Wednesday, 31 October 2018

Child and adult exposure and health risk evaluation following the use of metal- and metalloid-containing costume cosmetics sold in the United States.

Regul Toxicol Pharmacol. 2017 Mar;84:54-63. doi: 10.1016/j.yrtph.2016.12.005. Epub 2016 Dec 19. Perez AL1, Nembhard M2, Monnot A2, Bator D3, Madonick E4, Gaffney SH2. Author information 1 Cardno ChemRisk, LLC, 101 2nd Street, Suite 700, San Francisco, CA 94105, United States. Electronic address: 2 Cardno ChemRisk, LLC, 101 2nd Street, Suite 700, San Francisco, CA 94105, United States. 3 Dept. of Environmental Health Sciences, University of Michigan School of Public Health, 1415 Washington Heights Ann Arbor, MI 48109-2029, United States. 4 Brooks Applied Labs, 18804 Northcreek Parkway, Bothell, WA 98011, United States. Abstract Costume cosmetics (lipstick, body paints, eyeshadow) were analyzed for metals using inductively coupled plasma mass spectrometry (ICP-MS). Sb was detected in all samples (range: 0.12-6.3 mg/kg; d.f. 100%), followed by Pb (<0.15-9.3 mg/kg), Ni (<0.20-6.3 mg/kg), Co (<0.5-2.0 mg/kg); with d.f. 80% each, Hg (<0.00015-0.0020 mg/kg; d.f. 50%) and As (0.53 mg/kg, d.f. 10%). Ingestion and dermal exposures were estimated for child- and adult-intermittent and adult-occupational users. Adult-occupational users exceeded the U.S. EPA Reference Dose (RfD) for Sb and the CA Proposition 65 maximum allowable dose level (MADL) for Pb was exceeded for all user scenarios. The Pb dose from body paint was sufficient to raise blood lead levels (BLL) in all user scenarios above baseline BLLs from 0.2 μg/dL to 1.9 μg/dL per the Adult Lead Model (ALM) and child Integrated Exposure Uptake Biokinetic (IEUBK) blood Pb models. Change in BLL was less than 1 μg/dL amongst the child and adult-intermittent users, the benchmark change in BLL developed for health risk assessments for children. Adult-occupational users exceeded the CA Proposition 65 NSRL intake value of 15 μg/day, which corresponds to an increase of 1.2 μg/dL above baseline levels using ALM. Exposure of occupational users of costume cosmetics should be evaluated further to prevent unnecessary metal exposure. KEYWORDS: Arsenic; Cadmium; Chromium; Cosmetic; Face paint; Halloween; Lead; Makeup; Metalloid; Metals PMID: 28007419 DOI: 10.1016/j.yrtph.2016.12.005 [Indexed for MEDLINE] Share on FacebookShare on TwitterShare on Google+

Halloween Costume Choices: Reflections of Gender Development in Early Childhood.

J Genet Psychol. 2017 May-Jun;178(3):165-178. doi: 10.1080/00221325.2017.1295223. Epub 2017 Apr 12. Halloween Costume Choices: Reflections of Gender Development in Early Childhood. Dinella LM1. Author information 1 a Department of Psychology , Monmouth University , West Long Branch, NJ , USA. Abstract The author examined whether preschoolers' Halloween costume choices reflect their gender development. The sample consisted of 110 (53 boys, 57 girls) infant through preschool-aged participants, and 1 parent of each child. Both observational methodologies and parent-report surveys were used to assess the gender-typed nature of children's Halloween costumes, information about the Halloween costume choice process, and about the children's gender development. Boys' costumes were more masculine and girls' costumes were more feminine. Younger children's costumes were consistently less gender typed than the older children's costumes were. Children whose parents chose their Halloween costumes for them had Halloween costumes that were less gender typed than did children who were involved in the Halloween costume decision-making process. Moreover, children's gender-typed play and desire to wear gender-stereotyped clothes were related to the gender stereotyped nature of their Halloween costume. Unexpectedly, gender typicality, a dimension of gender identity, was not related to children's Halloween costume choices. Overall, the findings support that children's Halloween costume choice is an indicator of children's gender development processes. KEYWORDS: Halloween costumes; femininity; gender development; masculinity PMID: 28402183 DOI: 10.1080/00221325.2017.1295223

What do clinicians consider when assessing chronic low back pain? A content analysis of multidisciplinary pain centre team assessments of functioning, disability, and health

Home > October 2018 - Volume 159 - Issue 10 > What do clinicians consider when assessing chronic low back... Bagraith, Karl S.a,b,c,d,*; Strong, Jennyb,d; Meredith, Pamela J.d,e; McPhail, Steven M.f,g PAIN: October 2018 - Volume 159 - Issue 10 - p 2128–2136 doi: 10.1097/j.pain.0000000000001285 Clinical Note aInterdisciplinary Persistent Pain Centre, Gold Coast Hospital and Health Service, Gold Coast, Queensland, Australia bOccupational Therapy Department, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia cProfessor Tess Cramond Multidisciplinary Pain Centre, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia dOccupational Therapy, School of Health and Rehabilitation Sciences, The University of Queensland, Brisbane, Queensland, Australia eOccupational Therapy, School of Health, Medical and Applied Sciences, Central Queensland University, Rockhampton, Queensland, Australia fCentre for Functioning and Health Research, Metro South Health, Brisbane, Queensland, Australia gInstitute of Health and Biomedical Innovation, School of Public Health and Social Work, Queensland University of Technology, Brisbane, Queensland, Australia Corresponding author. Address: Interdisciplinary Persistent Pain Centre, 2 Investigator Dr, Robina, Gold Coast, Queensland 4226, Australia. Tel.: +61756686825; fax: +61756809539. E-mail address: (K.S. Bagraith). Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site ( Received January 26, 2018 Received in revised form May 10, 2018 Accepted May 13, 2018 PAIN: October 2018 - Volume 159 - Issue 10 - p 2128–2136 doi: 10.1097/j.pain.0000000000001285 Clinical Note Global Year 2018 Abstract In Brief Author Information Beyond expert suggestions as to the appropriate subject matter for chronic pain assessments, little is known about the actual content of multidisciplinary pain centre (MPC) clinical assessments. The International Classification of Functioning, Disability and Health Low Back Pain Core Set (ICF LBP-CS) provides a universal language to support the consistent description of LBP-related assessments across disciplines within multidisciplinary teams (MDTs). This study sought to map the content of MPC clinical assessments to the ICF to: (1) identify and compare the content of clinical MDT assessments using a cross-disciplinary framework and (2) examine the content validity of the LBP-CS. A qualitative examination of MPC team clinical assessments of chronic low back pain was undertaken. Multidisciplinary team (pain medicine, psychiatry, nursing, physiotherapy, occupational therapy, and psychology) assessments were audio-recorded and transcribed. Concepts were extracted from transcripts using a meaning condensation procedure and then linked to the ICF. Across 7 MDT assessments, comprised 42 discipline-specific assessments and 241,209 transcribed words, 8596 concepts were extracted. Contextual factors (ie, the person and environment), except for physiotherapy, accounted for almost half of each discipline's assessments (range: 49%-58%). Concepts spanned 113 second-level ICF categories, including 73/78 LBP-CS categories. Overall, the findings revealed novel insights into the content of MPC clinical assessments that can be used to improve health care delivery. International Classification of Functioning, Disability and Health–based assessment profiles demonstrated unique contributions from each discipline to chronic low back pain assessment. Finally, users of the LBP-CS can be confident that the tool exhibits sound content validity from the perceptive of MDT assessments of functioning, disability, and health. Back to Top | Article Outline 1. Introduction Chronic low back pain (CLBP) affects approximately 1 in 5 people34 and is the most frequently reported condition in patients attending Multidisciplinary Pain Centers (MPCs).42 On entering MPCs, patients commonly undergo a multidisciplinary team (MDT) assessment to ascertain their functioning problems and guide treatment planning; an approach originally championed by Bonica.41 Multidisciplinary pain centre assessments typically entail input from multiple professionals, including pain medicine physicians, psychiatrists, nurses, psychologists, occupational therapists, and physiotherapists.28 Generally, each professional conducts their assessments independently, with findings integrated at a case conference.54 Beyond expert suggestions as to the appropriate subject matter for chronic pain assessments,22,32,59 little is known about the actual content and focus of MPC clinical assessments. Multidisciplinary pain centre professionals use differing frames of reference to guide and document their assessments,37 which often hampers interdisciplinary collaboration.31 Similarly, understanding each team member's contribution to MDT assessments remains a challenge because of discipline-specific terminology.52 The International Classification of Functioning, Disability and Health (ICF) provides a universal language and standard framework for functioning and health.60 This ICF is considered to be a Rosetta Stone,53 crossing disciplinary, contextual, and geographic boundaries, harmonising the description of patient functioning.10 The ICF has been recommended as a basis for pain practice55 and is guiding the Initiative on Methods Measurement and Pain Assessment in Clinical Trials (IMMPACT).51 With over 1400 categories, the ICF is exhaustive and impractical for use in its entirety.53 To operationalise the ICF in daily pain practice, salient selections of categories have been compiled for various conditions, the so-called ICF Core Sets.19 The 78-category Low Back Pain Core Set (LBP-CS) includes “as few categories as possible to be practical, but as many as necessary to be sufficiently comprehensive to describe in a comprehensive multidisciplinary assessment the typical spectrum of problems in functioning of patients (with CLBP)” [19(p9); 21]. The LBP-CS has been put forth as a practical tool to permit consistent description of patient functioning across disciplines, facilitating more effective interdisciplinary communication and better integrated care.49 The LBP-CS was compiled by experts through a formal decision-making and consensus process19,21 that considered evidence from preparatory studies.12,25,56 Despite the potential benefits afforded by use of the LBP-CS, it has been suggested that clinical practice uptake is less than ideal.1,15,50,58 One potential reason for limited utilisation may be inadequate evidence regarding the LBP-CS's content validity.36 Whether the LBP-CS is sufficiently comprehensive to cover diverse health professional's perspectives, or more importantly, the content of multidisciplinary clinical assessments, remains unanswered. Bagraith and Strong5 provided proof-of-concept that the content of clinical MPC assessments can be mapped to the ICF, with each discipline's assessment described using the same ICF-based yardstick. This study sought to map the content of MPC clinical assessments to the ICF to: (1) identify the content and focus of clinical MDT assessments using a cross-disciplinary framework and (2) examine the content validity of the LBP-CS from the perspective of clinical MDT assessments of functioning, disability, and health. Back to Top | Article Outline 2. Methods 2.1. Overview This study entailed a qualitative examination of the routine MDT assessments undertaken by patients attending a tertiary-referral MPC at a metropolitan hospital in Australia. As part of routine practice, patients attending the MPC for a rehabilitation program underwent an MDT assessment on day 1 of the program. The MDT consisted of pain medicine (in Australia, Pain Medicine is recognised as a medical speciality in its own right []. A career in pain medicine is generally obtained by qualifying as a Fellow of the Faculty of Pain Medicine, Australian and New Zealand College of Anaesthetists. Fellowship of this multidisciplinary medical academy is an “add-on” specialist degree. Fellows also have a specialist qualification in one of the participating specialties [eg, anaesthesia or rheumatology]), psychiatry, nursing, physiotherapy, occupational therapy, and psychology disciplines. Each discipline was allocated up to 50 minutes to assess patients, with patients undergoing 6 separate successive assessments (1 for each discipline) as part of their MDT assessment. For the purposes of this study, clinicians audio-recorded their assessments using a small MP3 device. As a complementary data collection strategy, the chart notes for the pain medicine and physiotherapy assessments were reviewed to further capture the physical examinations of these 2 disciplines' assessments (eg, palpation of structures, reflex tests, and assessment of gait pattern). The study was approved by the Royal Brisbane and Women's Hospital and The University of Queensland human research ethics committees. Back to Top | Article Outline 2.2. Participants 2.2.1. Patients Patients who met the following criteria were eligible to participate: (1) nonspecific LBP16 of >3-month duration as the primary reason for attendance, (2) aged 18 years or older, (3) able to read and write English, and (4) no known cognitive deficits. Patients meeting these eligibility criteria were invited to participate in the study on arriving at the MPC and before commencement of their MDT assessment. Consenting patients provided written informed consent and their background details. Participant's diagnosis was available before MDT assessment through their medical practitioner referral and affirmed, to be in line with Chou et al.'s16 criteria for chronic nonspecific LBP, by reviewing the ensuing MDT assessment, inclusive of physical examinations. Participants were recruited to maximize variation in sex, age, marital status, and employment status, according to the principals of maximum variation sampling,43 to enhance the diversity of findings that were likely to arise from MDT assessments. Back to Top | Article Outline 2.2.2. Clinicians This study took place within the context of routine service delivery to enhance generalisability; ie, MPC clinical procedures and processes were not altered for the research study. Hence, all the MPC's clinicians were eligible and invited to participate. To be included in the study, each clinician was required to provide written informed consent and details regarding their experience and expertise. Back to Top | Article Outline 2.3. Procedure for extracting and linking concepts to the International Classification of Functioning, Disability and Health Audio-recordings were transcribed verbatim. The concept extraction and linking process reported by Bagraith and Strong5 was implemented. In brief, the meaning condensation procedure described by Kvale40 was applied. Transcripts were read and divided into meaning units. Meaning units comprised discrete segments of text, not necessarily related to grammatical conventions, that were discerned to be related to a common theme.38 From each meaning unit, identified concepts, one or more, were extracted and documented. The ICF-Linking Rules18,20 were then applied to link-extracted concepts to the ICF, and where possible to second-level ICF categories. Each concept could be linked to more than one ICF category if necessary to suitably represent the concept. The concept extraction and linking process was also applied to the objective physical examination information extracted from the pain medicine and physiotherapy chart notes (eg, from the meaning unit “obj/gait Ax—moderately antalgic,” the concept of “objective assessment of gait pattern” was identified, which was linked to b770 gait pattern functions). A senior pain occupational therapist (K.S.B.) independently undertook the concept extraction and linking procedure with additional reference to a guideline developed by the ICF Research Branch. K.S.B. had previously undertaken training in the ICF and the procedure for linking health information to the ICF. In addition, K.S.B. had previous experience with linking clinical assessments to the ICF.5,11 A research diary was used throughout analyses to enhance methodological rigour by providing context for decisions on application of the ICF linking rules.48 To assess methodological rigour, a peer-review process was undertaken, whereby a second investigator (J.S., who had experience with qualitative analysis2 and the linking of MDT assessments to the ICF5) independently extracted concepts from 2 of the MDT assessments and linked them to the ICF. To further examine the validity of the findings, clinician member checking was undertaken following the concept extraction and linking procedures.23 Clinicians were asked to rate the extent to which: (1) the extracted concepts represented their assessment focus, (2) the linked ICF categories represented the extracted concepts, and (3) the linked ICF categories represented their typical assessments. Clinicians undertook the member checking process for one of their recorded assessments. Back to Top | Article Outline 2.4. Sample size The number of patients recruited to the study was determined by data saturation, which refers to the point where no additional information is obtained from the data.46 Data saturation is the most frequently used criterion for determining sample size in ICF-linking studies.26,61 For the purpose of this study, data saturation was considered to be achieved when no new second-level ICF categories were identified from 2 consecutive MDT assessments. After each participant's MDT assessment was linked to the ICF, data saturation was assessed. If data saturation was not achieved, a further participant was sampled, as detailed in section 2.2.1, and their MDT assessment was linked to the ICF. This process was repeated until data saturation was achieved. Because of the use of maximum variation sampling and the time required to perform the linking process outlined in section 2.3, participants were not necessarily consecutive patients being assessed by the MPC MDT. Back to Top | Article Outline 2.5. Data analysis The relative distribution of ICF-linking outcomes for extracted concepts was examined in relation to: (1) the total number of concepts extracted from each MDT assessment and (2) the total number of concepts extracted from all MDT assessments. The linking outcomes were: not covered in the ICF (eg, assessment of a patient's knowledge regarding an assessor's role in pain management), not defined in the ICF (ie, encompassed within the framework but not able to be linked to a specific component; eg, assessment of general functioning), and linked to an ICF component or category (eg, assessment of driving limitations, which was linked to d475 driving). The absolute frequency of linkage of each ICF category was also calculated. Comparisons between disciplines were made in terms of the components and categories that accounted for their assessments. The content validity of a LBP-CS category was considered confirmed if it was linked in at least one MDT assessment. Categories that were linked, and are not included in the LBP-CS, were considered potentially relevant if they were linked in at least 2 MDT assessments. Cohen's nominal kappa was used to quantify the interrater reliability of the multiple linking that occurred as part of the peer-review process. Bootstrap resampling (1000 replications) was used to generate 95% confidence intervals for kappa. All analyses were performed with Microsoft Excel 2010 and IBM SPSS v23.0. Back to Top | Article Outline 3. Results Saturation was achieved with MDT assessments of 7 patients (3 females and 4 males; see Table 1 for patient's background details). Table 2 outlines the characteristics of the MDT assessments, which were inclusive of 42 separate assessments (ie, each of the 7 patients underwent pain medicine, psychiatry, nursing, physiotherapy, occupational therapy, and psychology assessments). In total, the multidisciplinary assessments were between 3:18 and 5:31 hours in duration, with 241,206 words recorded across all assessments. The pain medicine, psychiatry, nursing, physiotherapy, occupational therapy, and psychology assessments were undertaken by 6, 3, 4, 2, 4, and 4 different clinicians, respectively. Each of the 23 clinicians (19 females) had experience in chronic pain management (0.5-16 years of practice) and rated their expertise 3 or higher (median: 4) on a 5-point scale (that ranged from 1 = low and 5 = excellent).39 They were all familiar with their role in the team, having been members of this particular MPC for at least 3 months (range: 0.25-12 years). Table 1 Table 1 Table 2 Table 2 Across all the MDT assessments, a total of 8596 concepts were extracted (Table 2). Of these, 334 (3.9%) were not covered within the ICF and 270 (3.1%) were designated as “not definable.” The remaining 7992 (93.0%) concepts were linked to the ICF. International Classification of Functioning, Disability and Health–linkable concepts spanned 113 second-level categories, inclusive of 31 body function, 5 body structure, 38 activity and participation, and 39 environmental factor categories. Table 3 details the distribution of linked concepts in relation to the LBP-CS. Inspection of Table 3 reveals that 73/78 comprehensive LBP-CS categories were assessed, including 19/19 body function, 5/5 body structure, 26/29 activity and participation, and 23/25 environmental factor categories. The most frequently linked categories within the body functions, body structures, activity and participation, and environmental factor components were b280 (sensation of pain), s760 (structure of trunk), d920 (recreation and leisure), and e310 (immediate family), respectively. Table 4 provides a list of 35 second-level categories that were assessed in at least 2 MDT assessments and are not contained in the LBP-CS. Carrying out daily routine (d230) accounted for the highest proportion of concepts linked to non–LBP-CS categories (16.6%). Table 3-a Table 3-a Table 3-b Table 3-b Table 4 Table 4 Figure 1 illustrates the focus of each discipline, as well as the collective MDT, in terms of the ICF components. Contextual factors (ie, the person and environment), except for physiotherapy, accounted for almost half of each discipline's assessments across the 7 patients (range: 49%-58%). Further details regarding the assessment of specific personal factor aspects are provided in supplementary Table S1 (available online at Notably, assessment of body structures was limited; accounting for 4% of physiotherapy, 2% of pain medicine, and 1% of the collective MDT assessments. Figure 1 Figure 1 Good interrater reliability17 (kappa = 0.72; 95% confidence interval: 0.67-0.76) was observed for the assessments that were subjected to the peer-review multiple rating procedure. The clinician member checking analyses (see supplementary Table 2, available online at supported the internal and external validity of the findings. Back to Top | Article Outline 4. Discussion This study sought to identify the content of MDT assessments using the ICF and to examine the content validity of the LBP-CS from the perspective of MDT assessments. Almost all the concepts extracted from the MDT assessments were ICF-linkable, facilitating description and comparison of assessments using the cross-disciplinary language and universal framework provided by the ICF. The findings provide novel insights into the content of MPC MDT assessments of patients with CLBP and reveal the unique contribution of each discipline to such assessments. The LBP-CS was shown to exhibit sound content validity from the perceptive of MDT assessments, with 73/78 LBP-CS categories confirmed. The present work demonstrated the utility of the ICF as a Rosetta Stone53 for describing MDT assessments of CLBP. Traditionally, aggregating and comparing the assessment foci of different disciplines has been challenging because of the dissimilar terminology and frameworks inherent across disciplines in MDTs.27,30,31,33,44 Accordingly, beyond expert suggestions as to the appropriate subject matter for chronic pain assessments,22,32,59 little was known about the actual content and focus of MPC MDT clinical assessments. The present findings provide evidence that different disciplines' clinical assessments of CLBP can be readily reconciled using the ICF's common language.5 The present results are the first to combine and display MPC MDT assessments using a common yardstick, and accordingly, considerably extend understanding regarding the content and focus of actual MPC clinical assessments of CLBP. Inspection of the ICF-based profiles reveals numerous novel and important insights into MPC clinical practice. Of such insights, 2 examples are particularly noteworthy. First, the results suggest that MPC MDTs assess personal factors and body structures more and less, respectively, than other ICF domains. Second, immediate family (e310), sensation of pain (b280), and products or substances for personal consumption (e110), as the 3 most frequently assessed areas, seem particularly important for MPC MDT assessment of CLBP. Aspects of these findings are consistent with established evidence regarding important contributors to CLBP-related functioning and provide reassurance that routine clinical practice assessments are aligned with the evidence base. For example, the importance of coping styles/strategies in chronic pain has been established,45 and the significant focus on coping strategies/styles revealed in the present findings (ie, the second most frequently assessed personal factor category; linked 437 times) is reassuring. On the other hand, future research is warranted to understand the perceived value of factors identified as especially important in this study, eg, immediate family (e310), for which the evidence base is still emerging.13,14 The potential of the ICF for clarifying team member roles has been posited52; however, the usefulness of the ICF for elucidating the actual contributions of team members to multidisciplinary assessments had yet to be substantiated before the present report. The present findings are the first to demonstrate that each discipline (ie, pain medicine, psychiatry, nursing, physiotherapy, occupational therapy, and psychology) makes unique contributions to the MDT assessment of CLBP when considering their overall focus across the spectrum of functioning, disability, and health. However, assessment duplication was also observed across each ICF domain. Feedback from the team suggests that aspects of the assessment duplication may be attributable to rapport building (eg, assessment of areas, such as pain interference, that patients expect to be assessed by each discipline) and collection of collateral information to enhance discussion at MDT meetings. On the other hand, it was noted that overlap may also represent redundancy and opportunities to improve efficiency and reduce patient burden. To this end, 2 applications of ICF-based profiles of MPC MDT clinical assessments seem worthwhile. First, use of ICF-based profiles to compare the focus of each discipline to identify duplication in clinical assessments. Second, use of ICF-based profiles to identify disciplines most suited to assess segments of ICF Core Sets. For example, with respect to these 2 applications, the profiles from this study suggest that within MPCs, there may be duplication across pain medicine and physiotherapy when assessing motor reflex functions (b750). Based on a review of the assessment profiles and skill sets, MPCs may consider allocating the assessment and rating of b750 to physiotherapists, thereby, extricating pain medicine resourcing for redistribution to maximise value from their specialised skill set. Discipline-specific allocation of ICF Core Set categories may also enhance practice uptake of the ICF by minimising implementation burden and providing context for application of user guides.3,9 Extending the presented ICF-linking approach to generate profiles of other MPC input (eg, management decisions) is recommended to understand the broader utility of this method and potentially provide further insights to guide improvements in the efficiency and effectiveness of health care delivery. In previous studies, the LBP-CS has been shown to be inclusive of physicians'29 and physiotherapists'39 perspectives, sourced from Delphi studies, regarding important aspects of functioning as well as physicians' work capacity reports47 and physiotherapists' assessment templates.24 However, each of these previous LBP-CS valuation studies has important methodological limitations. Delphi methods rely on retrospective accounts and opinion-based judgements, while assessment templates and reports represent abbreviated or summarised versions of assessments. The present findings extend understanding of the LBP-CS's content validity, demonstrating that the LBP-CS is sufficiently comprehensive to describe the typical spectrum of problems in functioning considered in a comprehensive multidisciplinary assessment of CLBP. Of note, the present findings provide initial validation evidence for the LBP-CS from the perspectives of disciplines that were not represented within the committee selecting LBP-CS categories (ie, nursing and psychology). Taken together with existing psychometric evidence,4,6–8,21,39,55 the present results suggest that the LBP-CS is likely to have good utility for supporting MDTs to guide and document their assessments using the standard cross-disciplinary language provided by the ICF.35 Although generally supportive of the LBP-CS's content validity, the present findings highlight opportunities to improve the LBP-CS. For example, from the activity and participation component, 11 categories that are not contained in the LBP-CS were assessed in more than one patient. Of these, 4 (d230, d520, d720, and d855) were linked over 15 times. Further research into the importance of categories identified as potentially relevant in this study is necessary to understand their usefulness for consideration of inclusion in LBP-CS revisions. Two study limitations merit consideration when interpreting the present findings. First, the study was conducted within the context of routine clinical practice. Although this approach is advantageous with respect to external validity, not all the participating clinicians considered themselves to be experts. The extent to which this may have influenced findings is unclear, and future comparisons between expert clinician assessments and those undertaken in routine practice may be worthwhile to understand any meaningful differences. Second, although the used methodological approach provides a comprehensive account of assessments, it cannot be considered a complete account of the clinical assessment process. For instance, information gathered by clinicians from preassessment chart reviews was not captured. In conclusion, this study provided novel insights into the content of clinical MPC team assessments of CLBP and provided evidence to support the content validity of the LBP-CS from the perceptive of MDT assessments. The generated ICF-based profiles of MPC assessments identified new opportunities to improve health care delivery and demonstrated the unique contribution of each discipline to such assessments. The present findings also suggest that users of the LBP-CS can be more confident that the tool mostly represents the aspects of functioning and contextual factors that MDTs consider when assessing patients with CLBP. Future research into the assessment practices of MPCs from other contexts is warranted to expand on the present findings. Back to Top | Article Outline Conflict of interest statement The authors have no conflict of interest to declare. Supported by grants from the Royal Brisbane and Women's Hospital Foundation, Australian NHMRC Centre for Clinical Research Excellence in Spinal Pain, Injury and Health, and Allied Health Professions' Office of Queensland. S.M. McPhail was supported by a National Health and Medical Research Council (of Australia) fellowship. These agencies did not provide input on any aspect of the study, decision to publish, manuscript preparation, or submission. Back to Top | Article Outline Acknowledgements The authors are grateful to the patients and clinicians for their participation. They are also appreciative of the input provided by Dr Libby Gibson and Emeritus Professor Roland Sussex during the early phase of this study. The authors are thankful for the training materials provided by the ICF Research Branch in collaboration with the WHO-FIC CC in Germany (at DIMDI). The authors also acknowledge the support provided to K.S.B. for the conduct of this work as part of the RBWH Cramond Fellowship in Pain Management and Occupational Therapy. Back to Top | Article Outline Supplemental digital content Supplemental digital content associated with this article can be found online at Back to Top | Article Outline References [1]. Alvarezz AS. The application of the International Classification of Functioning, Disability, and Health in Psychiatry: possible reasons for the lack of implementation. Am J Phys Med Rehabil 2012;91(13 suppl 1):S69–73. Cited Here... [2]. Andrews NE, Strong J, Meredith PJ, Gordon K, Bagraith KS. “It's very hard to change yourself”: an exploration of overactivity in people with chronic pain using interpretative phenomenological analysis. PAIN 2015;156:1215–31. Cited Here... [3]. Australian Institute of Health and Welfare (AIHW) 2003. ICF Australian User Guide. Version 1.0. Disability Series. AIHW Cat. No. DIS 33. Canberra: AIHW. 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Diet and Psychosis: A Scoping Review

Neuropsychobiology Aucoin M.a · LaChance L.b,c · Cooley K.a,d · Kidd S.b Author affiliations Corresponding Author Keywords: Dietary constituentsNutritional guidelinesMental healthSchizophrenia spectrum disorders Neuropsychobiology Abstract FullText PDF References Extras : 16 Abstract Introduction: Schizophrenia spectrum disorders (SSD) represent a cluster of severe mental illnesses. Diet has been identified as a modifiable risk factor and opportunity for intervention in many physical illnesses and more recently in mental illnesses such as unipolar depression; however, no dietary guidelines exist for patients with SSD. Objective: This review sought to systematically scope the existing literature in order to identify nutritional interventions for the prevention or treatment of mental health symptoms in SSD as well as gaps and opportunities for further research. Methods: This review followed established methodological approaches for scoping reviews including an extensive a priori search strategy and duplicate screening. Because of the large volume of results, an online program (Abstrackr) was used for screening and tagging. Data were extracted based on the dietary constituents and analyzed. Results: Of 55,330 results identified by the search, 822 studies met the criteria for inclusion. Observational evidence shows a connection between the presence of psychotic disorders and poorer quality dietary patterns, higher intake of refined carbohydrates and total fat, and lower intake or levels of fibre, ω-3 and ω-6 fatty acids, vegetables, fruit, and certain vitamins and minerals (vitamin B12 and B6, folate, vitamin C, zinc, and selenium). Evidence illustrates a role of food allergy and sensitivity as well as microbiome composition and specific phytonutrients (such as L-theanine, sulforaphane, and resveratrol). Experimental studies have demonstrated benefit using healthy diet patterns and specific vitamins and minerals (vitamin B12 and B6, folate, and zinc) and amino acids (serine, lysine, glycine, and tryptophan). Discussion: Overall, these findings were consistent with many other bodies of knowledge about healthy dietary patterns. Many limitations exist related to the design of the individual studies and the ability to extrapolate the results of studies using dietary supplements to dietary interventions (food). Dietary recommendations are presented as well as recommendations for further research including more prospective observational studies and intervention studies that modify diet constituents or entire dietary patterns with statistical power to detect mental health outcomes. © 2018 S. Karger AG, Basel Introduction Schizophrenia spectrum disorders (SSD) represent a cluster of severe mental illnesses with a lifetime prevalence of 0.7% [1]. The aetiology of schizophrenia remains to be fully elucidated though it is understood that this group of disorders results from a combination of genetic, biological, and social factors. Symptoms of SSD include positive symptoms such as delusions and hallucinations, as well as negative and cognitive symptoms. Typically, the first episode of psychosis is preceded by a prodromal or clinical high-risk state where the individual experiences attenuated or brief psychotic symptoms, as well as other symptoms such as social withdrawal, depression, and a decline in social or occupational functioning. While recovery rates from the first episode of illness are high, over 80% of individuals will relapse [2]. Relapses vary in their duration, intensity, and frequency, and they are often precipitated by factors such as stress, substance use, medication non-adherence, social adversity, and medical factors. Approximately 50% of individuals will experience episodic as opposed to continuous disability [2]. Conventional treatment of schizophrenia includes a combination of medical and psychosocial interventions. In addition to the impact on emotional well-being, functioning, and quality of life, patients suffering from psychotic disorders are at dramatically elevated risk of medical comorbidities, which have a significant impact on mortality and morbidity. As a result, the life-expectancy of patients with schizophrenia has been estimated to be 8–20 years shorter than in the general population [3, 4]. A recent Canadian study evaluated causes of death in individuals with SSD compared to the general population living in the developed world. This group found that circulatory conditions are the number 1 cause of death in individuals with SSD whereas the general population is most likely to die as a result of cancer/neoplasm [3]. Many factors account for this difference and the increased risk of mortality such as low socioeconomic status, tobacco use, poor diet, and physical inactivity that compound any genetic predisposition and metabolic complications caused by anti-psychotic medication [5–9]. While it is known that nutritional factors can influence the course of medical and metabolic illness in schizophrenia, uptake of such interventions is low. The field of nutritional psychiatry is beginning to uncover how food choice impacts mental health in SSD; thus, nutritional interventions have the potential to improve both mental and physical health in this vulnerable population [10]. Currently, limited nutritional treatment guidelines exist for mental health in general [11], and none exists for SSD specifically. The field of nutritional psychiatry research is relatively new although, at present, it has accumulated a robust collection of observational studies, preclinical studies demonstrative of mechanisms by which nutritional factors can impact neurological, cognitive, and emotional health, as well as a small number of intervention studies. The evidence is most robust in the area of unipolar depression. A 2017 meta-analysis found that a healthier dietary pattern was associated with a decreased risk of depression, and a “Western diet” was associated with an increased risk of depression [12]. While reverse causality has been suggested, prospective studies have also demonstrated an increased risk of depression related to poorer diet patterns over the long term [13]. Recently, 2 single-blind randomized controlled trials (RCTs) of individuals with major depressive disorder found that an adjunctive dietary intervention reduced depressive symptoms compared with placebo [14, 15]. In 1 trial, the number needed to treat for remission was 4 [15]. Additionally, there is an increasing amount of research demonstrating that other forms of lifestyle-based interventions, such as exercise, have been shown to be highly effective adjunctive treatments in SSD [16, 17]. Clinicians often accurately cite obstacles and challenges in implementing a dietary intervention in patients with psychosis. These include cognitive barriers, motivational difficulties, cultural acceptance, and social determinants of health, as well as psychotic symptoms themselves [18]. However, intervention studies have been undertaken which have demonstrated the feasibility and acceptability of dietary interventions in this population. One study in first episode psychosis (FEP) patients showed an increase in vegetable intake as well as a reduction in discretionary food intake and calories [4]. Another reported that a Mediterranean diet (MD)-based intervention resulted in improvements in diet quality associated with a reduced risk of cardiovascular disease in individuals with severe mental illness [19]. These studies were designed to assess diet in relation to metabolic and physical health outcomes. Unfortunately, intervention studies that assess the effect of diet on symptoms of psychotic disorders are fewer in number. This apparent lack of evidence prompted the undertaking of the present review with the following primary objective: to conduct a scoping review of the existing literature on nutritional interventions to improve mental health in SSD individuals. Methods Scoping reviews are conducted to identify and describe key concepts, and types and sources of evidence when the topic at hand is either complex or being reviewed for the first time [20]. Because of the broad, diverse, and poorly developed nature of the literature relating to psychosis and nutrition, we have adopted Arskey and O’Malley’s [20] 5-stage framework for conducting a scoping review. These stages include: identifying the research question, identifying relevant results, selecting studies, charting data, and reporting results. Our research question is as follows. What is the current evidence base for nutritional interventions for primary prevention, secondary prevention, or treatment of mental health symptoms in individuals suffering from or at risk for SSD? What are potential opportunities and gaps for further study within this emerging area? Identifying Relevant Studies An a priori search strategy was developed and then refined and tested through an iterative process by an experienced medical information specialist in consultation with the review team. Using the OVID platform, we searched Embase and Embase Classic on January 6, 2017, and Ovid MEDLINE® including In-Process and Other Non-Indexed Citations and Epub ahead of print on December 12, 2016. Strategies utilized a combination of controlled vocabulary (e.g., “Psychotic Disorders” or “Nutritional Physiological Phenomena”), and keywords (e.g., “nutrition,” “diets,” or “vegan”). Vocabulary and syntax were adjusted across databases. There were no language, date, or methodology restrictions, but opinion pieces and reviews were removed from the results. Specific details regarding the strategies appear in online supplementary Appendix 1 (for all online suppl. material, see Searches were repeated on April 15, 2018, for the years 2017 and 2018 only. Our updated search was modified based on our refined list of dietary constituents that was developed and refined throughout the initial screening process (online suppl. Appendix 1), for instance, search terms found not to be relevant by the study authors such as “alcohol,” “citric acid,” and “glutathione.” Additional relevant results were identified through forward and backward tracking of key search results, grey literature search, and leveraging existing networks and conferences. Duplicates were removed. Study Selection Title and abstract screening was completed using Abstrackr, an online open-source program that facilitates rapid screening decisions and concurrent tagging of results [21]. Studies were assessed for eligibility according to the following criteria: Inclusion Criteria Studies of participants with psychotic disorders or symptoms or pre-clinical studies of models of psychotic disorders or symptoms that report on a mental health-related outcome. Studies assessing or modifying participant diet; this includes whole diet, or use of a food, supplement, or natural health product that provides an active constituent naturally occurring in the general North American diet. Exclusion Criteria Studies assessing or administering herbal medicines (apart from those used for culinary purposes in the general North American diet) or other constituents not typically found in significant quantities in the human diet (i.e., St. John’s Wort, GABA, or S-adenosylmethionine). Studies of endogenously produced dietary components (i.e., cholesterol, vitamin D, or non-essential amino acids) without reference to dietary intake or supplementation. Studies with outcomes related to the impact on medication side effects or physical health outcomes only (i.e., tardive dyskinesia or weight gain). Studies of vitamin B1 (thiamine) were excluded due to the large volume of studies and the previously established link between thiamine deficiency and psychosis (Wernicke-Korsakoff syndrome). Review articles, opinion papers, letters, and systematic reviews. Non-English language papers unless an English abstract with sufficient information for data extraction was available. Duplicate screening was completed by a team of 4 reviewers, which included both primary investigators and 2 research assistant volunteers providing independent assessment of each study identified. We engaged the artificial intelligence function of Abstrackr to rank-order abstracts based on the likelihood of relevance [22]. Screening was completed so that all studies with a probability of at least 0.4 of relevance were screened manually. This process ensures that the inherent inaccuracy of machine learning of Abstrackr (∼4.2% of studies are incorrectly identified for exclusion) would be buttressed by duplicate screening by a member of our research team [22]. Concurrently, tags related to dietary constituents, methodology, population, and mechanism were applied to the studies selected for inclusion based on title and abstract review. Discrepancies between reviewers were resolved by consensus between the study primary investigators (M.A. and L.L.). Charting the Data A data extraction template was created and piloted among study authors for each broad study design category: pre-clinical, observational, and experimental. It was refined and finalized based on data extracted from a sample of studies. Data were extracted from abstracts or full texts as appropriate. Collating, Summarizing, and Reporting Results Data were analyzed and presented primarily according to dietary constituents. When possible, the scope of the current literature for a given section was displayed in one or more charts to provide the reader with an overall impression of the available information, gaps, broad study methodology, and directionality of findings. In order to concisely display directionality of findings, studies reporting improvement in at least one outcome of interest (such as positive, negative or cognitive symptoms, anxiety, depression, or quality of life) were categorized as “decreasing psychopathology,” even if other outcomes assessed reported no effect. Studies reporting worsening in at least one outcome of interest were categorized as “increasing psychopathology.” No studies reported both an increase and decrease in psychopathology outcomes. Additionally, to allow for concise display, studies that reported an association between worsening symptoms with higher levels of a nutrient and improved symptoms with lower levels of a nutrient were combined, and all tables were oriented to display the effects of a higher intake of the dietary constituent of interest. A narrative summary of each section highlighted themes, trends, promising areas, and gaps for each broad study type to accompany the charts. In addition, authors emphasized any reported adverse effects of a given dietary constituent and potential biological mechanisms underpinning the association between dietary constituents and mental health outcomes in individuals with psychosis. Given the heterogeneity of the literature, a flexible and iterative approach was taken by both principal investigators to summarize and present the literature in a meaningful and relevant way. Results Our initial search revealed 73,063 results, which was reduced to 52,634 after de-duplication. Using Abstrackr to facilitate screening allowed study authors to manually screen just under 50% of results (26,053), relying on the artificial intelligence feature of the program to screen the remaining articles. The current project would not have been feasible without the support of this technology. An additional 438 articles were excluded at the data extraction phase resulting in 718 relevant articles that underwent data extraction via full-text or abstract review (Fig. 1; PRISMA flow diagram). Fig. 1. PRISMA flow chart. AI, artificial intelligence. /WebMaterial/ShowPic/1020315 The updated search resulted in 1,135 results in OVID MEDLINE and 2,691 in Embase and Embase Classic with a total of 2,696 following conservative automatic de-duplication using EndNote X7. The same double screening process resulted in 112 abstracts identified as potentially relevant, 1,886 abstracts excluded manually, and 698 abstracts excluded by the artificial intelligence feature. Manual de-duplication was conducted during the data extraction phase. Thirty abstracts were excluded at the data extraction phase resulting in an additional 82 articles. An additional 22 articles were identified through backward tracking of identified articles during the data extraction phase. Distribution of Studies Figures 2-4 display the distribution of the articles included with respect to year of publication, methodology, and geographic location, respectively (please see online supplementary File 1 for a full list of studies included). It is evident that the field of nutritional psychiatry has recently gained interest and an expanding volume of literature with nearly half of the included studies published in the last 8 years and two-thirds in the last 2 decades. Earlier studies were largely related to vitamins, minerals, amino acids, and food sensitivities. Most recent areas of study include dietary patterns, dietary macronutrients, microbiome, and phytochemicals. The geographic location is reported for all studies assessing or involving human participants as traditional diets vary by region. Fig. 2. Distribution of articles by year of publication. /WebMaterial/ShowPic/1020313 Fig. 3. Distribution of articles by study methodology. /WebMaterial/ShowPic/1020311 Fig. 4. Distribution of articles by geographic location. /WebMaterial/ShowPic/1020309 Dietary Patterns Primarily motivated by the concerns of obesity and physical comorbidity in schizophrenia, many studies have assessed the overall diet of patients with psychosis, and many intervention studies have aimed to help their patients improve their diet (Fig. 5). Fig. 5. Studies assessing dietary patterns. Dec, decreased psychopathology or decreased risk/incidence of SSD; Inc, increased psychopathology or increased risk/incidence of SSD; Equ, equivocal/no association. /WebMaterial/ShowPic/1020307 The observational studies show a clear trend. Eight studies show an overall poorer quality diet or higher intake of unhealthy foods, and 5 show higher intake of convenience foods. Patients with psychosis are more likely to skip breakfast and eat evening snacks [23], eat quickly [24], avoid hard foods [25], and lack structure in their meals [26]. Two studies reported that a healthier diet was associated with less psychopathology. One study of 200 participants reported a higher incidence of psychosis among patients eating a vegetarian diet; these patients were also more likely to be deficient in vitamin B12 [27]. One study that lacked a comparison group reported an “adequate diet” in 73% of patients [28]. The association between total caloric intake and psychosis was unclear. Nine cross-sectional studies found that patients consumed fewer calories or found an association between fasting or malnutrition and worse psychopathology. Eleven cross-sectional studies reported that patients consumed higher calories; 2 showed no association. One case series (n = 35) reported that fasting had a beneficial effect while 1 case series reported on 10 cases of FEP following rapid self-induced weight loss. Some cross-sectional studies reported different levels of intake of individual foods between SSD and healthy populations. These are listed in Table 1. Table 1. Specific foods associated with psychosis in cross-sectional studies /WebMaterial/ShowPic/1020321 Additionally, 3 individual foods have been studied through animal studies with Black seed (Nigella sativa) conferring benefit to positive symptoms [29, 30] and fennel and pear juice improving both positive and negative symptoms [31, 32]. Two animal studies showed connection between soft diet and worsened biological markers of psychosis and positive symptoms. Twenty-two experimental studies assessed the impact of dietary programs in patients with psychosis. An additional 2 protocols lacking results were located. The interventions consisted of diet and nutrition education programs advocating for an overall healthier diet. Many contained components of cooking classes, budgeting, and grocery shopping. Some contained additional components related to a healthy lifestyle such as exercise (19 of 22 studies), smoking cessation, and psychosocial interventions such as cognitive behavioural therapy or motivational interviewing. In 6 of these studies, mental health symptoms or quality of life were the primary outcome; in contrast, the remaining studies were designed to detect changes in cardiovascular risk factors, weight, or metabolic parameters. The completed studies ranged from 10 to 770 participants (mean 160 ± 196) with durations spanning 4–120 weeks (mean 32 ± 32 weeks). Eleven of the completed studies used a control group, 7 employed randomization, and 2 reported the use of blinding. Overall, 17 of 22 studies reported at least 1 positive mental health outcome. One meta-analysis has been completed in this area, assessing the impact of lifestyle programs on depression in patients with psychotic disorders [33]. While it found a benefit, this analysis included studies and patient populations beyond the scope of the present review (ex. exercise and psychosocial component only; patients with “serious mental illness”). Carbohydrates and Fibre Observational evidence has found an association between the consumption of higher-glycaemic-index foods and increasing odds of anxiety and depression. Serum glucose levels are known to effect cognition, mood, and anxiety in healthy and diabetic populations as demonstrated in a small number of observational and experimental studies [34]. As a result, there is interest in a possible role of dietary carbohydrate intake in the pathogenesis of mental illnesses. The 13 observational studies assessing total dietary carbohydrates showed mixed results with 4 reporting a higher intake in SSD, 2 reporting a lower intake in SSD, and 7 reporting no association. Of the 10 studies which assessed refined sugar, breakfast cereals, and sweetened drinks, all found an association between higher intake and psychosis. Observational studies assessing fibre intake also showed a fairly consistent trend with 9 finding a lower intake in SSD patients and 2 finding a higher intake (Fig. 6). Fig. 6. Studies assessing dietary carbohydrates and fibre. Dec, decreased psychopathology or decreased risk/incidence of SSD; Inc, increased psychopathology or increased risk/incidence of SSD; Equ, equivocal/no association; Carb, carbohydrate. /WebMaterial/ShowPic/1020305 There is research in the use of low carbohydrate diets in the treatment of psychotic disorders. Four case reports present cases of patients eating low-carbohydrate diets. Two described the precipitation of psychotic episodes (1 in a patient with a previous history) while the other 2 reports describe 3 patients with chronic schizophrenia whose psychopathology improved significantly while following a ketogenic diet. Two animal studies that implemented ketogenic diets reported improvements in positive, negative, cognitive, and biological outcomes, and 1 open label experimental study using the ketogenic diet in 10 patients for 2 weeks reported significant improvement in symptoms. In both the case reports and the intervention trial, authors note that a return to the previous diet caused a rapid relapse in symptoms. Fats Seventeen observational studies have examined total and saturated fat intake in patients with schizophrenia compared to a control group. Results are mixed, though more studies found an association between increased consumption of total fat or saturated fat and schizophrenia (Fig. 7). Regarding intake of essential fatty acids (EFA), including ω-3 and ω-6 series, a clearer trend emerges. In collating findings from studies that compared consumption of ω-3 and ω-6 fatty acids in patients with SSD relative to a healthy control group, we see that 5 studies reported that individuals with SSD are more likely to consume a diet that is lower in ω-3 fatty acids, and 2 studies reported that individuals with SSD are more likely to consume a diet that is higher in ω-6 fatty acids. One case-control study reported lower levels of ω-6 consumption in patients with schizophrenia compared to controls. Furthermore, 1 study compared intake of ω-3 and ω-6 fatty acids in 146 community-dwelling participants with schizophrenia to national averages in the USA. They found there was no significant difference [35]. On the contrary, a large prospective cohort study (n = 33,623) reported that decreased consumption of ω-3, docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), and eicosapentaenoic acid (EPA), and ω-6, arachidonic acid (AA) and linoleic acid (LA), was associated with psychosis spectrum symptoms in women [36]. Fig. 7. Studies assessing fat and essential fatty acid intake and essential fatty acid levels. Dec, decreased psychopathology or decreased risk/incidence of SSD; Inc, increased psychopathology or increased risk/incidence of SSD; Equ, equivocal/no association; EFA, essential fatty acids; PUFA, polyunsaturated fatty acids. /WebMaterial/ShowPic/1020303 Numerous (n = 72) studies have either assessed tissue levels of EFA in individuals with SSD relative to a control group, or they have measured the association between symptoms of psychosis and EFA including: EPA, DHA, α-LA (ALA), LA, and γ-LA (GLA). EFA levels are measured in a variety of tissue samples, including blood (RBC membranes, serum, and phospholipids), and post-mortem brain. In Figure 7, we have charted the number of studies that showed an association between elevated levels of EFA (either ω-3, ω-6, or undifferentiated EFA/polyunsaturated fatty acid, PUFA) and psychopathology or risk/incidence of SSD. Two meta-analyses of EFA levels in RBC membranes in patients with schizophrenia versus a control group have been published. In summary, medication-naïve individuals with SSD were found to have decreased levels of DHA, DPA, and AA relative to controls. Individuals taking atypical anti-psychotics were found to have reduced levels of DHA, individuals taking typical anti-psychotics were noted to have reduced levels of DHA, DPA, AA, LA, and GLA, and those taking any anti-psychotics were found to be associated with reduced levels of DPA, DHA, and LA [37, 38]. Case reports provide anecdotal evidence that manipulating EFA intake, status, or stores may contribute to clinical improvement in patients with SSD. Three case reports of ω-3 interventions showed benefit in patients with schizophrenia, in addition to 1 case report of evening primrose oil (contains primarily GLA and LA) [39], and 1 case series of a low-fat diet. Clinical trials (n = 28) have focused on assessing the efficacy and safety of ω-3 fatty acids with sample sizes ranging from n = 9 to n = 320 and treatment duration from 6 to 104 weeks. As shown in Figure 7, findings have been heterogeneous with 13 positive trials, 14 equivocal (including 3 study protocols), and 1 negative. Reported adverse effects include: mild nausea, diarrhoea, indigestion, irritable bowel syndrome, and upper respiratory tract infection. In many clinical trials (n = 11/28), no adverse effects and gastrointestinal symptoms could be ameliorated by taking ω-3 supplements with food. Deas et al. [40] attempted to conduct a meta-analysis of RCTs of ω-3 interventions to prevent transition to psychosis in a clinical high-risk population. Due to limited available data at the time, they simply reported on findings of 2 positive trials. Three additional meta-analyses have been conducted along the spectrum of schizophrenic illness, 2 included any ω-3 interventions, 1 only EPA. All 3 found that the effect of ω-3s was insignificant on symptoms of chronic schizophrenia though it may be beneficial for its prevention or at the early stages of the illness [41–43]. Pre-clinical studies support the efficacy of ω-3-enriched diets to attenuate behaviours induced by animal models of schizophrenia. In addition, 1 study found that oleanolic acid (found in olive oil) attenuated psychotic-like symptoms in mice [44]. Protein Dietary protein provides a source of amino acids, which play critical building block roles in the synthesis of a range of neurotransmitters. While some observational studies have looked at dietary protein intake, a larger body of studies has explored the relative amounts of the tissue levels of different amino acids and interventions using amino acid supplements (Fig. 8). Fig. 8. Studies assessing dietary protein or individual amino acid intake and levels. Dec, decreased psychopathology or decreased risk/incidence of SSD; Inc, increased psychopathology or increased risk/incidence of SSD; Equ, equivocal/no association. /WebMaterial/ShowPic/1020301 Three studies revealed a lower intake of protein in patients with psychosis, while 2 showed a higher intake, and in 5 there was no association. One found an association between higher protein intake and lower symptom severity, and 1 case report suggested a benefit from a higher intake of protein and additional amino acids. The effects of increased dietary protein may be mediated by the supply of essential amino acids or by decreasing the relative amount of dietary carbohydrates or saturated fatty acids, which have postulated mechanisms for harmful effects as discussed in other sections. Of the observational studies examining levels of individual essential amino acids, many displayed a mixture of positive and negative results with a few exceptions. The following amino acids were not included in Figure 8 because 2 or fewer studies existed for each: alanine, arginine, tyrosine, and cysteine-rich whey protein. Observational studies assessing tryptophan levels were more likely to show decreased levels in patients with psychosis. Two animal studies showed that tryptophan depletion worsened positive symptoms and that tryptophan supplementation mitigated this effect. In humans, 6 experimental studies using tryptophan supplementation reported a benefit to at least 1 symptom domain (including positive and negative symptoms, cognitive symptoms, and quality of life), and 1 showed no effect. One study reported a worsening of psychopathology in a subset of patients [45] while the remaining did not report adverse events. Four human studies showed worsening psychopathology as a result of depleting levels of tryptophan (or a combination of amino acids including tryptophan), 2 showed no effect, and 1 showed a benefit. The amino acid lysine was found to improve positive symptoms in 2 animal studies and at least 1 symptom domain in all 5 human studies. The non-essential amino acids glycine and serine have been studied through experimental trials using supplements. Several pre-clinical and experimental studies using adjunctive glycine have reported a benefit (17 of 23) in a variety of domains; 1 meta-analysis found benefits in positive and depressive symptoms [46], and 1 in positive and total symptoms [47] when analyzing patients taking non-clozapine medications. Sixteen of 17 animal studies using serine found benefit, primarily with respect to cognitive and positive symptoms. Seven of 13 studies using supplemental serine in patients with psychosis have reported a benefit; 1 meta-analysis found significant reductions in negative and cognitive symptoms [46] and another in negative and total symptoms [47]. In contrast, the amino acid methionine was found to be elevated in psychosis populations in 4 of 7 observational studies; 2 animal studies and 6 human experimental studies reported worsening psychopathology with methionine supplementation. Food Sensitivity and Intolerance Over the last 4 decades, 18 observational studies (cross-sectional) have measured antibodies to foodstuffs in patients with schizophrenia compared to a reference group (Fig. 9). All of these studies report on antibodies to gluten/wheat, and a meta-analysis of biomarkers of gluten sensitivity in patients with schizophrenia was published in 2014 [48]. This study found that certain biomarkers of gluten sensitivity are elevated in patients with schizophrenia, but that the immune response pattern to gluten is distinct from that seen in coeliac disease. Only 1 observational study of gluten-related antibodies has been published since this meta-analysis. This recent paper by Severance et al. [49] found that anti-TTG6 IgG was elevated in 166 patients with FEP compared to controls. This finding is interesting in that this is the only study that has measured anti-TTG6 IgG in individuals with schizophrenia, and this isoform of TTG (anti-TTG2 IgA is one of the diagnostic markers of coeliac disease) is expressed in brain. Fig. 9. Studies of gluten sensitivity (GS), gluten intake, or gluten-free (GF) diet in schizophrenia. /WebMaterial/ShowPic/1020299 Three epidemiological studies have reported on the association between gluten/wheat intake and the prevalence or incidence of schizophrenia. In 1966, Dohan [50] stated that wheat intake during World War II in Finland, Norway, Sweden, Canada, and the United States was associated with rates of hospitalization for schizophrenia in women. In 1980, Templer and Veleber [51] published that wheat intake was correlated with schizophrenia prevalence (r = 0.53, p = 0.01) across 18 countries. Lastly, a large epidemiological study found that the rate of schizophrenia was only 2 per 65,000 in the Pacific Islands, at a time when there was very low exposure to grain [52]. Thirteen experimental studies assessing the impact of an elimination diet to target food sensitivity in patients with schizophrenia were published between 1969 and 2013. Twelve of these studies involved a gluten-free diet. The remainder assessed a dairy (casein)-free diet (n = 1) or a “cereal-free, milk-free” diet (n = 5). Sample sizes ranged from n = 2 to n = 157. No adverse effects of the dietary interventions were reported although only 4 studies reported specifically on adverse effects. In addition, 8 case reports of a gluten-free therapeutic diet have been reported, including 6 patients with multi-episode schizophrenia and 2 FEP patients. De Santis et al. [53] reported that a GF diet resulted in reversal of left frontal hypoperfusion on SPECT scan, and 6/7 case reports were positive. Microbiome Diet has emerged as an accessible target for intervention to modify the gut microbiome (GMB) composition whether by consuming probiotics via fermented foods, prebiotics (“food” to support and stimulate the growth of beneficial microorganisms), or by avoiding foods that contribute to gut dysbiosis. Pre-clinical studies have found that administration of probiotics (Bifidobacterium longum) to mice attenuated rearing behaviours induced by a dopamine agonist (animal model of schizophrenia) and that prebiotics (B-GOS) given to rats had pro-cognitive effects, and increased levels of Bifidobacterium species [54, 55]. Regarding data in humans, 4 studies have assessed and found differences in the oropharynx microbiome composition in patients with SSD versus controls, and 3 studies reported differences in GBM composition. Overall, high-level differences were found between patients and controls at both the phylum and genus levels in the oropharynx and GBM. These differences were associated with particular metabolic pathways, clinical response, levels of intestinal immune activation, and antibodies to gluten [56–58]. One case report demonstrated improvements in constipation and positive symptoms as well as changes in GMB composition with a 1-month adjunctive prebiotic intervention [59]. One placebo-controlled RCT of a probiotic intervention has been conducted in outpatients with schizophrenia. This group did not find an impact of the intervention on the positive and negative syndrome scale score though they did report significant improvement in gastrointestinal symptoms and a reduction in antibodies to Candida albicans, a marker of intestinal inflammation, in the intervention group [60, 61]. Vegetables and Fruits The observational data consisted primarily of cross-sectional studies comparing the consumption of fruits and vegetables by patients with psychosis to control subjects, and the results were highly consistent (Fig. 10). Twenty-two cross-sectional studies reported on the relationship between dietary intake of fruits and vegetables and the presence of psychosis (average sample size 506, range of 8–1,825). Twenty studies showed an association between a lower intake and the presence of psychosis, and 1 found a relationship between increased intake and decreased psychosis. One showed no association. One case report reported improved symptoms with higher intake of fruit and vegetable juice in combination with vitamins, minerals, and enzymes [62]. Fig. 10. Studies assessing dietary fruit and vegetable intake. Dec, decreased psychopathology or decreased risk/incidence of SSD; Inc, increased psychopathology or increased risk/incidence of SSD; Equ, equivocal/no association. /WebMaterial/ShowPic/1020297 One randomized, placebo-controlled experimental study provided 6 months of free fruits and vegetables, with or without instructions and support, to 102 schizophrenia patients. It failed to detect an impact on positive or negative symptoms [63]. The study found a significant increase in fruit and vegetable intake at the end of the intervention based on patient report; however, using the last observation carried forward, there was no difference in the primary outcome, the number of fruit and vegetable servings consumed 12 months after the intervention as reported consumption returned to pre-intervention levels. Interestingly, there was no change in blood levels of folate, vitamins C and E, or carotenoids, which were measured as an additional objective assessment of diet. It is possible that patients were reporting changes in their diet that were not consistent with their actual intake, which raises concerns about compliance and the accuracy of the reported increase in intake. The power calculation of the study was also based on the primary outcome of changes in fruit and vegetable intake. The study reported that participants’ diets did not change in terms of intake of oil-rich fish, potatoes, pasta or rice, or whole-grain bread; the vegetables were in addition to their previous diets. It is possible that the mental health effects of increasing vegetable intake may be related to multiple factors in dietary patterns containing more of these foods. Phytonutrients Phytonutrients are chemical compounds produced by plants, which possess biological activity. While they are not defined as essential nutrients, some confer effects on human health [64]. Research has been conducted on a range of phytonutrients with respect to psychosis in the form of human experimental, observational, and pre-clinical studies (Table 2). Due to the heterogeneity of constituents studied, the results are displayed in Table 2 with a description of dietary sources and a summary of the current evidence. The intervention studies using phytonutrients were generally small with 10 to 143 participants. No adverse events were reported. Many human and pre-clinical studies assessed mechanism as a secondary outcome and found decreases in lipid peroxidation and inflammatory cytokines, and effects on glutamate, dopamine, acetylcholinesterase, and brain-derived neurotrophic factor. Table 2. Summary of dietary sources of phytonutrients and research related to psychosis /WebMaterial/ShowPic/1020319 Minerals Studies related to minerals were primarily observational in nature, looking at tissue levels of various minerals in both SSD and healthy populations (Fig. 11). Not included in the chart were minerals with ≤3 cross-sectional studies including boron, cobalt, lithium, molybdenum, sulphur, and vanadium. For many minerals, the results were mixed with studies showing associations between psychosis and both higher and lower levels of the minerals. These included calcium, cobalt, iron, magnesium, molybdenum, phosphorus, potassium, and sodium. Studies finding higher levels of copper in an SSD population were more common as were studies finding lower levels of zinc, selenium, and manganese (Fig. 11). A recent meta-analysis of observational studies found lower serum concentrations of zinc in patients with schizophrenia compared to healthy controls [65]. Fig. 11. Studies assessing mineral intake and levels. Dec, decreased psychopathology or decreased risk/incidence of SSD; Inc, increased psychopathology or increased risk/incidence of SSD; Equ, equivocal/no association. /WebMaterial/ShowPic/1020295 A small number of experimental studies have been completed. One used 50 mg of zinc in 30 patients and found significant reductions in positive and negative symptoms and aggression risk [66]. One using zinc in combination with vitamins C, E, and B6 demonstrated a reduction in anxiety but not depression or overall psychopathology [67]. One study using chromium supplementation failed to show a benefit. One research group attempted to complete a double-blind RCT of a multivitamin and mineral formula with an open label run-in; however, all of the 19 participants declined randomization. The study compared these results to the results of patients who had declined participation and those waiting to participate, and observed significant reduction in anti-psychotic medication use as well as positive and negative symptoms at 15 and 24 months, respectively [68]. A small number of case reports reported benefit from zinc supplementation, low levels of magnesium in patients with psychosis and benefit of magnesium supplementation, benefit from molybdenum supplementation, decreased levels of iron and resolution of a first episode with iron supplementation as well as decreased levels of phosphorus. Two animal studies reported a decrease in positive symptoms and anxiety with zinc supplementation. Vitamins The family of B vitamins has received extensive interest with respect to their role in mental health and particularly in psychotic disorders (Fig. 12). A large number of observational studies show lower folate, B12, B6, and choline in patients with psychosis. Many case reports have reported low levels of vitamin B12 in this population as well as improvement in symptoms with supplementation. Vitamins B5 and B7 were excluded from the results table having only 1 study each. Studies assessing vitamin B1 were excluded from the review due to the previously established connection with neuropsychiatric symptoms such as confusion, inattention, and disorientation [69]. Fig. 12. Studies assessing vitamin intake and levels. Dec, decreased psychopathology or decreased risk/incidence of SSD; Inc, increased psychopathology or increased risk/incidence of SSD; Equ, equivocal/no association. /WebMaterial/ShowPic/1020293 A number of experimental studies using vitamins B6, B12, and folate have shown benefit, most frequently to total psychopathology, and a recent meta-analysis combined RCTs using adjunctive B6, folate, and B12 and found a significant improvement in total psychopathology but not in positive or negative symptoms individually [70]. Ten studies of B6 ranged from 8 to 40 participants and used doses of 30 to 1,200 mg for 1–48 weeks in length. Four were double-blind, randomized, and placebo-controlled studies. Five double-blind, randomized, placebo-controlled studies of B12 and folate in combination ranged from 22 to 140 participants and used B12 doses of 400 μg and 2 mg of folate for 12–16 weeks in length. Studies of folate ranged from 8 to 55 participants and used doses of 0.5–15 mg for 4–12 weeks in length. Six of 8 were randomized, double-blind and placebo-controlled studies. Regarding the antioxidant vitamins, the majority of observational studies showed lower levels of vitamins C and A and a lower intake of vitamin D. A small number of case reports and experimental studies using vitamin C supplementation have reported benefit. These experimental studies used a wide range of doses in < 40 participants for up to 8 weeks. In 4 experimental studies that demonstrated a benefit of vitamin E supplementation in the treatment of anti-psychotic-associated movement disorders, secondary outcomes of psychosis symptoms failed to demonstrate a benefit in most of these studies. One study in which psychopathology was the primary outcome reported improvement. A meta-analysis which combined studies utilizing vitamins A, C, and/or E found no impact on total psychopathology [70]. Perinatal Exposure A small body of evidence has explored the impact of perinatal exposure to different dietary constituents and the risk of psychosis in the offspring. The exposure of interest is highly heterogeneous; however, a small number of factors have received more attention. Five animal studies and 3 experimental studies used choline or phosphatidylcholine interventions pre- and/or postnatally, and reported benefit to positive and cognitive symptoms in susceptible animals and improved sensory gating in human infants with elevated genetic risk. Eight observational studies connected psychosis risk with maternal malnutrition or famine, and 4 with maternal iron deficiency. A smaller number of studies reported connection with maternal obesity, vitamin deficiency, maternal immune reactions against food constituents, decreased levels of copper and manganese, high levels of maternal serum DHA, and low maternal folate. Safety Overall, the majority of studies reported that the interventions were safe or did not report on safety. A small number of studies reported adverse events, but these were exclusively in the studies assessing high doses of individual nutrients such as vitamin B3 (300–3,000 mg/day), folate (2 studies only at a dose of 1 mg/day and 0.3–1 mg/kg/day, 6 studies did not report or reported no adverse events), and choline (2 g/day). Reported adverse effects for ω-3 fatty acids include: mild nausea, diarrhoea, indigestion, irritable bowel syndrome, and upper respiratory tract infection. Many clinical trials (n = 11/28) reported an absence of adverse effects with some suggesting that gastrointestinal symptoms could be ameliorated by taking ω-3 supplements with food. Discussion Our results revealed a number of constituents and mechanisms potentially relevant to the development and progression of psychosis (Fig. 13). Fig. 13. Summary of mechanisms linking food and psychosis. /WebMaterial/ShowPic/1020291 Dietary Pattern Overall, significant evidence exists that dietary patterns are associated with psychosis and that therapeutic intervention can impact psychopathology. There is a need for more randomized, controlled, and blinded intervention studies powered to detect changes in mental health rather than metabolic outcomes. There is also an opportunity for greater clarity with respect to the dietary recommendations provided. Carbohydrates and Fibre While the relationship between psychosis and total dietary carbohydrates is unclear, there appears to be an association with higher intake of refined carbohydrates in observational studies. None of the studies included assessed the mechanism by which dietary carbohydrates might be affecting psychosis symptoms; however, some have been proposed. Higher glycaemic index foods may cause reactive hypoglycaemia which includes a number of neuropsychiatric symptoms when induced in a laboratory setting [34]. The ketogenic diet is a high-fat, low-carbohydrate diet that has been used since the 1920s as a therapy for paediatric epilepsy. The diet results in the use of ketone bodies, rather than glucose, as the fuel source for the brain. Abnormalities in glucose tolerance and insulin resistance as well as mitochondrial dysfunction and energy metabolism disturbances have all been associated with the pathogenesis of psychosis and could be potential mechanisms for this diet to exert an effect [71]. With respect to dietary fibre, increased intake lowers the glycaemic index of food [72]; as such, fibre may also exert an effect by way of decreasing reactive hypoglycaemia. Preliminary evidence exists suggesting that fibre may affect mental health by way of modifying the GBM. Indigestible dietary carbohydrates provide a food source for gut bacteria and affect the relative levels of different species with MD and leafy green vegetables contributing to more beneficial species [73]. The relevance of GBM composition to mental health in SSD will be discussed later in this review. Fats The recommended amount and type of dietary fat to consume is a controversial area in the field of nutrition science at the present time. For example, in recent years, we have seen a shift away from emphasizing the importance of a low-fat (and therefore often high-carbohydrate) diet towards including healthier fats in the diet [11, 74]. In parallel to this, industrialization has brought a dramatic change in the relative amount of ω-3 and ω-6 fatty acids consumed as part of the standard North American diet, in part due to the ubiquitous consumption of processed seed oils, which are relatively high in ω-6 PUFAs. An imbalance of ω-6 to ω-3 fatty acids impacts antagonistic biological pathways that can lead to an overproduction of inflammatory cytokines [75]. Several potential mechanisms have been proposed to explain the potential efficacy of EFA in SSD. It has been suggested that individuals with SSD may have abnormalities in EFA metabolism leading to abnormal levels [76] and that treatment with anti-psychotic medications can lead to normalization of EFA levels [77]. The balance of EFA can impact levels of inflammation [41] and oxidative stress [78], and alter serotonin responsivity and dopamine neurotransmission [79, 80]. EFAs have demonstrated neuroprotective effects [81]. Within the scope of nutritional interventions for psychosis, much attention has been paid to the role of EFAs. Treatment or prevention of psychosis and related symptoms with EFAs represents a safe adjunctive intervention with strong biological plausibility, particularly in the symptom domains of cognitive and negative symptoms, where treatment options are much more limited. That being said, several important gaps remain to be clarified by subsequent research studies. For instance, given the abundance of studies that have measured tissue levels of EFA in individuals with SSD, an analysis by stage of illness is warranted. In addition, further exploration of ω-6 to ω-3 ratios in patients with SSD versus controls is necessary, given the opposing impact of these types of fatty acids on inflammation. Perhaps most striking is the potential confounder of dietary intake of ω-3 and ω-6 fatty acids in experimental studies of EFA supplements in individuals with schizophrenia. Future studies should either be conducted in individuals with more homogenous dietary intake or include dietary questionnaires in order to statistically account for differences in diet. Alternatively, whole-diet interventions impacting intake of fats or EFA in individuals with SSD powered to detect changes in mental health outcomes are necessary. Protein Overall, there is a lack of prospective and experimental research into the effects of dietary protein, which warrants further study. Some observational evidence suggests a possible association between levels of amino acids and psychopathology. However, it is noted that a lack of a clearly defined deficiency status limits the interpretation of these results. Studies measuring tryptophan levels were more likely to show an association between lower levels and psychopathology; pre-clinical and experimental studies reported benefit. Tryptophan is the precursor for serotonin synthesis, and animal and human studies have shown that manipulation of tryptophan intake can affect brain levels of serotonin resulting in relapse of depression in patients and susceptible healthy subjects [82]. Second-generation anti-psychotic medications are known to modulate serotonergic neurotransmission. Additionally, the amino acids lysine, glycine, and serine have shown benefit in patients with psychosis when used in a supplemental form in experimental studies. Glycine and serine can modulate NMDA receptors and are hypothesized to exert an effect as a result of the glutamatergic NMDA receptor hypofunction theory of schizophrenia [46]. Observational and experimental studies have reported an association between the amino acid methionine and harm. The mechanism by which methionine is involved in mental health appears to be related to methylation and its role in the 1-carbon metabolism, a complex pathway that relies on adequate levels of vitamins B6 and B12 and the active form of folic acid [83]. Disruptions in this pathway due to vitamin deficiency or mutations to the MTHFR gene may increase levels of homocysteine, which is known to be neurotoxic, as well as impacting the synthesis of glutathione [84]. One study included in this review stated that although they did not assess dietary intake, they hypothesize that the elevated CSF methionine seen in patients with psychosis is related to metabolism rather than excess intake [84]. Clinicians may consider encouraging patients to include adequate amounts of protein in their diet to ensure the provision of essential amino acids, which cannot be synthesized endogenously if consumed in inadequate quantities. Due to the larger body of evidence and proposed mechanism, emphasis may be placed on strong sources of tryptophan, lysine, serine, and glycine. Because dietary sources of many amino acids overlap significantly, there may be limited opportunity to modify these levels selectively through dietary intervention as in the supplement studies. Food Sensitivity and Intolerance An association between gluten sensitivity and schizophrenia was described by Dohan [50] in 1966. More recently, mechanisms linking gluten sensitivity and schizophrenia have been hypothesized supported by findings that patients with schizophrenia show elevated levels of gastrointestinal inflammation, systemic markers of inflammation, and immune dysregulation, and evidence of altered gut permeability. The composition of the GBM has been implicated in the relationship between food sensitivities and schizophrenia, in part due to its crucial role in the gut-brain axis and immune system regulation. The interested reader is directed to the following review articles for further discussion of these mechanisms [85, 86]. In summary, gluten-free diets represent a potential safe adjunctive therapeutic strategy for a subset of patients with schizophrenia. Further experimental studies are needed, and none has been conducted in the last 5 years. Given the challenges with monitoring compliance, perhaps a clinical trial in an inpatient setting could be considered. Furthermore, the feasibility of this kind of treatment would be improved if it were possible to identify patients who would be more likely to benefit from a GF diet based on biomarkers. As such, clarification of which biomarkers of gluten sensitivity to measure clinically is needed. Subsequent studies could consider including measurement of anti-TTG6 IgG, the isoform of TTG expressed in brain, or anti-gliadin IgG based on the current literature. Studies assessing other food sensitivities or intolerances in patients with schizophrenia with the exception of dairy and gluten are lacking. Microbiome The impact of the GMB composition on health and disease is a rapidly growing area of research. We are beginning to understand that the GMB composition is a major factor influencing key bodily systems such as immune functioning, metabolic health, mental health, and the gut-brain axis. Preliminary findings suggest that individuals with SSD may show differences in microbiome composition, and that this may represent a potential target for therapeutic intervention. Diet is of particular interest here in that it is one of the modifiable determinants of microbiome composition (i.e., dietary prebiotics, probiotics, and avoidance of foods that contribute to dysbiosis). Further research is needed to clarify the specific differences in microbiome composition between patients with SSD versus healthy controls. These types of studies could lead to the development of a biomarker to identify patients who would specifically benefit from microbiome-directed interventions. Further research is also needed to inform dose and strain of probiotic, dose and type of prebiotic, and type of dietary intervention required for efficacy. In addition, no controlled studies of a prebiotic or synbiotic (combined prebiotic and probiotic) intervention have been conducted in individuals with schizophrenia. Vegetables and Fruit A significant body of observational data shows a lower intake of vegetables and fruits in patients with psychosis. However, experimental data are lacking with only 1 study published. There are several proposed mechanisms by which fruits and vegetables may have a positive impact on mental health. These are related to the provision of constituents such as fibre, vitamins, minerals, and phytonutrients, which are discussed in other sections of this review. In addition to possibly being relevant in psychosis pathogenesis, vegetable intake is known to affect many of the medical comorbidities common in patients with SSD. Meta-analyses have associated higher intakes of vegetables with reduced cardiovascular risk [87], reduced all-cause mortality [88], and reduced risk of type 2 diabetes [89]. Despite these results, more experimental research into the mental health effects of dietary fruit and vegetable intake is warranted. The studies assessing vegetables and fruits should also be interpreted in conjunction with the studies assessing dietary patterns. While the values of certain dietary constituents have included controversy and differing opinions, the beneficial role of fruits and vegetables is highly consistent, and the studies reporting or manipulating diet quality, which largely showed associations with less disease or improvement in disease progression, emphasized fruit and vegetable intake. There is a need for more prospective studies and experimental studies, which evaluate or manipulate intake of vegetables and fruits. Phytonutrients Although preliminary, the majority of these studies assessing phytonutrients in animal models or clinical populations reported positive outcomes, lack of adverse events, and plausible mechanisms of action; however, small sample size and limited scope of phytonutrients that have been studied to date limit generalizability. Further intervention studies, especially in humans, appear to be warranted. Because these nutrients are obtained from fruits and vegetables, these data provide a further rationale for inclusion of fruits and vegetables in the diet. Clinicians and patients may consider emphasizing sources of phytonutrients with the most evidence to support their utility. These include: green tea, broccoli, onions, and berries. Minerals Overall, the studies on the relationship between minerals and psychosis are few in number and limited in quality. The vast majority were of cross-sectional design, and, given the poor diet known to be consumed by patients with psychosis, it is unclear if mineral deficiencies preceded the disorder or were a result of it. Prospective studies would be beneficial in differentiating these two possibilities. None of the studies included in this review assessed the mechanism by which minerals may be affecting mental health; however, several have been studied. Zinc plays a role in a vast range of cellular functions, including signal transduction, gene expression, and apoptosis [65]. It is concentrated in the limbic system of the brain in glutamatergic zinc-enriched neurons and is known to modulate NMDA receptor activity as an antagonist as well as interacting with GABA and serotonin receptors. Schizophrenia has been linked to variants in a number of zinc transporters. Selenium functions as a cofactor for the reduction in antioxidant enzymes such as glutathione [90]; the role of oxidative stress in psychosis is mounting [91]. This review excluded studies related to Wilson disease (WD), an autosomal recessive condition related to impaired copper metabolism resulting in accumulation of copper in the brain and other organs – psychosis is a well-established symptom [92]. Patients with WD display changes on electroencephalogram and hypoperfusion on SPECT scan, and it has been proposed that serum copper affects dopamine activity through several copper-dependent enzymes involved in synthesis and degradation. Cuprizone, a copper chelator which is known to cause white-matter abnormalities, is used to induce a schizophrenia-like syndrome in animal models for research [92]. It is known that copper and zinc levels in the body are related. While one study reported decreased absorption and increased excretion of zinc with a high-copper diet, it is well established that prolonged intake of high levels of zinc (50 mg/day) decreases copper absorption and depletes body levels [90]. Taken together, zinc/copper homeostasis may be of relevance to psychosis pathogenesis and warrant further research. The mineral with the most evidence to suggest a beneficial role in the prevention or management of psychosis is zinc. Further research in the form of clinical trials appears to be warranted. Clinicians may consider emphasizing foods that provide a good source of dietary zinc. Vitamins There is observational and experimental evidence suggesting a possible protective role of vitamin B6, B12, and folate in psychosis. As highlighted previously, B12, B6, and folate play a role in the 1-carbon metabolism cycle, affecting levels of neurotoxic homocysteine [83]. Each of these vitamins also plays a role in neurotransmitter synthesis and affects oxidative stress levels [93, 94]. As oxidative stress is an established concern in the pathogenesis of psychosis, this mechanism has been proposed for the potential relevance of vitamin A, C, and E adequacy or supplementation. Because vitamins are found in fruits and vegetables, nuts, and seeds, these results may provide a further rationale for the inclusion of these diet components; however, the relevance of these studies to diet is potentially limited by the very large doses used in these studies. The recent meta-analysis found that studies using higher doses of B vitamins were more likely to show benefit than those using lower doses. Perinatal Studies Perinatal studies have highlighted maternal dietary choline, iron, and overall nutritional adequacy as relevant in the primary prevention of psychotic disorders. While the primary objective of this review is to identify dietary strategies to implement in patients with or at high risk of psychosis, knowledge about the importance of adequate choline intake and avoidance of maternal iron deficiency and malnutrition is potentially relevant from a population health perspective. Context of Findings within the Current Literature Although heterogeneity exists among the studies reported in this review, there are many common themes as well as consistency with established information about healthy eating patterns and traditional diets. For example, MD has an extensive body of research to support its use in preventing and treating a range of health concerns including cardiovascular disease and cognitive health [95] as well as, more recently, major depressive disorder [15]. Many of the foods that were highlighted in this review as having potential beneficial effects in the prevention or treatment of psychosis are present in abundance in the MD. This dietary pattern is abundant in vegetables, fruits, fish, and seafood (sources of ω-3 fatty acids), legumes, and nuts (source of prebiotic fibre), yogurt (dietary source of probiotics), and healthy fats such as olive oil. Many of the constituents that have been proposed as beneficial, including fibre, vitamins, minerals, phytonutrients, and ω-3 fatty acids, are present in these healthy foods, and higher body levels of these constituents may be markers for intake. Conversely, foods limited in the MD include processed foods, sweets, and refined grains, all of which were associated with harm in the present review. The MD is but one example of a traditional, whole-food dietary pattern that has received much research attention. It is worth acknowledging that the perception of what constitutes a “healthy diet” has changed significantly over the past several decades. This may be of relevance in interpreting studies that evaluated entire dietary patterns and assessed them as “healthy” or “unhealthy.” For example, the American Dietary Guidelines removed cholesterol as a nutrient of concern in 2015 due to lack of evidence that dietary cholesterol impacts serum cholesterol levels [96]. Additionally, perception about total dietary fat, saturated fat, and total dietary carbohydrates has all changed [74]. This limits the generalizability of observational studies and experimental studies assessing or implementing “healthy diets” and necessitates a thorough assessment of individual constituents such as macro- and micro-nutrients. Many of the intervention studies that implemented a whole-diet approach were unclear about the nutrition education that was provided or the recommendation given, simply stating that they advocated for improved nutrition. This is a limitation in interpreting these studies. Strengths This scoping review has a number of strengths. It involved a highly extensive search strategy and screening of a very large volume of abstracts in order to capture the full breadth and depth of literature in this field. It was completed by an interdisciplinary team of clinicians/researchers offering unique and complementary expertise and perspectives. Limitations One limitation of this review is the very large scope. Because of the very large volume of studies included it was not feasible to analyze each with a high level of detail, and the results obtained may include over-simplifications and a lack of attention to the unique characteristics of individual studies. The interpretation of the results is also limited by a number of characteristics of the studies included in the review. Study Design Many of the studies included were observational in design with the vast majority being cross-sectional studies. This limits the ability to draw conclusions about causality and the directionality of the association between inadequate nutrition and psychosis. Due to a multitude of factors, it is likely that this association is complex and bidirectional. While the number of prospective studies obtained in this review was very limited, prospective studies in unipolar depression have shown that poor dietary choices precede the increased risk of developing this mental disorder [13]. Also, many studies that contribute to our mechanistic understanding have utilized animal models. Given the differences between animal and human diets and the limitations of the animals for psychosis, these data may be limited in their applicability to humans with SSD. Further research should focus on human studies. Studies included in this review assessed patients in both early and chronic stages of psychotic illnesses and were analyzed collectively. These different stages may be unique in their responsiveness to nutritional interventions [97, 98]. Many of the intervention studies assessed where designed to assess metabolic outcomes and assessed mental health symptoms or quality of life as secondary outcomes. There is a need for more whole-diet interventions powered to detect changes in mental health outcomes. Perhaps most striking is the potential confounder of heterogeneity in dietary intake among study participants both between and within groups. For instance, many experimental studies of ω-3 fatty acid supplements fail to consider dietary intake of both ω-3 and ω-6 fatty acids. Because of the antagonistic effects on inflammation possessed by these 2 fatty acids, the relative proportion is of importance, and a very high intake of dietary ω-6 in some or all study participants could have a significant impact on study outcomes [75]. Failing to account for dietary intake could result in within-group differences large enough to obscure the impact of the intervention under study. Future studies should either be conducted in individuals with more homogenous dietary intake or include dietary questionnaires in order to statistically account for differences in diet. Measurement Error Although a small number of studies looked at CSF or brain levels, the vast majority of observational studies assessing vitamins, minerals, and amino acids assessed serum or plasma levels which may be less relevant. For example, only 1% of the body’s magnesium is present in the blood; as such, there are concerns about the utility of blood levels in assessing magnesium sufficiency [99]. It has been suggested that assessment of RBC magnesium is more useful, but only a minority of studies included in this review used this measurement. Zinc also lacks an accepted, reliable measurement to assess individual zinc sufficiency making the assessment of suboptimal zinc challenging [90]. The different tissue sources used to measure levels of vitamins, minerals, fatty acids, and amino acids may account for some of the variability in results. Additionally, many of the observational studies relied on patient report to assess intake quantities and frequencies, with some using only one 24-h recall. A recent editorial highlighted a number of issues related to the use of this type of assessment in diet/psychosis research [100, 101]. As a result of daily and seasonal variation in diet, a single-time-point 24-h diet recall is unsuitable for capturing interindividual and intergroup differences. A second issue raised is that of misreporting, particularly underreporting in the overweight and obese population and among those with severe mental illness affected by cognitive, memory, and motivational difficulties. Lastly, there are limitations related to using existing general popu­lation data as a comparison as opposed to recruiting matched healthy controls. Even minor differences in the methodology used for assessing diet intake could have significant effects. Extrapolating from Studies of Dietary Supplements Another limitation of this review is the applicability of some of the experimental studies, which used vitamin, mineral, phytochemical, fatty acid, and amino acid interventions in the form of dietary supplements. Some used doses of nutrients that can be feasibly obtained in the diet including sulforaphane (30 mg), zinc (50 mg), folate (0.5 mg), vitamin C (500 mg), and vitamin B12 (400 µg). In contrast, some of the intervention studies using vitamins used very high doses that cannot be achieved through dietary modification such as L-theanine, curcumin, vitamin B3, and vitamin B6. Because this distinction is unclear, we chose to include all intervention studies regardless of dose while acknowledging this as a limitation. Feasibility of Dietary Interventions in Individuals with SSD Throughout this review, it has been acknowledged that modifying the diet of individuals with psychotic disorders requires consideration of a number of barriers related largely to symptoms and socio-economic status [18]. It is important to note that many of the experimental studies which showed positive outcomes in psychopathology employed a multimodal approach, including educational and practical skill components, self-care, and wellness components, motivational enhancement strategies, and planning and budgeting skills. Mental health teams supporting individuals with SSD are often well equipped to address these barriers by harnessing an interdisciplinary team to support behavioural changes such as taking medication, decreasing substance use, and other self-care and instrumental activities. Unfortunately, dieticians, naturopaths, and other nutrition-informed professionals are often not included in these teams and may be inaccessible for patients to consult with privately due to financial barriers. Inclusion of these nutrition-focused professions within the interdisciplinary team may be an opportunity to improve efficacy and feasibility of dietary interventions in this complex population [102]. Future Directions Implications for Clinical Practice While the evidence obtained in this review is preliminary in nature, it is largely consistent with general dietary recommendations as well as recommendations known to be therapeutic in treating the comorbidities found in this population. The evidence suggests that these dietary approaches are of very low risk, are of low cost [103], and have at least some compelling potential for benefit. As such, the following recommendations are put forward in Table 3. Table 3. Summary of evidence-informed dietary recommendations for individuals with psychotic disorders /WebMaterial/ShowPic/1020317 Need for Further Research Overall, there is a need for more observational studies, which are prospective in nature and able to distinguish factors which play a causal role in the development of psychosis from those that result from the poor diet choices made by this population. Future research studies need to be attentive to ontological issues in nutrition research [104], as well as address a lack of clarity of associations between intake, biomarker, and nutritional status. This will help to further clarify macro- and micro-nutrients which are harmful or protective to guide additional research. Constituents that are particularly lacking in experimental data include carbohydrates, fibre, microbiome, vegetables, and protein. More importantly, there is a significant need for intervention studies, which modify intake of dietary constituents or entire dietary patterns with statistical power to detect changes in mental health outcomes. Acknowledgements We would like to acknowledge the valuable contribution of the following individuals: Jason Clifford (study planning), Lauren McKinney (abstract screening), Alyssa Robbins (abstract screening), and Rob Mikulec (data management and technical assistance). Disclosure Statement The authors report no conflicts of interest. Related Articles: J Nutrigenet Nutrigenomics 2017;10:93-125 11th Congress of the International Society of Nutrigenetics/Nutrigenomics (ISNN) : Abstracts Go to Article Inflamm Intest Dis 2017;2:1-92 1st International Conference on Fatty Liver (ICFL). 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ONS: an ontology for a standardized description of interventions and observational studies in nutrition. Genes Nutr. 2018 Apr;13(1):12. External Resources Pubmed/Medline (NLM) Crossref (DOI) Author Contacts Monique Aucoin Canadian College of Naturopathic Medicine 1255 Sheppard Avenue East Toronto, ON M2K 1E2 (Canada) E-Mail Laura LaChance Centre for Addiction and Mental Health 250 College Street, 7th Floor Toronto, ON M5T 1R8 (Canada) E-Mail Article / Publication Details First-Page PreviewAbstract of Review Received: June 05, 2018 Accepted: August 29, 2018 Published online: October 25, 2018 Number of Print Pages: 23 Number of Figures: 13 Number of Tables: 3 ISSN: 0302-282X (Print) eISSN: 1423-0224 (Online) For additional information: Copyright / Drug Dosage / Disclaimer Copyright: All rights reserved. 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