Pharmacogenomic Clinical Support Tools for the Treatment of Depression.

OBJECTIVE: In this review, the authors update the 2018 position statement of the American Psychiatric Association Council of Research Workgroup on Biomarkers and Novel Treatments on pharmacogenomic (PGx) tools for treatment selection in depression. METHODS: The literature was reviewed for new clinical trials and meta-analyses, published from 2017 to 2022, of studies using PGx tools for treatment selection in depression. The blinding and control conditions, as well as primary and secondary outcomes and post hoc analyses, were summarized. RESULTS: Eleven new clinical trials and five meta-analyses were identified; all studies had primary outcome measures related to speed or efficacy of treatment response. Three trials (27%) demonstrated efficacy on the primary outcome measure with statistical significance; the three studies used different PGx tools; one study was open-label and the other two were small single-blind trials. Five trials (45%) did not detect efficacy with statistical significance on either primary or secondary outcome measures. Only one trial (9%) used adverse events as a primary outcome measure. All studies had significant limitations; for example, none adopted a fully blinded study design, only two studies attempted to blind the treating clinician, and none incorporated measures to estimate the effectiveness of the blinds or the influence of lack of blinding on the study results. CONCLUSIONS: The addition of these new data do not alter the recommendations of the 2018 report, or the advice of the U.S. Food and Drug Administration, that the evidence does not support the use of currently available combinatorial PGx tools for treatment selection in major depressive disorder. Priority efforts for future studies and the development and testing of effective tools include fully blinded study designs, inclusion of promising genetic variants not currently included in any commercially available tests, and investigation of other uses of pharmacogenomics, such as estimating the likelihood of rare adverse drug effects, rather than increasing the speed or magnitude of drug response.

CSMD1 regulates brain complement activity and circuit development.

Complement proteins facilitate synaptic elimination during neurodevelopmental pruning, but neural complement regulation is not well understood. CUB and Sushi Multiple Domains 1 (CSMD1) can regulate complement activity in vitro, is expressed in the brain, and is associated with increased schizophrenia risk. Beyond this, little is known about CSMD1 including whether it regulates complement activity in the brain or otherwise plays a role in neurodevelopment. We used biochemical, immunohistochemical, and proteomic techniques to examine the regional, cellular, and subcellular distribution as well as protein interactions of CSMD1 in the brain. To evaluate whether CSMD1 is involved in complement-mediated synapse elimination, we examined Csmd1-knockout mice and CSMD1-knockout human stem cell-derived neurons. We interrogated synapse and circuit development of the mouse visual thalamus, a process that involves complement pathway activity. We also quantified complement deposition on synapses in mouse visual thalamus and on cultured human neurons. Finally, we assessed uptake of synaptosomes by cultured microglia. We found that CSMD1 is present at synapses and interacts with complement proteins in the brain. Mice lacking Csmd1 displayed increased levels of complement component C3, an increased colocalization of C3 with presynaptic terminals, fewer retinogeniculate synapses, and aberrant segregation of eye-specific retinal inputs to the visual thalamus during the critical period of complement-dependent refinement of this circuit. Loss of CSMD1 in vivo enhanced synaptosome engulfment by microglia in vitro, and this effect was dependent on activity of the microglial complement receptor, CR3. Finally, human stem cell-derived neurons lacking CSMD1 were more vulnerable to complement deposition. These data suggest that CSMD1 can function as a regulator of complement-mediated synapse elimination in the brain during development.

Cognitive Symptoms of Post-COVID-19 Condition and Daily Functioning.

Importance: The frequent occurrence of cognitive symptoms in post-COVID-19 condition has been described, but the nature of these symptoms and their demographic and functional factors are not well characterized in generalizable populations. Objective: To investigate the prevalence of self-reported cognitive symptoms in post-COVID-19 condition, in comparison with individuals with prior acute SARS-CoV-2 infection who did not develop post-COVID-19 condition, and their association with other individual features, including depressive symptoms and functional status. Design, Setting, and Participants: Two waves of a 50-state nonprobability population-based internet survey conducted between December 22, 2022, and May 5, 2023. Participants included survey respondents aged 18 years and older. Exposure: Post-COVID-19 condition, defined as self-report of symptoms attributed to COVID-19 beyond 2 months after the initial month of illness. Main Outcomes and Measures: Seven items from the Neuro-QoL cognition battery assessing the frequency of cognitive symptoms in the past week and patient Health Questionnaire-9. Results: The 14 767 individuals reporting test-confirmed COVID-19 illness at least 2 months before the survey had a mean (SD) age of 44.6 (16.3) years; 568 (3.8%) were Asian, 1484 (10.0%) were Black, 1408 (9.5%) were Hispanic, and 10 811 (73.2%) were White. A total of 10 037 respondents (68.0%) were women and 4730 (32.0%) were men. Of the 1683 individuals reporting post-COVID-19 condition, 955 (56.7%) reported at least 1 cognitive symptom experienced daily, compared with 3552 of 13 084 (27.1%) of those who did not report post-COVID-19 condition. More daily cognitive symptoms were associated with a greater likelihood of reporting at least moderate interference with functioning (unadjusted odds ratio [OR], 1.31 [95% CI, 1.25-1.36]; adjusted [AOR], 1.30 [95% CI, 1.25-1.36]), lesser likelihood of full-time employment (unadjusted OR, 0.95 [95% CI, 0.91-0.99]; AOR, 0.92 [95% CI, 0.88-0.96]) and greater severity of depressive symptoms (unadjusted coefficient, 1.40 [95% CI, 1.29-1.51]; adjusted coefficient 1.27 [95% CI, 1.17-1.38). After including depressive symptoms in regression models, associations were also found between cognitive symptoms and at least moderate interference with everyday functioning (AOR, 1.27 [95% CI, 1.21-1.33]) and between cognitive symptoms and lower odds of full-time employment (AOR, 0.92 [95% CI, 0.88-0.97]). Conclusions and Relevance: The findings of this survey study of US adults suggest that cognitive symptoms are common among individuals with post-COVID-19 condition and associated with greater self-reported functional impairment, lesser likelihood of full-time employment, and greater depressive symptom severity. Screening for and addressing cognitive symptoms is an important component of the public health response to post-COVID-19 condition.

Returning Individual Research Results from Digital Phenotyping in Psychiatry.

Psychiatry is rapidly adopting digital phenotyping and artificial intelligence/machine learning tools to study mental illness based on tracking participants' locations, online activity, phone and text message usage, heart rate, sleep, physical activity, and more. Existing ethical frameworks for return of individual research results (IRRs) are inadequate to guide researchers for when, if, and how to return this unprecedented number of potentially sensitive results about each participant's real-world behavior. To address this gap, we convened an interdisciplinary expert working group, supported by a National Institute of Mental Health grant. Building on established guidelines and the emerging norm of returning results in participant-centered research, we present a novel framework specific to the ethical, legal, and social implications of returning IRRs in digital phenotyping research. Our framework offers researchers, clinicians, and Institutional Review Boards (IRBs) urgently needed guidance, and the principles developed here in the context of psychiatry will be readily adaptable to other therapeutic areas.

Community Mobility and Depressive Symptoms During the COVID-19 Pandemic in the United States.

Importance: Marked elevation in levels of depressive symptoms compared with historical norms have been described during the COVID-19 pandemic, and understanding the extent to which these are associated with diminished in-person social interaction could inform public health planning for future pandemics or other disasters. Objective: To describe the association between living in a US county with diminished mobility during the COVID-19 pandemic and self-reported depressive symptoms, while accounting for potential local and state-level confounding factors. Design, Setting, and Participants: This survey study used 18 waves of a nonprobability internet survey conducted in the United States between May 2020 and April 2022. Participants included respondents who were 18 years and older and lived in 1 of the 50 US states or Washington DC. Main Outcome and Measure: Depressive symptoms measured by the Patient Health Questionnaire-9 (PHQ-9); county-level community mobility estimates from mobile apps; COVID-19 policies at the US state level from the Oxford stringency index. Results: The 192 271 survey respondents had a mean (SD) of age 43.1 (16.5) years, and 768 (0.4%) were American Indian or Alaska Native individuals, 11 448 (6.0%) were Asian individuals, 20 277 (10.5%) were Black individuals, 15 036 (7.8%) were Hispanic individuals, 1975 (1.0%) were Pacific Islander individuals, 138 702 (72.1%) were White individuals, and 4065 (2.1%) were individuals of another race. Additionally, 126 381 respondents (65.7%) identified as female and 65 890 (34.3%) as male. Mean (SD) depression severity by PHQ-9 was 7.2 (6.8). In a mixed-effects linear regression model, the mean county-level proportion of individuals not leaving home was associated with a greater level of depression symptoms (ß, 2.58; 95% CI, 1.57-3.58) after adjustment for individual sociodemographic features. Results were similar after the inclusion in regression models of local COVID-19 activity, weather, and county-level economic features, and persisted after widespread availability of COVID-19 vaccination. They were attenuated by the inclusion of state-level pandemic restrictions. Two restrictions, mandatory mask-wearing in public (ß, 0.23; 95% CI, 0.15-0.30) and policies cancelling public events (ß, 0.37; 95% CI, 0.22-0.51), demonstrated modest independent associations with depressive symptom severity. Conclusions and Relevance: In this study, depressive symptoms were greater in locales and times with diminished community mobility. Strategies to understand the potential public health consequences of pandemic responses are needed.

Media use and vaccine resistance.

Public health requires collective action-the public best addresses health crises when individuals engage in prosocial behaviors. Failure to do so can have dire societal and economic consequences. This was made clear by the disjointed, politicized response to COVID-19 in the United States. Perhaps no aspect of the pandemic exemplified this challenge more than the sizeable percentage of individuals who delayed or refused vaccination. While scholars, practitioners, and the government devised a range of communication strategies to persuade people to get vaccinated, much less attention has been paid to where the unvaccinated could be reached. We address this question using multiple waves of a large national survey as well as various secondary data sets. We find that the vaccine resistant seems to predictably obtain information from conservative media outlets (e.g. Fox News) while the vaccinated congregate around more liberal outlets (e.g. MSNBC). We also find consistent evidence that vaccine-resistant individuals often obtain COVID-19 information from various social media, most notably Facebook, rather than traditional media sources. Importantly, such individuals tend to exhibit low institutional trust. While our results do not suggest a failure of sites such as Facebook's institutional COVID-19 efforts, as the counterfactual of no efforts is unknown, they do highlight an opportunity to reach those who are less likely to take vital actions in the service of public health.

A 50-state survey study of thoughts of suicide and social isolation among older adults in the United States.

BACKGROUND: We aimed to characterize the prevalence of social disconnection and thoughts of suicide among older adults in the United States, and examine the association between them in a large naturalistic study. METHODS: We analyzed data from 6 waves of a fifty-state non-probability survey among US adults conducted between February and December 2021. The internet-based survey collected the PHQ-9, as well as multiple measures of social connectedness. We applied multiple logistic regression to analyze the association between presence of thoughts of suicide and social disconnection. Exploratory analysis, using generalized random forests, examined heterogeneity of effects across sociodemographic groups. RESULTS: Of 16,164 survey respondents age 65 and older, mean age was 70.9 (SD 5.0); the cohort was 61.4 % female and 29.6 % male; 2.0 % Asian, 6.7 % Black, 2.2 % Hispanic, and 86.8 % White. A total of 1144 (7.1 %) reported thoughts of suicide at least several days in the prior 2 week period. In models adjusted for sociodemographic features, households with 3 or more additional members (adjusted OR 1.73, 95 % CI 1.28-2.33) and lack of social supports, particularly emotional supports (adjusted OR 2.60, 95 % CI 2.09-3.23), were independently associated with greater likelihood of reporting such thoughts, as was greater reported loneliness (adjusted OR 1.75, 95 % CI 1.64-1.87). The effects of emotional support varied significantly across sociodemographic groups. CONCLUSIONS: Thoughts of suicide are common among older adults in the US, and associated with lack of social support, but not with living alone. TRIAL REGISTRATION: NA.

Incidental Findings from Deep Phenotyping Research in Psychiatry: Legal and Ethical Considerations.

Substantial advancement in the diagnosis and treatment of psychiatric disorders may come from assembling diverse data streams from clinical notes, neuroimaging, genetics, and real-time digital footprints from smartphones and wearable devices. This is called "deep phenotyping" and often involves machine learning. We argue that incidental findings arising in deep phenotyping research have certain special, morally and legally salient features: They are specific, actionable, numerous, and probabilistic. We consider ethical and legal implications of these features and propose a practical ethics strategy for managing them.

Prevalence and Correlates of Long COVID Symptoms Among US Adults.

Importance: Persistence of COVID-19 symptoms beyond 2 months, or long COVID, is increasingly recognized as a common sequela of acute infection. Objectives: To estimate the prevalence of and sociodemographic factors associated with long COVID and to identify whether the predominant variant at the time of infection and prior vaccination status are associated with differential risk. Design, Setting, and Participants: This cross-sectional study comprised 8 waves of a nonprobability internet survey conducted between February 5, 2021, and July 6, 2022, among individuals aged 18 years or older, inclusive of all 50 states and the District of Columbia. Main Outcomes and Measures: Long COVID, defined as reporting continued COVID-19 symptoms beyond 2 months after the initial month of symptoms, among individuals with self-reported positive results of a polymerase chain reaction test or antigen test. Results: The 16 091 survey respondents reporting test-confirmed COVID-19 illness at least 2 months prior had a mean age of 40.5 (15.2) years; 10 075 (62.6%) were women, and 6016 (37.4%) were men; 817 (5.1%) were Asian, 1826 (11.3%) were Black, 1546 (9.6%) were Hispanic, and 11 425 (71.0%) were White. From this cohort, 2359 individuals (14.7%) reported continued COVID-19 symptoms more than 2 months after acute illness. Reweighted to reflect national sociodemographic distributions, these individuals represented 13.9% of those who had tested positive for COVID-19, or 1.7% of US adults. In logistic regression models, older age per decade above 40 years (adjusted odds ratio [OR], 1.15; 95% CI, 1.12-1.19) and female gender (adjusted OR, 1.91; 95% CI, 1.73-2.13) were associated with greater risk of persistence of long COVID; individuals with a graduate education vs high school or less (adjusted OR, 0.67; 95% CI, 0.56-0.79) and urban vs rural residence (adjusted OR, 0.74; 95% CI, 0.64-0.86) were less likely to report persistence of long COVID. Compared with ancestral COVID-19, infection during periods when the Epsilon variant (OR, 0.81; 95% CI, 0.69-0.95) or the Omicron variant (OR, 0.77; 95% CI, 0.64-0.92) predominated in the US was associated with diminished likelihood of long COVID. Completion of the primary vaccine series prior to acute illness was associated with diminished risk for long COVID (OR, 0.72; 95% CI, 0.60-0.86). Conclusions and Relevance: This study suggests that long COVID is prevalent and associated with female gender and older age, while risk may be diminished by completion of primary vaccination series prior to infection.

Prevalence of Firearm Ownership Among Individuals With Major Depressive Symptoms.

Importance: Both major depression and firearm ownership are associated with an increased risk for death by suicide in the United States, but the extent of overlap among these major risk factors is not well characterized. Objective: To assess the prevalence of current and planned firearm ownership among individuals with depression. Design, Setting, and Participants: Cross-sectional survey study using data pooled from 2 waves of a 50-state nonprobability internet survey conducted between May and July 7, 2021. Internet survey respondents were 18 years of age or older and were sampled from all 50 US states and the District of Columbia. Main Outcomes and Measures: Self-reported firearm ownership; depressive symptoms as measured by the 9-item Patient Health Questionnaire. Results: Of 24 770 survey respondents (64.6% women and 35.4% men; 5.0% Asian, 10.8% Black, 7.5% Hispanic, and 74.0% White; mean [SD] age 45.8 [17.5]), 6929 (28.0%) reported moderate or greater depressive symptoms; this group had mean (SD) age of 38.18 (15.19) years, 4587 were female (66.2%), and 406 were Asian (5.9%), 725 were Black (10.5%), 652 were Hispanic (6.8%), and 4902 were White (70.7%). Of those with depression, 31.3% reported firearm ownership (n = 2167), of whom 35.9% (n = 777) reported purchasing a firearm within the past year. In regression models, the presence of moderate or greater depressive symptoms was not significantly associated with firearm ownership (adjusted odds ratio [OR], 1.07; 95% CI, 0.98-1.17) but was associated with greater likelihood of a first-time firearm purchase during the COVID-19 pandemic (adjusted OR, 1.77; 95% CI, 1.56-2.02) and greater likelihood of considering a future firearm purchase (adjusted OR, 1.53; 95% CI, 1.23-1.90). Conclusions and Relevance: In this study, current and planned firearm ownership was common among individuals with major depressive symptoms, suggesting a public health opportunity to address this conjunction of suicide risk factors.

Association of Major Depressive Symptoms With Endorsement of COVID-19 Vaccine Misinformation Among US Adults.

Importance: Misinformation about COVID-19 vaccination may contribute substantially to vaccine hesitancy and resistance. Objective: To determine if depressive symptoms are associated with greater likelihood of believing vaccine-related misinformation. Design, Setting, and Participants: This survey study analyzed responses from 2 waves of a 50-state nonprobability internet survey conducted between May and July 2021, in which depressive symptoms were measured using the Patient Health Questionnaire 9-item (PHQ-9). Survey respondents were aged 18 and older. Population-reweighted multiple logistic regression was used to examine the association between moderate or greater depressive symptoms and endorsement of at least 1 item of vaccine misinformation, adjusted for sociodemographic features. The association between depressive symptoms in May and June, and new support for misinformation in the following wave was also examined. Exposures: Depressive symptoms. Main Outcomes and Measures: The main outcome was endorsing any of 4 common vaccine-related statements of misinformation. Results: Among 15 464 survey respondents (9834 [63.6%] women and 5630 [36.4%] men; 722 Asian respondents [4.7%], 1494 Black respondents [9.7%], 1015 Hispanic respondents [6.6%], and 11 863 White respondents [76.7%]; mean [SD] age, 47.9 [17.5] years), 4164 respondents (26.9%) identified moderate or greater depressive symptoms on the PHQ-9, and 2964 respondents (19.2%) endorsed at least 1 vaccine-related statement of misinformation. Presence of depression was associated with increased likelihood of endorsing misinformation (crude odds ratio [OR], 2.33; 95% CI, 2.09-2.61; adjusted OR, 2.15; 95% CI, 1.91-2.43). Respondents endorsing at least 1 misinformation item were significantly less likely to be vaccinated (crude OR, 0.40; 95% CI, 0.36-0.45; adjusted OR, 0.45; 95% CI, 0.40-0.51) and more likely to report vaccine resistance (crude OR, 2.54; 95% CI, 2.21-2.91; adjusted OR, 2.68; 95% CI, 2.89-3.13). Among 2809 respondents who answered a subsequent survey in July, presence of depression in the first survey was associated with greater likelihood of endorsing more misinformation compared with the prior survey (crude OR, 1.98; 95% CI, 1.42-2.75; adjusted OR, 1.63; 95% CI, 1.14-2.33). Conclusions and Relevance: This survey study found that individuals with moderate or greater depressive symptoms were more likely to endorse vaccine-related misinformation, cross-sectionally and at a subsequent survey wave. While this study design cannot address causation, the association between depression and spread and impact of misinformation merits further investigation.

Association Between Social Media Use and Self-reported Symptoms of Depression in US Adults.

Importance: Some studies suggest that social media use is associated with risk for depression, particularly among children and young adults. Objective: To characterize the association between self-reported use of individual social media platforms and worsening of depressive symptoms among adults. Design, Setting, and Participants: This survey study included data from 13 waves of a nonprobability internet survey conducted approximately monthly between May 2020 and May 2021 among individuals aged 18 years and older in the US. Data were analyzed in July and August 2021. Main Outcomes and Measures: Logistic regression was applied without reweighting, with a 5 point or greater increase in 9-item Patient Health Questionnaire (PHQ-9) score as outcome and participant sociodemographic features, baseline PHQ-9, and use of each social media platform as independent variables. Results: In total, 5395 of 8045 individuals (67.1%) with a PHQ-9 score below 5 on initial survey completed a second PHQ-9. These respondents had a mean (SD) age of 55.8 (15.2) years; 3546 respondents (65.7%) identified as female; 329 respondents (6.1%) were Asian, 570 (10.6%) Black, 256 (4.7%) Hispanic, 4118 (76.3%) White, and 122 (2.3%) American Indian or Alaska Native, Pacific Islander or Native Hawaiian, or other. Among eligible respondents, 482 (8.9%) reported 5 points or greater worsening of PHQ-9 score at second survey. In fully adjusted models for increase in symptoms, the largest adjusted odds ratio (aOR) associated with social media use was observed for Snapchat (aOR, 1.53; 95% CI, 1.19-1.96), Facebook (aOR, 1.42; 95% CI, 1.10-1.81), and TikTok (aOR, 1.39; 95% CI, 1.03-1.87). Conclusions and Relevance: Among survey respondents who did not report depressive symptoms initially, social media use was associated with greater likelihood of subsequent increase in depressive symptoms after adjustment for sociodemographic features and news sources. These data cannot elucidate the nature of this association, but suggest the need for further study to understand how social media use may factor into depression among adults.

Gender-specificity of resilience in major depressive disorder.

INTRODUCTION: The major stressors associated with the COVID-19 pandemic provide an opportunity to understand the extent to which protective factors against depression may exhibit gender-specificity. METHOD: This study examined responses from multiple waves of a 50 states non-probability internet survey conducted between May 2020 and January 2021. Participants completed the PHQ-9 as a measure of depression, as well as items characterizing social supports. We used logistic regression models with population reweighting to examine association between absence of even mild depressive symptoms and sociodemographic features and social supports, with interaction terms and stratification used to investigate sex-specificity. RESULTS: Among 73,917 survey respondents, 31,199 (42.2%) reported absence of mild or greater depression-11,011/23,682 males (46.5%) and 20,188/50,235 (40.2%) females. In a regression model, features associated with greater likelihood of depression-resistance included at least weekly attendance of religious services (odds ratio [OR]: 1.10, 95% confidence interval [CI]: 1.04-1.16) and greater trust in others (OR: 1.04 for a 2-unit increase, 95% CI: 1.02-1.06), along with level of social support measured as number of social ties available who could provide care (OR: 1.05, 95% CI: 1.02-1.07), talk to them (OR: 1.10, 95% CI: 1.07-1.12), and help with employment (OR: 1.06, 95% CI: 1.04-1.08). The first two features showed significant interaction with gender (p < .0001), with markedly greater protective effects among women. CONCLUSION: Aspects of social support are associated with diminished risk of major depressive symptoms, with greater effects of religious service attendance and trust in others observed among women than men.

Comparison of post-COVID depression and major depressive disorder.

BACKGROUND: During the COVID-19 pandemic rates of depressive symptoms are markedly elevated, particularly among survivors of infection. Understanding whether such symptoms are distinct among those with prior SARS-CoV-2 infection, or simply a nonspecific reflection of elevated stress, could help target interventions. METHOD: We analyzed data from multiple waves of a 50-state survey that included questions about COVID-19 infection as well as the Patient Health Questionnaire examining depressive and anxious symptoms. We utilized multiple logistic regression to examine whether sociodemographic features associated with depression liability differed for those with or without prior COVID-19, and then whether depressive symptoms differed among those with or without prior COVID-19. RESULTS: Among 91,791 respondents, in regression models, age, gender, race, education, and income all exhibited an interaction with prior COVID-19 in risk for moderate or greater depressive symptoms (p<0.0001 in all cases), indicating differential risk in the two subgroups. Among those with such symptoms, levels of motoric symptoms and suicidality were significantly greater among those with prior COVID-19 illness. Depression risk increased with greater interval following acute infection. DISCUSSION: Our results suggest that major depressive symptoms observed among individuals with prior COVID-19 illness may not reflect typical depressive episodes, and merit more focused neurobiological investigation.

Persistence of symptoms up to 10 months following acute COVID-19 illness.

IMPORTANCE: COVID-19 symptoms are increasingly recognized to persist among a subset of individual following acute infection, but features associated with this persistence are not well-understood. OBJECTIVE: We aimed to identify individual features that predicted persistence of symptoms over at least 2 months at the time of survey completion.Design: Non-probability internet survey. Participants were asked to identify features of acute illness as well as persistence of symptoms at time of study completion. We used logistic regression models to examine association between sociodemographic and clinical features and persistence of symptoms at or beyond 2 months. SETTING: Ten waves of a fifty-state survey between June 13, 2020 and January 13, 2021. PARTICIPANTS: 6,211 individuals who reported symptomatic COVID-19 illness confirmed by positive test or clinician diagnosis. EXPOSURE: symptomatic COVID-19 illness. RESULTS: Among 6,211 survey respondents reporting COVID-19 illness, with a mean age of 37.8 (SD 12.2) years and 45.1% female, 73.9% white, 10.0% Black, 9.9% Hispanic, and 3.1% Asian, a total of 4946 (79.6%) had recovered within less than 2 months, while 491 (7.9%) experienced symptoms for 2 months or more. Of the full cohort, 3.4% were symptomatic for 4 months or more and 2.2% for 6 months or more. In univariate analyses, individuals with persistent symptoms on average reported greater initial severity. In logistic regression models, older age was associated with greater risk of persistence (OR 1.10, 95% CI 1.01-1.19 for each decade beyond 40); otherwise, no significant associations with persistence were identified for gender, race/ethnicity, or income. Presence of headache was significantly associated with greater likelihood of persistence (OR 1.44, 95% CI 1.11-1.86), while fever was associated with diminished likelihood of persistence (OR 0.66, 95% CI 0.53-0.83). CONCLUSION AND RELEVANCE: A subset of individuals experience persistent symptoms from 2 to more than 10 months after acute COVID-19 illness, particularly those who recall headache and absence of fever. In light of this prevalence, strategies for predicting and managing such sequelae are needed. TRIAL REGISTRATION: NA. KEY POINTS: Question: Which individuals are at greatest risk for post-acute sequelae of COVID-19?Findings: In this non-probability internet survey, among 6,211 individuals with symptomatic COVID-19 illness, 7.9% experienced persistence of symptoms lasting 2 months or longer. Older age, but not other sociodemographic features, was associated with risk for persistence, as was headache.Meaning: Identifying individuals at greater risk for symptomatic persistence may facilitate development of targeted interventions.