There are many new findings in the area of comorbid insomnia. Almost 50% of all cases of chronic insomnia are due to a mental disorder, with depressive illness explaining the majority of cases related to mental disorder (Slide 1). Other common causes of comorbid, or secondary, insomnia include chronic respiratory disease such as asthma and chronic obstructive pulmonary disease, chronic pain, degenerative neurological disease, and some medications such as glucocorticoids and serotonin reuptake inhibitors. A general principle of management of insomnia related to mental or medical disorders is that the principal disorder must be fully treated as part of the insomnia treatment plan. If there is an offending medication, it must be discontinued if possible.

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 Thus, if one were to include all unpublished along with published double-blind, placebo-controlled trials of antidepressants for MDD, this efficacy margin could be ≤10%.

The last 4 years have seen a rapid burst of development of medications used to treat epileptic seizures. While none of these medications has replaced the “standards” in the field, they collectively offer additional treatment options for patients, particularly for those with difficult-to-control seizures. As experience with these novel medications grows, each will occupy its own niche in the treatment strategy for patients with epilepsy.

The obsessive-compulsive (OC) spectrum is a group of related disorders that appear to share symptomatology, neurobiology, and treatment response with obsessive-compulsive disorder. To collect data on the appreciation of the OC spectrum concept among clinicians, 800 participants completed a questionnaire to help determine their understanding and appreciation of this concept, at a workshop on the OC spectrum.

The diagnosis of human immunodeficiency virus type 1 (HIV-1)–associated cognitive-motor disorder—either minor cognitive-motor disorder (MCMD) or HIV-1-associated dementia (HAD)—is fraught with potential pitfalls for the clinician. Before making such a diagnosis, clinicians should exclude other etiologies by using neuroimaging, lumbar puncture, and serum chemistries to screen for opportunistic and non-opportunistic infections of the brain and meninges. Clinicians should also consider psychoneurotoxicity (caused from the use of psychoactive substances and prescribed medications) and psychopathology, such as mood, anxiety, and other disorders. In addition, a thorough medical history and physical examination, including a complete neurologic and neuropsychiatric mental status examination, are necessary for an accurate diagnosis. There is also a need for standardized neuropsychological and functional status tests, since the diagnostic criteria for these disorders are partly based on these criteria. Treatment targets should include subclinical cognitive-motor impairment and neuroprotection, as well as MCMD and HAD. Currently, zidovudine remains the best proven treatment for these disorders, but other nucleoside reverse transcriptase inhibitors, as well as nonnucleoside reverse transcriptase inhibitors and protease inhibitors, show promise, and selected agents from these classes are being tested in clinical trials. Other areas that should be investigated are the modulation of inflammatory mediators (such as tumor necrosis factor α), neurotransmitter manipulation (especially of dopamine), and nutritional interventions.

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.

Sexual dysfunction is common among patients with epilepsy, but many clinicians do not include inquiries about this aspect of the patient's health in their routine evaluations. This article presents approaches for taking a sexual history and for discussing sexual problems. The utility of standardized sexual dysfunction questionnaires is reviewed and the important elements of appropriate and effective counseling are highlighted.

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.

Irritable bowel syndrome (IBS) is one of over 20 functional gastrointestinal disorders. There is considerable overlap of IBS with panic disorder as well as other anxiety disorders and depression. It has been proposed that the high prevalence of psychiatric disorders in clinical samples of IBS patients is a result of self-selection of individuals with anxiety and depression, which drives treatment-seeking behavior. Over the past several years, data from some community studies have shown that there is a high prevalence of psychiatric disorders in individuals with IBS who never sought treatment. This suggests that there may be a more fundamental linnk between IBS, anxiety and mood disorders, such as shared pathophysiology.

This month's issue of CNS Spectrums brings together reviews on the brain-gut axis, each of which provides a unique perspective, which is complementary to the other reviews.

Kirsten Tillisch, MD, and Emeran A. Mayer, MD, review the neurobiology of visceral sensation, focusing on visceral hyperalgesia in IBS. In their paper, the importance of expectancy, comorbidity, gender, and other issues on pain perception is discussed. One of the most fascinating points the authors make is that extra-intestinal functional disorders, such as fibromyalgia, which often coexists with IBS, may affect somatic perception and pain thresholds. The observation that these disorders not only co-exist, but can affect each other raises an important and often overlooked issue for researchers. Comorbid disorders should be assessed and taken into account when conducting studies in patients with IBS. The authors highlight advances in methodology and new conceptual frameworks for understanding the functional gastrointestinal disorders (FGIDs) as well as remaining gaps in our knowledge about visceral hyperalgesia.

As an individual with autism, I have learned that, unfortunately, some therapists and physicians are unaware of autistics' overly acute senses, specifically hyperacute hearing. For example, the birthday party fun of noise-makers for a normal child was torture for me. There are many first-person reports of people with autism who, like me, find certain loud sounds intolerable.

Some children and adults with autism also have visual sensitivity problems. I enjoyed visually stimulating things such as flags or automatic supermarket doors, but individuals with severe visual sensitivities cannot tolerate even fluorescent lights. In her book, Somebody Somewhere, autistic Donna Williams describes how the flicker from fluorescent lights causes her visual overload. A study conducted by Coleman et al indicates that fluorescent lights can increase repetitive behavior in children with autism.

Autistic sensory problems are highly variable. When I was a child, I liked to play with running water; however, another child with autism may not be able to tolerate the same sound. I was attracted to automatic supermarket doors and I liked to watch them move. Another autistic child or adult may scream and run away from these same automatic doors because sudden movement hurts his or her eyes. Maybe a small anomaly in my visual processing caused me to be attracted to the movement of the doors. A greater anomaly may cause another individual to avoid the same stimulus. Waterhouse et al found it puzzling that I was attracted to strong visual stimuli, yet high-pitched auditory stimuli hurt my ears.

Although most patients with depression ultimately respond to antidepressant therapy, >50% have inadequate response to an individual antidepressant trial. The desire to avoid adverse drug reactions is common among patients, and is an important determinant of drug selection among psychiatrists. However, since the major classes of antidepressants and antipsychotics appear to be comparable in efficacy, clinicians have little basis for selecting the most effective agent for an individual patient. Pharmacogenetics, often described as the study of genetic variation that explains differential response to medication, represents an important new avenue toward improving treatment outcomes. Genetic variation in drug-metabolizing enzymes has been recognized for decades. The main focus of current psychiatric pharmacogenetic testing is on the cytochrome P450 (CYP) 2D6 and, to a somewhat lesser extent, on the 2C19 genes. Data suggest that poor metabolizer status can be associated with an increased risk of adverse drug reactions with certain medications, and that ultra-rapid metabolizers may require higher-than-usual doses to achieve a therapeutic response. The importance of CYP enzymes in the metabolism of several antidepressant and antipsychotic drugs suggest that genetic variation may aid in medication selection or dosing. Advances in pharmacogenetic research may facilitate the development of personalized medicine in which genetic information can inform drug selection, leading to optimal drug effectiveness and minimal drug toxicity.

In this monograph, David A. Mrazek, MD, provides an overview of the context of genetic testing in clinical psychiatric practice. Next, Jordan W. Smoller, MD, ScD, discusses some of the practical issues related to medication selection. Finally, Jose de Leon, MD, presents a comprehensive review of antidepressant and antipsychotic treatment based on drug metabolism, and reviews the available testing methods for CYP 2D6 and 2C19 genotypes.

Psychoneuroendocrinology (PNE) has been a method used in the past to investigate brain biochemical functions in normal and pathological mentation. These studies have subsequently uncovered variations in normal biochemical functioning. It is still being debated, however, how these variations correlate with well-defined psychopathologies.

Future studies in PNE shows promise in many areas of contemporary neurospychiatry. For example, research focusing on variations in neurotransmitter, neuropeptide, and neurohormone secretory tonus might enhance our understanding of specific personality characteristics and behavior. PNE may also be essential in investigating the correlation between hormonal variations and symptoms observed across various psychiatric disorders. PNE might likewise be important for new therapeutic approaches. Finally, PNE can be used to investigate psychoneuroimmunoendocrine relationships.

New PNE methodologies must be developed to make this branch of neuroscience more appropriate for the study of localized brain functions.

Epilepsy is common, but conditions that imitate epilepsy are even more common. In order to make a correct diagnosis of epilepsy, the clinician must carefully elicit a detailed history of the seizure episode. Realizing the overlap that exists between seizures that define epilepsy and those of other psychiatric conditions can also help in differentiating between epilepsy and an imitator of epilepsy. Deciphering the features of a seizure episode is also key to correct diagnosis.

In this article, the physiological and psychological imitators of epilepsy are described, as well as the features of a seizure episode that should be considered in making a diagnosis. Seizure presentations are also explained followed by a description of common diagnostic pitfalls to avoid.

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.