With our emphasis on treatment-refractory depression, one cannot help but think about recent media coverage and regulatory events surrounding antide-pressant therapy. The current debate about the safety of antidepressant therapy for children and adolescents stands out in particular.

Recently, a pediatrician attending a symposium at the University of Pennsylvania asked me whether I thought that primary care pediatricians should continue to prescribe antidepressants for children with depression and anxiety disorder. As is now well known, data have emerged suggesting a link between selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and an increase in suicidal ideation involving children and adolescents during clinical trials. It is important to bear in mind that no actual suicides occurred and that some of the “suicidal acts” were far from lethal and, arguably, not suicidal. Nevertheless, overall ~1 in 50 children on active medication—significantly more than those on placebo—had new-onset suicidal ideation or actions. The effect was most noticeable for venlafaxine and paroxetine and least noticeable for fluoxetine. As all of these drugs block the presynaptic reuptake of serotonin, it is not clear if the differences among these medications are real.

While the public health perspective prioritizes large populations of affected individuals, our job as clinicians is to help one patient at a time. Over the last 10–20 years, there has been marked improvement in pharmacologic and psychosocial interventions available for patients with anxiety disorders (Slide 8).

The use of antidepressants, particularly the serotonergic and serotonergic noradrenergic agents, have received increased attention as first-line treatment for most of the anxiety disorders, including panic disorder, social phobia, posttraumatic stress disorder (PTSD), and generalized anxiety disorder (GAD). Antidepressants are often used as first-line therapy for anxiety disorders because of their broad spectrum of efficacy against common comorbidities, especially depression, and because of concern about benzodiazepine-associated dependence, abuse liability, and lack of efficacy for depression and other comorbidities (Slide 9).

These newer antidepressants have advantages over the older antidepressants, particularly the tricyclics and the monoamine oxidase inhibitors, in that they are generally better tolerated and more appropriate for use in potentially suicidal patients because they are less lethal in overdose. However, there are some side effects that may limit their use in some patients. In the case of the serotonergic antidepressants, many patients are hesitant to initiate or maintain treatment due to concerns about sexual dysfunction.

Understanding common pharmacologic and clinical “class” actions associated with atypical antipsychotics certainly reveals how these agents are alike, but what about unique differences from one agent to another? Atypical antipsychotics are also a heterogeneous group of agents that have complex pharmacologic entities, acting upon multiple dopamine receptors (D2, D1 (D3, and D4) and multiple serotonin receptors (5-HT2A, 5-HT2C, 5-HT1A, and 5-HT1D, among others). Atypical antipsychotics also interact with noradrenergic (α1- and α2-adrenergic receptor blockade), histaminergic (H1-receptor blockade), and cholinergic (muscarinic M1 blockade) neurotransmitter systems as well as with monoamine (D, 5-HT, and norepinephrine reuptake blockade) transporters. However, no two atypical antipsychotics possess the same portfolio of actions upon all of these additional neurotransmitter systems.

Alzheimer's disease (AD) is characterized by the abnormal extracellular accumulation of amyloid β-peptide (Aβ) into neuritic plaques and the intraneuronal aggregation of the microtubule-associated protein tau to form neurofibrillary tangles. These molecular events are implicated in the selective damage to neural systems critical for the brain functions that are impaired in AD. Impairment of cholinergic neurotransmission may be an important factor underlying the defects in cognition and memory that characterize AD. Cholinesterase (ChE) inhibitors, such as donepezil, rivastigmine, and galantamine, cause symptomatic improvement by inhibiting the breakdown of the neurotransmitter acetylcholine to increase its synaptic availability and, in the case of galantamine, by also allosterically potentiating nicotinic cholinergic receptors. Other agents, including vitamin E, monoamine oxidase inhibitors, and statins, have shown some benefit in epidemiological studies and clinical trials although compelling evidence of their efficacy is lacking. Memantine, shown to cause cognitive and functional improvement, is not an ChE inhibitor and does not interact with marketed ChE inhibitors. While the mechanism of action of memantine in AD is not known, the principal pharmacologic actions at therapeutic dose are inhibition of ionotropic neurotransmitter receptors, specifically N-methyl-D-aspartate (NMDA), 5-HT3, and nicotinic receptors. Like other NMDA antagonists, memantine causes behavioral activation associated with enhanced cerebral glucose utilization. Studies have shown that memantine can reverse the decreased metabolic activity associated with AD, possibly accounting for its beneficial effects on cognition and global functioning. Memantine also has neuroprotective properties and can inhibit Aβ-induced neurodegeneration.

Bipolar disorder in women presents special diagnostic and treatment challenges to the clinician. The presentation of female bipolar may resemble depressive disorders, comorbid Axis I disorders, Axis II personality disorders, behavioral dysregulation, or general medical disorders; thus, it is critically important for clinicians to assess for a history of hypomania or mania when determining diagnosis in any woman presenting with psychological symptoms. Several gender differences may exist in the epidemiology and symptomatology of bipolar disorder, and each must be kept in mind during assessment. Rapid cycling and mixed states have been associated with female gender and may present diagnostic challenges as each often presents as major depression. Symptoms of postpartum psychosis tend to differ from the symptoms typically seen in bipolar mania; therefore, if postpartum psychosis is actually a manifestation of bipolar disorder, accurate diagnosis depends upon a knowledge of these differences. Special treatment considerations for bipolar disorder in women involve interactions between the illness and the female reproductive cycle. A risk of fetal malformation exists when some mood-stabilizing agents are used during conception and/or during the first trimester of pregnancy. Neurobehavioral teratogenicity and neonatal toxicity is also possible. Careful treatment management is necessary to reduce the risks to the fetus/infant and to effectively manage bipolar disorder in the mother. In treating women with bipolar disorder, clinicians should discuss the issue of pregnancy and associated risks of treatment versus no treatment with every patient of reproductive age. Further studies are needed on gestational timing and exposure to mood-stabilizing agents, especially newer agents recently approved or currently being considered for the treatment of bipolar disorder.

There are several options and approaches available to practicing psychiatrists for the pharmacologic management of acute psychotic episodes that present in emergency room settings. This article focuses on the first hours and days of such episodes, the goals of treatment, and comparison of the “old favorites,” such as combination haloperidol and lorazepam (in liquid, tablet or injectable formulations), with the newer second-generation antipsychotic agents, such as olanzapine, ziprasidone, risperidone, quetiapine, or aripiprazole, which are available in different formulations. The speed of titration to an effective target dose for these newer agents are addressed as well.

Accurate comparisons of the prevalence of psychiatric disorders across Eastern and Western cultures are difficult and limited by methodological problems. Nevertheless, using standardized diagnostic and evaluation techniques, recent surveys have suggested that depression and anxiety disorders exist in all countries and cultures examined thus far, although variations in the prevalence rates and symptomatology may exist. This article discusses the influence and impact that culture can have on recognizing and treating mood and anxiety disorders, with a particular focus on Japan. Over the last 20 years, studies have consistently reported an increase in mental illness in Japan, especially symptoms of depression and anxiety. While such symptoms have had an adaptive cultural role in the past, current social and economic changes in Japan have turned any adaptive advantage into a potentially significant disadvantage, with a major impact on the capacity of individuals to function adequately. The situation is compounded by the fact that Japanese patients are reluctant to openly discuss disturbances of mood, since these are considered to be indicative of personal weakness rather than treatable medical conditions. Reluctance to discuss personal mental health hinders timely recognition and appropriate treatment.

The study of social cognition in psychiatric disorders has become increasingly popular in recent years. This is due to the its proposed link to social functioning and the inability of general neurocognitive skills to explain the spectrum of impairments observed in patients. This article reviews research into two of the processes thought to underlie social cognition (emotion perception and theory of mind) in schizophrenia and autism. This is followed by a look at neuroimaging studies and their efforts to localize the neural correlates of emotion perception and theory of mind in the two disorders. We concluded that while a specific impairment in emotion perception and theory of mind skills cannot be generalized to all individuals with autism and schizophrenia, there are subpopulations that have lingering deficits of social cognition tasks. Neuroimaging work consistently points to the involvement of the fusiform gyrus and amygdala in emotion processing, while the medial prefrontal and frontal cortex are implicated in tasks invoking theory of mind. We propose that deficits of social cognition may benefit from cognitive remediation therapy and pharmacological cognitive enhancers.

Antipsychotics have been utilized in the treatment of bipolar disorder for many decades and were the mainstay of treatment before lithium was reintroduced in the late 1960s. Today, many bipolar patients who present with psychotic features are misdiagnosed and prescribed an antipsychotic for another disorder. Estimates of psychotic symptoms in bipolar disorder, particularly during a manic episode, are ≥50% by clinical assessment and even higher by individual reports. Thus, antipsychotics are frequently used: as first treatment for psychosis not recognized as bipolar disorder, and as an adjunct to a mood-stabilizing agent in bipolars with psychotic symptoms.

Most recently, antipsychotics have been examined for their mood-stabilizing properties as well (Slide 9). One may conceptualize using a selective serotonin reuptake inhibitor (SSRI) antidepressant for disorders such as panic disorder or obsessive-compulsive disorder, and using an antiepileptic as a mood-stabilizing agent; however, it is more difficult to accept that an agent approved for treatment of psychosis can be a primary therapy for bipolar disorder. Data from the monotherapy trials suggest that second-generation antipsychotics (SGAs) are at least as effective as lithium and valproic acid for acute mania. There is a very large database indicating that SGAs can be utilized as monotherapy for acute mania. However, there is limited data on the role of these agents in prevention of relapse and recurrence and in their efficacy for depression in the context of bipolar disorder. More studies will be needed to clarify whether SGAs should be used as monotherapy or whether they would be best used as augmenting agents in severe and psychotically manic or depressed patients.

Effective cognitive-behavioral therapy (CBT) programs have been developed for aU of the anxiety disorders. Common elements of CBT for these disorders include exposure to feared objects, situations, activities, thoughts, memories, and sensations; cognitive restructuring of dysfunctional beliefs; and training in anxiety management skills, such as controlled breathing and relaxation. This article describes CBT procedures for anxiety disorders and summarizes the research documenting its efficacy. Next, the article discusses the factors that influence the efficacy of these treatment program. Finally, emotional-processing theory is discussed to explain the efficacy of CBT for anxiety and how this theory can assist in selecting optimal treatment brocedures.

Bipolar disorders are prevalent, disabling, and costly diseases that often pursue an inexorable course. Underdetection, misdiagnosis, and diagnostic delay frequently and unnecessarily interfere with appropriate treatment of the disorder. Mortality studies in bipolar disorder underscore the relevance of both unnatural and natural causes of death, inviting the need for improved preventative and primary health care for bipolar patients. The treatment framework for bipolar disorder must recognize and anticipate the multidirnensionality and comorbidity of this illness. Pharmacotherapy is necessary, with multiple concomitant medications required for most patients, In addition, adjunctive psychosocial interventions offer enhanced compliance and may beneficially influence psychopathological and functional outcomes. This article emphasizes the public health concern of bipolr disorder, and provides tactics to enhance detection of cryptic bipolar states, underscore the clinical and pathophysiological relevance of comorbidity in bipolar disorder, and provide a framework for multimodality therapy for this condition.