Multifunctional drugs are those with more than one therapeutic mechanism. Trazodone is a multifunctional drug with dose-dependent pharmacologic actions. That is, it has hypnotic actions at low doses due to blockade of 5-HT2A receptors, as well as H1 histamine receptors and α1 adrenergic receptors. Higher doses recruit the blockade of the serotonin transporter (SERT) and turn trazodone into an antidepressant. Although trazodone has traditionally been used as a low dose hypnotic, a new controlled release formulation that has the potential to improve the tolerability of high doses may provide an opportunity to revisit this multifunctional drug as an antidepressant as well.

Psychosis is now widely hypothesized to involve neural networks beyond the classical dopaminergic mesolimbic pathway, including serotonin and glutamate systems as well.

Anxiety, stress, and trauma-related disorders are a major public health concern in the United States. Drugs that target the γ-aminobutyric acid or serotonergic system, such as benzodiazepines and selective serotonin reuptake inhibitors, respectively, are the most widely prescribed treatments for these disorders. However, the role of glutamate in anxiety disorders is becoming more recognized with the belief that drugs that modulate glutamatergic function through either ionotropic or metabotropic glutamate receptors have the potential to improve the current treatment of these severe and disabling illnesses. Animal models of fear and anxiety have provided a method to study the role of glutamate in anxiety. This research has demonstrated that drugs that alter glutamate transmission have potential anxiolytic action for many different paradigms including fear-potentiated startle, punished responding, and the elevated plus maze. Human clinical drug trials have demonstrated the efficacy of glutamatergic drugs for the treatment of obsessive-compulsive disorder, posttraumatic stress disorder, generalized anxiety disorder, and social phobia. Recent data from magnetic resonance imaging studies provide an additional link between the glutamate system and anxiety. Collectively, the data suggest that future studies on the mechanism of and clinical efficacy of glutamatergic agents in anxiety disorders are appropriately warranted.

Cognitive dysfunction is a symptomatic domain identified across many mental disorders. Cognitive deficits in individuals with major depressive disorder (MDD) contribute significantly to occupational and functional disability. Notably, cognitive subdomains such as learning and memory, executive functioning, processing speed, and attention and concentration are significantly impaired during, and between, episodes in individuals with MDD. Most antidepressants have not been developed and/or evaluated for their ability to directly and independently ameliorate cognitive deficits. Multiple interacting neurobiological mechanisms (eg, neuroinflammation) are implicated as subserving cognitive deficits in MDD. A testable hypothesis, with preliminary support, posits that improving performance across cognitive domains in individuals with MDD may improve psychosocial function, workplace function, quality of life, and other patient-reported outcomes, independent of effects on core mood symptoms. Herein we aim to (1) provide a rationale for prioritizing cognitive deficits as a therapeutic target, (2) briefly discuss the neurobiological substrates subserving cognitive dysfunction, and (3) provide an update on current and future treatment avenues.

Neurodevelopmental disorders, specifically autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) have undergone considerable diagnostic evolution in the past decade. In the United States, the current system in place is the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), whereas worldwide, the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) serves as a general medical system. This review will examine the differences in neurodevelopmental disorders between these two systems. First, we will review the important revisions made from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) to the DSM-5, with respect to ASD and ADHD. Next, we will cover the similarities and differences between ASD and ADHD classification in the DSM-5 and the ICD-10, and how these differences may have an effect on neurodevelopmental disorder diagnostics and classification. By examining the changes made for the DSM-5 in 2013, and critiquing the current ICD-10 system, we can help to anticipate and advise on the upcoming ICD-11, due to come online in 2017. Overall, this review serves to highlight the importance of progress towards complementary diagnostic classification systems, keeping in mind the difference in tradition and purpose of the DSM and the ICD, and that these systems are dynamic and changing as more is learned about neurodevelopmental disorders and their underlying etiology. Finally this review will discuss alternative diagnostic approaches, such as the Research Domain Criteria (RDoC) initiative, which links symptom domains to underlying biological and neurological mechanisms. The incorporation of new diagnostic directions could have a great effect on treatment development and insurance coverage for neurodevelopmental disorders worldwide.

The nature of depression has recently been reconceptualized, being conceived as the clinical expression of activated immune-inflammatory, oxidative, and nitrosative stress (IO&NS) pathways, including tryptophan catabolite (TRYCAT), autoimmune, and gut–brain pathways. IO&NS pathways are similarly integral to the pathogenesis of inflammatory bowel disease (IBD). The increased depression prevalence in IBD associates with a lower quality of life and increased morbidity in IBD, highlighting the role of depression in modulating the pathophysiology of IBD.This review covers data within such a wider conceptualization that better explains the heightened co-occurrence of IBD and depression. Common IO&NS underpinning between both disorders is evidenced by increased pro-inflammatory cytokine levels, eg, interleukin-1 (IL-1) and tumor necrosis factor-α, IL-6 trans-signalling; Th-1- and Th-17-like responses; neopterin and soluble IL-2 receptor levels; positive acute phase reactants (haptoglobin and C-reactive protein); lowered levels of negative acute phase reactants (albumin, transferrin, zinc) and anti-inflammatory cytokines (IL-10 and transforming growth factor-β); increased O&NS with damage to lipids, proteinsm and DNA; increased production of nitric oxide (NO) and inducible NO synthase; lowered plasma tryptophan but increased TRYCAT levels; autoimmune responses; and increased bacterial translocation. As such, heightened IO&NS processes in depression overlap with the biological underpinnings of IBD, potentially explaining their increased co-occurrence. This supports the perspective that there is a spectrum of IO&NS disorders that includes depression, both as an emergent comorbidity and as a contributor to IO&NS processes. Such a frame of reference has treatment implications for IBD when “comorbid” with depression.

Major depression is associated with a 4-fold increased risk for premature death, largely accounted by cardiovascular disease (CVD). The relationship between depression and CVD is thought to be mediated by the so-called metabolic syndrome (MeS). Epidemiological studies have consistently demonstrated a co-occurrence of depression with MeS components, ie, visceral obesity, dyslipidemia, insulin resistance, and hypertension. Although the exact mechanisms linking MeS to depression are unclear, different hypotheses have been put forward. On the one hand, MeS could be the hallmark of the unhealthy lifestyle habits of depressed patients. On the other, MeS and depression might share common alterations of the stress system, including the hypothalamus–pituitary–adrenal (HPA) axis, the autonomic nervous system, the immune system, and platelet and endothelial function. Both the conditions induce a low grade chronic inflammatory state that, in turn, leads to increased oxidative and nitrosative (O&NS) damage of neurons, pancreatic cells, and endothelium. Recently, neurobiological research revealed that peripheral hormones, such as leptin and ghrelin, which are classically involved in homeostatic energy balance, may play a role in mood regulation. Metabolic risk should be routinely assessed in depressed patients and taken into account in therapeutic decisions. Alternative targets should be considered for innovative antidepressant agents, including cytokines and their receptors, intracellular inflammatory mediators, glucocorticoids receptors, O&NS pathways, and peripheral mediators.

A growing body of evidence suggests that mitochondrial abnormalities are involved in aging and in age-related neurodegenerative diseases as well as cancer, diabetes, and several other diseases known to be affected by mitochondria. Causal factors for most age-related neurodegenerative diseases—including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and Friedrich ataxia (FRDA)—are largely unknown. Genetic defects are reported to cause a small number of neurodegenerative diseases (Slide 1), but cellular, molecular, and pathological mechanisms of disease progression and selective neuronal cell death are not understood fully in these diseases. However, based on several cellular, molecular, and animal model studies of Alzheimer's disease, Parkinson's disease, ALS, FRDA, cancer, and diabetes, aging may play a large role in cell death in these diseases. Age-dependent, mitochondrially-generated reactive oxygen species (ROS) have been identified as important factors responsible for disease progression and cell death, particularly in late-onset diseases, in which genetic mutations are not causal factors.

The consequences of epilepsy can be quite severe and include shortened lifespan, excessive bodily injury, neuropsychological and psychiatric impairment, and social disability. There is evidence that seizures cause brain injury, including neuronal death and physiological dysfunction. Mortality rates are 4—7 times higher in people with medically refractory seizures, and injury rates are substantial, ranging from one per 20 person-years to as much as one per 3 person-years. Quality of life is impaired in epilepsy, and relates to seizure control. Psychosocial disabilities, including lower social interaction with reduced marriage rates and reduced employment levels, are more common in people with refractory seizures. Complete seizure control is desirable, since seizures potentially constitute a serious threat to health and well-being. Therefore, satisfactory seizure control should be defined as having no seizures. Treatment should be directed to preventing seizures whenever possible and achieving control early in the course of illness. The risks of uncontrolled seizures outweigh the risks of aggressive medical or surgical therapy.

Anxiety disorders are common and often disabling. They fall into five main categories: panic disorder, social anxiety disorder, generalized anxiety disorder, obsessive-compulsive disorder and posttraumatic stress disorder, each of which have characteristic symptoms and cognitions. All anxiety disorders respond to drugs and psychological treatments. This review will focus on drug treatments. Recent research has emphasized the value of antidepressants especially the selective serotonin reuptake inhibitors, benzodiazepines, and related sedative-like compounds. The common co-existence of depression with all of the anxiety disorders means that the selective serotonin reuptake inhibitors are now generally considered to be the first-line treatments but the benzodiazepines have some utility especiaRy in promoting sleep and working acutely to reduce extreme distress.

Individuals with substance use disorders typically show an “attentional bias” for substance-related cues: Those cues are able to grab and hold the attention, in preference to other cues in the environment. We discuss the theoretical context for this work before reviewing the measurement of attentional bias, and its relationship to motivational state and relapse to substance use after a period of abstinence. Finally, we discuss the implications of this research for the treatment of substance use disorders. We conclude that attentional bias is associated with subjective craving, and that moment-by-moment fluctuations in attentional bias may precede relapse to substance use. The evidence regarding the predictive relationship between attentional bias assessed in treatment contexts and subsequent relapse is inconsistent. Furthermore, there is currently insufficient evidence to endorse attentional bias modification as a treatment for substance use disorders. Clinical implications and suggestions for future research are highlighted.

Bipolar disorders are prevalent, often severe, and disabling illnesses with elevated lethality largely due to suicide. Suicide rates average ∼1% annually, or perhaps 60 times higher than the international population rate of 0.015% annually. Suicidal acts typically occur early in bipolar disorders and in association with severe depressive or mixed states. The high lethality of suicidal acts in bipolar disorders is suggested by a much lower ratio of attempts:suicide (∼3:1) than in the general population (∼30:1). Risk factors can help to identify patients at increased suicidal risk, but ongoing clinical assessment is essential to limit risk. Empirical short-term interventions to manage acute suicidal risk include close clinical supervision, rapid hospitalization, and electroconvulsive therapy. Remarkably, however, evidence of the long-term effectiveness of most treatments against suicidal behavior is rare. A notable exception is lithium prophylaxis, which is associated with consistent evidence of major (∼80%), sustained relative reductions of risk of suicides and attempts, and lower lethality (increased attempts:suicide ratio). Such benefits are unproved for other treatments commonly used to treat bipolar disorder patients, including anticonvulsants, antipsychotics, antidepressants, and psychosocial interventions. Applying available knowledge systematically, with close and sustained clinical supervision, can enhance management of suicidal risk in bipolar disorders patients.

In this contribution to the CNS Spectrums neuroanatomy series, Stefanie Geisler, MD, discusses the lateral habenula (LHb). This nuclear complex is one of the areas of the brain that forms part of the cross-talk between limbic fore-brain and some important ascending modulatory pathways. Situated at the caudal end of the dorsal diencephalon and classically regarded as projecting largely to the brainstem, including the serotoninergic raphe nuclei, the LHb receives afferents from widespread forebrain areas. Therefore, the LHb is able to influence serotonin tone in the brain, and has long interested neuroanatomists as a potential limbic-motor interface. Nonetheless, the LHb was not much discussed outside neuroanatomical circles until recently, when it was discovered that its impact on the mesotelencephalic dopamine system is probably much greater than had been assumed. The LHb has become a hot topic. This article-addresses these developments and emphasizes the clinical relevance of this interesting brain structure.

Antidepressants are important in the treatment of depression, and selective serotonin reuptake inhibitors are first-line pharmacologic options. However, only 50% to 70% of patients respond to first treatment and <40% remit. Since depression is associated with substantial morbidity, mortality, and family burden, it is unfortunate and demanding on health resources that patients must remain on their prescribed medications for at least 4 weeks without knowing whether the particular antidepressant will be effective. Studies have suggested a number of predictors of treatment response, including clinical, psychophysiological, neuroimaging, and genetics, each with varying degrees of success and nearly all with poor prognostic sensitivity and specificity. Studies are yet to be conducted that use multiple measures from these different domains to determine whether sensitivity and specificity can be improved to predict individual treatment response. It is proposed that a focus on standardized testing methodologies across multiple testing modalities and their integration will be crucial for translation of research findings into clinical practice.