# Exploratory study of ultraviolet B (UVB) radiation and age of onset of bipolar disorder

Michael Bauer, Tasha Glenn, Eric D Achtyes, Martin Alda, Esen Agaoglu, Kürsat Altınbaş, Ole A Andreassen, Elias Angelopoulos, Raffaella Ardau, Memduha Aydin, et al.

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## To cite this version:

Michael Bauer, Tasha Glenn, Eric D Achtyes, Martin Alda, Esen Agaoglu, et al.. Exploratory study of ultraviolet B (UVB) radiation and age of onset of bipolar disorder. International Journal of Bipolar Disorders, 2023, 11 (1), pp.22. 10.1186/s40345-023-00303-w. inserm-04165238

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# Exploratory study of ultraviolet B (UVB) radiation and age of onset of bipolar disorder

Michael Bauer¹*, Tasha Glenn², Eric D. Achtyes³,⁴, Martin Alda⁵, Esen Agaoglu⁶, Kürsat Altınbaş⁷, Ole A. Andreassen⁸, Elias Angelopoulos⁹, Raffaella Ardau¹⁰, Memduha Aydin¹¹, Yavuz Ayhan⁶, Christopher Baethge¹², Rita Bauer¹, Bernhard T. Baune¹³,¹⁴,¹⁵, Ceylan Balaban¹⁶, Claudia Becerra-Palars¹⁷, Aniruddh P. Behere¹⁸, Prakash B. Behere¹⁹, Habte Belete²⁰, Tilahun Belete²⁰, Gabriel Okawa Belizario²¹, Frank Bellivier²², Robert H. Belmaker²³, Francesco Benedetti²⁴,²⁵, Michael Berk²⁶,²⁷, Yuly Bersudsky²⁸, Şule Bicakci⁶,²⁹, Harriet Birabwa-Oketcho³⁰, Thomas D. Bjella⁸, Conan Brady³, Jorge Cabrera³², Marco Cappucciati³³, Angela Marianne Paredes Castro²⁶, Wei-Ling Chen³⁴, Eric Y. W. Cheung³⁵, Silvia Chiesa³³, Marie Crowe³⁶, Alessandro Cuomo³⁷, Sara Dallaspezia²⁵, Maria Del Zompo¹⁰, Pratikkumar Desai³,⁴, Seetal Dodd²⁶,³⁸, Bruno Etain²², Andrea Fagiolini³⁷, Frederike T. Fellendorf³⁹, Ewa Ferensztajn-Rochowiak⁴⁰, Jess G. Fiedorowicz⁴¹, Kostas N. Fountoulakis⁴², Mark A. Frye⁴³, Pierre A. Geoffroy⁴⁴,⁴⁵,⁴⁶, Michael J. Gitlin¹²⁵, Ana Gonzalez-Pinto⁴⁷, John F. Gottlieb⁴⁸, Paul Grof⁴⁹, Bartholomeus C. M. Haarman⁵⁰, Hirohiko Harima⁵¹, Mathias Hasse-Sousa⁵²,⁵³, Chantal Henry⁵⁴, Lone Hoffding⁵⁵, Josselin Houenou⁵⁶,⁵⁷, Massimiliano Imbesi³³, Erkki T. Isometsä⁵⁸,⁵⁹, Maja Ivkovic⁶⁰, Sven Janno⁶¹, Simon Johnsen⁶², Flávio Kapczinski⁵², Gregory N. Karakatsoulis⁴², Mathias Kardell⁶³, Lars Vedel Kessing⁶⁴, Seong Jae Kim⁶⁵, Barbara König⁶⁶, Timur L. Kot⁶⁷, Michael Koval⁶⁸, Mauricio Kunz⁵², Beny Lafer²¹, Mikael Landén⁶³,⁶⁹, Erik R. Larsen⁷⁰, Melanie Lenger³⁹, Rasmus W. Licht⁷¹,⁷², Carlos Lopez-Jaramillo⁷³, Alan MacKenzie⁷⁴, Helle Østergaard Madsen⁷⁵, Simone Alberte Kongstad A. Madsen⁶², Jayant Mahadevan⁷⁶, Agustine Mahardika⁷⁷, Mirko Manchia⁷⁸,⁷⁹,⁸⁰, Wendy Marsh⁸¹, Monica Martinez-Cengotitabengoa⁸²,⁸³, Julia Martini¹, Klaus Martiny⁷⁵, Yuki Mashima⁸⁴, Declan M. McLoughlin⁸⁵, Ybe Meesters⁵⁰, Ingrid Melle⁸, Fátima Meza-Urzúa⁸⁶, Pavol Mikolas¹, Yee Ming Mok⁸⁷, Scott Monteith⁸⁸, Muthukumaran Moorthy⁷⁶, Gunnar Morken⁸⁹,⁹⁰, Enrica Mosca¹⁰, Anton A. Mozzhegorov⁹¹, Rodrigo Munoz⁹², Starlin V. Mythri⁹³, Fethi Nacef⁹⁴, Ravi K. Nadella⁷⁶, Takako Nakanotani⁹⁵, René Ernst Nielsen⁷¹,⁷², Claire O'Donovan⁵, Adel Omrani⁹⁶, Yamima Osher²⁸, Uta Ouali⁹⁴, Maja Pantovic-Stefanovic⁶⁰, Pornjira Pariwatcharakul⁹⁷, Joanne Petite⁵, Johannes Petzold¹, Andrea Pfennig¹, Yolanda Pica Ruiz⁹⁸, Marco Pinna⁷⁹,⁹⁹, Maurizio Pompili¹⁰⁰, Richard J. Porter³⁶, Danilo Quiroz¹⁰¹, Francisco Diego Rabelo-da-Ponte¹⁰², Raj Ramesar¹⁰³, Natalie Rasgon¹⁰⁴, Woraphat Ratta-apha⁹⁷, Michaela Ratzenhofer³⁹, Maria Redahan³¹, M. S. Reddy¹⁰⁵, Andreas Reif¹⁶, Eva Z. Reininghaus⁹³, Jenny Gringer Richards¹⁰⁶, Philipp Ritter¹, Janusz K. Rybakowski⁴⁰, Leela Sathyaputri¹⁰⁶, Angela M. Scippa¹⁰⁷, Christian Simhandl¹⁰⁸, Daniel Smith¹⁰⁹, José Smith¹¹⁰, Paul W. Stackhouse Jr¹¹¹, Dan J. Stein¹¹², Kellen Stilwell³,⁴, Sergio Strejilevich¹¹⁰, Kuan-Pin Su¹¹³,¹¹⁴, Mythily Subramaniam¹¹⁵, Ahmad Hatim Sulaiman¹¹⁶, Kirsi Suominen¹¹⁷, Andi J. Tanra¹¹⁸, Yoshitaka Tatebayashi⁹⁵, Wen Lin Teh¹¹⁵, Leonardo Tondo¹¹⁹,¹²⁰, Carla Torrent¹²¹, Daniel Tuinstra³,⁴, Takahito Uchida⁸⁴,¹²², Arne E. Vaaler⁸⁹,⁹⁰, Eduard Vieta¹²¹, Biju Viswanath⁷⁶, Maria Yoldi-Negrete¹²³, Oguz Kaan Yalcinkaya⁶, Allan H. Young¹²⁴, Yosra Zgueb⁹⁴ and Peter C. Whybrow¹²⁵

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<footnote>*Correspondence:
Michael Bauer
michael.bauer@uniklinikum-dresden.de
Full list of author information is available at the end of the article</footnote>
**Abstract**

**Background** Sunlight contains ultraviolet B (UVB) radiation that triggers the production of vitamin D by skin. Vitamin D has widespread effects on brain function in both developing and adult brains. However, many people live at latitudes (about > 40 N or S) that do not receive enough UVB in winter to produce vitamin D. This exploratory study investigated the association between the age of onset of bipolar I disorder and the threshold for UVB sufficient for vitamin D production in a large global sample.

**Methods** Data for 6972 patients with bipolar I disorder were obtained at 75 collection sites in 41 countries in both hemispheres. The best model to assess the relation between the threshold for UVB sufficient for vitamin D production and age of onset included 1 or more months below the threshold, family history of mood disorders, and birth cohort. All coefficients estimated at P ≤ 0.001.

**Results** The 6972 patients had an onset in 582 locations in 70 countries, with a mean age of onset of 25.6 years. Of the onset locations, 34.0% had at least 1 month below the threshold for UVB sufficient for vitamin D production. The age of onset at locations with 1 or more months of less than or equal to the threshold for UVB was 1.66 years younger.

**Conclusion** UVB and vitamin D may have an important influence on the development of bipolar disorder. Study limitations included a lack of data on patient vitamin D levels, lifestyles, or supplement use. More study of the impacts of UVB and vitamin D in bipolar disorder is needed to evaluate this supposition.

**Background**

The sunlight that penetrates the atmosphere and reaches the Earth's surface has profound effects on human physiology and behavior, and is fundamental to human health (Wirz-Justice 2021). Daylight is the most powerful signal to entrain the human circadian system to the 24 h rotation of the Earth (Foster 2021; Roenneberg 2007). Daylight contains ultraviolet B radiation (UVB) that is absorbed by skin, triggers production of vitamin D, and is the major source of vitamin D for both children and adults (Holick 2017). Some of the many aspects of human health affected by daylight include sleep, mood, alertness, cognition, bone health, calcium homeostasis, neuroendocrine and cardiovascular regulation, and eyesight (Wirz-Justice 2021; Holick 2004; Paul 2019; LeGates 2014; Blume 2019; Crnko 2019; Lagreze 2017).

In prior studies, we analyzed the impact of solar insolation (incoming solar radiation) on several aspects of bipolar I disorder. Solar insolation is defined as the total amount of electromagnetic energy from the Sun striking a surface area of the Earth, and includes all wavelengths of visible and invisible light (NASA 2021). An inverse relation was found between the maximum monthly increase in solar insolation in springtime and the age of onset of bipolar I disorder (Bauer 2017). Due to the frequent symptoms of circadian disruption in patients with bipolar disorder, our studies of solar insolation focused the discussion on visible light and circadian entrainment (Bellivier 2015; Gonzalez 2014; Takaesu 2018).

The purpose of this exploratory analysis was to investigate the association between UVB and the age of onset of bipolar I disorder using a large, global sample. Recent findings emphasize the broad range of non-skeletal vitamin D functions including actions on the developing and

adult brain and the association of vitamin D deficiency with neurological and psychiatric disorders (Cuomo 2019; Hoilick 2004; Mayne 2019; Cui 2021; Bailon 2012; Berk 2009; Patrick 2015; Eyles 2020). Although UVB is approximately the same proportion of the total broadband solar insolation at all locations, many people live at latitudes that do not receive enough UVB during winter months to produce vitamin D from skin absorption (Webb 1988; Wacker 2013). The association of the age of onset of bipolar disorder with UVB is of particular importance given the high global rate of vitamin D deficiency (Holick 2017; Palacios 2014), and relevance of the age of onset to the outcome in bipolar disorder (Joslyn 2016; Menculini 2022).

**Methods**

All patients included in the study had a diagnosis of bipolar disorder made by a psychiatrist according to DSM-IV or DSM-5 criteria. The researchers were from university medical centers and specialty clinics, as well as individual practitioners. Data were collected retrospectively between 2010 and 2016 and 2019–2021, by patient questioning, record review or both. Details about the methodology for data collection were previously published (Bauer 2012; Bauer 2017; Bauer 2022). Study approval, including for data collection, was obtained according to local requirements, using local institutional review boards.

**Data collection sites**

Data were obtained at 75 data collection sites located in 41 countries in both hemispheres. The data collection sites in the northern hemisphere were in Austria: Graz, Wiener Neustadt; Canada: Calgary, Halifax, Ottawa;
China: Hong Kong; Colombia: Medellín; Denmark: Aalborg, Aarhus, Copenhagen; Ethiopia: Barhir Dar; Estonia: Tartu; Finland: Helsinki; France: Paris (2 sites); Germany: Dresden, Frankfurt, Würzburg; Greece: Athens, Thessaloniki (2 sites); India: Bengaluru, Hyderabad, Wardha; Ireland: Dublin; Israel: Beer Sheva; Italy: Cagliari, Sardegna (2 sites), Milan, Piacenza, Rome, Siena; Japan: Tokyo (3 sites); Malaysia: Kuala Lumpur; Mexico: Mexico City; Netherlands: Groningen; Norway: Oslo, Trondheim; Poland: Poznan; Russia: Khanti-Mansiysk, Serbia: Belgrade; Singapore; South Korea: Jincheon; Spain: Barcelona, Vitoria; Sweden; Gothenburg; Stockholm; Taiwan: Taichung; Thailand: Bangkok; Turkey: Ankara; Konya; Tunisia: Tunis; Uganda: Kampala; UK: Glasgow; and USA: Grand Rapids, MI, Iowa City, IA, Kansas City, KS, Los Angeles, CA, Palo Alto, CA, Rochester, MN, San Diego, CA, and Worcester, MA. The collection sites in the southern hemisphere were in Australia: Adelaide, Melbourne/Geelong; Argentina: Buenos Aires; Brazil: Porto Alegre, Salvador, São Paulo; Chile: Santiago (2 sites); Indonesia: Mataram; New Zealand: Christchurch; and South Africa: Cape Town.

## Data variables

The data collected for each patient included sex, age of onset, onset location, family history of mood disorders, polarity of first episode, history of psychosis, episode course, history of alcohol and substance abuse, and history of suicide attempts. Four birth cohort groups were used: born before 1940, between 1940 and 1959, between 1960 and 1979, and after 1979.

All the patient actual onset locations were grouped into reference onset locations, which represent all the onset locations within a 1x1 degree grid of latitude and longitude. The reference onset location was used to obtain the UVB data for each patient and used in the analysis.

## UVB

The surface UVB (280–315 nm) data are estimated by the NASA CERES ((Clouds and Earth’s Radiant Energy System), Wielicki 1996; Su 2005) and were downloaded from the NASA POWER database, based on 20-year Meteorological and Solar Monthly & Annual Climatologies (January 2001—December 2020), and accessed via the POWER Climatology API, Version: v2.2.22 (NASA 2022). For each reference onset location, the monthly average UVB expressed in watts/square meter (W/m²), and the daily average daylight hours for each month were obtained. For consistency with prior research, the average monthly W/m² values for UVB for each reference site were converted to the average total daily kilojoule/square meter as:

$$kJ/m^2/day = W/m^2 * 3600/1000 * \text{daylight hours}$$

for each month.

The UVB received at the Earth’s surface varies greatly by geographical location. See Fig. 1. UVB transmission through the atmosphere is greatly reduced by clouds, ozone and heavy air pollution (NASA 2022; Su 2005). For locations at the same latitude with similar cloud patterns, increasing elevation will increase surface UVB.

Above approximately 40° latitude N or S, there is insufficient UVB for vitamin D synthesis in winter (November through February in the northern hemisphere) (Webb 1988; Holick 2004). This study analyzed the relation between the threshold for UVB sufficient for vitamin D production in skin and the age of onset of bipolar disorder. Several researchers have estimated thresholds from 0.7 to 1.0 kJ/m²/day UVB (McKenzie 2009; O'Neill 2016). This analysis used a threshold of 0.75 kJ/m²/day UVB.

<figure><img src="image_5.png" /><figcaption>Fig. 1 Total UVB kJ/m²/day by Month for Selected Reference Locations</figcaption></figure>
## Statistics

The generalized estimating equations (GEE) statistical technique was used to accommodate the correlated data, and unbalanced number of patients within each reference onset location. The GEE model uses a marginal or population-averaged approach, to estimate the effect across the entire population rather than within a cluster (Zeger 1986). The dependent variable was the age of onset. An exchangeable correlation matrix was selected, which is appropriate for a large number of clusters including many with a single observation (Stedman 2008). Sidak's adjustment for multiple comparisons was used to make pair-wise comparisons between the birth-cohorts. A significance level of 0.001 was used for all evaluations to reduce the chance of type I error. The corrected quasi-likelihood independence model criterion was used to assist with model fitting (Pan 2001). SPSS version 28.0.0.0 was used for all analyses.

## Results

Data for 11,063 patients with bipolar disorder were obtained from the 75 collection sites, including 8080 patients with a diagnosis of bipolar I disorder. Of those with bipolar I disorder, 6972 patients had all variables in the best model. The demographic characteristics of the 6972 patients with bipolar I disorder are shown in Table 1. The mean age of onset for the 6972 patients was 25.6 years, shown distributed by latitude range in Table 2. The 6972 patients had an onset in 582 onset locations in 70 countries. There was a mean of 12 patients at each onset location, with 4% of the 582 locations having only one patient. Of the 6972 patients, 1293 (18.5%) had an onset in the southern hemisphere, and 1598 (22.9%) had an onset in the tropics.

The best fitting model estimated the age of onset using an intercept, 1 or more months of less than 0.75 mean monthly kJ/m²/day of UVB at the patient onset location, family history of mood disorders and patient birth cohort. All estimated coefficients were significant at the P < 0.001 level. The age of onset for patients at an onset location with at least 1 month < 0.75 mean monthly kJ/m²/day of UVB was 1.66 (99% CI [-2.614, -0.712]) years younger than for patients at an onset location elsewhere as shown in Table 3.

Of the 582 onset locations, 198 (34.0%) had at least 1 month of less than 0.75 mean monthly kJ/m²/day of UVB. All of these onset locations were at latitudes of 40 degrees or greater N or S, and included 2247 (32.2%) of patients.

## Discussion

An association between UVB and the age of onset of bipolar disorder was observed. Patients at locations with 1 or more months of less than the threshold for UVB

<table><caption>**Table 1** Demographics of Bipolar I patientsª (N = 6972)</caption><thead><tr><th>Parameter</th><th>Value</th><th>N</th><th>%</th></tr></thead><tbody><tr><td rowspan="2">Gender</td><td>Female</td><td>4054</td><td>58.3</td></tr><tr><td>Male</td><td>2894</td><td>41.7</td></tr><tr><td rowspan="2">First Episode</td><td>Manic/Hypomanic</td><td>3384</td><td>50.2</td></tr><tr><td>Depressed</td><td>3358</td><td>49.8</td></tr><tr><td rowspan="2">Family History of Mood Disorder</td><td>No</td><td>3328</td><td>47.7</td></tr><tr><td>Yes</td><td>3644</td><td>52.3</td></tr><tr><td rowspan="2">History of Alcohol or Substance Abuse</td><td>No</td><td>3492</td><td>69.5</td></tr><tr><td>Yes</td><td>1531</td><td>30.5</td></tr><tr><td rowspan="2">History of psychosis</td><td>No</td><td>1986</td><td>35.4</td></tr><tr><td>Yes</td><td>3622</td><td>64.6</td></tr><tr><td rowspan="2">Comorbid Anxiety/Panic/OCD</td><td>No</td><td>3854</td><td>77.4</td></tr><tr><td>Yes</td><td>1123</td><td>22.6</td></tr><tr><td rowspan="4">Cohort Age Group</td><td>DOB after 1979</td><td>1732</td><td>24.8</td></tr><tr><td>DOB 1979–1960</td><td>3234</td><td>46.4</td></tr><tr><td>DOB 1959–1940</td><td>1738</td><td>24.9</td></tr><tr><td>DOB before 1940</td><td>268</td><td>3.8</td></tr><tr><td rowspan="2">Onset Hemisphere</td><td>Northern</td><td>5679</td><td>81.5</td></tr><tr><td>Southern</td><td>1293</td><td>18.5</td></tr><tr><td>Parameter</td><td></td><td>Mean</td><td>SD</td></tr><tr><td>Age of Onset</td><td></td><td>25.6</td><td>10.4</td></tr></tbody></table>

<table><caption>**Table 2** Mean Age of Onset by Latitude Range (N = 6972)</caption><thead><tr><th>Latitude Range North + South</th><th>Mean Age of Onset</th><th>N</th><th>Standard Deviation</th></tr></thead><tbody><tr><td>0–9</td><td>26.6</td><td>511</td><td>9.97</td></tr><tr><td>10–19</td><td>24.3</td><td>797</td><td>9.49</td></tr><tr><td>20–29</td><td>24.8</td><td>375</td><td>11.39</td></tr><tr><td>30–39</td><td>25.5</td><td>2023</td><td>10.38</td></tr><tr><td>40–49</td><td>26.6</td><td>2368</td><td>10.59</td></tr><tr><td>50–59</td><td>24.4</td><td>682</td><td>10.16</td></tr><tr><td>60–69</td><td>22.7</td><td>216</td><td>11.29</td></tr><tr><td>Total</td><td>25.6</td><td>6972</td><td>10.43</td></tr></tbody></table>

sufficient for vitamin D production had an onset that was 1.66 years younger. However, there are major limitations to this exploratory study. There is no data on patient vitamin D levels, lifestyle, sun exposure, sunscreen use or if taking vitamin D supplements. There is no data

<footnote>ª Missing values excluded</footnote>
<table><caption>**Table 3** Estimated parameters explaining age of onset for patients with bipolar I disorder below a threshold of mean monthly kJ/m²/day of 0.75 UVB light for 1 or more months during the year (N = 6972)</caption><thead><tr><th rowspan="2">Parameters</th><th rowspan="2">Coefficient estimate (β)</th><th rowspan="2">Standard Error</th><th colspan="2">99% Confidence Interval</th><th colspan="2">Coefficient Significance</th></tr><tr><th>Lower</th><th>Upper</th><th>Wald Chi-squared</th><th>P</th></tr></thead><tbody><tr><td>Intercept</td><td>40.300</td><td>1.0867</td><td>38.107</td><td>42.429</td><td>1375.305</td><td>&lt; 0.001</td></tr><tr><td>Family history of mood disorders</td><td>- 1.914</td><td>0.2316</td><td>- 2.368</td><td>- 1.460</td><td>68.309</td><td>&lt; 0.001</td></tr><tr><td>Cohort age groups</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>DOB after 1979</td><td>- 19.768</td><td>1.0344</td><td>- 21.796</td><td>- 17.741</td><td>365.219</td><td>&lt; 0.001</td></tr><tr><td>DOB 1979-1960</td><td>- 13.575</td><td>1.0509</td><td>- 15.635</td><td>- 11.516</td><td>166.865</td><td>&lt; 0.001</td></tr><tr><td>DOB 1959-1940</td><td>- 7.509</td><td>1.0339</td><td>- 9.536</td><td>- 5.483</td><td>52.750</td><td>&lt; 0.001</td></tr><tr><td>DOB before 1940</td><td>0</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>UVB kJ/m²/day &lt; 0.75 for 1 or more months</td><td>- 1.663</td><td>0.4853</td><td>- 2.614</td><td>- 0.712</td><td>11.739</td><td>&lt; 0.001</td></tr></tbody></table>

Dependent variable: Age of onset (years). Model: intercept, family history of mood disorders (Y/N), cohort age groups, UVB kJ/m²/day < 0.75 for 1 or more months (Y/N). All Sidak pairwise comparisons between family history of mood disorders and cohort age groups were significant at the < 0.001 level

on dietary habits, although lower vitamin D levels were reported in vegetarians (Crowe 2011), or on skin pigmentation which effects absorption of UV radiation (Jablonski 2010). There is no data on whether patients take medications that interact with vitamin D such as many anti-epileptic drugs (Wakeman 2021; Fan 2016). There is no data on country vitamin D fortification. Yet, despite these limitations, an association between UVB and the age of onset of bipolar disorder was seen. This suggests that the role of UVB and vitamin D in bipolar disorder needs to be studied.

Vitamin D deficiency is frequently present in patients with psychiatric disorders. Many studies have reported vitamin D deficiency in patients with schizophrenia and major depressive disorder (MDD), with some opposite findings in MDD (Cui 2021; Valipour 2014; Bivona 2019). There are fewer studies of patients with bipolar disorder, but vitamin D status in these patients was similar to that of patients with other psychiatric disorders (Cereda 2021). The frequent medical comorbidity in patients with bipolar disorder may lead to poor eating habits, and limit exercise and sunlight exposure, which may also contribute to findings of vitamin D deficiency (Eyles 2020). Additionally, vitamin D deficiency and insufficiency is very common in international studies of people admitted for inpatient psychiatric treatment (Seiler 2022).

Vitamin D is a neurosteroid that has multiple roles in the brain throughout life. Vitamin D is involved in regulating brain development, maintaining function in the adult brain, and protecting the aged brain (Cui 2021; Eyles 2020; Groves 2014). Vitamin D acts on the brain by both genomic and non-genomic pathways. The genomic pathway involves vitamin D receptors that are found throughout most regions of the brain (Cui 2021; Eyles 2020; Groves 2014).

The actions of vitamin D within the brain influence neurotransmission, neuroprotection, synaptic plasticity, immunomodulation, and calcium signaling. This includes involvement of vitamin D in the release of neurotransmitters including dopamine, gamma-aminobutyric acid (GABA), and serotonin, and neuroprotective effects that suppress oxidative stress and inhibit inflammation (Cui 2021; Eyles 2020; Groves 2014). The role of vitamin D in the development and severity of psychiatric disorders is an area of active research, including for bipolar disorder (Berridge 2017; Berridge 2015; Patrick 2015; Eghedarian 2022; Eyles 2013).

## Other Limitations

Details about vitamin D production, and mechanisms of action in the brain were out of scope. Issues related to vitamin D assay methods, and differences between international guidelines for thresholds and supplementation were not discussed (Guistina 2020; Bouillon 2017). Changing needs for vitamin D across the lifespan, and strategies to address global vitamin D deficiency were not discussed (Bouillon 2017; Mendes 2020). UVB-related pathologies related to excessive exposure including skin cancers and ocular diseases were not discussed (Gies 2018). The potential use of vitamin D supplements as a treatment for bipolar disorder was out of scope (Marsh 2017). The surface UVB values were estimated from available satellite data and may differ slightly from direct surface UVB measurements (Su 2005). The global procedures implemented to prevent depletion of stratospheric ozone and resultant decreases in UVB were not included (Barnes 2019; NASA 2021).
## Conclusion

UVB is fundamental to the development of vitamin D, which is widely involved in the regulation of brain activities. In this large global study, patients at locations where the available UVB was below the threshold required for vitamin D production for at least 1 month had a younger age of onset of bipolar I disorder. UVB and vitamin D may have an important influence on the development of bipolar disorder. Further investigation of the role of UVB exposure and vitamin D in bipolar disorder is needed to evaluate this supposition.

## Acknowledgements

None.

## Author contributions

MB and TG completed the initial draft, which was reviewed by all authors. All authors read and approved the final manuscript.

## Funding

Open Access funding enabled and organized by Projekt DEAL. Ole A. Andreasen is supported by the Research Council of Norway (#223273) and the South Eastern Norway Health Region (#2019-108). Michael Berk is supported by a NHMRC Senior Principal Research Fellowship (1156072). Pierre A. Geoffroy, Chantal Henry and Josselin Houenou received grants from the French Agence Nationale pour la Recherche (ANR-11-IDEX-0004 Labex BioPsy "Olfaction and Bipolar Disorder" collaborative project, ANR-10-COH0-10-01 psyCOH and ANR-DFG ANR-14-CE35-0035 FUNDO). Seong Jae Kim is supported by research funds from the Institute of Medical Science, Chosun University, Republic of Korea, 2022. Mok Yee Ming, Mythily Subramaniam, and Wen Lin Teh received funding from the National Medical Research Centre (NMRC) Centre Grant (Ref No: NMRC/CG/M002/ 2017_IMH). Raj Ramesar is supported by the South African Department of Science and Innovation and Medical Research Council. Eduard Vieta acknowledges the support by CIBER -Consorcio Centro de Investigación Biomédica en Red- (CB07/09/0004), Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation. EV thanks the support of the Spanish Ministry of Science and Innovation (PI18/00805, PI21/00787) integrated into the Plan Nacional de I+D+I and co-financed by the ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER); the Instituto de Salud Carlos III; the Secretaria d'Universitat i Recerca del Departament d'Economia i Coneixement (2017 SGR 1365), the CERCA Programme, and the Departament de Salut de la Generalitat de Catalunya for the PERIS grant SLT006/17/00357. Thanks the support of the European Union Horizon 2020 research and innovation program (EU.3.1.1. Understanding health, wellbeing and disease: Grant No 754907 and EU.3.1.3. Treating and managing disease: Grant No 945151). Biju Viswanath is supported by the Intermediate (Clinical and Public Health) Fellowship (IA/ CPHI/20/1/505266) of the DBT/ Wellcome Trust India Alliance.

## Availability of data and materials

The data will not be shared or made publicly available.

## Declarations

### Ethics approval and consent to participate

Not applicable.

### Consent for publication

The authors provide consent for publication.

### Competing interests

Eric D. Achtyes has served on advisory boards or consulted for Alkermes, Atheneum, Janssen, Karuna, Lundbeck/Otsuka, Roche, Sunovion and Teva. He has received research support from Alkermes, Astellas, Biogen, Boehringer-Ingelheim, InnateVR, Janssen, National Network of Depression Centers, Neurocrine Biosciences, Novartis, Otsuka, Pear Therapeutics, and Takeda.

Ole A. Andreasen is a consultant to CorTechs.ai and has received speakers honorarium from Janssen, Lundbeck, and Sunovion. Alessandro Cuomo is /has been a consultant and/or a speaker and/or has received research grants from Angelini, Glaxo Smith Kline, Italfarmaco, Lundbeck, Janssen, Mylan, Neuraxpharm, Otsuka, Pfizer, Recordati, Sanofi Aventis, Viatris. Andrea Fagiolini is /has been a consultant and/or a speaker and/or has received research grants from Angelini, Apsen, Boheringer Ingelheim, Glaxo Smith Kline, Italfarmaco, Lundbeck, Janssen, Mylan, Neuraxpharm, Otsuka, Pfizer, Recordati, Sanofi Aventis, Viatris, Vifor. Lars Vedel Kessing has within the preceding three years been a consultant for Lundbeck and Teva. Rasmus W. Licht has received research grants from Glaxo Smith Kline, honoraria for lecturing from Pfizer, Glaxo Smith Kline, Eli Lilly, AstraZeneca, Bristol-Myers Squibb, Janssen Cilag, Lundbeck, Otsuka, Servier and honoraria from advisory board activity from Glaxo Smith Kline, Eli Lilly, AstraZeneca, Bristol-Myers Squibb, Janssen Cilag, Sunovion and Sage. Richard J. Porter has received research software by SBT-pro, and travel support from Servier and Lundbeck. Andreas Reif has received honoraria for ad boards and talk from Medice, Shire/Takeda, Janssen, LivaNova, Boehringer, SAGE/Biogen, cyclerion and COMPASS. Eduard Vieta has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, AbbVie, Adamed, Angelini, Biogen, Boehringer-Ingelheim, Celon Pharma, Compass, Dainippon Sumitomo Pharma, Ethypharm, Ferrer, Gedeon Richter, GH Research, Glaxo-Smith Kline, Janssen, Lundbeck, Medincell, Merck, Novartis, Orion Corporation, Organon, Otsuka, Roche, Rovi, Sage, Sanofi-Aventis, Sunovion, Takeda, and Viatris, outside the submitted work. All other authors report no competing interests.

## Author details

¹Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.

²ChronoRecord Association, Fullerton, CA, USA. ³Division of Psychiatry and Behavioral Medicine, Michigan State University College of Human Medicine, Grand Rapids, MI, USA. ⁴Pine Rest Christian Mental Health Services, Grand Rapids, MI, USA. ⁵Department of Psychiatry, Dalhousie University, Halifax, NS, Canada. ⁶Department of Psychiatry, Hacettepe University Faculty of Medicine, Ankara, Turkey. ⁷Department of Psychiatry, Selcuk University Faculty of Medicine, Mazhar Osman Mood Center, Konya, Turkey. ⁸NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway. ⁹Department of Psychiatry, National and Capodistrian University of Athens, Medical School, Egition Hospital, Athens, Greece. ¹⁰Section of Neurosciences and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Sardinia, Italy. ¹¹Department of Psychiatry, Selcuk University Faculty of Medicine, Konya, Turkey. ¹²Department of Psychiatry and Psychotherapy, University of Cologne Medical School, Cologne, Germany. ¹³Department of Psychiatry, University of Münster, Münster, Germany. ¹⁴Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Melbourne, Australia. ¹⁵The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia. ¹⁶Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Johann Wolfgang Goethe-Universität Frankfurt Am Main, Frankfurt Am Main, Germany. ¹⁷National Institute of Psychiatry "Ramón de la Fuente Muñiz", Mexico City, Mexico. ¹⁸Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, MI, USA. ¹⁹Department of Psychiatry, Jawaharlal Nehru Medical College, Datta Meghe Institute of Medical Sciences (Deemed University), Wardha, India. ²⁰Department of Psychiatry, College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar, Ethiopia. ²¹Bipolar Disorder Research Program, Department of Psychiatry, University of São Paulo Medical School, São Paulo, Brazil.

²²Département de Psychiatrie et de Médecine Addictologique, Assistance Publique, Hôpitaux de Paris, INSERM UMR-S1144, Université Paris Cité, Fondation FondaMental, Paris, France. ²³Division of Psychiatry, Ben Gurion University of the Negev, Beer Sheva, Israel. ²⁴University Vita-Salute San Raffaele, Milan, Italy. ²⁵Psychiatry and Clinical Psychobiology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy. ²⁶IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Australia. ²⁷Oxygen The National Centre of Excellence in Youth Mental Health, Centre for Youth Mental Health, Florey Institute for Neuroscience and Mental Health and the, Department of Psychiatry, The University of Melbourne, Melbourne, Australia. ²⁸Department of Psychiatry, Faculty of Health Sciences, Beer Sheva Mental Health Center, Ben Gurion University of the Negev, Beer Sheva, Israel. ²⁹Department
of Psychiatry, Baskent University Faculty of Medicine, Ankara, Turkey.

³⁰Butabika Hospital, Kampala, Uganda. ³¹Department of Psychiatry, Trinity College Dublin, St Patrick's University Hospital, Dublin, Ireland. ³²Mood Disorders Clinic, Dr. Jose Horwitz Psychiatric Institute, Santiago de Chile, Chile.

³³Department of Mental Health and Substance Abuse, Piacenza, Italy.

³⁴Department of Psychiatry, Chiayi Branch, Taichung Veterans General Hospital, Chiayi, Taiwan. ³⁵Private Practice, Central, Hong Kong, China.

³⁶Department of Psychological Medicine, University of Otago, Christchurch, New Zealand. ³⁷Department of Molecular Medicine, University of Siena School of Medicine, Siena, Italy. ³⁸Department of Psychiatry, University of Melbourne, Parkville, VIC, Australia. ³⁹Department of Psychiatry and Psychotherapeutic Medicine, Medical University Graz, Graz, Austria. ⁴⁰Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland. ⁴¹Department of Psychiatry, School of Epidemiology and Public Health, University of Ottawa and The Ottawa Hospital, Ottawa, ON, Canada. ⁴²³rd Department of Psychiatry, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece. ⁴³Department of Psychiatry and Psychology, Mayo Clinic Depression Center, Mayo Clinic, Rochester, MN, USA. ⁴⁴Département de Psychiatrie et d'addictologie, AP-HP, GHU Paris Nord, DMU Neurosciences, Hôpital Bichat, Claude Bernard, 75018 Paris, France.

⁴⁵GHU Paris, Psychiatry and Neurosciences, 1 Rue Cabanis, 75014 Paris, France.

⁴⁶Université de Paris, NeuroDiderot, Inserm, FHU 1D2D, 75019 Paris, France.

⁴⁷BIOARABA, Department of Psychiatry, University Hospital of Alava, University of the Basque Country, CIBERSAM, Vitoria, Spain. ⁴⁸Department of Psychiatry, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

⁴⁹Mood Disorders Center of Ottawa and the Department of Psychiatry, University of Toronto, Toronto, Canada. ⁵⁰Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. ⁵¹Department of Psychiatry, Tokyo Metropolitan Matsuzawa Hospital, Setagaya, Tokyo, Japan. ⁵²Department of Psychiatry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. ⁵³Programa de Pós-Graduação em Psicologia, Departamento de Psicologia do Desenvolvimento e da Personalidade, Instituto de Psicologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. ⁵⁴Department of Psychiatry, GHU Paris Psychiatrie and Neurosciences, Université de Paris, F-75014, F-75006 Paris, France.

⁵⁵Department of Clinical Research, University of Southern Denmark, Odense, Denmark. ⁵⁶Université Paris Est Créteil, INSERM, IMRB, Translational Neuropsychiatry, APHP, Mondo Univ Hospitals, Fondation FondaMental, F-94010 Créteil, France. ⁵⁷Université Paris Saclay, CEA, Neurospin, F-91191 Gif-Sur-Yvette, France. ⁵⁸Department of Psychiatry, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. ⁵⁹National Institute for Health and Welfare, Helsinki, Finland. ⁶⁰Clinic for Psychiatry, University Clinical Center of Serbia, Belgrade, Serbia. ⁶¹Department of Psychiatry, University of Tartu, Tartu, Estonia. ⁶²Unit for Psychiatric Research, Aalborg University Hospital, Aalborg, Denmark. ⁶³Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. ⁶⁴Copenhagen Affective Disorder Research Center (CADIC), Psychiatric Center Copenhagen, Copenhagen, Denmark. ⁶⁵Department of Psychiatry, Chosun University School of Medicine, Gwangju, Republic of Korea. ⁶⁶BIPOLAR Zentrum Wiener Neustadt, Wiener Neustadt, Austria. ⁶⁷Khanty-Mansiysk Clinical Psychoneurological Hospital, Khanty-Mansiysk, Russia. ⁶⁸Neuroscience Program, Michigan State University, East Lansing, MI, USA. ⁶⁹Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. ⁷⁰Mental Health Department Odense, University Clinic and Department of Regional Health Research, University of Southern Denmark, Esbjerg, Denmark. ⁷¹Psychiatry, Aalborg University Hospital, Aalborg, Denmark. ⁷²Department of Clinical Medicine, Aalborg University, Aalborg, Denmark. ⁷³Mood Disorders Program, Hospital Universitario San Vicente Fundación, Research Group in Psychiatry, Department of Psychiatry, Faculty of Medicine, Universidad de Antioquia, Medellín, Colombia. ⁷⁴Forensic Psychiatry, University of Glasgow, NHS Greater Glasgow and Clyde, Glasgow, UK. ⁷⁵Psychiatry Centre Copenhagen, Copenhagen University Hospitals, Copenhagen, Denmark. ⁷⁶Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India. ⁷⁷Department of Psychiatry, Faculty of Medicine, Mataram University, Mataram, Indonesia. ⁷⁸Department of Pharmacology, Dalhousie University, Halifax, NS, Canada. ⁷⁹Section of Psychiatry, Department of Medical Science and Public Health, University of Cagliari, Cagliari, Italy. ⁸⁰Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, Cagliari, Italy. ⁸¹Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA, USA.

⁸²Osakidetza, Basque Health Service, BioAraba Health Research Institute,

University of the Basque Country, Bilbao, Spain. ⁸³The Psychology Clinic of East Anglia, Norwich, UK. ⁸⁴Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan. ⁸⁵Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College Dublin, St Patrick's University Hospital, Dublin, Ireland. ⁸⁶Department of Child and Adolescent Psychiatry Und Psychotherapy, SHG Klinikum, Idar-Oberstein, Germany. ⁸⁷Department of Mood and Anxiety Disorders, Institute of Mental Health, Singapore City, Singapore. ⁸⁸Michigan State University College of Human Medicine, Traverse City Campus, Traverse City, MI, USA. ⁸⁹Department of Mental Health, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.

⁹⁰Department of Psychiatry, St Olavs' University Hospital, Trondheim, Norway.

⁹¹Soviet Psychoneurological Hospital, Urai, Russia. ⁹²Department of Psychiatry, University of California San Diego, San Diego, CA, USA. ⁹³Makunda Christian Leprosy and General Hospital, Bazaricherra, Assam 788727, India. ⁹⁴Razi Hospital, Faculty of Medicine, University of Tunis-El Manar, Tunis, Tunisia.

⁹⁵Tokyo Metropolitan Hiroo Hospital, 2-34-10 Ebisu, Shibuya-Ku, Tokyo 150-0013, Japan. ⁹⁶Tunisian Bipolar Forum, Erable Médical Cabinet 324, Lac 2, Tunis, Tunisia. ⁹⁷Department of Psychiatry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. ⁹⁸Hospital "Angeles del Pedregal", Mexico City, Mexico. ⁹⁹Lucio Bini Mood Disorder Center, Cagliari, Italy. ¹⁰Department of Neurosciences, Mental Health and Sensory Organs, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy. ¹⁰¹Department of Psychiatry, Diego Portales University, Santiago de Chile, Chile. ¹⁰²School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, Lancashire, UK. ¹⁰³SA MRC Genomic and Precision Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa. ¹⁰⁴Department of Psychiatry and Behavioral Sciences, Stanford School of Medicine, Palo Alto, CA, USA. ¹⁰⁵Asha Bipolar Clinic, Asha Hospital, Hyderabad, Telangana, India. ¹⁰⁶Departments of Psychiatry, Epidemiology, and Internal Medicine, Iowa Neuroscience Institute, The University of Iowa, Iowa City, IA, USA. ¹⁰⁷Department of Neuroscience and Mental Health, Federal University of Bahia, Salvador, Brazil. ¹⁰⁸Bipolar Zentrum Wiener Neustadt, Sigmund Freud Privat Universität, Vienna, Austria.

¹⁰⁹Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Scotland, UK. ¹¹⁰AREA, Assistance and Research in Affective Disorders, Buenos Aires, Argentina. ¹¹¹Science Directorate/Climate Science Branch, NASA Langley Research Center, Hampton, VA, USA. ¹¹²Department of Psychiatry, MRC Unit on Risk and Resilience in Mental Disorders, University of Cape Town, Cape Town, South Africa. ¹¹³College of Medicine, China Medical University (CMU), Taichung, Taiwan. ¹¹⁴An-Nan Hospital, China Medical University, Tainan, Taiwan.

¹¹⁵Research Division, Institute of Mental Health, Singapore, Singapore.

¹¹⁶Department of Psychological Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. ¹¹⁷Department of Social Services and Health Care, Psychiatry, City of Helsinki, Helsinki, Finland. ¹¹⁸Department of Psychiatry, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia.

¹¹⁹McLean Hospital-Harvard Medical School, Boston, MA, USA. ¹²⁰Mood Disorder Lucio Bini Centers, Cagliari e Rome, Italy. ¹²¹Clinical Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain. ¹²²Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne, Melbourne, Australia.

¹³Subdirección de Investigaciones Clínicas, Instituto Nacional de Psiquiatria Ramón de la Fuente Muñiz, Mexico City, Mexico. ¹²⁴Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. ¹²⁵Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles (UCLA), Los Angeles, CA, USA.

Received: 9 December 2022 Accepted: 16 May 2023

Published online: 22 June 2023

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