Using a generative model of affect to characterize affective variability and its response to treatment in bipolar disorder.

The affective variability of bipolar disorder (BD) is thought to qualitatively differ from that of borderline personality disorder (BPD), with changes in affect persisting longer in BD. However, quantitative studies have not been able to confirm this distinction. It has therefore not been possible to accurately quantify how treatments like lithium influence affective variability in BD. We assessed the affective variability associated with BD and BPD as well as the effect of lithium using a computational model that defines two subtypes of variability: affective changes that persist (volatility) and changes that do not (noise). We hypothesized that affective volatility would be raised in the BD group, noise would be raised in the BPD group, and that lithium would impact affective volatility. Daily affect ratings were prospectively collected for up to 3 y from patients with BD or BPD and nonclinical controls. In a separate experimental medicine study, patients with BD were randomized to receive lithium or placebo, with affect ratings collected from week -2 to +4. We found a diagnostically specific pattern of affective variability. Affective volatility was raised in patients with BD, whereas affective noise was raised in patients with BPD. Rather than suppressing affective variability, lithium increased the volatility of positive affect in both studies. These results provide a quantitative measure of the affective variability associated with BD and BPD. They suggest a mechanism of action for lithium, whereby periods of persistently low or high affect are avoided by increasing the volatility of affective responses.

Artificial intelligence and increasing misinformation.

With the recent advances in artificial intelligence (AI), patients are increasingly exposed to misleading medical information. Generative AI models, including large language models such as ChatGPT, create and modify text, images, audio and video information based on training data. Commercial use of generative AI is expanding rapidly and the public will routinely receive messages created by generative AI. However, generative AI models may be unreliable, routinely make errors and widely spread misinformation. Misinformation created by generative AI about mental illness may include factual errors, nonsense, fabricated sources and dangerous advice. Psychiatrists need to recognise that patients may receive misinformation online, including about medicine and psychiatry.

Implications of Online Self-Diagnosis in Psychiatry.

Online self-diagnosis of psychiatric disorders by the general public is increasing. The reasons for the increase include the expansion of Internet technologies and the use of social media, the rapid growth of direct-to-consumer e-commerce in healthcare, and the increased emphasis on patient involvement in decision making. The publicity given to artificial intelligence (AI) has also contributed to the increased use of online screening tools by the general public. This paper aims to review factors contributing to the expansion of online self-diagnosis by the general public, and discuss both the risks and benefits of online self-diagnosis of psychiatric disorders. A narrative review was performed with examples obtained from the scientific literature and commercial articles written for the general public. Online self-diagnosis of psychiatric disorders is growing rapidly. Some people with a positive result on a screening tool will seek professional help. However, there are many potential risks for patients who self-diagnose, including an incorrect or dangerous diagnosis, increased patient anxiety about the diagnosis, obtaining unfiltered advice on social media, using the self-diagnosis to self-treat, including online purchase of medications without a prescription, and technical issues including the loss of privacy. Physicians need to be aware of the increase in self-diagnosis by the general public and the potential risks, both medical and technical. Psychiatrists must recognize that the general public is often unaware of the challenging medical and technical issues involved in the diagnosis of a mental disorder, and be ready to treat patients who have already obtained an online self-diagnosis.

Gabapentin and pregabalin in bipolar disorder, anxiety states, and insomnia: Systematic review, meta-analysis, and rationale.

The gabapentinoids, gabapentin, and pregabalin, target the α2δ subunits of voltage-gated calcium channels. Initially licensed for pain and seizures, they have become widely prescribed drugs. Many of these uses are off-label for psychiatric indications, and there is increasing concern about their safety, so it is particularly important to have good evidence to justify this usage. We conducted a systematic review and meta-analysis of the evidence for three of their common psychiatric uses: bipolar disorder, anxiety, and insomnia. Fifty-five double-blind randomised controlled trials (RCTs) and 15 open-label studies were identified. For bipolar disorder, four double-blind RCTs investigating gabapentin, and no double-blind RCTs investigating pregabalin, were identified. A quantitative synthesis could not be performed due to heterogeneity in the study population, design and outcome measures. Across the anxiety spectrum, a consistent but not universal effect in favour of gabapentinoids compared to placebo was seen (standardised mean difference [SMD] ranging between -2.25 and -0.25). Notably, pregabalin (SMD -0.55, 95% CI -0.92 to -0.18) and gabapentin (SMD -0.92, 95% CI -1.32 to -0.52) were more effective than placebo in reducing preoperative anxiety. In insomnia, results were inconclusive. We conclude that there is moderate evidence of the efficacy of gabapentinoids in anxiety states, but minimal evidence in bipolar disorder and insomnia and they should be used for these disorders only with strong justification. This recommendation applies despite the attractive pharmacological and genetic rationale for targeting voltage-gated calcium channels.

Modeling transit time distributions in microvascular networks.

The time a red blood cell (RBC) spends in the microvasculature is of prime importance for a number of physiological processes. In this work, we present a methodology for computing an approximation of the so-called transit time distribution (TTD), i.e., the probabilistic description of how long a RBC will reside within the network. As a proof of concept, we apply this methodology to three flavors of the mesh networks. We show that each network type supports multiple distinct steady-state configurations and we present tools for analyzing the associated collection of TTDs, ranging from standard measures like mean capillary transit time (MCTT) and capillary transit time heterogeneity (CTTH) to novel metrics.

Telepsychiatry in an Era of Digital Mental Health Startups.

PURPOSE OF REVIEW: Telepsychiatry practiced by psychiatrists is evidence-based, regulated, private, and effective in diverse settings. The use of telemedicine has grown since the COVID-19 pandemic as people routinely obtain more healthcare services online. At the same time, there has been a rapid increase in the number of digital mental health startups that offer various services including online therapy and access to prescription medications. These digital mental health firms advertise directly to the consumer primarily through digital advertising. The purpose of this narrative review is to contrast traditional telepsychiatry and the digital mental health market related to online therapy. RECENT FINDINGS: In contrast to standard telepsychiatry, most of the digital mental health startups are unregulated, have unproven efficacy, and raise concerns related to self-diagnosis, self-medicating, and inappropriate prescribing. The role of digital mental health firms for people with serious mental illness has not been determined. There are inadequate privacy controls for the digital mental health firms, including for online therapy. We live in an age where there is widespread admiration for technology entrepreneurs and increasing emphasis on the role of the patient as a consumer. Yet, the business practices of digital mental health startups may compromise patient safety for profits. There is a need to address issues with the digital mental health startups and to educate patients about the differences between standard medical care and digital mental health products.

Cervical lymph nodes and ovarian teratomas as germinal centres in NMDA receptor-antibody encephalitis.

Autoantibodies against the extracellular domain of the N-methyl-d-aspartate receptor (NMDAR) NR1 subunit cause a severe and common form of encephalitis. To better understand their generation, we aimed to characterize and identify human germinal centres actively participating in NMDAR-specific autoimmunization by sampling patient blood, CSF, ovarian teratoma tissue and, directly from the putative site of human CNS lymphatic drainage, cervical lymph nodes. From serum, both NR1-IgA and NR1-IgM were detected more frequently in NMDAR-antibody encephalitis patients versus controls (both P < 0.0001). Within patients, ovarian teratoma status was associated with a higher frequency of NR1-IgA positivity in serum (OR = 3.1; P < 0.0001) and CSF (OR = 3.8, P = 0.047), particularly early in disease and before ovarian teratoma resection. Consistent with this immunoglobulin class bias, ovarian teratoma samples showed intratumoral production of both NR1-IgG and NR1-IgA and, by single cell RNA sequencing, contained expanded highly-mutated IgA clones with an ovarian teratoma-restricted B cell population. Multiplex histology suggested tertiary lymphoid architectures in ovarian teratomas with dense B cell foci expressing the germinal centre marker BCL6, CD21+ follicular dendritic cells, and the NR1 subunit, alongside lymphatic vessels and high endothelial vasculature. Cultured teratoma explants and dissociated intratumoral B cells secreted NR1-IgGs in culture. Hence, ovarian teratomas showed structural and functional evidence of NR1-specific germinal centres. On exploring classical secondary lymphoid organs, B cells cultured from cervical lymph nodes of patients with NMDAR-antibody encephalitis produced NR1-IgG in 3/7 cultures, from patients with the highest serum NR1-IgG levels (P < 0.05). By contrast, NR1-IgG secretion was observed neither from cervical lymph nodes in disease controls nor in patients with adequately resected ovarian teratomas. Our multimodal evaluations provide convergent anatomical and functional evidence of NMDAR-autoantibody production from active germinal centres within both intratumoral tertiary lymphoid structures and traditional secondary lymphoid organs, the cervical lymph nodes. Furthermore, we develop a cervical lymph node sampling protocol that can be used to directly explore immune activity in health and disease at this emerging neuroimmune interface.

Challenges and Ethical Considerations to Successfully Implement Artificial Intelligence in Clinical Medicine and Neuroscience: a Narrative Review.

This narrative review discusses how the safe and effective use of clinical artificial intelligence (AI) prediction tools requires recognition of the importance of human intelligence. Human intelligence, creativity, situational awareness, and professional knowledge, are required for successful implementation. The implementation of clinical AI prediction tools may change the workflow in medical practice resulting in new challenges and safety implications. Human understanding of how a clinical AI prediction tool performs in routine and exceptional situations is fundamental to successful implementation. Physicians must be involved in all aspects of the selection, implementation, and ongoing product monitoring of clinical AI prediction tools.

A co-produced online cultural experience compared to a typical museum website for mental health in people aged 16-24: A proof-of-principle randomised controlled trial.

OBJECTIVE: We aimed to compare a co-produced online intervention encompassing the diverse human stories behind art and artefacts, named Ways of Being (WoB), with a typical museum website, the Ashmolean (Ash) on negative affect (NA), positive affect (PA) and psychological distress (K10). METHODS: In this parallel group RCT, 463 YP aged 16-24 were randomly assigned, 231 to WoB and 232 to Ash. RESULTS: Over the intervention phase (an aggregate score including all post-allocation timepoints to day-five) a group difference was apparent in favour of WoB for NA (WoB-Ash n=448, NA -0.158, p=0.010) but no differences were detected for PA or K10 and differences were not detected at week six. Group differences in NA in favour of WoB were detected in specific subgroups, e.g. ethnic minorities and males. Across participants (from both groups) mean K10 and NA improved between baseline and six weeks despite increased COVID-19 restrictions. Trial recruitment was rapid, retention high and feedback positive with broad geographical, occupational and ethnic diversity. CONCLUSIONS: Online engagement with arts and culture has the potential to impact on mental health in a measurable way in YP with high unmet mental health needs.

Community interventions for anxiety and depression in adults and young people: A systematic review.

BACKGROUND: Growing evidence suggests that community-based interventions may be effective for anxiety and depression. This study aimed to describe studies of community interventions delivered to adults and/or young people, either in person or online, evaluated in randomised controlled trials and provide an indication as to their effectiveness, acceptability, quality of data and where possible, mechanisms of action. We included interventions delivered at and/or by museums, art galleries, libraries, gardens, music groups/choirs and sports clubs. METHOD: We developed and followed a preregistered protocol: PROSPERO CRD42020204471. Randomised controlled trials in adults and young people were identified in an extensive search with no date/time, language, document type and publication status limitations. Studies were selected according to predetermined eligibility criteria and data independently extracted and then assessed using Risk of Bias 1. The studies were deemed too heterogeneous for meta-analysis and were therefore reported using a narrative synthesis. RESULTS: Our analysis included 31 studies, with 2898 participants. Community interventions most studied in randomised controlled trials were community music (12 studies, 1432 participants), community exercise (14 studies, 955 participants) and community gardens/gardening (6 studies, 335 participants). The majority of studies were from high-income countries - many were in specific populations (such as those with physical health problems) and were generally of low quality. Dropout rates across the included studies were low (1 participant on average per 100 participants). The inadequate description of interventions limited identification of potential mechanisms of action. DISCUSSION: The uncertainty of the evidence allows only a weak recommendation in support of community interventions for anxiety and depression. The results suggest community engagement is a promising area for wide-reaching interventions to be implemented and evaluated, but more high-quality trials are needed, especially in young people and under-represented communities.

Joint patient and clinician priority setting to identify 10 key research questions regarding the long-term sequelae of COVID-19.

Given the large numbers of people infected and high rates of ongoing morbidity, research is clearly required to address the needs of adult survivors of COVID-19 living with ongoing symptoms (long COVID). To help direct resource and research efforts, we completed a research prioritisation process incorporating views from adults with ongoing symptoms of COVID-19, carers, clinicians and clinical researchers. The final top 10 research questions were agreed at an independently mediated workshop and included: identifying underlying mechanisms of long COVID, establishing diagnostic tools, understanding trajectory of recovery and evaluating the role of interventions both during the acute and persistent phases of the illness.

Association between serum lithium level and incidence of COVID-19 infection.

An antiviral effect of lithium has been proposed, but never investigated for coronavirus disease 2019 (COVID-19). Using electronic health records of 26 554 patients with documented serum lithium levels during the pandemic, we show that the 6-month COVID-19 infection incidence was lower among matched patients with 'therapeutic' (0.50-1.00) versus 'subtherapeutic' (0.05-0.50) lithium levels (hazard ratio (HR) = 0.82, 95% CI 0.69-0.97, P = 0.017) and among patients with 'therapeutic' lithium levels versus matched patients using valproate (HR = 0.79, 95% CI 0.67-0.92, P = 0.0023). Lower rates of infection were observed for both new COVID-19 diagnoses and positive polymerase chain reaction tests, regardless of underlying psychiatric diagnosis and vaccination status.

Mental health prior to and during the COVID-19 pandemic in individuals with bipolar disorder: Insights from prospective longitudinal data.

OBJECTIVES: Many studies have examined the impact of COVID-19 on the mental health of the public, but few have focused on individuals with existing severe mental illness with longitudinal data before and during the pandemic. AIMS: To investigate the impact of the COVID-19 pandemic on the mental health of people with bipolar disorder (BD). METHODS: In an ongoing study of people with BD who used an online mood monitoring tool, True Colours, 356 participants provided weekly data on their mental health. Symptoms of depression, mania, insomnia, and suicidal thoughts were compared in 2019 and 2020. From May 2020, participants also provided weekly data on the effect of the COVID-19 pandemic on anxiety, coping strategies, access to care, and medications. RESULTS: On average, symptoms of depression, mania, insomnia, and suicidal thoughts did not significantly differ in 2020 compared to 2019, but there was evidence of heterogeneity. There were high rates of anxiety about the pandemic and its impact on coping strategies, which increased to over 70% of responders in January 2021. A significant proportion of participants reported difficulty accessing routine care (27%) and medications (21%). CONCLUSIONS: Although mood symptoms did not significantly increase during the pandemic overall, we observed heterogeneity among our BD sample and other impacted areas. Individuals' unique histories and psychosocial circumstances are key and should be explored in future qualitative studies. The significant impacts of the pandemic may take time to manifest, particularly among those who are socioeconomically disadvantaged, highlighting the need for further long-term prospective studies.

Commercial Use of Emotion Artificial Intelligence (AI): Implications for Psychiatry.

PURPOSE OF REVIEW: Emotion artificial intelligence (AI) is technology for emotion detection and recognition. Emotion AI is expanding rapidly in commercial and government settings outside of medicine, and will increasingly become a routine part of daily life. The goal of this narrative review is to increase awareness both of the widespread use of emotion AI, and of the concerns with commercial use of emotion AI in relation to people with mental illness. RECENT FINDINGS: This paper discusses emotion AI fundamentals, a general overview of commercial emotion AI outside of medicine, and examples of the use of emotion AI in employee hiring and workplace monitoring. The successful re-integration of patients with mental illness into society must recognize the increasing commercial use of emotion AI. There are concerns that commercial use of emotion AI will increase stigma and discrimination, and have negative consequences in daily life for people with mental illness. Commercial emotion AI algorithm predictions about mental illness should not be treated as medical fact.

Expectations for Artificial Intelligence (AI) in Psychiatry.

PURPOSE OF REVIEW: Artificial intelligence (AI) is often presented as a transformative technology for clinical medicine even though the current technology maturity of AI is low. The purpose of this narrative review is to describe the complex reasons for the low technology maturity and set realistic expectations for the safe, routine use of AI in clinical medicine. RECENT FINDINGS: For AI to be productive in clinical medicine, many diverse factors that contribute to the low maturity level need to be addressed. These include technical problems such as data quality, dataset shift, black-box opacity, validation and regulatory challenges, and human factors such as a lack of education in AI, workflow changes, automation bias, and deskilling. There will also be new and unanticipated safety risks with the introduction of AI. The solutions to these issues are complex and will take time to discover, develop, validate, and implement. However, addressing the many problems in a methodical manner will expedite the safe and beneficial use of AI to augment medical decision making in psychiatry.

Incidence, co-occurrence, and evolution of long-COVID features: A 6-month retrospective cohort study of 273,618 survivors of COVID-19.

BACKGROUND: Long-COVID refers to a variety of symptoms affecting different organs reported by people following Coronavirus Disease 2019 (COVID-19) infection. To date, there have been no robust estimates of the incidence and co-occurrence of long-COVID features, their relationship to age, sex, or severity of infection, and the extent to which they are specific to COVID-19. The aim of this study is to address these issues. METHODS AND FINDINGS: We conducted a retrospective cohort study based on linked electronic health records (EHRs) data from 81 million patients including 273,618 COVID-19 survivors. The incidence and co-occurrence within 6 months and in the 3 to 6 months after COVID-19 diagnosis were calculated for 9 core features of long-COVID (breathing difficulties/breathlessness, fatigue/malaise, chest/throat pain, headache, abdominal symptoms, myalgia, other pain, cognitive symptoms, and anxiety/depression). Their co-occurrence network was also analyzed. Comparison with a propensity score-matched cohort of patients diagnosed with influenza during the same time period was achieved using Kaplan-Meier analysis and the Cox proportional hazard model. The incidence of atopic dermatitis was used as a negative control. Among COVID-19 survivors (mean [SD] age: 46.3 [19.8], 55.6% female), 57.00% had one or more long-COVID feature recorded during the whole 6-month period (i.e., including the acute phase), and 36.55% between 3 and 6 months. The incidence of each feature was: abnormal breathing (18.71% in the 1- to 180-day period; 7.94% in the 90- to180-day period), fatigue/malaise (12.82%; 5.87%), chest/throat pain (12.60%; 5.71%), headache (8.67%; 4.63%), other pain (11.60%; 7.19%), abdominal symptoms (15.58%; 8.29%), myalgia (3.24%; 1.54%), cognitive symptoms (7.88%; 3.95%), and anxiety/depression (22.82%; 15.49%). All 9 features were more frequently reported after COVID-19 than after influenza (with an overall excess incidence of 16.60% and hazard ratios between 1.44 and 2.04, all p < 0.001), co-occurred more commonly, and formed a more interconnected network. Significant differences in incidence and co-occurrence were associated with sex, age, and illness severity. Besides the limitations inherent to EHR data, limitations of this study include that (i) the findings do not generalize to patients who have had COVID-19 but were not diagnosed, nor to patients who do not seek or receive medical attention when experiencing symptoms of long-COVID; (ii) the findings say nothing about the persistence of the clinical features; and (iii) the difference between cohorts might be affected by one cohort seeking or receiving more medical attention for their symptoms. CONCLUSIONS: Long-COVID clinical features occurred and co-occurred frequently and showed some specificity to COVID-19, though they were also observed after influenza. Different long-COVID clinical profiles were observed based on demographics and illness severity.

Prediction of individuals at high risk of chronic kidney disease during treatment with lithium for bipolar disorder.

BACKGROUND: Lithium is the most effective treatment in bipolar disorder. Its use is limited by concerns about risk of chronic kidney disease (CKD). We aimed to develop a model to predict risk of CKD following lithium treatment initiation, by identifying individuals with a high-risk trajectory of kidney function. METHODS: We used United Kingdom Clinical Practice Research Datalink (CPRD) electronic health records (EHRs) from 2000 to 2018. CPRD Aurum for prediction model development and CPRD Gold for external validation. We used elastic net regularised regression to generate a prediction model from potential features. We performed discrimination and calibration assessments in an external validation data set. We included all patients aged ≥ 16 with bipolar disorder prescribed lithium. To be included patients had to have ≥ 1 year of follow-up before lithium initiation, ≥ 3 estimated glomerular filtration rate (eGFR) measures after lithium initiation (to be able to determine a trajectory) and a normal (≥ 60 mL/min/1.73 m2) eGFR at lithium initiation (baseline). In the Aurum development cohort, 1609 fulfilled these criteria. The Gold external validation cohort included 934 patients. We included 44 potential baseline features in the prediction model, including sociodemographic, mental and physical health and drug treatment characteristics. We compared a full model with the 3-variable 5-year kidney failure risk equation (KFRE) and a 3-variable elastic net model. We used group-based trajectory modelling to identify latent trajectory groups for eGFR. We were interested in the group with deteriorating kidney function (the high-risk group). RESULTS: The high risk of deteriorating eGFR group included 191 (11.87%) of the Aurum cohort and 137 (14.67%) of the Gold cohort. Of these, 168 (87.96%) and 117 (85.40%) respectively developed CKD 3a or more severe during follow-up. The model, developed in Aurum, had a ROC area of 0.879 (95%CI 0.853-0.904) in the Gold external validation data set. At the empirical optimal cut-point defined in the development dataset, the model had a sensitivity of 0.91 (95%CI 0.84-0.97) and a specificity of 0.74 (95% CI 0.67-0.82). However, a 3-variable elastic net model (including only age, sex and baseline eGFR) performed similarly well (ROC area 0.888; 95%CI 0.864-0.912), as did the KFRE (ROC area 0.870; 95%CI 0.841-0.898). CONCLUSIONS: Individuals at high risk of a poor eGFR trajectory can be identified before initiation of lithium treatment by a simple equation including age, sex and baseline eGFR. Risk was increased in individuals who were younger at commencement of lithium, female and had a lower baseline eGFR. We did not identify strong predicters of eGFR decline specific to lithium-treated patients. Notably, lithium duration and toxicity were not associated with high-risk trajectory.

Incidence and outcomes of eating disorders during the COVID-19 pandemic.

There are concerns that eating disorders have become commoner during the coronavirus disease 2019 (COVID-19) pandemic. Using the electronic health records of 5.2 million people aged under 30, mostly in the USA, we show that the diagnostic incidence was 15.3% higher in 2020 overall compared with previous years (relative risk 1.15, 95% CI 1.12-1.19). The relative risk increased steadily from March 2020 onwards, exceeding 1.5 by the end of the year. The increase occurred solely in females, and primarily related to teenagers and anorexia nervosa. A higher proportion of patients with eating disorders in 2020 had suicidal ideation (hazard ratio HR = 1.30, 1.16-1.47) or attempted suicide (HR = 1.69, 1.21-2.35).

Bipolar disorder: Trimodal age-at-onset distribution.

OBJECTIVE: Bipolar disorder (BD) is a chronic mental health disorder with significant morbidity and mortality. Age at onset (AAO) may be a key variable in delineating more homogeneous subgroups of BD patients. However, no known research has systematically assessed how BD age-at-onset subgroups should be defined. METHODS: We systematically searched the following databases: Cochrane Central Register of Controlled Trials, PsycINFO, MEDLINE, Embase, CINAHL, Scopus, Proquest Dissertations and Theses, Google Scholar and BIOSIS Previews. Original quantitative English language studies investigating AAO in BD were sought. RESULTS: A total of 9454 unique publications were identified. Twenty-one of these were included in data analysis (n = 22981 BD participants). Fourteen of these studies (67%, n = 13626 participants) found a trimodal AAO distribution: early-onset (µ = 17.3, σ = 1.19, 45% of sample), mid-onset (µ = 26.0, σ = 1.72, 35%), and late-onset (µ = 41.9, σ = 6.16, 20%). Five studies (24%, n = 1422 participants) described a bimodal AAO distribution: early-onset (µ = 24.3, σ = 6.57, 66% of sample) and late-onset (µ = 46.3, σ = 14.15, 34%). Two studies investigated cohort effects on BD AAO and found that when the sample was not split by cohort, a trimodal AAO was the winning model, but when separated by cohort a bimodal distribution fit the data better. CONCLUSIONS: We propose that the field conceptualises bipolar disorder age-at-onset subgroups as referring broadly to life stages. Demarcating BD AAO groups can inform treatment and provide a framework for future research to continue to investigate potential mechanisms of disease onset.

Effect of lithium on circadian rhythm in bipolar disorder: A systematic review and meta-analysis.

OBJECTIVES: Circadian rhythm disruption is commonly reported in patients with bipolar disorder. Lithium has been suggested to have effects on the circadian clock, the biological basis of the circadian rhythm. The objective of the current review was to review systematically the existing studies on the effect of lithium on circadian rhythm in patients with bipolar disorder. METHODS: We systematically searched the scientific literature up to September 2020 for experimental or observational studies which measured circadian rhythm in bipolar patients taking lithium (in comparison with placebo or other active treatments) and carried out a meta-analysis. Circadian rest-activity was our primary outcome, but we also collected data about sleep quality and chronotype (Morningness-Eveningness). The protocol was registered in PROSPERO (CRD42018109790). RESULTS: Four observational studies (n = 668) and one experimental study (n = 29) were included. Results from the meta-analysis suggest a potential association between lithium and shifts towards morningness (standardized mean difference [SMD]: 0.42, 95% confidence interval [CI]: -0.05 to 0.90). One cohort study with 21 days of follow-up found that patients treated with lithium had significantly larger amplitude (0.68, 0.01 to 1.36) when compared to anticonvulsants. CONCLUSION: This review highlights the insufficient evidence to inform us about the effect of lithium on circadian rhythm. However, we found that chronotype can be a potential target for further exploration of biomarkers or biosignatures of lithium treatment in patients with bipolar disorder. Further studies with prospective and longitudinal study design, adopting actigraphy to monitor daily circadian rest-activity changes are needed.