The articles in this supplement demonstrate that ethnicity and ethnopharmacology have emerged as important considerations in the treatment of patients with mental illness. Patients from ethnically diverse backgrounds often demonstrate varying levels of response and tolerability to drugs such as atypical antipsychotics. In part, this response may be due to the particular agent itself, yet metabolic differences between populations may also impact these varied effects. Specific isoforms of the cytochrome P450 enzyme system can dictate the rate at which patients metabolize certain medications, thus genotypic variability among these enzymes predicts the phenotypic response or metabolic rate. For example, patients from certain ethnic groups such as Caucasians and Hispanics tend to be extensive metabolizers, while African Americans and Asians tend to be slower metabolizers.

Total dose and resulting plasma drug levels are closely related to adverse effects. Thus, patients exhibiting slow or poor oxidative enzyme activity may face increased drug exposure and potentially higher rates of adverse events. The undesirable antipsychotic-induced side effects include metabolic issues such as weight gain, insulin resistance, and dyslipidemia. Certain ethnic groups are at a higher risk for developing these metabolic problems. Side effects such as extrapyramidal symptoms and tardive dyskinesia, which have traditionally been attributed to conventional antipsychotics, may occur with atypicals although much less frequently. Movement disorders caused by the use of an atypical antipsychotic become particularly apparent when plasma drug levels are high. Patients with a slow metabolism will be exposed to high plasma drug levels, even on standard dosages of an atypical antipsychotic.

Therefore, given a genetic predisposition and the potential for metabolic side effects with atypical antipsychotics, a careful risk/benefit assessment is crucial for the successful management of patients with mental illness.

Other patient factors as well as clinician factors can influence the response and tolerability of treatment. Provider biases can affect access to certain medications, while misconceptions about how to treat certain ethnic groups can affect the initial choice of medication and dosage. Ultimately, sensitivity and an awareness of pharmacologic issues as they relate to an expanding and ethnically diverse population must become a high priority for clinicians treating patients with atypical antipsychotics. Side effects of these medications can be minimized with vigilance and a thorough understanding of the risks and benefits.

Continued research is necessary to further understand the field of ethnopharmacology and to lead psychiatry into the future of individualized, metabolically directed therapies.

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.

Background: Affective disorders present an important clinical challenge in multiple sclerosis (MS). Due to prohibitive sample size requirements, population-based studies have not yet provided an adequate description of the underlying epidemiology of this association.

Objective: To describe the epidemiology of affective disorders in MS in a general population sample.

Methods: The study presented here accessed administrative data from a universal healthcare insurance plan in the Canadian province of Alberta. Physician billing data recorded in the Alberta Health Care Insurance Plan was used to identify members of the population ≥15 years of age with and without MS. Crude and stratified estimates of the association between affective disorders and MS were made. Logistic regression analysis was used to evaluate statistical interactions and to provide adjusted estimates of the association.

Results: The estimated prevalence of MS in the population within the targeted age range (2.3 million individuals) was 386/100,000 and that of affective disorders was 7.7%. As expected, an association between MS and affective disorders was identified (crude relative prevalence: 2.2). The association varied in strength over age-sex categories. Although the prevalence of affective disorder was higher in women with MS than men with MS, the association of MS with affective disorders was stronger in men. The strength of association declined with age in both men and women. Affective disorder prevalence in people with MS becomes similar to that of the general population in older age groups.

Conclusion: Affective disorders occur with an increased frequency in MS. This is true in men and women and across all relevant age groups, although the association gets weaker with advancing age. Higher frequencies of affective disorder occur in women with MS than in men with MS. The frequency of affective disorder in people with MS is highest in the 25–44 age group, and declines in older age categories.

Stroke is a common cause of death and disability throughout the world. Acute neurologic deficits due to ischemic injury deserve rapid recognition and diagnosis in order to provide effective therapy. Intravenous tissue plasminogen activator (t-PA) provided to carefully selected patients that can be treated within 3 hours of stroke onset results in improved outcome in these patients. Intra-arterial administration of t-PA within a 6-hour window is performed at several academic centers in patients with middle cerebral and other intracranial artery occlusions based on results of one randomized clinical trial and numerous case reports. Although acute therapy of ischemic stroke has received much attention since the approval of intravenous t-PA, only a small percentage of individuals suffering a stroke actually receive t-PA. This article will review the optimal management of the acute stroke patient and discuss thrombolytic clinical trials that have been completed as well as those that are in progress.

Benzodiazepines (BZs) are clinically used as anxiolytic, hypnotic, anticonvulsant, and antispasmodic drugs. Research using transgenic mouse models has suggested that the effects of BZs involve multiple subtypes of the γ-aminobutyric acid type A (GABAA) receptor, identified by specific α subunits (α1, α2, α3, α5). This review discusses the experimental uses of β-carboline-3-carboxylate-t-butyl ester (βCCT), a drug that binds preferentially to the GABAA α1 subtype but exerts no action (ie, is a pharmacologic antagonist at the GABAA α1 subtype receptor). βCCT blocks the anxiolytic-like effects of BZs, although studies in primates suggests this antagonism may reflect multiple receptor populations. βCCT antagonized the ataxic but not muscle relaxant effects of BZs, a finding that implicates the GABAA α1 subtype receptor in ataxia but not muscle relaxation. The potential clinical utility of βCCT is discussed, both in terms of treatment (ie, hepatic encephalopathy) and as a diagnostic imaging agent. Altogether, these results indicate that subtype-selective antagonists represent a useful approach to studying receptor mechanisms underlying the behavioral effects of BZ-type drugs.

Since 1984, 447 articles have been published using the acronym “SAD” for seasonal affective disorder in the heading of the publication, and since 1992, 59 articles have used “SAD” in the heading of the publication as an acronym for social anxiety disorder, according to MEDLINE. Using the acronym SAD for social anxiety disorder has been used with more frequency in recent scientific publications—interestingly, mostly in connection with newer antidepressants that have been found to be of therapeutic potential for this indication. To avoid possible confusions in research, the acronym “SOAD” was proposed for social anxiety disorder by Kasper and Winkler and “SAnD” by Nutt (D.J. Nutt, MD, PhD, unpublished data, 2004)—seemingly without success since these abbreviations are not seen in the literature. This month, CNS Spectrums focuses on the existing literature on the original acronym for SAD—seasonal affective disorder and its worldwide recognition.

In the early 1980s, Rosenthal and colleagues at the National Institute of Mental Health (NIMH) set out to describe a syndrome called SAD, not to be confused with the other, more recent SAD, social anxiety disorder. The original has been known to physicians since ancient times, dating back to Aretaeus the Cappadocian. However, the NIMH researchers for the first time systematically described the clinical symptomatology, compared it with healthy controls, and differentiated SAD from nonseasonal depression. Their work in tandem with emerging technology led to the discovery of the underlying pathophysiology of SAD and treatment approaches. The most important of these approaches were light therapy and pharmacotherapeutic options.

Many neuropsychiatric diseases present with concomitant dermatologic manifestations. These manifestations may help the clinician formulate a correct diagnosis when it is otherwise unclear. In this article, we present six cases with clinical photographs of associated skin findings discussed from a neuropsychiatrist's perspective. Each case will be followed by a discussion and a brief review of the associated neuropsychiatric and dermatologic aspects of the disease.

The class of serotonin and norepinephrine reuptake inhibitors (SNRIs) now comprises three medications: venlafaxine, milnacipran, and duloxetine. These drugs block the reuptake of both serotonin (5-HT) and norepinephrine with differing selectivity. Whereas milnacipran blocks 5-HT and norepinephrine reuptake with equal affinity, duloxetine has a 10-fold selectivity for 5-HT and venlafaxine a 30-fold selectivity for 5-HT. All three SNRIs are efficacious in treating a variety of anxiety disorders. There is no evidence for major differences between SNRIs and SSRIs in their efficacy in treating anxiety disorders. In contrast to SSRIs, which are generally ineffective in treating chronic pain, all three SNRIs seem to be helpful in relieving chronic pain associated with and independent of depression. Tolerability of an SNRI at therapeutic doses varies within the class. Although no direct comparative data are available, venlafaxine seems to be the least well-tolerated, combining serotonergic adverse effects (nausea, sexual dysfunction, withdrawal problems) with a dose-dependent cardiovascular phenomenon, principally hypertension. Duloxetine and milnacipran appear better tolerated and essentially devoid of cardiovascular toxicity.

Neuropathic pain is defined as a chronic pain condition that occurs or persists after a primary lesion or dysfunction of the peripheral or central nervous system. Traumatic injury of peripheral nerves also increases the excitability of nociceptors in and around nerve trunks and involves components released from nerve terminals (neurogenic inflammation) and immunological and vascular components from cells resident within or recruited into the affected area. Action potentials generated in nociceptors and injured nerve fibers release excitatory neurotransmitters at their synaptic terminals such as L-glutamate and substance P and trigger cellular events in the central nervous system that extend over different time frames. Short-term alterations of neuronal excitability, reflected for example in rapid changes of neuronal discharge activity, are sensitive to conventional analgesics, and do not commonly involve alterations in activity-dependent gene expression. Novel compounds and new regimens for drug treatment to influence activity-dependent long-term changes in pain transducing and suppressive systems (pain matrix) are emerging.

Animal models are invaluable in preclinical research on human psychopathology. Valid animal models to study the pathophysiology of depression and specific biological and behavioral responses to antidepressant drug treatments are of prime interest. In order to improve our knowledge of the causal mechanisms of stress-related disorders such as depression, we need animal models that mirror the situation seen in patients. One promising model is the chronic psychosocial stress paradigm in male tree shrews. Coexistence of two males in visual and olfactory contact leads to a stable dominant/subordinate relationship, with the subordinates showing obvious changes in behavioral, neuroendocrine, and central nervous activity that are similar to the signs and symptoms observed during episodes of depression in patients.

Recent studies on the epidemiology of obsessive-compulsive disorder (OCD) estimate 50 million patients suffer from OCD worldwide, thus making it a global problem. The treatment of OCD has changed substantially over the last 2 decades following the introduction of selective serotonin reuptake inhibitors, which provide symptom improvement in ~60% of patients. However, some patients remain resistant to the standard pharmacologic and behavioral treatments. Although some treatment-resistant patients respond to pharmacologic augmentations, others do not, and there is evidence that some of the most severe cases benefit from treatment with neurosurgical interventions. Besides pharmacologic, behavioral, and neurosurgical approaches, different brain stimulation methods—transcranial magnetic stimulation, deep brain stimulation, and electroconvulsive therapy—have been investigated in treatment-resistant patients with OCD. However, available data about the use of these techniques in OCD treatment are quite limited in terms of sample size and study design, given the difficulty in conducting standard blinded trials for these procedures. In addition, none of the mentioned treatments have received Food and Drug Administration approval for the treatment of OCD. Nevertheless, promising findings regarding efficacy, tolerability, and non-invasiveness and/or reversibility of these techniques have increased interest in investigating their use in treatment-resistant OCD.

Background: Lifetime prevalence rates of cognitive dysfunction and depression in multiple sclerosis (MS) have typically been reported to be ∼50%. However, an inconsistent relationship between these two common features of MS has been reported in the literature. Because neurovegetative depression symptoms overlap with MS symptoms, it may be that literature inconsistencies can partly be explained by the fact that only those depression symptom clusters unambiguously reflective of depression are associated with cognitive dysfunction.

Objective: To explore the relationship between different depression symptom clusters and a battery of tests measuring cognitive domains commonly impaired in MS and was examined at two time points 3 years apart.

Methods: The Chicago Multiscale Depression Inventory was employed to measure mood, negative evaluative, and neurovegetative symptom clusters in 53 MS patients who were also administered a battery of neuropsychological tests.

Results: At time point 1, Mood and Evaluative Chicago Multiscale Depression Inventory scales were significantly associated with tasks of complex speeded attention, planning, and working memory. At time point 2, the Evaluative scale was still significantly associated with these domains, in addition to spatial memory; however, all of the significant correlations with the Mood scale dropped out.

Conclusion: These results show that negative evaluative depression symptoms are most consistently predictive of cognitive dysfunction in MS. It may be that negative evaluative depression symptoms use up available cognitive capacity, thus compromising performance on cognitive capacity demanding tasks in MS patients.