Pregnancy is a period of substantial neuroendocrine changes. These changes are not limited to the hypothalamic-pituitary-gonadal hormones, but also involve the placenta and its secreted hormones, especially the corticotropin releasing hormone that is a major component of the stress axis. These hormonal changes are also associated with changes in the immune/inflammatory and cardiovascular systems. The cumulative evidence that dysregulation in this multifactorial interactional field may cause deleterious effects on the fetus and its future development emphasizes the importance and clinical relevance of this line of research. When vulnerability and genetic predisposition to gestational stress and its adverse effects are added to the equation, the importance of adequate treatments and possible preventive interventions is underscored.

Pregnancy is usually perceived as a happy period. However, as demonstrated by Uriel Halbreich, MD, severe mood, behavior, and cognitive symptoms are quite prevalent during pregnancy. The magnitude of the problem is probably not reflected by the reported prevalence of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition or International Classification of Diseases, Ninth Edition major mental disorders. A closer evaluation and treatment of symptoms, especially when they are associated with impairment, stress, and distress, may improve the mental health of the mother and the expected baby.

Bipolar disorder is a chronic, frequently relapsing illness with a prevalence of 1.2% to 3.4% in the general population. It is associated with high disability, higher comorbidity due to medical illnesses, and significant social and economical consequences for patients, their families, and society. The episodic nature of this disease warrants rational use of medications and proper monitoring for adverse events. Various drug classes, such as mood stabilizers, antipsychotics, benzodiazepines, and antidepressants, are used for the acute and maintenance treatment of bipolar disorder. Each group of drugs is associated with wide array of adverse events and drug interactions, which are the main hurdles in treatment outcome and compliance. Common side effects seen with several agents, particularly antipsychotics, are somnolence, weight gain, extrapyramidal symptoms, dyslipidemia, type-2 diabetes, and hyperprolactinemia. Major drug interactions are seen with drugs such as carbamazepine, due to hepatic enzyme induction. Adverse effects such as somnolence are tolerability concerns and can be managed easily; others, such as diabetes mellitus, are safety concerns. It is prudent to have precise knowledge of the individual drug's side-effect profile, pharmacokinetics, and pharmacodynamics, to plan a treatment regimen. More research is needed to understand potential rish of various drugs and to devise and incorporate monitoring protocols in the treatment regimen.

Epilepsy is a significant health problem. Ten percent of people living a normal lifespan will experience at least one epileptic seizure and one third will develop a chronic epileptic condition. At any given time, 0.5% to 1% of the world's population has active epilepsy, amounting to over 40 million people. A World Health Organization-sponsored study determined that epilepsy accounts for 1% of the global burden of disease, measured as disability-adjusted life years equivalent to the global burden of lung cancer in men and to breast cancer in women. Disability-adjusted life years measure years of productivity lost as a result of disability or death, which is relatively high for epilepsy because this condition often begins in childhood. The cost of epilepsy in the United States has been estimated at $12.5 billion/year, and 80% of this cost is borne by the 30% of patients whose seizures are not controlled.

The cost of uncontrolled epileptic seizures to society, and to individuals with epilepsy and their families, is measured not only in economic terms, but also in terms of human suffering. In this month's first article, Michael R. Sperling, MD, who has authored seminal papers on consequences of epilepsy, provides evidence that epilepsy is not a benign disorder; that early control of epileptic seizures is important to avoid irreversible disability due to the development of psychological and social disturbances and progressive cerebral dysfunction, as well as epilepsy-related death. The burden imposed on society and on individuals by uncontrolled epileptic seizures is all the more tragic because many suffer needlessly. For a significant number of adults who have had recurrent seizures since infancy, childhood, or adolescence, more aggressive early intervention might have rescued them from a lifetime of disability. Consequently, the goal of therapy today should be no seizures and no side effects, as soon as possible.

The past decade has seen an increased focus on the developmental trajectory of attention-deficit/hyperactivity disorder (ADHD), with the recognition that ADHD is, for many, a life-long condition akin to many other chronic illnesses. There has been an increase in the extent to which young children, adolescents, and adults receive a diagnosis of ADHD, yet there remain many poorly understood and controversial issues within the scientific community and the lay public. Do ADHD patients of different ages present with similar manifestations of the disorder, and if so, why was this not recognized for so long? Are there alternative clinical presentations among ADHD patients of different ages? What is the nature of comorbidity in ADHD over the course of development, and what are its functional consequences? How can we best measure and define ADHD, differentiating it from normal activity in young children, on the one hand, and other psychiatric disorders in older children and adults on the other? This is a key issue because ADHD has been a controversial diagnostic entity to many nonpsychiatrists because there is no one laboratory task that defines it. Most importantly, how do we understand issues related to risk and resilience in a longitudinal model, and can we identify factors that predict different clinical outcomes or pathways?

While resilience has been overlooked in the therapeutics area, it has been well-documented in the literature. Since at least the 1970s, there has been an extensive literature published on child resilience including the longitudinal follow up studies of children from the Hawaiian island of Kawaii.

The Anxiety and Traumatic Stress Program at Duke University Medical Center in Durham, North Carolina, became interested in resiliency as a slightly serendipitous observation during the course of a trial studying fluoxetine and placebo in people with PTSD. A measure evaluating how upset a person had been in the last week by life stresses, showed that fluoxetine was very effective in helping people cope with daily stresses (Slide 13).

The simple definition of resilience is the ability to bounce back from adversity. However, the literature cites a number of other aspects to resilience (Slide 14). Kobasa, a psychologist who has worked extensively in the area of resilience, tends to see it as similar to hardiness, in which there are certain components that are very salient. The first component is the view of stress, or difficulty, as a challenge. Second, is to have a sustained commitment to overcome whatever is necessary. Third, is the ability to possess internal control while being able to accept things one does not have complete control over.

The importance of having support from other people has been emphasized by Rutter. He theorized that one has the capacity to have close and secure attachments and a good sense of self-efficacy. He also notes the strengthening effects of stress. In children who cope well with difficulties, it is useful to tap into previous successes in order to harness some confidence from prior success. An action-oriented approach to problems, called active coping, can be useful.

Bipolar disorder is presenting at a younger ageof onset. In the past, many children with bipolar disorder wereundiagnosed and ended up in juvenile detention centers. These childrenwere also often misdiagnosed with severe attention-deficit/hyperactivitydisorder (ADHD) or conduct disorder. In addition, an increasedprevalence rate of substance use disorders and possibly stimulantprescriptions may be responsible for the shift in age of onset ofbipolar disorder. The most compelling epidemiological observations havecome out of the Netherlands, where they typically treat ADHDbehaviorally rather than with stimulants. Childhood bipolar disorderremains unidentified in the Netherlands despite aggressive searching,whereas adolescent and adult bipolar disorder has been found in numberssimilar to those in the United States. This providescross-sectional epidemiological evidence that stimulants may be shiftingthe age of onset in patients who are presenting with potentiallyprodromal bipolar symptoms. Lastly, several researchers speculate thattrinucleotide repeats in the DNA (deoxyribonucleic acid) may beresponsible for so-called genetic anticipation phenomenon, by whichexpansion of trinucleotide repeats in successive generations may beshifting the age of onset to an earlier age. These are just some of themechanistic possibilities for why we are seeing a shift in the age ofonset of bipolar disorder.

Lewinsohn and colleagues found thatthe lifetime prevalence of adolescent bipolar I and II disorder is ~1%,with a 5% lifetime prevalence rate of subsyndromal bipolar disorder.Many symptomatic children and adolescents do not meet full durationcriteria for a hypomanic or manic episode, or they may be one symptomshort of meeting criteria for the disorder.

Greater attention has been given to the cognitive dimension in schizophrenia in recent years. This has resulted from increased recognition that cognitive impairment and negative symptoms of the disease have a greater impact on quality of life (QOL) compared to positive symptoms. Successful treatment of positive symptoms in patients with schizophrenia has not been shown to robustly translate into improvements in employment status or social relationships, while cognitive improvements are strongly associated with these important aspects of QOL and independence. These findings are based on extensive testing with standard cognitive tests for measuring executive function, verbal learning and memory, word recall, verbal working memory, spatial working memory, attention, and vigilance. Verbal learning and executive function, in particular, have been found to be valid predictors of employment success independent of the degree of severity of positive symptoms.

This issue of CNS Spectrums represents a milestone for both those affected by autism and related disorders and for clinicians and researchers who provide help and support to these individuals. In order to improve the lives of a rapidly increasing number of patients with this diagnosis, it is critical for the medical and research community to apply a collaborative and consistent strategy for clinical studies in autism.

The five articles that follow are a synopsis of the five subcommittees of the Autism Clinical Trials Task Force (ACTTF), a collaborative panel of experts convened by the Cure Autism Now (CAN) foundation in the spring of 2002. These subcommittees focused on key issues in clinical trials of autism, including subject selection, outcome measures, study design, biological measures, and governmental issues. CAN brought together this panel of participants from academia, government, and industry for the ACTTF think tank. The panel was organized and chaired by Eric Hollander, MD, and Ricki Robinson, MD, MPH. The overarching goal was to clarify what was known about the state of the art of the field in this area, what key information was still unknown, and to implement specific approaches and suggestions for studies which would provide information to fill in the missing gaps in our knowledge base.

While rapid cycling was first identified by Dunner and Fieve in 1974, there is quite a good historical background on the concept. In the 1800s Falret and colleagues identified what they called a “circular course distinct from alternating.” What they meant by “alternating” was a period of remission following an episode. Currently, all types and ranges of cycling are lumped under one rubric; the spectrum ranges from having >4 cycling episodes, the minimum required for rapid cycling, through ultradian cycling, which is far more severe.

While some patients manifest chronic depression with periodic hypermania, which is known as bipolar II, others have ultradian cycles, which are often seen as pure affective instability. We do not know whether these types represent different stages of a disorder that exists on a spectrum or whether they are actually distinct categories of the disorder: one being patients who experience mania, depression, and then remission; the second being those with more continuous cycling that includes ultradian cycling. Greater understanding of the biological underpinnings of the illness will help to determine whether these conditions exist on a spectrum.

Rapid cycling may become less prevalent with age. In the Depression Collaborative Study, Coryell and colleagues found a diminishment of rapid cycling over the course of 13 years. Studies from the Stanley Bipolar Foundation group suggest that the cycling may accelerate in some, but not others. Over a long observation period in ~100 patients, Koukopoulos and colleagues found that once a pattern of rapid cycling is established in a patient, this pattern may become a hallmark of their illness.

Alzheimer's disease (AD) is a debilitating condition affecting millions of elderly citizens. The quality of life for AD patients significantly deteriorates in the face of worsening cognitive deficits and disabling functional declines, both contributing to manifestations of difficult behaviors. Of the estimated 4 million individuals with AD, only 60% of probable AD cases are diagnosed, with little more than half of those receiving treatment. One of the possible reasons for this problem is the large role primary care physicians (PCPs) have in diagnosing and treating AD. The barriers that PCPs confront to adequately manage these patients will be discussed. Finally, the specific challenges that geriatric psychiatrists will face in addressing these issues in an environment where there is only a limited number of trained geriatric psychiatrists will be discussed, as well as the possible role that new technology could have in finding the solution to this difficult problem.

Mood and anxiety disorders are among the most prevalent psychiatric illnesses and are associated with considerable morbidity and mortality. Selective serotonin reuptake inhibitors (SSRIs) are safe and effective treatments for major depression and anxiety disorders, and have become the most widely prescribed antidepressants worldwide. However, several issues limit SSRI treatment outcomes. Although SSRIs have a wider therapeutic margin and a milder side-effect profile compared to earlier antidepressants, even minor SSRI side effects can have a major impact on treatment outcomes by interfering with patient compliance. Nausea is one of the most common early SSRI side effects, and advances in SSRI delivery systems can diminish this. A controlled-release formulation of paroxetine targets the site of absorption for a more distal region of the small intestine, thereby avoiding the stimulation of upper gastrointestinal serotonin receptors that mediate nausea. The sustained-release characteristics also reduce the amplitude in blood level peaks and troughs, which may lead to diminished side effects and enhanced efficacy. Sexual side effects and weight gain are important sustained SSRI side effects, which affect compliance during continuation and maintenance phases of treatment. Several strategies address SSRI sexual side effects, including the use of adjunctive medication and/or manipulations in the scheduling of drug administration. Depression negatively impacts the management of many medical illnesses, including cardiovascular disease, cancer, and infectious diseases. The recognition and treatment of depression leads to improved outcomes in the management of breast cancer. Prophylactic SSRI treatment significantly reduces the incidence of interferon-associated depression and enhances completion rates in malignant melanoma.

The notion that subtle cognitive, emotional, behavioral, and functional deviations from norms are present in many individuals several years before a formal diagnosis of schizophrenia has been around for almost a century. This notion has been at the base of the developmental hypothesis of schizophrenia and has been the impetus for the use of cognition as an endophenotype for studying the illness. The recent enthusiasm for prodromal research derives from two unrelated and controversial claims: that short duration of untreated psychosis is associated with better prognosis and that novel antipsychotic drugs have a better safety profile, supposedly enabling early intervention at a relatively lower risk of side effects to the patient.

At the current level of knowledge, the risk-benefit assessment of prodromal interventions turns out to be an almost unsolvable conundrum. On one hand, the age of onset of psychosis and schizophrenia, early and mid-ado-lescence, coincides with the age at which life-long social and vocational characteristics are shaped. Any intervention that could produce even minimal delay in onset of active psychosis or ameliorate its early course might have a life-long impact. Therefore, the idea of prodromal intervention cannot be easily dismissed. On the other hand, in absence of accurate markers for imminent psychosis and strong data indicating that treatment during the prodromal phase is effective, exposing adolescents to the stigma associated with the illness and the adverse effects of antipsychotics has raised serious hesitations among many researchers and clinicians.

The need for long-term management of bipolar disorder is evident. Bipolar patients spend more time depressed than manic; however, few agents used for maintenance therapy of bipolar disorder have demonstrated good efficacy in delaying relapse into depression. This article provides a comprehensive review of open-label and randomized, controlled studies examining prophylactic efficacy in bipolar disorder, especially bipolar depression. Lithium, considered the gold standard for bipolar disorder maintenance therapy may be more effective in delaying manic relapse than in delaying depressive relapse. Evidence for the efficacy of divalproex and carbamazepine in delaying depressive relapse is yet to be fully elucidated. Lamotrigine has demonstrated efficacy in delaying time to depressive relapse. Unpublished studies show ohnzapine's efficacy in preventing manic recurrence, while its efficacy in preventing depressive recunence is yet to be proven. As patients with bipohr disorder are prone to experiencing depressive episodes, more attention needs to be focused on preventing depressive relapse. To date, three agents—lithium, lamotrigine, and olanzapine—have been shown to have prophylactic benefits in treating this highly recunent disorder.

Clinical pathways generally recommend potential steps in the diagnosis and treatment of a condition or procedure for individual patients. Their usefulness in guiding clinicians through the steps of nonresponse or partial response to interventions has been documented. They are predominantly management tools based on clinical information developed from evidence-based psychiatry, practice guidelines, or expert consensus statements. Pathways may not be appropriate for use in all circumstances, nor are they a substitute for the practitioner's experience and judgment. Their applicability must be assessed by the responsible practitioner in light of relevant circumstances presented by individual patients in order to optimize treatment.