In September 2005, the National Institute of Mental Health published phase 1 results of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, a large-scale, double-blind trial comparing the relative effectiveness of five antipsychotics used to treat patients with schizophrenia: perphenazine, a conventional antipsychotic that has been commercially available since the 1950s, and four atypical agents—olanzapine, quetiapine, risperidone, and ziprasidone—that were introduced in the 1990s. The broad intention of the CATIE study is to determine if the atypical agents used offer any demonstrable clinical and public health advantages over the conventional agents. Concerns over costs and side effects (eg, pronounced weight gain and lipid disturbances) associated with the newer, atypical antipsychotics, as well as doubts about superior efficacy relative to older, conventional agents, served as an impetus to the trial.

The study design chosen for the CATIE study—that of a “large, simple” trial—sought to bypass the limitations of clinical studies that are conducted when pharmaceutical companies seek regulatory approval of a new medication. Studies done in pursuance of drug approval attempt to establish safety and efficacy in controlled clinical settings so as to determine if a drug works at all, and if its use entails specific side effects. Hence, they are typically placebo-controlled and short-term, enroll a small homogeneous population (eg, initially hospitalized patients with no psychiatric or medical comorbidities), forbid or restrict the use of concomitant medications, and take as their endpoints well-defined side effects and measures of core psychopathology. These restrictions heighten the risk that the study findings may not be widely applicable to patients outside the confines of the protocol.

Uncontrollable episodes of emotional expression occur in a variety of neurological conditions. This emotional disinhibition syndrome is characterized by episodes of crying or laughing that are unrelated to or out of proportion to the eliciting stimulus. This syndrome is common among patients with amyotrophic lateral sclerosis, multiple sclerosis, stroke, and traumatic brain injury and a variety of terms and definitions have been used to describe it. The confusing nomenclature has been a barrier to understanding, diagnosis, and treatment of this disorder. The authors propose a unifying term, involuntary emotional expression disorder (IEED), and provide diagnostic criteria for this disorder.

Despite a high prevalence in the United States, insomnia remains underdiagnosed and undertreated. Extensive research has identified several factors that contribute to the inadequate treatment of insomnia, including the failure of patients to report insomnia to physicians, limited physician training, and physician misconceptions about the risks associated with hypnotic medications. To achieve optimal patient outcomes, physicians differentiate acute from chronic insomnia and distinguish primary insomnia from sleep disorders that occur with comorbid conditions, most notably psychiatric illnesses such as circadian rhythm disturbances. In addition, they utilize sleep hygiene measures, behavioral therapy, and/or pharmacologic medications to improve sleep problems in patients with insomnia. Newer nonbenzodiazepine receptor agonists are effective with fewer side effects than older benzodiazepine agonists; however, in 2005 a National Institutes of Health panel on chronic insomnia management indicated that clinical trials are needed to establish the long-term benefits of the newer drugs. Since 2005, data from clinical trials lasting 6 months to 1 year have been published for hypnotics including eszopiclone, zaleplon, and zolpidem extended-release. As the result of potentially altered dosing and monitoring, elderly patients require special consideration.

Sexual desire, arousal, and orgasm are mediated by complex—and as yet not fully understood—interactions of the somatic and autonomic nervous systems, operating at cerebral, spinal, and peripheral levels. Furthermore, neural activity within these systems is modulated by the presence of steroid and peptide hormones, which affect male and female response differentially. At the central level, dopaminergic and serotonergic systems appear to play a significant role in various components of sexual response, although adrenergic, cholinergic, nitergic, γ-aminobutyric acidergic, and other neuropeptide transmitter systems may contribute as well. At the peripheral level, adrenergic, cholinergic, and nitergic activation mechanisms control vascular changes that underlie vaginal lubrication and penile erection. In addition, these systems respond to descending brain and spinal influences that generate orgasmic response. Disruption of endocrine, neural, or vascular response—caused by aging, disease, surgery, or medication—has the potential to lead to sexual inadequacy. At the same time, psychological and relationship factors play an important role in healthy sexual response and may enhance or impair sexual functioning.

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.

Specific phobia is the most prevalent of the anxiety disorders. Although there have been relatively few studies of its psychobiology and pharmacotherapy, there is a rich laboratory of literature on fear conditioning and extinction and a clear evolutionary perspective. Advances in the cognitive-affective neuroscience of fear processing may ultimately lead to new approaches to the clinical management of phobias.

There is considerable symptom overlap and high levels of comorbidity between anxiety disorders and depression. The recognition of this comorbidity has both academic interest and clinical significance. Epidemiological studies have demonstrated that depressed individuals with a history of anxiety disorders are at increased risk for hospitalization, suicide attempt, and greater impairment from the depression. These individuals also tend to have a more chronic course of depression, as observed in psychiatric patients, primary care patients, and epidemiological samples. Van Valkenberg and colleagues reported that depressed patients with anxiety had poorer outcome and greater psychosocial impairment than those without an anxiety disorder. In the National Institute of Mental Health Collaborative Depression Study, the presence of panic attacks predicted a lower rate of recovery during the first 2 years of the follow-up interval. Similarly, Grunhaus found poorer outcome in depressed patients with comorbid panic disorder than in depressed patients without panic. In an 8-month follow-up study, depressed primary care patients with a history of generalized anxiety disorder (GAD) or panic disorder were less likely to have recovered from their depressive episode.

Gaynes and colleagues prospectively followed primary care patients with major depressive disorder (MDD) every 3 months for 1 year after their initial diagnostic evaluation. At baseline, half of the original 85 patients had a coexisting anxiety disorder, the most frequent being social phobia (n=38). Twelve months after intake, 68 of the patients were available for the final interview. Those with a comorbid anxiety disorder were significantly more likely to still be in an episode of depression (82% vs 57%; risk ratio=1.44; 95% CI 1.02-2.04), and they experienced more disability days during the course of the 12 months than the depressed patients without an anxiety disorder (67.1 days vs 27.5 days).

In human terms, resilience is an ability to cope with stress and varies with context, time, age, gender, and cultural origin. Resilience shifts the focus of psychological investigation onto increasing the positive rather than reducing the negative. Inquiry into resilience has evolved from descriptions of resilient qualities, to discovery of the process to attain resilience, to uncovering the motivation to reintegrate in a resilient manner. Much of the research on resilience has focused on children in settings such as family violence, extreme poverty, war, and natural disasters. A coherent pattern of characteristics associated with successful adaptation has emerged. Salient characteristics include commitment, dynamism, humor in the face of adversity, patience, optimism, faith, and altruism. As such, resilience may represent an important target of treatment in anxiety, depression, and stress reactions. Resilience can be quantified, but available measures need to be validated transculturally. There exist many possible determinants of resilience, including neurobiologic, genetic, temperament, and environmental influences. Resilience is modifiable on individual and cultural levels. Posttraumatic stress disorder is an example of a serious disorder associated with impaired stress coping that can improve with treatment.

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.”