Scott Alexander proposes a theory of depression as a recalibrated happiness set point, drawing parallels with fever and anorexia, to explain why depressed people seek out sad stimuli. Longer summary

Scott Alexander explores the puzzling behavior of depressed people preferring sad music, despite it making them feel worse. He proposes a theory based on control theory and set points, comparing depression to conditions like fever and anorexia. The post suggests that depression might involve a recalibrated happiness set point, where the body defends an abnormally low mood through both biological and behavioral mechanisms. Scott also discusses potential research directions and connects this theory to predictive coding concepts. Shorter summary

Scott Alexander examines a study challenging ketamine's effectiveness as an antidepressant, discussing potential confounding factors and maintaining his belief in ketamine's utility despite the study's results. Longer summary

Scott Alexander discusses a recent study on ketamine's effectiveness as an antidepressant when administered during anesthesia. The study found no significant difference between ketamine and placebo groups, challenging previous beliefs about ketamine's antidepressant properties. Scott analyzes the study's methodology and results, pointing out several factors that might have influenced the outcomes, such as the strong placebo effect, the antidepressant properties of anesthetics, and the potential impact of surgery on depression symptoms. He concludes that while the study raises questions, it doesn't completely invalidate previous research showing ketamine's effectiveness, and he maintains his belief in ketamine's potential as an antidepressant for some patients. Shorter summary

Scott Alexander provides a comprehensive guide on ketamine as a depression treatment, covering administration methods, effectiveness, safety, dosage, and potential side effects. Longer summary

This post is a comprehensive guide on ketamine as a treatment for depression, covering various aspects such as methods of administration, effectiveness, safety, dosage, and potential side effects. Scott Alexander explains the differences between IV ketamine, esketamine (Spravato), and oral/intranasal ketamine, discussing their relative costs and accessibility. He also delves into ketamine-assisted psychotherapy, the duration of ketamine's effects, and current theories on how it works. The post is written in a FAQ format, aiming to provide thorough and evidence-based information while acknowledging areas of uncertainty in the research. Shorter summary

Scott Alexander reviews 'Crazy Like Us', exploring how Western mental health concepts spread globally and whether raising awareness of mental health problems might make them worse. Longer summary

Scott Alexander reviews 'Crazy Like Us' by Ethan Watters, which explores how Western mental health concepts are spreading globally. The book presents case studies on anorexia in Hong Kong, depression in Japan, PTSD in Sri Lanka, and schizophrenia in Zanzibar. While Scott finds the book's main thesis only moderately interesting, he's intrigued by a recurring sub-theme: whether raising awareness of mental health problems might actually make them worse. He discusses each case study, offering his own insights and critiques, and concludes by imagining a culture that runs 'Mental Health Unawareness Campaigns'. Shorter summary

Scott Alexander examines a review of a paper on serotonin receptors, discussing prediction error, suffering, and the effects of different serotonin receptor activations on problem-solving approaches and psychedelic experiences. Longer summary

Scott Alexander reviews George from CerebraLab's analysis of a paper by Nutt and Carhart-Harris on serotonin receptors. The post explores two main points: the relationship between prediction error and suffering in the context of active inference theory, and the different effects of 5-HT1A and 5-HT2A receptor activation. Scott discusses how these concepts relate to depression, psychedelics, and problem-solving approaches. He also considers George's suggestion that using psychedelics for introspection might be more harmful than using them for fun or practical problem-solving. Shorter summary

Scott Alexander presents a detailed guide on depression, covering its causes, symptoms, and various treatment options, including lifestyle changes, therapies, medications, and other interventions. Longer summary

Scott Alexander provides a comprehensive guide on depression, covering its causes, symptoms, and various treatment options. He discusses lifestyle changes, therapies, medications, supplements, and other interventions like TMS and ECT. The post offers practical advice on how to approach treatment, including specific regimens for different situations, and guidelines on how long to continue treatment once it starts working. Shorter summary

Scott examines the relationship between sleep, synaptic homeostasis, and depression, exploring how sleep deprivation temporarily alleviates depression symptoms. Longer summary

Scott Alexander discusses a phenomenon where sleep deprivation temporarily alleviates depression, and explores the potential connection between sleep, synaptic homeostasis, and depression. He reviews the synaptic homeostasis hypothesis of sleep, which suggests that sleep helps renormalize synaptic connections, and connects this to research indicating that depression involves a deficit of synapses. The post then delves into various subtopics related to this theory, including the roles of REM and non-REM sleep, the effects of TMS and electroconvulsive therapy, and potential connections to circadian rhythms and bipolar disorder. Shorter summary

Scott Alexander critically examines a new theory on antidepressant mechanisms, expressing skepticism while acknowledging its potential significance if proven true. Longer summary

Scott Alexander reviews a recent study proposing a new theory for how antidepressants work, which suggests they bind directly to TrkB receptors rather than acting through serotonin. He explains the study's findings and their potential implications, but expresses skepticism about the theory. Scott outlines several reasons why he finds the new theory unconvincing, including existing evidence supporting the serotonin hypothesis, issues with the study's claims about drug accumulation, and expert opinions on the difficulties of TrkB research. He concludes by stating he will stick with the conventional theory for now, while remaining open to future developments. Shorter summary

Scott Alexander examines a theory proposing that depression, anxiety, and trauma are characterized by low precision of sensory evidence, leading to overreliance on negative priors. Longer summary

Scott Alexander discusses a paper by Van der Bergh et al. that proposes a unified theory of negative emotionality, including depression, anxiety, and trauma. The theory suggests that these conditions are characterized by a processing style that assigns unusually low precision to sensory evidence, leading to an overreliance on negative priors. Scott explores the implications of this theory, including its support for various psychotherapies, somatic therapies, and meditation. He also discusses potential pharmacological interventions and how this model ties together various concepts in psychiatry and predictive processing. Shorter summary

Scott Alexander examines mental disorders through the lens of dynamical systems theory, exploring how this perspective complements and contrasts with taxometric approaches. Longer summary

Scott Alexander explores the concept of mental disorders as dynamical systems with attractor states, contrasting this with the taxometric approach. He uses examples like Alice's health insurance situation and Bob's depression to illustrate how complex systems can have stable states that attract nearby unstable situations. The post discusses how this perspective can help understand the nature of depression and other mental disorders, showing how they can be both dimensional and categorical. Scott also draws parallels between the complexity of mental disorders and the global economy, emphasizing the intricate interconnections and the difficulty of predicting outcomes or effective interventions. Shorter summary

Scott examines the bidirectional relationship between depression and sense of smell, exploring potential mechanisms and treatment implications. Longer summary

This post discusses the relationship between depression and olfactory function. It reviews studies showing that depressed people have a worse sense of smell, and people with impaired smell are more likely to be depressed. The post explores potential reasons for this connection, including depression's general effect on sensory acuity and the unique emotional salience of smell. It also discusses implications for depression treatment, including the effects of antidepressants on smell and potential olfactory-based therapies. The tone is analytical and somewhat humorous, with Scott critically examining various studies and hypotheses. Shorter summary

Scott Alexander analyzes the PANDA Study, a large real-world antidepressant trial, discussing its methodology, results, and implications for understanding antidepressant efficacy. Longer summary

This post discusses the PANDA (Prescribing ANtiDepressants Appropriately) Study, the largest non-pharma antidepressant trial ever conducted. The study aimed to measure the real-world efficacy of antidepressants, specifically sertraline, in a naturalistic setting. Scott Alexander analyzes the results, which show small to low-medium effect sizes for various depression and anxiety measures. He notes that while the effects are modest, they are not clinically insignificant. The study found that patient-reported improvement had a higher effect size than researcher-measured tests, potentially indicating a disconnect between clinical measures and patient experiences. Scott discusses the implications of these findings for antidepressant efficacy and suggests that targeted treatment approaches might yield better results. Shorter summary

Scott Alexander argues that psychiatric diagnoses, while imperfect, are useful tools despite potentially combining multiple conditions with different causes. Longer summary

Scott Alexander discusses the criticism that psychiatric conditions like autism or depression are not unitary categories but rather collections of different conditions with different causes. He argues that this view, while correct, is not as revolutionary as some think and doesn't invalidate the usefulness of these diagnoses. Scott compares psychiatric conditions to medical conditions like pulmonary edema or stroke, which can have multiple causes but are still useful diagnostic categories. He suggests that psychiatric disorders might ultimately be understood as computational conditions, with various biological, psychological, and environmental factors affecting the brain's computational parameters. The post emphasizes that while research into subtypes of conditions like depression hasn't been very productive, current psychiatric diagnoses remain the most useful tool available, despite their limitations. Shorter summary

Scott examines how the 5-HTTLPR gene was wrongly linked to depression for years, discussing the implications for psychiatric research and genetic testing products. Longer summary

This post discusses the history and eventual debunking of the 5-HTTLPR gene's supposed role in depression. Initially, numerous studies claimed to find links between 5-HTTLPR and various mental health conditions, interactions with stress, and even antidepressant efficacy. However, a recent large-scale study by Border et al. found no evidence for these claims, suggesting that hundreds of previous studies were likely false positives. The post explores the implications of this finding, including concerns about the reliability of psychiatric research, the tendency for studies to reinforce existing beliefs, and the questionable validity of pharmacogenomic testing products that rely on genes like 5-HTTLPR. Shorter summary

Scott Alexander presents results from an SSC Survey on SSRI usage, covering effectiveness, side effects, and discontinuation experiences among 2,090 users. Longer summary

Scott Alexander presents the results of an SSC Survey on SSRI usage, covering their effectiveness, side effects, and discontinuation experiences. The survey included 2,090 SSRI users and explored various aspects of SSRI use. Key findings include: most users found SSRIs helpful, with Lexapro rated highest and Paxil lowest; SSRIs seemed more effective for anxiety than depression; 70% of users experienced side effects, with sexual difficulties being most common; 15% reported persistent side effects after discontinuation; and discontinuation difficulty varied among different SSRIs, with Prozac being easiest to discontinue. The survey largely confirmed existing psychiatric consensus, with the high rate of persistent side effects being the main surprise. Shorter summary

Scott Alexander discusses new research suggesting ketamine's antidepressant effects may be linked to the opioid system, exploring the implications and potential future directions for depression treatment. Longer summary

Scott Alexander provides an update on ketamine research, discussing a new study that suggests ketamine's antidepressant effects may be related to the opioid system rather than NMDA receptors as previously thought. He compares this to a study on buprenorphine's effects on suicidal ideation and explores the implications of these findings. The post touches on the medical establishment's response, potential future directions for research and treatment, and the historical context of opiate use in medicine. Scott also raises questions about the relationship between opiates and depression, and the potential risks and benefits of using opioid-related treatments for depression. Shorter summary

Scott Alexander revisits his stance on SSRIs, discussing new meta-analyses, broader trends in psychiatric medication efficacy, and potential explanations for the discrepancy between statistical and clinical observations. Longer summary

Scott Alexander updates his views on SSRIs, addressing four key points: 1) A meta-analysis confirming the effect size of antidepressants is about 0.3. 2) The low effect size of SSRIs is part of a broader trend of low effect sizes in psychiatric medications. 3) A hypothesis to reconcile the small statistical effect with strong clinical observations, suggesting SSRIs might work very well for a subset of patients. 4) The possibility that SSRIs' efficacy for anxiety might contribute to their perceived effectiveness for depression. Shorter summary

Scott Alexander uses the evolution of genetic science as a metaphor to explore how other fields might benefit from recognizing the polycausal nature of complex phenomena. Longer summary

Scott Alexander discusses the evolution of genetic science, from the search for single genes responsible for complex traits to the current understanding that almost all genes contribute to these traits. He uses this as a metaphor for other sciences, particularly psychiatry, suggesting that many fields may be more polycausal than initially thought. The post explores the implications of this shift, including skepticism about personalized medicine and the potential need for new approaches to scientific research that can handle massive numbers of interacting causes. Scott concludes by imagining a hypothetical alien society where science is centered around polycausal scores, presenting this as a thought experiment for what science could aspire to be. Shorter summary

Scott Alexander examines melatonin's effects, proper dosage, and uses for sleep disorders and circadian rhythm issues, emphasizing its dual role as a hypnotic and chronobiotic. Longer summary

Scott Alexander provides an in-depth analysis of melatonin, its effects, and proper usage. He explains that melatonin functions as both a hypnotic (inducing sleep) and a chronobiotic (shifting circadian rhythms). The post covers optimal dosing (0.3 mg, much lower than commonly available doses), use in treating circadian rhythm disorders, jet lag, and potential connections to other psychiatric conditions like seasonal affective disorder and depression. Scott also discusses personal experiences with melatonin, including its tendency to cause early waking and vivid dreams in some people. Shorter summary

Scott Alexander examines whether psychiatrists should test for lead more often, concluding that while it could be relevant in some cases, there's not enough evidence to justify universal testing. Longer summary

Scott Alexander discusses the question of whether psychiatrists should test for lead more often in patients with mental health issues. He presents a case where lead poisoning was found to be a factor in a patient's psychiatric symptoms, and explores the broader implications of this. Scott then examines the complexities of deciding which potential factors to test for in psychiatric practice, given the numerous possible causes of depression and other mental health issues. He argues that while lead could be a factor in some cases, there's insufficient evidence to justify universal testing. He also discusses the challenges of interpreting and acting on test results, especially when they fall within normal ranges. Scott concludes by reflecting on different approaches to medical practice and the difficulties of balancing evidence-based guidelines with emerging theories and individual clinical judgment. Shorter summary

The post reviews research on adult neurogenesis, initially presenting evidence for its existence and importance, then reveals a new study suggesting it doesn't occur in humans, examining the implications of this potential field-wide error. Longer summary

This post reviews the literature on adult neurogenesis, initially presenting numerous studies that claimed to find evidence for the generation of new neurons in adult human brains. These studies linked adult neurogenesis to various aspects of brain function, including memory, learning, and depression. However, the post then reveals a new study suggesting that adult neurogenesis doesn't actually occur in humans, or is so rare as to be insignificant. The author examines how this field-wide error could have occurred, discussing the extrapolation of rat studies to humans and the role of confirmation bias. The post ends by reflecting on the implications of this for scientific research and the replication crisis. 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

The post examines research suggesting placebos are largely ineffective, explores exceptions, and proposes explanations for observed placebo effects based on brain function and study design. Longer summary

This post discusses the placebo effect, focusing on Hróbjartsson and Gøtzsche's research which found that placebos have little benefit over no treatment in most conditions. The author explores the reasons behind this, suggesting that regression to the mean may have been mistaken for placebo effects in earlier studies. The post also discusses exceptions where placebos seem more effective, such as pain and nausea, and offers a potential explanation for the placebo effect based on the brain's predictive processing model. The author concludes by speculating on why depression might not show strong placebo effects in clinical trials despite common assumptions. Shorter summary

Scott Alexander examines the rise, fall, and alleged resurrection of the antidepressant NSI-189, expressing skepticism about its efficacy and the broader challenges in developing new antidepressants. Longer summary

Scott Alexander discusses the disappointing results of NSI-189, a promising new antidepressant, in FDA trials. He explains how the drug initially failed to outperform placebo on the primary endpoint, leading to a stock crash for Neuralstem. However, the company later released positive secondary endpoint results, causing their stock to rise again. Scott expresses skepticism about these new results, suggesting they may be due to statistical manipulation rather than true efficacy. He reflects on the challenges of developing new antidepressants and the tendency to get overly excited about new drugs, ending with a sardonic hope for another new antidepressant, SAGE-217. 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