant agents with different mechanisms of action. Early proof of concept (POC) studies with such novel agents play a significant role in helping drug developers identify agents and mechanisms of action that merit more intensive research. Studies have demonstrated that high affinity N-methyl-Daspartate (NMDA) receptor blockers (eg, ketamine) can produce rapid antidepressant effects in patients who have not responded to currently available agents, but treatment with these agents is accompanied by psychotomimetic effects that make their use problematic. This column describes a POC study involving GLYX-13, an N-methyl-D-aspartate receptor glycine site functional partial agonist.nnnMETHODnIn this double-blind, randomized, placebo-controlled study, a single intravenous (IV) dose of GLYX-13 (1, 5, 10, or 30 mg/kg) or placebo was administered to 116 subjects with MDD who had not benefitted from a trial of at least one biogenic amine antidepressant during the current episode. The primary outcome measure was score on the Hamilton Depression Rating Scale-17 (Ham-D17), which was used to rate overall depressive symptoms at baseline and at 24 hours and days 3, 7, 14, and, in some arms, days 21 and 28 after administration.nnnRESULTSnGLYX-13, 5 or 10 mg/kg IV, reduced depressive symptoms as assessed by the Ham-D17 at days 1 through 7. Onset of action as assessed using the Bech-6 occurred within 2 hours. GLYX-13 did not elicit psychotomimetic or other significant side effects.nnnCONCLUSIONnIn this early POC study, GLYX-13 reduced depressive symptoms within 2 hours and this effect was maintained for 7 days on average in subjects with MDD who had not responded to another antidepressant agent during the current depressive episode. The findings of this study support the hypothesis that modulation of the NMDA receptor is a valid target for the development of antidepressant drugs and the need for additional studies to further evaluate the effects of GLYX-13. POC studies such as the one described here play a pivotal role in allowing drug researchers to decide whether to move forward with larger and more expensive studies, and they enable them to focus available resources on those molecules that appear to have the most therapeutic promise. Based on the POC study described here, a multiple dose study has been completed which showed sustained therapeutic benefit with repeated dosing of GLYX-13 for more than 6 weeks. Phase 3 studies are now being planned.

How biomarkers will change psychiatry: from clinical trials to practice. Part I: introduction.

Part I of this series defines biomarkers and discusses their research utility and potential application in clinical practice. To provide a frame of reference, biomarkers commonly used in general medicine are reviewed, with a focus on low density lipoprotein as a biomarker for risk of developing atherosclerosis. The use of biomarkers in research on psychiatric illnesses is then reviewed. While biomarkers currently have only a limited role in psychiatric care, their use has improved our ability to assess potential efficacy and safety of investigational new drugs. For example, positron emission tomography can be used to measure dopamine D2 receptor occupancy (relevant for antipsychotic effects) or serotonin transporter occupancy (relevant for antidepressant effects), to establish whether an agent reaches and to what extent it affects a specific target in the brain. In the future, biomarkers are likely to become an integral component of psychiatric treatment, providing information concerning a patient’s odds of developing an illness, diagnosis, severity of illness, and level of response to therapeutic interventions. The second part of this series will discuss research on derivatives of the inflammatory biomarker thromboxane and depression. (Journal of Psychiatric Practice 2012;18:118–121)

The adjunctive use of metformin to treat or prevent atypical antipsychotic-induced weight gain: a review.

Patients with schizophrenia have a greater incidence of being overweight or obese compared with the general population. Such individuals are often treated with second-generation (atypical) antipsychotics (SGAs), which are associated with weight gain, dyslipidemia, and other metabolic derangements. As a result, frequent monitoring of weight and other metabolic parameters is recommended. In addition, several pharmacologic strategies to help prevent or reduce SGA-induced weight gain have been proposed. Despite this, clinicians often struggle to manage obesity and metabolic issues in such patients. Metformin has attracted attention as a potential treatment option because it is thought to result in weight reduction and improved glycemic control in obese patients with and without type 2 diabetes mellitus. This article focuses on relevant pharmacologic aspects of metformin and reviews currently available evidence on the use of metformin as an augmentation agent for the treatment or prevention of SGA-induced weight gain.

Twenty percent of a representative sample of patients taking bupropion have abnormal, asymptomatic electroencephalographic findings.

The risk of dose-dependent seizures is a safety issue with bupropion hydrochloride. To evaluate the presence of specific electroencephalographic (EEG) waveforms, 210 adult subjects taking stable doses of bupropion hydrochloride were recruited to undergo 2 EEGs in a prospective, single-center cohort study. The occurrence of spike waves, sharp waves, and focal slowing was recorded and assessed with a continuation ratio logit model for polytomous responses. This model showed that there was a relationship between sex and the incidence of these waveforms, such that the odds of female subjects having sharp waves was increased by a factor of 2.53 (P = 0.05) when compared with male subjects and controlled for both age and dose. Similarly, female subjects were 2.45 (P = 0.09) times more likely than males to have focal slowing on EEG. Overall, 19.8% (39/197) of this representative population was found to have abnormal, asymptomatic EEG findings. The presence of these waveforms in individuals taking a medication known to lower the seizure threshold may be a risk factor for developing seizures.

Duloxetine for the treatment of generalized anxiety disorder: a review.

Approximately 16 million people in the United States suffer from anxiety disorders alone, while another 12 million experience both anxiety and at least one other psychiatric condition. Generalized anxiety disorder (GAD) has lifetime prevalence rates between 5% and 6%. Treatment of GAD is aimed primarily at symptom reduction. Duloxetine, a serotonin norepinephrine reuptake inhibitor (SNRI), received Food and Drug Administration (FDA) approval for the treatment of GAD in 2007. This article reviews the pharmacologic profile and seminal clinical trials associated with the FDA indication of duloxetine for GAD. A literature search performed using PubMed with the keywords “duloxetine”, “gad”, “generalized anxiety disorder”, and “venlafaxine XR” yielded 27 articles. We also focused on papers that pooled data from these seminal studies. Data on file from Eli Lilly were also reviewed, including data from the Eli Lilly website. Based on this search, duloxetine was found to be an FDA-approved treatment option for GAD that has been studied in several double-blind, placebo-controlled clinical trials. This review of duloxetine will help physicians to interpret clinical studies properly and also help them to make an informed decision about which patients are the most appropriate candidates for a trial of duloxetine.

Phase I trials: from traditional to newer approaches part II.

Phase I clinical trials have traditionally been focused on populations of normal healthy volunteers with the goal of determining the safety, tolerability, and pharmacokinetic profile of new investigational agents. As CNS drug development shifts its focus to the development of novel molecular entities, this approach will undergo an evolution. In this first part of a two-part series, the authors describe the traditional Phase I approach as well as challenges facing CNS drug development. The second half of the series will propose modifications to the traditional phase I design, including the incorporation of different populations, bio-marker surrogates, and adaptive designs.

How biomarkers will change psychiatry. Part II: Biomarker selection and potential inflammatory markers of depression.

Part I of this series defined biomarkers and discussed their current use in general medicine and their potential research and clinical utility in psychiatry. In this second column in the series, the authors first discuss the rationale for selecting a biomarker. The second half of the column discusses the potential use of inflammatory biomarkers in depression, with a specific focus on derivatives of the inflammatory biomarker, thromboxane, to illustrate how biomarkers can be developed for use in clinical practice. In the future, biomarkers are likely to become an integral component of psychiatric treatment, providing information about a patient’s odds of developing an illness, the severity of illness, and level of response to therapeutic interventions. (Journal of Psychiatric Practice 2012;18:281–286)

Introduction of the DSM-5 Levels of Personality Functioning Questionnaire.

With the introduction in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) of a hybrid system of personality disorder assessment, the ability to assess patients’ traits, as well as their level of personality functioning, has become increasingly important. To assess this criterion, the DSM-5 Levels of Personality Functioning Questionnaire (DLOPFQ) was developed. The DLOPFQ assesses individuals’ self-impairments and other impairments in several domains (self-direction, identity, empathy, and intimacy) and across 2 contexts (work/school and relationships). A sample of 140 psychiatric and medical outpatients was administered the DLOPFQ and several other measures to assess its reliability and construct, incremental, and discriminant validity. The internal consistency and convergence with validation measures yielded generally meaningful and expected results. Several DLOPFQ scales and subscales were significantly correlated with measures of DSM-5 trait domains and levels of personality functioning. DLOPFQ scales also correlated with self-reported ratings of overdependence, detachment, healthy dependency, and overall mental health and well-being. The DLOPFQ also predicted interpersonal and general functioning beyond DSM-5 trait domains. These results support the reliability and validity of the DLOPFQ, which appears to be suitable for clinical use and warrants ongoing study.

How commonly used inclusion and exclusion criteria in antidepressant registration trials affect study enrollment

In clinical trials, each specific inclusion and exclusion criterion eliminates a percentage of the potentially eligible population from trial participation and thus increases the time and effort needed for enrollment in a study. Drug developers often do not have data on how these criteria affect the pool of potentially eligible subjects for their trials and, hence, they cannot factor in the impact of these criteria when designing a study and planning the time needed to complete it. Consequently, drug developers often have ambitious timelines that are unrealistic and can lead to actions that may interfere with the ability to separate the efficacy of drug versus placebo. To investigate the effects of inclusion and exclusion criteria on study enrollment, the authors quantified the effects of the inclusion and exclusion criteria commonly used in antidepressant registration trials (ARTs) by applying these criteria to the population treated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. In essence, the STAR*D study population was used as a surrogate for the general population of individuals with major depressive disorder. The effect of each criterion commonly used in ARTs was assessed in terms of the percentage of the STAR*D population that would have been excluded individually and collectively (ie, when all criteria were applied at once). For continuous criteria such as age and severity of depression, the resulting effects have been presented graphically. Collectively, the typical inclusion and exclusion criteria used in ARTs would have eliminated at least 82% of the STAR*D population. This result means that more than 5 times the number of subjects would have to be screened to find a population that would meet the typical inclusion and exclusion criteria for an ART, directly determining the screening effort required in terms of both resources and time. Thus, developers of antidepressant drugs can use the data from this study to plan the recruitment effort required and to weigh any potential benefit of each criterion alone and in aggregate versus their cost in terms of recruitment support and time. These data also graphically illustrate for prescribers how restrictive the population likely to be enrolled in ARTs is relative to the patients whom they treat with such medications.

Determining Whether a Definitive Causal Relationship Exists Between Aripiprazole and Tardive Dyskinesia and/or Dystonia in Patients With Major Depressive Disorder, Part 2: Preclinical and Early Phase Human Proof of Concept Studies.

This series of columns has 3 main goals: (1) to explain class warnings as used by the United States Food and Drug Administration, (2) to increase awareness of movement disorders that may occur in patients treated with antipsychotic medications, and (3) to understand why clinicians should refrain from immediately assuming a diagnosis of tardive dyskinesia/dystonia (TD) in patients treated with antipsychotics. The first column in this series began with the case of a 76-year-old man with major depressive disorder who developed orofacial dyskinesias while being treated with aripiprazole as an antidepressant augmentation strategy. It was alleged that a higher than intended dose of aripiprazole (ie, 20u2009mg/d for 2u2009wk followed by 10u2009mg/d for 4u2009wk instead of the intended dose of 2u2009mg/d) was the cause of the dyskinetic movements in this man, and the authors were asked to review the case and give their opinion. The principal basis for this theory of causation was the class warning about TD in the package insert for aripiprazole. The rationale for concluding aripiprazole caused TD in the 76-year-old man led to this series of columns about aripiprazole, its potential—if any—to cause TD, and the presence of a class warning about TD in its package insert. The central point is to illustrate why class warnings exist and their implications for practice. The first column in this series focused on the historical background, incidence, prevalence, risk factors, and clinical presentations of tardive and spontaneous dyskinesias and concluded with a discussion of diagnostic considerations explaining why clinicians should avoid making a diagnosis of TD until a thorough differential diagnosis has been considered. This second column in the series reviews the pharmacology of aripiprazole and the preclinical and phase I translational human studies that suggest aripiprazole should have a low to nonexistent risk of causing TD compared with other antipsychotics. The third column in the series will review the systematic clinical trial data and “real-world” data on TD and the use of aripiprazole as adjunctive treatment with antidepressants for major depressive disorder to see whether these data support the conclusion of a low to nonexistent relationship between aripiprazole treatment and the development of TD. The fourth and final column in the series will consider the type of study that would need to be performed to avoid a specific class warning, focusing on the TD class warning as an example and discussing why such studies are rarely done.