Lancet | Comprehensive Research on Bipolar Disorder: From Pathophysiological Mechanisms to Personalized Treatment

This article systematically reviews the epidemiology, diagnostic challenges, pathophysiological mechanisms, and multi-level treatment strategies of bipolar disorder, emphasizing future research directions in cognitive impairment, rapid-acting antidepressant interventions, and disease management.

 

Literature Overview

This article, 'Comprehensive Research on Bipolar Disorder: From Pathophysiological Mechanisms to Personalized Treatment,' published in The Lancet, reviews and summarizes the clinical features, epidemiological burden, diagnostic difficulties, pathophysiological mechanisms, and current treatment strategies for bipolar disorder (BD). The article emphasizes that while BD is predominantly characterized by depressive episodes, its core hallmark is hypomanic or manic episodes, which often lead to misdiagnosis due to symptom overlap. The study systematically outlines multifactorial mechanisms including genetics, mitochondrial dysfunction, inflammation, and neural circuit abnormalities, and details the current status and challenges of pharmacological treatments, psychological interventions, lifestyle modifications, and neuroregulatory approaches. Additionally, it discusses the management of special populations, comorbidities, and the importance of patient self-management. The paragraph is coherent and logical, ending with a Chinese period.

Background Knowledge

Bipolar disorder is a chronic, recurrent mental illness affecting approximately 40 million people worldwide, primarily characterized by alternating episodes of mania/hypomania and depression, often accompanied by mixed states and rapid cycling. Current diagnosis mainly relies on DSM-5-TR and ICD-11 criteria, but symptom overlap with attention-deficit/hyperactivity disorder, major depressive disorder, and personality disorders often leads to delayed diagnosis, with an average delay of 6 years. Recent genomic studies have revealed high heritability of BD (60–80%), with genome-wide association studies identifying 298 risk loci involving synaptic function, dopamine, and calcium signaling pathways. Additionally, mitochondrial dysfunction, circadian rhythm disturbances, neuroinflammation, and brain structural changes (e.g., cortical thinning in the prefrontal cortex) are believed to contribute to disease pathogenesis. In treatment, mood stabilizers and second-generation antipsychotics are central to acute and maintenance phases, but treating bipolar depression still faces limited efficacy and the risk of inducing mania. Psychosocial interventions such as cognitive behavioral therapy and family-focused therapy are supported by evidence but suffer from poor accessibility. Emerging treatments like transcranial magnetic stimulation, electroconvulsive therapy, and rapid-acting antidepressants (e.g., ketamine) are being explored for treatment-resistant cases. However, cognitive impairment, comorbid substance use disorders, and management in older adults remain unmet clinical needs. This review integrates the latest research advances, providing a theoretical foundation and practical direction for future precision medicine and comprehensive management models.

 

 

Research Methods and Experiments

This study employed a systematic literature review approach, searching PubMed for English-language articles on 'bipolar disorder' and related keywords (e.g., 'depression,' 'mania,' 'mixed features,' 'rapid cycling,' 'treatment guidelines') published between January 1, 2017, and July 22, 2024. Meta-analyses, randomized controlled trials, and large cohort studies were prioritized. Clinical practice guidelines from major international psychiatric associations were also referenced, and patient-reported experience studies were included to enhance clinical applicability. The research team consisted of international experts in psychiatry, psychology, and patient advocacy, ensuring comprehensive and practical content.

Key Conclusions and Perspectives

• The global 12-month prevalence of bipolar disorder is 1.5%, with type I accounting for 0.4%, type II for 0.3%, and subthreshold forms for 0.8%; incidence is similar between sexes, though women more frequently present with depressive episodes
• Diagnosis is often delayed, with an average untreated period of 6 years; some patients are initially misdiagnosed with unipolar depression, leading to inappropriate antidepressant use that may trigger mania or rapid cycling
• BD has high heritability (60–80%); GWAS studies have identified 298 risk loci involving synaptic function, dopamine, and calcium signaling pathways, with shared genetic mechanisms observed with schizophrenia and major depression
• Core pathophysiological mechanisms include mitochondrial dysfunction, neuroinflammation, circadian rhythm disturbances, and prefrontal-limbic system dysregulation; neuroimaging shows cortical thinning and reduced white matter integrity
• In pharmacotherapy, lithium, valproate, quetiapine, and aripiprazole are first-line choices for acute mania; for bipolar depression, olanzapine+fluoxetine, quetiapine, and lurasidone show significant efficacy, though antidepressant use requires caution
• Psychosocial interventions such as psychoeducation, cognitive behavioral therapy, family-focused therapy, and interpersonal and social rhythm therapy can reduce relapse risk by up to 50%, especially during maintenance phases
• Electroconvulsive therapy is highly effective for treatment-resistant bipolar depression and severe mixed states, with response rates exceeding 70%, and should be considered earlier rather than as a last resort
• Special populations such as women of childbearing age must consider drug teratogenicity (e.g., valproate is contraindicated), with perinatal relapse risk as high as 39%, requiring multidisciplinary management
• Cognitive impairment affects 50–70% of patients and is associated with elevated inflammatory markers, sleep disturbances, and frequent episodes, representing a treatment target independent of mood symptoms
• Future directions include developing pro-cognitive therapies, exploring rapid-acting antidepressants like ketamine, optimizing neuroregulatory technologies, and enhancing patient-centered self-management support

Research Significance and Prospects

This study comprehensively integrates the latest scientific evidence on bipolar disorder, emphasizing the importance of early recognition, accurate diagnosis, and personalized treatment. By elucidating the multisystem pathophysiological mechanisms, it provides a theoretical basis for developing novel targeted therapies, particularly in the areas of neuroinflammation, mitochondrial function, and circadian regulation.

The study also highlights the central role of psychosocial interventions and self-management in long-term recovery, advocating for broader use of digital health tools to improve accessibility. For treatment-resistant cases, neuroregulatory technologies such as ECT and rTMS show promise and require further parameter optimization to enhance response rates and safety.

Additionally, the article promotes incorporating patient experiences into clinical decision-making and advancing comorbidity management (e.g., substance use disorders, cardiovascular disease) and lifespan care models. Future research should focus on biomarker discovery, predictive models for treatment response, and longitudinal tracking of long-term outcomes to achieve true precision psychiatry.

 

 

Conclusion

This article provides a systematic summary of the epidemiological characteristics, diagnostic challenges, pathophysiological mechanisms, and multi-level treatment strategies for bipolar disorder. It highlights that although BD affects approximately 40 million people and imposes a substantial socioeconomic burden, diagnosis is often delayed, partly due to symptom overlap with various psychiatric disorders. Genetic studies have revealed a polygenic risk architecture, while mitochondrial dysfunction, neuroinflammation, and brain network abnormalities collectively contribute to disease pathogenesis. In treatment, medication combined with psychological interventions remains the cornerstone, but individual variability necessitates patient-centered management. Psychoeducation, CBT, FFT, and IPSRT can significantly reduce relapse risk. For treatment-resistant depression, ECT has clear efficacy and should be used earlier. Emerging therapies such as ketamine, rTMS, and digital self-management tools are expanding treatment horizons. Special populations, including women of childbearing age, older adults, and those with comorbidities, require individualized approaches. Cognitive impairment affects over half of patients and urgently needs targeted interventions. Future directions include deepening mechanistic research, developing pro-cognitive therapies, optimizing neuroregulation, and integrating real-world data to advance precision medicine. This review serves as an authoritative reference for clinical practice and research.

 

Balwinder Singh, Prof Holly A Swartz, Prof Alfredo B Cuellar-Barboza, Prof Katherine E Burdick, and Prof Mark A Frye. Bipolar Disorder. Lancet (London, England).