Innovations in Clinical Neuroscience

Objective: Major depressive disorder is often chronic, with relapse and recurrence common. Levomilnacipran extended-release is a potent and selective serotonin and reuptake inhibitor approved in the United States for treatment of major depressive disorder in adults. The objective of this study (NCT01085812) was to evaluate the efficacy, safety, and tolerability of levomilnacipran extended-release in the prevention of relapse in patients with major depressive disorder. Design: A 24-week Phase III randomized, double-blind, controlled trial comparing levomilnacipran extended-release 40-120mg/day with placebo for relapse prevention in patients with major depressive disorder who had responded to 12-week, open-label treatment with levomilnacipran extended-release. Statistical power was calculated on the assumption that 38 percent of placebo and 20 percent of levomilnacipran extended-release patients would relapse. Setting: Thirty-six outpatient study centers throughout the United States and Canada. Participants: Of 348 patients who met randomization criteria and entered double-blind treatment, three discontinued prior to treatment, 112 were randomized to placebo, and 233 to levomilnacipran extended-release. Measurements: Primary outcome: Time to relapse was analyzed using the Cox proportional hazard-regression model with treatment group and baseline Montgomery-Åsberg Depression Rating Scale score as explanatory variables. Safety was also evaluated. Results: Time to relapse was longer for levomilnacipran extended-release versus placebo (hazard ratio [95% confidence interval] = 0.68 [0.40][1.17]), but the treatment difference was not statistically significant (P=0.165). A relatively low percentage of patients from either group relapsed (placebo=20.5%, levomilnacipran extended-release=13.9%). Conclusion: This study did not detect between-treatment group differences, potentially due to lower than expected relapse rates in the placebo group. Levomilnacipran extended-release was generally well tolerated.
This case report describes a 13-year-old girl whose family requested a referral from the pediatrician for Child and Adolescent Mental Health Services in order to understand her recent onset of bizarre behavior. On assessment, she was found to have episodes of complex audiovisual hallucinations and panic attacks with intervals of complete recovery associated with episodes of migraine headaches. The "Alice in Wonderland Syndrome," which is intimately associated with migraine and epilepsy, as well as a number of other neurological conditions, could explain her episodic neurobehavioral disturbance.
Objective: No study has yet compared the efficacy of endoscopic thoracic sympathectomy for treating facial blushing with other treatment or no treatment. We conducted a prospective, observational, open-label, clinical study to compare endoscopic thoracic sympathectomy for blushing with generalized social anxiety disorder versus sertraline treatment and no treatment. Method: Three-hundred and thirty consecutive patients seeking treatment for their blushing were assessed by psychiatric interview and patient-rated scales. The Brief Social Phobia Scale was the primary outcome measure. Patients meeting Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition criteria for generalized social anxiety disorder, scoring 20 points or more in the Brief Social Phobia Scale and 19 points or more in the Social Phobia Inventory were considered eligible and followed up for a mean of 11 months (range 1-64) after endoscopic thoracic sympathectomy or initiation of sertraline. Results: At baseline, 97 percent of the endoscopic thoracic sympathectomy-treated group, 87 percent of the sertraline-treated group, and 78 percent of the nontreated group rated their blushing as being "severe" or "extreme." At follow up, 16 percent of endoscopic thoracic sympathectomy-treated patients, 32 percent of sertraline-treated patients, and 57 percent of untreated patients reported this degree of blushing. At endpoint, Brief Social Phobia Scale total scores exhibited a greater decline with either treatment than with no treatment. Nonetheless, in comparison to no treatment, only the results obtained with endoscopic thoracic sympathectomy achieved statistical significance (p=0.003). Compensatory sweating occurred in 99 percent of patients who underwent endoscopic thoracic sympathectomy. High degrees of satisfaction with treatment were reported by 89 percent of patients undergoing endoscopic thoracic sympathectomy and by 59 percent of patients taking medication. Conclusion: Endoscopic thoracic sympathectomy was associated to a greater reduction of blushing and Brief Social Phobia Scale scores, and higher degrees of satisfaction with treatment, in comparison to sertraline and no treatment.
Psychodynamic psychotherapy is effective for a variety of mental health symptoms. This form of psychotherapy uses patient self reflection and self examination, as well as the therapeutic relationship between the patient and psychiatrist, to explore maladaptive coping strategies and relationship patterns of the patient. A thorough understanding of resistance and the core conflictual relationship theme afford the psychiatrist the ability to facilitate this work. In this article, the composite case illustrates some of the psychodynamic psychotherapy techniques that can be employed in a psychotherapy case. In this example, the case is about a certified public accountant that came to treatment because of an acute stressor that put her career goals at risk. An acute episode or event can bring to light chronic and ongoing symptoms, which have had a remitting and relapsing course, and leave the patient unable to compensate on his or her own.
N-acetyl-cysteine, N-acetylcysteine, N-acetyl cysteine, and N-acetyl-L-cysteine are all designations for the same compound, which is abbreviated as NAC. NAC is a precursor to the amino acid cysteine, which ultimately plays two key metabolic roles. Through its metabolic contribution to glutathione production, cysteine participates in the general antioxidant activities of the body. Through its role as a modulator of the glutamatergic system, cysteine influences the reward-reinforcement pathway. Because of these functions, NAC may exert a therapeutic effect on psychiatric disorders allegedly related to oxidative stress (e.g., schizophrenia, bipolar disorder) as well as psychiatric syndromes characterized by impulsive/compulsive symptoms (e.g., trichotillomania, pathological nail biting, gambling, substance misuse). While the dosages, pharmacological strategies (monotherapy versus augmentation), and long-term risks are not fully evident, NAC appears to be a promising, relatively low-risk intervention. If so, NAC might be an ideal treatment strategy for a variety of psychiatric conditions in both psychiatric and primary care settings.
The United States Physician Payments Sunshine Act requires pharmaceutical and device manufacturers that participate in United States federal healthcare programs to report certain payments and items of value given to physicians and teaching hospitals. One of these "transfers of value" is the cost of expediting the preparation and publication of industry-sponsored journal articles with the use of outside editorial assistance. This can be problematic for those United Statesbased physician-authors whose home institutions have implemented policies to distance their faculty from pharmaceutical and device manufacturers. Potential strategies include using in-house editorial assistance when available, but transfers of value remain subject to further interpretation, and company policies are not uniform industrywide.
Mean (95% confidence interval) Positive and Negative Syndrome Scale total score during the first 36 days of treatment (last observation carried forward): intent-to-treat analysis set  
Demographic and other baseline characteristics of the ITT post-hoc analysis population
Mean (95% confidence interval) Clinical Global Impression-Severity Score during the first 36 days of treatment (last observation carried forward): intent-to-treat analysis set  
Percentage of patients who were classified as Positive and Negative Syndrome Scale responder during the first 36 days of treatment: intent-to-treat analysis set  
Objective: First-month data of a 13-week acute schizophrenia study were used to compare paliperidone palmitate to oral risperidone during initiation of long-acting injectable risperidone. Design: Double-blind, randomized study. Setting: Outpatient or inpatient. Participants: Adults with established (≥1 year) schizophrenia. Those assigned to risperidone long-acting injectable (n=460) received 25mg on Days 8 and 22 with oral risperidone (l-6mg) supplementation for the first 28 days. The paliperidone palmitate group (n=453) received 150mg eq. on Day 1, l00mg eq. on Day 8, and oral placebo supplementation for the first 28 days. Measurements: Positive and Negative Syndrome Scale, Personal and Social Performance Scale, Clinical Global Impression-Severity score, and responder rate (percentage of patients with ≥30% reduction in PANSS total score). An analysis of covariance model estimated least-square mean differences between treatment groups. A post-hoc analysis of efficacy data for the period of interest, i.e., at the time points before and after the first 28 days, was conducted. Results: Positive and Negative Syndrome Scale, Personal and Social Performance Scale, Clinical global Impression-Severity scores showed similar efficacy between the treatment groups during the first weeks of treatment, corresponding to the risperidone long-acting injection initiation period. Mean Positive and Negative Syndrome Scale total score at baseline was 84.7 for paliperidone palmitate and 84.4 for oral risperidone, on Day 22 was 73.6 and 74.1, respectively, and on Day 36 was 71.8 and 72.8, respectively. Overall incidence of adverse events in the first 28 days was generally similar (45% for paliperidone palmitate vs. 35% for oral risperidone), except for injection site pain (4.6% vs. 0.7%). Similar active moiety plasma concentrations were obtained during this period. Conclusion: During the first month, paliperidone palmitate without oral supplementation has similar efficacy and safety to oral risperidone (during initiation of risperidone long-acting injectable) in acutely exacerbated schizophrenia.
Steady-state, peak-to-trough fluctuation in plasma concentration over the recommended dosing interval. Peak-to-trough fluctuations were calculated as the ratio of mean C max to mean C min at the steady-state following administration according to the recommended dosing interval. Source data. 14,19–25 *Dose and injection site affect the pharmacokinetics (including peak-to-trough fluctuation) of paliperidone palmitate. Here the steady-state fluctuation of paliperidone palmitate 117mg was administered in the deltoid muscle. Administration of higher doses and/or gluteal administration may result in less steady-state, peak-to-trough fluctuation. Source data. 27,40,41  
Peak-to-trough methods of calculation and data source DRUG METHOD OF CALCULATION AND DATA SOURCE LAI medications
Key clinical studies used to obtain pharmacokinetic data
Background: Small peak-to-trough drug levels have been suggested to be related to improved tolerability. The aim of this study is to review the steady-state, peak-to-trough, plasma-concentration fluctuation of long-acting injectable antipsychotics and equivalent oral formulations. Methods: A review of published literature and clinical study reports identified references that reported, depicted, or permitted derivation of the steady-state, peak-to-trough, plasma-concentration fluctuation of antipsychotics (the ratio of maximum concentration to minimum concentration following administration according to the recommended dosing interval) over the dosing interval. Suitable references were identified for haloperidol decanoate, olanzapine pamoate, paliperidone palmitate, risperidone long-acting injectable, and zuclopenthixol decanoate and their oral equivalents except zuclopenthixol. The single-dose time to maximum plasma concentration (T(max)) and half-life (t(1/2)) were also identified. Results: The steady-state, peak-to-trough, plasma-concentration ratios of oral antipsychotics varied from 1.47 (paliperidone extended-release, once daily) to 3.30 (active-moiety risperidone, once daily). Among long-acting injectable antipsychotics, the ratios varied from 1.56 (paliperidone palmitate, once monthly) to approximately 4 (olanzapine pamoate, once every four weeks). Among drugs with similar dosing intervals, longer T(max) and/or t(1/2) generally correlated with less peak-to-trough fluctuation. Conclusion: Peak-to-trough fluctuations in plasma concentrations vary widely and may be affected by differences in dosing, pharmacokinetic sampling, subjects' phenotypes, concomitant medications, comorbid diseases, and formulation. These fluctuations may affect clinical response and tolerability. Along with other patient-specific and drug-specific factors, these fluctuations warrant consideration when selecting an antipsychotic and antipsychotic formulation. Further study is needed with more robust and generalizable peak-to-trough fluctuation data.
Patient accounting  
Patient demographics and baseline characteristics 
Investigator-rated assessments of mild injection-site reactions in Study 2 by reaction type at 2 hours post-injection STUDY 2 (N=53)
Mean patient-rated changes in injection-site pain values from baseline to 2 hours post-injection in Study 1 (100mm VAS scores) 
Background: Risperidone long-acting injectable was previously approved for treatment of schizophrenia as biweekly injections in the gluteal muscle only. We present data on local injection-site tolerability and safety of risperidone long-acting injectable and comparability of systemic exposure of deltoid versus gluteal injections. Methods: Risperidone long-acting injectable was administered in an open-label, single-dose, two-way crossover study, with patients randomized to receive either 25mg gluteal/37.5mg deltoid crossover in two treatment periods or 50mg gluteal/50mg deltoid injections crossover; each treatment period was separated by an 85-day observation period (Study 1) and an open-label, multiple-dose study (4 sequential 37.5mg or 50mg deltoid injections every 2 weeks) (Study 2). The pharmacokinetic results from both the studies have already been published. Results: In Study 1 (n=170), the majority of patients had no local injection-site findings, based on investigator and patient-rated evaluations. In Study 2 (n=53), seven of the 51 patients who received at least two deltoid injections discontinued (primary endpoint). However, none of the discontinuations were due to injection-site related reasons. The 90-percent upper confidence limit of the true proportion of injection-site issue withdrawals was 5.7 percent. No moderate or severe injection-site reactions were reported. Conclusion: Intramuscular injections via the deltoid and gluteal sites are equivalent routes of administration of risperidone long-acting injectable with respect to local injection-site tolerability. The overall safety and tolerability profile of risperidone long-acting injectable was comparable when administered as an intramuscular injection in the deltoid (37.5mg and 50mg) and gluteal (25mg and 50mg) sites.
The efficacy of antidepressant treatment of major depression remains a matter of controversy. A review of acute treatment studies suggests that for relatively more severe episodes of major depression, antidepressants are superior to treatment in the "placebo group;" however, there are numerous methodological confounds in the available literature. (Some recent, preliminary evidence suggests that antidepressants may also be of benefit in some less severely depressed populations).There is moderately strong evidence that, compared with placebo, maintenance antidepressant treatment reduces six-month relapse rates in major depression; however, it is less clear that antidepressants prevent actual recurrence of depression in the longer term. There is evidence of both over-use and under-use of antidepressant treatment, and there appears to be a "mismatch" between diagnosis and optimal treatment of depression in some clinical settings. Better designed studies are needed to resolve these uncertainties and to investigate such putative conditions as "oppositional tolerance" to long-term antidepressant treatment. The author advocates a conservative approach to antidepressant treatment, as well as a substantially extended "tapering" period when antidepressants are discontinued.
Baseline characteristics of included subjects (N=28)
Mean CGI-I scores over time. CGI:I scores: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse  
Participation by treatment day
Mean MADRS scores over time  
Percent of subjects experiencing adverse events reported by treatment group
Objective: When treating acute bipolar mania, the speed of onset of anti-manic effects is crucial. Quetiapine and divalproex ER are widely used agents to treat acute mania. Rapid dose administration regimens for divalproex ER and for quetiapine have been described. We conducted a naturalistic, head-to-head, pilot study comparing the efficacy and safety of rapidly titrated divalproex ER and quetiapine in acutely manic inpatients, with the primary outcome being improvement within the first seven days. Method: Thirty consenting bipolar patients with acute mania (Young Mania Rating Scale >17 ) needing hospitalization due to acute mania were randomized to receive rapidly loaded divalproex ER (30mg/kg/day) or rapidly titrated quetiapine (200mg Day 1, raised by 200mg/day up to 800mg as tolerated). Assessments were made on Day 1 (baseline), Day 3, Day 7, Day 14, and Day 21 and included Young Mania Rating Scale, Clinical Global Impressions-Severity, Clinical Global Impressions-Improvement, and Montgomery-Asberg Depression Rating Scale. Raters but not patients or treating physicians were blinded (single-blinded study). Results: Subjects in both treatment groups exhibited significant and rapid improvement in their mania starting at Day 3 with few significant adverse effects; however, there were no significant differences in the degree or rate of improvement between the two treatment groups in any of the efficacy or adverse effects scales. Conclusion: RESULTS of this small study indicate that rapid-dose administration of both quetiapine and divalproex ER produce rapid improvement in acute mania within the first seven days and both seem to be well tolerated.
Ketamine is an N-methyl-D- aspartate antagonist with rapid antidepressant effects. Research shows that ketamine has a fast onset of reduction in depressive symptoms and shows sustained remission of suicidal ideation in some patients. This article provides a brief review of the literature on the use of ketamine for depression and in acute cases of suicidality. The authors conclude that, while further investigation is needed, ketamine may be a useful treatment option for acute suicidality in emergency room settings.
This ongoing column is dedicated to providing information to our readers on managing legal risks associated with medical practice. We invite questions from our readers. The answers are provided by PRMS, Inc. (, a manager of medical professional liability insurance programs with services that include risk management consultation, education and onsite risk management audits, and other resources to healthcare providers to help improve patient outcomes and reduce professional liability risk. The answers published in this column represent those of only one risk management consulting company. Other risk management consulting companies or insurance carriers may provide different advice, and readers should take this into consideration. The information in this column does not constitute legal advice. For legal advice, contact your personal attorney. Note: The information and recommendations in this article are applicable to physicians and other healthcare professionals so "clinician" is used to indicate all treatment team members.
Groups who showed significant effect of training in ICC 
Unlabelled: GRID-HAMD is a semi-structured interview guide developed to overcome flaws in HAM-D, and has been incorporated into an increasing number of studies. Objectives: Carry out the transcultural adaptation of GRID-HAMD into the Brazilian Portuguese language, evaluate the inter-rater reliability of this instrument and the training impact upon this measure, and verify the raters' opinions of said instrument. Methods: The transcultural adaptation was conducted by appropriate methodology. The measurement of inter-rater reliability was done by way of videos that were evaluated by 85 professionals before and after training for the use of this instrument. Results: The intraclass correlation coefficient (ICC) remained between 0.76 and 0.90 for GRID-HAMD-21 and between 0.72 and 0.91 for GRID-HAMD-17. The training did not have an impact on the ICC, except for a few groups of participants with a lower level of experience. Most of the participants showed high acceptance of GRID-HAMD, when compared to other versions of HAM-D. Conclusion: The scale presented adequate inter-rater reliability even before training began. Training did not have an impact on this measure, except for a few groups with less experience. GRID-HAMD received favorable opinions from most of the participants.
A–D. Estimates of the dose-response as they were made available to the Data Monitoring Committee over time (Weeks 11, 13, 18, when the algorithm first recommended stopping the study, and Week 26, when all follow-up data had become available). The y-axis describes the change from Baseline to Day 28 on the total Positive and Negative Syndrome Scale (a decrease describes a benefit to the patient). The x-axis lists the different treatment arms, framing the 7 doses of study drug with placebo to the left and risperidone to the right. The first number in [ ] behind the treatment arm indicates the total number of patients with some available data, as used by the model; the second number indicates the number of patients with complete datasets—this is the dataset from which the mean observed (not model based) response was derived. The modeled dose response is shown in black (point estimate for mean response, including 95% confidence interval), and the dose-response curve is interpolated across all doses with available data. The observed (not model-based) data are shown in grey (point estimate for mean response and 95% confidence intervals), and the dose-response curve is interpolated across doses only if final data were available on at least one patient. As the dose-response model excludes the active comparator, the dose-response curve is not interpolated to risperidone. The evolution of information over time is illustrated by the time sequence shown in the figures.  
Summary of baseline patient characteristics by treatment group
Allocation of subjects to the different treatment arms over time. Note the initial burn-in period of 11 weeks, during which only a subset of doses of study drug was available.  
Number and percentage of patients who completed or discontinued from the study due to either tolerability/safety issues or lack of efficacy
Course of the weekly updated predictive probability of stopping early either for futility or success, as calculated by the algorithm and communicated to the Data Monitoring Committee (DMC). Note that the predictive probability of futility is high from the very start, due to the high placebo response. Eighteen weeks after first-subject-first-visit (FSFV), the DMC recommended stopping the study for futility (posterior probability of futility: 0.97), as only at this time point were all stopping criteria of the algorithm met, including having a minimum number of subjects on each treatment arm. Twenty-one weeks after FSFV, the DMC recommendation was endorsed by the Executive Sponsor Committee and recruitment into the study was stopped immediately thereafter.  
This paper uses a recently completed study to illustrate how adaptive trial designs can increase efficiency of psychiatric drug development. The design employed allowed a continuous reassessment of the estimated dose-response such that patients were randomized in a double-blind fashion to one of seven doses of the investigational drug, placebo, or active comparator. The study design also permitted early detection of futility allowing for early study termination. By using the adaptive trial design approach, only 202 patients were needed to make the determination of futility. In contrast, a conventional design would have required enrollment of 450 patients and considerably more time and expense to reach the same conclusion. Adaptive trial designs are important at this time when many pharmaceutical companies are abandoning the development of psychiatric medications because of the inefficiency of conventional approaches.
Adderall (dextroamphet-amine/amphetamine) is a psychostimulant medication approved by the United States Food and Drug Administration for the treatment of attention deficit hyperactivity disorder. This medication is usually well tolerated with minimal side effects. We report a case of a 12-year-old girl who was prescribed Adderall by her primary care physician to treat her attention deficit hyperactivity disorder and who subsequently developed trichotillomania. A short time following the initiation of the medication, the patient's family members noticed the patient displaying unusual hair-pulling behavior. The patient was referred to a psychiatrist for an evaluation of trichotillomania. Following a thorough evaluation, the decision was made to discontinue the Adderall and switch the patient to guanfacine. The urge to pull her hair along with her anxiety dissipated following this change. Close follow-up was maintained for over a year with both the psychiatrist and the primary care physician, and during this time the patient did not display any unusual hair pulling behaviors. This case appears to display a very unusual side effect of Adderall.
Chronic adrenal insufficiency, known as Addison's disease, presents with a constellation of symptoms and signs. The neuropsychiatric aspect of this condition is not fully understood and not much has been documented about it in the English literature. This article presents a case of a 41-year old male patient who presented initially with depression after a recent life stressor. After his condition escalated and therapy continued to fail, the medical team revised its diagnosis to Addison's disease. Neuropsychiatric symptoms could be the first presentation of Addison's disease, and thus should be kept in mind whenever such a case presents to the physician.
In between group difference for buprenorphine and buprenorphine/naloxone combination prescribed as OST for adherence based on urinalysis findings 
Objective: The objective of the current study was to explore the difference in treatment adherence to directly supervised buprenorphine and take-home buprenorphine/ naloxone combination for opioid substitution therapy. Urinalysis findings have been used to check treatment adherence on opioid substitution therapy agent. Additionally the study aimed to explore the misuse rate of buprenorphine/naloxone combination based on urinalysis findings. Design: Cross-sectional chart reviewSetting: Laboratory of a tertiary care drug dependence treatment centerParticipants: One-year laboratory urinalysis records of a tertiary care, drug-dependence treatment center in India were analyzed. All the urine samples of subjects on opioid substitution therapy with buprenorphine or buprenorphine/naloxone combination were included in the study. Measurements: Urinalysis using thin layer chromatography for buprenorphine and naloxone. In between group difference for treatment adherence on buprenorphine and buprenorphine/ naloxone combination was done using Mantel-Haenszel test. Results: A higher proportion of samples from subjects on buprenorphine/naloxone tested positive for buprenorphine as compared to subjects on buprenorphine. Twelve (7.6%) urine samples from patients on buprenorphine/naloxone tested positive for naloxone. Conclusions: The findings of the current study suggest that buprenorphine/naloxone combination has a higher adherence rate as compared to buprenorphine when used for opioid substitution therapy.
Depression is a relatively common clinical disorder and can be difficult to effectively treat according to findings from the Sequenced Treatment Alternatives to Relieve Depression study. Given this working terrain, patient adherence with antidepressant therapy is a critical aspect of effective clinical management. However, according to contemporary data (i.e., over the past 10 years), approximately 50 percent of psychiatric patients and 50 percent of primary care patients prematurely discontinue antidepressant therapy (i.e., are nonadherent when assessed at six-months after the initiation of treatment). The reasons behind patient nonadherence to antidepressants are varied and include both patient factors (e.g., concerns about side effects, fears of addiction, belief that these medications will not really address personal problems) as well as clinician factors (e.g., lack of sufficient patient education, poor follow-up). An awareness of the high rates of antidepressant nonadherence among patients hopefully will underscore to the prescriber the importance of carefully exploring patient concerns about these medications and closely monitoring patients while on therapy.
Bulimia nervosa is associated with bipolar disorder, substance dependence, attention-deficit hyperactivity disorder, and anxiety disorders. Few reports, however, have addressed the treatment of patients with all of these conditions. We describe a young woman with bulimia nervosa, bipolar I disorder, cocaine and alcohol dependence, attention-deficit hyperactivity disorder, and panic disorder who achieved a sustained (>1 year) remission of her bulimia nervosa symptoms and significant improvement of her attention-deficit hyperactivity disorder symptoms with adjunctive methylphenidate after her bipolar, substance use, and panic disorders were successfully treated with hospitalization, intensive psychotherapy, quetiapine, and lamotrigine. Further research into the use of stimulants in bulimia nervosa, including in patients with complex comorbidity, is required.
Hyperemesis gravidarum occurs in 0.3 to 10 percent of pregnant women, with a 0.8 percent hospital admission rate. While older theories supported the psychosocial model as a cause for hyperemesis gravidarum, more recent studies have shown significant data to support a biological etiology. Hyperemesis gravidarum has serious complications including include increased risk for miscarriage, low birth weight infants, dehydration, Wernicke's encephalopathy, secondary depression, and negative attitudes toward a consecutive pregnancy. Because of these life-threatening complications and complexity of the disease, it is important to treat both somatic and psychosocial causes of hyperemesis gravidarum to provide the best care for the patient. This paper presents a case of a woman with anxiety symptoms who was experiencing severe nausea and vomiting since Week 2 of pregnancy, with minimal reduction of these symptoms on standard medications utilized in hyperemesis gravidarum. The patient had marked reduction of nausea and vomiting with adjunctive gabapentin. After a brief review of relevant neurogastroenterology, we discuss a possible mechanism for the added gabapentin.
Objective: The purpose of this study was to determine if the drop in white blood cell/absolute neutrophil count for clozapine patients on antibiotics is a normal response to the resolution of infection or if the concurrent administration resulted in an abnormal drop in blood counts and further reduction of white blood cell/absolute neutrophil below baseline prior to infection. Design: This was a retrospective record review of all patients who received clozapine and antibiotics concurrently between June 30, 2010, and June 30, 2011. Setting: Subjects included inpatients on clozapine therapy at a state psychiatric facility. Participants: This protocol was approved by the Institutional Review Board of record. A total of 42 patients prescribed 93 antibiotic regimens were found to meet all of the above requirements. Measurements and methods: Medications were placed into distinct groups based on approved use and mechanism of action. Pearson Correlation Coefficients were utilized and were found to be 0.409 (p<0.01), indicating that a statistically significant relationship existed between the use of systemic antibiotics and alterations in hematologic parameters. Results: Each regimen was classified by specific agent as well as whether the final white blood cell/absolute neutrophil was above or below the baseline established for each patient. Conclusion: Antibiotics have been identified as one category of medications that may cause decreased white blood cell/absolute neutrophil counts when combined with clozapine. Our study supports the use of either ciprofloxacin or moxifloxacin as agents that may have less risk of reductions in white blood cell/absolute neutrophil counts than are seen with penicillins, cephalosporins, and other antibiotics that may ultimately require interruption or discontinuation of clozapine therapy.
The time course of plasma concentrations of various doses of atypical antipsychotics administered at steady state. The denotation "act" is the total active moiety of the antipsychotics. 
Fluctuation indices (peak-to trough fluctuations) calculated as the ratio of (C ss(max)-C ss(min) ) to C ss(ave) at steady-state according to the recommended dosing regimens. Data were collected from package inserts. 
Lower fluctuation, i.e., lower peak-to-trough plasma-concentration variation at steady-state pharmacokinetics, has several advantages for the treatment of schizophrenia with antipsychotics. The reduction of peak concentration can decrease the risk of dose-dependent side effects, such as extrapyramidal symptom and somnolence, and by contrast the increase in trough concentration can decrease the incidence of lack of efficacy due to subtherapeutic drug concentration. Using a one-compartment simulation technique with pharmacokinetic parameters of each atypical antipsychotic collected from package inserts, the fluctuation index was calculated. Among the antipsychotics, the indices varied from 0.018 to 1.9, depending on dosing regimens, formulations and several pharmacokinetic properties. The order of simulated fluctuation index is active-moiety aripiprazole (b.i.d.) <paliperidone extended release (q.d.) <active-moiety aripiprazole (q.d.) <active-moiety blonanserin (b.i.d.) <olanzapine (q.d.) <active-moiety risperidone (b.i.d.) <amisulpride (q.d.) <active-moiety risperidone (q.d.) <quetiapine (t.i.d.) <perospirone (t.i.d.) <quetiapine (b.i.d.). Since the fluctuation indices of aripiprazole and paliperidone extended-release are less than 0.2, which predominantly attributed to their long elimination half-lives, aripiprazole and paliperidone extended-release may have advantages in that the plasma concentration could be kept within appropriate therapeutic range.
The death of a young patient is a difficult but universal experience in the field of medicine. It is less common in the field of child and adolescent psychiatry. However, when a child or adolescent patient commits suicide, a child and adolescent psychiatry trainee's response could include shock, denial, disbelief, sadness, sleep difficulties, rumination about patient's death, fears of litigation, social withdrawal, and a sense of failure. Trainees generally find themselves dealing with the academic, personal, administrative, and legal consequences of this unfortunate but unavoidable event. This article attempts to review the literature on the experience of patients' unexpected death, including suicide, on child and adolescent psychiatry trainees.
Given the limited empirical data on antidepressant use and weight change in children, we performed a historical cohort study to assess change in age- and sex-standardized body mass index associated with antidepressant use among overweight adolescents diagnosed with a depressive disorder. We systematically reviewed electronic medical records from a tertiary academic medical center and identified adolescents (age 13-18 years) who were overweight (body mass index >85th percentile) and had a depression diagnosis. Patients were seen from January 1, 2000, through January 1, 2010. Age- and sex-standardized body mass index scores were calculated at initiation of antidepressant medication and at the end of treatment. Unmedicated patients had baseline and final age- and sex-standardized body mass index calculated using the first and last recorded measurements in the study period (maximum time between measures was 5 years). In total, 435 patients (301 female) met our inclusion criteria; of these, 255 were prescribed an antidepressant (selective serotonin reuptake inhibitor, serotonin norepinephrine reuptake inhibitor, tricyclic antidepressant, or dopamine-norepinephrine reuptake inhibitor). Age- and sex-standardized body mass index significantly increased (F1,193=14.34; P<0.001) only for adolescents treated with selective serotonin reuptake inhibitors. For patients receiving other medications or no medication, age- and sex-standardized body mass index did not change significantly. This study provides initial empiric evidence for a link between selective serotonin reuptake inhibitor use and weight gain in already overweight adolescents. Further study of antidepressant use and weight gain in other pediatric populations and in prospective studies is warranted.
Many psychopathology research assessment tools can be used easily and productively in clinical practice. We conducted a workshop in 2009 and 2010 at the American Psychiatric Association annual meeting designed to bring clinicians some commonly used adult research measures with broad applicability to a variety of conditions. This article reviews what was most helpful to the practicing clinicians at the workshop.
Objective: To evaluate the efficacy and safety of lisdexamfetamine dimesylate in participants with attention deficit hyperactivity disorder and a history of depression and/or substance use disorder. History of these comorbidities was recorded from medical history forms completed by the study clinicians. Design/setting: An exploratory, post-hoc analysis was conducted using data from a randomized, double-blind, placebo-controlled, forced-dose titration study of lisdexamfetamine dimesylate. Participants: Adults with attention deficit hyperactivity disorder. Measurements: Changes in Attention Deficit Hyperactivity Disorder Rating Scale IV total scores and Clinical Global Impressions-Improvement scale were used to evaluate the efficacy of lisdexamfetamine dimesylate. The incidence of treatment-emergent adverse events was also evaluated. Results: The intention-to-treat population included 36 participants with a history of depression and 17 participants with a history of substance use disorder. Mean changes in Attention Deficit Hyperactivity Disorder Rating Scale IV and Clinical Global Impressions-Improvement from baseline to endpoint for these subpopulations were similar to those of participants without a history of depression and/or history of substance use disorder. Lisdexamfetamine dimesylate was generally well tolerated in all subgroups. Conclusion: The response to lisdexamfetamine dimesylate and the treatment-emergent adverse event profiles of participants with a history of depression and/or a history of substance use disorder were similar to those of participants with no history of these disorders. Larger studies that prospectively enroll participants with attention deficit hyperactivity disorder and these comorbid disorders are needed to more conclusively evaluate the safety and efficacy of stimulant treatment in these populations.
Studies investigating QoL instruments in adult ADHD 
Studies of the impact of ADHD on QoL 
Studies of the impact of treatment on QoL of adults with ADHD 
Across all medical specialties, quality of life has become an important measure of outcomes in both research and clinical settings. However, to date, there has not been a systematic review of the research relevant to quality of life in populations with adult attention deficit hyperactivity disorder. We approach quality of life in adult attention deficit hyperactivity disorder by answering the following questions: 1) What specific metrics are used to assess quality of life in adult attention deficit hyperactivity disorder? 2) What is the impact of adult attention deficit hyperactivity disorder on quality of life? 3) What effects do attention deficit hyperactivity disorder treatments have on quality of life? Searches of major electronic databases were conducted, and reference lists from the identified articles were searched for additional studies, with a focus on studies that utilized quality of life measures. Thirty-six relevant studies are included in our review. There are multiple unique measures currently used to measure quality of life in adult attention deficit hyperactivity disorder, ranging from general quality of life scales to those specifically designed for use in attention deficit hyperactivity disorder. Attention deficit hyperactivity disorder was found to significantly worsen the quality of life in adults. Treatment with atomoxetine and mixed amphetamine salts has shown beneficial effects on quality of life even in cases without symptomatology improvement. Pharmacological treatment and early diagnosis have a positive impact on outcomes, longterm prognosis, and quality of life in adults with attention deficit hyperactivity disorder. Having multiple unique measures of quality of life have limited the direct comparison of different classes of attention deficit hyperactivity disorder medication treatments and future research should be aimed to address this.
Criteria for ADHD symptom clusters
Demographics and disposition by symptom cluster categories
TEAEs with overall incidence >5% 15
Vitals signs at baseline and endpoint 15
To evaluate the efficacy of lisdexamfetamine dimesylate in adults with attention deficit hyperactivity disorder symptom subtypes who exhibit predominantly inattention, hyperactivity/ impulsivity, or combined symptom clusters. This is a post-hoc analysis from a multicenter, one-year, open-label lisdexamfetamine dimesylate study in adults with attention deficit hyperactivity disorder previously completing two weeks or more in a four-week, randomized, placebo-controlled lisdexamfetamine dimesylate study, using Attention Deficit Hyperactivity Disorder Rating Scale IV symptom ratings as an attention deficit hyperactivity disorder subtype proxy (N=349).Measurements: Attention Deficit Hyperactivity Disorder Rating Scale IV was measured at baseline of prior study and throughout the open-label study. Proxy subtypes were based on item scores of 2 (moderate) or 3 (severe), representing endorsement of at least six of nine symptoms on respective subscales; predominantly combined type endorsed at least six of nine symptoms on each subscale. Overall safety evaluations included treatment-emergent adverse events. At baseline, 93 of 345 participants exhibited predominantly inattention, 13 predominantly hyperactivity/ impulsivity, 236 combined symptom clusters, and three were unassigned. For the three subgroups, respectively, mean (standard deviation) Attention Deficit Hyperactivity Disorder Rating Scale IV total scores at baseline were 34.5 (4.02), 33.8 (3.27), and 43.6 (5.24); change from baseline to endpoint scores were -19.3 (9.48), -24.0 (7.22), and -27.3 (11.78). Mean (standard deviation) end-of-study lisdexamfetamine dimesylate dose was 57.7 (14.75), 53.1 (16.01), and 56.9 (14.94)mg/day, respectively.Treatment-emergent adverse events (>5%) were upper respiratory tract infection (21.8%), insomnia (19.5%), headache (17.2%), dry mouth (16.6%), decreased appetite (14.3%), irritability (11.2%), anxiety (8.3%), nasopharyngitis (7.4%), sinusitis (6.6%), decreased weight (6.0%), back pain (5.4%), and muscle spasms (5.2%). Lisdexamfetamine dimesylate was effective in participants with predominantly inattention, hyperactivity/ impulsivity, and combined attention deficit hyperactivity disorder symptom clusters. Groups exhibiting specific predominant subtype symptoms did not differ in clinical response to lisdexamfetamine dimesylate.
Workplace bullying is defined as the repetitive and systematic engagement of interpersonally abusive behaviors that negatively affect both the targeted individual and the work organization. According to the findings of 12 studies, being bullied in the workplace affects approximately 11 percent of workers. Victims are frequently blue-collar and unskilled workers. However, there also appear to be gender and milieu/management factors. Emotional/psychological consequences of workplace bullying may include increased mental distress, sleep disturbances, fatigue in women and lack of vigor in men, depression and anxiety, adjustment disorders, and even work-related suicide. Medical consequences of workplace bullying may include an increase in health complaints such as neck pain, musculoskeletal complaints, acute pain, fibromyalgia, and cardiovascular symptoms. Finally, socioeconomic consequences of workplace bullying may include absenteeism due to sick days and unemployment. Clinicians in both mental health and primary care settings need to be alert to the associations between bullying in the workplace and these potential negative consequences, as patients may not disclose workplace maltreatment due to embarrassment or fears of retribution.
The Phipps Aggression Screening Tool (PAST)  
Agreement between nuses and physicians and between physicians only AGREEMENT BETWEEN NURSES AND PHYSICIAN (N=61) (VERSION 1 OF PAST)
Prediction of subsequent aggression by physician screening questions
Objective: Identification and skilled management of aggressive patients are a continued safety concern for inpatient psychiatric settings. We studied aggression reduction and the use of seclusion and restraints on our inpatient unit by developing aggression management tools. Our objectives were to systematically identify potential aggressors among admitted patients within 24 to 48 hours of admission and develop a seclusion documentation form that simultaneously trains staff to use less restrictive interventions while collecting data on its use. Methods: Prior to patient assessment and data collection, we systematically trained all medical staff on interviewing patients using the Phipps Aggression Screening Tool. We prospectively screened 229 consecutive admissions using the Phipps Aggression Screening Tool and determined its inter-rater reliability and predictive validity. We systematically recorded the use of a variety of interventions, including seclusion, when applicable. We also documented details of acts of aggression on a comprehensive form and collected demographics, casemix severity, and outcomes. Results: Twenty-two acutely ill patients were responsible for 68 violent acts, all identified by the Phipps Aggression Screening Tool. There were highly significant differences between aggressive and nonaggressive groups for length-ofstay, cost of hospitalization, and illness complexity. With the use of the new form, seclusion decreased from 32 percent to 22.4 percent in 2007. Our current use of seclusion is 0.1/1000 patient hours in 2011. Conclusion: The seclusion documentation form appropriately guides aggression management with less restrictive alternatives to seclusion, once potentially aggressive patients have been identified by screening.
Over the past 20 or so years, a number of studies have examined patient aggression toward healthcare professionals. While the majority of these studies has focused on healthcare professionals in the fields of emergency medicine, psychiatry, and primary care, available data extends beyond these three specialties. Studies have been done in the United States, other English-speaking countries, and elsewhere- all reporting surprisingly high rates of patient aggression. Results indicate that patient aggression toward healthcare professionals is common and worldwide. In addition, one study examined aggressive patient behaviors as reported by the patients themselves, and their self-report data reinforce the mainstream data. While these data do not enable us to determine if patient aggression is genuinely on the increase, we can safely say that these behaviors are rampant.
Individuals with borderline personality disorder are diagnostically and clinically characterized by self-harm behavior, as indicated by the criterion in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision, "recurrent suicidal behavior, gestures, or threats, or self-mutilating behavior." However, individuals with borderline personality disorder can display externalized aggressive behavior, as well. In an area characterized by considerably less research, empirical evidence indicates that individuals with borderline personality disorder may exhibit physical violence toward partners, physical violence toward known but nonintimate individuals, criminal behaviors that embody externalized violence (e.g., property damage), and, on very rare occasion, murderous behavior (either of family members or anonymous others through serial killing). Given this under-researched area, there are probably other types of externalized aggressive behaviors that have not been empirically revealed. However, externalized aggressive behaviors in individuals with borderline personality disorder clearly exist and need to be assessed in both psychiatric and primary care settings in an effort to promote safety of medical personnel and effective patient management.
Depression is highly prevalent in community and primary care samples. According to the findings of the Sequential Treatment Alternatives to Relieve Depression study, after multiple clinical interventions, approximately one-third of patients never fully experienced remission from depression. This somber finding invites consideration of novel antidepressant options, which may in the near future include agomelatine. Agomelatine is a melatonergic agonist and a 5HT(2c) antagonist (i.e., it has a unique mechanism of action). The melatonergic function appears to improve sleep patterns, whereas the serotonergic antagonism results in the release of norepinephrine and dopamine. Given the current information, the overall side-effect profile of agomelatine appears relatively mild. For example, agomelatine has no discontinuation syndrome, exhibits infrequent sexual dysfunction, and is generally weight neutral. The drug appears to be relatively safe in overdose. On a cautionary note, however, one percent of patients experience elevated hepatic transaminases while on treatment. Overall, agomelatine may be a unique pharmacological addition in the clinical war on depression in both psychiatric and primary care settings-if further evaluation in clinical trials supports reasonable risk.
Selected substances involved in emergency department visits for drug-related suicide attempts by young adults, by sex: 2008. Source: SAMHSA  
Reward pathway for alcohol  
Connections of the amygdala. B = brain stem; T = thalamus; S = septal nuclei; Hip = hippocampus; PHG = parahippocampal gyrus; H = hypothalamus; OF = orbital frontal cortex; CG = cingulate gyrus. Source: Swenson, Chapter 9: Limbic System  
Alcohol, hippocampus damage, increased self-destructive behavior, and suicidality  
Suicide is a major public health problem in the United States as well as around the world. The significant role that alcohol plays in suicidality is well known and accepted in the scientific community. The use of alcohol does not necessarily lead to suicide, but through its action and effects, alcohol is an important proximal risk factor for suicidal behavior. There is very little data showing how and why alcohol exerts such tremendous influence and "lubricates the gears" to propel the act of committing suicide. This article will elucidate the complex relationship between alcohol and suicide and how alcohol use can lead to suicide. The article also describes how alcohol affects brain neurophysiology in regards to suicidal behavior.
Alcohol dependence is often seen in a variety of clinical settings and requires attention to reduce medical complications, set up appropriate treatments, and minimize utilization of healthcare resources. Patient responses to questionnaires are often used to screen for alcohol problems, but can be misleading in the context of altered mental states or in a patient hesitant to disclose a pattern of alcohol use. Identifying the biochemical consequences of alcohol dependence has led to further study, including correlating laboratory findings to increase accuracy of identifying problem drinkers. Understanding the normal function, mechanism of abnormal findings, sensitivity, and specificity of the current laboratory studies can substantiate clinical suspicion of alcohol use. In this article, we provide results from our literature search regarding laboratory abnormalities in alcohol dependence, review options available to complement a thorough history and physical, and provide a brief overview of future biomarkers for detection of alcohol use.
In this article, the authors examine the preponderance of publications pertaining to relationships between allergies and anxiety and mood syndromes. Through a review of the relevant articles in the PubMed and PsycINFO databases, the authors found that the majority of studies (9 of 11 studies on anxiety syndromes, 10 of 12 studies on depressive syndromes) indicate associations between allergies and anxiety/mood syndromes, despite a number of methodological variances. In addition, there appear to be a number of potential variables that mediate the relationship between allergies and these two psychiatric phenomena (e.g., allergies may heighten risk for these syndromes by triggering the immune system and cytokines; allergies may impair sleep through nasal obstruction and secondarily exacerbate psychiatric symptoms; and allergies may negatively affect cognitive functioning and contribute to psychiatric disturbance) as well as a possible shared genetic risk. The authors review and discuss these variables.
Objective. Major depressive disorder is associated with sleep disturbances. An electroencephalographic pattern of alpha wave intrusion in delta wave sleep (alpha-delta sleep) is observed in some subjects with major depressive disorder. The treatment-resistant symptoms in major depressive disorder, nonrestorative sleep and fatigue, are associated with alpha-delta sleep. The objective of this study is to identify the prevalence and clinical correlates of alpha-delta sleep in major depressive disorder.Design. Retrospective studySetting. Sleep Disorders Center, Cleveland Clinic, Cleveland, OhioParticipants. Polysomnograms were conducted on 150 subjects 18 years of age or older (75 with and 75 without major depressive disorder) were reviewed.Measurements. The percent of delta waves with alpha intrusion was collected and analyzed.Results. Subjects with major depressive disorder compared to nondepressed subjects had a higher sleep efficiency (83.0±9.6; 78.1±8.2%), shorter rapid eye movement latency (85.0±44.5; 189.9±25.6 min), less slow wave sleep (8.3±3.0; 13.5±6.2%), and greater rapid eye movement (24.7±7.0; 19.2±8.2%), and all of these findings were statistically significant. Patients with major depressive disorder had higher alpha-delta sleep (23.4±14.2%; 2.3±6.7%, p<0.01). Patients with major depressive disorder were categorized into high and low alpha-delta sleep based on percentage of alpha-delta sleep present in slow wave sleep (alpha-delta sleep was present ≥15% or ≤15% of slow wave sleep, respectively). Patients with major depressive disorder with high alpha-delta sleep were at 3.15 greater odds (1.22-8.14; p=0.018) to have excessive daytime sleepiness.Conclusion. Patients with major depressive disorder have a higher prevalence of alpha-delta sleep. Alpha-delta sleep is associated with daytime sleepiness in patients with major depressive disorder. Study limitations include the retrospective nature of the project and the fact that the principle investigator, who scored and interpreted alpha intrusion, was not blind to group membership.
Top-cited authors
Waguih William IsHak, MD, FAPA
  • Cedars-Sinai Medical Center
Itai Danovitch
  • Cedars-Sinai Medical Center
Brennan Spiegel
  • Cedars-Sinai Medical Center
Bradley T Rosen
  • Cedars-Sinai Medical Center
Steven D Targum
  • Clintara LLC