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.

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.

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.

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.

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.

Presence of rapid cycling appears to be the rule rather that the exception in children with bipolar disorder, although there is not much data to support this clinical notion. Geller and colleagues studied 93 pediatric patients with bipolar disorder, mean age 10.9 years. They found that 87% had rapid cycling defined as ≥4 episodes/year and 77% had ultradian cycling, defined as >365 episodes/year. In addition, Findling and colleagues studied 90 bipolar patients with a mean age of 10.8 years and found that 50% had rapid cycling by veteran CV criteria. (The study did not look at ultra-rapid or ultradian cycling.) Finally, using clinical interviews to study children with affective illness, Schraufnagel and colleagues found that 41% experienced >365 cycles/year (Slide 6).

It is difficult to figure out the difference between a cycle and an episode when children are cycling so quickly. Tillman and Geller proposed that any kind of mood switching constitutes a cycle. An episode, they proposed, is defined as having ≥2 weeks of mood symptoms with either onset and offset of one mood state within that 2 weeks, or onset and offset of a period of ultra-rapid or ultradian cycling. It appears that with younger age comes more rapid cycling and more mixed states, which can be confused with ultra-rapid cycling. In turn, the older the child gets, the less rapid cycling occurs, and the more episodic the disorder becomes with more euphoria and less irritability. However, this tendency has not been well studied.

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.