Attention-deficit/hyperactivity disorder is a prevalent and disabling disorder that is characterized by inattention and/or hyperactivity-impulsivity, impairment in executive functions, structural and functional abnormalities in frontal-striatal circuitry, associations with particular catecholamine gene variants, and responsiveness to dopaminergic and noradrenergic agents. There is a growing integration of findings from basic and clinical studies, of data from different methods (eg, genetics and imaging), and of empirical data with hypotheses drawn from evolutionary thinking. Here we briefly summarize work on the cognitive-affective neuroscience of attention-deficit/hyperactivity disorder.

A large proportion of the persons who join terrorist groups as well as lone-acting terrorists have a history of violent behavior or mental disorder that predated their becoming terrorists. This suggests that brain alterations found to occur in violent perpetrators may also be present in a significant percentage of terrorists. After a short delineation of phylogenetically old neuronal networks that are important for the generation of aggressive behavior in inconspicuous brains, this review summarizes structural and functional brain-imaging studies in violent offenders published over the last 10 years. Depending on the subtype of violence (impulsive or instrumental), deviations in structure or function were mainly found in the prefrontal, orbitofrontal, and insular cortex, as well as in temporolimbic structures (e.g., the amygdala, hippocampus, and parahippocampus). These brain areas are essentially responsible for the control of the archaic neuronal generators of aggression located in the hypothalamus and limbic system. This regional distribution of brain alterations also shows a remarkable overlap with those brain regions that are crucial for such prosocial traits as empathy and compassion. Feelings of superiority, dominance, and satisfaction gained by performing violent and terroristic attacks suggest that a hedonistic component via an activation of brain reward systems plays an additional role. In our current debate about the causes of terrorism, aspects of brain dysfunction should receive more attention.

There is a complex overlap between major depressive disorder (MDD) and attention-deficit/hyperactivity disorder (ADHD). The different therapeutic options for adult ADHD mirror those used for children with ADHD. Both stimulant and nonstimulant medications are used to treat the disorder.

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 two approved treatments for tardive dyskinesia both inhibit the vesicular monoamine transporter type 2 (VMAT2) yet have pharmacologic properties that distinguish one from the other. Knowing these differences may help optimize which treatment to select for individual patients.

The medications used to treat narcolepsy are targeted toward alleviating symptoms such as excessive sleepiness and cataplexy. The cause of this neurological sleep disorder is still not completely clear, though a destruction of hypocretin/orexin neurons has been implicated. The destruction of these neurons is linked to inactivity of neurotransmitters including histamine, norepinephrine, acetylcholine, and serotonin, causing a disturbance in the sleep/wake cycles of narcoleptic patients. Stimulants and MAOIs have traditionally been used to counteract excessive daytime sleepiness and sleep attacks by inhibiting the breakdown of catecholamines. Newer drugs, called wake-promoting agents, have recently become first-line agents due to their better side-effect profile, efficacy, and lesser potential for abuse. These agents similarly inhibit reuptake of dopamine, but have a novel mechanism of action, as they have been found to increase neuronal activity in the tuberomamillary nucleus and in orexin neurons. Sodium oxybate, a sodium salt of gamma-hydroxybutyrate (GHB), is another class that is used to treat many symptoms of narcolepsy, and is the only U.S. Food and Drug Administration (FDA)-approved medication for cataplexy. It has a different mechanism of action than either stimulants or wake-promoting agents, as it binds to its own unique receptor. Antidepressants, like selective serotonin re-uptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), have also been used, as similar to stimulants, they inhibit reuptake of specific catecholamines. In this article, we seek to review the mechanisms behind these classes of drugs in relation to the proposed pathophysiology of narcolepsy. Appropriate clinical strategies will be discussed, including specific combinations of medications that have been shown to be effective.

Obsessive-compulsive disorder (OCD) has been recognized as mainly characterized by compulsivity rather than anxiety and, therefore, was removed from the anxiety disorders chapter and given its own in both the American Psychiatric Association (APA) Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and the Beta Draft Version of the 11th revision of the World Health Organization (WHO) International Classification of Diseases (ICD-11). This revised clustering is based on increasing evidence of common affected neurocircuits between disorders, differently from previous classification systems based on interrater agreement. In this article, we focus on the classification of obsessive-compulsive and related disorders (OCRDs), examining the differences in approach adopted by these 2 nosological systems, with particular attention to the proposed changes in the forthcoming ICD-11. At this stage, notable differences in the ICD classification are emerging from the previous revision, apparently converging toward a reformulation of OCRDs that is closer to the DSM-5.

Introduction: The characteristics of Asian American and white problem gamblers using a gambling helpline were examined to identify race-related differences.

Methods: Logistic regression analyses were conducted on data obtained from callers to a gambling helpline serving southern New England in 2000–2003, inclusive.

Results: Of the 144 phone calls used in the analyses, 72 were from Asian American callers and 72 were from white callers who were matched on gender, education, income, marital/cohabitation status, and age. Race-related differences were observed in forms of gambling problems, psychiatric problems secondary to gambling, substance use problems, and family history. Asian American gamblers were more likely to report suicide attempts related to gambling and problems with non-strategic gambling. White gamblers were more likely to report both casino and non-casino gambling problems and personal and familial alcohol use problems. High proportions of both groups reported problems with strategic gambling, gambling-related anxiety, family and financial problems secondary to gambling, financial debt, daily tobacco use, and a family history of problem gambling.

Conclusion: Race-related differences should be considered in optimizing prevention and treatment strategies related to problem gambling.

Neuropathic pain and fibromyalgia are prevalent diseases which have major consequences on healthcare resources and the individual. From the clinical point of view neuropathic pains represent a heterogeneous group of aetiologically different diseases ranging from cancer to diabetes. Patients with fibromyalgia also display clinical features common in neuropathic pain suggesting that there might be some overlap. The mechanisms responsible for symptoms and signs in both diseases are still unknown. Recently, there have been numerous reports of various pharmacological treatments of neuropathic pain and fibromyalgia with often disappointing results. Most of the studies were of short duration, had high attrition rates, and displayed other methodological problems. Some compounds had high rates of adverse effects which makes it often difficult for the patients to tolerate the treatment, especially in the long-term. At present, the best options for medication treatment are tricyclic antidepressants in lower dosage than usual in psychiatric disorders and a wide range of anticonvulsants. Opioids are sometimes recommended but have been found to have minor efficacy. Recently, there have been more controlled trials, which are reported here if they had been published between 2002 and 2004. Various compounds have been tested in different studies. Treatment of fibromyalgia, which has many features in common with depressive symptoms, became the focus of interest. New promising studies with dual serotonin-norepinephrine reuptake inhibitors (duloxetine and milnacipram) and a newer antiepileptic drug (pregabalin) are in progress. Future research will have to apply new approaches (eg, using a mechanism based classification of neuropathic pain and carrying out studies in populations with the same symptom but not necessarily the same disease) in order to find effective treatments for these common and often debilitating diseases.

Ziprasidone is a second-generation antipsychotic that received Food and Drug Administration approval in February 2001. It has a unique receptor profile that includes high-affinity antagonist activity at dopamine D2 receptors, inverse agonist activity at serotonin (5-HT)2A receptors, agonist activity at 5-HT1A receptors, and a relatively high affinity for the serotonin and norepinephrine transporters. The 5-HT1A affinity, together with the inhibitory effect on monoamine reuptake, may underlie the hypothesized beneficial effects on comorbid affective and cognitive abnormalities in schizophrenia and schizoaffective disorder. The short-term efficacy of ziprasidone for core positive symptoms of schizophrenia appears to be comparable to other conventional and atypical antipsychotics. The short-term efficacy of ziprasidone in acute mania has been established based on two 3-week, double-blind, placebo-controlled trials. Open-label treatment for up to 52 weeks confirms the sustained efficacy and safety of ziprasidone in bipolar disorder. Maintenance studies in schizophrenia and schizoaffective disorder indicate that long-term ziprasidone therapy is effective in preventing relapse, while maintaining cognitive and psychosocial benefits. The safety database suggests that the overall cardiovascular and cerebrovascular risk associated with ziprasidone is lower than with other atypicals, with notably lower risk of drug-related increases in weight, glucose, or lipids. The data also suggest a modestly increased risk of QTc prolongation that is not dose related or linked to torsades de pointes. Switching to ziprasidone from other atypicals appears to improve both clinical symptoms and metabolic parameters, though more studies are needed to fully characterize these benefits. This monograph summarizes the efficacy, tolerability, and safety of oral ziprasidone in the treatment of schizophrenia, schizoaffective disorder, and bipolar mania.

This article focuses on the controversial decision to exclude the overlapping symptoms of distractibility, irritability, and psychomotor agitation (DIP) with the introduction of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) mixed features specifier. In order to understand the placement of mixed states within the current classification system, we first review the evolution of mixed states. Then, using Kraepelin’s original classification of mixed states, we compare and contrast his conceptualization with modern day definitions. The DSM-5 workgroup excluded DIP symptoms, arguing that they lack the ability to differentiate between manic and depressive states; however, accumulating evidence suggests that DIP symptoms may be core features of mixed states. We suggest a return to a Kraepelinian approach to classification—with mood, ideation, and activity as key axes—and reintegration of DIP symptoms as features that are expressed across presentations. An inclusive definition of mixed states is urgently needed to resolve confusion in clinical practice and to redirect future research efforts.

Basic animal studies and human imaging studies have contributed to our understanding of the psychobiology of love and attachment. There are overlaps and distinctions in the neuronal circuitry of maternal love, romantic love, and long-term attachment. In these circuits, important molecules, which have been demonstrated to play a role in the psychobiology of social bonding include dopamine, serotonin, opioids, oxytocin, and vasopressin. Particular genetic and environmental variations contribute to social-bonding phenotypes, consistent with an evolutionary perspective on the value of these behaviors. Advances in the psychobiology of social bonds have led to hypotheses about the pharmacotherapy of disorders of attachment.

The threat of violence is a major concern for all individuals working or receiving treatment in an inpatient psychiatric setting. One major focus in forensic psychology and psychiatry over the past several decades has been the development of risk assessments to aid in the identification of those individuals most at risk of exhibiting violent behavior. So-called second- and third-generation risk assessments were developed to improve the accuracy of decision making. While these instruments were developed for use in the community, many have proven to be effective in identifying patients more likely to exhibit institutional aggression. Because the purpose of risk assessment is the reduction of violence, dynamic factors were included in third-generation risk instruments to provide opportunities for intervention and methods for measuring change. Research with these instruments indicates that both static factors (second-generation) and dynamic factors (third-generation) are important in identifying those patients most likely to engage in institutional aggression, especially when the aggression is categorized by type (impulsive/reactive, organized/predatory/instrumental, psychotic). Recent research has indicated that developing a typology of aggressive incidents may provide insight both into precipitants to assaults as well as appropriate interventions to reduce such aggression. The extant literature suggests that both static and dynamic risk factors are important, but may be differentially related to the type of aggression exhibited and the characteristics of the individuals exhibiting the aggression.

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.

Introduction: Major depressive disorder (MDD) is thought to negatively impact cognitive function; however, the relationship has not been well explored.

Objective: This study examined the association between depression severity and global cognitive function and memory in subjects with severe, treatment-resistant MDD.

Methods: We enrolled 66 subjects with Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosed unipolar MDD in a multicenter trial to assess the efficacy and neurocognitive effects of electroconvulsive therapy (ECT). We measured depression severity with the 24 item Hamilton Rating Scale for Depression (HRSD24). Neuropsychologic measures included the Mini Mental State Examination (MMSE), Rey Auditory Verbal Learning Test (RAVLT), and the Complex Figure Test (CFT). Correlational and regression analyses were conducted to explore associations between depression severity and cognitive function.

Results: The mean age of the subjects was 53.6 years (SD=15.8), 65% were female, and mean HRSD24 was 33.9 (SD=6.7). Mean demographic-corrected T-scores for each neurocognitive measure were in the average to borderline range, and HRSD24 values were unrelated to performance on the MMSE, RAVLT immediate and delayed recall, and CFT immediate and delayed recall.

Conclusion: In this sample of severely depressed subjects referred for ECT, depression severity was unrelated to global cognitive function or memory. Future research should examine the interactions between other depressive characteristics and neurocognitive function.

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.

Anxiety disorders are a common focus of clinical concern and certain forms of anxiety may be conceptualized as disorders of emotional learning. Behavior therapies effective in the treatment of anxiety are modeled on extinction training as a means of reducing pathological anxiety. The present understanding of human anxiety has been informed by preclinical research using rodent models to study the acquisition and extinction of fear. Glutamate appears to have a central role in both of these processes. The authors review this literature and discuss novel applications of D-cycloserine, a partial N-methyl-D-aspartate agonist, for the treatment of anxiety.

Current guidelines for the treatment of patients with schizophrenia advocate that patients receive treatment with a long-acting injectable (LAI) antipsychotic medication if they prefer such treatment or if they have a history of poor or uncertain adherence. Available LAI formulations in the United States include first-generation antipsychotics (fluphenazine decanoate and haloperidol decanoate), risperidone/paliperidone containing products (risperidone microspheres, paliperidone palmitate, and risperidone subcutaneous), aripiprazole containing products (aripiprazole monohydrate and aripiprazole lauroxil), and olanzapine pamoate. LAI antipsychotics can address the guesswork about adherence status and patients may prefer them if they are offered this as a choice, including individuals early in their disease course. Additional approved indications in the United States for LAI antipsychotics include bipolar I disorder maintenance treatment for risperidone microspheres and aripiprazole monohydrate, and schizoaffective disorder for paliperidone palmitate once monthly. Differences and similarities among the different products are discussed, including guidance regarding optimal treatment selection. Tips are provided to enhance effective patient communication to maximize the likelihood of acceptance of this treatment modality.

Introduction: Recent data suggest that escitalopram may be more effective in severe depression than other selective serotonin reuptake inhibitors.

Methods: Individual patient data from four randomized, double-blind comparative trials of escitalopram versus a serotonin/norepinephrine reuptake inhibitor (SNRI) (two trials with duloxetine and two with venlafaxine extended release) in outpatients (18–85 years of age) with moderate-to-severe major depressive disorder were pooled. The primary efficacy parameter in all four trials was mean change in the Montgomery-Asberg Depression Rating Scale (MADRS) score.

Results: Significantly fewer escitalopram (82/524) than SNRI (114/527) patients prematurely withdrew from treatment due to all causes (15.6% vs. 21.6%, Fisher Exact: P=.014) and adverse events (5.3% vs. 12.0%, Fisher Exact: P <.0001). Mean reduction in MADRS score from baseline to Week 8 was significantly greater for the escitalopram group versus the SNRI group using the last observation carried forward (LOCF) approach [mean treatment difference at Week 8 of 1.7 points (P <.01)]. Similar results were observed in the severely depressed (baseline MADRS score ≥30) patient subset (mean treatment difference at Week 8 of 2.9 points [P <.001, LOCF]). Observed cases analyses yielded no significant differences in efficacy parameters.

Conclusion: This pooled analysis indicates that escitalopram is at least as effective as the SNRIs (venlafaxine XR and duloxetine), even in severe depression, and escitalopram treatment was better tolerated.