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.

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.

Serious mental illness is associated with a significant reduction in life expectancy of ≤30 years. Among patients with schizophrenia, mortality due to coronary heart disease is ∼50% higher than that of the general population.

Patients with schizophrenia have substantially higher rates of cardiovascular risk factors (smoking, high cholesterol, hypertension, physical inactivity, obesity/overweight, and diabetes) than the general population. Approximately 75% of individuals with schizophrenia smoke compared to ∼25% of the general population. Patients with schizophrenia also have lipid profiles that are significantly worse than those of individuals in the general population.

In 2004, more people died in Europe from suicide than from road accidents. The lifetime prevalence of major depression is 20% for women and 10% for men. Depression is a leading cause of disability and decreased quality of life. In spite of this, numerous studies have shown that only ~50% of depressed patients are recognized as such in primary care. In a recent international survey of everyday management of depression we observed that only ~15% of patients became symptom-free following treatment. In spite of this low level of remission primary care physicians and psychiatrist only rarely increased the dose of antidepressant or switched to another medication as unanimously recommended by different guidelines. Numerous studies have demonstrated the importance of maintaining treatment for ≥6 months after remission is obtained in order to prevent relapse and recurrence. However, a recent study reported that only 19% of a cohort of patients in primary care continued treatment for 6 months as recommended. Antidepressants can be very effective but only when used correctly at adequate doses and for a sufficient duration. Although new improved antidepressants are obviously desirable, a greater recognition of depression and its treatment by the correct use of currently available antidepressant drugs could greatly improve the management of this major public health problem.

When levodopa (L-dopa) is administered intravenously to patients with severe Parkinson's disease, a therapeutic response may be seen within a 1/2 hour. However, when the drug is administered orally in lower doses to less disabled patients, a delay of 1–2 weeks often occurs before motor deficits start to improve. Recent data from the Early versus Late Levodopa study suggest that maximum improvement at a fixed dosage may take ≤3 months to develop. A nonspecific feeling of well-being and reduced tiredness are often the first benefits to occur, followed by greater alacrity and less stiffness. Rest tremor is slower to improve, but may eventually disappear altogether and remain well controlled throughout the rest of the course of the malady. Gait, balance, and speech may also improve, but the effect is usually more modest and a decline is common after several years of sustained treatment.

Until recently, little was known about the epidemiology of attention-deficit/hyperactivity disorder (ADHD) in adults. Bottom-up studies following children with ADHD into adolescence had shown variable rates of persistence, some of which depended on the definitions used. The traditional diagnosis was complicated by the introduction of the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, which stated that ADHD could be diagnosed with inattentive symptoms alone. This resulted in diagnostic inconsistency as earlier investigations demanded the presence of hyperactivity while others did not. Diagnosis also depended on the site, the cohort, whether interviews versus rating scales were employed, and whether the subject or their parent were the source of information.

There are several important issues regarding the manner in which medications are tested prior to their release and monitored after approval that must be appreciated in considering issues related to cardiovascular safety of medication treatments for attention-deficit/hyperactivity disorder (ADHD) in adults. First, patients treated in clinical trials are not necessarily representative of those seen in practice settings, as specific inclusion/exclusion criteria in studies limit a variety of psychiatric, medical, and social factors that could potentially introduce confounds related to the collection and/or interpretation of efficacy, tolerability, and safety data. However, many of these factors are present in patients treated in clinical practice. In addition, the manner in which medications are administered in clinical trials does not necessarily replicate the way they are used in the community. Often, there are differences in titration schemes and dosing options. Also, in clinical trials, drugs are rarely studied in combination, although they are often used in this manner in practice settings. Further, Phase III clinical trials (at least in psychiatry) often do not enroll a large enough sample to evaluate infrequently occurring adverse events. Rather, the predominance of information regarding rare side effects is derived from voluntary reports made after a drug comes to market—and therefore likely under-reports the phenomenon. Finally, information regarding drug safety that comes to practitioners in the form of medication warnings or advisories may reflect concerns that extend beyond the strict interpretation of clinical trials data. These and other issues represent major obstacles in attempting to fully understand issues related to safety and tolerability of medication in “real world” settings.

Adult attention-deficit/hyperactivity disorder (ADHD) and the spectrum of depressive disorders have high overlapping prevalence rates. Rates of depression in adults with ADHD and rates of ADHD in depressed adults provide an important epidemiologic background for clinicians treating either or both of these populations. There is a distinctive phenomenology of ADHD and depression, and distinctive diagnostic issues that present with the coexistence of these two disorders.

Creativity in the context of neurologic illness is extremely complicated, but fascinating and inspiring to those who study it. Artistic people with degenerative diseases often are still compelled to engage in their creative talents after developing a neurologic illness. In some cases, people with these disorders even develop new abilities that did not exist prior to onset of illness. Those who study creativity and dementia must first address a fundamental neurologic question: Where in this elegant structure does the ability to produce art come from?

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.

As a result of clinical, epidemiological, neuroimaging, and therapy studies that took place in the late 1980s, obsessive-compulsive disorder (OCD) has been well-characterized in the field of anxiety disorders. Other disorders attracted attention for their similarities to OCD, and were located in the orbit of the disorder. OCD has become known as the “primary domain” of a scientific “metaphor” comprising the putative cluster of OCD-related disorders (OCRDs). It is a “paradigm” with which to explore basal ganglia dysfunction. The OCRDs share common phenomenology, comorbidities, lifetime course, demographics, possible genetics, and frontostriatal dysfunction (particularly caudate hyperactivity.) The adoption of this metaphor analogy has proven useful. However, 15 years since its emergence, the spectrum of obsessive-compulsive disorders remains controversial. Questions under debate include whether OCD is a unitary or split condition, whether it is an anxiety disorder, and whether there exists only one spectrum or several possible spectrums. Further work is needed to clarify obsessive-compulsive symptoms, subtypes, and endophenotypes. There is need to integrate existing databases, better define associated symptom domains, and create a more comprehensive endophenotyping protocol for OCRDs. There is also a need to integrate biological and psychological perspectives, concepts, and data to drive this evolution. By increasing research in this field, the OCD spectrum may evolve from a fragmented level of conceptualization as a “metaphor” to one that is more comprehensive and structured.

In discussions of diversion and misuse of medications in adult attention-deficit/hyperactivity disorder (ADHD), the word “misuse” is intentionally used. Abuse of a medication refers to excessive use of a drug to achieve a “high,” which may result in addiction to the medication and which causes dysfunction in a patient's life. However, misuse refers to usage of a medication without a prescription or for reasons other than that which it was prescribed. Diversion refers to the diverting of legally prescribed medication into illegal use by other than the patient. Sahakian and Morein-Zamir recently discussed the use of cognitive-enhancing drugs by individuals with a variety of disorders as well as off-label and non-prescription use by the general public. In addition to inappropriate use of medications, patients with ADHD often turn to other substances that are detrimental to their health, such as nicotine.