bluuebunny/crossref_metadata_2025 huggingface dataset:
Introduction The Transition from Reproductive Age to Menopause: Implications for Mental Health
Authors: Halbreich Uriel , Kornstein Susan
Published: August 2016

The transition from reproductive age to menopause is a major milestone in the female lifecycle. It is a hormonal process with a very clear end result: a menopausal state—though its commencement is gradual and vague. It is unavoidable and perfectly normal. The age of the transition varies widely, a fact that hints at the possibility that the reproductive clock is individualized, ticking at a diversified pace. Therefore, the study of the menopausal transition may actually be a derivative of the study of reproduction because it marks the closing of that chapter in a woman's life.

In a sequential approach, the period of transition is defined as perimenopause, or the menopausal transition, the beginning of the second phase in the life of the adult woman, characterized by a stable, low level of gonadal steroids, as opposed to the cyclic fluctuations during the reproductive phase. This imposed, though anticipated, closing of the reproductive chapter of life is often associated with mixed feelings.

As reviewed by Andrea Riccardo Genazzani, MD, PhD, and colleagues, gonadal steroids exercise a profound effect on many body systems, including the brain, in which they have specific receptors, influencing neurotransmitters and other central nervous system (CNS) mechanisms that are considered to be involved in the regulation of mood, cognition, and behavior. Therefore, it would be anticipated that the menopausal decrease in activity levels of female gonadal hormones, ie, estrogen and progesterone, resulting in substantial changes in mood, cognition, and behavior of menopausal women—but this is not the case. This fact illuminates two issues of social and clinical significance: Menopause, per sé, is a normal healthy situation, and even though it is normal it is characterized by age-related processes that may be slowed down or delayed by gonadal steroids.
The Impact of Mood Stabilizers on Suicide in Bipolar Disorder: A Comparative Analysis
Authors: Goodwin Frederick K. , Ghaemi S. Nassir
Published: August 2016

Which mood stabilizers are the most effective in reducing suicide rates in patients with bipolar disorder? This paper reviews the literature and compares the data on two types of mood-stabilizing agents, lithium and anticonvulsants. Compared with the large amount of data on lithium, there is surprising little information available on the effects of anticonvulsants on mortality in manic-depressive illness. Each was also assessed in terms of suicide risk factors such as depression and mixed episodes, rapid cycling, substance abuse, anxiety and panic, and central serotonergic function. Only two studies that provide data demonstrating anticonvulsant efficacy in preventing suicide in bipolar disorder are available, and the data are incomplete at best. Further research in this area should include an emphasis on the outcome of mortality in patients treated with any of the anticonvulsants or with lithium-anticonvulsant combinations.
Current and Emerging Treatments for Cervical Dystonia
Authors: Factor Stewart A. , Lew Mark F. , Trosch Richard M.
Published: August 2016

Cervical dystonia (CD), also known as spasmodic torticollis, is the most common of the focal dystonias. Muscle hypertrophy is present in nearly all patients, and neck pain is associated with CD in about 80% of patients. Remissions can occur in about 20% of patients, though most last under a year.

Medical therapies have not generally worked well for patients with CD, and are typically associated with many side effects. Botulinum toxin (BT), which causes fewer side effects, has been considered the treatment of choice. Beyond medical therapy, various surgeries for CD have been performed for many decades. Of surgical treatments now in use, selective peripheral denervation is the most common.

In CD, botulinum toxin type A (BT-A) targets pain, dystonic posturing, limited range of motion, and tremor. BT type B (BT-B) is a serotype of BT that is ontogenetically distinct from the type A toxin. There have been three randomized, multicenter, double-blind, placebo-controlled trials of BT-B. It appears that BT-B is a safe and effective treatment for patients with CD who are responsive or resistant to BT-A.
The Role of Residual Symptoms in Nonadherence to Treatment
Authors: Shelton Richard C.
Published: August 2016

Nonadherence to antidepressants is the rule rather than the exception. A variety of factors contribute to the problem of nonadherence, including side effects, costs, and stigma. However, residual symptoms may represent the single major risk factor for nonadherence.
Adherence to Antidepressant Medication: Patient-Centered Shared Decision Making Communication to Improve Adherence
Authors: Hahn Steven R.
Published: August 2016

For clinicians, primary care physicians (PCPs), and other health professionals treating patients with any ailment, including depression, the first task in addressing nonadherence to treatment is to detect it. Patients conceal treatment nonadherence because it is a socially undesirable behavior, and patients want their clinicians or PCPs to think that they are “good” patients. They may hope that their clinicians will be understanding, but assume that clinicians will adopt a judgmental attitude. There is evidence that, as a result of these psychological barriers, self-report and physician interview assessments have poor correlation with adherence as measured by virtually any other methodology. Three studies have been conducted that dramatically indicate the force of this need to conceal nonadherence.
What Does Imaging Add to the Management of Alzheimer's Disease?
Authors: Small Gary W.
Published: August 2016

The prevalence of Alzheimer's disease (AD) and dementia continues to rise. However, a significant number of patients are undiagnosed or untreated. Given the complexities of detecting cognitive impairment and the early signs of AD, this review discusses how advances in brain imaging can help assist in improving overall management. Imaging techniques and surrogate markers may provide unique opportunities to diagnose accurately AD in presymptomatic stages with practical consequences for patients, caregivers, and physicians. The possible outcomes for using imaging and surrogate markers as adjuncts to clinical examination and as screening tools for AD, as well as tangible and intangible advantages to early diagnosis and treatment, will be discussed. The specific value of using advanced serial imaging in patients with a genetic disposition to AD will be evaluated. If neurons can be protected from neurodegenerative damage in early stages, this may preserve patient cognition, function, and quality of life, and may confer considerable societal healthcare benefits.
Dimebon as a Potential Therapy for Alzheimer's Disease
Authors: Doody Rachelle S.
Published: August 2016

Excellent treatment for Alzheimer's disease remains an unmet medical need. Although current therapies improve patients' abilities compared to placebo and temporarily maintain performance above baseline on a number of outcome measures, additional therapies are needed to augment the benefits over baseline and to prolong these improvements.
Quality of Life in Obsessive-Compulsive Disorder
Authors: Stein Dan J. , Allen Andrea , Bobes Julio , Eisen Jane L. , Figuera M. L. , Iikura Yasuro , Koran Lorrin M. , Hollander Eric
Published: August 2016

The construct of quality of life (QOL), which has both subjective and objective components, has gained increasing importance in psychiatric research for several important reasons, not the least being the current importance of pharmacoeconomic issues. Obsessive-compulsive disorder (OCD) has been suggested to be the worlds 10th most disabling disorder, and pharmacoeconomic studies have indicated that its cost to the world economy runs into the billions of dollars. The use of QOL scales derived from general medicine and other areas of psychiatry has demonstrated the enormous negative impact of OCD on several domains, including occupational function, social function, and family function. Further work to ascertain the extent of changes in QOL during treatment of OCD is necessary.
Clinical Considerations in Selecting and Using Atypical Antipsychotics
Authors: Newcomer John W.
Published: August 2016

Patients with schizophrenia have a 20% shorter lifespan than people without the disorder. An increased risk of cardiovascular morbidity and mortality is also associated with schizophrenia. Atypical antipsychotics may contribute to the prevalence of cardiovascular disease by causing weight gain and increased adiposity, risk of insulin resistance, hyperglycemia, diabetes, and hyperlipidemia. Atypical antipsychotics that produce the greatest degree of weight gain also appear to impose the greatest risk of diabetes and hyperlipidemia. Recent evidence suggests that atypical antipsychotics may even affect glucose and lipid metabolism independent of weight gain. Among the currently marketed antipsychotics, clozapine and olanzapine appear to produce the greatest degree of weight gain. Moderate increases in weight are also observed with quetiapine and risperidone. Only ziprasidone and aripiprazole appear to be weight neutral. Atypical antipsychotics that produce the greatest degree of weight gain also appear to carry the greatest risk of diabetes and hyperlipidemia. Because of the potential for atypical antipsychotics to cause weight gain and adversely affect glucose and lipid metabolism, clinical monitoring of these parameters is critical. Dietary modification and exercise may be critical to addressing antipsychotic-induced weight gain and its consequences. In patients with persistent weight gain, evaluation of the risks and benefits of ongoing medications and consideration of switching to an antipsychotic with lower weight-gain liability may improve health outcomes.
A Prospective Pilot Study of Levetiracetam for Body Dysmorphic Disorder
Authors: Phillips Katharine A. , Menard William
Published: August 2016

Introduction:Body dysmorphic disorder (BDD) is an often severe disorder, but few treatment studies have been conducted.

Objective:This pilot study explored the efficacy and safety of the antiepileptic medication levetiracetam for BDD.

Methods:Seventeen subjects withDiagnostic and Statistical Manual of Mental Disorders, Fourth EditionBDD participated in a 12-week open-label levetiracetam trial. Subjects were assessed at regular intervals with standard measures.

Results:In intent-to-treat analyses, scores on the Yale-Brown Obsessive Compulsive Scale Modified for BDD (BDD-YBOCS), the primary outcome measure, decreased from 32.5±4.7 at baseline to 21.5±11.0 at endpoint (P<.001). Approximately 60% (n=9) of subjects were responders (≥30% decrease on the BDD-YBOCS). The mean time to response was 4.6±2.8 (range: 2-10) weeks. Scores also significantly improved on the Brown Assessment of Beliefs Scale, the Hamilton Rating Scale for Depression, the Global Assessment of Functioning Scale, and the Social and Occupational Functioning Assessment Scale. Scores did not significantly improve on the Quality of Life Enjoyment and Satisfaction Questionnaire, the Beck Anxiety Inventory, or the Social Phobia Inventory. The mean endpoint dose of levetiracetam was 2,044.1±1,065.2 (range: 250–3,000) mg/day, and it was relatively well-tolerated.

Conclusion:Randomized, double-blind placebo-controlled studies of levetiracetam for BDD are needed to confirm these preliminary findings.
The Pathogenesis of Alzheimer's Disease and the Role of Aβ42
Authors: Golde Todd E.
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.
Early Identification and Treatment of Schizophrenia
Authors: Perkins Diana O.
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.
Introduction-The Brain as a Substrate for Psychotropic Therapeutics
Authors: Keck Paul E.
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.
The Complexity of ADHD: Diagnosis and Treatment of the Adult Patient With Comorbidities
Authors: Newcorn Jeffrey H. , Weiss Margaret , Stein Mark A.
Published: August 2016

Attention-deficit/hyperactivity disorder (ADHD) is an impairing but usually treatable condition. Popular culture propagates the myth that ADHD recedes with age; this is not the case. Although it is common, <20% of adults with ADHD are diagnosed or treated. Adults with ADHD show significant comorbidities with depressive disorders, anxiety disorders, substance use, oppositional defiant disorder, personality disorders, sleep problems, and learning disabilities. However, symptoms that result from ADHD, such as mood symptoms or lability, are often mistaken for comorbid disorders. Comorbidity with ADHD impacts treatment compliance, treatment response, and patient insight. Insufficient data on the interaction between ADHD and comorbidities impedes proper diagnosis and treatment. Better clinical tools for assessing these conditions are needed. Food and Drug Administration-approved pharmacologic treatments for adult ADHD include stimulants, dexmethylphenidate, and the nonstimulant atomoxetine. Effect sizes of approved medicines at approved doses are half those seen in children. Adults may also need longer duration of medication effects than children. Short-acting stimulants are likely to result in poorer adherence and have a higher risk for diversion or abuse. Risk of abuse is a major concern; stimulant treatments are controlled substances, and children with ADHD show increased risk of substance abuse. Psychosocial interventions may be beneficial in treating both ADHD and comorbidities.

In this expert roundtable supplement, Margaret Weiss, MD, PhD, presents a comprehensive overview of complications surrounding differential diagnosis in adults with ADHD. Next, Mark A. Stein, PhD, reviews evaluation, comorbidity, and development of a treatment plan in this population. Finally, Jeffrey H. Newcorn, MD, provides a discussion on the pharmacologic options available for adults with ADHD, considering dosages specific to adults and common comorbidities.
Pharmacoepidemiology: Examples of Databases and Studies
Authors: Wang Philip
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
Veterans Affairs Databases
Authors: Cunningham Francesca
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.
Managing the Acutely Agitated and Psychotic Patient
Authors: Nordstrom Kimberly , Allen Michael H.
Published: August 2016

Agitation can present as an emergency in the course of numerous psychiatric conditions including intoxication, schizophrenia, bipolar disorder, and delirium. This article reviews relevant literature regarding the definition, etiology, measurement, and management of episodic agitation and pays particular attention to intramuscular treatments. The impact of changes in methodology between the era of first- and second-generation antipsychotics, the implications of those changes for external validity of studies of second-generation studies, and the recent evolution of expert consensus are discussed.
Panic Disorder: Broadening Conceptualizations and Improving Treatment
Authors: Pollack Mark H.
Published: August 2016

Attempts to understand the underlying etiology of panic disorder have, at times, oscillated between reductionistic biologic or psychologic characterizations that have put pharmacotherapists and cognitive-behavioral therapists on opposite sides of a fence with patients caught in the middle. However, research emerging over the last couple of decades is pointing to a more complex interplay between dysregulated neurobiological systems and psychological factors that influence the manifestations of fear and anxiety and permit a more nuanced view of the etiology of panic disorder while pointing to potential rational strategies for treating patients. The articles in this supplement explore a range of explanatory models relevant to the underlying etiology of panic disorder, and then focus on treatment, including pharmacologic agents, and a paradigm in which cognitive-behavioral therapy (CBT) can be efficiently and effectively integrated with pharmacotherapy in an attempt to optimize patient care.

In the first article, David Baldwin, MB, BS, DM, FRCPsych, discusses the burden of panic disorder to patients and society; the difficulties associated with misdiagnosis and inadequate treatment; the challenges imposed by excess healthcare utilization, reduced quality of life, and psychiatric and medical comorbidity; and the implications for therapeutics.
Easing the Burden of Panic Disorder: Comorbidity, Diagnosis, and Implications for Treatment
Authors: Baldwin David
Published: August 2016

Panic disorder (PD) is typically a distressing, chronic, and recurrent mental disorder associated with a high rate of comorbidity with other mood, anxiety, and substance abuse disorders, increased risk of medical morbidity and mortality, and marked impairment of functioning and reduced quality of life. Most patients with PD first seek treatment in emergency room or general practice settings. In the overwhelming majority of cases, PD patients present with primarily somatic symptoms, many of which are common to medical illnesses. It is, therefore, not surprising that PD is often misdiagnosed and that patients with this disorder often spend years seeking treatment and undergoing costly and unnecessary tests and medical consultations before receiving a correct diagnosis. Better diagnosis and treatment of PD to achieve remission and prevent relapse has the potential to reduce the burden of this illness to the individual and society.
Metabolic Differences of Antipsychotics Among the Races
Authors: Henderson David C.
Published: August 2016

As the United States population continues to grow and diversify, physicians must be equipped to treat patients of different races and ethnicities. Current data suggest that certain ethnic minority groups may be predisposed to a variety of clinical conditions, including obesity, diabetes mellitus, hypertension, dyslipidemia, and cardiovascular disease. Furthermore, as physicians begin to turn more frequently to atypical antipsychotics in psychiatric illness, they face a growing concern regarding the development of metabolic side effects, especially in a US population that is gradually becoming more obese from a demographic standpoint. In addition, certain ethnic groups may be more susceptible to these metabolic effects. The metabolic side effects induced by the atypical antipsychotics vary greatly, with the newer agents generally displaying fewer and less severe side effects, indicating that the particular agent chosen is of critical importance. A risk/benefit assessment, taking into consideration any genetic predisposition, preexisting risk factors, and the side-effect profile of the specific agent, is paramount to the successful management of these patients. The ultimate goal is careful consideration of possible metabolic side effects in patients taking atypical antipsychotics, in order to avoid serious consequences.
Avoiding Side Effects in Ethnically Diverse Patients
Authors: Nasrallah Henry A.
Published: August 2016

Optimal treatment for patients with mental health illness depends upon accurate diagnosis, individualized treatment, patient adherence to effective agents, and an intact family support system. Healthcare system (eg, limited access to certain medications), provider (eg, bias and discrimination), and patient factors (eg, biologic and cultural) greatly influence the level of mental health care given, especially to minority populations. Furthermore, limited data in African Americans, Hispanics, and Asians suggest that there are racial, ethnic, and cultural variations in responsiveness to antipsychotic medications, as well as potential differences in the types, rates, and severity of adverse events. Non-Caucasian patients tend to receive older, less-expensive agents, sometimes at higher doses (African Americans, leading to potentially intolerable side effects and early withdrawal of therapy or a less than optimal therapeutic response, respectively. Differences in response may have a biologic, pharmacokinetic, or pharmacodynamic basis and may also be influenced by lifestyle factors (eg, diet, smoking). Variations in dopamine receptor occupancy and cytochrome P450 polymorphism may explain some racial/ethnic differences in antipsychotic effects and adverse-event profiles, suggesting that dosing may need to be individualized based on ethnicity. The newer atypical antipsychotics, while seemingly better tolerated compared with conventional antipsychotics, may not be totally devoid of bothersome side effects (eg, extrapyramidal side effects) in minorities. While further research is needed, recognition of potential interracial/ethnic pharmacogenetic differences may help minimize intolerable side effects and achieve optimal psychosis management.
Sexual Dysfunction in Major Depression
Authors: Williams Katherine , Reynolds Margaret F.
Published: August 2016

Little is known about the prevalence, typology, and natural course of non—drug-induced sexual dysfunction in patients with depression. Loss of libido has been reported in various studies to affect from 25% to 75% of patients with unipolar depression, and its prevalence appears to be correlated with the severity of depression. Disorders of arousal also appear to be relatively common in both men and women with major depression, of whom ~25% may experience problems with erection or lubrication. The scant available data regarding orgasmic difficulties in patients with depression who have not yet taken antidepressant medication suggest that they are more common than in the general population. The potential causes of sexual dysfunction in patients with depression are complex and little investigated, and future research must distinguish and explore the various biological, psychological, and psychosocial factors that are likely to be involved.
Fibromyalgia Syndrome: New Developments in Pathophysiology and Management
Authors: Russell I. Jon
Published: August 2016

Fibromyalgia syndrome (FMS) is a common, chronically painful condition that is still seeking a home among the clinical professions. It is characterized by moderately severe soft-tissue pain and allodynia, which suggests a role for one group of specialists, but its pathogenesis is in the nociceptive machinery of the central nervous system, which defines the territory of other specialties. Comorbidities such as insomnia, cognitive dysfunction, depression, anxiety, recurrent headaches, dizziness, fatigue, morning stiffness, dysesthesia, irritable bowel syndrome, and irritable urethra logically invoke input from practitioners from almost every field of medicine.

The precipitating causes of FMS may vary among individuals, but a mechanism underlying the painful symptoms involves central sensitization leading to an amplified perception of pain. As a result, this condition is recognized as the human model for chronic widespread allodynia. Biological abnormalities that are detected in most patients by objective methods include dysfunctional sleep (polysomnography), central sensitization (functional magnetic resonance imaging), temporal summation (windup, second pain), and facilitation of nociception (elevated spinal fluid levels of substance P, deficient biogenic amines that fail to maintain descending inhibition, and, in primary FMS, elevated spinal fluid levels of nerve growth factor).

Treatment of FMS is symptomatic and multimodal, including education, physical modalities, and medications that target central neural pathways. Rehabilitation goals include improved physical function, social adaptation, emotional balance, and a better quality of life. Several series of placebo-controlled clinical trials have made available new medications with unique therapeutic mechanisms. Thus, it can be predicted that the next 10 years will see validation of a clinical case definition, more interest in the underlying pathogenesis, a better understanding of how medical care should be adapted to subgroup variations, new medications with specific domain indications, mechanism-directed polypharmacy, characterization of the genetic predisposition, and more emphasis on preventable inciting events.
Use of Magnetic Resonance Imaging to Identify Mild Cognitive Impairment: Who Should Be Imaged?
Authors: Apostolova Liana G.
Published: August 2016

Problems with memory are a very common complaint in the elderly and are not synonymous with dementia. Some degree of cognitive decline, manifested as greater difficulty in learning and retrieving new information for instance, develops with normal aging. Thus many older patients do not perform at the same level they did when they were younger but they do perform well when compared to their peers. For many, cognitive change ends at this stage and they proceed to lead normal, healthy, dementia-free lives.

The cohort that has cognitive changes beyond what is expected in normal aging but does not yet meet criteria for dementia concerns clinicians greatly as many of these patients eventually become demented. These patients usually go through a latent stage in which neurodegenerative pathology silently spreads in the brain. Once there is enough pathological burden, cognitive decline beyond what is expected for normal aging can be detected by formal neuropsychological testing. Frequently such patients go through a state called mild cognitive impairment (MCI). In this state patients are still functionally intact and live independently, but show cognitive impairment relative to the age- and education-adjusted norms.

The MCI state in itself is a prominent risk factor for developing dementia. Most patients with amnestic MCI develop Alzheimer’s disease (AD) dementia over time. At six years, as many as 80% progress to AD. Thus, MCI is a very important topic of research and an increasingly important topic of clinical care.
FDG and Amyloid Positron Emission Tomography
Authors: Mintun Mark A.
Published: August 2016

For over 20 years, researchers have used the tracer [18F]fluorodeoxyglucose (FDG) in positron emission tomography (PET) imaging. FDG PET imaging has been utilized to study the characteristic metabolic changes in Alzheimer’s disease (AD), and as more molecular imaging tracers become available for human research, PET will likely assume many new roles for investigating more specific abnormalities, such as amyloid deposition, in the future.

FDG is a glucose analog that images glucose metabolism and also illustrates neural firing. Different synapse activity, particularly excitatory activity from glutamate release, appears to change FDG uptake. AD will affect both brain infrastructure by decreasing the amount of cell bodies and synapses as well as decreasing synaptic activity, which are both changes that decrease the amount of FDG. AD is not a perfectly uniform process, and this is reflected by distinct progressive patterns of decreased FDG and decreased metabolism across different regions of the brain.

FDG enters the brain via blood flow, and then into brain tissue by both diffusion and facilitated transport. Once it enters the glia and neurons, FDG can be phosphorylated, a step that is essentially irreversible, but then cannot be processed further by the cells, effectively trapping the FDG in situ. The amount of trapping that occurs in the brain over the first 10–20 minutes is very high and constitutes over 80% of the uptake. Thus, after the first 10–20 minutes uptake phase, a pattern of FDG emerges that mirrors the distribution of glucose metabolism in all subcortical and cortical structures.
Treatment of Bipolar Mania
Authors: Post Robert M. , Janicak Philip G. , DelBello Melissa P. , Ginsberg David L.
Published: August 2016

While severity of manic episodes can be successfully reduced, repeated recurrences are common with ~40% of patients meeting criteria for rapid cycling after aggressive treatment. Manic episodes present much earlier in children of bipolars and due to unique presentation physicians often mistakenly diagnose such children with attention-deficit/hyperactivity disorder. Differential symptoms include suicidal thoughts, grandiosity, hallucinations, and depressive withdrawal. Such children may require the usual combination treatment with a mood stabilizer and an antipsychotic, with the addition of a stimulant as well. Treatment of adults and children often includes second-generation antipsychotics, which have increasingly shown efficacy both as monotherapy and adjunctive treatments of acute mania. Most recently, some anticonvulsants have demonstrated acute antimanic properties as well and more studies of their role in bipolar disorder are underway.
The Expanding Role of Antipsychotics
Authors: Janicak Philip G.
Published: August 2016

Antipsychotics have been utilized in the treatment of bipolar disorder for many decades and were the mainstay of treatment before lithium was reintroduced in the late 1960s. Today, many bipolar patients who present with psychotic features are misdiagnosed and prescribed an antipsychotic for another disorder. Estimates of psychotic symptoms in bipolar disorder, particularly during a manic episode, are ≥50% by clinical assessment and even higher by individual reports. Thus, antipsychotics are frequently used: as first treatment for psychosis not recognized as bipolar disorder, and as an adjunct to a mood-stabilizing agent in bipolars with psychotic symptoms.

Most recently, antipsychotics have been examined for their mood-stabilizing properties as well (Slide 9). One may conceptualize using a selective serotonin reuptake inhibitor (SSRI) antidepressant for disorders such as panic disorder or obsessive-compulsive disorder, and using an antiepileptic as a mood-stabilizing agent; however, it is more difficult to accept that an agent approved for treatment of psychosis can be a primary therapy for bipolar disorder. Data from the monotherapy trials suggest that second-generation antipsychotics (SGAs) are at least as effective as lithium and valproic acid for acute mania. There is a very large database indicating that SGAs can be utilized as monotherapy for acute mania. However, there is limited data on the role of these agents in prevention of relapse and recurrence and in their efficacy for depression in the context of bipolar disorder. More studies will be needed to clarify whether SGAs should be used as monotherapy or whether they would be best used as augmenting agents in severe and psychotically manic or depressed patients.
Prevalence and the Shift in Age of Onset
Authors: DelBello Melissa P.
Published: August 2016

Bipolar disorder is presenting at a younger age of onset. In the past, many children with bipolar disorder were undiagnosed and ended up in juvenile detention centers. These children were also often misdiagnosed with severe attention-deficit/hyperactivity disorder (ADHD) or conduct disorder. In addition, an increased prevalence rate of substance use disorders and possibly stimulant prescriptions may be responsible for the shift in age of onset of bipolar disorder. The most compelling epidemiological observations have come out of the Netherlands, where they typically treat ADHD behaviorally rather than with stimulants. Childhood bipolar disorder remains unidentified in the Netherlands despite aggressive searching, whereas adolescent and adult bipolar disorder has been found in numbers similar to those in the United States. This provides cross-sectional epidemiological evidence that stimulants may be shifting the age of onset in patients who are presenting with potentially prodromal bipolar symptoms. Lastly, several researchers speculate that trinucleotide repeats in the DNA (deoxyribonucleic acid) may be responsible for so-called genetic anticipation phenomenon, by which expansion of trinucleotide repeats in successive generations may be shifting the age of onset to an earlier age. These are just some of the mechanistic possibilities for why we are seeing a shift in the age of onset of bipolar disorder.

Lewinsohn and colleagues found that the lifetime prevalence of adolescent bipolar I and II disorder is ~1%, with a 5% lifetime prevalence rate of subsyndromal bipolar disorder. Many symptomatic children and adolescents do not meet full duration criteria for a hypomanic or manic episode, or they may be one symptom short of meeting criteria for the disorder.
Introduction—Recent Advances in Understanding and Treating the Anxiety Disorders
Authors: Stein Dan J. , Denys Damiaan
Published: August 2016

Anxiety disorders are the most common of the psychiatric disorders, with an estimated prevalence of 2% to 18% worldwide. Psychiatry is gradually progressing towards a clinical neuroscience with an improved understanding of the pathophysiology of psychiatric disorders, an individualized approach to diagnosis and treatment of patients, and the potential for early disorder detection and prevention. Recently, there has been not only a growing literature on effective interventions for anxiety disorders, but also new proof of principle treatment studies based on laboratory research.

Anxiety disorders are frequently discussed at international psychiatric conferences; however, the attention these disorders receive by researchers at large is often minimal compared with their overall contribution to the substantial clinical burden and economic costs of mental disorders. There are potential advantages for clinicians and researchers to convene for the purpose of reviewing recent advances in anxiety disorder research and to exchange ideas about future progress in this field. The Anxiety Disorders Association of America has sponsored highly productive meetings in the United States for many years as well as successful meetings in other countries. Positive outcomes from these meetings encouraged the initiation of an international conference series that centers specifically on anxiety disorders.
Everyday Problems in Treating Depression: Focus on SNRIs
Authors: Kasper Siegfried
Published: August 2016

Most effective antidepressants directly or indirectly increase the synaptic concentrations of serotonin (5-HT) and/or norepinephrine (NE) by blocking the reuptake of one or both of the neurotransmitters. This property was initially discovered with the tricyclic antidepressants (TCAs). Their various additional interactions at different receptors and ion channels are not required for antidepressant action, but are responsible for the poor tolerability and toxicity in overdose of the early antidepressants.

The selective serotonin reuptake inhibitors are effective and well tolerated. Selective norepinephrine reuptake inhibitors, such as reboxetine, also have proven antidepressant activity. A selective action on one or the other of the principal monoamines thus appears to be sufficient for antidepressant activity. The idea that a dual action on both neurotransmitters might produce greater efficacy in certain patients led to the development of the serotonin norepinephrine reuptake inhibitor (SNRI) antidepressants, which block the reuptake of both 5-HT and NE without the nonspecific, side-effect–inducing interactions of the TCAs. The three SNRIs—venlafaxine, milnacipran, and duloxetine—constitute a new class of antidepressants.

Antidepressant response rates rarely exceed 60% to 70% and remission rates are usually <50%. Although SNRIs clearly provide superior efficacy in certain populations, their use has not dramatically changed antidepressant therapy. The search for agents that are more effective, rapidly acting, and better tolerated continues. However, clinicians must find ways to better use the antidepressants that are available today. This supplement, based on a symposium held at the International Forum on Affective Disorders in Budapest in December 2007, discusses several everyday problems in the treatment of depression, with a focus on SNRIs.
Treatment of Comorbid Pain with Serotonin Norepinephrine Reuptake Inhibitors
Authors: Briley Mike , Moret Chantal
Published: August 2016

Comorbid chronic pain is common in depressed patients. It is predictive of a poor prognosis for depression and is a major risk factor for suicidal behavior. Depression and chronic pain may result from a common neurobiological dysfunction of monoamine cell bodies in the basal ganglia. Amitriptyline, which inhibits both serotonin and norepinephrine reuptake, is a preferred treatment of chronic pain although it is not officially indicated for this condition. Chronic pain can be modeled in animals where amitriptyline has been shown to be highly effective. Similar effects are obtained with the serotonin norepinephrine reuptake inhibitors milnacipran, duloxetine, and venlafaxine, whereas selective serotonin reuptake inhibitors (SSRIs) are only weakly active. Both animal and clinical studies of chronic pain show that dual-acting reuptake inhibitors are more active than selective norepinephrine reuptake inhibitors, which are, in turn, more active than SSRIs. A meta-analysis of placebo-controlled studies confirmed that dual-action antidepressants, but not SSRIs, were effective in reducing chronic lower-back pain. Milnacipran, duloxetine, and venlafaxine, have all been reported to be effective in a number of chronic pain conditions, including the treatment of fibromyalgia where their analgesic effects are independent of comorbid depression.
Introduction
Authors: Black Jed
Published: August 2016

Excessive daytime sleepiness (EDS) is a prevalent topic in clinical care. Tiredness, fatigue, lack of energy, and sleepiness are complaints commonly encountered by psychiatrists and other physicians. Many surveys and epidemiological studies indicate that pathological daytime sleepiness, which is sleepiness that interferes with an individual's function most of the time, occurs in 7% to 13% of the population. Studies of patients within primary care practices suggest that this population suffers an even greater prevalence of sleepiness than the general public. Estimates of 20% to 25% or higher have been suggested by studies of large samples of primary care patient populations. Causal or contributing factors leading to a patient's experience of EDS range from the process of simply chronically allowing too little time for sleep on an ongoing basis, to idiopathic but profound central nervous system (CNS)-mediated debilitating hypersomnolence. Common among the causes of EDS are insufficient sleep, circadian rhythm disorders such as delayed sleep-phase syndrome, sleep disorders such as obstructive sleep apnea (OSA), CNS-related disorders such as post-infectious syndromes or CNS injury or lesions, and drugs—prescribed or otherwise.