Although the vagus nerve has traditionally been considered to perform efferent functions, in reality it performs significant afferent functions as well, carrying information from the body, head, and neck to the brain. Preliminary studies examining this afferent activity led to the theory that vagus nerve stimulation (VNS) could successfully control seizure activity in persons who are refractory to antiepileptic medications. Unlike other forms of brain stimulation, VNS is unable to directly stimulate multiple discrete areas of the brain; however, through several pathways, it is able to relay sensory information to higher brain regions. An implantable VNS device known as the VNS™ NeuroCybernetic Prosthesis (NCP) System has been used in approximately 9,000 epilepsy patients in Europe and the United States since 1994. The implant has reduced seizure frequency by an average of 25% to 30%, with minimal side effects. Studies underway are also showing some degree of success in the management of treatment-refractory depression. The future efficacy of the implantable system in other disorders may depend on whether the implant can be more precisely focused to affect different brain regions. Research in this area is underway.

Background:This study examined the prevalence of irritability in patients with bipolar I disorder during an episode of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) major depression who do not meet criteria for a mixed episode.

Method:A chart review of 111 patients with bipolar I disorder treated at the Massachusetts General Hospital Bipolar Clinic between 1998 and 2000 identified 34 patients who met criteria for a DSM-IV major depressive episode in the absence of (1) mood elevation and/or (2) irritability associated with any additional above threshold DSM-IV symptoms of mania. Data gathered from the charts utilized prospective ratings made routinely at each clinic visit using the Clinical Monitoring Form (CMF), a structured assessment instrument which includes modified versions of the mood modules of the Structured Clinical Interview for DSM-IV. Data from these 34 patients were reviewed to determine the presence of irritability.

Results:The frequency of abnormal irritability in these 34 patients followed a bimodal distribution: 26% of the patients showed abnormal irritability ≥75% of the time, compared with 68% of the patients with abnormal irritabihty ≤30% of the time. Of the high-irritability patients, psychomotor agitation was rated as definitely present to a significant degree in 44%. Talkativeness and distractibility were rated present but subthreshold in one patient each. All other symptoms of DSM-IV mania were absent.

Conclusion:Approximately 25% of patients with bipolar I disorder who meet criteria for a DSM-IV major depressive episode also experienced substantial irritability in the absence of associated symptoms of mania. Our results suggest that abnormal irritability is not limited to mania or mixed states.

Here we provide comprehensive guidelines for the assessment and treatment of violence and aggression of various etiologies, including psychotic aggression and impulsive aggression due to schizophrenia, mood disorders, ADHD, or trauma, and predatory aggression due to psychopathy and other personality disorders. These guidelines have been developed from a collection of prescribing recommendations, clinical trial results, and years of clinical experience in treating patients who are persistently violent or aggressive in the California Department of State Hospital System. Many of the recommendations provided in these guidelines employ off-label prescribing practices; thus, sound clinical judgment based on individual patient needs and according to institution formularies must be considered when applying these guidelines in clinical practice.

Neural mechanisms underlying the regulation of ingestive behavior and energy balance are well conserved among mammals. Many neural pathways, each reflecting the function of many genes, interact to regulate these processes. Systematic genetic perturbations are not feasible in humans—the examination of gene functions relevant to feeding regulation must be performed in other species. Many advances in this field have been made through molecular genetic studies of mice, the most genetically tractable of mammalian species. The relevance of mouse ingestive behavior to the mechanisms underlying the regulation of feeding in humans is discussed. Approaches for evaluating the contribution of genes to the regulation of energy balance and to the actions of anorectic drugs are described in the context of studies focused on a line of mice lacking the serotonin 5-HT2C receptor subtype. These animals display reduced responsiveness to serotonergic anorexic drugs and a late-onset obesity syndrome associated with features reminiscent of common forms of human obesity. Developmental studies of energy balance uncovered a novel age-dependent physiological process that may contribute generally to the predisposition of humans and other mammals to accumulate fat stores during “middle-age.” These findings are presented to illustrate considerations in the use of mouse molecular genetic technologies to investigate genetic influences on ingestive behavior and energy balance.

Research on deep brain stimulation (DBS) for treatment-resistant psychiatric disorders has established preliminary efficacy signals for treatment-resistant depression. There are only few studies on DBS that included patients suffering from bipolar disorder. This article gives an overview of these studies concerning DBS targets, antidepressant efficacy, and the occurrence of manic/hypomanic symptoms under stimulation. First, promising results show that all patients experienced significant improvement in depressive symptomatology. In a single case, hypomanic symptoms occurred, but they could be resolved by adjusting stimulation parameters. Furthermore, this article highlights important clinical differences between unipolar and bipolar depression that have to be considered throughout the course of treatment.

Cerebrotendinous xanthomatosis (CTX) is a rare inborn disorder of sterol storage with autosomal recessive inheritance and a variable clinical presentation. We describe two siblings with an early psychiatric presentation of CTX-associated attention-deficit/hyperactivity disorder and oppositional defiant disorder, also associated with a mild intellectual disability and major behavioral impairments. In both cases, treatment with chenodeoxycholic acid improved externalized symptoms and a partial recovery of cognitive impairments was observed. This suggests that CTX is potentially reversible, demonstrating the need for early diagnosis and treatment of this disorder before irreversible neurological lesions can occur.

More than 36,000 people in the United States die from suicide annually, and suicide is the third leading cause of death in adolescence. Adolescence is a time of high risk for suicidal behavior, as well as a time that intervention and treatment may have the greatest impact because of structural brain changes and significant psychosocial development during this period. Functional and structural neuroimaging studies in adults who have attempted suicide suggest distinct gray matter volume abnormalities in cortical regions, as well as prefrontal cortical and dorsal anterior cingulate gyrus neural circuitry differences compared with affective and healthy adult controls. Recent functional neuroimaging studies in adolescents with a history of suicide attempt suggest differences in the attention and salience networks compared with adolescents with depression and no history of suicide attempt and healthy controls when viewing angry faces. In contrast, no abnormalities are seen in these areas in the absence of emotional stimuli. These networks may represent promising targets for future neuroimaging studies to identify markers of risk for future suicide attempt in adolescents.

Traditional guidelines call for treatment of major depression with a sequence of single antidepressants. Augmentation with a second agent generally only occurs when the first agent is well tolerated and when it also provides at least some symptomatic improvement on its own. Since this standard approach leads to low rates of attaining and sustaining remission by the first agent, with diminishing returns for each subsequent agent, there is growing dissatisfaction with this approach to the treatment of major depression. One new trend is to attempt to enhance the rates of sustained remission from a major depressive episode by combining two therapeutic agents from the very initiation of treatment of a major depressive episode.

Traditional treatment of major depression begins with a single “first line” antidepressant, and if it does not work or is not tolerated, trying another and then another. Unfortunately, this strategy results in disappointing remission rates for the first antidepressant (Figure 1), and disappointing rates of maintaining any improvement that is attained by this first agent because of high relapse rates over the next year despite continuing treatment with the first antidepressant (Figure 2A). And that is the good news. The bad news is that with each subsequent antidepressant treatment administered remission rates are progressively reduced (Figure 1). For those patients who do improve, they are progressively less likely to sustain their therapeutic gains despite continuing to take the drug that led to their initial improvement (Figure 2).

Patient nonadherence to pharmacologic and psychosocial treatments for geriatric depression and anxiety poses a serious barrier to effective clinical care. Rates of nonadherence may be as high as 60% in older adults. Factors associated with nonadherence include lack of information and misperceptions about mental illness and its treatment, stigma, lack of family support, cognitive impairment, adverse events, side effects, cost of treatments, poor physician-patient communication or relationship, and other barriers, such as lack of transportation. Effective interventions to improve adherence are personalized and include both behavioral and educational components. Several current projects that combine pharmacotherapy and psychotherapy for geriatric depression in an integrated care model show promise as interventions to improve rates of treatment and adherence.

The modern therapeutic approach to most psychiatric diseases involves a combination of well-supervised psychotherapy, pharmacotherapy, and electroconvulsive therapy. Patients who fail to adequately respond to these modern treatment methods and remain severely disabled may be considered for surgical intervention. Cingulotomy, capsulotomy, subcaudate tractotomy, and limbic leucotomy are the most common psychosurgical procedures performed today, with response rates in the 35% to 65% range. Modern stereotactic techniques have reduced complication rates, but controversy remains regarding the optimal surgical procedure. The major psychiatric diagnostic categories that might respond to surgery include treatment-refractory major affective disorders, obsessive-compulsive disorder, and chronic anxiety states. Surgery should be considered as one part of an entire treatment plan and must be followed by an appropriate psychiatric rehabilitation program. It should only be carried out by an expert multidisciplinary team consisting of a neurologist a neurosurgeon, and a psychiatrist with experience in these disorders. Surgical intervention remains a reasonable therapeutic option for select patients with a disabling psychiatric disease and may be underutilized.

The clinical use of mood stabilizers and antipsychotics in children and adolescents with bipolar disorders has increased significantly over the past few years. These agents have multiple effects and interactions. This articles reviews the studies that support the use of mood stabilizers and atypical antipsychotics in children and adolescents with bipolar disorders and presents information on these agent's pharmacokinetics, dosing, and drug interactions.

The majority of studies that have examined the usefulness of pharmacotherapies selective for serotonin (5-hydroxytryptamine; 5-HT) as a treatment for alcohol dependence have been standard, double-blind clinical trials that include patients with a variety of clinical presentations. Almost all of the early studies evaluated heavy social drinkers and found only a modest advantage for 5-HT pharmacotherapies in reducing the number of drinks per day. Also, the advantage of these pharmacotherapies was observed primarily when these agents were given at higher daily dosages than suggested prescribing practices for use as an antidepressant. The few studies that evaluated treatment-seeking patients found that 5-HT pharmacotherapies were not instrumental in reducing drinking rates compared with placebo. These results led to a dampening of enthusiasm for use of these agents in treating alcohol dependence. However, more recent investigations have begun to target subgroups with potential abnormalities in 5-HT neurotransmission. The thinking is that these medications should be most useful in alcohol-dependent individuals who have more clearly delineated suggestive signs of 5-HT dysfunction, such as concomitant depression or anxiety. Although few results are available to date, there is growing evidence to suggest that alcohol-dependent subgroups are differentially responsive to 5-HT pharmacotherapies with respect to drinking-related outcomes. This may explain the modest and variable 5-HT pharmacotherapeutic effects that were reported in the earlier studies, which included large heterogeneous patient groups. Further investigations are needed to confirm these initial optimistic results.

Leptin is an adipocyte-derived hormone, which is involved predominantly in the long-term regulation of body weight and energy balance by acting as a hunger suppressant signal to the brain. Leptin is also involved in the modulation of reproduction, immune function, physical activity, and some endogenous endocrine axes. Since anorexia nervosa (AN) and bulimia nervosa (BN) are characterized by abnormal eating behaviors, dysregulation of endogenous endocrine axes, alterations of reproductive and immune functions, and increased physical activity, extensive research has been carried out in the last decade in order to ascertain a role of this hormone in the pathophysiology of these syndromes. In this article, we review the available data on leptin physiology in patients with eating disorders. These data support the idea that leptin is not directly involved in the etiology of AN or BN. However, malnutrition-induced alterations in its physiology may contribute to the genesis and/or the maintenance of some clinical manifestations of AN and BN and may have an impact on the prognosis of AN.

Hypertensive encephalopathy is one of the manifestations of a hypertensive crisis. It is not the absolute value of the blood pressure that causes the encephalopathy, rather the presence of an abrupt rise in pressure. In terms of clinical and radiographic findings, there are many similarities among a group of entities, including hypertensive encephalopathy, eclampsia, and immunosuppressant neurotoxicity. Hyperperfusion syndromes may represent these clinical disease states that may share the same pathophysiology. Magnetic resonance imaging fluid attenuated inversion recovery sequences have recognized the prominent cortical involvement of the disease that had been previously missed on computed tomography. Studies have found cortical involvement in 94% of their patients, particularly in mild cases. Animal models demonstrate endothelial damage and enhanced pinocytosis in the cortex as reasons why edema may begin in that region of the brain. Patients diagnosed with hypertensive encephalopathy should be diagnosed and treated promptly in order to avoid further neurological complications. The mean arterial pressure should be lowered by 20% to 25% within the first hour of patient presentation, followed by further gradual reduction in blood pressure over the following 24 hours. Hypertensive emergency in acute ischemic stroke should be managed with more caution. According to the 2003 American Stroke Association treatment guidelines, for patients with ischemic stroke not eligible for thrombolytic therapy, target blood pressures are a diastolic blood pressure <120 mmHg and systolic blood pressure <220 mmHg. The systolic pressure must be <185 mmHg and diastolic pressure <110 mmHg at all times if eligible for thrombolytic therapy.

The historical development of the concept of catatonia in affective disorders and contemporary papers on this topic are reviewed. In addition, data from a current study on the frequency of catatonia in mixed mania are reported. Differences between catatonic and noncatatonic patients with mixed mania are presented and their relevance to clinical practice is discussed.