For neurologists and psychiatrists, this month's edition of CNS Spectrums contains both original research articles and review papers surrounding a central theme of enormous importance: how the environment can harm brain function and how the brain can repair itself. We are extremely fortunate to have Jeremy Coplan as our guest editor. Dr. Coplan, with whom I have enjoyed years of collaboration on many projects of mutual interest, is professor of psychiatry at the State University of New York (SUNY) Downstate Medical Center in Brooklyn and senior scientist in the Department of Clinical Psychobiology at the New York State Psychiatric Institute in New York City. Let me now summarize why I believe the area covered this month is so vital.

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.

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.

A bidirectional regulatory interaction between the central nervous system and the immune system is largely provided by cytokines and their specific receptors, which are expressed by cells of both systems. Transforming growth factor-β1 (TGF-β1), produced by glial cells and lymphocytes and regulated by steroid hormones, is one such cytokine. In the current study, we examined the relationship between TGF-β1 and peer affiliation in bonnet macaques (Macaca radiata) either reared normally or exposed as infants to conditions in which their mothers faced fluctuating requirements for food procurement (variable foraging demand [VFD]). Rearing under VFD conditions has been previously shown to produce dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in these animals. Serum levels of TGF-β1 after exposure to a moderate stressor had no correlation with peer affiliation under baseline conditions (r=.07), but were highly correlated with affiliation after subsequent challenge with a fear stimulus (r=.62). Affiliation after the fear stimulus also was inversely correlated with baseline levels of affiliation (r=−.71). These data suggest that changes in peripheral TGF-β1 may be reflective of latent behavioral and biochemical propensities possibly related to affect. Further examination of the effects of early adversity will improve our understanding of the relationship between the HPA axis and immune function.

Obesity has negative health consequences related to fat distribution, particularly the central or visceral accumulation of fat. The major complications associated with visceral obesity, termed the “Metabolic Syndrome of Obesity,” or “Syndrome X,” are type II diabetes, hypertension, and dyslipidemia. As with certain mood disorders, the syndrome may be a consequence of neuroendocrine perturbations typically associated with chronic stress. Our work with bonnet macaque monkeys provides an animal model for the relationship between early stress, behavioral and hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and Syndrome X. During their infant's first half-year, mothers face a variable foraging demand (VFD), in which ample food varies unpredictably in the difficulty of its acquisition, and the offspring show persistent abnormalities in systems known to modulate stress and affective regulation. Early work on the bonnet macaque noted the emergence of a sample of spontaneously obese subjects as they matured. Using the VFD model, the current study showed that there was a clear relationship between early cerebrospinal fluid corticotropin-releasing factor levels and subsequently measured body mass index, supporting the hypotheses regarding the interactive roles of early experience and HPA axis dysregulation in the ontogeny of both metabolic and mood disorders.

Research has provided considerable evidence for the hypothesis that corticotropin-releasing hormone (CRH), the key central coordinator of stress-hormone homeostasis, also plays a role in the development and course of depression and anxiety disorders. Studies using animal models of anxiety, as well as mouse mutants, in which the gene coding for the CRH type 1 receptor (CRHR1) was genetically deleted supported the notion that enhanced CRH/CRHR1 signaling underlies depression and anxiety disorders. Therefore, a number of small nonpeptide molecules that antagonize CRHR1 have been developed. In animal models, these molecules had anxiolytic and other stress-alleviating effects. An initial clinical study showed that CRHR1 antagonism has beneficial effects on depression and anxiety symptoms at doses unharmful to neuroendocrine stress responsivity.

Eight new antiepileptic drugs (AEDs) have been introduced since 1993 and clinicians are now faced with a complex array of treatment choices. In evaluating the newly available drugs, it is important to analyze the different aspects of these agents. Some of the more important characteristics to be aware of are efficacy, adverse effects, pharmacokinetics, and mechanisms of action.

One of the factors complicating treatment choice is the absence of comparative head-to-head clinical trials between the new AEDs. While in some cases it is possible to draw conclusions from the results of randomized, controlled trials that have tested medications against placebo or older drugs, often physicians have to rely on open-label data or personal experiences in selecting the right medications for specific cases.

Trends suggest that the new AEDs are more efficacious compared to the older AEDs, but the major potential benefits of the new drugs are their better safety, tolerability, and cognitive profiles and more desirable pharmacokinetics.

It is obvious that there is a need to redefine the concept of “successful” treatment of epilepsy. Patients need to be individually evaluated and, in addition to controlling seizures, tolerability should be taken into consideration in finding the most appropriate treatment regimen.

The search for novel anxiolytics and antidepressants has focused on compounds with the potential to reduce excessive hypothalamic-pituitary-adrenal (HPA) axis activity. L-glutamate, an excitatory neurotransmitter ubiquitously present within the central nervous system, conceivably plays an important role in activating the neural sites involved in stress modulation. Deactivation of the HPA axis by glutamatergic neurotransmission modulation may represent a novel therapeutic approach. Accordingly, the acute intravenous effects of the novel metabotropic (mGlu2/3) agonist LY354740 were tested on bonnet macaques (Macaca radiata) undergoing acute infusions of yohimbine, a noradrenergic stimulant. Dependent measures were the magnitude of the increase of plasma cortisol and plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) customarily elicited by yohimbine. Next, the effects of 6 weeks of chronic oral administration of LY354740 on baseline (postcapture) plasma cortisol and MHPG levels in comparison to the identical measure in untreated controls were assessed. Subjects chronically treated with LY354740 received yohimbine infusions which were compared to yohimbine infusions and saline infusions in non-LY354740-treated subjects. Preliminary evidence supports the view that acute LY354740 infusion resulted in a marked diminution of yohimbine-induced stress response, as manifest by a substantial attenuation of cortisol and MHPG response observed in comparison to the saline-treated yohimbine condition. Chronic oral administration of LY354740 led to postcapture baseline cortisol levels which were markedly reduced (∼50%) in comparison to untreated control subjects; however, there were no significant parallel differences in MHPG levels. Yohimbine infusions elicited an increase in cortisol and MHPG levels in both LY354740-treated and non-LY354740-treated subjects, in comparison to declines in cortisol values observed following vehicle infusions (group X time interaction; P<.0001). Chronic LY354740-treated subjects failed to achieve cortisol levels comparable in range to those of untreated subjects primarily because of their low baseline cortisol levels. In contrast, despite equivalent baselines, yohimbine-induced MHPG values were increased overall in the chronically treated group compared to the saline and yohimbine-alone groups. Thus, LY354740 markedly reduced the acute corticoid and noradrenergic response elicited by yohimbine infusion. Chronic administration of LY354740 appears to present a safe and effective mechanism to markedly down-modulate the HPA axis while retaining noradrenergic responsivity.