Epidemiologic studies have consistently demonstrated a greater incidence of depressive disorders and anxiety among women. Many women experience these conditions during the reproductive years. The dramatic expanse of literature focusing on the use of medications often has failed to pay homage to the potential impact of the disorders. When considering the extant human and laboratory data on mental illness and stress during pregnancy and the postpartum period, it is evident that some degree of exposure (be it treatment or illness) always occurs. The primary goal of the risk-benefit assessment for the treatment of mental illness during these periods is to assist patients and their families in choosing the path of potential exposure that possesses the least risk for them. Once this decision is made, the goal is to limit the number of exposures for the fetus/neonate.

Women with epilepsy are at risk for reproductive health dysfunction. Sex-steroid hormone abnormalities have been reported in women with epilepsy, but it has been difficult to determine whether these abnormalities are due to epilepsy-related hypothalamic-pituitary axis dysfunction, or to pharmacokinetic actions of antiepileptic drugs (AEDs). Sex-steroid hormones were evaluated in 84 reproductive-aged women with epilepsy receiving an AED in monotherapy, and in 20 nonepileptic controls. Estrone, free testosterone, and androstenedione were significantly lower in subjects receiving enzyme-inducing AEDs than in nonepileptic controls. Free testosterone was significantly elevated in subjects receiving valproate compared to nonepileptic controls. Subjects with epilepsy receiving gabapentin or lamotrigine were no different from the nonepileptic controls in any of the endocrine variables. Subjects with epilepsy who are receiving AEDs that alter cytochrome P450 enzymes are at risk for significant abnormalities in sex-steroid hormones. In contrast, subjects receiving AEDs that do not alter cytochrome P450 enzymes show no differences in sex-steroid hormones compared with nonepileptic controls. With new AEDs available that do not alter cytochrome P450 enzymes, physician selection of therapy should consider not only seizure control, but also potential effects on reproductive physiology.

Obesity has negative health consequences related to fat distribution, particularly the central or visceral accumulation of fat. The major complications associated with visceral obesity, termed the “Metabolic Syndrome of Obesity,” or “Syndrome X,” are type II diabetes, hypertension, and dyslipidemia. As with certain mood disorders, the syndrome may be a consequence of neuroendocrine perturbations typically associated with chronic stress. Our work with bonnet macaque monkeys provides an animal model for the relationship between early stress, behavioral and hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and Syndrome X. During their infant's first half-year, mothers face a variable foraging demand (VFD), in which ample food varies unpredictably in the difficulty of its acquisition, and the offspring show persistent abnormalities in systems known to modulate stress and affective regulation. Early work on the bonnet macaque noted the emergence of a sample of spontaneously obese subjects as they matured. Using the VFD model, the current study showed that there was a clear relationship between early cerebrospinal fluid corticotropin-releasing factor levels and subsequently measured body mass index, supporting the hypotheses regarding the interactive roles of early experience and HPA axis dysregulation in the ontogeny of both metabolic and mood disorders.

In this paper we will review recent neuroimaging research in schizophrenia, with an aim to critically evaluate several recent proposals concerning the nature and the timing of the neuroanatomic abnormalities underlying the disorder. Specifically, enlargement of cerebrospinal fluid spaces, deficits in cortical gray matter, and reduced volume of mesiotemporal structures have all been reported in patients in the first episode of schizophrenia, their first-degree relatives, and individuals with schizotypal personality disorder, supporting the possibility that these abnormalities reflect a genetically mediated neurodevelopmental disorder. These findings from the empirical literature will be synthesized from the perspective of dual cytoarchitectonic trends theory of neurodevelopment, as well as in relation to current conceptions of the schizophrenia prodrome. We believe that the evidence shows that sufficient groundwork has been laid to begin longitudinal neuroimaging studies of adolescents at clinical risk for schizophrenia, in order to more definitively determine the pathophysiology of the disorder. Such information could have significant implications in terms of understanding the prediction, treatment, and ultimately the prevention of schizophrenia.

Environmental stimuli and drugs affect the norepinephrine (NE) system and may be linked to the manifestation and treatment of anxiety and affective disorders. The activity of locus ceruleus NE neurons in the brainstem can alter the function offorebrain structures associated with several psychiatric disorders. In particular, NE neurons send and receive projections from sensory afferents, limbic areas, and cortical areas implicated in higher-order brain malfunctions and the symptomatology of anxiety and affective disorders. In turn, anxiolytic and antidepressant drugs are able to offset perturbations of NE activity and forebrain structures with a time course congruent with their therapeutic action. All antide-pressants, even the agents selective for other biogenic amines or peptides, act on the NE system. In the present review, the effects of antidepressants on NE neurons are summarized and applied to the treatment of neuropsychiatric disorders, with emphasis placed on mechanisms of action.

Biological aging is often associated with sleep problems and daytime napping. Complaints of difficulty in initiating and maintaining sleep, as well as daytime drowsiness, are more common in the elderly than in any other age group. This report reviews evidence that impaired melatonin secretion is associated with sleep disorders in old age. Circulating melatonin levels have been found to be significantly lower and onset and peak times have been delayed in elderly insomniacs as compared to age-matched control subjects. In view of these findings, we investigated the effects of melatonin treatment on melatonin-deficient insomnia in the elderly. From the results of our study, it seems likely that melatonin replacement therapy may be beneficial in the initiation and maintenance of sleep in this population.

This review characterizes perimenopause, including biologic changes, the influence of psychosocial factors, and the most common clinical manifestations. Clinic-based studies and community-based surveys addressing the prevalence of depressive symptoms in perimenopausal women are critically reviewed. Also discussed is the potentially greater vulnerability to mood disturbance during perimenopause in response to hormonal variability. A therapeutic algorithm for management of depressive symptoms in middle-aged perimenopausal women is presented. The role of estrogen in the treatment of perimenopausal depressive symptoms is addressed. In addition, the article contains a review of the existing data on the potential efficacy of estrogen as an antidepressant agent (monotherapy, augmentation strategy, or prophylaxis).

Stiff-person syndrome (SPS) is a rare disease of severe progressive muscle stiffness in the spine and lower extremities with superimposed muscle spasms triggered by external stimuli. Patients with SPS are often referred for psychiatric evaluation and the psychiatrist may be the first to diagnosis SPS. Psychosocial stressors often precede the first manifestations of the disease; depression, anxiety, and alcohol abuse are comorbid illnesses. The identification of an association with antibodies to glutamic acid decarboxylase (GAD) was invaluable for definitively establishing a pathological basis for the disease; antibodies to amphiphysin and gephyrin are also found in cases of SPS but at much lower frequencies. Whether the antibodies inhibit GAD activity in vivo, target GAD-expressing neurons for immune-mediated destruction, are part of a wider immune process, or are merely a marker for destruction of GAD-expressing neurons by an independent neurodegenerative process is not yet clear. Both electromyography and the detection of GAD antibodies are useful in establishing a diagnosis of SPS. Treatment of SPS includes the use of immunomodulating therapies (plasmapheresis and intravenous immunoglobulins) and symptomatic treatment with benzodiazepines and baclofen. The use of tricyclic antidepressants and rapid withdrawal from therapy should be avoided.

Use of augmenting agents in schizophrenia is a common practice in response to resistant symptoms or comorbid illness. Increasingly, clinicians are combining more than one antipsychotic agent, despite a lack of evidence from controlled studies to support this approach. A rationale can be made for adding higher-potency agents to clozapine in an attempt to optimize D2 dopamine receptor blockade, but this strategy requires further study before it should be adopted in clinical practice. Older reports have explored the use of antidepressants, mood stabilizers, and anxiolytics as augmenting agents. These agents appear to improve comorbid affective or anxiety symptoms, but earlier evidence of improvement in psychotic or negative symptoms has not been replicated consistently. Glutamatergic agents acting at the glycine coagonist site of the N-methyl-D-aspartate receptor, including glycine, D-cycloserine, and D-serine, have demonstrated impressive therapeutic effects for negative symptoms when added to conventional neuroleptic agents, but do not appear to enhance clozapine efficacy. Given the high rates of symptom persistence and disability associated with schizophrenia, the need for augmentation strategies is great, but no approach has clearly emerged as effective for a substantial portion of patients. Although certain approaches may prove helpful for individual patients, augmentation should not be used unless monotherapy has been optimized, and should not be continued long-term unless benefits are clear.

Traumatic grief is a common and debilitating syndrome whose clinical presentation is well recognized but whose diagnostic criteria have only recently been delineated. Though it shares features with major depressive disorder, adjustment disorder, and posttraumatic stress disorder, none of these subsume the criteria set for traumatic grief, and the diagnostic overlap is limited in community samples. Furthermore, diagnosis of traumatic grief appears to have prognostic value for clinical course and treatment response among bereaved individuals. In the absence of empirically supported treatments of pathological grief, a new, manualized treatment for traumatic grief symptoms has been developed and is currently undergoing testing in a randomized controlled trial. The conceptual basis for Traumatic Grief Treatment (TGT) is presented, the structure of the treatment is outlined, and the primary clinical strategies employed are described.

Antidepressant treatments have evolved over the last 20 years, and many new drugs with complex mechanisms of action are available. It has become apparent that mechanism of action is significant in terms of treatment impact. We may have some capacity to predict the potential outcomes of treatment based on what drugs we use. Depression management requires elaborate assessment in order to keep track of treatment progress and know how to move through the sequences of therapy. Many patients with depression who are treated with antidepressants do not experience full remission, and a large number of patients who do recover eventually relapse. Remission as a treatment goal is difficult to achieve. One of the reasons why remission rates are low is that the currently available treatment choices are implemented improperly. Also, our understanding of the neurobiology of depression is still in the early stages. As we gain more knowledge about what this disorder truly entails, we will be able to achieve better treatment outcomes, and we can hope that remission will become the standard of care in treating patients with depression.

This paper addresses the importance of affect regulation (AR) in relation to a broad range of behavioral and emotional health problems that emerge during adolescence. AR is defined as the adaptive modulation of emotional experience to serve a goal or purpose. This conceptualization of AR emphasizes the use of cognitive skills to guide, inhibit, or modify emotion and behavior, including the expression of emotional responses, in learned, strategic ways—skills that ultimately underpin adult levels of social maturity and the ability to show “responsible” behavior across a range of emotional situations. Neurobehavioral systems that subserve these AR skills include areas of the inferior and orbital prefrontal cortex (PFC), with rich interconnections to several limbic structures and other cortical areas, including the dorsolateral PFC. Adolescence represents an important developmental period in the functional maturation of adult AR skills; it is also a critical time in the development of clinical disorders of AR (eg, rates of depression increase dramatically and gender differences in depression emerge). Maturational changes in AR that occur during adolescence—particularly with respect to the role of emotions influencing responsible decision making—are also relevant to understanding key aspects of the developmental pathways of some behavioral health problems, such as alcohol use and nicotine dependence. A strong case is made for developmental research in affective neuroscience aimed at this important maturational period, particularly the kind of transdisciplinary research leading toward mechanistic understanding of the development of adolescent-onset disorders. Improving understanding in these areas could ultimately lead to the development of early interventions in targeted high-risk populations, and has enormous clinical and social policy relevance.

This paper focuses on treatments for schizophrenia (SZ)—treatments we have now and those we hope to have in the future. The treatments we have are based on serendipity, but are effective nonetheless. Pharmacologic characteristics of the most-prescribed drugs are reviewed. It is apparent that a spectrum of effective drugs exist to support individualized therapy. With a view to future discovery, a strategy is proposed for rational antipsychotic drug development. A few concrete examples from the author's own laboratory illustrate an application of the proposal. These data would support the existence of a drugtarget in the anterior cingulate and/or hippocampal cortex. The studies suggest a focus on the limbic cortex for SZ pathophysiology. It would depend on future discovery to test whether this proposal will be productive. For sure, the rapid advance of basic neuroscience provides untold promise for the future.

Research has provided considerable evidence for the hypothesis that corticotropin-releasing hormone (CRH), the key central coordinator of stress-hormone homeostasis, also plays a role in the development and course of depression and anxiety disorders. Studies using animal models of anxiety, as well as mouse mutants, in which the gene coding for the CRH type 1 receptor (CRHR1) was genetically deleted supported the notion that enhanced CRH/CRHR1 signaling underlies depression and anxiety disorders. Therefore, a number of small nonpeptide molecules that antagonize CRHR1 have been developed. In animal models, these molecules had anxiolytic and other stress-alleviating effects. An initial clinical study showed that CRHR1 antagonism has beneficial effects on depression and anxiety symptoms at doses unharmful to neuroendocrine stress responsivity.

Valerian is a medicinal agent deriving from the plant Valeriana officinalis L. We reviewed the available literature on the use of valerian preparations in the treatment of neuropsychiatric disorders. Preclinical studies suggest that valerian has sedative and muscle-relaxant effects. Few clinical trials with valerian have been carried out in conditions other than insomnia. The insomnia studies have methodologic shortcomings but suggest that some preparations lead to significant subjective improvement in sleep complaints with remarkably few side effects. Furthermore, some evidence indicates that valerian preparations may have a mechanism of action and clinical characteristics that differ from the benzodiazepine-related sedative/hypnotics, making them more suitable for long-term use. If this safety profile and the plant's sedative/hypnotic efficacy are confirmed in double-blind, placebo-controlled trials with carefully and consistently prepared valerian compounds, then those compounds would fill an important and presently unfilled niche in the treatment of insomnia.

Since the introduction of clozapine, several novel antipsychotic agents have been introduced and more are in Phase II/III studies. Because these agents are used clinically as first-line treatment, we need to be more familiar with their side-effect profiles. This manuscript reviews the cardiovascular side effects of currently available novel antipsychotics. The medications reviewed include clozapine, risperidone, olanzapine, quetiapine, and ziprasidone. Guidelines are suggested for the use of these medications in clinical practice.

Sleep problems, day somnolence, and fatigue as a result of psychotropic drugs are very common. Psychiatrists usually consider these effects a result of insomnia and treat them by prescribing sleeping pills or other benzodiazepine agents.

We describe here 10 cases of circadian rhythm sleep disorders (CRSD)—and not merely insomnia—as a possible side effect of fluvoxamine (FVA). Two other serotonin reuptake inhibitors, fluoxetine and clomipramine, did not induce CRSD in any of these 10 patients. We speculate that FVA-induced CRSD is caused by the effect of FVA on serotonin and melatonin levels in the central nervous system.

CRSD as a side effect of FVA can be treated by replacing the suspected FVA or adding melatonin to a beneficial FVA treatment. Thus, it is important to be aware of possible iatrogenic CRSD in order to treat appropriately. Prospective studies are needed to confirm our observation and to study the influence of other psychotropic drugs on sleep-wake schedule.

Eight new antiepileptic drugs (AEDs) have been introduced since 1993 and clinicians are now faced with a complex array of treatment choices. In evaluating the newly available drugs, it is important to analyze the different aspects of these agents. Some of the more important characteristics to be aware of are efficacy, adverse effects, pharmacokinetics, and mechanisms of action.

One of the factors complicating treatment choice is the absence of comparative head-to-head clinical trials between the new AEDs. While in some cases it is possible to draw conclusions from the results of randomized, controlled trials that have tested medications against placebo or older drugs, often physicians have to rely on open-label data or personal experiences in selecting the right medications for specific cases.

Trends suggest that the new AEDs are more efficacious compared to the older AEDs, but the major potential benefits of the new drugs are their better safety, tolerability, and cognitive profiles and more desirable pharmacokinetics.

It is obvious that there is a need to redefine the concept of “successful” treatment of epilepsy. Patients need to be individually evaluated and, in addition to controlling seizures, tolerability should be taken into consideration in finding the most appropriate treatment regimen.

In a variety of mammalian species, prenatal androgens organize brain structures and functions that are later activated by steroid hormones in postnatal life. In humans, studies of individuals with typical and atypical development suggest that sex differences in reproductive and nonreproductive behavior derive in part from similar prenatal and postnatal steroid effects on brain development. This paper provides a summary of research investigating hormonal influences on human behavior and describes how sex differences in the prevalences and natural histories of developmental psychopathologies may be consistent with these steroid effects. An association between patterns of sexual differentiation and specific forms of psychopathology suggests novel avenues for assessing the effects of sex steroids on brain structure and function, which may in turn improve our understanding of typical and atypical development in women and men.