This supplement to CNS Spectrums focuses on exciting emerging data on therapeutic approaches that can help the clinician with difficult-to-treat patients. Over the last decade, there have been tremendous advances in our conceptualization of difficult-to-treat patients, including diagnostic, psychotherapeutic, pharmacotherapeutic, and somatic approaches. A series of articles addressing these advances in the field are presented in this supplement.

Edna B. Foa, PhD, has been a leading expert in cognitive-behavioral therapy (CBT) for anxiety disorders for many years. Foa and colleagues provide a thoughtful analysis of the particular components of CBT that may be responsible for its efficacy in anxiety disorders. This article goes beyond simple trials looking at the efficacy of CBT or combined treatment with pharmacotherapy and CBT. Foa and colleagues identify individual treatment and patient factors as well as the interaction between the two, that may influence treatment response. Treatment of posttraumatic stress disorder is used as a model for helping us understand this exciting work.

Next, Waguih William IsHak, MD, presents important data about the use of practical and pragmatic treatment paradigms in patients with mood and anxiety disorders. Dr. IsHak emphasizes the importance of standardized structured approaches to facilitate understanding of the breadth of psychopathology present in the patient. The model Dr. IsHak proposes for the evaluation and conceptualization of the patient facilitates the integration of biological factors, psychological factors, and psychosocial variables. His algorithms go beyond merely a technique for assessment and present a rational approach to therapy for patients. These algorithms are limited by existing data, but the steps elaborated within the algorithm are powerful and useful for the clinician. This article serves as a useful guide for both trainees and clinicians with many years in practice.

One of the major developments in psychiatry in the last decade is the development and widespread use of the new antipsychotics. The field has moved from the typical dopamine D2-blocking neuroleptics into the new era of antipsychotics with the addition of the serotonin 5-HT2A properties to the classical D2 antagonism. These “atypical” antipsychotic drugs (APDs) provide us with new tools with which to treat our patients. However, do we really know how to make the most of these new medications? Are we equipped with the knowledge to do the best matching between the different APDs and the patients that we will see in an hour's time?

One potential way to get the maximum therapeutic effect of a specific medication is to improve the matching between the compound and the patient that we are seeing, ie, to try and get the best medication for the patient. For example, the medication one would choose for a patient with cognitive decline and a tendency to be overweight, would likely be different from an antipsychotic one would select for a patient with the same diagnosis, but who is slim and has paranoid delusions. It is also intuitively clear to us that we should treat first-episode patients differently from those with a 20-year history of social decline. Similarly, a patient with pronounced affective component would receive a different treatment regimen from a patient who is affectively “flat.”

Although we have been hearing and reading a lot about all the different APDs, it would be quite accurate to postulate that a concise updated summary of the different APDs, examining them around four different critical axes, might be welcomed by our readers.

The topics covered in this supplement are: the differential receptor's profile of APDs and their clinical implications, the issue of cognitive impairment in schizophrenia and APDs, monitoring guidelines to assess metabolic abnormalities that may occur with APDs, and an update on treatment after first-episode psychosis.

Cognition in schizophrenia is a topic of major importance and steadily increasing interest. As evidence of this fact, the Mount Sinai School of Medicine Conference on cognition in schizophrenia has had increased attendance at each of its six meetings over the last 10 years. These meetings are official satellites of the International Congress on Schizophrenia Research, a meeting that has had skyrocketing attendance figures over the last decade. The articles in this issue of CNS Spectrum are among those presented at the latest Mount Sinai meeting, in April of 2003 in Colorado Springs, Colorado.

One of the factors that has lead to the increased interest in cognition is a clearer appreciation of the functional relevance of cognitive impairments. Since functional deficits are a major source of the indirect cost of schizophrenia and a major source of the reductions in quality of life seen in schizophrenia, which are substantial, cognition has the potential to be a major point of intervention. In addition to “purely cognitive” impairments, patients with schizophrenia have deficits in what is typically referred to as “social cognition” as well. This ability area is defined as the ability to understand social cues and affective displays. It may serve as a critical intermediate function that mediates the performance of socially skilled acts.

Approximately 40% of bipolar patients experience rapid cycling, and half of these suffer from ultra-rapid or ultradian cycling. These patterns are also common in children. Rapid-cycling bipolar disorder is difficult to bring to remission and often requires treatment with four or more classes of psychotropic medications. Lithium, even in combination with anticonvulsants or antidepressants, is often associated with residual episodic depressions. Concerns with adjunctive antidepressant treatment include their low response and remission rates and their tendency to cause switch into mania. Atypical antipsychotics and selected agents within the anticonvulsant class are becoming increasingly important in the treatment of rapid cycling. In the absence of clear treatment guidelines, the use and sequencing of drugs in complex combination treatment remains exploratory, but should be individualized based on careful prospective mood charting by the patient. Use of several drugs below their side-effect thresholds may prevent certain side effects. In children, long-term safety considerations are particularly important in the absence of a strong controlled clinical trials database.

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.

Anxiety disorders are highly prevalent, are increasing in incidence, affect individuals early in life, and significantly impact health care and quality of life. As such, they are serious public health problems that deserve attention now and in the future. Over the last 10–20 years, there has been marked improvement in pharmacologic and psychosocial interventions for anxiety. Due to their broad spectrum of efficacy against common comorbidities and lack of association with abuse and dependence, serotonergic and mixed serotonergic noradrenergic antidepressants are first-line therapies for anxiety disorders. Benzodiazepines are still widely used in clinical practice because they are well tolerated and work quickly and effectively. Other medications that are emerging as potentially useful for selected populations with anxiety include atypical neuroleptics and anticonvulsants. Cognitive-behavioral therapy (CBT) is at least as effective as medication for many patients with anxiety disorders and facilitates maintenance of benefit over the long term. Resilience, the capacity to bounce back from adversity, can be reliably measured with a psychometrically valid scale, the Connor-Davidson Resilience Scale. Compared with the general population, individuals with anxiety disorders exhibit decreased resilience. Studies have shown that pharmacologic treatment combined with CBT may increase resilience within 2–3 months. Emerging neurobiologic research indicates that noradrenergic pathways and 5-HT2 transporter efficiency may mediate effects on resiliency.

This academic supplement to CNS Spectrums high-lights the impact of the broader bipolar spectrum as a considerable public health concern, the side effects that must be considered in a risk/benefit analysis of effective pharmacologic treatments of bipolar disorder, and the state of the art of psychosocial interventions utilized to manage the disorder.

One important development in the conceptualization of bipolar disorder is that a common underlying endophenotype may mediate a range of presentations manifesting as the broader bipolar spectrum. This includes variants of bipolar disorder, such as bipolar II, cyclothymia, and mixed states; disorders characterized by affective instability, such as cluster B personality disorders; and disorders characterized by impulsivity associated with affective instability, such as impulse-control disorders. Since there may be various phenotypic expressions of a common underlying endophenotype, this may also help to explain the high rate of comorbidity found in bipolar disorder.

Mood and anxiety disorders are prevalent in all countries and cultures, which becomes obvious when standardized diagnostic and evaluation techniques are utilized. It is estimated that ~450 million people worldwide suffer from psychiatric illness. In the United States alone, epidemiologic research has identified that tens of millions of Americans suffer from major depressive disorder (MDD) annually, with many of them being in the prime of their adult lives. In addition to medical, personal, and social costs, depression is also believed to have a significant impact on work productivity. Further epidemiologic research indicates that nearly half of all individuals meeting lifetime criteria for MDD also have met criteria for a comorbid anxiety disorder. With an average age of 16 years for the onset of any lifetime anxiety disorder, anxiety disorders appear to predispose affected individuals to a substantial lifetime risk for MDD. In order to improve outcomes in depression and anxiety disorders, clinicians must enhance the entire process of recognition, diagnosis, and treatment.

Alzheimer's disease (AD) is a debilitating condition currently affecting 4.5 million elderly citizens in the United States alone. It is the most common form of dementia and is associated with significant disability. For many years the prognosis of the disease has remained largely unchanged. Those patients who develop AD face progressive cognitive and functional decline that ultimately shortens their life expectancy and destroys their quality of life. At the same time, the disease has a significant adverse impact on the lives of those family members who serve as caregivers. With the aging of the baby-boomer generation and the expected associated increase in the number of patients with AD, clinicians who treat the elderly will clearly be in need of some new answers. Recent advances in assessment, diagnosis, and treatment offer some hope for relief from this bleak prognosis.

Advances in AD include the establishment of clear diagnostic criteria, the validation of disease-specific assessment instruments, and pharmacologic and behavioral therapies for management of symptoms. A handful of medications that enhance cognition have obtained the approval of the Food and Drug Administration, and more are currently in development. Trials of existing medications have demonstrated benefit in the management of the psychiatric symptoms (eg, psychosis and agitation) typically associated with the disease. But much still remains to be done.

In the first article in this supplement, Michael A. Rogawski, MD, PhD, explains what is known about the pathogenesis and the behavioral and psychological symptoms of AD. He discusses the scientific basis for empirical therapies currently being used to relieve the symptoms of this disease, focusing on drug therapies approved by the FDA, including the newest AD medication to market memantine.

With our emphasis on treatment-refractory depression, one cannot help but think about recent media coverage and regulatory events surrounding antide-pressant therapy. The current debate about the safety of antidepressant therapy for children and adolescents stands out in particular.

Recently, a pediatrician attending a symposium at the University of Pennsylvania asked me whether I thought that primary care pediatricians should continue to prescribe antidepressants for children with depression and anxiety disorder. As is now well known, data have emerged suggesting a link between selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and an increase in suicidal ideation involving children and adolescents during clinical trials. It is important to bear in mind that no actual suicides occurred and that some of the “suicidal acts” were far from lethal and, arguably, not suicidal. Nevertheless, overall ~1 in 50 children on active medication—significantly more than those on placebo—had new-onset suicidal ideation or actions. The effect was most noticeable for venlafaxine and paroxetine and least noticeable for fluoxetine. As all of these drugs block the presynaptic reuptake of serotonin, it is not clear if the differences among these medications are real.