Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a pathologic feature of certain mood and anxiety disorders that results in the increased production and secretion of corticotropin-releasing factor. There is increasing preclinical evidence that glutamate, an excitatory amino acid, plays an important role in the regulation of the HPA axis. Activation of glutamatergic projections to limbic structures such as the amygdala and brainstem structures such as the nucleus tractus solitarius is implicated in the stress response. There are laboratory and clinical suggestions that glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonists function as antidepressants, and that chronic antidepressant treatments have a significant impact on NMDA receptor function. Clinical investigations of glutamate antagonists in patients with mood and anxiety disorders are in their infancy, with a few reports suggesting the presence of mood-elevating properties. Ultimately, HPA axis modulators, serotonin-enhancing agents, and glutamate antagonists might serve to increase neurotropic factors in key brain regions for affective and anxiety regulation, providing a putative final common pathway.

Proponents of herbal therapies frequently insist that traditional physicians must be made ready to accept so-called “alternative” or “complementary” treatments. In this month's issue of CNS Spectrums, two wonderful guest editors, Drs. Jonathan Davidson and Kathryn M. Connor, both of Duke University, help us turn that issue around. The real question for psychiatrists, neurologists, and neuroscientists is whether herbal treatments are ready for us.

Due in large part to recent Congressional mandates, dietary supplements, even when proposed to work for medical conditions like depression and generalized anxiety disorder, do not require approval in the United States by the Food and Drug Administration as pharmaceutical agents.

Abnormal light-related behaviors have been described for patients with panic disorder (PD). The present study was undertaken to investigate the retinal light response in PD using electroretinography (ERG). The authors conducted bwave ERG measurements with a bright light (after dark adaptation) in 28 patients with PD and 28 control subjects. There were no significant differences in the mean b-wave amplitude between the two groups, but the retinal response to light in PD patients was generally lower than in healthy subjects. A large interindividual variability was found; also noted was a significant difference in the mean b-wave amplitude between the right and left eyes in the control group. The data indicate subtle variation of retinal photosensitivity in a subgroup of patients with PD. Because dopaminergic retinal activity affects b-ERG amplitude, the authors hypothesize that the dopaminergic system is involved in the response to light in PD patients.

The clinical manifestation of epileptic seizures may vary widely from patient to patient, depending on the region of the brain involved. Over the centuries, many seizure classific systems have been used, and the current most widely used classification system is that of the International League Against Epilepsy (ILAE). The ILAE system divides seizures into those of partial onset and those of generalized onset, depending on whether the initial clinical manifestations indicate that one cortical region or both hemispheres are involved at the onset of the seizure. Partial seizures are then divided into simple partial seizures, in which a fully conscious state is retained, or complex partial seizures, in which consciousness is impaired. A more recent classification system based purely on symptom features and signs has been proposed, and this system may provide advantages for localization, and especially for surgical evaluation. Epilepsy is a condition characterized by recurrent unprovoked seizures. Epilepsy may be idiopathic, cryptogenic, or symptomatic. Idiopathic epilepsies are generally genetic, and while man such syndromes have been described, advances in molecular genetics will undoubtedly reveal many more syndromes in near future. Cryptogenic epilepsies are those in which an underlying cause is suspected, but the etiology remains undetected. Epilepsies for which there is an underlying structural cause or major metabolic derangement are considered symptomatic. Common causes and diagnostic evaluation are described in this article.

Prior to adolescence, the rates of depression are similar in girls and boys, or are slightly higher in boys. However, with the onset of puberty, the gender proportion of depression dramatically shifts to a 2:1 female to male ratio. What is the relationship between menarche and the onset of major depression in early adolescence? A recent theoretical model proposes that vulnerability to depression may be rooted in normal female hormonal maturational processes and gender socialization. Information regarding the management of depression in adolescent and young adult women is provided, including gender differences in the presentation of depressive symptoms, instruments to facilitate assessment, and treatment options. Pubertal and other hormonal changes should be monitored prospectively along with individual, genetic, constitutional, and psychological characteristics. The burden of illness associated with onset of depression following menarche reinforces the importance of expeditious recognition and intervention.

Initial investigations of the possible interaction between schizophrenia and the immune system began in the early 1900s and have proceeded in a rather halting fashion because of the methodological challenges faced by investigators. However, a confluence of recent data suggests that activation of the inflammatory response system, the cellular immune system, and the humoral immune system may be present in some patients with schizophrenia. Some of the most compelling data support the hypothesis that minor levels of immune activation may be associated with acute psychotic exacerbations. However, a second body of evidence suggests that some individuals with schizophrenia may have chronic, evolving autoimmune processes. This article is an overview of the history, rationale, and some of the recent findings on the interaction between schizophrenia and the immune system.

During the past 10 years, there has been a welcome influx of novel agents for the treatment of epilepsy. Many show advantages compared to older agents, including better adverse effect profiles and lack of drug-drug interactions. The sheer number of agents now available makes distinction among them confusing at times. Agents differ in spectrum of action, pharmacokinetic profile (affecting dosing schedule and drug interactions), and titration time. This review highlights the differences between the various new agents and the more traditional antiseizure drugs. Evidence for the widespread use of these compounds outside their indication, particularly for diseases other than epilepsy, is reviewed as well.

The latest and most generative biological theories of major depression center on two major hypotheses. The first focuses on the concept that hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis leads to many of the pathological changes in the brain that accompany major depression. The second posits that neurogenesis leads to the repair of depression-related injuries. These two hypotheses are complementary: the former alludes to the etiology or consequences of depression, while the latter suggests mechanisms of antidepressant action. Significant crosstalk occurs between these two systems at many levels. Protein kinase A (PKA) may play an important role in this crosstalk at the intracellular level of signaling cascades. PKA is involved in the formation of long-term potentiation and fear conditioning in response to stress. Chronic stress leads to the suppression of hippocampal activity, which may cause the hyperactivity of the HPA axis during melancholic depression. PKA is also involved in the stimulation of hippocampal neurogenesis after antidepressant treatment. In theory, neurogenesis may lead to the restoration of hippocampal function, and this may be the mechanism that leads to antidepressant-mediated normalization of HPA hyperactivity. Thus, PKA is active during processes that potentially lead to depression and other processes that lead to the resolution of the illness. These opposing processes may be mediated by separate PKA isozymes that activate two distinct pathways. This review highlights the dual role of this enzyme in two biological hypotheses pertaining to depression and its treatment.

Norepinephrine and epinephrine are involved in the control of several important functions of the central nervous system (CNS), including sleep, arousal, mood, appetite, and autonomic outflow. Catecholamines control these functions through activation of a family of adrenergic receptors (ARs). The ARs are divided into three subfamilies (α1, α2, and β) based on their pharmacologic properties, signaling mechanisms, and structure. ARs in the CNS are targets for several therapeutic agents used in the treatment of depression, obesity, hypertension, and other diseases. Not much is known, however, about the role of specific AR sub-types in the actions of these drugs. In this paper, we provide an overview of adrenergic pharmacology in the CNS, focusing on the pharmacologic properties of subtype-selective AR agonists and antagonists, the accessibility of these drugs to the CNS, and the distribution of ARs in different areas of the brain.

Various agents have been used for the treatment of epilepsy. Standard antiepileptics (AEDs) have been available in the United States for many years and although they continue to play an important role in the treatment of epilepsy, these agents have limitations. Many have a lack of efficacy, side effects or toxicities, or potentially cause interactions with other agents. While the mechanism of action for AEDs is still not entirely clear, most experts agree that it is related to ion channels and ultimately to the balance between neural inhibition and excitation. The ultimate goal of all AEDs is to either reduce excitation or promote inhibition. There is an opportunity for newer AEDs to be developed and marketed; these newer agents have the promise of fewer adverse effects and greater efficacy. A challenge for the new AEDs is to actually prevent the initiation of epileptiform activity and prophylactically suppress seizure induction.

The purpose of this study was to test the hypothesis that orbitofrontal cortical volume would be reduced following anterior cingulotomy for obsessive-compulsive disorder (OCD). Whole brain cortical parcellation was performed on magnetic resonance imaging (MRI) data from nine patients, before and 9(±6) months following anterior cingulotomy. No significant volumetric reductions were found in the orbitofrontal cortex. Exploratory findings of reduced volume in ventral temporo-fusiform and posterior cingulate regions were consistent with chance differences, in the face of multiple comparisons. Therefore, though the circumscribed lesions of anterior cingulotomy have recently been associated with corresponding volumetric reductions in the caudate nucleus, no comparable volumetric reductions are evident in cortical territories. Taken together, these results are most consistent with a model of cingulo-striatal perturbation as a putative mechanism for the efficacy of this procedure. While limitations in sensitivity may have also contributed to these negative findings, the methods employed have previously proven sufficient to detect cortical volumetric abnormalities in OCD. The current results may reflect a relatively diffuse pattern of cortico-cortical connections involving the neurons at the site of cingulotomy lesions. Future functional neuroimaging studies are warranted to assess possible cortical or subcortical metabolic changes associated with anterior cingulotomy, as well as predictors of treatment response.

The inconsistency in linkage results that has bedeviled psychiatric genetics has been observed to occur regularly in common diseases with complex inheritance. Nonetheless, in two such instances—noninsulin-dependent diabetes mellitus (NIDDM) and inflammatory bowel disease (IBD)—susceptibility genes have been discovered based on the follow-ups of linkage findings. In bipolar illness disorder (BPD) and schizophrenia (SZ), there are some linkage reports with replication of other studies similar to the situation in NIDDM and IBD before the successful positional cloning efforts. Two of the regions with linkage reports, BPD and SZ, on the long arms of chromosomes 13 and 22, show linkage to the same markers in both diseases. This lends some plausibility to the hypothesis of some shared genetic predispositions for both disorders. Cytogenetic evidence offers another positional approach to susceptibility genes. The velocardiofacial syndrome is associated with deletions very close to the linkage region on chromosome 22, and with psychiatric manifestations of both BPD and SZ. Endophenotypes ofSZ, previously demonstrated to be heritable, have been found to have chromosomal linkage in at least one study. These include eye-tracking abnormalities linked to 6p, and an abnormality of the P50 cortical evoked potential linked to chromosome 15. Variants in specific genes have been associated with susceptibility to the psychiatric illnesses. These genetic findings may contribute to etiologic subcategorization of BPD and SZ, and the development of new treatment approaches. A table of genetic terms is included for review.