Alzheimer’s disease (AD) research is progressing rapidly and on multiple fronts. Advances are being made in early diagnosis, neuroimaging, and biomarkers; optimal care uses currently available medications and strategies; and new therapies are emerging. Early diagnosis is necessary for optimal patient management. Biomarkers are critical to early diagnosis, and biomarker development is dependent on better understanding of disease pathophysiology (Slide 1). The discussions in this supplement examine how progress in AD research can be translated into clinical care.

Primary care practitioners (PCPs) provide most of the care of patients with AD, and these clinicians are optimally poised to discover new cases emerging among elderly patients. Caregivers are most likely to voice concerns about declining memory in a family member to a PCP before seeking specialty evaluation. PCPs, however, have little time to devote to complex assessments and cannot have specialty-level expertise in all disorders. PCPs must have clinical tools that assist them in rapidly identifying potential problems and triaging them for further evaluation or specialty referral.

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.

Parkinson's disease was first described in 1817 by James Parkinson. Based on his observation of only six individuals, Parkinson accurately described the resting tremor and festinate gait, bradykinesia, and postural instability associated with the disease today. Parkinson's disease primarily affects people >50 years of age and causes progressive neurological degeneration, physical disability, and worsening quality of life.

Consequently, most currently available drugs aim to restore striatal dopamine signaling. This can be best reached by increasing the supply of dopamine with oral levodopa (L-dopa), but also by stimulating dopamine receptors directly using dopamine agonists, or by inhibiting the reuptake of endogenous dopamine. Unfortunately, mainly due to the short half-life of L-dopa and the erratic absorption of oral L-dopa (causing pulsatile dopaminergic stimulation) these treatment strategies become increasingly ineffective in the course of this disease, and motor complications may further reduce the quality of life in these patients.

In the mid-1970s, attention-deficit/hyperactivity disorder (ADHD) was still believed to be a childhood disorder that disappeared with the onset of adolescence. At this time, Wender studied a cohort of adults presenting with ADHD-like symptoms, all of whom had been diagnosed with ADHD in childhood. Wender prescribed psycho-stimulants, which successfully produced a response in the adults, thus fostering research into adult ADHD.

The task of prescribing, dosing, and switching antipsychotics is generally characterized by a process of trial and error, often resulting in suffering from side effects and/or lack of response while searching for the optimum treatment. Clinical trials often inaccurately predict optimum doses and titration schedules, leaving prescribers without precise guidance for how to use newer therapies in clinical practice. A tremendous amount of individual response variability further complicates the task of effectively dosing antipsychotics.

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.

Several of this month's articles and interviews touch on themes that relate to spectrum phenomena as well as the Diagnostic and Statistical Manual of Mental Disorders developmental process.

First, Darrel A. Regier, MD, MPH, director of the Division of Research at American Psychiatric Association, discusses, in an interview with CNS Spectrums, the developmental process for DSM-V. He emphasizes the use of dimensional measures to determine both thresholds for disorders, and to assess response to treatments. He also highlights a focus on spectra of disorders that cut across traditional diagnostic boundaries as one way to deal with issues of comorbidity. Finally, he discusses new approaches to the five DSM axes, and the need to link together the DSM and International Classification of Diseases processes. Three other articles in this issue also clearly relate to these obsessive-compulsive spectra issues.

For example, Leonardo F. Fontenelle, MD, PhD, describes how, although much attention has been paid to patients who lack insight into their obsessional beliefs, less importance has been given to individuals with obsessive-compulsive disorder (OCD) who display perceptual disturbances typically found in psychotic disorders, including schizophrenia, schizoaffective disorders, or mood disorders with psychotic features. The authors call attention to a phenomenon that has been neglected in the psychiatric literature (ie, the occurrence of hallucinations and related phenomena in patients with OCD). They describe five patients with OCD with hallucinations in several different sensory modalities, including the auditory, the visual, the tactile, the olfactory, and the cenesthetic modalities, and suggest that further psychopathological research should clarify the clinical significance of hallucinations among patients with OCD.

According to the National Comorbidity Study Replication, >25% of people in the United States have some type of mental illness. The prevalence of serious mental illness has been estimated at 6.2%. Patients with severe and persistent mental illness have significantly reduced life expectancy relative to the general population. On average, pooled populations of public sector inpatients and outpatients die 25–30 years earlier than unaffected individuals in the general population, according to recent data from multiple states in the US. Schizophrenia and bipolar disorder together account for ∼23,000 deaths and >20 million life-years of disability worldwide each year. The most common cause of mortality in these individuals is cardiovascular disease (CVD), not, as might be assumed, suicide (Figure 1). Heart disease and stroke are the most common causes of death in patients with serious mental illness, accounting for ∼40% of deaths, underlying the dramatically decreased life expectancy in these patients.

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).

Fibromyalgia syndrome (FMS) presents with widespread soft tissue pain. Common comorbidities include severe insomnia, body stiffness, affective symptoms, irritable bowels, and urethral syndrome. A 1990 research classification depends on a history of widespread pain and prominent tenderness to palpation at 11 or more of 18 specific tender points. It is a criteria-based diagnosis rather than one by exclusion and can accompany other medical conditions. FMS occurs worldwide, and can present any age, but is most common in adult females. Although numerous studies and reviews contend that FMS may be caused by psychological stress such as sexual abuse, a critical epidemiological review fails to support that concept. Existing data suggest that some individuals with FMS may have a dysregulated physiological stress response system that predates the onset of symptoms.

Epidemiologic studies have shown a significantly greater likelihood of substance misuse in persons with psychiatric disorders. One of the largest studies showed that 60.7% of people with bipolar I disorder had a lifetime diagnosis of a substance use disorder (SUD). Moreover, 32% of individuals with any mood disorder, including depression, were found to suffer from substance abuse or dependence. In general population surveys, it has been found that the presence of a mood disorder at least doubles the odds of having SUD.

Insomnia is an extremely prevalent condition, affecting large segments of the population. There is a broad spectrum of risk factors for this disorder, most of which are various types of social, economic, or interpersonal stressors. Risk factors include age, female gender (especially post- and perimenopausal women), divorce/separation/widowhood, psychiatric illness (mood and anxiety disorders), medical conditions, cigarette smoking, alcohol consumption, coffee consumption, and certain prescription drugs. It is important to recognize that the symptom of insomnia (ie, disturbed or poor quality sleep) may be due to the presence of another primary sleep disorder, such as restless legs syndrome, periodic limb movements in sleep, or sleep apnea.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline, functional disability, and neuropsychiatric symptoms. Initial diagnosis is often delayed to a point when there is significant neurodegenerative pathology and secondary downstream pathogenic sequelae. The disease should be diagnosed during its earliest stage, as this would likely represent an ideal therapeutic window for disease-modifying therapies. Despite recent research that has focused on defining the clinically identifiable at-risk phase that precedes AD, reliable criteria for identifying patients in the prodromal to incipient stages of AD remain elusive.

In addressing the prodrome of AD, it has been clearly recognized that there are age-inappropriate cognitive declines that fall short of meeting the criteria for dementia. Most broadly, patients in this category have been classified as cognitively impaired not demented (CIND). In epidemiological studies, it has been estimated that 19% to 37% of patients ≥65 years of age are CIND. Conditions within the taxonomy of CIND include age-associated memory impairment (AAMI), age-associated cognitive decline (AACD), and mild cognitive impairment (MCI) (Slide 1).

AAMI is defined psychometrically by memory test scores that are ≥1 standard deviation below scores of young healthy control patients. AACD is characterized by scores in any cognitive domain that are ≥1 standard deviation below age- and education-adjusted normal measures. MCI is identified by memory function at a level ≥1.5 standard deviations below age- and education-adjusted means. Of these three conditions, MCI has been investigated most thoroughly and is defined by a clinical phenotype.

Sleep dysfunction is common among patients with Parkinson's disease and occurs in approximately two thirds of patients. The problems range from nocturnal issues such as difficulty with sleep initiation, sleep fragmentation, disturbance of circadian rhythm, and rapid eye movement sleep behavior disorder, to daytime problems such as excessive daytime sleepiness. Frequent nighttime awakening and sleep disruption are the most common sleep problems in Parkinson's disease. Dopamine plays an important role in maintaining wakefulness. To improve sleep in Parkinson's disease, it is important to achieve the critical balance of adequate dopaminergic therapy and control of symptoms. Increased dopaminergic agents can cause dyskinesias and painful dystonia, and undertreatment can cause nighttime akinesia, rigidity, and worse quality of sleep. Other nondopaminergic drugs commonly used in Parkinson's disease can also affect sleep. In patients with advanced Parkinson's disease, deep brain stimulation of the subthalamic nucleus has a favorable impact on sleep quality and sleep architecture.