Introduction
Valproic acid (VPA) is an antiepileptic drug (AED) frequently prescribed for the treatment of bipolar disorder, epilepsy, and migraine.Reference McIntyre, Berk and Brietzke 1 In 2023, the Medicines and Healthcare products Regulatory Agency (MHRA) provided guidance to healthcare practitioners that VPA should not be prescribed in the treatment of male or female patients under 55 unless agreed upon by independent consultants before its teratogenic risk. 2 The MHRA opined that the teratogenic risks warranted the proscriptive recommendation. The teratogenic effects of VPA are well documented,Reference Robert and Guibaud 3 , Reference Lindhout, Omtzigt and Cornel 4 including major congenital malformations (MCMs) (eg, neural tube defects [NTD], cardiac malformations, and limb malformations),Reference Blotière, Raguideau and Weill 5 behavioral disturbance (eg, autism spectrum disorder [ASD] and neurodevelopmental disorder [NDD]),Reference Christensen, Grønborg and Sørensen 6 , Reference Daugaard, Pedersen, Sun, Dreier and Christensen 7 and cognitive abnormalities (eg, intellectual disability [ID] and lower IQ).Reference Nadebaum, Anderson, Vajda, Reutens, Barton and Wood 8 – 10
Recommendations from the US Preventive Services Task Force (USPSTF), Centers for Disease Control and Prevention (CDC), and the World Health Organization (WHO) are that women should receive 0.4 mg/daily starting 1–2 months before planned pregnancy up until 12 weeks of pregnancy to prevent anatomical teratogenicity (ie, NTD). 11 – 13 Notwithstanding the hazard-mitigating effects of folic acid in the general population, its effect on mitigating or abrogating the hazard of teratogenicity in women exposed to VPA has not been convincingly established.Reference Bjørk, Vegrim and Alvestad 14 , Reference Vegrim, Dreier and Alvestad 15
Herein, we systematically review and comprehensively estimate anatomical, behavioral, and cognitive teratogenicity hazards associated with prenatal/early gestation VPA exposure as well as the hazard-mitigating effect of folic acid supplementation. Although this topic has been reviewed elsewhere,Reference Jentink, Loane and Dolk 16 –Reference Gotlib, Ramaswamy, Kurlander, DeRiggi and Riba 18 given the seriousness of this topic, there is an ongoing need for a real-time up-to-date summary of this particular literature. Hence, the overarching aim is to provide an up-to-date risk assessment of VPA to inform algorithmic recommendations for treatment and treatment selection for bipolar disorder, epilepsy, and migraine.
Methods
Data sources and search strategy
This review was conducted based on the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.Reference Page, McKenzie and Bossuyt 19 A systematic search was conducted on PubMed, Medline, Cochrane Library, PsycInfo, Embase, Scopus, and Web of Science from inception to June 10, 2024. A manual search on Google Scholar was also performed. The search string can be found in eTable1.
Study selection
Study screening and selection were conducted independently by two reviewers (KV and KT). Titles and abstracts were screened for relevance. We sought articles reporting data relevant to any primary outcome (ie, Anatomical, Behavioral, or Cognitive), as defined in Table 1. Studies were eligible for inclusion if they: (1) followed a cross-sectional, case–control, or cohort study design; (2) assessed either the anatomical, behavioral, or cognitive effects of in utero VPA exposure or the effect of folic acid supplementation in reducing VPA-associated teratogenicity, and (3) utilized validated scales for measurement. Studies were excluded if they: (1) were not written in English; (2) were not peer-reviewed; (3) did not have full-text availability.
Table 1. Definition of primary outcomes
Data extraction
Published summary data from included articles were independently extracted by KV and KT using a piloted data extraction form, and then corroborated. Discrepancies were resolved through discussion with all additional authors. Information to be extracted was determined a priori and included: (1) year of publication, (2) country/region of the population studied, (3) study design, (4) sample size, (5) sample characteristics, (6) assessment tools, and (7) data relevant to the primary outcome(s). Full statistics are reported where relevant.
Quality assessment
The Newcastle–Ottawa Scale (NOS) was applied to assess cohort, case–control, and cross-sectional studies.Reference Luchini, Veronese and Nottegar 20 Studies where the design was unclear were assessed using the cohort NOS. Cohort studies were penalized if they failed to include a non-exposed cohort, in addition to other items tested. All component studies were independently rated by KV and KT and results were corroborated, with discrepancies resolved via discussion with all additional authors. All applied NOSs can be found in eTables 2–4.
Results
Search results
The literature search yielded 795 studies. Following the removal of duplicates and screening of titles and abstracts, 188 studies were eligible for full-text screening against the eligibility criteria. Following the full-text screening, 41 studies were further excluded before full-text unavailability. Details of study selection are provided in Figure 1. In total, 122 studies were included.
Figure 1. Study selection flow diagram.
Study characteristics
Study characteristics and findings are summarized in eTable 5. Sample sizes ranged from 31 to 4 494 926, and included 27 238 488 participants. Maternal age ranged from 12 to 55 years of age. The age of sampled offspring ranged from neonates to 39 years of age. Based on reported numbers, females made up 48.7% of the total offspring. Reported follow-up periods ranged from 1 month to 6 years for anatomical studies, 2 years to 22 years for behavioral studies, 7 months to 16 years for cognitive studies, and 3 months to 8 years for folic acid studies. There were 82 prospective cohort studies, 20 retrospective cohort studies, 9 prospective case–control studies, 5 retrospective case–control studies, and 6 cross-sectional studies. Exactly 67 studied anatomical outcomes associated with prenatal VPA exposure, 28 studied behavioral outcomes, 47 studied cognitive outcomes, and 20 studied folic acid. Measurement tools can be found in eTable 6.
Quality appraisal
Quality appraisal results are presented in eTables 7–9. Awarded stars varied from 5 to 9. In general, the studies received a moderate rating. The mean score for case–control studies was 7.1/9, the mean score for cross-sectional studies was 6.7/8, and the mean score for the cohort studies was 6.4/9. Common methodological limitations were an insufficient adjustment for age and sex as baseline covariates as well as whether the outcome of interest (eg, anatomical teratogenicity) was present before VPA exposure.Reference Veiby, Daltveit, Engelsen and Gilhus 21 –Reference Vajda, O’Brien, Graham, Lander and Eadie 33
Anatomical teratogenicity
We identified 67 studies that reported anatomical events associated with VPA use. Reported diagnoses include MCMs and congenital anomalies (CAs) (eg, impaired hearing and low birth weight).
The odds ratio (OR) for MCMs and CAs ranged from 2.47 to 9.30 (p < 0.005).Reference Veiby, Daltveit, Engelsen and Gilhus 21 , Reference Mawer, Briggs and Baker 22 The OR for MCM and CA without including neural tube defect (NTD) ranged from 4.86 to 5.71 (p = 0.008).Reference Kawai, Pak and Iwamoto 23 , Reference Rodríguez-Pinilla, Mejías, Prieto-Merino, Fernández and Martínez-Frías 34 Specific MCMs reported include but were not limited to, hypospadias, cleft lip, polydactyly, kidney, gastrointestinal tract, limb defects, and congenital heart defects.Reference Blotière, Raguideau and Weill 5 , Reference Battino, Tomson and Bonizzoni 24 , Reference Vajda, O’brien and Hitchcock 25 Dosage/blood levels were shown as a baseline covariate, where an increased dose was associated with elevated odds of developing MCMs (p < 0.01) (Unreported maternal levels),Reference Tomson, Battino and Bonizzoni 26 , Reference Kaneko, Battino and Andermann 27 and maternal VPA blood level was correlated with malformation occurrence (regression coefficient = 0.052, p = 0.005).Reference Güveli, Rosti and Güzeltaş 28 Reducing VPA dose was also associated with reduced hazard, however, at the risk of reduced pre-pregnancy seizure control.Reference Vajda, O’Brien, Graham, Hitchcock, Lander and Eadie 29 , Reference Vajda, O’Brien, Graham, Lander and Eadie 33 Results were consistent when comparing prenatal VPA exposure to AED unexposed controls or children exposed to a different AED (eg, carbamazepine [CBZ], lamotrigine [LTG], and clonazepam [CZP]).Reference Vajda, O’brien and Hitchcock 25 , Reference Tomson, Battino and Bonizzoni 26 Differences between VPA monotherapy and polytherapy including VPA were inconclusive.
Independent of MCMs, prenatal VPA exposure was significantly associated with hearing impairments (adjusted OR [aOR] 6.88),Reference Foch, Araujo and Weckel 30 low birth weight (OR 3.141, Kappa: 0.147 [p < 0.001], χ 2: 14.623 [p < 0.001])35, and poorer Apgar scores (p = 0.0015) (the clinical state of a newborn based on five physical signs).Reference Pennell, Klein and Browning 35
Neural tube defects
Neural tube defects (NTDs) were assessed in eight studies. The ORs for NTD ranged from 3.9 to 19.4Reference Blotière, Raguideau and Weill 5 , Reference Medveczky, Puhó and Czeizel 36 and were significant when compared with CBZ (OR 4.45; 95% CI [1.45, 13.69], p = 0.009) and LTG (OR 11.29; 95% CI [2.54, 50.12], p = 0.0002).Reference Campbell, Kennedy and Russell 31 Dose was positively correlated with spina bifida (+0.0010, p < 0.01).Reference Vajda, Graham, Hitchcock, Lander, O’Brien and Eadie 32 It was reported in a single study that the mean VPA dose during the first trimester was higher in mothers whose offspring had spina bifida (2000 ± 707 vs 1257 ± 918 mg/day) (p < 0.05).Reference Foch, Araujo and Weckel 30 A separate observed an aOR of 19.4 for spina bifida (95% CI 8.6, 43.5).Reference Blotière, Raguideau and Weill 5
Behavioral teratogenicity
We identified 28 studies meeting our eligibility criteria that reported on behavioral alterations associated with VPA exposure. Reported outcomes include autism, attention-deficit/hyperactivity disorder (ADHD), poor motor skills, and neurodevelopmental delay.Reference Hernández-Díaz, Straub and Bateman 37 –Reference Veiby, Daltveit and Schjølberg 39 Hazard ratios (HR) for autism ranged from 1.70 to 4.38 when compared with unexposed controls,Reference Christensen, Grønborg and Sørensen 6 , Reference Hernández-Díaz, Straub and Bateman 37 with higher doses tending to yield a higher OR.Reference Hernández-Díaz, Straub and Bateman 37 The OR for ADHD associated with VPA ranged from 1.39 to 1.77 when compared with unexposed controls.Reference Pennell, Klein and Browning 35 , Reference Hernández-Díaz, Straub and Bateman 37 When compared with LTG, CBZ, and CZP, the ORs for ADHD were 2.16, 1.79, and 1.96, respectively.Reference Pennell, Klein and Browning 35 Ceasing VPA use before pregnancy was associated with a reduced, but not eliminated, risk of ADHD (aHR 1.66).Reference Christensen, Pedersen, Sun, Dreier, Brikell and Dalsgaard 38 Exposure to VPA during the 2nd or 3rd trimester only was associated with a reduced risk of autism (HR 3.44 to HR 1.94).Reference Bjørk, Zoega and Leinonen 40
The scales used to measure motor development and functioning varied across the included studies. A singular study reported an OR of 7.0 (p < 0.05) using the Ages and Stages Questionnaire (ASQ).Reference Veiby, Daltveit and Schjølberg 39 A separate study reported that relative to non-AED exposed controls, VPA-exposed children scored −11.7 points (Standard Error [SE]: 3.9, [95% CI −19.4, −4.1] p = 0.003) lower on gross motor development, and −15.8 points (SE: 4.4, p < 0.001) lower relative to levetiracetam (LEV) exposed children.Reference Shallcross, Bromley and Cheyne 41 VPA dose was also inversely correlated with motor development (Pearson MoDQ correlation: −0.239, p = 0.042; BSID-II Motor Index and VPA correlation: −0.60 [p < 0.0001]).Reference Thomas, Ajaykumar, Sindhu, Nair, George and Sarma 42 , Reference Cohen, Meador and Browning 43
Similarly, prenatal VPA exposure was associated with poorer adaptive function and behavioral development. ORs for neurodevelopmental delay ranged from 2.44 to 26.1 relative to controls.Reference Bjørk, Zoega and Leinonen 40 , Reference Cohen, Meador and Browning 43 A dose-dependent effect was observed relative to LTG and CBZ.Reference Blotière, Miranda and Weill 44 A dose-related decline was also observed for adaptive functioning (p = 0.0252).Reference Cohen, Meador and Browning 45 Additionally, the mean adaptive behavior composite for VPA-exposed children was significantly lower than CBZ- and LTG-exposed children (ANOVA; p = 0.017).Reference Deshmukh, Adams and Macklin 46
Poor language development was also associated with VPA exposure. One study reported an adverse development in sentence skills (OR 3.4; 95% CI [1.0, 12.0] p < 0.05).Reference Veiby, Daltveit and Schjølberg 39 A separate study reported an expressive language score to be on average −9.5 points (p < 0.001) below levetiracetam (LEV) exposed children and poorer language comprehension relative to non-AED exposed controls by −8.7 points (p < 0.001).Reference Shallcross, Bromley and Cheyne 41 VPA plasma concentrations were also correlated with a poor language score (r = −0.50, p = 0.04),Reference Husebye, Gilhus, Riedel, Spigset, Daltveit and Bjørk 47 and an ASQ communication score (Spearman’s rho: −0.77, p = 0.02).Reference Husebye, Gilhus, Spigset, Daltveit and Bjørk 48
Cognitive teratogenicity
We identified 47 studies reporting on cognitive teratogenicity associated with VPA exposure. Outcomes included poorer IQ and cognitive impairment, poorer performance on standardized tests, and increased risk for mental disorders and learning disabilities.
IQ scores for VPA-exposed children were significantly lower than non-VPA-exposed (p = 0.007),Reference Kini, Adab, Vinten, Fryer and Clayton-Smith 49 , Reference Baker, Bromley and Briggs 50 including CBZ-, LTG-, and LEV-exposed children.Reference Huber-Mollema, van Iterson, Oort, Lindhout and Rodenburg 51 Multivariate analysis demonstrated VPA exposure to be predictive for full-scale IQ (FSIQ) (β, − 12.04; p = 0.006).Reference Kasradze, Gogatishvili and Lomidze 52 When evaluating discrete domains of intelligence, verbal IQ (VIQ) was associated with poorer outcomes. Specifically, a singular study reported a significant negative correlation between dysmorphic face features and verbal intelligence (Spearman’s ρ = −0.436, p = 0.007).Reference Kini, Adab, Vinten, Fryer and Clayton-Smith 49 A separate observed a significant relationship between VPA dose and verbal comprehension (r = −0.265, p = 0.046).Reference Nadebaum, Anderson, Vajda, Reutens, Barton and Wood 53 Another reported impaired verbal abilities with VPA doses at <800 mg daily (VIQ: −5.6, p = 0.04).Reference Baker, Bromley and Briggs 50 Additional affected cognitive domains include attention (r = −0.38, p = 0.0075),Reference Cohen, Meador and May 54 memory (free recall, r = −0.402, p = 0.006; recognition, r = −0.292, p = .038),Reference Barton, Nadebaum, Anderson, Vajda, Reutens and Wood 55 language (Pearson correlation: −0.48, p = 0.001),Reference Meador, Baker and Browning 56 executive function (r = −0·42, p = 0·0004),Reference Meador, Baker and Browning 57 perceptual–motor function (r = −0.46, p = 0.02),Reference Rihtman, Parush and Ornoy 58 and socialization (relative to LTG and CBZ) (p = 0.026).Reference Nadebaum, Anderson, Vajda, Reutens, Barton and Wood 8
Hazard ratios (HR) for intellectual disability (ID) ranged from 2.40 to 4.48.Reference Daugaard, Pedersen, Sun, Dreier and Christensen 7 , Reference Bjørk, Zoega and Leinonen 40 HR for mental retardation was reported to be 5.1 relative to unexposed controls.Reference Nadebaum, Anderson, Vajda, Reutens, Barton and Wood 59 Further tests also showed that general memory (p = 0.0434),Reference Meador, Baker and Browning 57 working memory (p ≤ 0.031),Reference Nadebaum, Anderson, Vajda, Reutens, Barton and Wood 59 inhibition (p = 0.069),Reference Huber-Mollema, van Iterson, Oort, Lindhout and Rodenburg 51 and internalization skills (p = 0.05),Reference Bluett-Duncan, Astill and Charbak 60 were negatively affected by prenatal VPA exposure relative to either AED-unexposed children or exposure to other AEDs (CBZ, LEV, and LTG).
Prenatal VPA exposure was also associated with poorer performance on academic and standardized tests. Relative to anti-seizure medication (ASM) unexposed children, VPA exposure was associated with lower 6th- and 8th-grade math and Danish scores.Reference Elkjær, Bech, Sun, Laursen and Christensen 9 , Reference Ren, Lee, Li and Li 61 Ranging from a −0.33 to −0.13 difference in Z score for Danish, and −0.33 to −0.08 for math. Results were similar when compared with lamotrigine.
A final affected cognitive outcome associated with in utero VPA exposure was mental disorders (HR 1.85),Reference Dreier, Bjørk and Alvestad 62 including Tic Disorder (HR 1.56), Attachment Disorder (HR 1.91), and Neuropsychiatric Developmental Delay (NDD) (OR 2.535, Kappa 0.099, χ2: 5.158).Reference Dreier, Bjørk and Alvestad 62 , Reference Li, Chen and Cao 63
Risk-mitigating effects of folic acid supplementation
We identified 20 studies that sought to determine the teratogenic risk-mitigating effects of folic acid supplementation in persons prescribed VPA, 3 of which evaluated the folic acid prevention effects in persons receiving VPA monotherapy. Results pooling VPA and other AEDs were included.
Pooled results suggest that folic acid supplementation is not proven effective in reducing VPA- or AED-associated malformations. With respect to major congenital malformations and folic acid supplementation, a singular study reported an aOR of 1.75 with high dose folic acid (≥ 5 mg daily) and 1.94 with low dose folic acid (< 5 mg daily), starting at least 4 weeks before conception (periconceptionally).Reference Ban, Fleming and Doyle 64 The aforementioned finding indicating no hazard mitigating effects has been replicated, in other studies of different methodologies.Reference Vajda, O’Brien, Hitchcock, Graham and Lander 65 , Reference Vajda, Graham, Hitchcock, Lander, O’Brien and Eadie 66 In contrast, some studies do suggest that folic acid may be effective in protecting against adverse cognitive and behavioral outcomes. For example, it was reported that periconceptional folic acid supplementation was associated with less impaired language function (no dose specification) (OR 0.4, p < 0.05).Reference Husebye, Gilhus, Spigset, Daltveit and Bjørk 48 A separate analysis found that the absence of periconceptional folic acid supplementation was associated with an increased risk of autism in AED-exposed women (aOR 5.9), with higher doses of folic acid decreasing risk (β = −0.5; p < 0.001) (Low dose = 0.4 mg/daily, high dose = 5.0 mg/daily).Reference Bjørk, Riedel and Spigset 67 It was additionally reported that the hazard for AED-associated language delay was reduced in women prescribed folic acid periconceptionally when compared with women receiving AEDs and not prescribed folic acid (≥ 0.4 mg folic acid daily, OR 3.9, p < 0.001 to OR 1.7, p = 0.01).Reference Husebye, Gilhus, Riedel, Spigset, Daltveit and Bjørk 47
Studies separately evaluating VPA monotherapy reported that folic acid supplementation does not significantly reduce the risk for anatomic and cognitive teratogencity.Reference Campbell, Kennedy and Russell 31 , Reference Meador, Baker and Browning 57 , Reference Morrow, Russell and Guthrie 68 For example, periconceptual folic acid supplementation (dose not specified) had no significant risk-mitigating effect on the risk for MCM (p = 0.23) and NTD (p = 0.78).Reference Vajda, Graham, Hitchcock, Lander, O’Brien and Eadie 32 , Reference Vajda, O’Brien, Hitchcock, Graham and Lander 65 Moreover, periconceptual folic acid did not protect against VPA-associated impairment in childhood IQ.Reference Cohen, Meador and May 54
Discussion
A highly replicated finding is that VPA as monotherapy or in combination with other AEDs is highly associated with all three subtypes of teratogenicity evaluated herein. Moreover, available evidence does not support the hypothesis that folic acid supplementation abrogates or significantly mitigates the risk for anatomical teratogenicity associated with any AED including VPA.Reference Campbell, Kennedy and Russell 31 , Reference Ban, Fleming and Doyle 64 The absence of compelling risk-mitigating effects contrasts with findings in the general population wherein the USPSTF has a Grade A recommendation for folic acid (0.4–0.8 mg 1 month prior and up to 2–3 months post conception). 11 Notwithstanding, preliminary evidence suggests that folic acid supplementation may attenuate the risk for behavioral and/or cognitive teratogenicity.Reference Husebye, Gilhus, Spigset, Daltveit and Bjørk 48 , Reference Bjørk, Riedel and Spigset 67 Possibly through the neurotrophic effects of maternal folic acid.Reference Chen, Qin and Gao 69 Our findings accord with published reviews and meta-analyses that have also reported on teratogenic hazards associated with VPA and the absence of an evidence-based mitigation study.Reference Jentink, Loane and Dolk 16 –Reference Gotlib, Ramaswamy, Kurlander, DeRiggi and Riba 18
Our analysis, to our knowledge, is the most updated synthesis of the risk of teratogenicity associated with VPA and the impact of folic acid supplementation. Notwithstanding, despite the calls to decrease the exposure of VPA in reproductive-aged women and some evidence of a downward trajectory of usage, overall rates of rates of usage continue to be considerable.Reference Samalin, Godin and Olié 70 Population-level literacy on the hazards of VPA with respect to teratogenicity is highly inadequate insofar as it was reported in a European sample that the majority of women were not familiar with hazards associated with VPA.Reference Mulryan, McIntyre, McDonald, Feeney and Hallahan 71 Along with inadequate population awareness of the hazard, as most persons prescribed VPA by healthcare providers are not routinely informed of this risk.Reference Paton, Cookson, Ferrier, Bhatti, Fagan and Barnes 72
There are many methodological limitations that affect inferences and interpretations of our findings. Firstly, the preponderance of the data reporting on anatomical teratogenicity utilizes observational designs of pregnancy registries and pharmacovigilance databases. Additionally, most studies reported herein evaluated prenatal VPA exposure in women with epilepsy and not in women living with other disorders (eg, bipolar disorder). Moreover, there is limited data with respect to posology or plasma levels of VPA and its association with teratogenicity. Also, most studies we identified evaluated the teratogenicity risk of VPA as part of a polytherapy regimen. However, we did not observe any lines of evidence suggesting that commonly prescribed co-agents necessarily accounted for the reported hazardous effects.
Conclusion
VPA is associated with anatomical, behavioral, and cognitive teratogenicity. Folic acid supplementation, although beneficial in the general population to mitigate the risk of congenital malformation, has not been shown to mitigate the risk of anatomical malformation specifically associated with VPA exposure. Available evidence supports limited and judicious use in reproductive-age women. Future research should determine the effects of VPA administration in males.
Supplementary material
The supplementary material for this article can be found at http://doi.org/10.1017/S1092852924002311.
Author contribution
Writing – review & editing: R.B.M., J.D.R., A.K., G.H.L., K.T., K.V., H.K.L., S.W., R.S.M.; Conceptualization: K.V., R.S.M.; Data curation: K.V.; Formal analysis: K.V.; Writing – original draft: K.V.; Methodology: R.S.M.; Supervision: R.S.M.
Disclosures
Roger S. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, Abbvie, Atai Life Sciences. Dr. Roger McIntyre is the CEO of Braxia Scientific Corp.
Dr. Joshua D Rosenblat has received research grant support from the Canadian Institute of Health Research (CIHR), Physician Services Inc (PSI) Foundation, Labatt Brain Health Network, Brain and Cognition Discovery Foundation (BCDF), Canadian Cancer Society, Canadian Psychiatric Association, Academic Scholars Award, American Psychiatric Association, American Society of Psychopharmacology, University of Toronto, University Health Network Centre for Mental Health, Joseph M. West Family Memorial Fund and Timeposters Fellowship and industry funding for speaker/consultation/research fees from iGan, Boehringer Ingelheim, Braxia Health (Canadian Rapid Treatment Centre of Excellence), Braxia Scientific, Janssen, Allergan, Lundbeck, Sunovion, and COMPASS.
Kayla M. Teopiz has received fees from Braxia Scientific Corp.
All other authors declare no disclosures.
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