From medical school, we all know the secret code words: “functional”, “supertentorial”, “idiopathic”, and so forth. These, of course, are some of the ways that physicians may refer to patients for whom they cannot make a definitive diagnosis. Such patients, often labeled “somatisizers”, frequent primary care and specialty care physicians' offices as well as emergency rooms.They present with complaints of a variety of aches and pains, fatigue, insomnia, poor concentration, diarrhea, constipation, etc. Any one of these could be the initial signal of a serious medical problem but for this group of patients nothing can be found on physical examination or laboratory and blood tests.

Depending on the specialty of the physician, somatisizers receive a variety of diagnoses. Neurologists cite tension headache, rheumatologists cite fibromyalgia, internists cite chronic fatigue syndrome, gastroenterologists cite irritable bowel syndrome, and psychiatrists cite depression or an anxiety disorder. With the exception of the latter, no treatment has proven particularly successful, and many of these patients, regardless of the diagnosis, wind up being prescribed antidepressants. Does that mean that all somatisizers are suffering from underlying depression or anxiety? Some insist that is the case, but advocacy groups and many patients themselves resist that classification. Physicians are often afraid to suggest to patients that what they are complaining about is really due to a psychiatric problem, fearful of insulting the person. Some doctors, fearing they might overlook something, send the patient for increasingly sophisticated tests, running up healthcare costs and exposing patients to some risk. Inevitably, a test result comes back on the border of abnormality, thus, creating a reason to push forward with even more tests.

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study for schizophrenia was designed to independently evaluate the effectiveness of antipsychotic treatment in “real-world” patients. To assess the effectiveness of the conventional antipsychotics compared to the atypicals as well as the differences among the atypicals, patients were randomized to one of four atypical antipsychotics (olanzapine, quetiapine, risperidone, ziprasidone) or a representative conventional antipsychotic (perphenazine). Effectiveness was defined by time to discontinuation and duration of successful treatment. Time to “all-cause” discontinuation reflects both efficacy (ability of a drug to reduce symptoms) and safety/tolerability. Phase I revealed discontinuation rates ranging from 64% for olanzapine to 82% for quetiapine.

Differences among the medications may be important in the selection of a drug for a particular patient. Physicians should involve the patient in choosing their medication by inquiring about the patient's past experience with medications and side effects, educating the patient on the risk-benefit ratio, and considering the patient's preference. To demonstrate how results of the CATIE study can contribute to the knowledge of practicing clinicians, this monograph presents a representative clinical case patient and illustrates how the CATIE safety and efficacy data has important implications for the patient.

Anxiety disorders are the most prevalent of the psychiatric disorders, account for a significant proportion of mental illness costs, and include some of the most disabling medical disorders. Anxiety disorders, which currently include the obsessive-compulsive disorders, continue to be poorly diagnosed and undertreated across a broad range of countries. It is possible that the universal experience of anxiety as an adaptive emotion makes it more difficult for patients and clinicians to conceptualize symptoms in terms of psychopathology.

Nonetheless, there have been significant advances in our understanding of anxiety and obsessive-compulsive disorders, and in our ability to manage these conditions successfully. Research on anxiety and obsessive-compulsive disorders exemplifies the goals of translational investigation; preclinical work has not only allowed an exploration of known clinical phenomena, but has also led directly to novel clinical interventions. Investigators around the globe are continuing to contribute to research on anxiety and obsessive-compulsive disorders.

Bipolar disorder is a seriously debilitating psychiatric disorder that greatly affects patients and their loved ones. Although bipolar disorder is one of the most frequently occurring mental disorders worldwide, many patients, particularly those with mixed mania, remain misdiagnosed. Compared to pure mania, mixed episodes of bipolar disorder present with symptoms that can be more challenging to treat. However, proper diagnosis and early treatment can usually alter the course of the illness, and remission is certainly possible.

This expert roundtable supplement reviews the differences between acute manic and mixed episodes in patients with bipolar disorder, explains proper dosing and the advantages of different dosage formulations, and identifies the rationale for monotherapy and combination therapy in these patient populations. The aim is to educate clinicians about ways to diagnose and treat the mood state aggressively and safely, especially in light of the many new treatment options available.

Quality-of-life issues in healthcare have come to be of paramount importance for a population that increasingly expects healthcare not only to treat major illnesses but also to optimize normal levels of physical and psychosocial functioning and overall well-being. Healthcare providers have also increasingly appreciated the impact that adverse effects of treatment can have on quality of life, as well as on compliance with and the effectiveness of treatment.

Many functional impairments and adverse treatment effects take the form of clinical complaints that patients and caregivers typically report to their healthcare providers without prompting. Other adverse effects are not so obviously clinical or treatment-related, and patients may not be inclined or may even be reluctant to bring them up when talking with the provider. Impairment of sexual function is a problem of this kind.

Sexual dysfunction appears to be common and frequently underrecognized in certain patient populations. For example, it has been estimated that 25% to 63% of women and 10% to 52% of men with epilepsy have some form of sexual dysfunction, yet in clinical reviews of sexual disorders, epilepsy is not listed as one of the medical conditions commonly associated with impaired sexual function.

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.

Schizophrenia is a complex disorder characterized by a broad spectrum of psychopathology. Aggressive efforts to bring the patient into remission should begin immediately after the first episode. Consequences of non-remission include poor prognosis, psychiatric and general medical complications, treatment resistance, and death from medical comorbidities and suicide. Prevention of relapse following remission is critical to the well-being and optimal functioning of patients with schizophrenia.

The key to optimizing patients' outcomes is to ensure a patient's long-term continuation on medication. As treatment discontinuation can greatly impact the progression of the illness and the patient's ultimate outcome, selecting a treatment with maximum treatment effectiveness is optimal. Nonadherence to treatment is extremely prevalent among patients with schizophrenia, due to such factors as impaired cognition, lack of insight, and side effects associated with antipsychotic treatment.

Atypical antipsychotics have shown some advantages over conventional antipsychotics in terms of reducing positive and negative symptoms of schizophrenia, preventing relapse, and incidence of tardive dyskinesia. Injectables and long-acting formulations of antipsychotics offer additional benefits in terms of ensuring treatment adherence.

Although most patients with depression ultimately respond to antidepressant therapy, >50% have inadequate response to an individual antidepressant trial. The desire to avoid adverse drug reactions is common among patients, and is an important determinant of drug selection among psychiatrists. However, since the major classes of antidepressants and antipsychotics appear to be comparable in efficacy, clinicians have little basis for selecting the most effective agent for an individual patient. Pharmacogenetics, often described as the study of genetic variation that explains differential response to medication, represents an important new avenue toward improving treatment outcomes. Genetic variation in drug-metabolizing enzymes has been recognized for decades. The main focus of current psychiatric pharmacogenetic testing is on the cytochrome P450 (CYP) 2D6 and, to a somewhat lesser extent, on the 2C19 genes. Data suggest that poor metabolizer status can be associated with an increased risk of adverse drug reactions with certain medications, and that ultra-rapid metabolizers may require higher-than-usual doses to achieve a therapeutic response. The importance of CYP enzymes in the metabolism of several antidepressant and antipsychotic drugs suggest that genetic variation may aid in medication selection or dosing. Advances in pharmacogenetic research may facilitate the development of personalized medicine in which genetic information can inform drug selection, leading to optimal drug effectiveness and minimal drug toxicity.

The presentations and clinical courses of patients with bipolar disorder differ greatly by gender. In addition, medical therapy must be tailored differently for men and women because of emerging safety concerns unique to the female reproductive system. In November 2005, these topics were explored by a panel of experts in psychiatry, neurology, and reproductive health at a closed roundtable meeting in Dallas, Texas. This clinical information monograph summarizes the highlights of that meeting.

Compared to men with bipolar disorder, women have more pervasive depressive symptoms and experience more major depressive episodes. They are also at higher risk for obesity and certain other medical and psychiatric comorbidities. Mood changes across the menstrual cycle are common, although the severity, timing, and type of changes are variable. Bipolar disorder is frequently associated with menstrual abnormalities and ovarian dysfunction, including polycystic ovarian syndrome. Although some cases of menstrual disturbance precede the treatment of bipolar disorder, it is possible that valproate and/or antipsychotic treatment may play a contributory role in young women.

Pregnancy does not protect against mood episodes in untreated women. Maintenance of euthymia during pregnancy is critical because relapse during this period strongly predicts a difficult postpartum course. Suspending therapy in the first months of pregnancy may be an option for some women with mild-to-moderate illness, or those with a long history of euthymia during pre-pregnancy treatment. However, a mood stabilizer should be reintroduced either in the later stages of pregnancy or in the immediate postpartum period. Preliminary data suggest that fetal exposure to some mood stabilizers may raise the risk of major congenital malformations and neurodevelopmental delays. For women planning to become pregnant, clinicians may consider switching to other drugs before conception. The value and drawbacks of breastfeeding during treatment must be considered in partnership with the patient, with close monitoring of nursing infants thereafter. The risks and benefits of medical treatment for women with bipolar disorder should be carefully reconsidered at each stage of their reproductive lives, with a flexible approach that is responsive to the changing needs of patients and their families.

Anxiety disorders are common in depressed patients. Several studies of the full range of Diagnostic and Statistical Manual of Mental Disorders-defined anxiety disorders in depressed psychiatric outpatients each found that when diagnoses are based on semi-structured diagnostic interviews >40% of the patients had a comorbid anxiety disorder. The recognition of comorbidity is not simply of academic interest, but it has important clinical significance. Epidemiological studies, such as the National Comorbidity Study, 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. The co-occurrence of anxiety disorders in depressed patients has been associated with a more chronic course of depression in psychiatric patients, primary care patients, and epidemiological samples. Recent research has suggested that clinicians underrecognize anxiety disorder comorbidity in depressed patients. The clinical significance of this underrecognition is highlighted by the finding that patients often want treatment to address their anxiety disorder comorbidity. When anxiety disorders are detected they often influence clinicians' selection of antidepressant medication, though some of clinicians' prescribing biases are not supported by empirical data.

In this monograph, Iwona Chelminski, PhD, reviews the significance of anxiety in patients with depression as well as diagnostic instruments for recognizing this comorbidity. Next, Mark Zimmerman, MD, addresses the factors that affect the clinician's choice of antidepressant, focusing on the influence of comorbid anxiety. Finally, Sidney Zisook, MD, discusses the differential efficacy of antidepressants as well as the role of psychotherapy in patients with comorbid anxiety and depression.

Major depressive disorder (MDD) is almost exclusively recurrent. The vast majority of patients who experience one episode of MDD will eventually experience at least one more episode during their lifetime. The recurrent nature of MDD increases the burden to both the individual and society. Hence, it is imperative that treatment strategies focus on achieving remission acutely, as well as maintaining of remission and preventing recurrence. The articles in this supplement are based on presentations and a dialogue among a group of experts who convened for a roundtable discussion on improving long-term outcomes with antidepressant therapy.

Improving long-term treatment of MDD begins with understanding the clinical course of recurrent depression and the ability to recognize those patients who are at greatest risk for recurrence. James H. Kocsis, MD, reviews the course of recurrent depression, emphasizing the tendency for it to progressively worsen. He also discusses patient characteristics and other risk factors for recurrence as well as current recommendations for long-term management of recurrent depression.

Although long-term antidepressant maintenance treatment studies are somewhat limited in number, they provide the evidence base that shapes existing guidelines for long-term management of recurrent depression. Michael E. Thase, MD, examines this evidence for the different classes of antidepressants. In addition, Thase reviews evidence for the efficacy of psychotherapy and discusses its potentially important role in long-term depression management.

Anxiety disorders are common in depressed patients. Several studies of the full range of Diagnostic and Statistical Manual of Mental

Disorders-defined anxiety disorders in depressed psychiatric outpatients each found that when diagnoses are based on semi-structured diagnostic interviews >40% of the patients had a comorbid anxiety disorder. The recognition of comorbidity is not simply of academic interest, but it has important clinical significance. Epidemiological studies, such as the National Comorbidity Study, 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. The co-occurrence of anxiety disorders in depressed patients has been associated with a more chronic course of depression in psychiatric patients, primary care patients, and epidemiological samples. Recent research has suggested that clinicians underrecognize anxiety disorder comorbidity in depressed patients. The clinical significance of this underrecognition is highlighted by the finding that patients often want treatment to address their anxiety disorder comorbidity. When anxiety disorders are detected they often influence clinicians' selection of antidepressant medication, though some of clinicians' prescribing biases are not supported by empirical data.

In this monograph, Iwona Chelminski, PhD, reviews the significance of anxiety in patients with depression as well as diagnostic instruments for recognizing this comorbidity. Next, Mark Zimmerman, MD, addresses the factors that affect the clinician's choice of antidepressant, focusing on the influence of comorbid anxiety. Finally, Sidney Zisook, MD, discusses the differential efficacy of antidepressants as well as the role of psychotherapy in patients with comorbid anxiety and depression.