bluuebunny/crossref_metadata_2025 huggingface dataset:
Schizophrenia Risk and Paternal Age: A Potential Role for De Novo Mutations in Schizophrenia Vulnerability Genes
Authors: Malaspina Dolores , Brown Alan , Goetz Deborah , Alia-Klein Nelly , Harkavy-Friedman Jill , Harlap Susan , Fennig Shmuel
Published: August 2016

How schizophrenia (SZ) is maintained at roughly 1% of the population despite diminished reproduction is one puzzle currently facing researchers. De novo mutations were first proposed over half a century ago as a source for new SZ genes. Current evidence linking advancing paternal age to SZ risk makes revisiting this hypothesis important. Advancing paternal age is the major source of new mutations in the human population. This article will examine potential mechanisms whereby parental age may impact new mutations, as well as review recent data supporting such a hypothesis.
Odor Identification Impairments in Schizophrenia: Relationship With Demographic Measures, Clinical Variables, and Diagnostic Subtypes
Authors: Coleman Eliza , Goetz Raymond R. , Leitman David , Yale Scott , Stanford Ariel , Gorman Jack M. , Malaspina Dolores
Published: August 2016

Smell identification deficits are consistently found in schizophrenia (SZ), but little is known about the nature and characterization of this deficit or its relationship to the phenomenology of the illness. This study aims to further delineate smell identification errors in SZ by examining the relationship of patient demographic differences with smell-identification performance. Our results showed that a patient's gender and education were related to odor-identification scores, with better performance seen in female patients and in those with greater educational attainment. However, there was no effect related to age, ethnicity, or socioeconomic status on odor identification. A smell identification deficit was also unrelated to clinical characteristics of the patients, including age at first hospitalization, number of psychiatric hospitalizations, and duration of illness. Odor identification also did not differ by SZ subtype, nor between SZ and schizoaffective disorder patients. These findings emphasize that odor identification deficits in SZ are unrelated to clinical illness features, cannot be explained by other confounds related to olfaction in the general population, and may be core features related to the SZ disease process.
Treatment-Resistant Posttraumatic Stress Disorder: Strategies for Intervention
Authors: Hamner Mark B. , Robert Sophie , Frueh B. Christopher
Published: August 2016

The mainstay of treatment for chronic posttraumatic stress disorder (PTSD) is a combination of psychotherapy and medication treatments. The first-line medications for PTSD are antidepressants, with two selective serotonin reuptake inhibitors (sertraline and paroxetine) currently Food and Drug Administration-indicated for PTSD. However, many patients do not have an adequate response to antidepressants, therefore, combinations with other antidepressants or with other classes of psychotropic medication are often utilized to enhance the therapeutic response. Other agents that have been used include mood stabilizers, antiadrenergics, anxiolytics, and atypical antipsychotics. The heterogeneity of symptom clusters in PTSD as well as the complex psychiatric comorbidities (eg, with depression or substance abuse) further support the notion that combinations of medications may be needed. To date, there is a paucity of data to support specific strategies for augmenting antidepressants in PTSD. This review will address representative existing studies and discuss several potential pharmacologic strategies for patients suffering from treatment refractory PTSD.
Neurocognitive Function in Schizophrenia at a 10-Year Follow-Up: A Preliminary Investigation
Authors: Kurtz Matthew M. , Seltzer James C. , Ferrand Jennifer L. , Wexler Bruce E.
Published: August 2016

Introduction:A wealth of evidence indicates that neurocognitive deficits are evident in patients with schizophrenia at both illness onset and after many years of treatment. Little is known regarding if or how these deficits change during the lifespan. The goal of the study was to evaluate changes in full-scale intelligence quotient and neurocognitive test performance over a 10-year interval in patients with schizophrenia.

Methods:Twelve patients were administered the Wechsler Adult Intelligence Scale-Revised as a measure of intellectual function and a neuropsycshological test battery including measures of attention, verbal and nonverbal memory, language, visuospatial function, problem-solving, and motor function at entry to the study and at a 10-year follow-up.

Results:With the exception of performance on a measure of speeded motor sequencing, there was no significant decline in any of the measures at 10-year follow-up. Results from a measure of sustained auditory attention showed improvement at follow-up.

Discussion:These data support a neurodevelopmental model of schizophrenia for young adult to middle-age patients by suggesting that neurocognitive deficits that emerge either before disease onset or early in the course of the illness remain stable as the patient ages.

Conclusion:Overall, measures of intelligence quotient as well as specific neurocognitive skills, do not decline over a 10-year period in at least a subgroup of patients with schizophrenia.
Genetic Factors in Neuromuscular Pain
Authors: Buskila Dan , Neumann Lily , Press Joseph
Published: August 2016

Recent evidence suggests that fibromyalgia, a chronic widespread pain condition and related syndromes (chronic fatigue syndrome, irritable bowel syndrome, etc.) may share heritable pathophysiologic features. We review the recent literature on genetic and familial factors found to participate in the pathogenesis of these syndromes, specifically fibromyalgia, including evidence suggesting that serotonin- and dopamine-related genes may play a role in the pathogenesis of these illnesses. The importance of environmental factors triggering these conditions in predisposed individuals is also discussed.
The Clenching-Grinding Spectrum and Fear Circuitry Disorders: Clinical Insights from the Neuroscience/Paleoanthropology Interface
Authors: Bracha H. Stefan , Ralston Tyler C. , Williams Andrew E. , Yamashita Jennifer M. , Bracha Adam S.
Published: August 2016

This review discusses the clenching-grinding spectrum from the neuropsychiatric/neuroevolutionary perspective. In neuropsychiatry, signs of jaw clenching may be a useful objective marker for detecting or substantiating a self-report of current subjective emotional distress. Similarly, accelerated tooth wear may be an objective clinical sign for detecting, or substantiating, long-lasting anxiety. Clenching-grinding behaviors affect at least 8% of the population. We argue that during the early paleolithic environment of evolutionary adaptedness, jaw clenching was an adaptive trait because it rapidly strengthened the masseter and temporalis muscles, enabling a stronger, deeper and therefore more lethal bite in expectation of conflict(warfare)with conspecifics. Similarly, sharper incisors produced by teeth grinding may have served as weaponry during early human combat. We posit that alleles predisposing to fear-induced clenching-grinding were evolutionarily conserved in the human clade (lineage) since they remained adaptive for anatomically and mitochondrially modern humans (Homo sapiens) well into the mid-paleolithic. Clenching-grinding, sleep bruxism, myofacial pain, craniomaxillofacial musculoskeletal pain, temporomandibular disorders, oro-facial pain, and the fibromyalgia/chronic fatigue spectrum disorders are linked. A 2003 Cochrane meta-analysis concluded that dental procedures for the above spectrum disorders are not evidence based. There is a need for early detection of clenching-grinding in anxiety disorder clinics and for research into science-based interventions. Finally, research needs to examine the possible utility of incorporating physical signs intoDiagnostic and Statistical Manual of Mental Disorders, Fifth Editionposttraumatic stress disorder diagnostic criteria. One of the diagnostic criterion that may need to undergo a revision inDiagnostic and Statistical Manual of Mental Disorders, Fifth Editionis Criterion D (persistent fear-circuitry activation not present before the trauma). Grinding-induced incisor wear, and clenching-induced palpable masseter tenderness may be examples of such objective physical signs of persistent fear-circuitry activation (posttraumatic stress disorder Criterion D).
The Paradox of Quetiapine in Obsessive-Compulsive Disorder
Authors: Tranulis Constantin , Potvin Stéphane , Gourgue Martin , Leblanc Gérard , Mancini-Marïe Adham , Stip Emmanuel
Published: August 2016

Schizophrenia and obsessive-compulsive disorder (OCD) have historical, clinical, and epidemiological links. The clinical use of atypical neuroleptics (ie, dual serotonin-dopamine antagonists) to treat both conditions sheds a new light on them. We report the first two cases of obsessive-compulsive symptoms (OCS) induced by quetiapine in schizophrenia patients. A case of successful augmentation by quetiapine in refractory OCD is also presented. A review of the literature on OCS induced by atypical neuroleptics follows. This paradoxically induced OCD symptomology in schizophrenia patients administered atypical neuroleptics is discussed from new pathophysiological and clinical perspectives. The discussion emphasizes the prognostic implications of OCS in schizophrenia and available therapies for this comorbidity.
Integrating Cognitive Function Screening and Assessment into the Routine Care of Multiple Sclerosis Patients
Authors: Benedict Ralph H.B.
Published: August 2016

Cognitive dysfunction, a common feature of multiple sclerosis (MS), frequently leads to impaired activities of daily living, social skills deficits, diminished social support, and unemployment. There is growing evidence indicating that cognitive impairment is amenable to the effects of medication and behavioral counseling. Unfortunately, routine neuropsychological testing is rare in MS clinics because screening is ineffective and testing strategies are often too cumbersome or expensive. Recent research supports the reliability of a brief screening test called the Multiple Sclerosis Neuropsychological Screening Questionnaire as well as a minimal neuropsychological battery called the Minimal Assessment of Cognitive Function in Multiple Sclerosis. Data indicate that the Multiple Sclerosis Neuropsychological Screening Questionnaire has excellent split-half and test-retest reliability, and that it predicts neuropsychological deficiency with good sensitivity and specificity. Recently acquired data also show that the Minimal Assessment of Cognitive Function in Multiple Sclerosis tests have good test-retest reliability, discriminate MS patients from normal controls, and predict unemployment in MS patients. Thus, these or similar methods should be employed for the routine monitoring of cognitive functioning of MS patients.
Can Telepsychiatry Replace In-Person Psychiatric Assessments? A Review and Meta-Analysis of Comparison Studies
Authors: Hyler Steven E. , Gangure Dinu P. , Batchelder Sarai T.
Published: August 2016

Objective: The authors conducted a review and meta-analysis of the literature comparing telepsychiatry with “in-person” psychiatric assessments.

Method:Approximately 380 studies on telepsychiatry published between 1956 and 2002 were identified using MEDLINE, PsycINFO, and cross-referenced bibliographies. Of these, 14 studies with an N>10 compared telepsychiatry with in-person psychiatry (I-P) using objective assessment instruments or satisfaction instruments. Three of these studies compared high bandwidth (HB) with low bandwidth (LB) telepsychiatry.

Results:Fourteen studies of 500 patients met inclusion criteria and were included in the meta-analysis. Telepsychiatry was found to be similar to I-P for the studies using objective assessments. Effect sizes were on average quite small, suggesting no difference between telepsychiatry and I-P. Bandwidth was found to be a significant moderator. Three moderators were tested, effect sizes remained largely heterogeneous, and further analyses are needed to determine the direction of effect. There was no difference between I-P and telepsychiatry between the HB and LB groups, although there are anecdotal data suggesting that H B was slightly superior for assessments requiring detailed observation of subjects.

Conclusion:Out of a large telepsychiatry literature published over the past 40+ years, only a handful of studies have attempted to compare telepsychiatry with I-P directly using standardized assessment instruments that permit meaningful comparisons. However, in those studies, the current meta-analysis concludes there is no difference in accuracy or satisfaction between the two modalities. Over the next few years, we expect telepsychiatry to replace I-P in certain research and clinical situations.
Early Onset Obsessive-Compulsive Disorder With and Without Tics
Authors: de Mathis Maria Alice , Diniz Juliana B. , Shavitt Roseli G. , Torres Albina R. , Ferrão Ygor A. , Fossaluza Victor , Pereira Carlos , Miguel Eurípedes C. , do Rosario Maria Conceição
Published: August 2016

Introduction:Research suggests that obsessive-compulsive disorder (OCD) is not a unitary entity, but rather a highly heterogeneous condition, with complex and variable clinical manifestations.

Objective:The aims of this study were to compare clinical and demographic characteristics of OCD patients with early and late age of onset of obsessive-compulsive symptoms (OCS); and to compare the same features in early onset OCD with and without tics. The independent impact of age at onset and presence of tics on comorbidity patterns was investigated.

Methods:Three hundred and thirty consecutive outpatients meetingDiagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for OCD were evaluated: 160 patients belonged to the “early onset” group (EOG): before 11 years of age, 75 patients had

Results:The EOG had a predominance of males, higher frequency of family history of OCS, higher mean scores on the “aggression/violence” and “miscellaneous” dimensions, and higher mean global DY-BOCS scores. Patients with EOG without tic disorders presented higher mean global DY-BOCS scores and higher mean scores in the “contamination/cleaning” dimension.

Conclusion:The current results disentangle some of the clinical overlap between early onset OCD with and without tics.
Gender Differences in the Association Between Body Mass Index and Psychopathology
Authors: Desai Rani A. , Manley Melinda , Desai Mayur M. , Potenza Marc N.
Published: August 2016

Introduction: The objective of the study was to examine gender differences in the relationship between weight group (under-weight to severely obese), and Axis I and Axis II psychopathology.

Methods: Data from the National Epidemiologic Survey of Alcohol and Related Conditions (NESARC) were analyzed. Logistic regression models examined the past-year likelihood for meeting diagnostic criteria for psychiatric disorders. Interactions between weight group and gender were utilized to determine whether associations were significantly different in men and women after adjusting for demographic characteristics.

Results: First, consistent with previous NESARC analyses, the prevalence estimates of psychiatric disorders were higher among people of higher body mass index groups, regardless of gender. However, these patterns differed across genders. Both severely obese women and men, in comparison to normal weight respondents, were much more likely to meet criteria for affective and anxiety disorders, but these associations were significantly (1.5–2 times) stronger among women. For Axis II disorders, while there were very few associations between personality disorders and weight in men, among women increases in weight group were associated with increases in the likelihood of meeting criteria for a personality disorder.

Conclusion: Weight and psychopathology appear more strongly associated in women than in men. While these data do not allow for identification of underlying mechanisms, they highlight the importance of assessing for psychopathology in overweight and obese patients, and suggest that weight management may be an important consideration in the treatment of psychiatric disorders.
Treatment of Menopause-Related Mood Disturbances
Authors: Soares Claudio N. , Prouty Jennifer , Born Leslie , Steiner Meir
Published: August 2016

More than 1.7 million American women are expected to reach menopause each year. Recent Canadian statistics show that a 50-year-old woman can now expect to live until her mid-80s, which implies living at least one-third of her life after menopause. The menopausal transition is typically marked by intense hormonal fluctuations, accompanied by vasomotor symptoms (eg, hot flashes, night sweats), sleeps disturbance, and changes in sexual function, as well as increased risk for osteoporosis, cardiovascular disease, and cognitive decline. More importantly, recent studies have demonstrated a significant association between menopausal transition and a higher risk for developing depression. In the post-Women's Health Initiative Study era, physicians and patients are questioning the safety and efficacy of long-term hormone therapy use. This article reviews the current literature on the benefits and risks of using hormone therapy for the treatment of menopause-related mood disturbances and alternate strategies currently available for the management of menopause-related problems, including antidepressants, complementary and alternative medicine, and selective estrogen receptor modulators.
Immunogenicity of Botulinum Toxin Therapy
Authors: Critchfield Jeff , Sanders Martin E. , Setler Paulette E.
Published: August 2016

The function of the immune system is to recognize foreign elements and identify them as normal or potentially harmful. The first step in this discrimination is surveillance by antigen-presenting cells (APCs), which are present throughout the body. Factors that affect the immunogenicity of a molecule include the presence of an adjuvant, the depot effect, the frequency of the antigen administration, and the quantity of the material administered.

For the various types of botulinum toxin, the issue of the effect on efficacy is particularly relevant to antibody formation. An antibody to one type of botulinum toxin may potentially bind to an antibody of a different type. Safety issues with therapeutic proteins involve allergic responses, as well as formation of immune complexes and the subsequent immune complex disease. The concerns with botulinum toxins primarily relate to the potential for inhibiting efficacy.

Protein therapeutics are important only if the antibodies have been generated against the administered therapeutic. This differs for the types of botulinum toxin. In the development of botulinum toxin type B, the factors that might increase the likelihood or magnitude of an immune response were considered and eliminated as much as possible. Only antibodies to the neurotoxin protein impact efficacy or safety.
Adequacy of Pharmacotherapy Among Medicaid-Enrolled Patients Newly Diagnosed with Obsessive-Compulsive Disorder
Authors: Hankin Cheryl S. , Koran Lorrin M. , Bronstone Amy , Black Donald W. , Sheehan David V. , Hollander Eric , Dunn Jeffrey D. , Culpepper Larry , Knispel John , Dougherty Darin D. , Wang Zhaohui
Published: August 2016

Objective: To determine the adequacy of pharmacotherapy received by patients with newly-diagnosed obsessive-compulsive disorder (OCD), based on current practice guidelines.

Methods: A 9 year (1997–2006) retrospective claims analysis of adults enrolled in Florida Medicaid for at least 3 continuous years was conducted to determine the percentage who received both a minimally effective duration (≥ 8 continuous weeks) and dose of first-line OCD pharmacotherapy during the year following their first (“index”) OCD diagnosis.

Results: Among 2,960,421 adult (≥ 18 years of age) enrollees, 2,921 (0.1%) were diagnosed with OCD. Among the 2,825 OCD patients without comorbid Asperger syndrome or autism, 843 had newly-diagnosed OCD and at least 12 months of follow-up data after their index diagnosis. Among these 843 patients, 588 (69.7%) received first-line OCD pharmacotherapy but only 323 (38.3%) received a minimally effective pharmacotherapy trial in the year following their index diagnosis.

Conclusions: Among clinically-diagnosed persons with OCD (<10% of those with the disorder), a minority of newly-diagnosed patients receive a minimally effective pharmacotherapy trial consistent with current standards of care. Reasons such as limited patient adherence and/or physician awareness of guidelines must be identified and redressed to ameliorate the patient, healthcare system, and economic burdens associated with OCD.
Current and Future Treatments for Alzheimer's Disease
Authors: Salloway Stephen
Published: August 2016

There are currently >5 million people in the United States who have been diagnosed with Alzheimer's disease. That prevalence rate is expected to triple as the population ages. The health and economic burden due to Alzheimer's disease is a worldwide problem, with some of the greatest burden coming from the developing world as people live longer in those societies. Throughout the world, the projected growth of Alzheimer's disease is dramatic. This is a worldwide public health problem of the highest order, and there is a compelling need to develop new treatments and methods of earlier diagnosis need to slow the progression of the disease and lessen its impact.
New Methods of Brain Stimulation Are Improving Research and Therapy in
Obsessive-Compulsive Disorder
Authors: George Mark S.
Published: August 2016

Over the past decade, new functional neuroimaging tools have enabled researchers to identify the specific brain regions involved in obsessive-compulsive disorder (OCD). More recently, researchers have perfected several new techniques for stimulating the brain. With some exceptions, these new brain stimulation techniques are regionally specific and less invasive than older methods. As a class, these “somatic interventions” build on prior neuroanatomic information about OCD. This article reviews the past and current status of these brain stimulation methodologies, which promise to revolutionize neuropsychiatric research and therapy over the next 10 to 20 years. As the brain circuits in OCD and the pharmacology within those circuits become better understood, these brain stimulation techniques hold particular promise in helping to understand and perhaps treat OCD.
New Directions in Anxiety: OCD Spectrum Disorders
Authors: Nutt David J.
Published: August 2016

This session was divided into two sections. The first explored the neurobiologic basis of stress and stress sensitivity and the second examined the issue of body dysmorphic disorder, a relatively underdiagnosed and poorly understood condition.
Atypical Antipsychotics: Matching Receptor Profile to Individual Patient's Clinical Profile
Authors: Shayegan Darius K. , Stahl Stephen M.
Published: August 2016

Understanding common pharmacologic and clinical “class” actions associated with atypical antipsychotics certainly reveals how these agents are alike, but what about unique differences from one agent to another? Atypical antipsychotics are also a heterogeneous group of agents that have complex pharmacologic entities, acting upon multiple dopamine receptors (D2, D1 (D3, and D4) and multiple serotonin receptors (5-HT2A, 5-HT2C, 5-HT1A, and 5-HT1D, among others). Atypical antipsychotics also interact with noradrenergic (α1- and α2-adrenergic receptor blockade), histaminergic (H1-receptor blockade), and cholinergic (muscarinic M1 blockade) neurotransmitter systems as well as with monoamine (D, 5-HT, and norepinephrine reuptake blockade) transporters. However, no two atypical antipsychotics possess the same portfolio of actions upon all of these additional neurotransmitter systems.
Transcultural Issues in Mood and Anxiety Disorders: A Focus on Japan
Authors: Radford Mark H.B.
Published: August 2016

Accurate comparisons of the prevalence of psychiatric disorders across Eastern and Western cultures are difficult and limited by methodological problems. Nevertheless, using standardized diagnostic and evaluation techniques, recent surveys have suggested that depression and anxiety disorders exist in all countries and cultures examined thus far, although variations in the prevalence rates and symptomatology may exist. This article discusses the influence and impact that culture can have on recognizing and treating mood and anxiety disorders, with a particular focus on Japan. Over the last 20 years, studies have consistently reported an increase in mental illness in Japan, especially symptoms of depression and anxiety. While such symptoms have had an adaptive cultural role in the past, current social and economic changes in Japan have turned any adaptive advantage into a potentially significant disadvantage, with a major impact on the capacity of individuals to function adequately. The situation is compounded by the fact that Japanese patients are reluctant to openly discuss disturbances of mood, since these are considered to be indicative of personal weakness rather than treatable medical conditions. Reluctance to discuss personal mental health hinders timely recognition and appropriate treatment.
Gender Differences in Bipolar Disorder
Authors: Suppes Trisha
Published: August 2016

The presentations and clinical courses of patients with bipolar disorder differ greatly by gender. In addition, medical therapy must be tailored differently for men and women because of emerging safety concerns unique to the female reproductive system. In November 2005, these topics were explored by a panel of experts in psychiatry, neurology, and reproductive health at a closed roundtable meeting in Dallas, Texas. This clinical information monograph summarizes the highlights of that meeting.

Compared to men with bipolar disorder, women have more pervasive depressive symptoms and experience more major depressive episodes. They are also at higher risk for obesity and certain other medical and psychiatric comorbidities. Mood changes across the menstrual cycle are common, although the severity, timing, and type of changes are variable. Bipolar disorder is frequently associated with menstrual abnormalities and ovarian dysfunction, including polycystic ovarian syndrome. Although some cases of menstrual disturbance precede the treatment of bipolar disorder, it is possible that valproate and/or antipsychotic treatment may play a contributory role in young women.

Pregnancy does not protect against mood episodes in untreated women. Maintenance of euthymia during pregnancy is critical because relapse during this period strongly predicts a difficult postpartum course. Suspending therapy in the first months of pregnancy may be an option for some women with mild-to-moderate illness, or those with a long history of euthymia during pre-pregnancy treatment. However, a mood stabilizer should be reintroduced either in the later stages of pregnancy or in the immediate postpartum period. Preliminary data suggest that fetal exposure to some mood stabilizers may raise the risk of major congenital malformations and neurodevelopmental delays. For women planning to become pregnant, clinicians may consider switching to other drugs before conception. The value and drawbacks of breastfeeding during treatment must be considered in partnership with the patient, with close monitoring of nursing infants thereafter. The risks and benefits of medical treatment for women with bipolar disorder should be carefully reconsidered at each stage of their reproductive lives, with a flexible approach that is responsive to the changing needs of patients and their families.
Question-and-Answer Forum
Authors: Ketter Terence A. , Suppes Trisha , Morrell Martha J. , Rasgon Natalie , Cohen Lee S. , Viguera Adele C.
Published: August 2016

The presentations and clinical courses of patients with bipolar disorder differ greatly by gender. In addition, medical therapy must be tailored differently for men and women because of emerging safety concerns unique to the female reproductive system. In November 2005, these topics were explored by a panel of experts in psychiatry, neurology, and reproductive health at a closed roundtable meeting in Dallas, Texas. This clinical information monograph summarizes the highlights of that meeting.

Compared to men with bipolar disorder, women have more pervasive depressive symptoms and experience more major depressive episodes. They are also at higher risk for obesity and certain other medical and psychiatric comorbidities. Mood changes across the menstrual cycle are common, although the severity, timing, and type of changes are variable. Bipolar disorder is frequently associated with menstrual abnormalities and ovarian dysfunction, including polycystic ovarian syndrome. Although some cases of menstrual disturbance precede the treatment of bipolar disorder, it is possible that valproate and/or antipsychotic treatment may play a contributory role in young women.

Pregnancy does not protect against mood episodes in untreated women. Maintenance of euthymia during pregnancy is critical because relapse during this period strongly predicts a difficult postpartum course. Suspending therapy in the first months of pregnancy may be an option for some women with mild-to-moderate illness, or those with a long history of euthymia during pre-pregnancy treatment. However, a mood stabilizer should be reintroduced either in the later stages of pregnancy or in the immediate postpartum period. Preliminary data suggest that fetal exposure to some mood stabilizers may raise the risk of major congenital malformations and neurodevelopmental delays. For women planning to become pregnant, clinicians may consider switching to other drugs before conception. The value and drawbacks of breastfeeding during treatment must be considered in partnership with the patient, with close monitoring of nursing infants thereafter. The risks and benefits of medical treatment for women with bipolar disorder should be carefully reconsidered at each stage of their reproductive lives, with a flexible approach that is responsive to the changing needs of patients and their families.
Are We Treating Schizophrenia Effectively? Understanding the Primary Outcomes of the CATIE Study
Authors: Glazer William M. , Conley Robert R. , Citrome Leslie
Published: August 2016

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study for schizophrenia was designed to independently evaluate the effectiveness of antipsychotic treatment in “real-world” patients. To assess the effectiveness of the conventional antipsychotics compared to the atypicals as well as the differences among the atypicals, patients were randomized to one of four atypical antipsychotics (olanzapine, quetiapine, risperidone, ziprasidone) or a representative conventional antipsychotic (perphenazine). Effectiveness was defined by time to discontinuation and duration of successful treatment. Time to “all-cause” discontinuation reflects both efficacy (ability of a drug to reduce symptoms) and safety/tolerability. Phase I revealed discontinuation rates ranging from 64% for olanzapine to 82% for quetiapine.

Differences among the medications may be important in the selection of a drug for a particular patient. Physicians should involve the patient in choosing their medication by inquiring about the patient's past experience with medications and side effects, educating the patient on the risk-benefit ratio, and considering the patient's preference. To demonstrate how results of the CATIE study can contribute to the knowledge of practicing clinicians, this monograph presents a representative clinical case patient and illustrates how the CATIE safety and efficacy data has important implications for the patient.
Measuring Disease Modification in Alzheimer's Disease
Authors: Cummings Jeffrey L.
Published: August 2016

We appear to be on the brink of a new epoch of treatment for Alzheimer's disease. Compelling evidence suggests that Aβ42 secretion is the triggering event in the pathogenesis of Alzheimer's disease, and that tau aggregation may be an important secondary event linked to neurodegeneration. Prophylactic administration of anti-amyloid agents designed to prevent Aβ accumulation in persons with subclinical disease is likely to be more effective than therapeutic interventions in established Alzheimer's disease. Drug development programs in Alzheimer's disease focus primarily on agents with anti-amyloid disease-modifying properties, and many different pharmacologic approaches to reducing amyloid pathology and tauopathy are being studied. Classes of therapeutic modalities currently in advanced-stage clinical trial testing include forms of immunotherapy (active β -amyloid immunoconjugate and human intravenous immunoglobulin), a γ-secretase inhibitor, the selective Aβ42-lowering agent R-flurbiprofen, and the anti-aggregation agent tramiprosate. Non-traditional dementia therapies such as the HMG-CoA reductase inhibitors (statins), valproate, and lithium are now being assessed for clinical benefit as anti-amyloid disease-modifying treatments. Positive findings of efficacy and safety from clinical studies are necessary but not sufficient to demonstrate that a drug has disease-modifying properties. Definitive proof of disease-modification requires evidence from validated animal models of Alzheimer's disease; rigorously controlled clinical trials showing a significantly improved, stabilized, or slowed rate of decline in cognitive and global function compared to placebo; and prospectively obtained evidence from surrogate biomarkers that the treatment resulted in measurable biological changes associated with the underlying disease process.
Involuntary Emotional Expression Disorder: Treating the Untreated
Authors: Brooks Benjamin Rix
Published: August 2016

Patients with involuntary emotional expression disorder (IEED) have impaired social and occupational functioning and there is currently no Food and Drug Administration-approved treatment. Treatment options include tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), dopaminergic agents, and a combination of dextromethorphan and quinidine. Studies of monaminergic agents have typically been small and executed in single-center settings. Assessment measures generally show significant symptomatic improvements, including a reduction in the number of laughing or crying episodes and improvements in patients' clinical condition. The tolerability profiles of these agents are well defined, and include dizziness, tachycardia, and QTc prolongation (TCAs), and sleep and sexual disturbances (SSRIs). The combination of dextromethorphan and quinidine has also been assessed in two large multicenter studies in patients with amyotrophic lateral sclerosis and multiple sclerosis. Compared with placebo and either agent alone, there were significant improvements in symptoms, quality of life, and relationships. The most common side effects were dizziness and nausea, and potential drug interactions with quinidine should also be considered. Choice of treatment should be evidence-based, taking into account both efficacy and tolerability.
ADHD: Prevalence, Diagnosis, and Issues of Comorbidity
Authors: Wilens Timothy E.
Published: August 2016

Attention-deficit/hyperactivity disorder (ADHD) is a lifelong condition that begins in childhood and continues with adult manifestations related to the core symptoms. Approximately 50% to 75% of children with ADHD continue to meet criteria for the disorder as adolescents and adults. Adults with the disorder increasingly present to primary care physicians, psychiatrists, and other practitioners for diagnosis and treatment. Understanding the diagnosis of ADHD in adults requires knowledge of age-dependent decline of symptoms over time. Retrospective recall of symptoms and impairment are valid methods of diagnosing the disorder. ADHD is also a brain disorder with a strong neurobiologic basis, complex etiology, and genetic component. Genetic and environmental vulnerabilities give rise to abnormalities in the brain and subsequent behavioral and cognitive deficits, which may produce the symptoms associated with ADHD. Magnetic resonance imaging studies of ADHD have provided evidence that abnormalities in the brain are caused by the disorder itself rather than treatment of the disorder. Psychiatric comorbidity is common among patients with ADHD and tends to complicate treatment. Acute and long-term use of long-acting stimulant formulations (methylphenidate and amphetamine compounds) have shown robust efficacy and tolerability consistent with the treatment response established in children with ADHD. Non-stimulant medications have demonstrated efficacy as well, and may be preferred in patients with tic and substance use disorders.
Antidepressant Drug-Drug Interactions: Clinical Relevance and Risk Management
Authors: Nemeroff Charles B. , Preskorn Sheldon H. , DeVane C. Lindsay
Published: August 2016

Multiple medication use is a common phenomenon, especially in patients with comorbid conditions and those treated with psychiatric drugs such as antidepressants. Combination treatment may result in potentially harmful drug-drug interactions (DDIs). Results of DDIs range from nuisance side effects to serious adverse consequences. DDIs may also result in improved efficacy. Augmentation strategies, for example, are intentional therapeutic DDIs. Pharmacokinetic DDIs occur when a second drug alters the absorption, distribution, metabolism, or clearance of the first drug. Research has concentrated on the relative effects of antidepressants on cytochrome P450 enzymes and, more recently, on drug transporters as potential mediators of clinically important pharmacokinetic DDIs. The most common, clinically relevant pharmacokinetic DDIs involve alteration in oxidative drug metabolism. Pharmacodynamic DDIs occur when the effects of a second drug quantitatively or qualitatively alters those of the first drug. Pharmacodynamic DDIs are not typically studied in vivo because of the potential for a serious adverse effect. All antidepressants can interact pharmacodynamically with certain other drugs. The risk of harmful DDIs can be reduced by recognizing variables that affect dose-concentration-effect relationships. It is important for physicians to weigh the risks and benefits of potential DDIs against the risks that accompany timid or ineffective disease treatment.
Brain Structures Involved in Bipolar Disorder: Findings from Structural and Functional Imaging
Authors: Strakowski Stephen M.
Published: August 2016

Bipolar disorder is a prevalent psychiatric disorder with a high rate of misdiagnosis and evidence of degenerative progression. Research indicates that the interval between bipolar episodes decreases steadily until the patient settles into a relatively frequent course of mania and depression. Various imaging techniques have been used in the understanding of the brain pathology underlying bipolar disorder through identification of patterns consistent with disruption of the normal brain activity in bipolar patients. These techniques have demonstrated evidence of abnormalities in the structure and function of the prefrontal cortex. In addition, the cerebellar vermis, which serves as an error-detection function to modulate the iterative network, appears to shrink with recurrent episodes. Functional imaging demonstrates that the anterior limbic network is overactivated and overresponsive in patients with bipolar disorder. In many patients, those deficits are often compensated for by activation of other brain areas. Ultimately, when the compensation fails, expression of bipolar symptoms arise. Using magnetic resonance spectroscopy, simple models can be constructed based on the hypothesis that mitochondrial function may be impaired in bipolar disorder. There is also increasing evidence that psychotropic medications can affect specific brain regions that are thought to be involved in the pathogenesis of psychiatric disorders. Glutamate levels appear to be elevated in untreated patients with bipolar disorder, which may cause glutamatergic neurotoxicity and negative therapeutic implications. Further advances in brain imaging may contribute to the improvement of available therapies and the understanding which treatments will be most suitable for specific patients.
Therapeutics for the Treatment of Insomnia
Authors: Lieberman Joseph A.
Published: August 2016

Insomnia is a disorder characterized by chronic sleep disturbance associated with daytime disability or distress, such as memory impairment and fatigue, that occurs despite adequate opportunity for sleep. Insomnia may present as difficulty falling/staying asleep or as sleep that is nonrestorative. Studies show a strong correlation between insomnia and impaired quality of life. Pain conditions and depression are commonly associated with insomnia, either as secondary or comorbid conditions. In addition, a greater incidence of anxiety, alcohol and drug dependence, and cardiovascular disease is found in people with insomnia. Data indicate insomnia results from over-engaged arousal systems. Insomnia patients experience increased metabolic rate, body temperature, and heart rate, and elevated levels of norepinephrine and catecholamines. Pharmacologic options for the treatment of insomnia include benzodiazepine hypnotics, a selective melatonin receptor agonist, and sedating antidepressants. However, insomnia may be best treated with cognitive-behavioral therapy and instruction in good sleep hygiene, either alone or in concert with pharmacologic agents. Studies on the effects of insomnia treatment use variable methodologies or do not publish negative results, and there are currently no studies of treatment focusing on morbidity. Further research is necessary to better understand the effects of insomnia therapies on medical and psychiatric disorders.

In this Clinical Information Supplement, Thomas Roth, PhD, describes the nature of insomnia and its pathophysiology. Next, Andrew D. Krystal, MD, MS, reviews morbidities associated with insomnia. Finally, Joseph A. Lieberman III, MD, MPH, provides an overview of therapeutics utilized in patients with insomnia, including behavioral therapies and pharmacologic options.
Akathisia: Problem of History or Concern of Today
Authors: Iqbal Naveed , Lambert Tim , Masand Prakash
Published: August 2016

Akathisia is a neurological side effect of antipsychotic medications, which are used to treat various psychiatric disorders. Akathisia is characterized by physical restlessness and a subjective urge to move. Although side effects such as akathisia, dystonia, and dyskinesia are common with the use of conventional antipsychotics, they occur in reduced frequency with the use of new-generation antipsychotics. Despite a lowered incidence profile, akathisia and similar conditions continue to affect patients. Neuroleptic-induced akathisia can present as fidgety movements while seated, rocking in place while standing, pacing, inability to sit or stand still for an extended period of time, and an overwhelming urge to move. These symptoms can cause severe distress and an increased risk of suicide for affected patients. First-line treatment of akathisia includes benzodiazepines or β-blockers for patients who do not have symptoms of Parkinson's disease and anticholinergic medications for patients with Parkinson's symptoms. Clinicians should ensure that an accurate diagnosis of akathisia is made and that target symptoms are decreasing due to treatment. At the same time, it must be ensured that the treatment used does not negatively affect the mental health of the patient. This expert roundtable supplement will address the diagnosis, pathophysiology, phenomenology, classification, and history of akathisia as well as discuss screening tools and treatment options for the condition.
First-Episode Psychosis: A Window of Opportunity for Best Practices
Authors: Buckley Peter F. , Correll Christoph U. , Miller Alexander L.
Published: August 2016

Patients experiencing a first psychotic episode or early stages of psychosis present with key diagnostic issues for clinicians. At the time of first-episode psychosis presentation, it is crucial that clinicians select the most effective treatment option as immediate intervention offers the best chance for containing the illness. Functional impairment occurs most rapidly at the early stage of illness, and such impairment can influence the patient's future prognosis, alter the level of necessary treatment, and affect morbidity. Although research has shown a decrease in brain gray matter as well as signs of functional impairment in those who develop psychosis, many of these patients remain untreated for extended periods of time and do not visit a clinician due to fear of stigma, a failure to recognize the problem, or complexities of their care system. Prior studies have shown that untreated psychosis results in worse outcome for patients compared to psychosis that is treated earlier in the course of illness. There is a range of treatment options for psychosis, including use of first-generation or second-generation antipsychotic medication. Clinicians should note that both medication types are associated with certain side effects, such as tardive dyskinesia and weight gain, respectively. For all antipsychotics, doses should be lower for patients with a first psychotic episode than for patients with chronic psychosis. Finally, clinicians must consider that patients may present with various comorbidities, such as substance abuse, that also may affect treatment.

This expert roundtable supplement will address the diagnosis and treatment selection for first-episode psychosis as well as comorbidities related to the condition. The use of first- or second-generation antipsychotics for psychosis treatment, dosing guidelines, and the antipsychotic side-effect profile will also be addressed.
The Appropriate Role of Computerized Postmarketing Surveillance
Authors: Strom Brian L.
Published: August 2016

Pharmacoepidemiology, the study of the effects of drugs in large numbers of people, is a relatively new discipline that applies the methods of epidemiology to clinical pharmacology. Premarketing clinical trials remain the only way to scientifically determine whether a drug is causally effective, yet these trials do not provide information that allows for estimates about rare, late, or off-label toxicities associated with the drug in question. Increasing concern about common and debilitating adverse effects of medications has highlighted the need for enhanced postmarketing surveillance to follow up on clinical trials. There is a further concern regarding the broader issue of the risk-benefit ratio of certain medications. Computerized databases are a good source of information on which to lay the foundations of postmarketing research. A system of cross-linked computerized medical records may better enable researchers and physicians to realistically monitor postmarketing safety and incorporate monitoring benefits. The same research could also elucidate the net public health effect of regulatory decisions. The Veterans Affairs database in the United States and PHARMO in the Netherlands may represent good models on which to base future postmarketing surveillance studies.

In this expert roundtable supplement, Brian L. Strom, MD, provides an overview of the appropriate use of large computer databases in pharmacoepidemiology studies. Philip Wang, MD, DrPH, discusses the advantages of pharmacoepidemiologic studies over clinical trials in correctly detecting drug safety issues. Francesca Cunningham, PharmD, reviews a large computer database that is currently in use within the VA healthcare system, and Ron M.C. Herings, PharmD, PhD, discusses the development of the PHARMO system in the Netherlands.

This summary is based heavily on the concepts presented in: Strom BL. What is pharmacoepidemiology. In: Strom BL, ed. Pharmacoepidemiology. 4th ed. Sussex: John Wiley; 2005:3–15; and Strom BL. Overview of study designs available for pharmacoepidemiology studies. In: Strom BL, ed. Pharmacoepidemiology. 4th ed. Sussex: John Wiley, 2005:17–28.