Does stress management affect psychological and immune functioning in persons with human immunodeficiency virus infections? Stress-management techniques, such as relaxation training and imagery, cognitive restructuring, coping-skills training, and interpersonal-skills training, may reduce anxiety, depression, and social isolation in HIV-infected persons by lowering physical tension and increasing a sense of control and self-efficacy. A psychoneuroimmunologic model is proposed wherein these psychological changes are hypothesized to be accompanied by an improved ability to regulate neuroendocrine functioning, which in turn may be associated with a partial normalization of immune system functions such as lymphocyte proliferation and cytotoxicity, providing more efficient surveillance of latent viruses that may contribute directly to increased HIV replication and generate opportunistic infections or cancer if left unchecked. Such a normalization of stress-associated immune system decrements are hypothesized to forestall or minimize increases in viral load and expression of clinical symptoms. This model is useful for testing the factors contributing to the health effects of stress-management interventions in HIV-infected persons. In this context, one general research strategy for testing the effects of stress-management interventions is to target them toward the more prevalent psychosocial challenges that HIV-infected people face at various points in the disease process; enroll an HIV-infected population (eg, HIV-positive homosexual and bisexual men) into a randomized trial; and monitor changes in cognitive, affective, behavioral, and social factors in parallel with hormonal, immunologic, viral, and clinical changes over the course of time. This article will review the major psychoneuroimmunologic findings that have emerged using this paradigm and suggest future research directions and clinical applications.

Quality of life (QoL) is increasingly recognized as a pivotal outcome parameter in research on obsessive-compulsive disorder (OCD). While the concept remains somewhat ill-defined, there is now little dispute that the patients’ personal goals deserve foremost consideration during the course of treatment as the primary aim of treatment should be relief from individual despair, which is related but by no means synonymous to symptom reduction. Studies using generic (ie, illness-unspecific) instruments have confirmed poor QoL in OCD patients across a wide range of domains, especially with respect to social, work role functioning, and mental health aspects. Scores are sometimes as low as those obtained by patients with schizophrenia. Depression and obsessions are the symptom clusters that most strongly contribute to low QoL. Findings from a novel survey of 105 OCD participants point to multiple daily life problems, poor work status, and tense social networks in these patients. In order to achieve therapeutic success and improve QoL, functional problems at work and comorbid disorders such as secondary depression and physical impairments should be targeted. While successful treatment sometimes positively impacts well-being, in some studies symptom decline did not translate into improved QoL.

Introduction: Individuals who have deep and periventricular white matter hyperintensities may have a higher risk for suicidal behavior. There are mixed results in the literature regarding whether unipolar or bipolar patients who have attempted suicide have more deep white matter hyperintensities (DWMH) or periventricular hyperintensities (PVH) relative to those who have no history of suicide attempts.

Methods: A meta-analysis of studies examining white matter hyperintensities (WMH) in mood disorder patients with and without a history of suicide attempts was performed.

Results: Four studies, including a total of 173 patients who attempted suicide and 183 who did not attempt suicide, were included. A significantly higher number of attempters were found to have WMH than non-attempters. Unipolar depressed patients who had attempted suicide had 1.9 times more DWMH and 2.1 times more PVH than those who did not. Bipolar patients who had attempted suicide had 5.4 times more PVH than those who had not. Taken together, unipolar and bipolar patients who had attempted suicide had 2.8 times more DWMH and 4.5 times more PVH than those who had never attempted suicide.

What is the role of stress and coping in changes in immunologic and clinical indicators of human immunodeficiency virus disease progression? There is substantial evidence that stressful life events and passive coping strategies, such as denial, may have a detrimental effect on HIV disease progression. Given the harmful effects of stress and passive coping, the author reviews the limited research testing the efficacy of interventions, such as cognitive-behavioral therapies for HIV-infected persons. Finally, in trying to understand psychoimmune relationships in HIV, the evidence is examined for the mediating and direct effects of cortisol, a hormone associated with stress, on HIV disease progression. Delineating the role of psychosocial factors and cortisol on HIV disease progression may aid in the development of new interventions for this devastating disease.

Psychotic major depression is a severe condition that frequently proves difficult-to-treat. The most effective traditional treatments (electroconvulsive therapy and combinations of antipsychotics with tricyclic antidepressants) are associated with significant side effects, and the use of tricyclic antidepressants alone is largely ineffective. Recent evidence has indicated that the selective serotonin reuptake inhibitors, either alone or in combination with antipsychotics, may provide a desirable alternative to traditional treatments. Among selective serotonin reuptake inhibitors, fluvoxamine has been the best studied and, somewhat surprisingly, has proven effective in several studies as a monotherapy without the need to combine with an antipsychotic. It is proposed that the apparent efficacy of fluvoxamine in psychotic major depression may be related to its unique property of high affinity for the σ1receptor, which is thought to play a role in psychosis and in the action of some antipsychotic drugs.

As a competitive adenosine antagonist, caffeine affects dopamine transmission and has been reported to worsen psychosis in people with schizophrenia and to cause psychosis in otherwise healthy people. We report of case of apparent chronic caffeine-induced psychosis characterized by delusions and paranoia in a 47-year-old man with high caffeine intake. The psychosis resolved within 7 weeks after lowering caffeine intake without use of antipsychotic medication. Clinicians might consider the possibility of caffeinism when evaluating chronic psychosis.

Relatively few studies of the psychobiology of hypersexuality have been undertaken. Nevertheless, the literature does suggest the possibility of a neurobiology of hypersexuality. Three cases of hypersexual behavior are presented in the context of neuropsychiatric disorders, and the literature on this phenomenon is briefly reviewed. These case studies and the literature provide evidence that different brain systems may play a role in this disorder. Frontal lesions may be accompanied by disinhibition, including impulsive hypersexual response to external cues, while striatal lesions may be accompanied by repetitive triggering of internally generated response patterns. Temporal-limbic lesions may be accompanied by disturbances in sexual appetite itself, including change in the direction of sexual drive. These case studies demonstrate that a neurobiology of hypersexuality may prove of some heuristic value in the clinic. However, further research is required to consolidate the literature in this area.

In a particular success for translational research agendas, characterization of the neuronal circuits underlying fear extinction, and basic research in animal extinction paradigms, has led to intervention studies examining the use of D-cycloserine (DCS) to enhance therapeutic learning from exposure-based cognitive-behavioral therapy (CBT). In this article, we review these intervention studies, and discuss DCS augmentation of CBT relative to more traditional combination-treatment strategies in the treatment of anxiety disorders. We offer an accounting, based on evidence for internal context effects, of current limitations in the combination of antidepressant or benzodiazepine medications with CBT and discuss the advantages of isolated-dosing strategies with DCS relative to these limitations. This strategy is contrasted with the chronic-dosing applications of DCS for schizophrenia and Alzheimer's disease, and future directions for isolated-dosing strategies are discussed.

Most people with epilepsy maintain normal reproductive and sexual lives. However, a significant minority of women with epilepsy (20% to 30%) have some degree of sexual dysfunction, including problems with libido, arousal, and orgasm. Men with epilepsy are at risk for decreased sexual functioning, including sexual interest and sexual performance, at least in part because of increased sex hormone-binding globulin levels and lower bioactive testosterone levels, particularly in association with the use of enzyme-inducing antiepileptic drugs, such as phenytoin and carbamazepine. A decrease in bioactive testosterone levels probably has a significant effect on the sexuality of women with epilepsy as well. Antiepileptic drugs may also affect sexual function in women through alterations of serotonergic neurotransmission. Epilepsy itself appears to have the potential to affect sexual function. The amygdala is emerging as a brain structure with significant involvement in sexuality in patients with epilepsy, as shown by alterations in sexual functioning after temporal lobectomy. Preliminary evidence suggests that people with temporal lobe epilepsy have reduced genital blood flow in response to erotic stimulation; the etiology of this phenomenon is not well understood, but disruption of the limbic and frontal cortex by epileptic activity may be implicated. Psychosocial factors, including sexual anxiety and stigma associated with epilepsy, can also affect the sexual life of patients with epilepsy.

Early-life adversity is a well-established risk factor for the development of depression later in life. Here we discuss the relationship between early-life adversity and depression, focusing specifically on effects of early-life caregiver deprivation on alterations in the neural and behavioral substrates of reward-processing. We also examine vulnerability to depression within the context of sensitive periods of neural development and the timing of adverse exposure. We further review the development of the ventral striatum, a limbic structure implicated in reward processing, and its role in depressive outcomes following early-life adversity. Finally, we suggest a potential neurobiological mechanism linking early-life adversity and altered ventral striatal development. Together these findings may help provide further insight into the role of reward circuitry dysfunction in psychopathological outcomes in both clinical and developmental populations.

Research on pathological gambling has begun to demonstrate the significant pathophysiologic role of several neurotransmitter systems in this disorder. Challenge studies with various pharmacologic agents have suggested the importance of potential dysregulation of the serotonergic system in pathological gambling, as this system is linked to dysfunction in behavioral initiation and inhibition. In addition, the noradrenergic system has been associated with mediation of arousal, increases of which are manifested by pathological gamblers. The interactions between these and other neurotransmitter systems, as well as the similarities between pathological gambling and other behavioral disorders, may provide important clues for pharmacologic intervention.

Somatization disorder is a somatoform disorder that overlaps with a number of functional somatic syndromes and has high comorbidity with major depression and anxiety disorders. Proposals have been made for revising the category of somatoform disorders, for simplifying the criteria for somatization disorder, and for emphasizing the unitary nature of the functional somatic syndromes in future classifications. A review of the cognitive-affective neuroscience of somatization disorder and related conditions suggests that overlapping psychobiological mechanisms mediate depression, anxiety, and somatization symptoms. Particular genes and environments may contribute to determining whether symptoms are predominantly depressive, anxious, or somatic, and there are perhaps also overlaps and distinctions in the distal evolutionary mechanisms that produce these symptoms.

After providing background information on the definition and nature of generalized anxiety disorder, this article describes cognitive-behavioral therapy (CBT) methods that have been empirically supported in the treatment of this disorder. Subsequent to this description, relevant outcome literature is briefly reviewed, along with evidence that the addition of other techniques beyond traditional CBT methods may be necessary to maximize clinical outcome. A description is then provided of an integrated interpersonal/emotional processing therapy that the authors have recently added to their CBT protocol. CBT with and without this integrated treatment is currently being evaluated in an experimental trial.

Various aspects of personality or dispositional style predict risk for psychiatric disorders among adults. In particular, signs of neuroticism, emotional reactivity, or sensitivity to stress are strong predictors of later mood or anxiety disorders. The current report extends this literature to adolescents. An epidemiologic sample of 776 young people living in upstate New York received psychiatric assessments based on the Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised, (DSM-III-R) and a self-report assessment of personality style in 1983 and 1985. Psychopathology was again assessed in 1992. The current study first examined demographic correlates of emotional reactivity. The study then considered the predictive relationship between emotionally reactive personality style at one study wave and psychopathology at later waves. In middle but not early adolescence, girls showed higher levels of emotional reactivity than boys. In turn, high levels of emotional reactivity predicted a range of psychiatric disorders at follow-up. The most consistent associations emerged for major depression and fearful spells, a term the authors use to describe a subclinical form of panic attacks. As in adults, midadolescent girls rate themselves as more emotionally reactive than midadolescent boys. Moreover, adolescents who rate themselves as emotionally reactive face a high risk for mood and anxiety disorders. High levels of emotional reactivity may represent a manifestation of underlying neurobiologic risk for mood and anxiety disorders.

It is widely accepted that cholinergic activity at muscarinic receptors is required to maintain cognitive functions, including learning and memory. Memory domains are especially impaired in schizophrenia, which may explain difficulties in psychosocial rehabilitation of individuals with this illness. However, little is known about the mechanism of this impairment. To understand our current knowledge, we reviewed the literature since 1990 via a PubMed search for the terms “muscarinic”, “schizophrenia” “cognition,” “memory,” “learning,” and “agonist” in combination. We found 89 basic science/laboratory studies, case reports/series, case-control studies, cross-sectional studies, standardized controlled animal trials, standardized controlled human trials, and reviews. Although further research is required to fully understand the neuropharmacology of the cholinergic system in cognitive function in schizophrenia, we have examined the data currently available. In general, these data suggest that agonist activity at acetylcholine muscarinic type 1 (M1) receptors would enhance memory and learning in schizophrenia. We present an overview of likely side effects of muscarinic agonists. We outline the anticholinergic activity of several available antipsychotics and review the available M1 muscarinic agonists.

Drugs modulating γ-aminobutyric acid (GABA) transmission via the benzodiazepine (BZ) site on the γ-aminobutyric acid type A (GABAA) receptor have been in widespread use for more than 40 years to treat anxiety, epilepsy, and sleep disorders. These drugs have been shown to be safe, well tolerated, and effective although the mechanism by they produce a myriad of pharmacologic effects remains elusive. In recent years it has been discovered that, although the GABAA receptor is widely distributed in the brain, the substructure and composition of the receptor differs from between brain regions. Termed “GABAA receptor subtypes” their discovery leads to speculation that different subtypes may mediate specific effects of BZs such as anxiety or sedation. The phenotypic analysis of transgenic knock-in and knock-out mice in which particular GABAA receptors were rendered insensitive to the effects of BZ while others were unaffected confirmed this speculation. Subsequently, subtype-specific GABAA ligands were developed that, for example, retained the anxiolytic effects of BZs but were devoid of their sedative effects. Therefore, it may be possible to develop effective anxiolytic compounds that have a much reduced side-effect profile compared with existing drugs.

A lack of motivation and anhedonia represent frequent and pervasive symptoms in depression, although with poor specificity. Historically described as a response bias, reward-related impairments in depression may account for the important aspects of the cognitive impairments associated with diagnosis of major depressive disorder. Reward processing is a broad psychological construct that can be parsed into 3 distinct components known as “reinforcement learning” (learning), “reward responsiveness” (liking), and “motivation to obtain a reward” (wanting). Depressed patients respond hyposensitively to reward and maladaptively to punishment: this pattern is related to a dysfunction in the frontostriatal systems modulated by the monoamine systems; seems to be observed in medicated and unmedicated patients with depression and in healthy individuals with high levels of anhedonia; and could be observed in patients with a history of depression, even when in full remission. Considered to be cognitive impairments, reward-related-impairments may also constitute part of an underlying neurobiological vulnerability to major depressive disorder (MDD). For example, the reward-related impairment is state dependent and, more or less, correlated with symptom severity in some studies but has also been proposed as being trait like, with endophenotype characteristics, possibly contributing to the persistence of the disease or treatment resistance. The 3 core aspects of reward processing have specific neurobiological correlates that involve the ventral and dorsal striatum, lateral habenula, ventral tegmental area, orbitofrontal cortex, anterior cingulate cortex, and ventromedial and dorsolateral prefrontal cortex. These structures underline the important role of the dopaminergic mesolimbic pathway, but glutamate and serotonin could also have an important role, at least in some aspects of reward-related impairments.