Repetitive transcranial magnetic stimulation (rTMS), defined as the administration of a series of magnetic stimuli to the brain for the purpose of altering brain function, is an experimental medical intervention. rTMS currently is used to probe various aspects of brain function in the context of research studies approved by local ethics committees. rTMS also is under investigation as a potential treatment for various neurologic and psychiatric disorders. In light of the growing interest in using rTMS in a variety of experimental and therapeutic settings, the International Society for Transcranial Stimulation has recognized the need to formulate a consensus statement to assist the field in developing guidelines for its safe application. Whether the intended use is experimental or therapeutic, certain principles regarding the safety of rTMS apply. This statement is not aimed at guiding the therapeutic use of rTMS in any given condition or its application in any research paradigm, but rather is meant to apply broadly wherever rTMS is used.

rTMS has significant risks, most importantly that of producing epileptic seizures. The degree of risk varies with the dosing parameters and individual subject factors. Therefore, rTMS should be administered only under a licensed physician's orders (ie, by prescription or through some other mechanism that makes a physician directly responsible for its administration to the individual patient or research subject). Because rTMS has potential behavior-changing effects, undesirable side effects, and therapeutic impact, careful assessment of the risk and appropriateness of rTMS in each clinical or scientific context is critical and can only be made by, or in consultation with, a physician knowledgeable and experienced in the use of rTMS and fully trained in neurology, psychiatry, or another appropriate specialty.

Violent behavior associated with mental disorders is a common reason for admission to a psychiatric inpatient unit. Once hospitalized, patients may continue to be intermittently agitated and have persistent aggressive behaviors, preventing their discharge back into the community. Managing agitation quickly with effective pharmacological agents can avoid further escalation to aggression and violence. In the acute setting, this usually involves the parenteral use of antipsychotics, with or without benzodiazepines. Within the past decade, short-acting intramuscular formulations of second-generation antipsychotics have become available and provide a means to induce calm with a substantially lower risk of acute dystonia or akathisia compared with haloperidol. New alternative formulations that avoid injections include inhalation and sublingual administration. Longer-term management of persistent aggressive behavior by reducing the frequency and intensity of future episodes of agitation is more complex. In contrast to agitation associated with schizophrenia or bipolar mania, no agents have yet been approved by regulatory agencies for the treatment of persistent aggressive behavior. The strongest evidence supports the use of clozapine as an antihostility agent, followed by olanzapine. Adjunctive strategies with anticonvulsants and beta-adrenergic agents may also be worthwhile to consider.

Introduction: The safety and tolerability profiles of antidepressants can often influence the treatment choices of clinicians treating major depressive disorder. The purpose of this investigation was to characterize the safety and tolerability of desvenlafaxine (administered as desvenlafaxine succinate) in treating depression.

Methods: An integrated analysis of all short-term, randomized, double-blind, placebo-controlled registration studies for major depressive disorder (four flexible-dose and five fixed-dose studies) was performed. Adult outpatients with major depressive disorder received desvenla-faxine doses ranging from 50–400 mg/day or placebo for 8 weeks. Treatment-emergent adverse events, laboratory values, vital signs, and discontinuation symptoms were evaluated. In the subset of fixed-dose studies, dose-related effects were analyzed.

Results: In the overall population (placebo: n=1,116; desvenlafaxine: n=1,834), adverse events resulted in discontinuations in 3% of placebo-treated patients and 12% of desvenla-faxine-treated patients; in the subset of fixed-dose studies, the rates were 4% with placebo and increased with desvenlafaxine dose (50 mg/ day: 4%; 400 mg/day: 18%). The most common treatment-emergent adverse event was transient nausea that was generally mild to moderate. The most common sexual dysfunction associated with desvenlafaxine treatment was erectile dysfunction in men (7% vs 1% with placebo) and anorgasmia in women (1% and 0%). One desvenlafaxine-treated patient died of a completed suicide; there were four suicide attempts (three desvenlafaxine, one placebo) and eight cases of suicidal ideation (five desvenlafaxine, three placebo) during the on-therapy period. Small but statistically significant changes in mean blood pressure occurred at all desvenlafaxine doses; clinically meaningful changes were observed in 1% of placebo-treated patients and 2% of desvenlafaxine-treated patients. Desvenlafaxine was associated with small but statistically significant mean changes in laboratory assessments, particularly lipid and liver enzyme elevations, and electrocardiograms; few cases of these changes were clinically relevant.

Conclusion: Desvenlafaxine in the treatment of major depressive disorder exhibited a safety and tolerability profile generally consistent with the serotonin-norepinephrine reuptake inhibitor class. The most common adverse event was transient nausea. At the recommended therapeutic dose of 50 mg/day, discontinuation due to adverse events was similar to placebo.

When benzodiazepines (BZs) supplanted barbiturates as a favored, safer treatment for anxiety and sleep disorders in the 1960s, the abuse liability and dependence potential of these drugs were little understood. Widespread recognition of the difficulty of stopping use of chronically taken BZs emerged through the popular press in the late 1970s, which resulted in reluctance to prescribe these otherwise clinically useful compounds. Evolution of the understanding of the biochemical basis for BZ effects in the 1980s and 1990s, coupled with regulatory emphasis on collection of data used in legal scheduling decisions, made possible a targeted search for drugs that would provide effective treatment for anxiety disorders in the absence of abuse liability or dependence potential. Compounds that have selective efficacy at subtypes of the γ-aminobutyric acid type A receptor, are active in preclinical anxiolytic screens, but negative in preclinical studies of behavior relevant to evaluation of abuse liability appear to be one promising means for achieving this end.

Mixed affective states, defined as the coexistence of depressive and manic symptoms, are complex presentations of manic-depressive illness that represent a challenge for clinicians at the levels of diagnosis, classification, and pharmacological treatment. The evidence shows that patients with bipolar disorder who have manic/hypomanic or depressive episodes with mixed features tend to have a more severe form of bipolar disorder along with a worse course of illness and higher rates of comorbid conditions than those with non-mixed presentations. In the updated Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM–5), the definition of “mixed episode” has been removed, and subthreshold nonoverlapping symptoms of the opposite pole are captured using a “with mixed features” specifier applied to manic, hypomanic, and major depressive episodes. However, the list of symptoms proposed in the DSM–5 specifier has been widely criticized, because it includes typical manic symptoms (such as elevated mood and grandiosity) that are rare among patients with mixed depression, while excluding symptoms (such as irritability, psychomotor agitation, and distractibility) that are frequently reported in these patients. With the new classification, mixed depressive episodes are three times more common in bipolar II compared with unipolar depression, which partly contributes to the increased risk of suicide observed in bipolar depression compared to unipolar depression. Therefore, a specific diagnostic category would imply an increased diagnostic sensitivity, would help to foster early identification of symptoms and ensure specific treatment, as well as play a role in suicide prevention in this population.

Impulsivity and compulsivity have been considered opposite poles of a continuous spectrum, but their relationship appears to be more complex. Disorders characterized by impulsivity often have features of compulsivity and vice versa. The overlaps of the constructs of compulsivity and impulsivity warrant additional investigation, not only to identify the similarities and differences, but also to examine the implications for prevention and treatment strategies of both compulsive and impulsive behaviors.

Introduction: To assess the efficacy of desvenlafaxine (administered as desvenlafaxine succinate) in outpatients with major depressive disorder.

Methods: A meta-analysis of individual patient data was performed on the complete set of registration trials (nine randomized, double-blind, placebo-controlled 8-week studies) of desvenlafaxine. Patients received fixed (50, 100, 200, or 400 mg/day; n = 1,342) or flexible doses (100–400 mg/day; n = 463) of desvenlafaxine or placebo (n = 1,108). The primary efficacy variable was the 17-item Hamilton Rating Scale for Depression (HAM-D17); the primary intent to treat analyses used the last-observation-carried-forward method.

Results: Significantly greater improvement with desvenlafaxine versus placebo on the HAM-D17 total score was observed for the full data set (difference in adjusted means: −1.9; P<.001), each fixed-dose group (all P<.001), and the flexible-dose group (P=.024). Overall rates of HAM-D17 response (≥50% decrease from baseline score: 53% vs 41%) and remission (HAM-D17 ≤7: 32% vs 23%) were significantly greater for desvenlafaxine versus placebo (all P<.001). Discontinuation rates due to adverse events increased with dose (4% to 18%; placebo: 3%).

Conclusion: Desvenlafaxine demonstrated short-term efficacy for treating major depressive disorder across the range of doses studied. No evidence of greater efficacy was observed with doses >50 mg/day; a strong dose-response effect on tolerability was observed.

N-acetyl cysteine (NAC) is a widely available nutraceutical with a variety of actions. As a precursor of cysteine and glutathione, it has antioxidant properties that may impact on mood and contribute to an effect on impulsivity and obsessive behaviour. Via its additional effect on glutamate via the cystine-glutamate exchange system, NAC has been shown to mediate impulsivity in preclinical models of addiction, reduce craving, and cue extinction. Further, by boosting glutathione, NAC acts as a potent antioxidant and has been shown in two positive, large-scale randomized placebo-controlled trials to affect negative symptoms in schizophrenia and depression in bipolar disorder. We describe three cases in which its actions specifically on nail-biting and associated anxiety may offer a potential treatment. The spontaneous findings are reported as part of an ongoing treatment trial examining the utility of NAC in bipolar disorder. Its actions, if robustly replicated, also point to potential treatment targets in glutathione or glutamate pathways in the brain.

Body dysmorphic disorder (BDD) and eating disorders are body image disorders that have long been hypothesized to be related to obsessive-compulsive disorder (OCD). Available data suggest that BDD and eating disorders are often comorbid with OCD. Data from a variety of domains suggest that both BDD and eating disorders have many similarities with OCD and seem related to OCD. However, these disorders also differ from OCD in some ways. Additional research is needed on the relationship of BDD and eating disorders to OCD, including studies that directly compare them to OCD in a variety of domains, including phenomenology, family history, neurobiology, and etiology.

What are the symptoms of panic disorder and how is the disorder most effectively treated? One of the most commonly encountered anxiety disorders in the primary care setting, panic disorder is a chronic and debilitating illness. The core symptoms are recurrent panic attacks coupled with anticipatory anxiety and phobic avoidance, which together impair the patient's professional, social, and familial functioning. Patients with panic disorder have medically unexplained symptoms that lead to overutilization of healthcare services. Panic disorder is often comorbid with agoraphobia and major depression, and patients may be at increased risk of cardiovascular disease and, possibly, suicide. Research into the optimal treatment of this disorder has been undertaken in the past 2 decades, and numerous randomized, controlled trials have been published. Selective serotonin reuptake inhibitors have emerged as the most favorable treatment, as they have a beneficial side-effect profile, are relatively safe (even if taken in overdose), and do not produce physical dependency. High-potency benzodiazepines, reversible monoamine oxidase inhibitors, and tricyclic antidepressants, have also shown antipardc efficacy. In addition, cognitive-behavioral therapy has demonstrated efficacy in the acute and long-term treatment of panic disorder. A n integrated treatment approach that combines pharmacotherapy with cognitive-behavioral therapy may provide the best treatment. Long-term efficacy and ease of use are important considerations in treatment selection, as maintenance treatment is recommended for at least 12–24 months, and in some cases, indefinitely.

An emerging body of evidence points to impairments in neuroplasticity, cell resilience, and neuronal survival as major pathophysiological mechanisms in bipolar disorder. Neuronal survival is influenced by several factors including an orchestrated action of neurotransmitters, hormones, and neurotrophins. Patients with bipolar disorder exhibit increased peripheral level of inflammatory mediators such as cytokines, mainly during acute mood episodes. These mediators interact in several pathways involved in regulation of mood and energy including hypothalamic-pituitary-adrenal axis and monoamine metabolism. Importantly, inflammatory cytokines have a potential role in controlling neuronal and glial cell loss that occurs during mood episodes, especially during mania, as they are the most powerful extracellular stimuli to apoptosis. Bipolar patients have been reported to show imbalanced peripheral production of cytokines both at the mRNA and protein levels, associated signal transduction machinery, as well as to have specific functional polymorphisms in the genes that encode these cytokines. Interestingly, lithium, valproate, and several antidepressants have demonstrated to have immunomodulatory properties. Growing evidence supports the involvement of inflammatory mechanisms in bipolar disorder, opening new paths of investigation using immunomodulatory medications. These findings can offer not only an opportunity of treating mood symptoms but also understanding and reverting neurobiological changes associated with the disorder.

Although currently available antidepressants increase monoamine levels soon after the start of treatment, therapeutic benefits are often delayed by several weeks and the majority of patients with major depressive disorder fail to achieve an adequate response to first- or second-line therapies targeting monoamines. The recent approval of the NMDA (N-methyl-d-aspartate) antagonist esketamine given intranasally for treatment-resistant depression has reinforced the need for agents with rapid onset with alternate mechanisms of action. Dextromethorphan/bupropion, an investigational medicine currently in development, is one such candidate.

Introduction: Despite numerous explanatory hypotheses, few studies have involved a large national clinical sample examining risk factors in the occurrence of rapid cycling during the course of bipolar illness.

Methods: From 1,090 manic bipolar I disorder inpatients included in a multicenter national study in France, 958 could be classified as rapid or non-rapid cyclers and assessed for demographic, illness course, clinical, psychometric, temperament, comorbidity, and treatment characteristics.

Results: Rapid cycling bipolar disorder occurred in 9% (n=86) of the study group. Compared to nonrapid cyclers (n=872), patients with rapid cycling experienced the onset of their illness at a younger age, a higher number of prior episodes, more depression during the first episode, and more suicide attempts. At study entry, they also experienced manic episodes with more depressive and anxious symptoms, but less psychotic features. The following independent variables were associated with rapid cycling: longer duration of illness, antidepressant treatment, episodes with no free intervals, cyclothymic temperament, lower scores on the Scale for Assessment of Positive Symptoms and presence of thyroid disorder. Retrospective study limited to bipolar I disorder inpatients; several factors previously associated with rapid cycling were not assessed.

Conclusion: Our findings may confirm previous descriptions, according to which rapid-cycling develops later in the course of illness following a sensitization process triggered by antidepressant use or thyroid dysfunction, in patients with a depression-mania-free interval course, and cyclothymic temperament.

Introduction: Late in utero exposure to antidepressants has been suspected of adversely impacting pregnancy outcome and compromising neonatal adaptation. Hence, the necessity exists to analyze published information on antidepressant use during late pregnancy to individuate potential recurrent patterns of iatrogenic complications.

Methods: Computerized searches on MEDLINE, PsyclNFO, ENBASE, and Cochrane Library through February 10, 2010 were performed for selecting literature information and investigating the safety of antidepressants when used during late pregnancy.

Results: Antidepressant treatment during late pregnancy may increase the rates of poor pregnancy outcome and neonatal withdrawal/ toxic reactions.

Conclusions: Because both gestational complications and neonatal adverse events acknowledge the same etiology, the author suggests including such iatrogenic events under the definition of prenatal antidepressant exposure syndrome, in order to increase clinicians' awareness about the spectrum of risks which may concern the mother-infant pair when antidepressant treatment is deemed indispensable during late pregnancy.

Introduction: Children and adolescents with bipolar disorder often present with higher rates of mixed episodes, rapid cycling, and co-occurring attention-deficit/hyperactivity disorder than adults with bipolar disorder. It is unclear whether the differences in clinical presentation between youth and adults with bipolar disorder are due to differences in underlying etiologies or developmental differences in symptom manifestation. Neuroimaging studies of children and adolescents with bipolar disorder may clarify whether neurobiological abnormalities associated with early-and adult-onset bipolar disorder are distinct. Moreover, children and adolescents with bipolar disorder are typically closer to their illness onset than bipolar adults, providing a window of opportunity for identifying core neurobiological characteristics of the illness (ie, disease biomarkers) that are independent of repeated affective episodes and other confounding factors associated with illness course.

Methods: Peer-reviewed publications of neuroimaging studies of bipolar children and adolescents were reviewed.

Results: Structural, neurochemical, and neurofunctional abnormalities in prefrontal and medical temporal and subcortical limbic structures, including the striatum, amygdala, and possibly hippocampus, are present in children and adolescents with bipolar disorder.

Conclusion: Differences between neurobiological abnormalities in bipolar youth and adults as well as recommendations for future research directions are discussed.