Scott Alexander examines the development and effectiveness of vilazodone and vortioxetine, two antidepressants designed to work faster and better than SSRIs, but which ultimately failed to live up to expectations. Longer summary

Scott Alexander discusses the development and effectiveness of two antidepressants, vilazodone and vortioxetine, which were designed to combine SSRI effects with 5-HT1A partial agonism. He explains the theoretical basis for their development, involving the role of presynaptic 5-HT1A autoreceptors in delaying SSRI effectiveness. The post then evaluates the clinical performance of these drugs, finding that despite their innovative design, they don't significantly outperform older antidepressants in efficacy, onset speed, or side effect profile. Scott expresses confusion about the theoretical underpinnings of these drugs and why pharmaceutical companies invested so heavily in their development. Shorter summary

Scott reviews a paper proposing a computational model of mood and emotions based on predictive processing, discussing its implications for understanding mood disorders. Longer summary

This post discusses a paper by Clark, Watson, and Friston that proposes a computational perspective on mood and emotions. The authors argue that emotions reflect changes in the uncertainty about the somatic consequences of action, while mood corresponds to hyperpriors about emotional states. The theory suggests that depression is a prediction of bad outcomes with high confidence, mania is a prediction of good outcomes with high confidence, and anxiety is a prediction of bad outcomes with low confidence. The post explores how this theory explains various aspects of mood disorders and their symptoms, including learned helplessness and the role of serotonin. The author finds the theory intriguing but notes some inconsistencies, particularly in unifying the concepts of 'prior on bad outcomes' and 'low precision of predictions'. Shorter summary

Scott reviews a theory about serotonin receptors that explains how they help cope with stress, and discusses its implications and limitations. Longer summary

This post reviews a theory about serotonin receptors proposed by Robin Carhart-Harris and David Nutt. The theory focuses on two key receptors: 5-HT1A and 5-HT2A. It suggests that 5-HT1A promotes 'passive coping' (stoicism, bearing stress), while 5-HT2A promotes 'active coping' (increasing brain plasticity to find new solutions). The author finds the theory plausible and explains how it accounts for various effects of antidepressants and psychedelics. However, he also points out some remaining questions and potential biases in the theory. The post combines a detailed explanation of the theory with critical analysis and broader reflections on brain function and drug effects. Shorter summary

Scott Alexander critically examines pharmacogenomic testing for antidepressants, particularly the GeneSight test, expressing skepticism about its current effectiveness and validity. Longer summary

Scott Alexander critically examines the field of pharmacogenomics for antidepressants, particularly focusing on the GeneSight test. He reviews the scientific evidence, discusses potential flaws in studies, and expresses skepticism about the current state and effectiveness of such testing. The post delves into the complexities of antidepressant metabolism, the challenges of predicting drug response, and the limitations of current genetic testing approaches. Shorter summary

Scott Alexander defends his stance on the 'chemical imbalance' theory of depression, arguing that Mad In America's critique actually supports his view of a more nuanced understanding in psychiatry. Longer summary

Scott Alexander responds to a critique of his previous post about the 'chemical imbalance' theory of depression by Mad In America. He argues that the critique misses his point and actually supports his thesis. Scott analyzes each example provided by Mad In America, showing how they generally present a nuanced view of depression and serotonin's role, rather than promoting a simplistic 'serotonin deficiency' model. He criticizes Mad In America for quoting out of context and misrepresenting the sources. Scott concludes that while the 'chemical imbalance' theory has been simplified in public discourse, the psychiatric community has generally been responsible in presenting the complexities and uncertainties of depression's causes and treatments. Shorter summary

Scott Alexander defends psychiatry's use of 'chemical imbalance' theory, arguing it was meant to emphasize depression's biological basis rather than claiming a simple serotonin deficiency. Longer summary

Scott Alexander responds to criticisms of psychiatry's use of the 'chemical imbalance' theory of depression. He argues that psychiatrists never claimed depression was simply a serotonin deficiency, but rather a complex interaction of brain chemicals. He explains that the term 'chemical imbalance' was used to emphasize depression's biological basis and help people take it seriously, rather than viewing it as a personal failure. Scott provides evidence that serotonin and other neurotransmitters are indeed involved in depression, while acknowledging the full picture is more complicated. He concludes that framing depression in terms of brain chemistry remains useful, even if 'chemical imbalance' is no longer the best terminology. Shorter summary