Agitation can present as an emergency in the course of numerous psychiatric conditions including intoxication, schizophrenia, bipolar disorder, and delirium. This article reviews relevant literature regarding the definition, etiology, measurement, and management of episodic agitation and pays particular attention to intramuscular treatments. The impact of changes in methodology between the era of first- and second-generation antipsychotics, the implications of those changes for external validity of studies of second-generation studies, and the recent evolution of expert consensus are discussed.

Augmentation strategies have become popular in patients with a partial response or residual symptoms. In a survey conducted by the American Society of Consultant Pharmacists, 65% of 169 psychiatrists indicated that they would augment treatment as the next step in a partial responder in contrast to non-responders in whom they would switch to another drug (J.C. Nelson, unpublished data). This decision is based on common sense and practicality rather than empirical evidence. Many clinicians and patients think that if a patient achieves at least a partial response to a medication, it makes sense to continue that drug and add a second. To some extent, the patient preferences for treatment shown in the Systematic Treatment Alternatives to Relieve Depression (STAR*D) study reflect this approach. This discussion will update clinicians on the use of augmentation agents for the treatment of major depressive disorder (MDD).

Lithium augmentation has been used since it was first described by de Montigny and colleagues in 1981. This strategy is based on a rational neurochemical hypothesis that lithium has a synergistic effect when added to a tricyclic antidepressant (TCA). Lithium increases serotonin turnover and the TCA increases postsynaptic serotonin receptor sensitivity. Recent debates have focused on whether lithium is as effective combined with selective serotonin reuptake inhibitors (SSRIs) as it is combined with a TCA. The rapid effects sometimes observed with lithium augmentation of TCAs does not seem to occur with SSRIs, conceivably because SSRIs do not increase postsynaptic serotonin receptor sensitivity.

Schizophrenia is a neurodevelopmental disorder associated with persistent symptomatology, severe functional disability, and residual morbidity characteristic of neurodegenerative brain diseases. The illness begins with genetic susceptibility and generally expresses itself after puberty through subtle changes that begin during the prodromal stage. Symptoms get progressively worse and tend to become more resistant to treatment with each relapse. Evidence for a neuroprotective effect of some forms of early treatment is beginning to emerge. While the underlying mechanisms remain uncertain, atypical antipsychotics may counteract some of the progressive deteriorative effects by enhancing synaptic plasticity and cellular resilience. However, identifying and treating patients in the earliest disease states presents methodological challenges as there is no consensus on the best methods of intervention and differences in at-risk children are not readily detectable or substantial enough to predict which ones will develop schizophrenia.

In this expert roundtable supplement, Jeffrey A. Lieberman, MD, reviews the historical context of progressive deterioration in schizophrenia. Next, Diana O. Perkins, MD, MPH, reviews some of the challenges to early identification of illness as well as the impact of early versus delayed treatment. Finally, L. Fredrik Jarskog, MD, focuses on the neurobiology of functional progression in schizophrenia as well as pharmacology and the potential for neuroprotection.

Over the next 2 years, CNS Spectrums will be publishing a series of articles on neuroanatomy. The purpose of these articles is to broaden knowledge and interest in neuroanatomy, with a special reference to some key brain structures that are important for neuropsychiatry. Interest in nuclear structures and hodology, in connectivity and circuitry between brain regions, and in neurochemical associations has increased in the last 3 decades due to new neuroanatomical staining methods, brain imaging, and new treatments, such as deep brain stimulation.These columns will enliven an understanding of the clinical neuroscience interface but also provide a solid framework of contemporary neuroanatomy for psychiatrists and neurologists.

The first in the series reviews the ventral striatum. Henk J. Groenewegen, MD, PhD, in a column dedicated to the late Lennart Heimer, MD, reveals the importance of this structure and its connectivity for a contemporary understanding of brain-behavior relationships. In earlier conceptions, the basal ganglia were solely related to motor function, uninvolved with emotion or cognition. This conception arose from a misunderstanding of basic neuroanatomy, which has been unravelled by careful neuroanatomical studies in the last 30 years with new tissue staining and tracing techniques.The basal ganglia are the main target structures of the limbic system, hence the motion in emotion.

Pharmacoepidemiology, the study of the effects of drugs in large numbers of people, is a relatively new discipline that applies the methods of epidemiology to clinical pharmacology. Premarketing clinical trials remain the only way to scientifically determine whether a drug is causally effective, yet these trials do not provide information that allows for estimates about rare, late, or off-label toxicities associated with the drug in question. Increasing concern about common and debilitating adverse effects of medications has highlighted the need for enhanced postmarketing surveillance to follow up on clinical trials. There is a further concern regarding the broader issue of the risk-benefit ratio of certain medications. Computerized databases are a good source of information on which to lay the foundations of postmarketing research. A system of cross-linked computerized medical records may better enable researchers and physicians to realistically monitor postmarketing safety and incorporate monitoring benefits. The same research could also elucidate the net public health effect of regulatory decisions. The Veterans Affairs database in the United States and PHARMO in the Netherlands may represent good models on which to base future postmarketing surveillance studies.

In this expert roundtable supplement, Brian L. Strom, MD, provides an overview of the appropriate use of large computer databases in pharmacoepidemiology studies. Philip Wang, MD, DrPH, discusses the advantages of pharmacoepidemiologic studies over clinical trials in correctly detecting drug safety issues. Francesca Cunningham, PharmD, reviews a large computer database that is currently in use within the VA healthcare system, and Ron M.C. Herings, PharmD, PhD, discusses the development of the PHARMO system in the Netherlands

There is mounting evidence to suggest that the efficacy of all available antidepressants when used as monotherapy to treat major depressive disorder (MDD) is, at best, modest. For example, a meta-analysis of all double-blind placebo-controlled studies of antidepressants published since 1980 revealed response rates of 53% for antidepressants versus 36% for placebo (difference in response rate of 16.8%) (Slide 1). To make matters worse, if one is to assume that “negative trials” (ie, trials which do not demonstrate the superiority of a drug over placebo) are less likely to be published than “positive trials” (trials which demonstrate the superiority of a drug versus placebo), it is quite possible that the margin of efficacy of antidepressants when compared to placebo is ≤16.8%. Thus, if one were to include all unpublished along with published double-blind, placebo-controlled trials of antidepressants for MDD, this efficacy margin could be ≤10%.

Major depressive disorder (MDD) is a highly prevalent, debilitating disorder that is often chronic, recurrent, and costly, with the economic burden in the United States for the year 2000 exceeding $83 billion. Recent data from the National Comorbidity Survey Replication (NCS-R) indicate that MDD has a lifetime prevalence of 16.2% and a 12-month prevalence of 6.6% in the US. Among those reporting at least one episode of MDD in the previous 12 months, mean episode duration was 16 weeks. Roughly 60% of patients experienced role impairment that was “severe” or “very severe,” and nearly 80% reported comorbid disorders as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, with MDD only rarely being primary. Although 51.6% of patients with MDD received health care treatment for the illness, treatment was “adequate,” as defined by the Agency for Health Care Policy and Research and the American Psychiatric Association guidelines (ie, ≥4 outpatient visits with any type of physician for pharmacotherapy that included use of either an antidepressant or a mood stabilizer for ≥30 days or ≥8 outpatient visits with any professional in the specialty mental health sector for psychotherapy lasting a mean of ≥30 visits) in 41.9% of treated cases. Only 21.6% of all MDD patients in the NCS-R, therefore, received minimal guideline-level treatment.

Antipsychotics have become the cornerstone of management for many severe mental disorders. Primarily developed for the treatment of schizophrenia, several antipsychotics have been indicated for bipolar mania, bipolar depression, and irritability associated with autistic disorder. Antipsychotics are also used off label for psychotic or refractory depression; refractory anxiety disorders; and conditions associated with agitated or aggressive behaviors. Due to the severity and chronicity of severe mental disorders, the broad range of potential treatment targets, and the relative ease of use of second-generation antipsychotics (SGAs), which are associated with a lower risk of extrapyramidal symptoms (EPS) and tardive dyskinesia (TD), prescribing rates have increased considerably over the last decade. With increased utilization of these medications comes a greater responsibility to appropriately recognize, monitor, and manage side-effect clusters that can adversely affect physical and mental outcomes.

Although the symptoms of attention-deficit/hyperactivity disorder (ADHD) can be found in many “normal” people, these symptoms are present to a greater extent in those affected by the disorder. In these patients, ADHD symptoms cause substantial functional impairment. Therefore, the goal of treatment is not simply to reduce core symptoms, but also to decrease the level of impairment caused by these symptoms.

Common impairments in adolescents and adults include academic and occupational problems that are particularly evident in the context of tasks requiring a high degree of organization or attentional function. These impairments result in problems related to task completion, prioritizing work and other obligations, and time management, etc. These symptoms often impact successful completion of tasks in school or at work, and can also result in a variety of problems in initiating and managing relationships (Slide 1).

Mood and anxiety disorders often co-occur with ADHD in adults. The accumulation of experiences related to impaired academic and/or occupational performance, and or persistent relationship problems, due to the symptoms of ADHD, can lead to either depressed mood or anxiety related to performance and/or social situations. Therefore, in treating adults with ADHD, reduction of those co-occurring symptom presentations is also an important goal.

Attention-deficit/hyperactivity disorder (ADHD) is a lifelong condition that begins in childhood and continues with adult manifestations related to the core symptoms. Approximately 50% to 75% of children with ADHD continue to meet criteria for the disorder as adolescents and adults. Adults with the disorder increasingly present to primary care physicians, psychiatrists, and other practitioners for diagnosis and treatment. Understanding the diagnosis of ADHD in adults requires knowledge of age-dependent decline of symptoms over time. Retrospective recall of symptoms and impairment are valid methods of diagnosing the disorder. ADHD is also a brain disorder with a strong neurobiologic basis, complex etiology, and genetic component. Genetic and environmental vulnerabilities give rise to abnormalities in the brain and subsequent behavioral and cognitive deficits, which may produce the symptoms associated with ADHD. Magnetic resonance imaging studies of ADHD have provided evidence that abnormalities in the brain are caused by the disorder itself rather than treatment of the disorder. Psychiatric comorbidity is common among patients with ADHD and tends to complicate treatment. Acute and long-term use of long-acting stimulant formulations (methylphenidate and amphetamine compounds) have shown robust efficacy and tolerability consistent with the treatment response established in children with ADHD. Non-stimulant medications have demonstrated efficacy as well, and may be preferred in patients with tic and substance use disorders.

In this expert roundtable supplement, Timothy E. Wilens, MD, reviews the epidemiology and clinical presentation of adult ADHD. Next, Joseph Biederman, MD, provides an overview of recent advances in the neurobiology of ADHD. Thomas J. Spencer, MD, reviews stimulant treatment of adult ADHD, and Lenard A. Adler concludes with a discussion of non-stimulant trials in adult ADHD.

The evidence for the involvement of the serotonergic system in the pathogenesis of obsessive-compulsive disorder (OCD) is circumstantial at best, despite being the focus for most pathophysiological research over the last 2 decades. This hypothesis was initially motivated by the observed differential efficacy of selective serotonin reuptake inhibitors in alleviating OCD symptoms. Direct evidence that serotonergic perturbations are implicated in the pathophysiology of OCD is still sparse. There is growing evidence, from both preclinical and clinical studies, that the dopamine system may also be involved in the pathogenesis of OCD, and that dopaminergic and serotonergic pathways play a role in the genesis and maintenance of obsessive-compulsive symptoms. The complex interactions between both systems, the phenotypic heterogeneity of the disorder, and the limitations of the available tests to probe both systems, make it as yet impossible to draw firm conclusions as to how these systems are implicated. Further studies with more selective pharmacologic agents and neurocognitive probes in humans, studies using deep brain stimulation in combination with neuroimaging, and the development of better animal models for OCD may further our understanding of this disabling condition.

Bipolar disorder is a prevalent psychiatric disorder with a high rate of misdiagnosis and evidence of degenerative progression. Research indicates that the interval between bipolar episodes decreases steadily until the patient settles into a relatively frequent course of mania and depression. Various imaging techniques have been used in the understanding of the brain pathology underlying bipolar disorder through identification of patterns consistent with disruption of the normal brain activity in bipolar patients. These techniques have demonstrated evidence of abnormalities in the structure and function of the prefrontal cortex. In addition, the cerebellar vermis, which serves as an error-detection function to modulate the iterative network, appears to shrink with recurrent episodes. Functional imaging demonstrates that the anterior limbic network is overactivated and overresponsive in patients with bipolar disorder. In many patients, those deficits are often compensated for by activation of other brain areas. Ultimately, when the compensation fails, expression of bipolar symptoms arise. Using magnetic resonance spectroscopy, simple models can be constructed based on the hypothesis that mitochondrial function may be impaired in bipolar disorder. There is also increasing evidence that psychotropic medications can affect specific brain regions that are thought to be involved in the pathogenesis of psychiatric disorders. Glutamate levels appear to be elevated in untreated patients with bipolar disorder, which may cause glutamatergic neurotoxicity and negative therapeutic implications. Further advances in brain imaging may contribute to the improvement of available therapies and the understanding which treatments will be most suitable for specific patients.