LAUSR

Once in a while, we all experience feelings of hopelessness, sadness, lack of self-esteem, lack of motivation and drive, and difficulties to focus and concentrate. In far too many individuals, these physiological responses to environmental, social, or internal insults or challenges become symptoms of one of the most disabling medical conditions: the major depressive disorder (MDD). While this ancient disorder, or better said syndrome, is well recognized, the underlying causes remain poorly understood. Psychosocial stress, inflammation, persistent pain, and long-lasting sleep problems can precipitate symptoms of depression in almost all humans (and animals) but why in some people the symptoms prevail, persist, and become debilitating, even when the primary trigger wears off is unknown. Patient’s emotional state is often Blocked in^ into melancholy, and uncontrollable self-focused rumination and negative thinking of the past, present, and future. Basic daily activities may become insurmountable leading into disability, social isolation, and further exacerbation of feelings of worthlessness, stress, and anxiety. If left untreated, major depression significantly increases the risk to develop many major chronic diseases and may lead to suicide. Unfortunately, there is a huge unmet medical need for better treatments. Commonly used prescription antidepressants often show poor efficacy and very slow onset of action and may bring numerous side effects. The discovery of the rapid antidepressant effects of ketamine is a remarkable improvement in the field and the treatment is already in clinical use for the acute management of depression. However, the beneficial effects of ketamine on mood fade out almost as fast as they emerge. Ketamine may also precipitate hallucinations and is thus warranted for people with high risk of psychosis. We thus clearly need to understand the factors behind depression and the mechanisms underlying antidepressant effects much better in order to develop faster, more effective, reliable, and safe treatments that bring sustained benefit for the patients. This special issue covers some selected reviews on this important topic.