Currently, a major hypothesis for the pathophysiology of schizophrenia proposes that numerous risk factors converge on the N-methyl-D-aspartate (NMDA) receptor for the neurotransmitter glutamate, resulting in neurodevelopmental abnormalities at glutamate synapses and hypofunction of NMDA receptors.This hypothesis was presented in a previous “Trends in Psychopharmacology” column. Novel treatments are now in development that can theoretically boost the function of NMDA receptors by enhancing actions at the glycine co-transmitter site of this receptor complex. Early studies already indicate that this may lead to improvement in negative and cognitive symptoms of schizophrenia, especially when added as augmenting agents to atypical antipsychotics.

Schizophrenia is associated with increased medical comorbidity likely caused by interactions between life-style, environment, and the disease itself. High rates of medical comorbidity exist among all forms of serious mental illness. Affective disorders such as bipolar disorder and unipolar depression are associated with 1.5–2 times the mortality rate observed in the general population, and high rates of HIV and hepatitis A, B, and C exist among patients with severe mental illness. However, schizophrenia is particularly affected by medical comorbidities, and is associated with a 20% shorter-than-normal lifespan. This discussion focuses on rates of medical comorbidity in people with schizophrenia and the effects of medication on cardiometabolic risk factors. It is also important to recognize that lifestyle and environmental factors associated with serious mental illness, as well as poor access to healthcare, contribute to the elevated rates of medical illnesses observed in these populations as well.

Studies of the association between schizophrenia and medical comorbidities have suggested that the introduction of second-generation antipsychotics (SGAs) may be responsible for the increases observed in cardiovascular disease rates in this patient population, and that cardiovascular disease mortality may be shifting to an earlier stage of life. Ösby and colleagues observed that while overall cardiovascular mortality in schizophrenia patients in Sweden increased from 1976–1995, an even greater increase occurred in men from 1991–1995. This latter increase corresponded temporally to an increased use of SGAs.

Osborne and colleagues recently confirmed the observation made by Osby and colleagues. They compared 46,000 people with serious mental illness and a general population sample of ∼300,000 people from 1987–2002.

The most common cause of sleepiness is sleep deprivation, which is often due to behaviorally induced sleep limitations. One method of preventing impaired or shortened sleep is to ensure good sleep hygiene. It is important to review with patients the principles of sleep hygiene so that they can rule out causal behaviors that might be relatively simple to correct. Principles of good sleep hygiene include maintaining a regular sleep/wake schedule, exposure to light in the morning hours, avoiding caffeine and nicotine especially 4–6 hours before bedtime, avoiding alcohol and heavy meals before sleep, regular exercise (vigorous exercise should be avoided 3–4 hours before sleep), limiting time in bed to the time spent sleeping, and allowing sufficient time to get comfortable and relaxed prior to sleep. Even if one can fall asleep after drinking alcohol or caffeine, sleep maintenance can be curtailed. Sensitivity to these stimulants is often apparent in the latter half of the night. People often fail to recognize that vigorous aerobic workouts close to bedtime makes it harder to fall asleep. This is because a revved up metabolism heats the body up, and thereby delays the normal cooling of the core body temperature which triggers the onset of sleep.

One study assessed the sleep of 259 subjects using the Multiple Sleep Latency Test (MSLT), an objective measure of daytime sleepiness that assesses how quickly someone can fall asleep in conducive conditions. The results indicated that many people in the general population carry a very heavy burden of sleepiness (Slide 1). Many physicians were shown to carry pathological levels of sleepiness because of their heavy call schedules and their foreshortened sleep on nights that they are not on call. The average adult needs 8.2 hours of sleep per night, and not surprisingly many studies have found that the sleepiest adults spent ≤6 hours in bed. What makes matters worse is that insight into the impairments of sleepiness erodes rapidly, but other cognitive and somatic impairments continue to mount with regular chronic under-sleeping. When sleepiness is due to chronic sleep deprivation, treatment often consists of scheduling enough time in bed to allow for an adequate amount of sleep.

Beginning this month, CNS Spectrums will publish this column, “Trends in Psychopharmacology,” on a bi-monthly basis. Developments in psychopharmacology are proceeding at a fast pace, and this column will cover important and emerging areas from the field in a format that will be brief, and hopefully understandable. Topics will include what is new, “hot,” controversial, or informative in the field, and, of course, suggestions for future columns are always welcome.

The successful management of schizophrenia is an enormous public health issue. Although antipsychotic medications can be very helpful in reducing rates of relapse and rehospitalization, nonadherence to medication is a frequent cause of exacerbations in psychopathology, psychotic relapse, and rehospitalization. Relapses can have devastating consequences in a variety of clinical and functional domains. Nonadherence can result from a variety of factors that vary from patient to patient and vary over time in individual patients. A number of strategies have been developed to assess and facilitate adherence. The first critical step is clinician awareness of the scope of the problem and consideration of appropriate strategies to address it.

There is growing basic-science interest in the mechanisms underpinning the positive effects of exercise on brain function and cognitive-affective performance. There is also increasing clinical evidence that exercise may prevent and treat various neuropsychiatric disorders. At the same time, there is growing awareness that athletic performance is mediated in crucial ways by central nervous system mechanisms. The relevant mechanisms in all these cases requires further exploration, but likely includes neurotrophic, neuroendocrine, and neurotransmitter systems, which in turn are crucial mediators of psychopathology and resilience. The hypothesis that Homo sapiens evolved as a specialist endurance runner provides an intriguing context against which to research the proximal mechanisms relevant to a cognitive-affective neuroscience of exercise.

Recent research shows that single genes do not cause schizophrenia, but that multiple “susceptibility” genes each provide a genetic “bias” towards schizophrenia. Each susceptibility gene codes for a subtle molecular abnormality that hypothetically causes inefficient information processing in brain circuits that mediate the symptoms of this disorder. It is therefore not surprising that many of the susceptibility genes that have been identified for schizophrenia are known to regulate neuronal connectivity, synaptogenesis, and N-methyl-D-aspartate (NMDA) glutamate receptor functions. This includes genes for brain-derived neurotrophic factor (BDNF), dysbindin, also known as dystrobrevin-binding protein 1, neuregulin, disrupted in schizophrenia-1 (DISC-1), D-amino acid oxidase activator (DAOA), and regulator of G-protein signaling (RGS4). Hypothetically, converging molecular abnormalities expressed by defective versions of these genes could cause dysregulation of NMDA receptors and NMDA synapses, leading to vulnerability for schizophrenia due to inefficient information processing at glutamate synapses.

Philosophers have long struggled with questions about the nature of personal identity and of the self, with some viewing the self as a transcendent entity, and others arguing that the self is a constructed fiction. An approach based in cognitive-affective neuroscience emphasizes that self-related structures and processes are based in the brain-mind, and emerge within the social processes of human development. Alterations in such structures and processes are present in a wide range of neurological and psychiatric disorders, and neuropsychiatric lesion and functional brain imaging studies have led to more detailed awareness of the precise neuronal circuitry underlying self-representations. A cognitive-affective neuroscience approach provides a conceptual basis from which clinical research can further explore how best to assess and treat a wide range of disruptions to the self.

What exactly is known today about the impact of the adult form of attention-deficit/hyperactivity disorder (ADHD) in society?:

In a recent study to examine the societal impact of attention-deficit/hyperactivity disorder (ADHD), 500 patients diagnosed with ADHD and 501 participants with no substantial signs or symptoms of ADHD were studied. Subjects were asked several questions about their quality of life, employment, job satisfaction, and other aspects of their well-being and functionality. Income, which is an important marker for the degree of productivity for an individual in society, was also assessed. ADHD can profoundly affect the performance of individuals in the workplace (Slide 1), and this study found that having ADHD reduced an individual's income by an average of ∼$10,000 per year. If that loss of income is extrapolated to all adults in the United States who have ADHD, it suggests that the economy is losing around $70 billion a year to $115 billion a year in productivity, as measured by loss of income. The range was broad because different models with varying assumptions were applied to project income loss over time. Nevertheless, based on these numbers, it is reasonable to estimate that the population is losing ∼$100 billion annually in productivity due to ADHD.

Income loss was found at all levels of education, but it was greatest among patients who had advanced degrees of education; so it seems that the disease may have a more pronounced impact on income among those in the higher income brackets.

Depression, which is increasingly regarded as a chronic condition, is associated with significant suffering, social and functional impairment, and an estimated $44 billion in direct and indirect costs annually in the United States. Despite this severe burden on the health care system, the management of depression remains suboptimal in primary care, where many depressed patients fail to receive adequate dosage and duration of treatment. Adherence to evidence-based guidelines, essential to improving outcomes, requires key structural changes to the US health care delivery system. Several health care models aimed at improving treatment adherence in patients with chronic illnesses have been evaluated in primary care settings with promising results. Those approaches that have been found to be effective advocate multifaceted collaborative interventions that target patients, families, physicians, and the organization of the health care system to improve adherence and depression outcomes. Enhancing education and the active participation of patients and their families are now considered important elements of interventions to improve adherence to the treatment of chronic illnesses, including depression.

Extensive clinical experience and research suggest that a cortico-limbic-subcortico-thalamic-ponto-cerebellar network plays a significant role in the expression of human emotions. This network includes specific cerebral, cerebellar, and brainstem areas and their multiple projections/pathways, with activity modulated through serotonergic, dopaminergic, glutamatergic, and possibly sigma receptor neurotransmitter systems. Disruptions of regulatory and inhibitory mechanisms in the structure and function of this network likely constitute a pathophysiological basis for the crying and laughing episodes characteristic of involuntary emotional expression disorder. Pharmacologic interventions targeting the neurochemical modulators of the emotional expression systems may afford opportunities for symptom control among persons affected by this disorder.

In spite of the tremendous advances made in developing antidepressant treatments and exploring augmentation with second-generation antipsychotics (SGAs), significant obstacles remain for psychiatrists: How should clinicians make use of cutting-edge augmentation studies? How should they use the antipsychotics in their treatment algorithm? How should they think about dosing and side effects?

The first major problem is there have been no great algorithmic studies on adjunctive strategies. In fact, the most useful algorithmic study was the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, from which SGAs were entirely absent. The second problem is that STAR*D showed a clear pattern in which the efficacy of an augmentation agent depended on its placement in the algorithm. Those agents occurring later in the algorithm, such as monoamine oxidase inhibitors (MAOIs), adjunctive triiodothyronine (T3), and adjunctive lithium, appeared to be less effective than adjunctive buspirone, which occurred earlier in the algorithm. This was not the result of a direct comparison. Because of these two problems, it is therefore difficult to determine how to rank the efficacy of SGAs among the agents investigated by the STAR*D study. Among clinical treatment strategies, SGAs might appear toward the end of first-line strategies, perhaps after combinations and stimulants but before buspirone.

Background: Many randomized controlled trials of the pharmacotherapy and psychotherapy of obsessive-compulsive disorder (OCD) have been undertaken. Several meta-analyses of these trials, and a number of expert consensus guidelines, have been published. This article summarizes these works, and suggests future research directions.

Methods: Meta-analyses of OCD were assessed with the QUORUM statement and the Oxman and Guyatt rating scale, and consensus guidelines on the treatment of OCD were assessed with the Appraisal of Guidelines Research and Evaluation (AGREE) instrument. Current principles in the treatment of OCD, and gaps in our knowledge, were reviewed.

Results: Selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavioral therapy are currently viewed as the first-line treatments of choice for adult and pediatric OCD.There is also good evidence for the efficacy of atypical antipsychotics in the augmentation of patients refractory to SSRIs. Important questions remain for the field.

Conclusions: There have been significant advances in both the pharmacotherapy and psychotherapy of OCD. Nevertheless, there is a paucity of longer-term trials, data on symptom remission and functional improvement, and data on treatment effectiveness in wider clinical practice. It is hoped that improved understanding of the mechanisms underlying OCD will lead to future advances.

We appear to be on the brink of a new epoch of treatment for Alzheimer's disease. Compelling evidence suggests that Aβ42 secretion is the triggering event in the pathogenesis of Alzheimer's disease, and that tau aggregation may be an important secondary event linked to neurodegeneration. Prophylactic administration of anti-amyloidagents designed to prevent Aβ accumulation in persons with subclinical disease is likely to be more effective than therapeutic interventions in established Alzheimer's disease. Drug development programs in Alzheimer's disease focus primarily on agents with anti-amyloid disease-modifying properties, and many different pharmacologic approaches to reducing amyloid pathology and tauopathy are being studied. Classes of therapeutic modalities currently in advanced-stage clinical trial testing include forms of immunotherapy (active β -amyloid immunoconjugate and human intravenous immunoglobulin), a γ-secretase inhibitor, the selective Aβ42-lowering agent R-flurbiprofen, and the anti-aggregation agent tramiprosate. Non-traditional dementia therapies such as the HMG-CoA reductase inhibitors (statins), valproate, and lithium are now being assessed for clinical benefit as anti-amyloid disease-modifying treatments. Positive findings of efficacy and safety from clinical studies are necessary but not sufficient to demonstrate that a drug has disease-modifying properties. Definitive proof of disease-modification requires evidence from validated animal models of Alzheimer's disease; rigorously controlled clinical trials showing a significantly improved, stabilized,or slowed rate of decline in cognitive and global function compared to placebo; and prospectively obtained evidence from surrogate biomarkers that the treatment resulted in measurable biological changes associated with the underlying disease process.

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.

The opioid systems play an important role in mediating both physical pain and negative affects (eg, the pain of social isolation). From an evolutionary perspective, it is not surprising that the neurocircuitry and neurochemistry of physical pain would overlap with that involved in complex social emotions. Exposure to trauma as well as a range of gene variants in the opioid system may be associated with alterations in opioid systems function, with changes in reward processing, and with vulnerability to substance abuse. A role for interventions with opioid agents in depression and anxiety disorders has been suggested.

Introduction: Selective serotonin reuptake inhibitors are considered the most effective and well-established pharmacotherapy for the treatment of obsessive-compulsive disorder (OCD), a chronic and disabling condition. However, ~40% of patients do not have a significant improvement, suggesting that new medications are needed. This study was designed to investigate the treatment response to escitalopram in OCD patients.

Methods: This open-label study involved 11 adult OCD outpatients diagnosed with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Axis I Disorders. Data were collected and the treatment response was assessed by an experienced psychiatrist by using the Yale-Brown Obsessive-Compulsive Scale. Subjects received escitalopram 30 mg/day for 12 weeks starting at 10 mg/day. Dosage adjustments were made within 2 weeks, depending on the tolerability of the patient.

Results: Six of the 11 patients (54.5%) presented a reduction of at least 40% in the baseline total Yale-Brown Obsessive-Compulsive Scale scores.

Conclusion: Despite the small sample size and the open-label nature of this trial, these data suggest that escitalopram may be a useful option for patients with OCD.