The hypothalamic-pituitary-adrenal axis is a key mediator of the stress response in humans. The corticotropin-releasing factor (CRF) type 1 receptor (CRFR-1) in the pituitary gland is a gatekeeper for that response, and the CRFR-1 receptor is also present in many other mood- and cognition-related neural structures. Behaviorally, a number of relationships between stress and psychiatric disorders can be observed: chronic or repeated stress is associated with onset of depression; stressors can cause a recovering alcoholic to relapse; overactive stress responses mark many anxiety disorders; and insomnia can arise from an overactive stress response. Thus, a CRFR-1 antagonist could be useful for treating or preventing the consequences of CRF-mediated stress in depression, anxiety, insomnia, and substance abuse.

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.

Multiple lines of evidence suggest that inflammation and glutamate dysfunction contribute to the pathophysiology of depression. In this review we provide an overview of how these two systems may interact. Excess levels of inflammatory mediators occur in a subgroup of depressed patients. Studies of acute experimental activation of the immune system with endotoxin and of chronic activation during interferon-α treatment show that inflammation can cause depression. Peripheral inflammation leads to microglial activation which could interfere with excitatory amino acid metabolism leading to inappropriate glutamate receptor activation. Loss of astroglia, a feature of depression, upsets the balance of anti- and pro-inflammatory mediators and further impairs the removal of excitatory amino acids. Microglia activated by excess inflammation, astroglial loss, and inappropriate glutamate receptor activation ultimately disrupt the delicate balance of neuroprotective versus neurotoxic effects in the brain, potentially leading to depression.

Varenicline is a promising agent with demonstrated efficacy in the promotion of smoking cessation. However, from the time of initial trials, it has been associated with significant psychiatric adverse effects. We describe a case where mixed mood and psychotic disturbance developed in an individual with a history of depression and a family history of bipolar disorder. Based on this case, we hypothesize a possible mechanism of action for these adverse effects and preventive measures that could be undertaken in its effective use.

Genetic factors are known to contribute to the development of schizophrenia and related psychoses. Cytogenetic abnormalities have been occasionally found in patients with psychotic disorders and, thus, have helped identify candidate gene contributors for these conditions. The individual described here first presented with mental retardation and anxiety disorder in his mid-childhood. In his early 20s, the patient started exhibiting various psychotic manifestations, including delusions and hallucinations. His psychotic symptoms were difficult to control with psychotropic medications. The family history was negative for psychiatric disorders. This patient was found to have a 6.2 megabase deletion of the terminal portion of the short arm of chromosome 12 that was characterized using fluorescence in situ hybridization and microarray comparative genomic hybridization analysis. The maternal chromosomes were normal, but the paternal chromosomes could not be tested. To date such a chromosomal abnormality has not been described in association with schizophrenia/psychosis. This case suggests that psychosis-associated gene(s) may be located in the terminal region of the short arm of chromosome 12.