A review of David Foster Wallace's 'The Pale King', examining its themes, the author's style and personal struggles, and the reviewer's evolving perspective on Wallace's work and legacy. Longer summary

This book review discusses David Foster Wallace's unfinished novel 'The Pale King', focusing on its themes, Wallace's writing style, and his personal struggles. The review explores Wallace's attempt to transcend postmodernism, his critique of consumer culture, and his vision for a more sincere and morally engaged society. It also delves into Wallace's mental health issues, his suicide, and the posthumous controversy surrounding his personal life. The reviewer reflects on their own journey with Wallace's work, from initial admiration to eventual disillusionment, while still acknowledging the value and limitations of his literary contributions. Shorter summary

The post challenges the notion that effect sizes below 0.50 for medications are clinically insignificant, using antidepressants as a case study and comparing them to other common drugs. Longer summary

This post discusses the interpretation of effect sizes in medical studies, particularly for antidepressants. It challenges the common notion that effect sizes below 0.50 are clinically insignificant. The author presents a Danish study that simulates various hypothetical medications, showing that even drugs that cure or significantly improve depression in a large percentage of patients might not meet traditional effect size thresholds. The post explains why these thresholds might be unrealistic due to factors like the placebo effect, high standard deviations in placebo groups, and patient dropouts. It also compares antidepressant effect sizes to those of other widely accepted medications, concluding that many common drugs would be considered 'clinically insignificant' by strict effect size standards. The author suggests that claims about 'meaningless effect sizes' should be given less weight compared to other evidence, such as clinical experience. 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 Alexander investigates the optimal dosage of Lexapro, comparing it to other antidepressants and exploring the reasons behind its effectiveness at lower doses. Longer summary

Scott Alexander explores the question of the right dose for Lexapro (escitalopram), an antidepressant. He examines official recommendations, compares Lexapro to other SSRIs, and investigates why Lexapro might be effective at lower doses. The post delves into studies on antidepressant dosing, the unique properties of Lexapro, and the potential benefits and risks of higher doses. Scott concludes that while there's no strong evidence for high doses of any antidepressant being more effective, prescribing higher doses of Lexapro might be as safe as other SSRIs and potentially more beneficial in some cases. 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 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 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 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 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 critically examines a major meta-analysis on antidepressant efficacy, noting potential biases and comparing its surprising drug rankings to his own previous analysis. Longer summary

This post reviews a major meta-analysis by Cipriani et al on the efficacy of antidepressants. The study claims to definitively show antidepressants work, but Scott notes it doesn't actually refute previous critiques about their effectiveness. He examines potential biases and methodological issues in the study, particularly around industry funding of trials. Scott also discusses the study's ranking of different antidepressants, noting some matches with conventional wisdom but also some surprising results. He compares these rankings to his own previous analysis, finding major discrepancies, and concludes by urging some caution in interpreting the study's results despite its impressive scope. 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

Scott Alexander examines the synapse hypothesis of depression, which links decreased synaptogenesis to various depression research findings, and raises questions for future investigation. Longer summary

This post explores the synapse hypothesis of depression, which proposes that decreased synaptogenesis, regulated by the protein complex mTORC1, may be the underlying cause of depression. Scott Alexander reviews various lines of research on depression, including life adversity, inflammation, serotonin, glutamate, folate, and electroconvulsive therapy, and shows how the synapse hypothesis could potentially unify these diverse findings. He then expresses some skepticism about the theory, noting that it's easy to find connections between any proposed cause and various symptoms. The post concludes with six questions or areas of confusion that the author hopes will be addressed in future research, including why decreased synaptogenesis should cause depression specifically, why BDNF can't be used as a direct treatment, and how bipolar disorder fits into this framework. 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 explores the complexities and inconsistencies of drug tolerance in psychiatry, highlighting how different drugs can produce varying tolerance effects across individuals. Longer summary

Scott Alexander discusses the complex and often unpredictable nature of drug tolerance in psychiatry. He explores various examples of how different drugs can lead to tolerance, no tolerance, or even reverse tolerance (increased sensitivity) in different individuals. The post highlights the inconsistencies in how tolerance develops across various drugs and patients, and how this impacts psychiatric treatment. Scott expresses frustration with the lack of attention given to tolerance in psychiatric literature and the difficulty in predicting or explaining tolerance patterns. He also touches on how this unpredictability relates to addiction, the potential for missed opportunities in drug development, and the need for better understanding of tolerance mechanisms. Shorter summary

Scott examines new research on ketamine's antidepressant effects and its implications for understanding depression and evaluating psychiatric literature. Longer summary

This post discusses new research on ketamine's antidepressant effects, which suggests they are caused by a metabolite rather than ketamine itself. The author examines how this finding impacts previous research and understanding of ketamine's mechanism of action. He reviews studies on NMDA antagonists and finds mixed results, with some potential bias when conflicts of interest are present. The post concludes by reflecting on the implications for trusting psychiatric literature, especially in cases with conflicts of interest. Shorter summary

Scott Alexander analyzes online drug ratings, finding patients prefer older antidepressants while doctors prefer newer ones, and explores potential explanations for this paradox. Longer summary

Scott Alexander analyzes patient ratings of antidepressants from online databases, finding that older drugs like MAOIs are rated higher than newer ones. He then compares this to doctor ratings, discovering a negative correlation between patient and doctor preferences. The post explores possible explanations for these paradoxical results, including confounding factors and the hypothesis that newer antidepressants may actually be less effective. Scott extends the analysis to other drug classes, finding the negative doctor-patient correlation holds broadly, while the preference for older drugs is specific to psychiatric medications. 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

Scott Alexander explains how psychiatric conditions like ADHD can be both over- and underdiagnosed simultaneously, due to statistical quirks in diagnosis and population prevalence. Longer summary

Scott Alexander discusses the counterintuitive phenomenon of simultaneous over- and underdiagnosis in psychiatry, using ADHD as an example. He explains how, even with a highly accurate psychiatrist, it's possible for the majority of people diagnosed with a condition to not have it, while the majority of people who actually have the condition remain undiagnosed. This is due to the interplay between disease prevalence, self-selection for evaluation, and the inherent limitations of diagnostic accuracy. The post demonstrates this concept using a hypothetical scenario with ADHD, and then suggests that this phenomenon likely applies to other conditions such as depression and pain medication prescriptions. Shorter summary

Scott analyzes various criticisms of antidepressants, concluding they have modest but real benefits over placebo, with important considerations about side effects and efficacy. Longer summary

This post examines various criticisms of SSRIs and antidepressants, addressing claims about their efficacy, side effects, and comparisons to placebo and psychotherapy. Scott analyzes studies on antidepressant effectiveness, discussing issues like publication bias, effect sizes, and the meaning of 'clinical significance'. He explores side effects, particularly sexual dysfunction, weight gain, and emotional blunting. The post concludes that while antidepressants are not miracle drugs, they do have a modest but statistically significant benefit over placebo and can be a reasonable option for many people with depression, especially if they understand and prepare for potential side effects. Shorter summary

Scott explores the fascinating etymology of 'placebo' from medieval funerals to medicine, then discusses the controversial placebo effect in depression treatment. Longer summary

This post explores the etymology of the word 'placebo' and its journey from funeral rites to medical terminology. Scott starts by debunking the common medical school explanation and delves into its medieval origins as part of funeral rites. He then discusses various theories on how it became an insult and eventually a medical term. The post then shifts to discussing the placebo effect in depression treatment, highlighting the controversy surrounding its effectiveness and the importance of understanding its true nature for patient care. Shorter summary

Scott Alexander offers a comprehensive guide for treating depression, covering professional help, lifestyle changes, and supplements, emphasizing the importance of persistence in finding effective treatments. Longer summary

Scott Alexander provides a comprehensive guide for people with depression, covering diagnosis, treatment options, and self-help strategies. He starts by explaining how to determine if one has depression and strongly recommends seeing a doctor or psychiatrist. He then outlines a step-by-step treatment algorithm for doctors to follow, including various medications and therapies. The post also covers lifestyle interventions, supplements, and other strategies for those who can't or won't see a doctor. Scott emphasizes the importance of persistence in finding effective treatments and reassures readers that depression is often treatable with sufficient effort. Shorter summary