In 1906, the German physician Alois Alzheimer provided the first description of the “serious and peculiar disease” of mental deterioration that would later on take his name. Alzheimer described the classic pathology of neuritic plaques and neurofibrillary tangles in an affected patient. Since that time, understanding of Alzheimer's disease (AD) has progressed substantially, although the ability to influence disease progression has not progressed as rapidly. It is likely that over the next decade these advances will lead to earlier diagnosis and development of disease-modifying treatments for AD.

It is known that two variants of AD exist: a rare hereditary form and a more prevalent sporadic form. As with many neurodegenerative diseases, early clues to the pathology of AD came from the inherited form of the disease. Hereditary links include mutations of the amyloid precursor protein (APP) and the presenilins, both of which are integrally involved in the cascade of events that leads to the deposition of the 42-amino-acid amyloid β protein and the eventual cell death responsible for AD.

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.

Since the development of selective serotonin reuptake inhibitors there has been a widening of the definition of depression and a decrease in the placebo-drug difference in controlled studies. In the early 1960s, ~33% of depressed patients improved with placebo and 66% with active compounds and current controlled studies suggest that the situation has certainly not improved. The Sequenced Treatment Alternatives to Relieve Depression Study found that response rates to new compounds after the failure of the first antidepressant are low. The monoamine hypothesis of depression was formulated in the mid 1960s based on the antidepressant efficacy of the monoamine reuptake inhibitors, monoamine oxidase inhibitors and the depressogenic effects of reserpine as a monoamine depleter. However, no monoamine-related finding has been found that is diagnostic for depression. A second major hypothesis regarding depression has been the stress cortisol hypothesis. However, blood cortisol levels are not diagnostic of depression. Every psychiatric clinician is convinced that there are patients for whom antidepressants have made the difference between life and death. However, physicians may generalize unjustifiably based on single dramatic cases to a much larger diagnostic group. Perhaps there are many causes of different types of human sadness, and perhaps only some of these involve mechanisms related to monoamines. Thus, Robert H. Belmaker, MD, suggests that perhaps only some kinds of depression are responsive to monoamine affecting antidepressants.

Alzheimer's disease was first described by Alois Alzheimer in 1906, and first appeared in the medical literature in 1907. The medical community has been ruminating about Alzheimer's disease for over 100 years, and only recently have Alzheimer's disease therapies begun to emerge. However, many vital questions remain, pertinent not only to physicians but to the public at large. For example, how likely is it that a particular individual will develop Alzheimer's disease? What can one do to avoid getting Alzheimer's disease? What are the current and promising treatments for Alzheimer's disease? While there are grey areas, the Alzheimer's disease field is beginning to find solid answers to these questions. There are risk factors that individuals can control, and emerging treatments are cause for optimism.

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.

Schizophrenia and bipolar disorder are two debilitating mental health disorders, both of which manifest early in adulthood and are associated with severe impairment as well as increased suicide risk. In addition, factors affecting disease severity, such as substance abuse, are often prevalent in these patient populations. In the United States, the prevalence of bipolar disorder is believed to be ~3.5%, while the rate for schizophrenia is ~1%. Although each disorder presents with its own symptom profile, the approaches to treatment are similar and include early diagnosis and use of psychosocial therapy. Research initiatives, such as genetic studies, are used in both disorders as well. For schizophrenia, treatment typically includes the combination of an antipsychotic and psychosocial intervention. For bipolar disorder, clinicians commonly prescribe mood-stabilizing drugs (eg, lithium, valproic acid) as first-line treatment. Many of the second-generation antipsychotics have been approved by the US Food and Drug Administration for bipolar disorder treatment in the manic phase. Patients who are affected by either disorder also face the challenges of treatment nonadherence, which can be affected by substance abuse and can hinder symptom remission as well as spur unnecessary medication switches due to nonresponse. Family members play a key role in the treatment of either disorder.

This expert review supplement focuses on treatment options and research strategies being utilized for the management and advanced understanding of schizophrenia and bipolar disorder. Research examining the pharmacology of commonly used medications for the treatment of both disorders is also presented.

Understanding the epidemiology of major depressive disorder (MDD) and the neurobiologic theories behind depression and antidepressant treatment is vital for physicians who must identify and treat patients with this disorder. The epidemiology of MDD reveals that this disorder is widespread: the lifetime prevalence of MDD is estimated to be ∼17% and the 12-month prevalence is ≥7%, according to the National Comorbidity Survey Replication. Epidemiologic studies suggest that in any 30-day period, 2% to 5% of the United States population meet criteria for MDD. In addition, nearly twice as many women as men (21% versus 13%, respectively) are affected by a depressive disorder during their lifetimes. These numbers reveal a vast population of people affected by MDD, making depression a tremendous social and medical concern.

In this issue of CNS Spectrums we examine some underserved populations who continue to have real unmet needs. For example, patients in forensic and correctional settings have serious psychopathology resulting in substantial morbidity and mortality, and yet human subjects concerns have led them to be very much understudied. Likewise, patients with treatment-resistant obsessive-compulsive disorder (OCD) are quite common, and yet, compared with other disorders such as schizophrenia, few resources have been devoted to addressing their substantial functional disability. Finally, cognitive dysfunction in the elderly is an enormous problem, yet little work has addressed the role of gonadal dysfunction, or male menopause, in specific cognitive deficits of the elderly.

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.