To date, the evidence to support the functional medicine model of care has been anecdotal, primarily published as case reports. Peer-reviewed evidence for functional medicine is based on specific interventions used by the model, including nutrition, lifestyle, or medications and dietary supplements (monotherapy or polytherapy). To our knowledge, this study is also the first systematic attempt to collect data from patients using validated measures to understand the association of HRQoL with the functional medicine model of care.

In this study, the functional medicine model of care was significantly associated with improved longitudinal PROMIS GPH scores in patients at 6 months, and these improvements remained significant for up to 12 months. Patients seen at the Center for Functional Medicine were more likely to experience a clinically meaningful change (change of ≥5 points) in their PROMIS GPH scores at 6 months, which were less likely to decrease over time. Comparing PROMIS GPH scores with those from the Family Health Center, patients seen at the Center for Functional Medicine experienced a significant longitudinal benefit for up to 12 months. However, a more robust sample size and consistent longitudinal tracking of patients are warranted to confirm this finding. The functional medicine model of care also significantly improved short-term PROMIS GMH scores in patients and demonstrated a larger association than care received in a primary care setting; however, long-term improvements were not statistically significant.

Several factors may have contributed to improvements in HRQoL associated with the functional medicine model of care. First, improvements in HRQoL associated with the functional medicine model of care may be due to the model itself. Functional medicine addresses chronic disease by delivering precision medicine. The ability to deliver precision medicine relies on one’s capability to not only collect data, but also organize it in a way that extracts an understanding of a patient’s biological processes and then maps these processes to human disease. The delivery of precision medicine also requires the ability to focus treatment around specific factors associated with a patient’s symptoms. The formal definition of functional medicine was first introduced in 1991 and tracks with the more recent precision medicine initiative.

Importance 
The incidence of chronic disease is increasing along with health care–related costs. The functional medicine model of care provides a unique operating system to reverse illness, promote health, and optimize function. The association between this model of care and patient’s health-related quality of life (HRQoL) is unknown.
Objective 
To assess the association between functional medicine and patient-reported HRQoL using Patient-Reported Outcome Measurement Information System (PROMIS) global health measures.
Design, Setting, and Participants 
A retrospective cohort study was performed to compare 7252 patients aged 18 years or older treated in a functional medicine setting with propensity score (PS)–matched patients in a primary care setting. Sensitivity analyses assessed improvement limited to patients seen at both 6 and 12 months. The study included patients who visited the Cleveland Clinic Center for Functional Medicine or a Cleveland Clinic family health center between April 1, 2015, and March 1, 2017.
Main Outcomes and Measures 
The primary outcome was change in PROMIS Global Physical Health (GPH) at 6 months. Secondary outcomes included PROMIS Global Mental Health (GMH) at 6 months and PROMIS GPH and GMH at 12 months. The PROMIS GPH and GMH scores were transformed to a T-score from 0 to 100 with a mean of 50. Higher scores indicate a better health-related quality of life.
Results 
Of the 7252 patients (functional medicine center: 1595; family health center: 5657), 4780 (65.9%) were women; mean (SD) age was 54.1 (16.0) years. At 6 months, functional medicine patients exhibited significantly larger improvements in PROMIS GPH T-score points than were seen in patients treated at a family health center (mean [SD] change, functional medicine center: 1.59 [6.29] vs family health center: 0.33 [6.09], P = .004 in 398 PS-matched pairs). At 12 months, functional medicine patients showed improvement similar to that observed at 6 months; however, comparisons with patients seen at the family health center were not significant. Patients in the functional medicine center with data at both 6 and 12 months demonstrated improvements in PROMIS GPH (mean [SD], 2.61 [6.53]) that were significantly larger compared with patients seen at a family health center (mean [SD], 0.25 [6.54]) (P = .02 in 91 PS-matched pairs).
Conclusions and Relevance 
In this study, the functional medicine model of care demonstrated beneficial and sustainable associations with patient-reported HRQoL. Prospective studies are warranted to confirm these findings.

The delivery of precision medicine also requires the ability to focus treatment around specific factors associated with a patient’s symptoms. The formal definition of functional medicine was first introduced in 1991 and tracks with the more recent precision medicine initiative. The use of the word function within the name is “aligned with the evolving understanding that disease is an endpoint and function is a process.” (p25) The functional medicine model uses a systems-based approach to care that looks upstream of a patient’s symptoms and considers the complex web of interactions within a patient’s history, physiologic status, genetics, lifestyle, and environment, and contributes to their physical and mental functional status. The organization of this information within an operating system affords trained caregivers the opportunity to develop patient-specific management strategies to improve function through nutritional, behavioral, and lifestyle interventions. Studies have suggested an association between biological pathways, genes, and molecular markers and quality-of-life domains (eg, physical function, fatigue, pain, emotional function, social function, and overall quality of life).

Although not inherent to all functional medicine practices, the Center for Functional Medicine requires that all new patients see a registered dietitian and health coach, in addition to a clinician, as part of their initial visit. Patients also have the option to meet with a behavioral health therapist as part of any visit. Dietitians and health coaches are integral because they address the nutritional, psychological, and social aspects of patients’ illnesses and promote long-term self-management, which are components needed for the treatment of various chronic conditions. This clinical operational structure is different from that delivered in conventional medicine where health coaches are not available and scheduling a visit with a registered dietitian may not be recommended and/or available. In addition, the findings reported herein may not be representative of other functional medicine private practices, because multidisciplinary teams are not ubiquitous.

Second, patients seen in the Center for Functional Medicine may be different from those seeking primary care in a family health center. Our attempt to circumvent this bias was to PS match patients from each center based on certain variables; however, there may be unmeasured confounders associated with the reported outcomes. For example, patients who request to be seen at the Center for Functional Medicine may be more motivated to make a nutrition-, lifestyle-, or behavior-related change in their life.

Functional medicine is essentially patient centered, rather than disease centered. A structure is presented for uniting a patient-centered approach to diagnosis and treatment with the fruits of modern clinical science (which evolved primarily to serve the prevailing model of disease-centered care). The core scientific concepts of disease pathogenesis are antecedents, triggers, and mediators. Antecedents are factors, genetic or acquired, that predispose to illness; triggers are factors that provoke the symptoms and signs of illness; and mediators are factors, biochemical or psychosocial, that contribute to pathological changes and dysfunctional responses. Understanding the antecedents, triggers, and mediators that underlie illness or dysfunction in each patient permits therapy to be targeted to the needs of the individual. The conventional diagnosis assigned to the patient may be of value in identifying plausible antecedents, triggers or mediators for each patient, but is not adequate by itself for the designing of patient-centered care. Applying the model of person-centered diagnosis to patients facilitates the recognition of disturbances that are common in people with chronic illness. Diet, nutrition, and exposure to environmental toxins play central roles in functional medicine because they may predispose to illness, provoke symptoms, and modulate the activity of biochemical mediators through a complex and diverse set of mechanisms. Explaining those mechanisms is a key objective of the Textbook of Functional Medicine (from which this article is excerpted). A patient's beliefs about health and illness are critically important for self-care and may influence both behavioral and physiological responses to illness. Perceived self-efficacy is an important mediator of health and healing. Enhancement of patients' self-efficacy through information, education, and the development of a collaborative relationship between patient and healer is a cardinal goal in all clinical encounters.

The functional medicine matrix provides us with an opportunity to understand how social determinants of health (SDOH) and health related social needs may be root causes and contributors to current health and illness among patients. The matrix also allows us to map and recognize the intersectionality of SDOH on exposures and behaviors that influence antecedents, triggers, mediators, lifestyle factors, and clinical imbalances. Incorporating SDOH into clinical evaluations helps uncover and address the complex factors that lead to health disparities in order to provide more optimal patient-centered care.

Background: Despite treatment advances for inflammatory arthritis, a significant amount of patients fail to achieve remission. Other modifiable factors such as diet, physical activity and environmental exposures may be an important area of focus to help patients achieve disease remission and greater overall health. Functional medicine focuses on these lifestyle factors and may be an important adjunctive therapy. In this study, we examined the impact of functional medicine on patient-reported outcomes in patients with inflammatory arthritis.

Materials And Methods: In this 12-week, retrospective study, patients with confirmed diagnoses of rheumatoid arthritis (RA) or psoriatic arthritis (PsA) were treated according to guidelines from the American College of Rheumatology for RA or PSA respectively. Those in the functional medicine group underwent a functional medicine program adjunctive to the standard of care. Patient reported outcomes, such as PROMIS (Patient Reported Outcomes Measurement Information System) global physical health, mental health and pain scores were collected at baseline and 12 weeks. Multivariable statistical modeling was used to identify the impact of functional medicine on patient-reported outcomes.

Results: 318 patients were screened and 54 patients (mean age 52.9±11.3 years, females 74(67.9%)), were included. Baseline characteristics were similar in both patient groups with the exception of PROMIS global physical health and pain (PROMIS global physical health score 43·2 ± 6·6 and 39·7 ± 8·7 and pain scores of 3·5 ± 1·9 and 5·2 ± 2·7 in the functional medicine group vs. standard of care group respectively). Using multivariable model to account for these differences, patients in the functional medicine group had a statistically significant reduction in pain (0.92, p-value = 0.007) and change in PROMIS physical health score (2·84, p-value = 0.001) as compared to the standard of care. Changes in PROMIS global mental health scores were also significant and were dependent on age and were greatest in those older than 55.

Limitations: Retrospective design, baseline difference in patient reported outcomes.

Conclusions: Functional medicine may have an important role as adjunctive therapy to improve patients' pain, physical and mental health in those who do not see improvement with conventional therapy alone.

Background: There is a subgroup of patients with type 2 diabetes (T2D) in whom traditional treatment does not work well. Traditional management of T2D does not address the autoimmune component seen in a subgroup of patients with T2D. Primary Study Objective: We sought to evaluate the effectiveness of using a personalized functional medicine (PFM) approach to managing T2D. Methods/Design: Patient files from 2010 to 2015 were culled for patients previously diagnosed with T2D and their deidentified data regarding medications and T2D biomarker test results were compiled. A total of 35 patients were contacted for permission to use their deidentified data for the purposes of this article. Of 35 patients, 11 provided written consent. Setting: All participants had entered a single, private, integrative medicine clinic based in Maryland, USA. Participants: The patient group consisted of 5 women and 6 men; age 50 to 77 years. Each patient was taking an antidiabetic medication and had reached a plateau in recovery, or wanted to reduce their medication intake. Allopathic physicians were retained by patients undergoing PFM treatment. Intervention: After a thorough intake history was completed, necessary specimens were collected for analysis. Once test results were reviewed to identify nutrient deficiencies, intestinal dysbiosis, hormone imbalances, chemical burden and food immune reactivities, a personalized plan was developed for each individual patient. Each patient was retested appropriately during treatment. Treatment lasted from 2 to 10 months based on the patients' goals. Primary Outcome Measures: The effectiveness of the PFM approach was measured by the reduction in medication needed to manage T2D and improvement in T2D biomarkers. Results: At the end of PFM treatment, 6 patients were completely off T2D-related medications, and 5 had their doses reduced by 50%. Diabetes biomarkers improved: glucose decreased by an average of 78.36 mg/dL and hemoglobin A1c (HbA1c) was lowered by an average of 2.71%. Conclusion: In individuals not well-managed using traditional protocols, the PFM approach should be considered as an adjunct therapy.

The functional medicine model of care is focused on patient-centered rather than disease-centered care. Patient-centered care incorporates the patient's voice or experience of their condition alongside conventional biological factors to provide a "more complete" account of health. PROMIS Global, an NIH-validated patient-reported outcome (PRO) measure that evaluates the health-related quality of life, can be incorporated within the functional medicine model of care to evaluate self-reported physical, mental and social well-being across various conditions and guide personalized management strategies. Proper incorporation of PROMIS Global into clinical care and research is warranted to expand the available evidence base.

Mental illness, including depression, anxiety and bipolar disorder, accounts for a significant proportion of global disability and poses a substantial social, economic and heath burden. Treatment is presently dominated by pharmacotherapy, such as antidepressants, and psychotherapy, such as cognitive behavioural therapy; however, such treatments avert less than half of the disease burden, suggesting that additional strategies are needed to prevent and treat mental disorders. There are now consistent mechanistic, observational and interventional data to suggest diet quality may be a modifiable risk factor for mental illness. This review provides an overview of the nutritional psychiatry field. It includes a discussion of the neurobiological mechanisms likely modulated by diet, the use of dietary and nutraceutical interventions in mental disorders, and recommendations for further research. Potential biological pathways related to mental disorders include inflammation, oxidative stress, the gut microbiome, epigenetic modifications and neuroplasticity. Consistent epidemiological evidence, particularly for depression, suggests an association between measures of diet quality and mental health, across multiple populations and age groups; these do not appear to be explained by other demographic, lifestyle factors or reverse causality. Our recently published intervention trial provides preliminary clinical evidence that dietary interventions in clinically diagnosed populations are feasible and can provide significant clinical benefit. Furthermore, nutraceuticals including n-3 fatty acids, folate, S-adenosylmethionine, N-acetyl cysteine and probiotics, among others, are promising avenues for future research. Continued research is now required to investigate the efficacy of intervention studies in large cohorts and within clinically relevant populations, particularly in patients with schizophrenia, bipolar and anxiety disorders.

Introduction: Individuals suffering from psychiatric disorders experience high levels of illness burden and a significantly reduced quality of life. Despite targeted psychopharmacological strategies and complementary psychotherapeutic procedures only moderate effects are obtained, and the risk of relapse is high in many patients. Worldwide, psychiatric diseases such as depression are continuously increasing, challenging the personal life of the affected as well as their families, but also whole societies by increasing disability, early retirement and hospitalization. According to current scientific knowledge psychiatric disorders are caused by a multifactorial pathogenesis, including genetics, inflammation and neurotransmitter imbalance; furthermore, also lifestyle-associated factors gain rising importance. In line with this, there is growing evidence that the gut microbiota and nutrition have an impact on the onset and course of psychiatric disorders.

Aim: This narrative review highlights the important role of nutrition in psychiatric care and underlines the significance of nutritional advice in the multifactorial, biopsychosocial treatment of patients. It focuses on current dietary interventions such as the Mediterranean diet, dietary supplements and modifications of the gut microbiota with pre-, pro- and postbiotics.

Results: Recent studies support the connection between the quality of diet, gut microbiota and mental health through regulation of metabolic functions, anti-inflammatory and antiapoptotic properties and the support of neurogenesis. Dietary coaching to improve mental health seems to be an additional, cost-effective, practical, nonpharmacological intervention for individuals with psychiatric disorders.

Conclusion: The use of nutritional interventions in psychiatry equips therapists with a promising tool for both the prevention and treatment of psychiatric disorders. Besides pharmacological therapy, psychotherapy and physical activity, nutritional interventions are an important pillar in the multifactorial, biopsychosocial treatment of psychiatric disease and could be used as a potential therapeutic target.

The 'monoamine hypothesis' is insufficient in approaching the aetiology of psychiatric disorders or in developing novel therapies. Accumulating evidence suggests that inflammatory regulation plays an important role in pathophysiology and therapeutic mechanism across the major psychiatric disorders. "Inflammation theory" might not be the full answer for the big picture of mental disorders, but it might explain high occurrence of somatic symptoms and comorbidity of physical illness in certain subtypes of the heterogeneous groups. Due to the complexity of clinical manifestations and bio-psycho-social etiology, each single treatment shows only small effectiveness with limited effect sizes when compared with placebo. Unfortunately, clinicians are still struggling with trial-and-error practice without any reliable clinical or biological markers to predict therapeutic responses. Therefore, it is important to open up our minds to integrative approaches such dietary modification and nutraceutical prescription. In this special issue, we included 15 papers discussing the role of nutrition (blueberries, omega-3 polyunsaturated fatty acids, melatonergic agonist, S-Adenosyl-L-Methionine, Cannabidiol and Kratom) in the context of immunoregulation across different psychiatric disorders from depression, bipolar disorders, and schizophrenia to alcohol-induced dementia and anorexia nervosa. Moreover, we also included research in perinatal depression that highlight the role of estradiol and the component of breast milk and the association with the neurodevelopment of the offspring. In addition, several articles focused on the role of microbiota in mental health and pain as recent research has pointed to the gut-brain axis as a main regulator of brain, behaviour and immunity. Lastly, inflammatory mechanisms underlying psychiatric disorders including alcohol induced dementia and anorexia nervosa are also highlighted in the special issue.

There is a strong relationship between a healthy diet and mental well-being. Several foods and food compounds are known to modulate biomarkers and molecular mechanisms involved in the aetiogenesis of several mental disorders, and this can be useful in containing the disease progression, including its prophylaxis. This is an updated systematic review of the literature to justify the inclusion and recognition of nutrition in the management of psychiatric illnesses. Such foods and their compounds include dietary flavanols from fruits and vegetables, notable antioxidant and anti-inflammatory agents, probiotics (fermented foods) known to protect good gut bacteria, foods rich in polyunsaturated fatty acids (e.g., Omega-3), and avoiding diets high in saturated fats and refined sugars among others. While the exact mechanism(s) of mitigation of many nutritional interventions are yet to be fully understood, the evidence-based approach warrants the inclusion and co-recognition of nutrition in the management of psychiatric illnesses. For the greater public health benefit, there is a need for policy advocacy aimed at bridging the knowledge gap and encouraging the integration of nutritional intervention with contemporary therapies in clinical settings, as deficiencies of certain nutrients make therapy difficult even with appropriate medication.

The field of 'nutritional psychiatry' has evolved with rapidity over the past several years, with an increasing amount of dietary or nutrient-based (nutraceutical) intervention studies being initiated, and more preclinical and epidemiological data being available. This emergent paradigm involves the clinical consideration (where appropriate) of prescriptive dietary modification/improvement, and/or the select judicious use of nutrient-based supplementation to prevent or manage psychiatric disorders. In the last several years, significant links have increasingly been established between dietary quality and mental health (although not all data are supportive). Maternal and early-life nutrition may also affect the mental health outcomes in offspring. In respect to nutraceutical research, like with many recent conventional drug studies, results are fairly mixed across the board, and in many cases there is not emphatic evidence to support the use of nutraceuticals in various psychiatric disorders. This may in part be due to a preponderance of recent studies within the field revealing marked placebo effects. Due to current indicators pointing towards mental disorders having an increasing burden of disease, bold and innovative approaches on a societal level are now required. In light of the widespread use of nutrient supplements by those with and without mental disorders, it is also critical that scientifically rigorous methodologies be brought to bear on the assessment of the efficacy of these supplements, and to determine if, or what dose of, a nutrient supplement is required, for whom, and when, and under what circumstances. More simple studies of additional isolated nutrients are not of great benefit to the field (unless studied in supra-dosage in an individualised, biomarker-guided manner), nor, based on recent data, is the research of 'shotgun' formulations of nutraceuticals. The next critical step for the field is to design psychiatric interventional studies for both dietary modification and nutraceuticals, based on more of a personalised medicine approach, using biomarkers (e.g. nutrient deficiencies, inflammatory cytokine levels, genomic assessment, microbiome analysis) and a person's dietary patterns and individual macro/micronutrient requirements.

Psychiatry is at an important juncture, with the current pharmacologically focused model having achieved modest benefits in addressing the burden of poor mental health worldwide. Although the determinants of mental health are complex, the emerging and compelling evidence for nutrition as a crucial factor in the high prevalence and incidence of mental disorders suggests that diet is as important to psychiatry as it is to cardiology, endocrinology, and gastroenterology. Evidence is steadily growing for the relation between dietary quality (and potential nutritional deficiencies) and mental health, and for the select use of nutrient-based supplements to address deficiencies, or as monotherapies or augmentation therapies. We present a viewpoint from an international collaboration of academics (members of the International Society for Nutritional Psychiatry Research), in which we provide a context and overview of the current evidence in this emerging field of research, and discuss the future direction. We advocate recognition of diet and nutrition as central determinants of both physical and mental health.

Correct nutrition and diet are directly correlated with mental health, functions of the immune system, and gut microbiota composition. Diets with a high content of some nutrients, such as fibers, phytochemicals, and short-chain fatty acids (omega-3 fatty acids), seem to have an anti-inflammatory and protective action on the nervous system. Among nutraceuticals, supplementation of probiotics and omega-3 fatty acids plays a role in improving symptoms of several mental disorders. In this review, we collect data on the efficacy of nutraceuticals in patients with schizophrenia, autism spectrum disorders, major depression, bipolar disorder, and personality disorders. This narrative review aims to provide an overview of recent evidence obtained on this topic, pointing out the direction for future research.

The nascent field of 'Nutritional Psychiatry' offers much promise for addressing the large disease burden associated with mental disorders. A consistent evidence base from the observational literature confirms that the quality of individuals' diets is related to their risk for common mental disorders, such as depression. This is the case across countries and age groups. Moreover, new intervention studies implementing dietary changes suggest promise for the prevention and treatment of depression. Concurrently, data point to the utility of selected nutraceuticals as adjunctive treatments for mental disorders and as monotherapies for conditions such as ADHD. Finally, new studies focused on understanding the biological pathways that mediate the observed relationships between diet, nutrition and mental health are pointing to the immune system, oxidative biology, brain plasticity and the microbiome-gut-brain axis as key targets for nutritional interventions. On the other hand, the field is currently limited by a lack of data and methodological issues such as heterogeneity, residual confounding, measurement error, and challenges in measuring and ensuring dietary adherence in intervention studies. Key challenges for the field are to now: replicate, refine and scale up promising clinical and population level dietary strategies; identify a clear set of biological pathways and targets that mediate the identified associations; conduct scientifically rigorous nutraceutical and 'psychobiotic' interventions that also examine predictors of treatment response; conduct observational and experimental studies in psychosis focused on dietary and related risk factors and treatments; and continue to advocate for policy change to improve the food environment at the population level.

There is increasing academic and clinical interest in how "lifestyle factors" traditionally associated with physical health may also relate to mental health and psychological well-being. In response, international and national health bodies are producing guidelines to address health behaviors in the prevention and treatment of mental illness. However, the current evidence for the causal role of lifestyle factors in the onset and prognosis of mental disorders is unclear. We performed a systematic meta-review of the top-tier evidence examining how physical activity, sleep, dietary patterns and tobacco smoking impact on the risk and treatment outcomes across a range of mental disorders. Results from 29 meta-analyses of prospective/cohort studies, 12 Mendelian randomization studies, two meta-reviews, and two meta-analyses of randomized controlled trials were synthesized to generate overviews of the evidence for targeting each of the specific lifestyle factors in the prevention and treatment of depression, anxiety and stress-related disorders, schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder. Standout findings include: a) convergent evidence indicating the use of physical activity in primary prevention and clinical treatment across a spectrum of mental disorders; b) emerging evidence implicating tobacco smoking as a causal factor in onset of both common and severe mental illness; c) the need to clearly establish causal relations between dietary patterns and risk of mental illness, and how diet should be best addressed within mental health care; and d) poor sleep as a risk factor for mental illness, although with further research required to understand the complex, bidirectional relations and the benefits of non-pharmacological sleep-focused interventions. The potentially shared neurobiological pathways between multiple lifestyle factors and mental health are discussed, along with directions for future research, and recommendations for the implementation of these findings at public health and clinical service levels.

Functional medicine is essentially patient centered, rather than disease centered. A structure is presented for uniting a patient-centered approach to diagnosis and treatment with the fruits of modern clinical science (which evolved primarily to serve the prevailing model of disease-centered care). The core scientific concepts of disease pathogenesis are antecedents, triggers, and mediators. Antecedents are factors, genetic or acquired, that predispose to illness; triggers are factors that provoke the symptoms and signs of illness; and mediators are factors, biochemical or psychosocial, that contribute to pathological changes and dysfunctional responses. Understanding the antecedents, triggers, and mediators that underlie illness or dysfunction in each patient permits therapy to be targeted to the needs of the individual. The conventional diagnosis assigned to the patient may be of value in identifying plausible antecedents, triggers or mediators for each patient, but is not adequate by itself for the designing of patient-centered care. Applying the model of person-centered diagnosis to patients facilitates the recognition of disturbances that are common in people with chronic illness. Diet, nutrition, and exposure to environmental toxins play central roles in functional medicine because they may predispose to illness, provoke symptoms, and modulate the activity of biochemical mediators through a complex and diverse set of mechanisms. Explaining those mechanisms is a key objective of the Textbook of Functional Medicine (from which this article is excerpted). A patient's beliefs about health and illness are critically important for self-care and may influence both behavioral and physiological responses to illness. Perceived self-efficacy is an important mediator of health and healing. Enhancement of patients' self-efficacy through information, education, and the development of a collaborative relationship between patient and healer is a cardinal goal in all clinical encounters.

To date, the evidence to support the functional medicine model of care has been anecdotal, primarily published as case reports. Peer-reviewed evidence for functional medicine is based on specific interventions used by the model, including nutrition, lifestyle, or medications and dietary supplements (monotherapy or polytherapy). To our knowledge, this study is also the first systematic attempt to collect data from patients using validated measures to understand the association of HRQoL with the functional medicine model of care.

In this study, the functional medicine model of care was significantly associated with improved longitudinal PROMIS GPH scores in patients at 6 months, and these improvements remained significant for up to 12 months. Patients seen at the Center for Functional Medicine were more likely to experience a clinically meaningful change (change of ≥5 points) in their PROMIS GPH scores at 6 months, which were less likely to decrease over time. Comparing PROMIS GPH scores with those from the Family Health Center, patients seen at the Center for Functional Medicine experienced a significant longitudinal benefit for up to 12 months. However, a more robust sample size and consistent longitudinal tracking of patients are warranted to confirm this finding. The functional medicine model of care also significantly improved short-term PROMIS GMH scores in patients and demonstrated a larger association than care received in a primary care setting; however, long-term improvements were not statistically significant.

Several factors may have contributed to improvements in HRQoL associated with the functional medicine model of care. First, improvements in HRQoL associated with the functional medicine model of care may be due to the model itself. Functional medicine addresses chronic disease by delivering precision medicine. The ability to deliver precision medicine relies on one’s capability to not only collect data, but also organize it in a way that extracts an understanding of a patient’s biological processes and then maps these processes to human disease. The delivery of precision medicine also requires the ability to focus treatment around specific factors associated with a patient’s symptoms. The formal definition of functional medicine was first introduced in 1991 and tracks with the more recent precision medicine initiative.

The delivery of precision medicine also requires the ability to focus treatment around specific factors associated with a patient’s symptoms. The formal definition of functional medicine was first introduced in 1991 and tracks with the more recent precision medicine initiative. The use of the word function within the name is “aligned with the evolving understanding that disease is an endpoint and function is a process.” (p25) The functional medicine model uses a systems-based approach to care that looks upstream of a patient’s symptoms and considers the complex web of interactions within a patient’s history, physiologic status, genetics, lifestyle, and environment, and contributes to their physical and mental functional status. The organization of this information within an operating system affords trained caregivers the opportunity to develop patient-specific management strategies to improve function through nutritional, behavioral, and lifestyle interventions. Studies have suggested an association between biological pathways, genes, and molecular markers and quality-of-life domains (eg, physical function, fatigue, pain, emotional function, social function, and overall quality of life).

Although not inherent to all functional medicine practices, the Center for Functional Medicine requires that all new patients see a registered dietitian and health coach, in addition to a clinician, as part of their initial visit. Patients also have the option to meet with a behavioral health therapist as part of any visit. Dietitians and health coaches are integral because they address the nutritional, psychological, and social aspects of patients’ illnesses and promote long-term self-management, which are components needed for the treatment of various chronic conditions. This clinical operational structure is different from that delivered in conventional medicine where health coaches are not available and scheduling a visit with a registered dietitian may not be recommended and/or available. In addition, the findings reported herein may not be representative of other functional medicine private practices, because multidisciplinary teams are not ubiquitous.

Second, patients seen in the Center for Functional Medicine may be different from those seeking primary care in a family health center. Our attempt to circumvent this bias was to PS match patients from each center based on certain variables; however, there may be unmeasured confounders associated with the reported outcomes. For example, patients who request to be seen at the Center for Functional Medicine may be more motivated to make a nutrition-, lifestyle-, or behavior-related change in their life.

Evidence-based medicine (EBM) has thus far failed to adequately account for the appropriate incorporation of other potential warrants for medical decision making into clinical practice. In particular, EBM has struggled with the value and integration of other kinds of medical knowledge, such as those derived from clinical experience or based on pathophysiologic rationale. The general priority given to empirical evidence derived from clinical research in all EBM approaches is not epistemically tenable. A casuistic alternative to EBM approaches recognizes that five distinct topics, 1) empirical evidence, 2) experiential evidence, 3) pathophysiologic rationale, 4) patient goals and values, and 5) system features are potentially relevant to any clinical decision. No single topic has a general priority over any other and the relative importance of a topic will depend upon the circumstances of the particular case. The skilled clinician must weigh these potentially conflicting evidentiary and non-evidentiary warrants for action, employing both practical and theoretical reasoning, in order to arrive at the best choice for an individual patient.

Evidence-based psychiatry (EBP) is an important and useful method. However, it covers only a limited range of clinical problems psychiatrists and psychotherapists encounter in daily work. This is due to some particularities of psychiatric diagnoses and therapeutic practice. (i) The validity of psychiatric diagnoses is limited. EBP is entirely depending on diagnoses, so one of its core assumptions is of doubtful applicability in the field of psychiatry and psychotherapy. (ii) Effects of complexity are more obvious in psychiatric and psychotherapeutic cases. Owing to its conceptual bases, EBP cannot sufficiently consider such effects and is therefore of limited usefulness addressing particular problems in fluctuating or symptomatically shifting diseases. (iii) EBP's strong focusing on decision making does not reflect appropriately the clinical reality of psychiatrists and psychotherapists. Diagnostic and therapeutic procedures are in fact more iterative, and decisions are constantly re-evaluated. EBP is not helpful to adjust this type of individual approach, which is needed to treat individual patients.

The proposed practice of "evidence-based medicine," which calls for careful clinical judgment in evaluating the "best available evidence," should be differentiated from the special collection of data regarded as suitable evidence. Although the proposed practice does not seem new, the new collection of "best available" information has major constraints for the care of individual patients. Derived almost exclusively from randomized trials and meta-analyses, the data do not include many types of treatments or patients seen in clinical practice; and the results show comparative efficacy of treatment for an "average" randomized patient, not for pertinent subgroups formed by such cogent clinical features as severity of symptoms, illness, co-morbidity, and other clinical nuances. The intention-to-treat analyses do not reflect important post-randomization events leading to altered treatment; and the results seldom provide suitable background data when therapy is given prophylactically rather than remedially, or when therapeutic advantages are equivocal. Randomized trial information is also seldom available for issues in etiology, diagnosis, and prognosis, and for clinical decisions that depend on pathophysiologic changes, psychosocial factors and support, personal preferences of patients, and strategies for giving comfort and reassurance. The laudable goal of making clinical decisions based on evidence can be impaired by the restricted quality and scope of what is collected as "best available evidence." The authoritative aura given to the collection, however, may lead to major abuses that produce inappropriate guidelines or doctrinaire dogmas for clinical practice.

Mental illness, including depression, anxiety and bipolar disorder, accounts for a significant proportion of global disability and poses a substantial social, economic and heath burden. Treatment is presently dominated by pharmacotherapy, such as antidepressants, and psychotherapy, such as cognitive behavioural therapy; however, such treatments avert less than half of the disease burden, suggesting that additional strategies are needed to prevent and treat mental disorders. There are now consistent mechanistic, observational and interventional data to suggest diet quality may be a modifiable risk factor for mental illness. This review provides an overview of the nutritional psychiatry field. It includes a discussion of the neurobiological mechanisms likely modulated by diet, the use of dietary and nutraceutical interventions in mental disorders, and recommendations for further research. Potential biological pathways related to mental disorders include inflammation, oxidative stress, the gut microbiome, epigenetic modifications and neuroplasticity. Consistent epidemiological evidence, particularly for depression, suggests an association between measures of diet quality and mental health, across multiple populations and age groups; these do not appear to be explained by other demographic, lifestyle factors or reverse causality. Our recently published intervention trial provides preliminary clinical evidence that dietary interventions in clinically diagnosed populations are feasible and can provide significant clinical benefit. Furthermore, nutraceuticals including n-3 fatty acids, folate, S-adenosylmethionine, N-acetyl cysteine and probiotics, among others, are promising avenues for future research. Continued research is now required to investigate the efficacy of intervention studies in large cohorts and within clinically relevant populations, particularly in patients with schizophrenia, bipolar and anxiety disorders.

Psychiatry is at an important juncture, with the current pharmacologically focused model having achieved modest benefits in addressing the burden of poor mental health worldwide. Although the determinants of mental health are complex, the emerging and compelling evidence for nutrition as a crucial factor in the high prevalence and incidence of mental disorders suggests that diet is as important to psychiatry as it is to cardiology, endocrinology, and gastroenterology. Evidence is steadily growing for the relation between dietary quality (and potential nutritional deficiencies) and mental health, and for the select use of nutrient-based supplements to address deficiencies, or as monotherapies or augmentation therapies. We present a viewpoint from an international collaboration of academics (members of the International Society for Nutritional Psychiatry Research), in which we provide a context and overview of the current evidence in this emerging field of research, and discuss the future direction. We advocate recognition of diet and nutrition as central determinants of both physical and mental health.

The field of 'nutritional psychiatry' has evolved with rapidity over the past several years, with an increasing amount of dietary or nutrient-based (nutraceutical) intervention studies being initiated, and more preclinical and epidemiological data being available. This emergent paradigm involves the clinical consideration (where appropriate) of prescriptive dietary modification/improvement, and/or the select judicious use of nutrient-based supplementation to prevent or manage psychiatric disorders. In the last several years, significant links have increasingly been established between dietary quality and mental health (although not all data are supportive). Maternal and early-life nutrition may also affect the mental health outcomes in offspring. In respect to nutraceutical research, like with many recent conventional drug studies, results are fairly mixed across the board, and in many cases there is not emphatic evidence to support the use of nutraceuticals in various psychiatric disorders. This may in part be due to a preponderance of recent studies within the field revealing marked placebo effects. Due to current indicators pointing towards mental disorders having an increasing burden of disease, bold and innovative approaches on a societal level are now required. In light of the widespread use of nutrient supplements by those with and without mental disorders, it is also critical that scientifically rigorous methodologies be brought to bear on the assessment of the efficacy of these supplements, and to determine if, or what dose of, a nutrient supplement is required, for whom, and when, and under what circumstances. More simple studies of additional isolated nutrients are not of great benefit to the field (unless studied in supra-dosage in an individualised, biomarker-guided manner), nor, based on recent data, is the research of 'shotgun' formulations of nutraceuticals. The next critical step for the field is to design psychiatric interventional studies for both dietary modification and nutraceuticals, based on more of a personalised medicine approach, using biomarkers (e.g. nutrient deficiencies, inflammatory cytokine levels, genomic assessment, microbiome analysis) and a person's dietary patterns and individual macro/micronutrient requirements.

There is increasing academic and clinical interest in how "lifestyle factors" traditionally associated with physical health may also relate to mental health and psychological well-being. In response, international and national health bodies are producing guidelines to address health behaviors in the prevention and treatment of mental illness. However, the current evidence for the causal role of lifestyle factors in the onset and prognosis of mental disorders is unclear. We performed a systematic meta-review of the top-tier evidence examining how physical activity, sleep, dietary patterns and tobacco smoking impact on the risk and treatment outcomes across a range of mental disorders. Results from 29 meta-analyses of prospective/cohort studies, 12 Mendelian randomization studies, two meta-reviews, and two meta-analyses of randomized controlled trials were synthesized to generate overviews of the evidence for targeting each of the specific lifestyle factors in the prevention and treatment of depression, anxiety and stress-related disorders, schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder. Standout findings include: a) convergent evidence indicating the use of physical activity in primary prevention and clinical treatment across a spectrum of mental disorders; b) emerging evidence implicating tobacco smoking as a causal factor in onset of both common and severe mental illness; c) the need to clearly establish causal relations between dietary patterns and risk of mental illness, and how diet should be best addressed within mental health care; and d) poor sleep as a risk factor for mental illness, although with further research required to understand the complex, bidirectional relations and the benefits of non-pharmacological sleep-focused interventions. The potentially shared neurobiological pathways between multiple lifestyle factors and mental health are discussed, along with directions for future research, and recommendations for the implementation of these findings at public health and clinical service levels.

Evidence-based medicine (EBM) has become a fixture in today's medical practice. Evidence consists of memorialized observations and should be contrasted with dogmatic pronouncements and/or hypotheses. Evidence has varying degrees of reliability. The randomized clinical trial (RCT) or a systematic review of RCTs is accorded the highest level of credibility and expert opinion the lowest. This ranking reflects the internal validity (degree to which factors in the study interfere with the gathering or interpretation of the observations) of the study design; more valid designs are more credible. The provision of healthcare requires an almost constant assessment of evidence. In so doing, there are a number of principles of EBM that need to be kept in mind: Association can never prove causation. Various methodologic biases can influence conclusions made in both RCTs and observational studies. The strength of RCTs is in the elimination of confounding bias. Surrogate outcomes must be validated in RCTs assessing how they are changed compared with the clinical outcomes. Subgroup analyses cannot prove hypotheses although they can generate them. P < 0.05 is not the same as truth. Type I errors are more likely to occur when multiple analyses are performed, when trials are prematurely stopped for perceived benefit when there was no a priori plan to do so, or in small papers with dramatic results that are selectively published. The failure to find a difference does not mean that no difference exists (type II error).

Modern medicine makes it possible for many people to live with multiple chronic diseases for decades, but this has enormous social, financial, and environmental consequences. Preclinical, epidemiological, and clinical trial data have shown that many of the most common chronic diseases are largely preventable with nutritional and lifestyle interventions that are targeting well-characterized signaling pathways and the symbiotic relationship with our microbiome. Most of the research priorities and spending for health are focused on finding new molecular targets for the development of biotech and pharmaceutical products. Very little is invested in mechanism-based preventive science, medicine, and education. We believe that overly enthusiastic expectations regarding the benefits of pharmacological research for disease treatment have the potential to impact and distort not only medical research and practice but also environmental health and sustainable economic growth. Transitioning from a primarily disease-centered medical system to a balanced preventive and personalized treatment healthcare system is key to reduce social disparities in health and achieve financially sustainable, universal health coverage for all. In this Perspective article, we discuss a range of science-based strategies, policies, and structural reforms to design an entire new disease prevention-centered science, educational, and healthcare system that maximizes both human and environmental health.

Chronic disease places an enormous economic burden on both individuals and the healthcare system, and existing fee-for-service models of healthcare prioritize symptom management, medications, and procedures over treating the root causes of disease through changing health behaviors. Value-based care is gaining traction, and there is a need for value-based care models that achieve the quadruple aim of (1) improved population health, (2) enhanced patient experience, (3) reduced healthcare costs, and (4) improved work life and decreased burnout of healthcare providers. Lifestyle medicine (LM) has the potential to achieve these four aims, including promoting health and wellness and reducing healthcare costs; however, the economic outcomes of LM approaches need to be better quantified in research. This paper demonstrates proof of concept by detailing four cases that utilized an intensive, therapeutic lifestyle intervention change (ITLC) to dramatically reverse disease and reduce healthcare costs. In addition, priorities for lifestyle medicine economic research related to the components of quadruple aim are proposed, including conducting rigorously designed research studies to adequately measure the effects of ITLC interventions, modeling the potential economic cost savings enabled by health improvements following lifestyle interventions as compared to usual disease progression and management, and examining the effects of lifestyle medicine implementation upon different payment models.

Lifestyle medicine (LM) is a rapidly emerging clinical discipline that focuses on intensive therapeutic lifestyle changes to treat chronic disease, often producing dramatic health benefits. In spite of these well-documented benefits of LM approaches to provide evidence-based care that follows current clinical guidelines, LM practitioners have found reimbursement challenging. The objectives of this paper are to present the results of a cross-sectional survey of LM practitioners regarding lifestyle medicine reimbursement and to propose policy priorities related to the ability of practitioners to implement and achieve reimbursement for these necessary services. Results from a closed, online survey in 2019 were analyzed, with a total of = 857 included in this analysis. Results were descriptively analyzed. This manuscript articulates policy proposals informed by the survey results. The study sample was 58% female, with median age of 51. A minority of the sample (17%) reported that all their practice was LM, while 56% reported that some of their practice was LM. A total of 55% of practitioners reported not being able to receive reimbursement for LM practice. Of those survey respondents who provided an answer to the question of what would make the practice of LM easier ( = 471), the following suggestions were offered: reimbursement overall (18%), reimbursement for more time spent with patients (17%), more support from leadership (16%), policy measures to incentivize health (13%), education in LM for practitioners (11%), LM-specific billing codes and billing knowledge along with better electronic medical record (EMR) capabilities and streamlined reporting/paperwork (11%), and reimbursement for the extended care team (10%). Proposed policy changes focus on three areas of focus: (1) support for the care process using a LM approach, (2) reimbursement emphasizing outcomes of health, patient experience, and delivering person-centered care, and (3) incentivizing treatment that produces disease remission/reversal. Rectifying reimbursement barriers to lifestyle medicine practice will require a sustained effort from health systems and policy makers. The urgency of this transition towards lifestyle medicine interventions to effectively address the epidemic of chronic diseases in a way that can significantly improve outcomes is being hindered by current reimbursement policies and models.

Mental illness, including depression, anxiety and bipolar disorder, accounts for a significant proportion of global disability and poses a substantial social, economic and heath burden. Treatment is presently dominated by pharmacotherapy, such as antidepressants, and psychotherapy, such as cognitive behavioural therapy; however, such treatments avert less than half of the disease burden, suggesting that additional strategies are needed to prevent and treat mental disorders. There are now consistent mechanistic, observational and interventional data to suggest diet quality may be a modifiable risk factor for mental illness. This review provides an overview of the nutritional psychiatry field. It includes a discussion of the neurobiological mechanisms likely modulated by diet, the use of dietary and nutraceutical interventions in mental disorders, and recommendations for further research. Potential biological pathways related to mental disorders include inflammation, oxidative stress, the gut microbiome, epigenetic modifications and neuroplasticity. Consistent epidemiological evidence, particularly for depression, suggests an association between measures of diet quality and mental health, across multiple populations and age groups; these do not appear to be explained by other demographic, lifestyle factors or reverse causality. Our recently published intervention trial provides preliminary clinical evidence that dietary interventions in clinically diagnosed populations are feasible and can provide significant clinical benefit. Furthermore, nutraceuticals including n-3 fatty acids, folate, S-adenosylmethionine, N-acetyl cysteine and probiotics, among others, are promising avenues for future research. Continued research is now required to investigate the efficacy of intervention studies in large cohorts and within clinically relevant populations, particularly in patients with schizophrenia, bipolar and anxiety disorders.

The field of 'nutritional psychiatry' has evolved with rapidity over the past several years, with an increasing amount of dietary or nutrient-based (nutraceutical) intervention studies being initiated, and more preclinical and epidemiological data being available. This emergent paradigm involves the clinical consideration (where appropriate) of prescriptive dietary modification/improvement, and/or the select judicious use of nutrient-based supplementation to prevent or manage psychiatric disorders. In the last several years, significant links have increasingly been established between dietary quality and mental health (although not all data are supportive). Maternal and early-life nutrition may also affect the mental health outcomes in offspring. In respect to nutraceutical research, like with many recent conventional drug studies, results are fairly mixed across the board, and in many cases there is not emphatic evidence to support the use of nutraceuticals in various psychiatric disorders. This may in part be due to a preponderance of recent studies within the field revealing marked placebo effects. Due to current indicators pointing towards mental disorders having an increasing burden of disease, bold and innovative approaches on a societal level are now required. In light of the widespread use of nutrient supplements by those with and without mental disorders, it is also critical that scientifically rigorous methodologies be brought to bear on the assessment of the efficacy of these supplements, and to determine if, or what dose of, a nutrient supplement is required, for whom, and when, and under what circumstances. More simple studies of additional isolated nutrients are not of great benefit to the field (unless studied in supra-dosage in an individualised, biomarker-guided manner), nor, based on recent data, is the research of 'shotgun' formulations of nutraceuticals. The next critical step for the field is to design psychiatric interventional studies for both dietary modification and nutraceuticals, based on more of a personalised medicine approach, using biomarkers (e.g. nutrient deficiencies, inflammatory cytokine levels, genomic assessment, microbiome analysis) and a person's dietary patterns and individual macro/micronutrient requirements.

Modern medicine makes it possible for many people to live with multiple chronic diseases for decades, but this has enormous social, financial, and environmental consequences. Preclinical, epidemiological, and clinical trial data have shown that many of the most common chronic diseases are largely preventable with nutritional and lifestyle interventions that are targeting well-characterized signaling pathways and the symbiotic relationship with our microbiome. Most of the research priorities and spending for health are focused on finding new molecular targets for the development of biotech and pharmaceutical products. Very little is invested in mechanism-based preventive science, medicine, and education. We believe that overly enthusiastic expectations regarding the benefits of pharmacological research for disease treatment have the potential to impact and distort not only medical research and practice but also environmental health and sustainable economic growth. Transitioning from a primarily disease-centered medical system to a balanced preventive and personalized treatment healthcare system is key to reduce social disparities in health and achieve financially sustainable, universal health coverage for all. In this Perspective article, we discuss a range of science-based strategies, policies, and structural reforms to design an entire new disease prevention-centered science, educational, and healthcare system that maximizes both human and environmental health.

A difficult dilemma has presented itself in the current era. Modern medicine and advances in the medical sciences are tightly focused on a quest to find ways to extend life-without considering either the consequences of success or the best way to pursue it. From the perspective of physicians treating their patients, it makes sense to help them overcome immediate health challenges, but further life extension in increasingly more aged bodies will expose the saved population to an elevated risk of even more disabling health conditions associated with aging. Extended survival brought forth by innovations designed to treat diseases will likely push more people into a "red zone"-a later phase in life when the risk of frailty and disability rises exponentially. The inescapable conclusion from these observations is that life extension should no longer be the primary goal of medicine when applied to long-lived populations. The principal outcome and most important metric of success should be the extension of health span, and the technological advances described herein that are most likely to make the extension of healthy life possible.

Most nations of the world are undergoing rapid and dramatic population ageing, which presents great socio-economic challenges, as well as opportunities, for individuals, families, governments and societies. The prevailing biomedical strategy for reducing the healthcare impact of population ageing has been 'compression of morbidity' and, more recently, to increase healthspan, both of which seek to extend the healthy period of life and delay the development of chronic diseases and disability until a brief period at the end of life. Indeed, a recently established field within biological ageing research, 'geroscience', is focused on healthspan extension. Superimposed on this background are new attitudes and demand for 'optimal longevity' - living long, but with good health and quality of life. A key obstacle to achieving optimal longevity is the progressive decline in physiological function that occurs with ageing, which causes functional limitations (e.g. reduced mobility) and increases the risk of chronic diseases, disability and mortality. Current efforts to increase healthspan centre on slowing the fundamental biological processes of ageing such as inflammation/oxidative stress, increased senescence, mitochondrial dysfunction, impaired proteostasis and reduced stress resistance. We propose that optimization of physiological function throughout the lifespan should be a major emphasis of any contemporary biomedical policy addressing global ageing. Effective strategies should delay, reduce in magnitude or abolish reductions in function with ageing (primary prevention) and/or improve function or slow further declines in older adults with already impaired function (secondary prevention). Healthy lifestyle practices featuring regular physical activity and ideal energy intake/diet composition represent first-line function-preserving strategies, with pharmacological agents, including existing and new pharmaceuticals and novel 'nutraceutical' compounds, serving as potential complementary approaches. Future research efforts should focus on defining the temporal patterns of functional declines with ageing, identifying the underlying mechanisms and modulatory factors involved, and establishing the most effective lifestyle practices and pharmacological options for maintaining function. Continuing development of effective behavioural approaches for enhancing adherence to healthy ageing practices in diverse populations, and ongoing analysis of the socio-economic costs and benefits of healthspan extension will be important supporting goals. To meet the demands created by rapid population ageing, a new emphasis in physiological geroscience is needed, which will require the collaborative, interdisciplinary efforts of investigators working throughout the translational research continuum from basic science to public health.

There is increasing academic and clinical interest in how "lifestyle factors" traditionally associated with physical health may also relate to mental health and psychological well-being. In response, international and national health bodies are producing guidelines to address health behaviors in the prevention and treatment of mental illness. However, the current evidence for the causal role of lifestyle factors in the onset and prognosis of mental disorders is unclear. We performed a systematic meta-review of the top-tier evidence examining how physical activity, sleep, dietary patterns and tobacco smoking impact on the risk and treatment outcomes across a range of mental disorders. Results from 29 meta-analyses of prospective/cohort studies, 12 Mendelian randomization studies, two meta-reviews, and two meta-analyses of randomized controlled trials were synthesized to generate overviews of the evidence for targeting each of the specific lifestyle factors in the prevention and treatment of depression, anxiety and stress-related disorders, schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder. Standout findings include: a) convergent evidence indicating the use of physical activity in primary prevention and clinical treatment across a spectrum of mental disorders; b) emerging evidence implicating tobacco smoking as a causal factor in onset of both common and severe mental illness; c) the need to clearly establish causal relations between dietary patterns and risk of mental illness, and how diet should be best addressed within mental health care; and d) poor sleep as a risk factor for mental illness, although with further research required to understand the complex, bidirectional relations and the benefits of non-pharmacological sleep-focused interventions. The potentially shared neurobiological pathways between multiple lifestyle factors and mental health are discussed, along with directions for future research, and recommendations for the implementation of these findings at public health and clinical service levels.

Since the mid-20th century, Western societies have considered productivity and economic outcomes are more important than focusing on people's health and wellbeing. This focus has created lifestyles with high stress levels, associated with overconsumption of unhealthy foods and little exercise, which negatively affect people's lives, and subsequently lead to the development of pathologies, including neurodegenerative and psychiatric disorders. Prioritizing a healthy lifestyle to maintain wellbeing may slow the onset or reduce the severity of pathologies. It is a win-win for everyone; for societies and for individuals. A balanced lifestyle is increasingly being adopted globally, with many doctors encouraging meditation and prescribing non-pharmaceutical interventions to treat depression. In psychiatric and neurodegenerative disorders, the inflammatory response system of the brain (neuroinflammation) is activated. Many risks factors are now known to be linked to neuroinflammation such as stress, pollution, and a high saturated and trans fat diet. On the other hand, many studies have linked healthy habits and anti-inflammatory products with lower levels of neuroinflammation and a reduced risk of neurodegenerative and psychiatric disorders. Sharing risk and protective factors is critical so that individuals can make informed choices that promote positive aging throughout their lifespan. Most strategies to manage neurodegenerative diseases are palliative because neurodegeneration has been progressing silently for decades before symptoms appear. Here, we focus on preventing neurodegenerative diseases by adopting an integrated "healthy" lifestyle approach. This review summarizes the role of neuroinflammation on risk and protective factors of neurodegenerative and psychiatric disorders.

To date, the evidence to support the functional medicine model of care has been anecdotal, primarily published as case reports. Peer-reviewed evidence for functional medicine is based on specific interventions used by the model, including nutrition, lifestyle, or medications and dietary supplements (monotherapy or polytherapy). To our knowledge, this study is also the first systematic attempt to collect data from patients using validated measures to understand the association of HRQoL with the functional medicine model of care.

In this study, the functional medicine model of care was significantly associated with improved longitudinal PROMIS GPH scores in patients at 6 months, and these improvements remained significant for up to 12 months. Patients seen at the Center for Functional Medicine were more likely to experience a clinically meaningful change (change of ≥5 points) in their PROMIS GPH scores at 6 months, which were less likely to decrease over time. Comparing PROMIS GPH scores with those from the Family Health Center, patients seen at the Center for Functional Medicine experienced a significant longitudinal benefit for up to 12 months. However, a more robust sample size and consistent longitudinal tracking of patients are warranted to confirm this finding. The functional medicine model of care also significantly improved short-term PROMIS GMH scores in patients and demonstrated a larger association than care received in a primary care setting; however, long-term improvements were not statistically significant.

Several factors may have contributed to improvements in HRQoL associated with the functional medicine model of care. First, improvements in HRQoL associated with the functional medicine model of care may be due to the model itself. Functional medicine addresses chronic disease by delivering precision medicine. The ability to deliver precision medicine relies on one’s capability to not only collect data, but also organize it in a way that extracts an understanding of a patient’s biological processes and then maps these processes to human disease. The delivery of precision medicine also requires the ability to focus treatment around specific factors associated with a patient’s symptoms. The formal definition of functional medicine was first introduced in 1991 and tracks with the more recent precision medicine initiative.

There is increasing academic and clinical interest in how "lifestyle factors" traditionally associated with physical health may also relate to mental health and psychological well-being. In response, international and national health bodies are producing guidelines to address health behaviors in the prevention and treatment of mental illness. However, the current evidence for the causal role of lifestyle factors in the onset and prognosis of mental disorders is unclear. We performed a systematic meta-review of the top-tier evidence examining how physical activity, sleep, dietary patterns and tobacco smoking impact on the risk and treatment outcomes across a range of mental disorders. Results from 29 meta-analyses of prospective/cohort studies, 12 Mendelian randomization studies, two meta-reviews, and two meta-analyses of randomized controlled trials were synthesized to generate overviews of the evidence for targeting each of the specific lifestyle factors in the prevention and treatment of depression, anxiety and stress-related disorders, schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder. Standout findings include: a) convergent evidence indicating the use of physical activity in primary prevention and clinical treatment across a spectrum of mental disorders; b) emerging evidence implicating tobacco smoking as a causal factor in onset of both common and severe mental illness; c) the need to clearly establish causal relations between dietary patterns and risk of mental illness, and how diet should be best addressed within mental health care; and d) poor sleep as a risk factor for mental illness, although with further research required to understand the complex, bidirectional relations and the benefits of non-pharmacological sleep-focused interventions. The potentially shared neurobiological pathways between multiple lifestyle factors and mental health are discussed, along with directions for future research, and recommendations for the implementation of these findings at public health and clinical service levels.

Mental illness, including depression, anxiety and bipolar disorder, accounts for a significant proportion of global disability and poses a substantial social, economic and heath burden. Treatment is presently dominated by pharmacotherapy, such as antidepressants, and psychotherapy, such as cognitive behavioural therapy; however, such treatments avert less than half of the disease burden, suggesting that additional strategies are needed to prevent and treat mental disorders. There are now consistent mechanistic, observational and interventional data to suggest diet quality may be a modifiable risk factor for mental illness. This review provides an overview of the nutritional psychiatry field. It includes a discussion of the neurobiological mechanisms likely modulated by diet, the use of dietary and nutraceutical interventions in mental disorders, and recommendations for further research. Potential biological pathways related to mental disorders include inflammation, oxidative stress, the gut microbiome, epigenetic modifications and neuroplasticity. Consistent epidemiological evidence, particularly for depression, suggests an association between measures of diet quality and mental health, across multiple populations and age groups; these do not appear to be explained by other demographic, lifestyle factors or reverse causality. Our recently published intervention trial provides preliminary clinical evidence that dietary interventions in clinically diagnosed populations are feasible and can provide significant clinical benefit. Furthermore, nutraceuticals including n-3 fatty acids, folate, S-adenosylmethionine, N-acetyl cysteine and probiotics, among others, are promising avenues for future research. Continued research is now required to investigate the efficacy of intervention studies in large cohorts and within clinically relevant populations, particularly in patients with schizophrenia, bipolar and anxiety disorders.

The field of 'nutritional psychiatry' has evolved with rapidity over the past several years, with an increasing amount of dietary or nutrient-based (nutraceutical) intervention studies being initiated, and more preclinical and epidemiological data being available. This emergent paradigm involves the clinical consideration (where appropriate) of prescriptive dietary modification/improvement, and/or the select judicious use of nutrient-based supplementation to prevent or manage psychiatric disorders. In the last several years, significant links have increasingly been established between dietary quality and mental health (although not all data are supportive). Maternal and early-life nutrition may also affect the mental health outcomes in offspring. In respect to nutraceutical research, like with many recent conventional drug studies, results are fairly mixed across the board, and in many cases there is not emphatic evidence to support the use of nutraceuticals in various psychiatric disorders. This may in part be due to a preponderance of recent studies within the field revealing marked placebo effects. Due to current indicators pointing towards mental disorders having an increasing burden of disease, bold and innovative approaches on a societal level are now required. In light of the widespread use of nutrient supplements by those with and without mental disorders, it is also critical that scientifically rigorous methodologies be brought to bear on the assessment of the efficacy of these supplements, and to determine if, or what dose of, a nutrient supplement is required, for whom, and when, and under what circumstances. More simple studies of additional isolated nutrients are not of great benefit to the field (unless studied in supra-dosage in an individualised, biomarker-guided manner), nor, based on recent data, is the research of 'shotgun' formulations of nutraceuticals. The next critical step for the field is to design psychiatric interventional studies for both dietary modification and nutraceuticals, based on more of a personalised medicine approach, using biomarkers (e.g. nutrient deficiencies, inflammatory cytokine levels, genomic assessment, microbiome analysis) and a person's dietary patterns and individual macro/micronutrient requirements.

Modern medicine makes it possible for many people to live with multiple chronic diseases for decades, but this has enormous social, financial, and environmental consequences. Preclinical, epidemiological, and clinical trial data have shown that many of the most common chronic diseases are largely preventable with nutritional and lifestyle interventions that are targeting well-characterized signaling pathways and the symbiotic relationship with our microbiome. Most of the research priorities and spending for health are focused on finding new molecular targets for the development of biotech and pharmaceutical products. Very little is invested in mechanism-based preventive science, medicine, and education. We believe that overly enthusiastic expectations regarding the benefits of pharmacological research for disease treatment have the potential to impact and distort not only medical research and practice but also environmental health and sustainable economic growth. Transitioning from a primarily disease-centered medical system to a balanced preventive and personalized treatment healthcare system is key to reduce social disparities in health and achieve financially sustainable, universal health coverage for all. In this Perspective article, we discuss a range of science-based strategies, policies, and structural reforms to design an entire new disease prevention-centered science, educational, and healthcare system that maximizes both human and environmental health.

Objective: While lifestyle medicine can be highly effective for treating a range of mental illnesses these approaches are grossly underutilised and have not been systematically implemented into health care systems. Understanding the acceptability of lifestyle medicine is a critical first step to remediate this. This study evaluated the acceptability of lifestyle medicine relative to pharmacotherapy and psychotherapy, and explore perspectives of people with and without lived experience of mental illness.

Methods: Six hundred and forty-nine adult Australian residents (62.6% female; 53.6% with a lifetime diagnosis of mental illness) completed an online survey based on the Theoretical Framework of Acceptability assessing the acceptability of lifestyle medicine, pharmacotherapy and psychotherapy for treating mental illness.

Results: Most participants felt positive about lifestyle medicine (76.9%) and felt that such approaches aligned with their personal values (74.9%). They understood how lifestyle medicine worked (86.4%) and believed it would be effective (69.6%). Lived experience of mental illness was associated with greater perceived burden and lower self-efficacy to engage in lifestyle medicine activities (both p < 0.001). While there was a clear preference for psychotherapy and lifestyle medicine over pharmacotherapy, pharmacotherapy was perceived as least effortful (p < .001) and participants were least confident in their ability to engage in lifestyle medicine (p < 0.05).

Conclusion: The findings indicate strong acceptability of lifestyle medicine for mental illness, a preference for non-pharmacological treatment approaches, and an understanding of the challenges associated with making long-term healthy lifestyle modifications amongst people who have lived experience of mental illness.

Substance use disorders are a growing concern for all ages, including adolescents. Even though there is an increase in recreational substance use and a wider variety of drugs is available to this young population, treatment options remain scarce. Most medications have limited evidence in this population. Few specialists treat individuals struggling with addiction along with mental health disorders. As the evidence grows, these treatments are usually included in complementary and integrative medicine. This article discusses available evidence for many complementary and integrative treatment approaches while briefly describing existing psychotherapeutic and psychotropic medications.

Prevention is the most promising way to reduce the high personal, familial, societal, clinical and economic costs of mental disorders in Europe and worldwide. A complementary approach is to go beyond the prevention of mental ill health, to promote good mental health. This manuscript highlights the first European consortium fostering cutting-edge multidisciplinary research in these two areas. The ECNP-funded Network on the Prevention of Mental Disorders and Mental Health Promotion (ECNP PMD-MHP) brings together European sites of excellence with different expertise for translational research collaboration, including partnerships with the industry. The ECNP PMD-MHP Network adopts a transdiagnostic, lifespan, clinical staging model which cuts across different mental disorders and different methodologies. The main aims of the ECNP PMD-MHP Network are to facilitate multidisciplinary collaboration, enhance knowledge and data sharing, standardise core assessment and outcome measures, promote clinical research, apply for grant funding, and generate research reports. By supporting collaborative research, the ECNP PMD-MHP Network will be vital for fostering European psychiatry in the field of prevention of mental disorders and promotion of good mental health.

The Federal Ministry of Education and Research (BMBF) issued a call for a new nationwide research network on mental disorders, the German Center of Mental Health (DZPG). The Munich/Augsburg consortium was selected to participate as one of six partner sites with its concept "Precision in Mental Health (PriMe): Understanding, predicting, and preventing chronicity." PriMe bundles interdisciplinary research from the Ludwig-Maximilians-University (LMU), Technical University of Munich (TUM), University of Augsburg (UniA), Helmholtz Center Munich (HMGU), and Max Planck Institute of Psychiatry (MPIP) and has a focus on schizophrenia (SZ), bipolar disorder (BPD), and major depressive disorder (MDD). PriMe takes a longitudinal perspective on these three disorders from the at-risk stage to the first-episode, relapsing, and chronic stages. These disorders pose a major health burden because in up to 50% of patients they cause untreatable residual symptoms, which lead to early social and vocational disability, comorbidities, and excess mortality. PriMe aims at reducing mortality on different levels, e.g., reducing death by psychiatric and somatic comorbidities, and will approach this goal by addressing interdisciplinary and cross-sector approaches across the lifespan. PriMe aims to add a precision medicine framework to the DZPG that will propel deeper understanding, more accurate prediction, and personalized prevention to prevent disease chronicity and mortality across mental illnesses. This framework is structured along the translational chain and will be used by PriMe to innovate the preventive and therapeutic management of SZ, BPD, and MDD from rural to urban areas and from patients in early disease stages to patients with long-term disease courses. Research will build on platforms that include one on model systems, one on the identification and validation of predictive markers, one on the development of novel multimodal treatments, one on the regulation and strengthening of the uptake and dissemination of personalized treatments, and finally one on testing of the clinical effectiveness, utility, and scalability of such personalized treatments. In accordance with the translational chain, PriMe's expertise includes the ability to integrate understanding of bio-behavioral processes based on innovative models, to translate this knowledge into clinical practice and to promote user participation in mental health research and care.

Psychiatry is at an important juncture, with the current pharmacologically focused model having achieved modest benefits in addressing the burden of poor mental health worldwide. Although the determinants of mental health are complex, the emerging and compelling evidence for nutrition as a crucial factor in the high prevalence and incidence of mental disorders suggests that diet is as important to psychiatry as it is to cardiology, endocrinology, and gastroenterology. Evidence is steadily growing for the relation between dietary quality (and potential nutritional deficiencies) and mental health, and for the select use of nutrient-based supplements to address deficiencies, or as monotherapies or augmentation therapies. We present a viewpoint from an international collaboration of academics (members of the International Society for Nutritional Psychiatry Research), in which we provide a context and overview of the current evidence in this emerging field of research, and discuss the future direction. We advocate recognition of diet and nutrition as central determinants of both physical and mental health.

There is increasing academic and clinical interest in how "lifestyle factors" traditionally associated with physical health may also relate to mental health and psychological well-being. In response, international and national health bodies are producing guidelines to address health behaviors in the prevention and treatment of mental illness. However, the current evidence for the causal role of lifestyle factors in the onset and prognosis of mental disorders is unclear. We performed a systematic meta-review of the top-tier evidence examining how physical activity, sleep, dietary patterns and tobacco smoking impact on the risk and treatment outcomes across a range of mental disorders. Results from 29 meta-analyses of prospective/cohort studies, 12 Mendelian randomization studies, two meta-reviews, and two meta-analyses of randomized controlled trials were synthesized to generate overviews of the evidence for targeting each of the specific lifestyle factors in the prevention and treatment of depression, anxiety and stress-related disorders, schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder. Standout findings include: a) convergent evidence indicating the use of physical activity in primary prevention and clinical treatment across a spectrum of mental disorders; b) emerging evidence implicating tobacco smoking as a causal factor in onset of both common and severe mental illness; c) the need to clearly establish causal relations between dietary patterns and risk of mental illness, and how diet should be best addressed within mental health care; and d) poor sleep as a risk factor for mental illness, although with further research required to understand the complex, bidirectional relations and the benefits of non-pharmacological sleep-focused interventions. The potentially shared neurobiological pathways between multiple lifestyle factors and mental health are discussed, along with directions for future research, and recommendations for the implementation of these findings at public health and clinical service levels.

Preventive approaches have latterly gained traction for improving mental health in young people. In this paper, we first appraise the conceptual foundations of preventive psychiatry, encompassing the public health, Gordon's, US Institute of Medicine, World Health Organization, and good mental health frameworks, and neurodevelopmentally-sensitive clinical staging models. We then review the evidence supporting primary prevention of psychotic, bipolar and common mental disorders and promotion of good mental health as potential transformative strategies to reduce the incidence of these disorders in young people. Within indicated approaches, the clinical high-risk for psychosis paradigm has received the most empirical validation, while clinical high-risk states for bipolar and common mental disorders are increasingly becoming a focus of attention. Selective approaches have mostly targeted familial vulnerability and non-genetic risk exposures. Selective screening and psychological/psychoeducational interventions in vulnerable subgroups may improve anxiety/depressive symptoms, but their efficacy in reducing the incidence of psychotic/bipolar/common mental disorders is unproven. Selective physical exercise may reduce the incidence of anxiety disorders. Universal psychological/psychoeducational interventions may improve anxiety symptoms but not prevent depressive/anxiety disorders, while universal physical exercise may reduce the incidence of anxiety disorders. Universal public health approaches targeting school climate or social determinants (demographic, economic, neighbourhood, environmental, social/cultural) of mental disorders hold the greatest potential for reducing the risk profile of the population as a whole. The approach to promotion of good mental health is currently fragmented. We leverage the knowledge gained from the review to develop a blueprint for future research and practice of preventive psychiatry in young people: integrating universal and targeted frameworks; advancing multivariable, transdiagnostic, multi-endpoint epidemiological knowledge; synergically preventing common and infrequent mental disorders; preventing physical and mental health burden together; implementing stratified/personalized prognosis; establishing evidence-based preventive interventions; developing an ethical framework, improving prevention through education/training; consolidating the cost-effectiveness of preventive psychiatry; and decreasing inequalities. These goals can only be achieved through an urgent individual, societal, and global level response, which promotes a vigorous collaboration across scientific, health care, societal and governmental sectors for implementing preventive psychiatry, as much is at stake for young people with or at risk for emerging mental disorders.

Modern medicine makes it possible for many people to live with multiple chronic diseases for decades, but this has enormous social, financial, and environmental consequences. Preclinical, epidemiological, and clinical trial data have shown that many of the most common chronic diseases are largely preventable with nutritional and lifestyle interventions that are targeting well-characterized signaling pathways and the symbiotic relationship with our microbiome. Most of the research priorities and spending for health are focused on finding new molecular targets for the development of biotech and pharmaceutical products. Very little is invested in mechanism-based preventive science, medicine, and education. We believe that overly enthusiastic expectations regarding the benefits of pharmacological research for disease treatment have the potential to impact and distort not only medical research and practice but also environmental health and sustainable economic growth. Transitioning from a primarily disease-centered medical system to a balanced preventive and personalized treatment healthcare system is key to reduce social disparities in health and achieve financially sustainable, universal health coverage for all. In this Perspective article, we discuss a range of science-based strategies, policies, and structural reforms to design an entire new disease prevention-centered science, educational, and healthcare system that maximizes both human and environmental health.

Modern medicine makes it possible for many people to live with multiple chronic diseases for decades, but this has enormous social, financial, and environmental consequences. Preclinical, epidemiological, and clinical trial data have shown that many of the most common chronic diseases are largely preventable with nutritional and lifestyle interventions that are targeting well-characterized signaling pathways and the symbiotic relationship with our microbiome. Most of the research priorities and spending for health are focused on finding new molecular targets for the development of biotech and pharmaceutical products. Very little is invested in mechanism-based preventive science, medicine, and education. We believe that overly enthusiastic expectations regarding the benefits of pharmacological research for disease treatment have the potential to impact and distort not only medical research and practice but also environmental health and sustainable economic growth. Transitioning from a primarily disease-centered medical system to a balanced preventive and personalized treatment healthcare system is key to reduce social disparities in health and achieve financially sustainable, universal health coverage for all. In this Perspective article, we discuss a range of science-based strategies, policies, and structural reforms to design an entire new disease prevention-centered science, educational, and healthcare system that maximizes both human and environmental health.

Chronic non-communicable diseases (NCDs) cause the majority of premature deaths, disability, and healthcare expenditures in the U.S. Six largely modifiable risk behaviors and factors (tobacco use, poor nutrition, physical inactivity, alcohol abuse, drug abuse, and poor mental health) account for more than 50% of premature mortality and considerably more morbidity and disability. The IOM proposed that population burden of disease and preventability should be major determinants of the amount of research funding provided by the U.S. NIH. Data on NIH prevention funding between fiscal years 2010 and 2012 for human behavioral interventions that target the modifiable risk factors of NCDs were analyzed during 2013-2014. The NIH prevention portfolio comprises approximately 37% human behavioral studies and 63% basic biomedical, genetic, and animal studies. Approximately 65% of studies were secondary prevention versus 23% for primary prevention, and 71% of studies intervened at the individual and family levels. Diet and exercise were the most-studied risk factors (41%), and few studies conducted economic analyses (12%). NIH spends an estimated $2.2-$2.6 billion annually (7%-9% of the total of $30 billion) on human behavioral interventions to prevent NCDs. Although NIH prevention funding broadly aligns with the current burden of disease, overall funding remains low compared to funding for treatment, which suggests funding misalignment with the preventability of chronic diseases.

Modelling studies suggest that less than 30% of the burden of mental disorders can be averted, even with optimal care and access to services. This points to the need to reduce the incidence of mental disorders, utilising evidence-based prevention strategies and policy action. In this cross-journal article collection (http://www.biomedcentral.com/series/PMD), the case for prevention is made by identifying initiatives with established efficacy, as well as opportunities and targets for the prevention of mental disorders in early life, in the workplace and at the population level. These articles provide reviews, systematic and narrative, outlining the evidence base for prevention approaches, as well as comment and debate designed to prompt discussion and a reconsideration of strategies for prevention. Barriers to expanding the research into prevention include the reluctance of governments and funding bodies to invest in research and policy action that may take many years to manifest benefits. The case for the cost-effectiveness of preventing mental disorders needs to be strongly argued and new cross-disciplinary, intersectoral initiatives and policies developed for the prevention of mental disorders across the lifespan.

Poor mental health has profound economic consequences. Given the burden of poor mental health, the economic case for preventing mental illness and promoting better mental health may be very strong, but too often prevention attracts little attention and few resources. This article describes the potential role that can be played by economic evidence alongside experimental trials and observational studies, or through modeling, to substantiate the need for increased investment in prevention. It illustrates areas of action across the life course where there is already a good economic case. It also suggests some further areas of substantive public health concern, with promising effectiveness evidence, that may benefit from economic analysis. Financial and economic barriers to implementation are then presented, and strategies to address the barriers and increase investment in the prevention of mental illness are suggested.

Many factors determine how funds for grants and cooperative agreements are allocated to address different health conditions and risk and protective factors across the research spectrum at the NIH. These factors include public health needs, scientific opportunities, the quality of the research applications submitted, and the staffing and infrastructure to support award administration. No level of support for prevention research relative to other types of research has been agreed on, and certainly the need for prevention research will depend on the stage of research for a given area (eg, mechanistic research, development of measures, identification of risk factors, or intervention development). In addition, no scheme for distributing prevention research support to specific exposures, outcomes, or populations or among the various types of research, including randomized clinical trials, observational studies, secondary data analyses, and methods research, has been agreed on. Given the disease and disability burden in the United States associated with the leading risk factors and causes of death and disability, the findings reported herein suggest that the nation may benefit from directing more of the prevention research portfolio supported by NIH grants and cooperative agreements to studies that focus on those risk factors and causes, to studies that address multiple risk factors and causes, and to studies that develop and evaluate preventive interventions to address those risk factors and causes. Doing so will require a multifaceted approach, including a shift in how research proposals are written and funded. Extramural researchers would need to submit proposals that address more than 1 leading risk factor or cause of death and to evaluate interventions to address those risk factors or causes. The NIH institutes and centers would need to prioritize projects that address the leading risk factors and causes of death and disability, projects that address multiple risk factors and causes, and projects that propose trials to evaluate interventions to address those risk factors and causes. This shift in prioritization will not be easy but could lead to major innovations and real progress in disease prevention and health promotion.

High-quality data on funding for mental health research are essential to mapping funding levels, identifying gaps in the funding landscape, and tracking the impact of research funding. To date, quantitative analyses of research funding in mental health have been restricted in scope. In this Health Policy paper, we present a comprehensive analysis of grant funding for mental health research as a starting point for discussion among stakeholders globally. We drew on a major international research database and used existing definitions and automated classification tools for mental health research. Our analysis shows a flat and stable trend over the years 2015-19 and highly unequal geographical distribution of funding, and reveals patterns of funding across different conditions and across the research spectrum. Improvements in data availability and quality, in the definitions delineating mental health research from other areas, and in automated classification tools are needed to ensure funders and policy makers can fully rely on the data and generate bespoke analyses as needed. We argue that collaborative reporting of funding for mental health research globally could help to inform and evaluate efforts to increase investments, to improve strategic dialogue, and to achieve the best possible allocation of finite resources.

One of the four major goals outlined in the National Institute of Mental Health (NIMH) strategic plan (2021) is to develop and test new treatments and prevention strategies. The aim of the Funding Opportunity Announcement (FOA) for the R61/R33 grant mechanism has been to support the efficient pilot testing of exploratory clinical trials of novel interventions for mental disorders in adults and children through an experimental therapeutics approach. The present commentary (a) describes the R61/R33 grant mechanism, defines terms, and summarizes information about current grants in the system, (b) outlines the review criteria, and (c) highlights several common critiques. Frequent concerns expressed by applicants as well as reviewers include defining and measuring the target/mechanism, establishing dose, selecting an appropriate control group, measuring fidelity, and determining power. Finally, alternative pathways for conducting randomized clinical trials for intervention development are discussed in contrast to or in addition to the experimental therapeutics approach for discovering novel interventions aimed at reducing and preventing mental illness across the lifespan.

Preventive approaches have latterly gained traction for improving mental health in young people. In this paper, we first appraise the conceptual foundations of preventive psychiatry, encompassing the public health, Gordon's, US Institute of Medicine, World Health Organization, and good mental health frameworks, and neurodevelopmentally-sensitive clinical staging models. We then review the evidence supporting primary prevention of psychotic, bipolar and common mental disorders and promotion of good mental health as potential transformative strategies to reduce the incidence of these disorders in young people. Within indicated approaches, the clinical high-risk for psychosis paradigm has received the most empirical validation, while clinical high-risk states for bipolar and common mental disorders are increasingly becoming a focus of attention. Selective approaches have mostly targeted familial vulnerability and non-genetic risk exposures. Selective screening and psychological/psychoeducational interventions in vulnerable subgroups may improve anxiety/depressive symptoms, but their efficacy in reducing the incidence of psychotic/bipolar/common mental disorders is unproven. Selective physical exercise may reduce the incidence of anxiety disorders. Universal psychological/psychoeducational interventions may improve anxiety symptoms but not prevent depressive/anxiety disorders, while universal physical exercise may reduce the incidence of anxiety disorders. Universal public health approaches targeting school climate or social determinants (demographic, economic, neighbourhood, environmental, social/cultural) of mental disorders hold the greatest potential for reducing the risk profile of the population as a whole. The approach to promotion of good mental health is currently fragmented. We leverage the knowledge gained from the review to develop a blueprint for future research and practice of preventive psychiatry in young people: integrating universal and targeted frameworks; advancing multivariable, transdiagnostic, multi-endpoint epidemiological knowledge; synergically preventing common and infrequent mental disorders; preventing physical and mental health burden together; implementing stratified/personalized prognosis; establishing evidence-based preventive interventions; developing an ethical framework, improving prevention through education/training; consolidating the cost-effectiveness of preventive psychiatry; and decreasing inequalities. These goals can only be achieved through an urgent individual, societal, and global level response, which promotes a vigorous collaboration across scientific, health care, societal and governmental sectors for implementing preventive psychiatry, as much is at stake for young people with or at risk for emerging mental disorders.

Extant literature has established the effectiveness of various mental health promotion and prevention strategies, including novel interventions. However, comprehensive literature encompassing all these aspects and challenges and opportunities in implementing such interventions in different settings is still lacking. Therefore, in the current review, we aimed to synthesize existing literature on various mental health promotion and prevention interventions and their effectiveness. Additionally, we intend to highlight various novel approaches to mental health care and their implications across different resource settings and provide future directions. The review highlights the (1) concept of preventive psychiatry, including various mental health promotions and prevention approaches, (2) current level of evidence of various mental health preventive interventions, including the novel interventions, and (3) challenges and opportunities in implementing concepts of preventive psychiatry and related interventions across the settings. Although preventive psychiatry is a well-known concept, it is a poorly utilized public health strategy to address the population's mental health needs. It has wide-ranging implications for the wellbeing of society and individuals, including those suffering from chronic medical problems. The researchers and policymakers are increasingly realizing the potential of preventive psychiatry; however, its implementation is poor in low-resource settings. Utilizing novel interventions, such as mobile-and-internet-based interventions and blended and stepped-care models of care can address the vast mental health need of the population. Additionally, it provides mental health services in a less-stigmatizing and easily accessible, and flexible manner. Furthermore, employing decision support systems/algorithms for patient management and personalized care and utilizing the digital platform for the non-specialists' training in mental health care are valuable additions to the existing mental health support system. However, more research concerning this is required worldwide, especially in the low-and-middle-income countries.

There is increasing academic and clinical interest in how "lifestyle factors" traditionally associated with physical health may also relate to mental health and psychological well-being. In response, international and national health bodies are producing guidelines to address health behaviors in the prevention and treatment of mental illness. However, the current evidence for the causal role of lifestyle factors in the onset and prognosis of mental disorders is unclear. We performed a systematic meta-review of the top-tier evidence examining how physical activity, sleep, dietary patterns and tobacco smoking impact on the risk and treatment outcomes across a range of mental disorders. Results from 29 meta-analyses of prospective/cohort studies, 12 Mendelian randomization studies, two meta-reviews, and two meta-analyses of randomized controlled trials were synthesized to generate overviews of the evidence for targeting each of the specific lifestyle factors in the prevention and treatment of depression, anxiety and stress-related disorders, schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder. Standout findings include: a) convergent evidence indicating the use of physical activity in primary prevention and clinical treatment across a spectrum of mental disorders; b) emerging evidence implicating tobacco smoking as a causal factor in onset of both common and severe mental illness; c) the need to clearly establish causal relations between dietary patterns and risk of mental illness, and how diet should be best addressed within mental health care; and d) poor sleep as a risk factor for mental illness, although with further research required to understand the complex, bidirectional relations and the benefits of non-pharmacological sleep-focused interventions. The potentially shared neurobiological pathways between multiple lifestyle factors and mental health are discussed, along with directions for future research, and recommendations for the implementation of these findings at public health and clinical service levels.

This review and meta-analysis aimed to describe the existing literature on interventions for bipolar disorder (BD) targeting the 6 pillars of Lifestyle Psychiatry: diet, physical activity (PA), substance use (SU), sleep, stress management, and social relationships (SR). Randomized Controlled Trials that examined the efficacy of lifestyle interventions targeting improvement in depressive/(hypo)manic symptom severity, lifestyle patterns, functioning, quality of life, and/or circadian rhythms were included. The systematic review included 18 studies, while the meta-analysis included studies targeting the same lifestyle domains and outcomes. Sleep (n = 10), PA (n = 9), and diet (n = 8) were the most targeted domains, while SU, SM and SR were least targeted (n = 4 each). Combined diet and PA interventions led to significant improvements in depressive symptoms (

Smd: -0.46; 95%

Ci: -0.88, -0.04; p = 0.03), and functioning (

Smd: -0.47; 95%

Ci: -0.89, -0.05; p = 0.03). Sleep interventions also led to significant improvements in depressive symptoms (

Smd: -0.80; 95%

Ci: -1.21, -0.39; p < 0.01). Future research should focus on developing more multidimensional lifestyle interventions for a potentially greater impact on clinical and functional outcomes of BD.

The prevalence of depression appears to have increased over the past three decades. While this may be an artefact of diagnostic practices, it is likely that there are factors about modernity that are contributing to this rise. There is now compelling evidence that a range of lifestyle factors are involved in the pathogenesis of depression. Many of these factors can potentially be modified, yet they receive little consideration in the contemporary treatment of depression, where medication and psychological intervention remain the first line treatments. "Lifestyle Medicine" provides a nexus between public health promotion and clinical treatments, involving the application of environmental, behavioural, and psychological principles to enhance physical and mental wellbeing. This may also provide opportunities for general health promotion and potential prevention of depression. In this paper we provide a narrative discussion of the major components of Lifestyle Medicine, consisting of the evidence-based adoption of physical activity or exercise, dietary modification, adequate relaxation/sleep and social interaction, use of mindfulness-based meditation techniques, and the reduction of recreational substances such as nicotine, drugs, and alcohol. We also discuss other potential lifestyle factors that have a more nascent evidence base, such as environmental issues (e.g. urbanisation, and exposure to air, water, noise, and chemical pollution), and the increasing human interface with technology. Clinical considerations are also outlined. While data supports that some of these individual elements are modifiers of overall mental health, and in many cases depression, rigorous research needs to address the long-term application of Lifestyle Medicine for depression prevention and management. Critically, studies exploring lifestyle modification involving multiple lifestyle elements are needed. While the judicious use of medication and psychological techniques are still advocated, due to the complexity of human illness/wellbeing, the emerging evidence encourages a more integrative approach for depression, and an acknowledgment that lifestyle modification should be a routine part of treatment and preventative efforts.

Mental illness, including depression, anxiety and bipolar disorder, accounts for a significant proportion of global disability and poses a substantial social, economic and heath burden. Treatment is presently dominated by pharmacotherapy, such as antidepressants, and psychotherapy, such as cognitive behavioural therapy; however, such treatments avert less than half of the disease burden, suggesting that additional strategies are needed to prevent and treat mental disorders. There are now consistent mechanistic, observational and interventional data to suggest diet quality may be a modifiable risk factor for mental illness. This review provides an overview of the nutritional psychiatry field. It includes a discussion of the neurobiological mechanisms likely modulated by diet, the use of dietary and nutraceutical interventions in mental disorders, and recommendations for further research. Potential biological pathways related to mental disorders include inflammation, oxidative stress, the gut microbiome, epigenetic modifications and neuroplasticity. Consistent epidemiological evidence, particularly for depression, suggests an association between measures of diet quality and mental health, across multiple populations and age groups; these do not appear to be explained by other demographic, lifestyle factors or reverse causality. Our recently published intervention trial provides preliminary clinical evidence that dietary interventions in clinically diagnosed populations are feasible and can provide significant clinical benefit. Furthermore, nutraceuticals including n-3 fatty acids, folate, S-adenosylmethionine, N-acetyl cysteine and probiotics, among others, are promising avenues for future research. Continued research is now required to investigate the efficacy of intervention studies in large cohorts and within clinically relevant populations, particularly in patients with schizophrenia, bipolar and anxiety disorders.

There is a strong relationship between a healthy diet and mental well-being. Several foods and food compounds are known to modulate biomarkers and molecular mechanisms involved in the aetiogenesis of several mental disorders, and this can be useful in containing the disease progression, including its prophylaxis. This is an updated systematic review of the literature to justify the inclusion and recognition of nutrition in the management of psychiatric illnesses. Such foods and their compounds include dietary flavanols from fruits and vegetables, notable antioxidant and anti-inflammatory agents, probiotics (fermented foods) known to protect good gut bacteria, foods rich in polyunsaturated fatty acids (e.g., Omega-3), and avoiding diets high in saturated fats and refined sugars among others. While the exact mechanism(s) of mitigation of many nutritional interventions are yet to be fully understood, the evidence-based approach warrants the inclusion and co-recognition of nutrition in the management of psychiatric illnesses. For the greater public health benefit, there is a need for policy advocacy aimed at bridging the knowledge gap and encouraging the integration of nutritional intervention with contemporary therapies in clinical settings, as deficiencies of certain nutrients make therapy difficult even with appropriate medication.

The 'monoamine hypothesis' is insufficient in approaching the aetiology of psychiatric disorders or in developing novel therapies. Accumulating evidence suggests that inflammatory regulation plays an important role in pathophysiology and therapeutic mechanism across the major psychiatric disorders. "Inflammation theory" might not be the full answer for the big picture of mental disorders, but it might explain high occurrence of somatic symptoms and comorbidity of physical illness in certain subtypes of the heterogeneous groups. Due to the complexity of clinical manifestations and bio-psycho-social etiology, each single treatment shows only small effectiveness with limited effect sizes when compared with placebo. Unfortunately, clinicians are still struggling with trial-and-error practice without any reliable clinical or biological markers to predict therapeutic responses. Therefore, it is important to open up our minds to integrative approaches such dietary modification and nutraceutical prescription. In this special issue, we included 15 papers discussing the role of nutrition (blueberries, omega-3 polyunsaturated fatty acids, melatonergic agonist, S-Adenosyl-L-Methionine, Cannabidiol and Kratom) in the context of immunoregulation across different psychiatric disorders from depression, bipolar disorders, and schizophrenia to alcohol-induced dementia and anorexia nervosa. Moreover, we also included research in perinatal depression that highlight the role of estradiol and the component of breast milk and the association with the neurodevelopment of the offspring. In addition, several articles focused on the role of microbiota in mental health and pain as recent research has pointed to the gut-brain axis as a main regulator of brain, behaviour and immunity. Lastly, inflammatory mechanisms underlying psychiatric disorders including alcohol induced dementia and anorexia nervosa are also highlighted in the special issue.

The field of 'nutritional psychiatry' has evolved with rapidity over the past several years, with an increasing amount of dietary or nutrient-based (nutraceutical) intervention studies being initiated, and more preclinical and epidemiological data being available. This emergent paradigm involves the clinical consideration (where appropriate) of prescriptive dietary modification/improvement, and/or the select judicious use of nutrient-based supplementation to prevent or manage psychiatric disorders. In the last several years, significant links have increasingly been established between dietary quality and mental health (although not all data are supportive). Maternal and early-life nutrition may also affect the mental health outcomes in offspring. In respect to nutraceutical research, like with many recent conventional drug studies, results are fairly mixed across the board, and in many cases there is not emphatic evidence to support the use of nutraceuticals in various psychiatric disorders. This may in part be due to a preponderance of recent studies within the field revealing marked placebo effects. Due to current indicators pointing towards mental disorders having an increasing burden of disease, bold and innovative approaches on a societal level are now required. In light of the widespread use of nutrient supplements by those with and without mental disorders, it is also critical that scientifically rigorous methodologies be brought to bear on the assessment of the efficacy of these supplements, and to determine if, or what dose of, a nutrient supplement is required, for whom, and when, and under what circumstances. More simple studies of additional isolated nutrients are not of great benefit to the field (unless studied in supra-dosage in an individualised, biomarker-guided manner), nor, based on recent data, is the research of 'shotgun' formulations of nutraceuticals. The next critical step for the field is to design psychiatric interventional studies for both dietary modification and nutraceuticals, based on more of a personalised medicine approach, using biomarkers (e.g. nutrient deficiencies, inflammatory cytokine levels, genomic assessment, microbiome analysis) and a person's dietary patterns and individual macro/micronutrient requirements.

Mental health professionals have significantly underestimated the importance of lifestyle factors (a) as contributors to and treatments for multiple psychopathologies, (b) for fostering individual and social well-being, and (c) for preserving and optimizing cognitive function. Consequently, therapeutic lifestyle changes (TLCs) are underutilized despite considerable evidence of their effectiveness in both clinical and normal populations. TLCs are sometimes as effective as either psychotherapy or pharmacotherapy and can offer significant therapeutic advantages. Important TLCs include exercise, nutrition and diet, time in nature, relationships, recreation, relaxation and stress management, religious or spiritual involvement, and service to others. This article reviews research on their effects and effectiveness; the principles, advantages, and challenges involved in implementing them; and the forces (economic, institutional, and professional) hindering their use. Where possible, therapeutic recommendations are distilled into easily communicable principles, because such ease of communication strongly influences whether therapists recommend and patients adopt interventions. Finally, the article explores the many implications of contemporary lifestyles and TLCs for individuals, society, and health professionals. In the 21st century, therapeutic lifestyles may need to be a central focus of mental, medical, and public health.

The use of probiotics, prebiotics, synbiotics or fermented foods can modulate the gut-brain axis and constitute a potentially therapeutic intervention in psychiatric disorders. This systematic review aims to identify current evidence regarding these interventions in the treatment of patients with DSM/ICD psychiatric diagnoses. Forty-seven articles from 42 studies met the inclusion criteria. Risk of bias was assessed in all included studies. Major depression was the most studied disorder (n = 19 studies). Studies frequently focused on schizophrenia (n = 11) and bipolar disorder (n = 5) and there were limited studies in anorexia nervosa (n = 4), ADHD (n = 3), Tourette (n = 1), insomnia (n = 1), PTSD (n = 1) and generalized anxiety disorder (n = 1). Except in MDD, current evidence does not clarify the role of probiotics and prebiotics in the treatment of mental illness. Several studies point to an improvement in the immune and inflammatory profile (e.g. CRP, IL6), which may be a relevant mechanism of action of the therapeutic response identified in these studies. Future research should consider lifestyle and dietary habits of patients as possible confounders that may influence inter-individual treatment response.

Lifestyle factors including diet, sleep, physical activity, and substance use cessation, are recognised as treatment targets for common mental disorders (CMDs). As the field of lifestyle-based mental health care evolves towards effectiveness trials and real-world translation, it is timely to consider how such innovations can be integrated into clinical practice. This paper discusses the utility and scale-up of lifestyle interventions for CMDs and draws on diabetes prevention literature to identify enablers and barriers to translation efforts. We discuss the extent to which lifestyle interventions aimed at managing CMDs and preventing diabetes share commonalities (program content, theoretical underpinnings, program structures, interventionists, frameworks promoting fidelity, quality, sustainability). Specific considerations when utilising these programs for mental health include personalising content with respect to symptoms and trajectories of depression and anxiety, medication regimen and genetic risk profile. As this field moves from efficacy to effectiveness and implementation, it is important to ensure issues in implementation science, including "voltage drop", "program drift", logistics, funding, and resourcing, are in line with evidence-based models that are effective in research settings. Ongoing considerations includes who is best placed to deliver this care and the need for models to support implementation including long-term financing, workforce training, supervision, stakeholder and organisational support.