Un estudio asocia el consumo de cannabis con todo tipo de trastornos mentales

A Cross-Sectional Study on the Prevalence and Risk Correlates of Mental Disorders: The GRANADΣP Study Abstract
This is a cross-sectional study of participants from a population census living in the province of Granada (Spain). A total of 1176 persons were contacted, 367 (31%) refused and 54 (6.7%) needed substitution. A final sample of 809 participants (response rate, 69.3%) were screened for mental disorder (MD) using the MINI International Neuropsychiatric Interview, a comprehensive interview validated to generate diagnoses compatible with ICD-10/DSM-4 criteria. Current (1-month) prevalence for any MD was 11.3% (95% confidence interval [CI], 9.7%–13.4%; affective 8.2%, anxiety 9.6%, psychotic 2.1%, addiction 1.8%, personality disorder 3.6%). Lifetime MD prevalence was 24.6% (95% CI, 21.6–27.6; affective 14.9%, anxiety 15.5%, psychotic 3.4%, addiction 4.4%, personality disorder 3.6%). Female sex was associated with MD, but this appeared partially due to higher levels of neuroticism among women. MD also correlated significantly with cannabis use, family history of MD, higher social adversity, higher suicide risk, poorer physical health, poorer cognitive performance, and personality problems.

Identifican un nuevo mediador en el daño vascular asociado a la hipertensión

mPGES-1 (Microsomal Prostaglandin E Synthase-1)Mediates Vascular Dysfunction in Hypertension ThroughOxidative Stress

Abstract

mPGES-1 (microsomal prostaglandin E synthase-1), the downstream enzyme responsible for PGE2 (prostaglandin E2) synthesis in inflammatory conditions and oxidative stress are increased in vessels from hypertensive animals. We evaluated the role of mPGES-1–derived PGE2 in the vascular dysfunction and remodeling in hypertension and the possible contribution of oxidative stress. We used human peripheral blood mononuclear cells from asymptomatic patients, arteries from untreated and Ang II (angiotensin II)–infused mPGES-1−/− and mPGES-1+/+ mice, and vascular smooth muscle cells exposed to PGE2. In human cells, we found a positive correlation between mPGES-1 mRNA and carotid intima-media thickness (r=0.637; P<0 .001="" span="" style="letter-spacing: -.8pt;"> and with NADPH oxidase–dependent superoxide production (r=0.417; P<0 .001="" span="" style="letter-spacing: -.8pt;">

In Ang II– infused mice, mPGES-1 deletion prevented all of the following: (1) the augmented wall:lumen ratio, vascular stiffness, and altered elastin structure; (2) the increased gene expression of profibrotic and proinflammatory markers; (3) the increased vasoconstrictor responses and endothelial dysfunction; (4) the increased NADPH oxidase activity and the diminished mitochondrial membrane potential; and (5) the increased reactive oxygen species generation and reduced NO bioavailability. In vascular smooth muscle cells or aortic segments, PGE2 increased NADPH oxidase expression and activity and reduced mitochondrial membrane potential, effects that were abolished by antagonists of the PGE2 receptors (EP), EP1 and EP3, and by JNK (c-Jun N-terminal kinase) and ERK1/2 (extracellular-signal–regulated kinases 1/2) inhibition. Deletion of mPGES-1 augmented vascular production of PGI2 suggesting rediversion of the accumulated PGH2 substrate. In conclusion, mPGES-1–derived PGE2 is involved in vascular remodeling, stiffness, and endothelial dysfunction in hypertension likely through an increase of oxidative stress produced by NADPH oxidase and mitochondria.

Efectividad y seguridad del fingolimod en la esclerosis múltiple remitente recurrente

Efficacy and safety of fingolimod in routine clinical practice in patients with relapsing-remitting multiple sclerosis in Spain: an intermediate analysis of the MS NEXT study.

Abstract

Fingolimod is a disease modifying therapies, which has showed clinical efficacy and an acceptable safety profile in clinical trials with relapsing-remitting multiple sclerosis (RRMS) patients.To assess fingolimod effectiveness and safety in patients with RRMS in clinical practice.We present an interim analysis (July 2015) of MS NEXT, an observational, retrospective and multicenter study. 442 patients were included (mean age: 41 ± 9 years; median baseline EDSS: 3.0; 70% female; 284 previously treated with first-line disease modifying therapies, 139 with natalizumab and 19 without a previous treatment; mean fingolimod treatment duration: 25 ± 9 months) treated with fingolimod from November 2011 and with at least 12 months follow-up. 56 neurology-unit Spanish hospitals enrolled patients. Basal clinical and demographic data were recorded. Relapses, EDSS scores and radiological activity were recorded at baseline and annually. Adverse events were also recorded during the follow-up period.After two years of follow-up: annual relapse rates decreased by 76%, the proportion of relapse-free patients was 67%, of disability progression-free patients confirmed at 3 months was 91%, of relapse and disability progression-free patients was 63%, of radiological activity-free patients was 50%, and the proportion of relapse, disability progression and radiological activity-free patients was 35%. Only 3.9% of patients discontinued fingolimod permanently during the first year of treatment.In this interim analysis, most of patients treated with fingolimod in clinical practice had a controlled clinical disease activity, stable disability progression and high persistency.

Vinculan los traumatismos repetitivos en la cabeza con formas de parkinsonismo

Lewy Body Pathology and Chronic Traumatic Encephalopathy Associated With Contact Sports

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Abstract

Traumatic brain injury has been associated with increased risk of Parkinson disease and parkinsonism, and parkinsonism and Lewy body disease (LBD) can occur with chronic traumatic encephalopathy (CTE). To test whether contact sports and CTE are associated with LBD, we compared deceased contact sports athletes (n = 269) to cohorts from the community (n = 164) and the Boston University Alzheimer disease (AD) Center (n = 261). Participants with CTE and LBD were more likely to have β-amyloid deposition, dementia, and parkinsonism than CTE alone (p < 0.05). Traditional and hierarchical clustering showed a similar pattern of LBD distribution in CTE compared to LBD alone that was most frequently neocortical, limbic, or brainstem. In the community-based cohort, years of contact sports play were associated with neocortical LBD (OR = 1.30 per year, p = 0.012), and in a pooled analysis a threshold of >8 years of play best predicted neocortical LBD (ROC analysis, OR = 6.24, 95% CI = 1.5–25, p = 0.011), adjusting for age, sex, and APOE ɛ4 allele status. Clinically, dementia was significantly associated with neocortical LBD, CTE stage, and AD; parkinsonism was associated with LBD pathology but not CTE stage. Contact sports participation may increase risk of developing neocortical LBD, and increased LBD frequency may partially explain extrapyramidal motor symptoms sometimes observed in CTE.

Keywords: American football, Chronic traumatic encephalopathy (CTE), Lewy body disease, Mild traumatic brain injury, Parkinson disease, Repetitive head impacts

Topic:

 

• parkinson disease
• dementia
• lewy body disease
• apolipoprotein e
• lewy bodies
• sports
• pathology
• chronic traumatic encephalopathy

Observan un vínculo entre ciertas patologías oculares y la enfermedad de Alzheimer

Associations between recent and established ophthalmic conditions and risk of Alzheimer's disease

Abstract

Introduction

Identifying ophthalmic diseases associated with increased risk of Alzheimer's disease (AD) may enable better screening and understanding of those at risk of AD.

Methods

Diagnoses of glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy (DR) were based on International Classification of Diseases, 9th revision, codes for 3877 participants from the Adult Changes in Thought study. The adjusted hazard ratio for developing probable or possible AD for recent (within 5 years) and established (>5 years) diagnoses were assessed.

Results

Over 31,142 person-years of follow-up, 792 AD cases occurred. The recent and established hazard ratio were 1.46 (P = .01) and 0.87 (P = .19) for glaucoma, 1.20 (P = .12) and 1.50 (P < .001) for AMD, and 1.50 (P = .045) and 1.50 (P = .03) for DR.

Discussion

Increased AD risk was found for recent glaucoma diagnoses, established AMD diagnoses, and both recent and established DR. People with certain ophthalmic conditions may have increased AD risk.

Keywords:

Alzheimer's disease, Adult Changes in Thought (ACT), Ophthalmology, Diabetic retinopathy, Age-related macular degeneration, Glaucoma, Cataract

No hay evidencia sólida del efecto neuroprotector de los suplementos de vitamina D

Are the protective benefits of vitamin D in neurodegenerative disease dependent on route of administration? A systematic review

Abstract

Background: The clinical and preclinical exploration of the therapeutic properties of vitamin D have significantly increased in the past decade, owing to the growing associative evidence suggesting vitamin D is neuroprotective. However, whether depletion of vitamin D contributes to the onset of neurological disorders or is a symptom of neurological disease has yet to be defined. Much remains unclear about the causal role of vitamin D and the method of use and forms of vitamin D.

Objectives: We sought to quantitatively assess if neuroprotective benefits from vitamin D in neurodegenerative diseases are dependent on route of administration: comparing the effect of endogenously sourced vitamin D from UV exposure to exogenously derived vitamin D through synthetic supplementation.

Design: We systematically searched PubMed, Embase and PsycInfo databases which included both pre-clinical and clinical studies investigating vitamin D in neurodegenerative diseases. Articles were subject to strict inclusion criteria and objectively assessed for quality. Additionally, Medline data was analysed to identify trends in topic publications and linguistic characteristics of papers.

Results: From a total of 231 screened articles, we identified 73 appropriate for review based on inclusion criteria: original studies that investigated vitamin D levels or levels of vitamin D supplementation in neurodegenerative diseases or investigated past/present sun exposure in disease cohorts. Results indicate there is insufficient evidence to comprehensively reflect on a potential neuroprotective role for vitamin D and if this was dependent on route of administration. The majority of current data supporting neuroprotective benefits from vitamin D are based on pre-clinical and observational studies. Solid evidence is lacking to support the current hypothesis that the beneficial effect of UV exposure results from the synthesis of vitamin D. Sun exposure, independent of vitamin D production, may be protective against multiple Sclerosis, Parkinson’s disease and Alzheimer’s disease. Yet, further research is required to elucidate the beneficial mechanism of actions of UV exposure. The literature of vitamin D and amyotrophic lateral sclerosis was limited, and no conclusions were drawn. Therefore, in cases where UV-derived vitamin D was hypothesized to be the beneficial mediator in the neuroprotective effects of sun exposure, we propose results are based only on associative evidence.

Conclusion: On the basis of this systematic review, strong recommendations regarding therapeutic benefits of vitamin D in neurodegenerative disease cannot be made. It is unclear if vitamin D mediates a protective benefit in neurodegenerative disease or whether it is an associative marker of UV exposure, which may contribute to as of yet unidentified neuroprotective factors.

KEYWORDS: Vitamin D, Neurodegenerative disease, Neuroprotection, Systematic review, Supplementation, Sunli

Niveles de hierro podrían predecir la gravedad de la esclerosis múltiple

Brain Iron at Quantitative MRI Is Associated with Disability in Multiple Sclerosis

Abstract

Purpose

To study deep gray matter susceptibility in multiple sclerosis (MS) by using quantitative susceptibility mapping (QSM) and to assess the relationship between susceptibility and clinical disability.

Materials and Methods

For this prospective study between March 2009 and November 2013, 600 participants with MS (452 with relapsing-remitting MS and 148 with secondary progressive MS) and 250 age- and sex-matched healthy control participants were imaged with 3.0-T MRI to measure magnetic susceptibility. Deep gray matter susceptibility (in parts per billion) was analyzed by using region of interest and voxelwise methods. QSM and MRI volumetric differences between study groups and associations with clinical outcomes were assessed. Analysis of covariance, multivariable linear regression, and voxelwise analyses, controlling for age and sex, were used to compare study groups and to explore associations between MRI and clinical outcomes.

Results

Compared with control participants, participants with MS presented with lower thalamic susceptibility (−7.5 ppb vs −1.1 ppb; P < .001) and higher susceptibility of basal ganglia (62 ppb vs 54.8 ppb; P < .001). Lower thalamic susceptibility was associated with longer disease duration (β = −0.42; P = .002), higher degree of disability (β = −0.64; P = .03), and secondary-progressive course (β = −4.3; P = .009). Higher susceptibility of the globus pallidus was associated with higher disability (β = 2; P = .03). After correcting for each individual structural volume in voxelwise analysis, lower thalamic susceptibility and higher susceptibility of the globus pallidus remained associated with clinical disability (P < .05).

Conclusion

Quantitative susceptibility mapping (QSM) suggests that altered deep gray matter iron is associated with the evolution of multiple sclerosis (MS) and on disability accrual, independent of tissue atrophy.

Un compuesto de toxina botulínica, posible alternativa a los opioides en el dolor crónico

Selective neuronal silencing using synthetic botulinum molecules alleviates chronic pain in mice

Relieving pain with botox

Chronic pain affects more than 25 million Americans and is associated with reduced life span, anxiety, and depression. Opioid administration is often effective in relieving pain but, unfortunately, opioids have serious side effects, including risk of addiction and overdose. In a new study, Maiarù et al. have leveraged the inhibitory effects of botulinum toxin on neuronal activity. They developed two botulinum-conjugated molecules (SP-BOT and Derm-BOT) that were able to silence subpopulations of pain-related spinal neurons in several mouse models of chronic pain. Intrathecal administration of one dose of SP-BOT or Derm-BOT produced long-term pain relief in the mouse models that was comparable to the effects of opioid treatment. The results suggest that botulinum-conjugated molecules could be an opioid-free alternative for treating chronic pain.

Abstract

Chronic pain is a widespread debilitating condition affecting millions of people worldwide. Although several pharmacological treatments for relieving chronic pain have been developed, they require frequent chronic administration and are often associated with severe adverse events, including overdose and addiction. Persistent increased sensitization of neuronal subpopulations of the peripheral and central nervous system has been recognized as a central mechanism mediating chronic pain, suggesting that inhibition of specific neuronal subpopulations might produce antinociceptive effects. We leveraged the neurotoxic properties of the botulinum toxin to specifically silence key pain-processing neurons in the spinal cords of mice. We show that a single intrathecal injection of botulinum toxin conjugates produced long-lasting pain relief in mouse models of inflammatory and neuropathic pain without toxic side effects. Our results suggest that this strategy might be a safe and effective approach for relieving chronic pain while avoiding the adverse events associated with repeated chronic drug administration.

Dolor y trastornos del sueño con frecuencia preceden a la esclerosis múltiple

Five years before multiple sclerosis onset: Phenotyping the prodrome

Abstract

Background:

The multiple sclerosis (MS) prodrome is poorly characterized.

Objective:

To phenotype the MS prodrome via health care encounters. 

Methods:

Using data from a population-based cohort study linking administrative and clinical data in four Canadian provinces, we compared physician and hospital encounters and prescriptions filled (via International Classification of Diseases chapters, physician specialty or drug classes) for MS subjects in the 5 years before the first demyelinating claim in an administrative cohort or the clinical symptom onset in an MS clinic-derived cohort, to age-, sex- and geographically matched controls. Rate ratios (RRs), 95% confidence intervals (95% CIs) and proportions were estimated. 

Results:

The administrative and clinical cohorts included 13,951/66,940 and 3202/16,006 people with and without MS (cases/controls). Compared to controls, in the 5 years before the first demyelinating claim or symptom onset, cases had more physician and hospital encounters for the nervous (RR (range) = 2.31; 95% CI: 1.05–5.10 to 4.75; 95% CI: 3.11–7.25), sensory (RR (range) = 1.40; 95% CI: 1.34–1.46 to 2.28; 95% CI: 1.72–3.02), musculoskeletal (RR (range) = 1.19; 95% CI: 1.07–1.33 to 1.70; 95% CI: 1.57–1.85) and genito-urinary systems (RR (range) = 1.17; 95% CI: 1.05–1.30 to 1.59; 95% CI: 1.48–1.70). Cases had more psychiatrist and urologist encounters (RR (range) = 1.48; 95% CI: 1.36–1.62 to 1.80; 95% CI: 1.61–2.01), and higher proportions of musculoskeletal, genito-urinary or hormonal-related prescriptions (1.1–1.5 times higher, all p < 0.02). However, cases had fewer pregnancy-related encounters than controls (RR = 0.78; 95% CI: 0.71–0.86 to 0.88; 95% CI: 0.84–0.92).

Conclusion:

Phenotyping the prodrome 5 years before clinical recognition of MS is feasible.

Keywords Multiple sclerosis, prodrome, health care utilization, population-based data, multi-centre

Desvelan un mecanismo involucrado en la pérdida de memoria asociada al envejecimiento

Age-related shift in LTD is dependent on neuronal adenosine A2A receptors interplay with mGluR5 and NMDA receptors

Abstract

Synaptic dysfunction plays a central role in Alzheimer’s disease (AD), since it drives the cognitive decline. An association between a polymorphism of the adenosine A2A receptor (A2AR) encoding gene—ADORA2A, and hippocampal volume in AD patients was recently described. In this study, we explore the synaptic function of A2AR in age-related conditions. We report, for the first time, a significant overexpression of A2AR in hippocampal neurons of aged humans, which is aggravated in AD patients. A similar profile of A2AR overexpression in rats was sufficient to drive age-like memory impairments in young animals and to uncover a hippocampal LTD-to-LTP shift. This was accompanied by increased NMDA receptor gating, dependent on mGluR5 and linked to enhanced Ca2+ influx. We confirmed the same plasticity shift in memory-impaired aged rats and APP/PS1 mice modeling AD, which was rescued upon A2AR blockade. This A2AR/mGluR5/NMDAR interaction might prove a suitable alternative for regulating aberrant mGluR5/NMDAR signaling in AD without disrupting their constitutive activity.

Relacionan el uso excesivo de medios digitales con síntomas de TDAH en adolescentes

Association of Digital Media Use With Subsequent Symptoms of Attention-Deficit/Hyperactivity Disorder Among Adolescents

Abstract

Importance  Modern digital platforms are easily accessible and intensely stimulating; it is unknown whether frequent use of digital media may be associated with symptoms of attention-deficit/hyperactivity disorder (ADHD).

Objective  To determine whether the frequency of using digital media among 15- and 16-year-olds without significant ADHD symptoms is associated with subsequent occurrence of ADHD symptoms during a 24-month follow-up.

Design, Setting, and Participants  Longitudinal cohort of students in 10 Los Angeles County, California, high schools recruited through convenience sampling. Baseline and 6-, 12-, 18-, and 24-month follow-up surveys were administered from September 2014 (10th grade) to December 2016 (12th grade). Of 4100 eligible students, 3051 10th-graders (74%) were surveyed at the baseline assessment.

Exposures  Self-reported use of 14 different modern digital media activities at a high-frequency rate over the preceding week was defined as many times a day (yes/no) and was summed in a cumulative index (range, 0-14).

Main Outcomes and Measures  Self-rated frequency of 18 ADHD symptoms (never/rare, sometimes, often, very often) in the 6 months preceding the survey. The total numbers of 9 inattentive symptoms (range, 0-9) and 9 hyperactive-impulsive symptoms (range, 0-9) that students rated as experiencing often or very often were calculated. Students who had reported experiencing often or very often 6 or more symptoms in either category were classified as being ADHD symptom-positive.

Results  Among the 2587 adolescents (63% eligible students; 54.4% girls; mean [SD] age 15.5 years [0.5 years]) who did not have significant symptoms of ADHD at baseline, the median follow-up was 22.6 months (interquartile range [IQR], 21.8-23.0, months). The mean (SD) number of baseline digital media activities used at a high-frequency rate was 3.62 (3.30); 1398 students (54.1%) indicated high frequency of checking social media (95% CI, 52.1%-56.0%), which was the most common media activity. High-frequency engagement in each additional digital media activity at baseline was associated with a significantly higher odds of having symptoms of ADHD across follow-ups (OR, 1.11; 95% CI, 1.06-1.16). This association persisted after covariate adjustment (OR, 1.10; 95% CI, 1.05-1.15). The 495 students who reported no high-frequency media use at baseline had a 4.6% mean rate of having ADHD symptoms across follow-ups vs 9.5% among the 114 who reported 7 high-frequency activities (difference; 4.9%; 95% CI, 2.5%-7.3%) and vs 10.5% among the 51 students who reported 14 high-frequency activities (difference, 5.9%; 95% CI, 2.6%-9.2%).

Conclusions and Relevance  Among adolescents followed up over 2 years, there was a statistically significant but modest association between higher frequency of digital media use and subsequent symptoms of ADHD. Further research is needed to determine whether this association is causal.

La obesidad empeora las consecuencias de un traumatismo craneoencefálico

Obesity and Overweight Problems Among Individuals 1 to 25 Years Following Acute Rehabilitation for Traumatic Brain Injury: A NIDILRR Traumatic Brain Injury Model Systems Study

Abstract

Objective:

Examine the prevalence of weight classifications and factors related to obesity/overweight among persons 1 to 25 years following traumatic brain injury (TBI) using the Traumatic Brain Injury Model Systems national database.

Design:

Multicenter, cross-sectional, observational design.

Setting:

Traumatic Brain Injury Model Systems inpatient rehabilitation facilities.

Participants:

Persons (N = 7287) 1, 2, 5, 10, 15, 20, or 25 years after TBI who required inpatient acute rehabilitation.

Main Outcome Measures:

Body mass index, demographic characteristics, functional, health, satisfaction with life, and global outcomes.

Results:

Overall postinjury weight prevalence rates were 23% obese, 36% overweight, 39% normal, and 3% underweight. Higher rates for obesity and overweight problems were associated with increasing time since injury. Younger (18-19 years) and older (80+ years) age, those in a vegetative state, and those reporting excellent health were less likely to be obese. Individuals with a history of hypertension, heart failure, or diabetes were more likely to be obese.

Conclusions:

Being obese or overweight presents a health risk in the years following rehabilitation for TBI. The findings support the need for longitudinal studies and highlight the advisability of monitoring weight and promoting healthy lifestyle behaviors over time in survivors of TBI.

La enfermedad de Alzheimer podría alterar la capacidad de percibir el dolor

Contact heat sensitivity and reports of unpleasantness in communicative people with mild to moderate cognitive impairment in Alzheimer’s disease: a cross-sectional study

Abstract

Background

Compared to healthy controls, people with Alzheimer’s disease (AD) have been shown to receive less pain medication and report pain less frequently. It is unknown if these findings reflect less perceived pain in AD, an inability to recognize pain, or an inability to communicate pain.

Methods

To further examine aspects of pain processing in AD, we conducted a cross-sectional study of sex-matched adults ≥65 years old with and without AD (AD: n = 40, female = 20, median age = 75; control: n = 40, female = 20, median age = 70) to compare the psychophysical response to contact-evoked perceptual heat thresholds of warmth, mild pain, and moderate pain, and self-reported unpleasantness for each percept.

Results

When compared to controls, participants with AD required higher temperatures to report sensing warmth (Cohen’s d = 0.64, p = 0.002), mild pain (Cohen’s d = 0.51, p = 0.016), and moderate pain (Cohen’s d = 0.45, p = 0.043). Conversely, there were no significant between-group differences in unpleasantness ratings (p > 0.05).

Conclusions

The between-group findings demonstrate that when compared to controls, people with AD are less sensitive to the detection of thermal pain but do not differ in affective response to the unpleasant aspects of thermal pain. These findings suggest that people with AD may experience greater levels of pain and potentially greater levels of tissue or organ damage prior to identifying and reporting injury. This finding may help to explain the decreased frequency of pain reports and consequently a lower administration of analgesics in AD.

Keywords

Pain Dementia Alzheimer’s disease Unpleasantness Psychophysics

El diagnóstico del trastorno bipolar podría estar retrasándose hasta seis años

Meta-analysis of the Interval between the Onset and Management of Bipolar Disorder

Objective:

To evaluate the length of the interval between the onset and the initial management of bipolar disorder (BD).

Method:

We conducted a meta-analysis using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Systematic searches located studies reporting estimates of the age of onset (AOO) and indicators of the age at initial management of BD. We calculated a pooled estimate of the interval between AOO and age at management. Factors influencing between-study heterogeneity were investigated using sensitivity analyses, meta-regression, and multiple meta-regression.

Results:

Twenty-seven studies, reporting 51 samples and a total of 9415 patients, met the inclusion criteria. The pooled estimate for the interval between the onset of BD and its management was 5.8 years (standardized difference, .53; 95% confidence interval, .45 to .62). There was very high between-sample heterogeneity (I2 = 92.6; Q = 672). A longer interval was found in studies that defined the onset according to the first episode (compared to onset of symptoms or illness) and defined management as age at diagnosis (rather than first treatment or first hospitalization). A longer interval was reported among more recently published studies, among studies that used a systematic method to establish the chronology of illness, among studies with a smaller proportion of bipolar I patients, and among studies with an earlier mean AOO.

Conclusions:

There is currently little consistency in the way researchers report the AOO and initial management of BD. However, the large interval between onset and management of BD presents an opportunity for earlier intervention.

Keywords: meta-analysis, bipolar disorders, age of onset, clinical management, duration of untreated bipolar disorder