bluuebunny/crossref_metadata_2025 huggingface dataset:
Maximizing Function After First-Episode Psychosis
Authors: Kopala Lili C.
Published: August 2016

Interest in early and preventive interventions in patients with psychotic disorders has increased over the past few years as a result of die intuitive appeal of such interventions. Results of studies point to an association between longer duration of untreated psychosis and poor outcome, atypical antipsychotic agents less likely to cause extrapyramidal side effects, and a shift from hospital to community-based care for many patients with severe mental illness. Treatment strategies specifically directed to firsUepisode psychosis may help to improve outcomes. Such strategies include the use of lower doses of antipsychotic medications, the predominant use of atypical antipsychotic agents, and the deployment of psychological interventions that address the unique needs of young, first-episode patients and their families.
Mechanisms of Action of Atypical Antipsychotics
Authors: Cañas Fernando
Published: August 2016

Atypical antipsychotics—clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole—differ from conventional antipsychotics primarily by virtue of their actions at multiple central receptor sites. Each agent has its own unique receptor profile. The discovery of dopaminergic receptor-blocking capabilities of conventionblockingal antipsychotic drugs led to the dopamine hypothesis of schizophrenia. More recently, the role of serotonergic and other receptors in the pathophysiology and symptomology of schizophrenia and schizoaffective disorder has been identified, and the receptor actions of atypical antipsychotics have been linked to both antipsychotic efficacy and the propensity for extrapyramidal symptoms and other adverse effects. Receptor occupancy is directly related to antipsychotic dose, and the nature of the relationship between clinical utility and receptor occupancy is beginning to emerge. As our understanding of this relationship becomes more clear, the mechanism underlying clinical distinctions between agents will be understood.
Non-Western Therapies for Affective Disorders: In Pursuit of Open-Minded Considerations of Concepts and Applications
Authors: Halbreich Uriel
Published: August 2016

Introduction: Complementary and alternative medicine (CAM) modalities are gaining popularity among patients in Western countries. They are especially popular among patients seeking treatment for mental and mood symptoms. Some CAMs are according to current Western approaches but have not achieved approval by regulatory agencies. Some other modalities are acording to non-Western concepts of mental order and disorder. This installment of “The Well-Rounded Brain” will illuminate some non-Western concepts with an example of treatment modality for affective disorders, and compare them to conventional Western approach.

Methods: Principles of the Chinese concept of affective disorders and acupuncture modalities for their treatments are briefly described from a culturally sensitive perspective.

Results: Traditional Chinese medicine and current conventional Western medicine substantially differ in underlying concepts, development of treatment modalities, as well as their goals and implementation.

Conclusion: Some non-Western concepts and treatment modalities have been meticulously and rigorously developed through trial and error, though the evidence for their efficacy and efficiency is not necessarily according to current Western standards. The consistent epidemiological demonstrations of the demand for CAM among patients suffering from mental disorders call for an open-minded, unbiased assessment of efficacy of non-Western treatment modalities for specific clusters of affective symptoms.
Lifetime Subthreshold Mania is Related to Suicidality in Posttraumatic Stress Disorder
Authors: Dell'Osso Liliana , Carmassi Claudia , Rucci Paola , Ciapparelli Antonio , Paggini Rosemma , Ramacciotti Carla Emilia , Conversano Ciro , Balestrieri Matteo , Marazziti Donatella
Published: August 2016

Introduction: Although the association between mood disorders, and particularly bipolar disorders, comorbidity and suicidality in posttraumatic (PTSD) patients is well established, less information is available on the impact of subsyndromal mood symptoms. The aim of the present study was, thus, to explore the frequency and relationship between subthreshold mood symptoms, assessed by a specific and validated questionnaire, and suicidality in PTSD patients.

Method: Sixty-five PTSD outpatients without bipolar disorders and 65 healthy control subjects were asked to complete the Mood Spectrum-SR-Lifetime Version (MOODS-SR), a questionnaire exploring the presence of subthreshold affective symptoms. Logistic regression models were used to analyze the relationships between suicidality, explored by six items of the MOODS-SR combined and dichotomized to denote the presence or absence of suicidal ideations/plans and/or attempts, and the number of manic/hypomanic or depressive symptoms.

Results: Statistically significant and positive associations were found between the presence of manic/hypomanic and depressive symptoms and the likelihood of suicidal ideation or attempts.

Conclusion: Besides depressive, even subthreshold manic/hypomanic features seem to be associated with higher suicidality in PTSD patients.
Effects of the Female Reproductive System on Bipolar Disorder
Authors: Ketter Terence A.
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.
Effects of In Utero Exposure to AEDs on Morphology and Neurodevelopment
Authors: Morrell Martha J.
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.
Comorbidity and Diagnosis of ADHD
Authors: Reimherr Frederick W.
Published: August 2016

Attention-deficit/hyperactivity disorder (ADHD), once considered to be a childhood disorder, is diagnosed in ~7 million adults in the United States, as reported by The National Comorbidity Study. Although it is now recognized that ADHD often persists into adulthood, the current diagnostic criteria is geared toward symptom identification in children. Symptoms of inattention, impulsivity, and hyperactivity evolve over the life cycle and present differently in adults. Further complicating diagnosis is that ADHD is associated with multiple functional impairments and comorbid psychiatric disorders. The Multi-Modal Treatment Study of ADHD reported that only 32% of the study population had ADHD alone; 29% had ADHD plus oppositional defiant disorder and/or conduct disorder, 14% had ADHD plus anxiety or depression, and 25% had all three disorders. Optimal treatment utilizes a multi-modal approach including behavioral treatments combined with pharmacologic treatment strategies. Food and Drug Administration-approved medications for ADHD include the stimulants and nonstimulants, although tricyclic antidepressants and bupropion are also commonly used.

In this monograph, Craig L. Donnelly, MD, reviews the history of ADHD and discusses the pathophysiologic progression of childhood symptoms into those commonly exhibited by adults. Next, Frederick W. Reimherr, MD, reviews comorbidity of ADHD and describes the Utah Criteria as a method of diagnosing adults through recollection of childhood problems. Finally, Joel L. Young, MD, reviews treatment approaches to adult ADHD and its comorbid conditions.
Calming the Bipolar Storm: Treating Acute Mania and Mixed Episodes in Patients with Bipolar Disorder
Authors: Zajecka John M.
Published: August 2016

Bipolar disorder is a seriously debilitating psychiatric disorder that greatly affects patients and their loved ones. Although bipolar disorder is one of the most frequently occurring mental disorders worldwide, many patients, particularly those with mixed mania, remain misdiagnosed. Compared to pure mania, mixed episodes of bipolar disorder present with symptoms that can be more challenging to treat. However, proper diagnosis and early treatment can usually alter the course of the illness, and remission is certainly possible.

This expert roundtable supplement reviews the differences between acute manic and mixed episodes in patients with bipolar disorder, explains proper dosing and the advantages of different dosage formulations, and identifies the rationale for monotherapy and combination therapy in these patient populations. The aim is to educate clinicians about ways to diagnose and treat the mood state aggressively and safely, especially in light of the many new treatment options available.
Introduction: Amyloid-Based Interventions in Alzheimer's Disease
Authors: Kennedy Gary J.
Published: August 2016

We appear to be on the brink of a new epoch of treatment for Alzheimer's disease. Compelling evidence suggests that Aβ 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.
Neurobiology and Functional Progression in Schizophrenia
Authors: Jarskog L. Fredrik
Published: August 2016

Schizophrenia is a neurodevelopmental disorder associated with persistent symptomatology, severe functional disability, and residual morbidity characteristic of neurodegenerative brain diseases. The illness begins with genetic susceptibility and generally expresses itself after puberty through subtle changes that begin during the prodromal stage. Symptoms get progressively worse and tend to become more resistant to treatment with each relapse. Evidence for a neuroprotective effect of some forms of early treatment is beginning to emerge. While the underlying mechanisms remain uncertain, atypical antipsychotics may counteract some of the progressive deteriorative effects by enhancing synaptic plasticity and cellular resilience. However, identifying and treating patients in the earliest disease states presents methodological challenges as there is no consensus on the best methods of intervention and differences in at-risk children are not readily detectable or substantial enough to predict which ones will develop schizophrenia.

In this expert roundtable supplement, Jeffrey A. Lieberman, MD, reviews the historical context of progressive deterioration in schizophrenia. Next, Diana O. Perkins, MD, MPH, reviews some of the challenges to early identification of illness as well as the impact of early versus delayed treatment. Finally, L. Fredrik Jarskog, MD, focuses on the neurobiology of functional progression in schizophrenia as well as pharmacology and the potential for neuroprotection.
Pharmacology of Adult ADHD with Stimulants
Authors: Spencer Thomas J.
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.

In this expert roundtable supplement, Timothy E. Wilens, MD, reviews the epidemiology and clinical presentation of adult ADHD. Next, Joseph Biederman, MD, provides an overview of recent advances in the neurobiology of ADHD. Thomas J. Spencer, MD, reviews stimulant treatment of adult ADHD, and Lenard A. Adler concludes with a discussion of non-stimulant trials in adult ADHD.
The PHARMO System
Authors: Herings Ron M.C.
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.
Management of Substance Use Disorder in Schizophrenia Patients: Current Guidelines
Authors: Drake Robert E.
Published: August 2016

Substance use disorder is the most frequent and clinically significant comorbidity among schizophrenia patients today. All schizophrenia patients should be assessed and monitored carefully regarding their substance use. Those with any regular use of alcohol or other drugs should be considered at risk for multiple adverse effects. As therapies for co-occurring substance use disorders have evolved over the past 20 years, medication management, psychosocial interventions, and rehabilitation models have increasingly emphasized the integration of mental health and substance abuse treatments, attention to group and residential interventions, matching interventions to stage of treatment, comprehensiveness, and long-term perspectives on recovery. Clinicians should understand the implications of each of these principles of care.
Introduction: Selecting an Antidepressant
Authors: Zimmerman Mark
Published: August 2016

Four years ago, my colleagues and I published an article titled “Why isn't bupropion the most frequently prescribed antidepressant?” The goal of that article was not to advocate bupropion as the preferred agent for treating depression, but rather to stimulate discussion about how psychiatrists choose an antidepressant as well as to highlight the gap between results of efficacy studies and clinical decision making in real-world practice.

The argument in support of bupropion being the preferred antidepressant was based on three premises: all antidepressants are equally effective; adverse effects (AEs) of greatest concern to patients who take antidepressants are weight gain and sexual dysfunction; and bupropion does not cause either of these AEs. Acceptance of these three premises suggested the title of that article.

Although many reviews of the antidepressant literature, including the revised American Psychiatric Association Practice Guideline for the Treatment of Major Depressive Disorder, conclude that antidepressants are equally effective in general, several experts in the treatment of depression have suggested that medications with >1 mechanism of action may be more effective than agents that have more selective neurotransmitter effects. In a meta-analysis of eight studies comparing the remission rates in patients treated with the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine or selective serotonin reuptake inhibitors (SSRIs), Thase and colleagues demonstrated that venlafaxine was more effective than SSRIs in achieving remission in depressed patients. However, these conclusions were tentative as most of the included studies were comparisons of venlafaxine and fluoxetine; only one study included sertraline, and there were no studies of citalopram included in the review. In addition, patients who had previously failed treatment with an SSRI were not excluded, and, although patients who fail with one SSRI may respond to subsequent treatment with another SSRI, the inclusion of SSRI failures may favor venlafaxine in comparisons with SSRIs. Lastly, all of the studies included in the meta-analysis were funded by the manufacturer of venlafaxine.
Considering Race and Ethnicity During Psychopharmacologic Interventions
Authors: Stewart Altha
Published: August 2016

The role of race and ethnicity in psychiatric diagnosis and treatment has received increased attention over the last 2 decades. In addition, recent studies conducted to determine the effects of psychotropic drugs among various racial and ethnic groups highlight the importance of considering race and ethnicity during psychopharmacologic interventions.

Information regarding differences in drug metabolism, effectiveness, and incidence of adverse effects provides opportunities for psychiatrists to adjust pharmacologic treatment to achieve optimal treatment outcomes while minimizing intolerable side effects. These differences have been explained by inconsistencies in access, stigma, fear of medicines, differing spiritual and cultural beliefs about mental illness, and general mistrust of the healthcare system by many racial and ethnic groups.

The articles in this supplement offer a significant contribution to the scientific foundation needed to minimize the patient and clinician factors contributing to the current disparities in mental health care. Recent data, such as those presented in this supplement, describe the role of ethnicity in the pharmacologic treatment of psychiatric disorders and offer hope for improved quality of care for ethnically diverse patient populations. The authors discuss differences in drug metabolism, the impact of these differences on development of various metabolic disorders, and how these differences may be useful in managing intolerable side effects and improving patient compliance and treatment outcome. The information included in these articles should assure that clinical decision making and prescribing practices include sensitivity to safety, tolerability, and dosing for an increasingly ethnically diverse population.
The Ethnopharmacology of Atypical Antipsychotics
Authors: Bradford L. DiAnne
Published: August 2016

Since the risk of antipsychotic-induced adverse events is often related to plasma drug concentrations, factors that influence the metabolic transformation of these agents can substantially influence this risk. The cytochrome P450 (CYP) enzyme system, particularly CYP2D6, is very important for the metabolism of many typical and atypical antipsychotic agents. However, there is substantial ethnic/racial pharmacogenetic variability in the phenotypic (ie, metabolic rate) or genotypic (ie, presence of functional or nonfunctional alleles) expression of these enzyme systems. Caucasians have a bimodal distribution of CYP2D6 enzyme activity, with individuals classified either as extensive or poor metabolizers. In contrast, while there are few poor metabolizers among people of Asian descent, a substantial proportion of this population exhibits an intermediate rate of metabolism. African American populations also have a substantial number of intermediate metabolizers, and about the same number of poor metabolizers as Caucasians. Mexican Americans may have a slightly higher metabolic rate than other ethnic groups. Numerous studies have demonstrated that CYP2D6 metabolic status influences the clearance of conventional and atypical antipsychotics. African Americans and Asians, with CYP2D6 phenotypes or genotypes indicative of poor metabolizers, frequently exhibit significantly higher plasma drug concentrations and longer half-lives compared to extensive metabolizers. Importantly, this increased drug exposure is associated with an increased risk of extrapyramidal symptoms. Data on metabolic polymorphism of antipsychotics are lacking among African Americans. There are also some data suggesting that genetic polymorphism can influence the risk of antipsychotic-induced weight gain. These findings highlight the need to consider race/ethnicity when prescribing, dosing, and monitoring antipsychotic agents.
Considering Ethnicity and Ethnopharmacology in the Treatment of Patients with Mental Illness
Authors: Nasrallah Henry A.
Published: August 2016

The articles in this supplement demonstrate that ethnicity and ethnopharmacology have emerged as important considerations in the treatment of patients with mental illness. Patients from ethnically diverse backgrounds often demonstrate varying levels of response and tolerability to drugs such as atypical antipsychotics. In part, this response may be due to the particular agent itself, yet metabolic differences between populations may also impact these varied effects. Specific isoforms of the cytochrome P450 enzyme system can dictate the rate at which patients metabolize certain medications, thus genotypic variability among these enzymes predicts the phenotypic response or metabolic rate. For example, patients from certain ethnic groups such as Caucasians and Hispanics tend to be extensive metabolizers, while African Americans and Asians tend to be slower metabolizers.

Total dose and resulting plasma drug levels are closely related to adverse effects. Thus, patients exhibiting slow or poor oxidative enzyme activity may face increased drug exposure and potentially higher rates of adverse events. The undesirable antipsychotic-induced side effects include metabolic issues such as weight gain, insulin resistance, and dyslipidemia. Certain ethnic groups are at a higher risk for developing these metabolic problems. Side effects such as extrapyramidal symptoms and tardive dyskinesia, which have traditionally been attributed to conventional antipsychotics, may occur with atypicals although much less frequently. Movement disorders caused by the use of an atypical antipsychotic become particularly apparent when plasma drug levels are high. Patients with a slow metabolism will be exposed to high plasma drug levels, even on standard dosages of an atypical antipsychotic.

Therefore, given a genetic predisposition and the potential for metabolic side effects with atypical antipsychotics, a careful risk/benefit assessment is crucial for the successful management of patients with mental illness.

Other patient factors as well as clinician factors can influence the response and tolerability of treatment. Provider biases can affect access to certain medications, while misconceptions about how to treat certain ethnic groups can affect the initial choice of medication and dosage. Ultimately, sensitivity and an awareness of pharmacologic issues as they relate to an expanding and ethnically diverse population must become a high priority for clinicians treating patients with atypical antipsychotics. Side effects of these medications can be minimized with vigilance and a thorough understanding of the risks and benefits.

Continued research is necessary to further understand the field of ethnopharmacology and to lead psychiatry into the future of individualized, metabolically directed therapies.
Clinical Trials in Schizophrenia with Results for the Real World
Authors: Perkins Diana O.
Published: August 2016

Most clinical data for antipsychotics come from studies designed to test the efficacy and safety of the drugs under ideal conditions, in limited subgroups of patients. In contrast, practical clinical trials (PCTs) are designed to test the effectiveness of different treatment options under conditions that more accurately reflect actual clinical practice. Consequently, PCTs are able to provide information that can be utilized by healthcare providers and other decision makers. Characteristics of PCTs include a clinically relevant question, a representative sample of patients and practice settings, sufficient power to identify modest relevant effects, randomization to protect against bias, uncertainty regarding the outcome of treatment, assessment and treatment protocols that enact best clinical practices, simple and relevant outcomes, and limited subject and investigator burden. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) research program is an example of a PCT. The CATIE study illustrates how PCTs, when properly designed, might be helpful in informing clinical decision making. Because the CATIE study was designed to reflect the effectiveness of antipsychotics under naturalistic clinical conditions, its results should have particular applicability to the arena of clinical practice. This article provides a discussion of the differences between efficacy and effectiveness studies. In assessing the practical utility of results from the CATIE study, much can be learned on how to shape future studies of effectiveness so as to better generate data that are applicable to the “real world.”
Implications of the CATIE Trial on Treatment: Extrapyramidal Symptoms
Authors: Casey Daniel E.
Published: August 2016

Development of extrapyramidal symptoms (EPS), particularly tardive dyskinesia (TD), has long been a troubling side effect for patients taking antipsychotics. Atypical antipsychotics have been hailed as an improvement over conventional antipsychotics, offering similar efficacy with more favorable EPS profiles. In the recent Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, which compared the conventional antipsychotic perphenazine with atypical antipsychotics olanzapine, quetiapine, risperidone, and ziprasidone in patients with schizophrenia, no significant differences in time to treatment discontinuation due to intolerability were observed between treatment groups. However, perphenazine was associated with a higher rate of patients experiencing EPS as well as a significantly higher rate of discontinuation due to EPS, despite the fact that patients with TD at baseline were excluded from the perphenazine group. Unfortunately, due to short treatment duration, the CATIE study did not have the assay sensitivity to detect differences in TD risk among any of the drugs. Thus, the atypical antipsychotics remain the first line of treatment for most patients, with specific drug selection based on benefit-risk profiles that best fit the individual patient's needs. Frequent monitoring, while noting a patient's subjective experience, remains the best strategy for choosing therapy to maximize symptom relief and minimize the impact of EPS and other side effects over the long-term. This article explores the reported results of the CATIE trial regarding EPS and emphasizes the differentiation of the atypicals from perphenazine on EPS and how these results should be incorporated into daily practice for the clinician.
Neurobiology, Pharmacology, and Emerging Treatment
Authors: Adler Lenard A.
Published: August 2016

Treatment of attention-deficit/hyperactivity disorder (ADHD) may positively impact the neurobiology of adult patients with ADHD. Treatment may also minimize impairment from core symptoms and may alter the course of co-morbid disorders such as depression and substance use disorder. However, much of the information on stimulant use in adult ADHD comes from studies conducted in children, and it remains unclear whether there is a difference between children and adults when it comes to the side effects and tolerability of ADHD treatments. It is known that clinical presentation differs between adults and children, with adults demonstrating a higher percentage of mood disorders. Current treatments for adult ADHD include psychosocial therapies and pharmacologic therapies, the latter of which include the stimulants d-methylphenidate extended release (XR), OROS methylphenidate, lisdexamfetamine, and mixed amphetamine salts XR; and the nonstimulant atomoxetine, a selective norepinephrine reuptake inhibitor. There is need for additional study of treatment strategies for adult ADHD. Although all classes of ADHD medications are approved in adults, there are fewer approved formulations for adults than for children. Efficacy in adults is more subjective than in children, which may affect how efficacy rates for adult treatments are calculated. Adults also present a greater diversion risk than children. In addition, there are several new and emerging medication treatments worth considering.

This Expert Roundtable Supplement represents part 2 of a 3-part supplement series on adult ADHD led by Lenard A. Adler, MD. In this activity, Thomas J. Spencer, MD, discusses the neurobiology and genetics of adult ADHD; Mark A. Stein, PhD, discusses stimulant therapy; and Jeffrey H. Newcorn, MD, reviews nonstimulants and psychosocial treatments.
Treating Adult ADHD with Stimulants
Authors: Stein Mark A.
Published: August 2016

Treatment of attention-deficit/hyperactivity disorder (ADHD) may positively impact the neurobiology of adult patients with ADHD. Treatment may also minimize impairment from core symptoms and may alter the course of co-morbid disorders such as depression and substance use disorder. However, much of the information on stimulant use in adult ADHD comes from studies conducted in children, and it remains unclear whether there is a difference between children and adults when it comes to the side effects and tolerability of ADHD treatments. It is known that clinical presentation differs between adults and children, with adults demonstrating a higher percentage of mood disorders. Current treatments for adult ADHD include psychosocial therapies and pharmacologic therapies, the latter of which include the stimulants d-methylphenidate extended release (XR), OROS methylphenidate, lisdexamfetamine, and mixed amphetamine salts XR; and the nonstimulant atomoxetine, a selective norepinephrine reuptake inhibitor. There is need for additional study of treatment strategies for adult ADHD. Although all classes of ADHD medications are approved in adults, there are fewer approved formulations for adults than for children. Efficacy in adults is more subjective than in children, which may affect how efficacy rates for adult treatments are calculated. Adults also present a greater diversion risk than children. In addition, there are several new and emerging medication treatments worth considering.

This Expert Roundtable Supplement represents part 2 of a 3-part supplement series on adult ADHD led by Lenard A. Adler, MD. In this activity, Thomas J. Spencer, MD, discusses the neurobiology and genetics of adult ADHD; Mark A. Stein, PhD, discusses stimulant therapy; and Jeffrey H. Newcorn, MD, reviews nonstimulants and psychosocial treatments.
Anxiety and the Spectrum of Obsessive-Compulsive Disorder
Authors: Black Donald W.
Published: August 2016

This supplement to CNS Spectrums focuses on the obsessive-compulsive spectrum of disorders and their relationship to anxiety. Hollander and others pioneered the concept of the obsessive-compulsive spectrum in the early 1990s, and have described its breadth and overlap with other psychiatric disorders. While its place in the psychiatric nomenclature is uncertain, the obsessive-compulsive spectrum is intertwined with the anxiety disorders in both its symptoms and biologic substrates.

Obsessive-compulsive disorder (OCD) has an important place at the center of the spectrum. While currently classified in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition as an anxiety disorder, OCD is distinct from these conditions in the International Classification of Diseases. There is a strong rationale for its separation from the anxiety disorders. First, OCD often begins in childhood, whereas other anxiety disorders typically have a later age of onset. OCD has a nearly equal gender distribution, unlike the other anxiety disorders, which are more common in women. Studies of psychiatric comorbidity show that, unlike the other anxiety disorders, persons with OCD generally tend not to have elevated rates of substance misuse. Family studies suggest that first-degree relatives of persons with OCD have an elevated prevalence of OCD-related disorders including body dysmorphic disorder, hypochondriasis, and grooming disorders, but not other anxiety disorders except for generalized anxiety disorder. The brain circuitry that mediates OCD appears to be different from that involved in other anxiety disorders. Lastly, OCD is unique with regard to its specific response to selective serotonin reuptake inhibitors, while noradrenergic medications, effective in the anxiety and mood disorders, are largely ineffective. On the other hand, the benzodiazepines, which have little effect on OCD, are often effective for the other anxiety disorders.
The Overlap of Obsessive-Compulsive Disorder and Social Phobia and its Treatment
Authors: Baldwin David S. , Brandish Emma K. , Meron Daniel
Published: August 2016

Both obsessive-compulsive disorder (OCD) and social phobia are common in community and clinical settings, and it should be expected that a proportion of patients with one of these conditions will also fulfill either current or lifetime criteria for the other condition. However, comorbid social phobia is more common among patients with a primary diagnosis of OCD than is comorbid OCD in patients with a primary diagnosis of social phobia. This article explores the extent of the association of OCD and social phobia in epidemiological studies, and examines the possible role of underlying depression and other disorders in mediating the appearance of the comorbid condition. Although there have been no published randomized controlled trials in patients with this particular pattern of co-morbidity, it seems sensible to adopt pharmacologic and psychologic treatment approaches which have been found efficacious in both OCD and social phobia. Pharmacologic management therefore centers on first-line treatment with a selective serotonin reuptake inhibitor. Psychologic intervention should draw on the range of cognitive and behavioral approaches required for optimal outcomes in OCD and social phobia, as discrete conditions.
Short Clinical Assessments Applicable to Busy Practices
Authors: Nasreddine Ziad
Published: August 2016

Because biomarkers to detect Alzheimer’s disease (AD) have not yet been validated, physicians must rely on clinical assessments. The Research Committee of the American Neuropsychiatric Association recommended that the ideal cognitive screening instrument have the following characteristics: First, it should take <15 minutes to administer by a clinician at any level of training. Second, it should sample all major cognitive domains, including memory, attention/concentration, executive function, visual-spatial skills, language, and orientation. Third, it should be reliable, having adequate test-retest and inter-rater validity. Finally, it should be able to detect cognitive disorders commonly encountered by neuropsychiatrists.

The American Academy of Neurology Practice Parameters from 1994 and 2001 and the Canadian Consensus Guidelines on Dementia from 2007 recommend that physicians screen subjects with suspected dementia or mild cognitive impairment (MCI), since these patients are at increased risk for AD. Currently, there are no data on the utility of screening subjects who are asymptomatic.

The most commonly used brief cognitive tests are the Mini-Mental State Examination (MMSE), according to a survey conducted by the International Psychogeriatric Association (IPA) in 2006, followed by the clock-drawing test, the delayed-word recall, the verbal fluency test, the similarities test, and the trail-making test. Clinicians appraised these assessments as the most effective and easiest to administer (Slide 1).
Cholinesterase Inhibitors and Memantine: Best Practices
Authors: Doody Rachelle S.
Published: August 2016

Today’s therapies must be put in the context of both currently available treatments as well as treatment trials with exciting potential for use in the near future. Current clinical trial methodologies do not allow for clear separation of symptomatic treatments from disease-modifying therapies; it may be unproductive to maintain this distinction given the current range of treatments available. A more currently relevant focus is added value. Therapies should aim to provide added value through incremental benefits above and beyond existing treatments, as well as enduring benefits.

Alzheimer’s disease (AD) treatment guidelines are not used by physicians only. Healthcare payers often make use of these guidelines to delimit coverage. Cost concerns will also impact AD treatments after generic cholinesterase inhibitors are made available; it is widely believed that a great number of patients will switch to generics. Therefore, treatment guidelines must account for the possible adverse effects of switching therapies as well as the desirability of persistent treatment. There are many AD treatment guidelines, among them the American Academy of Neurology (AAN) Management of Dementia Guidelines, which are currently being revised. The Institute for the Study on Aging (ISOA) Management of Alzheimer’s Disease in Managed Care Guideline also presents a different approach for a different audience.

The first step to creating evidence-based best practices guidelines is to determine what is meant by “evidence.” A system of classification exists for examining forms of evidence: Class I evidence is provided by one or more well-designed, randomized, controlled clinical trials, including overviews or meta-analyses of such trials. Class II evidence is provided by well-designed observational studies with concurrent controls; for example, case-control studies that generate hypotheses about epidemiologic associations. Class III evidence is provided by expert opinion, case series, case reports, and studies with historical controls.
Amyloid-Based Therapeutics: Findings Translated into Novel Treatments
Authors: Aisen Paul S.
Published: August 2016

For decades following the 1906 identification of Alzheimer’s disease (AD), it was believed that the disorder was untreatable. Only in the late 1970s, with the introduction of the cholinergic hypothesis of the underlying mechanisms of AD, were treatment options considered possible. The first positive treatment study was conducted in 1985. In 1993, tacrine, a cholinesterase inhibitor, was approved for the treatment of AD; three similar drugs soon followed. Memantine, an NMDA receptor antagonist, was approved in 2003, representing a second therapeutic class for AD.

Cholinesterase inhibitors were the first therapeutic options successfully employed, and there is strong evidence these agents confer benefits. The addition of memantine to the standard course of therapy can be beneficial as well, particularly at the moderate stages of the disorder (Mini-Mental State Exam score of ≤14). For patients without cardiovascular disease, diabetes, or statin use, 1,000 IU vitamin E BID is a consideration to mitigate the effects of AD. However, there is presently concern over the risks involved in vitamin E therapy. Unfortunately, there are no established treatments for mild cognitive impairment (MCI). Vitamin E is ineffective in treating MCI, and cholinesterase inhibitors, while possibly risky, are only minimally effective. The need for effective treatment remains expansive. The benefits of the available agents are modest, and there are currently no treatments for individuals with memory impairment who do not yet meet the diagnostic criteria for AD.