Opinions Regarding Benzodiazepine Teaching and Prescribing Among Trainees in Psychiatry.

OBJECTIVES: Benzodiazepines are widely prescribed for a variety of symptoms and illnesses. There has been limited investigation on the training psychiatry residents receive regarding benzodiazepine prescribing. This study surveyed US psychiatric trainees about their didactic and clinical experience with benzodiazepines, investigating how experience with benzodiazepines may shape trainees' opinions and likelihood to prescribe. METHODS: The 14-question online survey was distributed to residents and fellows at US training programs through an invitation from their training directors. RESULTS: Of 466 programs contacted, with an estimated 1345 trainees, a total of 97 programs (20.8%) and 424 trainees (31.5%) responded. The analyses focused only on the 342 general psychiatry trainees who responded. Most trainees reported having formal didactics on benzodiazepines, and earlier training was correlated with higher trainee quality of instruction assessments (p < 0.01). Most trainees rated their instructors as Above or Well Above Average. Trainees cited the observation and opinion of supervisors as the two most important factors affecting likelihood of future benzodiazepine prescribing. Trainees commonly reported pressure from patients to prescribe benzodiazepines but were split on perceived pressure from supervisors about prescribing and whether a bias exists against prescribing at their program or in general. CONCLUSION: The survey indicated that psychiatry trainees generally feel adequately trained through didactic and clinical experience with benzodiazepines. Trainees perceived pressure by patients to prescribe benzodiazepines, but generally felt comfortable in managing benzodiazepine usage. Psychiatry attendings' opinions on benzodiazepines most impacted trainees. Influences on trainees' prescribing patterns are important variables that can impact future benzodiazepine prescribing.

The Significance of the Default Mode Network (DMN) in Neurological and Neuropsychiatric Disorders: A Review.

The relationship of cortical structure and specific neuronal circuitry to global brain function, particularly its perturbations related to the development and progression of neuropathology, is an area of great interest in neurobehavioral science. Disruption of these neural networks can be associated with a wide range of neurological and neuropsychiatric disorders. Herein we review activity of the Default Mode Network (DMN) in neurological and neuropsychiatric disorders, including Alzheimer's disease, Parkinson's disease, Epilepsy (Temporal Lobe Epilepsy - TLE), attention deficit hyperactivity disorder (ADHD), and mood disorders. We discuss the implications of DMN disruptions and their relationship to the neurocognitive model of each disease entity, the utility of DMN assessment in clinical evaluation, and the changes of the DMN following treatment.

First-Episode of Synthetic Cannabinoid-Induced Psychosis in a Young Adult, Successfully Managed with Hospitalization and Risperidone.

Synthetic cannabinoids- (SCs-) induced psychosis is a growing public health concern. It leads to significant impairment, including emotional distress, difficulty communicating, and other debilitating symptoms. In this case report, we discuss a patient with no previous history of psychotic symptoms, presenting with first-episode psychosis in the context of progressive, acutely worsening, disorganized, psychotic thoughts and behaviors following prolonged use of SCs. We also discuss relevant literature on SCs-induced psychosis, highlighting its prevalence, presentation, diagnosis, and recommended management. It is important to diagnose and treat SCs-induced psychosis as early and efficiently as possible, in order to alleviate symptoms while limiting functional impairment and emotional distress to the patient.

The impact of simulated patient death on medical students' stress response and learning of ACLS.

INTRODUCTION: There is considerable controversy as to whether the simulator should die during high-fidelity simulation (HFS). We sought to describe the physiologic and biochemical stress response induced by simulated patient death as well as the impact on long-term retention of Advanced Cardiovascular Life Support (ACLS) knowledge and skills. METHODS: Twenty-six subjects received an American Heart Association (AHA) ACLS provider course. Following the course, subjects participated in HFS and were randomized to simulated death or survival. Heart rate and salivary cortisol (SC) and dihydroepiandrosterone (DHEA) were collected at this time. Subjects returned six months later for a follow-up simulation in which ACLS knowledge and skills were tested. RESULTS: For all participants, there was an increase in heart rate during simulation compared with baseline heart rate (+ 32 beats/minute), p < 0.0001. Similarly, SC and DHEA were higher compared with baseline levels (+ 0.115 µg/dL, p <0.01 and + 97 pg/mL, p < 0.001, respectively). However, the only statistically significant difference between groups was an increase in heart rate response at the end of the simulation compared with baseline in the death group (+ 29.2 beats/minute versus + 18.5 beats/minute), p < 0.05. There was no difference on long-term knowledge or skills. CONCLUSIONS: Learners experience stress during high-fidelity simulation; however, there does not appear to be a readily detectable difference or negative response to a simulated patient death compared with simulated survival.

Elevated prefrontal cortex GABA in patients with major depressive disorder after TMS treatment measured with proton magnetic resonance spectroscopy.

BACKGROUND: GABAergic and glutamatergic neurotransmitter systems are central to the pathophysiology of depression and are potential targets of repetitive transcranial magnetic stimulation (rTMS). We assessed the effect of 10-Hz rTMS over the left dorsolateral prefrontal cortex (DLPFC) of patients with major depressive disorder on the levels of medial prefrontal cortex (MPFC) γ-aminobutyric acid (GABA) and the combined resonance of glutamate and glutamine (Glx) as assessed in vivo with proton magnetic resonance spectroscopy ((1)H MRS). METHODS: Currently depressed individuals between the ages of 23 and 68 years participated in a 5-week naturalistic, open-label treatment study of rTMS, with (1)H MRS measurements of MPFC GABA and Glx levels at baseline and following 5 weeks of the rTMS intervention. We applied rTMS pulses over the left DLPFC at 10 Hz and 80%-120% of motor threshold for 25 daily sessions, with each session consisting of 3000 pulses. We assessed therapeutic response using the 24-item Hamilton Rating Scale for Depression (HAMD24). The GABA and Glx levels are expressed as ratios of peak areas relative to the area of the synchronously acquired and similarly fitted unsuppressed voxel water signal (W). RESULTS: Twenty-three currently depressed individuals (7 men) participated in the study. GABA/W in the MPFC increased 13.8% (p = 0.013) in all depressed individuals. There were no significant effects of rTMS on Glx/W. GABA/W and Glx/W were highly correlated in severely depressed patients at baseline but not after TMS. LIMITATIONS: The primary study limitations are the open-label design and the inclusion of participants currently taking stable regimens of antidepressant medications. CONCLUSION: These results implicate GABAergic and glutamatergic systems in the mechanism of action of rTMS for major depression, warranting further investigation in larger samples.

Adolescent catatonia successfully treated with Lorazepam and aripiprazole.

Catatonia is especially concerning in children and adolescents. It leads to significant impairment, including emotional distress, difficulty communicating, and other debilitating symptoms. In this case report, we discuss a patient with no previous history of neuroleptic medication or psychotic symptoms, presenting with first-episode catatonia in the presence of disorganized, psychotic thoughts. We then review the catatonia syndrome, citing examples in the literature supporting its underdiagnosis in children and adolescents, and discuss successful treatment modalities. It is important to diagnose and treat catatonia as efficiently as possible, to limit functional and emotional distress to the patient.

Obsessive-compulsive disorder.

This article reviews the clinical features and neurochemical hypotheses of obsessive-compulsive disorder (OCD) with a focus on the serotonin system. In DSM-5, OCD was moved from the anxiety disorders to a new category of Obsessive-Compulsive and Related Disorders. OCD is a common, typically persistent disorder marked by intrusive and disturbing thoughts (obsessions) and repetitive behaviors (compulsions) that the person feels driven to perform. The preferential efficacy of serotonin reuptake inhibitors (SRIs) in OCD led to the so-called serotonin hypothesis. However, direct support for a role of serotonin in the pathophysiology (e.g., biomarkers in pharmacological challenge studies) of OCD remains elusive. A role of the glutamatergic system in OCD has been gaining traction based on imaging data, genomic studies and animal models of aberrant grooming behavior. These findings have spurred interest in testing the efficacy of medications that modulate glutamate function. A role of glutamate is compatible with circuit-based theories of OCD.

Neuromodulation for obsessive-compulsive disorder.

Neuromodulation shows increasing promise in the treatment of psychiatric disorders, particularly obsessive-compulsive disorder (OCD). Development of tools and techniques including deep brain stimulation, transcranial magnetic stimulation, and electroconvulsive therapy may yield additional options for patients who fail to respond to standard treatments. This article reviews the motivation for and use of these treatments in OCD. We begin with a brief description of the illness followed by discussion of the circuit models thought to underlie the disorder. These circuits provide targets for intervention. Basal ganglia and talamocortical pathophysiology, including cortico-striato-thalamo-cortical loops is a focus of this discussion. Neuroimaging findings and historical treatments that led to the use of neuromodulation for OCD are presented. We then present evidence from neuromodulation studies using deep brain stimulation, electroconvulsive therapy, and transcranial magnetic stimulation, with targets including nucleus accumbens, subthalamic nucleus inferior thalamic peduncle, dorsolateral prefrontal cortex, supplementary motor area, and orbitofrontal cortex. Finally, we explore potential future neuromodulation approaches that may further refine and improve treatment.

A randomized controlled trial of intranasal ketamine in major depressive disorder.

BACKGROUND: The N-methyl-D-aspartate glutamate receptor antagonist ketamine, delivered via an intravenous route, has shown rapid antidepressant effects in patients with treatment-resistant depression. The current study was designed to test the safety, tolerability, and efficacy of intranasal ketamine in patients with depression who had failed at least one prior antidepressant trial. METHODS: In a randomized, double-blind, crossover study, 20 patients with major depression were randomly assigned, and 18 completed 2 treatment days with intranasal ketamine hydrochloride (50 mg) or saline solution. The primary efficacy outcome measure was change in depression severity 24 hours after ketamine or placebo, measured using the Montgomery-Åsberg Depression Rating Scale. Secondary outcomes included persistence of benefit, changes in self-reports of depression, changes in anxiety, and proportion of responders. Potential psychotomimetic, dissociative, hemodynamic, and general adverse effects associated with ketamine were also measured. RESULTS: Patients showed significant improvement in depressive symptoms at 24 hours after ketamine compared to placebo (t = 4.39, p < .001; estimated mean Montgomery-Åsberg Depression Rating Scale score difference of 7.6 ± 3.7; 95% confidence interval, 3.9-11.3). Response criteria were met by 8 of 18 patients (44%) 24 hours after ketamine administration compared with 1 of 18 (6%) after placebo (p = .033). Intranasal ketamine was well tolerated with minimal psychotomimetic or dissociative effects and was not associated with clinically significant changes in hemodynamic parameters. CONCLUSIONS: This study provides the first controlled evidence for the rapid antidepressant effects of intranasal ketamine. Treatment was associated with minimal adverse effects. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with major depression.

In vivo (1)H MRS study of potential associations between glutathione, oxidative stress and anhedonia in major depressive disorder.

Inflammation and oxidative stress are important mechanisms that have been implicated in the pathophysiology of major depressive disorder (MDD). Glutathione (GSH) is the most abundant antioxidant in human tissue, and a key index of antioxidant capacity and, hence, of oxidative stress. The aims of this investigation were to examine possible relationships between occipital GSH and dimensional measures of depressive symptom severity, including anhedonia - the reduced capacity to experience pleasure - and fatigue. We hypothesized that the magnitude of anhedonia and fatigue will be negatively correlated with occipital GSH levels in subjects with MDD and healthy controls (HC). Data for eleven adults with MDD and ten age- and sex-matched HC subjects were included in this secondary analysis of data from a previously published study. In vivo levels of GSH in a 3cm×3cm×2cm voxel of occipital cortex were obtained by proton magnetic resonance spectroscopy ((1)H MRS) on a 3T MR system, using the standard J-edited spin-echo difference technique. Anhedonia was assessed by combining interest items from depression and fatigue rating scales, and fatigue by use of the multidimensional fatigue inventory. Across the full sample of participants, anhedonia severity and occipital GSH levels were negatively correlated (r=-0.55, p=0.01). No associations were found between fatigue severity and GSH in this sample. These preliminary findings are potentially consistent with a pathophysiological role for GSH and oxidative stress in anhedonia and MDD. Larger studies in anhedonic depressed patients are indicated.

Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial.

IMPORTANCE: Few pharmacotherapies have demonstrated sufficient efficacy in the treatment of posttraumatic stress disorder (PTSD), a chronic and disabling condition. OBJECTIVE: To test the efficacy and safety of a single intravenous subanesthetic dose of ketamine for the treatment of PTSD and associated depressive symptoms in patients with chronic PTSD. DESIGN, SETTING, AND PARTICIPANTS: Proof-of-concept, randomized, double-blind, crossover trial comparing ketamine with an active placebo control, midazolam, conducted at a single site (Icahn School of Medicine at Mount Sinai, New York, New York). Forty-one patients with chronic PTSD related to a range of trauma exposures were recruited via advertisements. INTERVENTIONS: Intravenous infusion of ketamine hydrochloride (0.5 mg/kg) and midazolam (0.045 mg/kg). MAIN OUTCOMES AND MEASURES: The primary outcome measure was change in PTSD symptom severity, measured using the Impact of Event Scale-Revised. Secondary outcome measures included the Montgomery-Asberg Depression Rating Scale, the Clinical Global Impression-Severity and -Improvement scales, and adverse effect measures, including the Clinician-Administered Dissociative States Scale, the Brief Psychiatric Rating Scale, and the Young Mania Rating Scale. RESULTS: Ketamine infusion was associated with significant and rapid reduction in PTSD symptom severity, compared with midazolam, when assessed 24 hours after infusion (mean difference in Impact of Event Scale-Revised score, 12.7 [95% CI, 2.5-22.8]; P = .02). Greater reduction of PTSD symptoms following treatment with ketamine was evident in both crossover and first-period analyses, and remained significant after adjusting for baseline and 24-hour depressive symptom severity. Ketamine was also associated with reduction in comorbid depressive symptoms and with improvement in overall clinical presentation. Ketamine was generally well tolerated without clinically significant persistent dissociative symptoms. CONCLUSIONS AND RELEVANCE: This study provides the first evidence for rapid reduction in symptom severity following ketamine infusion in patients with chronic PTSD. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with this disabling condition. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00749203.

Increased metabolic activity in the septum and habenula during stress is linked to subsequent expression of learned helplessness behavior.

Uncontrollable stress can have a profound effect on an organism's ability to respond effectively to future stressful situations. Behavior subsequent to uncontrollable stress can vary greatly between individuals, falling on a spectrum between healthy resilience and maladaptive learned helplessness. It is unclear whether dysfunctional brain activity during uncontrollable stress is associated with vulnerability to learned helplessness; therefore, we measured metabolic activity during uncontrollable stress that correlated with ensuing inability to escape future stressors. We took advantage of small animal positron emission tomography (PET) and 2-deoxy-2[(18)F]fluoro-D-glucose ((18)FDG) to probe in vivo metabolic activity in wild type Sprague Dawley rats during uncontrollable, inescapable, unpredictable foot-shock stress, and subsequently tested the animals response to controllable, escapable, predictable foot-shock stress. When we correlated metabolic activity during the uncontrollable stress with consequent behavioral outcomes, we found that the degree to which animals failed to escape the foot-shock correlated with increased metabolic activity in the lateral septum and habenula. When used a seed region, metabolic activity in the habenula correlated with activity in the lateral septum, hypothalamus, medial thalamus, mammillary nuclei, ventral tegmental area, central gray, interpeduncular nuclei, periaqueductal gray, dorsal raphe, and rostromedial tegmental nucleus, caudal linear raphe, and subiculum transition area. Furthermore, the lateral septum correlated with metabolic activity in the preoptic area, medial thalamus, habenula, interpeduncular nuclei, periaqueductal gray, dorsal raphe, and caudal linear raphe. Together, our data suggest a group of brain regions involved in sensitivity to uncontrollable stress involving the lateral septum and habenula.

Low-dose right unilateral electroconvulsive therapy (ECT): effectiveness of the first treatment.

BACKGROUND: Electroconvulsive therapy (ECT) is a widely used, highly effective antidepressant treatment. Except for the most severely ill patients, right unilateral (RUL) electrode placement is the most frequent initial treatment choice. In current practice, RUL ECT is administered at several multiples of seizure threshold (ST) based on reports that lower stimulus intensity results in lower response/remission rates. Many patients, as part of an initial dose titration to determine ST, will receive a single treatment with low-dose RUL ECT and subsequent treatments with a stimulus at a multiple of ST. OBJECTIVE: To assess response to the first ECT. METHODS: A retrospective analysis of charts from clinical practice at Mount Sinai Medical Center was performed. RESULTS: A single treatment with low-dose (presumably near ST) RUL ECT had a significant and immediate antidepressant effect in our sample of patients with major depression. We determined that this response is similar to that of patients receiving a single initial treatment with high-dose RUL ECT (at a multiple of ST). CONCLUSIONS: These data suggest, contrary to commonly held belief, that RUL ECT may be effective at a low stimulus dose. This argues against restimulating at 6 times ST in the initial session, based on the belief that the near-threshold seizure has no antidepressant efficacy. Our findings suggest a need for further investigation of cases in which low-dose RUL ECT may be an effective antidepressant treatment. Further prospective studies, including larger numbers of patients who receive randomized treatment with low- or high-dose RUL with longer follow-up, are indicated.

History of psychosurgery: a psychiatrist's perspective.

Interest in using neuromodulation to treat psychiatric disorders is rapidly increasing. The development of novel tools and techniques, such as deep brain stimulation (DBS), increases precision and minimizes risk. This article reviews the history of psychosurgical interventions and recent developments of DBS to provide a framework for understanding current options and future goals. We begin by discussing early approaches to psychosurgery, focusing on the widespread use of lobotomy and the subsequent backlash from the public and professionals in the field. Next, we discuss the development of stereotaxis. This technique allows for more targeted, precise interventions that produce discrete subcortical lesions. We focus on four stereotactic procedures that were developed using this technique: cingulotomy, capsulotomy, subcaudate tractotomy, and limbic leucotomy. We subsequently review contemporary theory and approaches with relevance to psychosurgery. We discuss the systems and neurocircuitry that are thought to be involved in psychiatric illness and provide targets for intervention. This discussion includes presentation of basal ganglia thalamocortical pathophysiology including cortico-striato-thalamo-cortical loops. We focus the discussion on two psychiatric disorders that have been targets of neurosurgical interventions: obsessive-compulsive disorder and mood disorders such as major depressive disorder. Evidence from studies of DBS in psychiatric disorders, including efficacy and tolerability, is reviewed. Finally, we look to the future, exploring the possibilities for these approaches to increase understanding, transform societal views of mental illness, and improve treatment.

Transgenic expression of ZBP1 in neurons suppresses cocaine-associated conditioning.

To directly address whether regulating mRNA localization can influence animal behavior, we created transgenic mice that conditionally express Zipcode Binding Protein 1 (ZBP1) in a subset of neurons in the brain. ZBP1 is an RNA-binding protein that regulates the localization, as well as translation and stability of target mRNAs in the cytoplasm. We took advantage of the absence of ZBP1 expression in the mature brain to examine the effect of expressing ZBP1 on animal behavior. We constructed a transgene conditionally expressing a GFP-ZBP1 fusion protein in a subset of forebrain neurons and compared cocaine-cued place conditioning in these mice versus noninduced littermates. Transgenic ZBP1 expression resulted in impaired place conditioning relative to nonexpressing littermates, and acutely repressing expression of the transgene restored normal cocaine conditioning. To gain insight into the molecular changes that accounted for this change in behavior, we identified mRNAs that specifically immunoprecipitated with transgenic ZBP1 protein from the brains of these mice. These data suggest that RNA-binding proteins can be used as a tool to identify the post-transcriptional regulation of gene expression in the establishment and function of neural circuits involved in addiction behaviors.

Brain stimulation in posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is a complex, heterogeneous disorder that develops following trauma and often includes perceptual, cognitive, affective, physiological, and psychological features. PTSD is characterized by hyperarousal, intrusive thoughts, exaggerated startle response, flashbacks, nightmares, sleep disturbances, emotional numbness, and persistent avoidance of trauma-associated stimuli. The efficacy of available treatments for PTSD may result in part from relief of associated depressive and anxiety-related symptoms in addition to treatment of core symptoms that derive from reexperiencing, numbing, and hyperarousal. Diverse, heterogeneous mechanisms of action and the ability to act broadly or very locally may enable brain stimulation devices to address PTSD core symptoms in more targeted ways. To achieve this goal, specific theoretical bases derived from novel, well-designed research protocols will be necessary. Brain stimulation devices include both long-used and new electrical and magnetic devices. Electroconvulsive therapy (ECT) and Cranial electrotherapy stimulation (CES) have both been in use for decades; transcranial magnetic stimulation (TMS), magnetic seizure therapy (MST), deep brain stimulation (DBS), transcranial Direct Current Stimulation (tDCS), and vagus nerve stimulation (VNS) have been developed recently, over approximately the past twenty years. The efficacy of brain stimulation has been demonstrated as a treatment for psychiatric and neurological disorders such as anxiety (CES), depression (ECT, CES, rTMS, VNS, DBS), obsessive-compulsive disorder (OCD) (DBS), essential tremor, dystonia (DBS), epilepsy (DBS, VNS), Parkinson Disease (DBS), pain (CES), and insomnia (CES). To date, limited data on brain stimulation for PTSD offer only modest guidance. ECT has shown some efficacy in reducing comorbid depression in PTSD patients but has not been demonstrated to improve most core PTSD symptoms. CES and VNS have shown some efficacy in reducing anxiety, findings that may suggest possible utility in relieving PTSD-associated anxiety. Treatment of animal models of PTSD with DBS suggests potential human benefit. Additional research and novel treatment options for PTSD are urgently needed. The potential usefulness of brain stimulation in treating PTSD deserves further exploration.

Diagnosis and treatment of major depressive disorder.

Major depressive disorder is a common illness, particularly in patients with medical and neurologic conditions. This article summarizes current data on the epidemiology, diagnosis, and treatment of major depression, with special emphasis on the diagnosis and treatment of depression in medical and neurologic patients. We reviewed the role of pharmacotherapies, psychotherapies, somatic treatments, and alternative remedies and we included practical advice for clinician regarding the timing and sequence of these treatments, the role of standardized depression scales, and the criteria for referrals to specialty consultants.