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.

Traumatic memories, and the mechanisms by which they operate, continue to occupy a central role in the scientific investigation of risk factors for the development of posttraumatic stress disorder (PTSD). However, empirically based studies are constrained by practical and ethical considerations and are limited to naturalistic models. Consequently, the paradigms most appropriate for the exploration of the relationship between traumatic memories and PTSD have been identified in conditions involving traumatic events where memories may be compromised. Indeed, traumatic brain injury, a condition that is commonly associated with memory impairment, has often been utilized as a naturally occurring model for the study of traumatic memory and its contribution to the development of PTSD. This article presents a critical review of these research efforts and discusses their theoretical and clinical implications.

Despite significant progress in the development of antidepressant therapies, tolerability remains an important factor associated with the selection of appropriate antidepressant treatment. Side effects commonly reported by depressed patients taking antidepressants include weight gain, sexual dysfunction, and gastrointestinal effects. Tolerability issues associated with antidepressants can negatively impact treatment outcomes for patients with major depressive disorder. In addition, a drug's tolerability profile substantially influences a physician's choice of specific antidepressant therapy. Despite the availability of many antidepressants, empirical clinical evidence to guide physicians in making the best choice is limited and not always clear. Thus, it is key for clinicians to understand the short- and long-term outcomes and side effect profiles of the available antidepressants.

Although the precise etiologic nature of obsessive-compulsive disorder (OCD), one of the most common psychiatric conditions, is unknown, several findings indicate involvement of the serotonin (5-HT) transporter. Apart from the specific effects of selective 5-HT reuptake inhibitors, other studies show decreased functionality of the platelet 5-HT transporter in OCD. In this report, the authors combine data from two independent studies of patients with OCD, showing both an increased activity of protein kinase type C (PKC) and a decreased activity of protein kinase type A (PKA). The authors propose a unifying hypothesis that OCD might be determined by an imbalance between PKC and PKA, with a prevalence of the former and, more generally, of the phosphoinositide over the cyclic adenosine monophosphate (cAMP) pathway. Should this hypothesis prove correct, the path would be open for new therapeutic interventions in the treatment of OCD.

Do antidepressants have an equivalent risk-benefit ratio? Venlafaxine, a serotonin-norepinephrine reuptake inhibitor, is an effective antidepressant for treating major depression. The results of some clinical studies have suggested that venlafaxine may have more potent efficacy in sustaining remission in patients with major depression. Comparative clinical studies, however, lack suitable power to discern treatment differences in safety and also lack a quantitative basis for comparing risk and benefit. A global benefit-risk analysis of pooled data from eight randomized, double-blind, clinical trials of the safety and efficacy of venlafaxine and selective serotonin reuptake inhibitors (SSRIs) was performed. By using the ratio measure of risk-benefit, patients treated with venlafaxine (n=851) for 6–8 weeks experienced a relative gain of 1.57 compared with SSRI-treated patients (n=743) and a relative gain of 2.27 compared with placebo-treated patients (n=439). Subgroup analyses showed a relative gain of 1.35 for venlafaxine-treated patients (n=538) compared with fluoxetine-treated patients (n=549) and a relative gain of 2.53 compared with placebo-treated patients (n=357). A dose-response relationship was apparent between low (<75 mg/day), medium (75–150 mg/day), and high (>150 mg/day) dosages of venlafaxine; r values were 0.758, 0.822, and 1.181, respectively (P=.023, high dosage versus placebo; P=.030, medium dosage versus placebo). Important differences in risk and benefit exist between venlafaxine and SSRIs as a group compared with fluoxetine alone. A significant gain in benefit-risk in the treatment of major depression was observed with an increase in venlafaxine dosage from 75–>150 mg/day.

Tourette syndrome (TS) has been conceptualized as a psychological problem, a neurological problem, and more recently a neurobehavioral problem. Each conceptual model has had an impact on how persons with TS view themselves and how practitioners view individuals with TS, as well as an impact on what both clinicians and patients expect from diagnosis and treatment. This article reviews the common comorbid psychiatric disorders and their relationship to TS, and discusses how the evolving conceptions of TS have impacted psychologically on persons with tics and TS, as well as on the providers who treat them.

Mood disorders including major depressive disorder and bipolar disorder are common during and after pregnancy. Timely identification and appropriate management of mood episodes is essential to maximize maternal well-being and minimize adverse outcomes. Failure to do so results in maternal suffering and impaired child bonding, and has the potential for devastating outcomes including suicide and infanticide. Women are routinely screened for unipolar depression during or after pregnancy but not for bipolar disorder, in spite of the fact that childbirth is associated with a major risk for onset or exacerbation of bipolar disorder. Delays in detection as well as misdiagnosis of bipolar disorder as major depressive disorder may put women at risk of many adverse consequences, including symptom exacerbation, psychiatric hospitalization, and suicide. A thorough psychiatric assessment is necessary to establish diagnosis, to address safety issues, and to formulate a treatment plan. Treatment of mood disorders during pregnancy is complicated by the potential risks of fetal exposure to psychotropic medications, and the use of these medications during the postpartum period may result in infant medication exposure through breastmilk. These risks of psychotropic medication exposure must be weighed against the risk of untreated mood disorders. This review will discuss the pathophysiology, epidemiology, diagnosis, and treatment of mood disorders during pregnancy and the postpartum period. Screening tools that can be used in the primary care and obstetrics settings to assist in identifying women with peripartum mood disorders will also be discussed.

Obsessive-compulsive disorder is currently classified as an anxiety disorder. However, there is growing interest in the concept of an obsessive-compulsive spectrum of disorders (OCSDs). The relationship between anxiety disorders and OCSDs has been questioned. The psychobiology of anxiety disorders and OCSDs is briefly reviewed in this article. While there appear to be several distinct contrasts in the underlying psychobiology of these conditions, there is also evidence of overlapping mechanisms. In addition, there are crucial gaps in our current database, confounding nosological decision-making. Conceptualizing various anxiety disorders and putative OCSDs as lying within a broader spectrum of emotional disorders may be useful. However, clinicians must also recognize that individual anxiety and obsessive-compulsive spectrum conditions, including disorders characterized by body-focused repetitive behaviors, have distinct psychobiological underpinnings and require different treatment approaches.

There are currently over two dozen agents targeting β-amyloid (Aβ) in human clinical trials. More than a dozen of these are forms of anti-amyloid immunotherapy. Although other anti-amyloid interventions are further along in the development process, thus far only immunotherapy has provided post-mortem evidence that it can alter elements of the underlying pathology of Alzheimer’s disease (AD) in actual patients.

In the past 30 years, there have been many attempts to develop treatments for AD. Early therapies were developed based on a limited understanding of the disease (Slide 1). Prior to the 1980s, a clear pathophysiologic mechanism for AD was not known; instead, symptomatic therapies targeted associated symptoms, such as agitation, insomnia, and psychosis. In the 1970s, several preclinical studies pointed toward synaptic transmission abnormalities, particularly neurochemical abnormalities, as the root cause of AD, and treatments with cholinesterase inhibitors grew out of that theory. Today, the cholinergic hypothesis has been largely discredited in the primary pathogenesis of AD. Another theory based on neurotransmitter abnormalities, the glutaminergic hypothesis, has also gone out of favor as a causal explanation for AD. This did not stop medications based on these mechanisms from finding a meaningful place in the clinical pharmacopeia for treatment of AD.

In the 1990s, many clinical trials followed up on epidemiologic studies suggesting systemic causes of AD. These clinical trials focused on anti-inflammatories, hormone replacement, and antioxidants. The trials performed have largely failed, with the possible exception of the trials of vitamin E, an antioxidant. None of these agents have proven useful as disease-modifying therapies for symptomatic AD.

With the introduction of conventional antipsychotics in the 1950s, clinicians began to expect effective treatment of positive symptoms of schizophrenia. However, these drugs do not resolve negative and cognitive symptoms of schizophrenia and are also associated with serious side effects, including extrapyramidal side effects (EPS) and tardive dyskinesia. In 1989, clozapine was introduced and labeled the first new antipsychotic owing to its improved efficacy and side-effect profile. Clozapine proved effective in alleviating many of the positive, negative, and cognitive symptoms of schizophrenia, without causing inevitable EPS or tardive dyskinesia. Over the past decade, a number of different new antipsychotics have been developed. These drugs have an affinity for multiple dopamine-receptor subtypes as well as serotonin, norepinephrine, and glutamate receptors, allowing for better treatment outcomes. The antagonism of the 5-HT2A receptor may be responsible for improvement in negative symptoms and decrease in EPS. In addition to providing enhanced efficacy, the affinity of the new drugs for multiple receptors introduces new side effects not seen with the conventional agents, including weight gain. Each new antipsychotic has a unique receptor-binding profile that corresponds to its pharmacologic and side-effect profile. Understanding the differences in mechanisms of action of new antipsychotics will allow physicians to better choose treatment that meets the needs of each individual patient.

The cause of the early death of Wolfgang Amadeus Mozart (1756–1791) at the age of 35 has been the source of much discussion in the medical community. Investigators attributed to Mozart nearly 150 different medical diagnoses. However, the neurosurgical aspect of the early death of Mozart has yet to be well-analyzed, and this subject was investigated herein. The key words “Mozart” and “Mozart’s death” were searched in PubMed as well as the libraries of universities. The main source was the archive and website of Internationale Stiftung MOZARTEUM/Salzburg (www.mozarteum.at) and the cranium stored in the Internationale Stiftung Mozarteum in Salzburg/Austria. The linear fracture of the cranium is important, since it shows the neurosurgical aspect of the early death of Mozart. Mozart’s disease was most likely a neurotraumatologic one. His fracture likely occurred several months before his death, as evidenced by signs of healing. Intense headaches and declining musical performance in his last year may have been influenced by intracranial hemorrhage induced by the linear fracture. His final disease therefore may have been chronic postconcussion syndrome depending on chronic calcified epidural hematoma.