No relationship between male pubertal timing and depression - new insights from epidemiology and Mendelian randomization.

BACKGROUND: In males, the relationship between pubertal timing and depression is understudied and less consistent than in females, likely for reasons of unmeasured confounding. To clarify this relationship, a combined epidemiological and genetic approach was chosen to exploit the methodological advantages of both approaches. METHODS: Data from 2026 males from a nationwide, representative study were used to investigate the non-/linear relationship between pubertal timing defined by the age at voice break and depression, considering a multitude of potential confounders and their interactions with pubertal timing. This analysis was complemented by Mendelian randomization (MR), which is robust to inferential problems inherent to epidemiological studies. We used 71 single nucleotide polymorphisms related to pubertal timing in males as instrumental variable to clarify its causal relationship with depression based on data from 807 553 individuals (246 363 cases and 561 190 controls) by univariable and multivariable MR, including BMI as pleiotropic phenotype. RESULTS: Univariable MR indicated a causal effect of pubertal timing on depression risk (inverse-variance weighted: OR 0.93, 95%-CI [0.87-0.99)], p = 0.03). However, this was not confirmed by multivariable MR (inverse-variance weighted: OR 0.95, 95%-CI [0.88-1.02)], p = 0.13), consistent with the epidemiological approach (OR 1.01, 95%-CI [0.81-1.26], p = 0.93). Instead, the multivariable MR study indicated a causal relationship of BMI with depression by two of three methods. CONCLUSIONS: Pubertal timing is not related to MDD risk in males.

No evidence for a causal contribution of bioavailable testosterone to ADHD in sex-combined and sex-specific two-sample Mendelian randomization studies.

The higher prevalence of attention-deficit/hyperactivity disorder (ADHD) in males raises the question of whether testosterone is implicated in ADHD risk. However, cross-sectional studies did not identify an association between ADHD and testosterone levels. Mendelian randomization (MR) studies can overcome limitations inherent to association studies, especially of reverse causation and residual confounding. In the current study, sex-combined and sex-specific two-sample MR analyses were conducted to address whether testosterone has a causal influence on ADHD risk. Sex-combined as well as sex-specific target-genetic variants for bioavailable testosterone were derived from a large genome-wide association study (GWAS) on up to 382,988 adult white European UK Biobank study participants. In our sex-specific analyses for ADHD, including data from 14,154 males and 4,945 females with ADHD (17,948 and 16,246 controls respectively), no association between bioavailable testosterone and ADHD risk was found, neither in males (inverse-variance weighted (IVW): beta = 0.09, 95%-CI [-0.10, 0.27]) nor in females (IVW: beta=-0.01, 95%-CI [-0.20, 0.19]). However, in the sex-combined analysis, including 38,691 cases and 186,843 controls, genetically predicted bioavailable testosterone was associated with ADHD risk (IVW: beta = 0.24, 95%-CI [0.09, 0.39]). The inclusion of birth weight and/or SHBG as additional variables in multivariable MR analyses did not alter this result. However, when correcting for potential BMI-driven pleiotropy by a multivariable MR study, all effect estimates for testosterone showed non-significant results. Taken together, no robust evidence for a causal effect of bioavailable testosterone on the risk for ADHD was found.

Unexpected identification of obesity-associated mutations in LEP and MC4R genes in patients with anorexia nervosa.

Mutations leading to a reduced or loss of function in genes of the leptin-melanocortin system confer a risk for monogenic forms of obesity. Yet, gain of function variants in the melanocortin-4-receptor (MC4R) gene predispose to a lower BMI. In individuals with reduced body weight, we thus expected mutations leading to an enhanced function in the respective genes, like leptin (LEP) and MC4R. Therefore, we have Sanger sequenced the coding regions of LEP and MC4R in 462 female patients with anorexia nervosa (AN), and 445 healthy-lean controls. In total, we have observed four and eight variants in LEP and MC4R, respectively. Previous studies showed different functional in vitro effects for the detected frameshift and non-synonymous variants: (1) LEP: reduced/loss of function (p.Val94Met), (2) MC4R: gain of function (p.Val103Ile, p.Ile251Leu), reduced or loss of function (p.Thr112Met, p.Ser127Leu, p.Leu211fsX) and without functional in vitro data (p.Val50Leut). In LEP, the variant p.Val94Met was detected in one patient with AN. For MC4R variants, one patient with AN carried the frameshift variant p.Leu211fsX. One patient with AN was heterozygous for two variants at the MC4R (p.Val103Ile and p.Ser127Leu). All other functionally relevant variants were detected in similar frequencies in patients with AN and lean individuals.

Differentiating anorexia nervosa and atypical anorexia nervosa with absolute weight cut-offs results in a skewed distribution for premorbid weight among youth.

OBJECTIVE: Anorexia nervosa (AN) and atypical AN are conceptualized as distinct illnesses, despite similar characteristics and sequelae. Whereas DSM-5 differentiates youth with AN and atypical AN by the presence of clinical 'underweight' (i.e., 5th BMI percentile for age-and-sex (BMI%)), we hypothesized that using this weight cut-off to discern diagnoses creates a skewed distribution for premorbid weight. METHOD: Participants included hospitalized youth with AN (n = 165, 43.1%) and atypical AN (n = 218, 56.9%). Frequency analyses and chi-square tests assessed the distribution of premorbid BMI z-scores (BMIz) for diagnosis. Non-parametric Spearman correlations and Stepwise Linear regressions examined relationships between premorbid BMIz, admission BMIz, and weight loss in kg. RESULTS: Premorbid BMIz distributions differed significantly for diagnosis (p < .001), with an underrepresentation of 'overweight/obesity' (i.e., BMI% ≥ 85th) in AN. Despite commensurate weight loss in AN and atypical AN, patients with premorbid 'overweight/obesity' were 8.31 times more likely to have atypical AN than patients with premorbid BMI% < 85th. Premorbid BMIz explained 57% and 39% of the variance in admission BMIz and weight loss, respectively. DISCUSSION: Findings support a homogenous model of AN and atypical AN, with weight loss predicted by premorbid BMI in both illnesses. Accordingly, premorbid BMI and weight loss (versus presenting BMI) may better denote the presence of an AN-like phenotype across the weight spectrum. Findings also suggest that differentiating diagnoses with BMI% < 5th requires that youth with higher BMIs lose disproportionately more weight for an AN diagnosis. This is problematic given unique treatment barriers experienced in atypical AN. PUBLIC SIGNIFICANCE: Anorexia nervosa (AN) and atypical AN are considered distinct conditions in youth, with differential diagnosis hinging upon a presenting weight status of 'underweight' (i.e., BMI percentile for age-and-sex (BMI%) < 5th). In our study, youth with premorbid 'overweight/obesity' (BMI% ≥ 85th) disproportionately remained above this threshold, despite similar weight loss. Coupled with prior evidence for commensurate characteristics and sequelae in both diagnoses, we propose that DSM-5 differentiation of AN and atypical AN inadvertently reinforces weight stigma and may contribute to treatment disparities in atypical AN.

Premorbid body weight predicts weight loss in both anorexia nervosa and atypical anorexia nervosa: Further support for a single underlying disorder.

OBJECTIVE: For adolescents, DSM-5 differentiates anorexia nervosa (AN) and atypical AN with the 5th BMI-centile-for-age. We hypothesized that the diagnostic weight cut-off yields (i) lower weight loss in atypical AN and (ii) discrepant premorbid BMI distributions between the two disorders. Prior studies demonstrate that premorbid BMI predicts admission BMI and weight loss in patients with AN. We explore these relationships in atypical AN. METHOD: Based on admission BMI-centile < or ≥5th, participants included 411 female adolescent inpatients with AN and 49 with atypical AN from our registry study. Regression analysis and t-tests statistically addressed our hypotheses and exploratory correlation analyses compared interrelationships between weight loss, admission BMI, and premorbid BMI in both disorders. RESULTS: Weight loss in atypical AN was 5.6 kg lower than in AN upon adjustment for admission age, admission height, premorbid weight and duration of illness. Premorbid BMI-standard deviation scores differed by almost one between both disorders. Premorbid BMI and weight loss were strongly correlated in both AN and atypical AN. DISCUSSION: Whereas the weight cut-off induces discrepancies in premorbid weight and adjusted weight loss, AN and atypical AN overall share strong weight-specific interrelationships that merit etiological consideration. Epidemiological and genetic associations between AN and low body weight may reflect a skewed premorbid BMI distribution. In combination with prior findings for similar psychological and medical characteristics in AN and atypical AN, our findings support a homogenous illness conceptualization. We propose that diagnostic subcategorization based on premorbid BMI, rather than admission BMI, may improve clinical validity. PUBLIC SIGNIFICANCE: Because body weights of patients with AN must drop below the 5th BMI-centile per DSM-5, they will inherently require greater weight loss than their counterparts with atypical AN of the same sex, age, height and premorbid weight. Indeed, patients with atypical AN had a 5.6 kg lower weight loss after controlling for these variables. In comparison to the reference population, we found a lower and higher mean premorbid weight in patients with AN and atypical AN, respectively. Considering previous psychological and medical comparisons showing little differences between AN and atypical AN, we view a single disorder as the most parsimonious explanation. Etiological models need to particularly account for the strong relationship between weight loss and premorbid body weight.

Does hypoleptinemia trigger entrapment in anorexia nervosa? Etiological and clinical considerations.

Based on the recent observation that human recombinant leptin (r-Met-hu-leptin; metreleptin) may induce a profound alleviation of the complex symptomatology of patients with anorexia nervosa (AN), we examine the implications for our conceptualisation of this eating disorder. Hypoleptinemia as a core endocrine feature of AN serves as a central and peripheral trigger of tissue-specific adaptations to starvation. In this narrative review, we argue that leptin deficiency may explain many of the puzzling features of this eating disorder. Weight loss can be viewed as a two-step process, with only the second step entailing hypoleptinemia and thereby the entrapment characteristic of AN. We discuss the central and peripheral distribution of leptin receptors and consider possible functional implications of hypoleptinemia. We contrast the slow psychological recovery of patients with AN and of people who experienced starvation upon weight recovery with the rapid onset of improvements upon off-label metreleptin treatment. Characteristics of the sex and age dependent secretion of leptin may contribute to the elevated vulnerability of young females to develop AN.

The Diagnosis and Treatment of Anorexia Nervosa in Childhood and Adolescence.

BACKGROUND: Anorexia nervosa (AN) is a serious disease with a lifetime prevalence of up to 3.6% in women and 0.3% in men. Abnormally low weight and the associated starvation partly account for its somatic and mental manifestations. METHODS: This review is based on publications retrieved by a selective search concerning AN in childhood and adolescence. RESULTS: The peak age of onset of AN is 15.5 years. The frequency of inpatient treatment for AN rose by 40% during the COVID pandemic, indicating the importance of environmental factors; the heritability of AN is estimated at 0.5. The ICD-11 sets the threshold for AN-associated underweight at the fifth percentile for age of the body mass index, as long as the remaining diagnostic criteria are met. The main goal of the multiprofessional treatment of AN is the return to normal body weight, which is a central prerequisite for regaining somatic and mental health. The mean duration of AN is 3.4 years, and approximately two-thirds of patients recover from the disease over the long term. CONCLUSION: Marked weight loss in childhood and adolescence can trigger AN in the presence of a predisposition to this disease. Patients and their families should receive psychoeducation regarding the symptoms of starvation and their overlap with those of AN. Important objectives are to shorten the duration of the illness, minimize mortality and the risk of chronic illness, and to identify pharmacological approaches to treatment.

[Genetic Diagnostics in Everyday Clinical Practice in Child and Adolescent Psychiatry: Indications, Framework Conditions, Hurdles, and Proposed Solutions]. / Genetische Diagnostik im klinischen Alltag der Kinder- und Jugendpsychiatrie ­ Indikationen, Rahmenbedingungen, Hürden und Lösungsvorschläge.

Genetic Diagnostics in Everyday Clinical Practice in Child and Adolescent Psychiatry: Indications, Framework Conditions, Hurdles, and Proposed Solutions Abstract: Health insurance covers medically necessary genetic testing in Germany. Diagnostic genetic testing has become increasingly important for child and adolescent psychiatry (CAP), reflected by the rising number of national guidelines relevant to CAP, including genetic testing in the recommended diagnostic work-up. However, implementation of theses guidelines in routine clinical care is lacking. This article provides a concise overview of the relevance of genetic testing in CAP-related national guidelines. It outlines the legal and financial framework for genetic testing in Germany. Furthermore, it points out barriers to implementation and offers potential solutions. It then provides examples from clinical practice highlighting the potential benefits patients and their family members might have from receiving a genetic diagnosis. The article closes by outlining future CAP-relevant areas in which genetic testing may become clinically relevant.

Case report: Rapid improvements of anorexia nervosa and probable myalgic encephalomyelitis/chronic fatigue syndrome upon metreleptin treatment during two dosing episodes.

A comorbidity of anorexia nervosa (AN) and myalgic encephalomyelitis (ME/CSF) is uncommon. A 17 years-old male adolescent with possible onset of ME/CFS after an Epstein Barr Virus infection (EBV) and later onset of AN during a second period of weight loss was twice treated off-label with metreleptin for 15 and 11 days, respectively. As in previous cases, eating disorder specific cognitions and mood improved. Interestingly, fatigue and post-exertional muscle pain (P-EMP) improved, too. We discuss potential mechanisms. Treatment with metreleptin may prove beneficial in AN and in ME/CSF associated with substantial weight loss.

Case report: clinical improvements observed in first off-label metreleptin treatment of a patient with atypical anorexia nervosa.

Off-label metreleptin treatment resulted in cognitive, emotional and behavioral improvements of patients with anorexia nervosa, who presented with hypoleptinemia. We now report a case study of a 16-year-old female patient with atypical anorexia nervosa who was treated off-label with metreleptin for 11 days. She had lost 21 kg over 6 months. Her body mass index at referral for inpatient treatment was 20 kg/m2, her serum leptin level was just within the normal range (2.4 ng/ml). Dosing resulted in prominent improvements of mood and weight phobia entailing a comparatively brief inpatient treatment. The observed improvements are similar to those observed in patients with AN, suggesting overlapping mechanisms with respect to clinical effects induced by elevations of absolute or relative hypoleptinemia. Randomized controlled trials are warranted for both eating disorders.

Evaluation of the MC3R gene pertaining to body weight and height regulation and puberty development.

Recent studies reported an impact of the melanocortin 3 receptor (MC3R) on the regulation of body weight, linear growth and puberty timing. Previously, allele p.44Ile of a frequent non-synonymous variant (NSV) p.Val44Ile was reported to be associated with decreased lean body mass (LBM) and later puberty in both sexes. We Sanger sequenced the coding region of MC3R in 185 children or adolescents with short normal stature (SNS) or 258 individuals with severe obesity, and 192 healthy-lean individuals. Eleven variants (six NSVs) were identified. In-silico analyses ensued. Three rare loss-of-function (LoF) variants (p.Phe45Ser, p.Arg220Ser and p.Ile298Ser) were only found in severely obese individuals. One novel highly conserved NSV (p.Ala214Val), predicted to increase protein stability, was detected in a single lean female. In the individuals with SNS, we observed deviation from Hardy-Weinberg Equilibrium (HWE) (p = 0.012) for p.Val44Ile (MAF = 11.62%). Homozygous p.44Ile carriers with SNS had an increased BMI, but this effect did not remain significant after Bonferroni correction. In line with previous findings, the detected LoF NSVs may suggest that dysfunction in MC3R is associated with decreased body height, obesity and delayed puberty.

Childhood body mass index and the subsequent risk of anorexia nervosa and bulimia nervosa among women: A large Danish population-based study.

OBJECTIVE: Evidence linking childhood body mass index (BMI) with subsequent eating disorders is equivocal. Potential explanations include different study populations and size, and that anorexia nervosa (AN) and bulimia nervosa (BN) should be studied separately. We examined whether birthweight and childhood BMI were associated with subsequent risk of AN and BN in girls. METHOD: We included 68,793 girls from the Copenhagen School Health Records Register born between 1960 and 1996 with information on birthweight and measured weights and heights obtained from school health examinations at ages 6-15 years. Diagnoses of AN and BN were retrieved from Danish nationwide patient registers. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We identified 355 cases of AN (median age: 19.0) and 273 cases of BN (median age: 21.8). Higher childhood BMI was linearly associated with decreasing risk of AN and increasing risk of BN at all childhood ages. At age 6, the HR for AN was 0.85 (95% CI: 0.74-0.97) per BMI z-score and the HR for BN was 1.78 (95% CI: 1.50-2.11) per BMI z-score. Birthweight >3.75 kg was associated with increased risk of BN compared to a birthweight of 3.26-3.75 kg. CONCLUSION: Higher BMI in girls at ages 6-15 years was associated with decreasing risk of AN and increasing risk of BN. Premorbid BMI could be relevant for the etiology of AN and BN, and in identifying high risk individuals. PUBLIC SIGNIFICANCE: Eating disorders are associated with elevated mortality, especially AN. Using a cohort of Copenhagen school children, we linked information on BMI at ages 6-15 years for 68,793 girls with nationwide patient registers. Low childhood BMI was associated with increased risk of AN, whereas high childhood BMI was associated with increased risk of BN. These findings may assist clinicians in identifying individuals at high-risk of these diseases.

Positive effect of leptin substitution on mood and behaviour in patients with congenital leptin deficiency.

BACKGROUND: States of starvation are characterized by reduced physical activity and social withdrawal. This has been suggested to be mediated at least in part via reduced leptin concentrations. OBJECTIVE: We therefore aimed to ascertain if leptin substitution in patients with congenital leptin deficiency (CLD) can improve physical activity and mood. METHODS: Seven patients with CLD were filmed prior to and after short- and long-term substitution (2-21 days; 3-4 months) in a play situation. Six independent, blinded investigators ranked each video according to specifically developed scales concerning motor activity, social interaction, emotionality, and mood with higher scores representing improvements. RESULTS: Short term metreleptin substitution significantly increased mean total score from 17.7 ± 4.1 to 22.6 ± 6.6 (p = 0.039), and mean scores for motor activity (4.1 ± 1.1 to 5.1 ± 1.5, p = 0.023) and social interaction (4.6 ± 1.1 to 6.2 ± 1.7, p = 0.016). After long term substitution means of all four single scales and of total score were even higher than at short-term follow-up. During a treatment pause of 3 months in two children, all four scale scores fell below substitution levels and rose again after restart. CONCLUSIONS: Metreleptin substitution improved indices of physical activity and psychological wellbeing in patients with CLD. This suggests that reduced leptin concentrations might be in part responsible for emotional and behavioural changes seen during starvation.

Genetic variants in genes involved in creatine biosynthesis in patients with severe obesity or anorexia nervosa.

Increased thermogenesis in brown adipose tissue might have an obesity-reducing effect in humans. In transgenic mice, depletion of genes involved in creatine metabolism results in disrupted thermogenic capacity and altered effects of high-fat feeding on body weight. Data analyses of a sex-stratified genome-wide association study (GWAS) for body mass index (BMI) within the genomic regions of genes of this pathway (CKB, CKMT1B, and GATM) revealed one sex-dimorphic BMI-associated SNP in CKB (rs1136165). The effect size was larger in females than in males. A mutation screen of the coding regions of these three candidate genes in a screening group (192 children and adolescents with severe obesity, 192 female patients with anorexia nervosa, and 192 healthy-lean controls) identified five variants in each, CKB and GATM, and nine variants in the coding sequence of CKMT1B. Non-synonymous variants identified in CKB and CKMT1B were genotyped in an independent confirmation study group (781 families with severe obesity (trios), 320 children and adolescents with severe obesity, and 253 healthy-lean controls). In silico tools predicted mainly benign yet protein-destabilizing potentials. A transmission disequilibrium test in trios with severe obesity indicated an obesity-protective effect of the infrequent allele at rs149544188 located in CKMT1B. Subsequent correlation analyses in 1,479 individuals of the Leipzig Obesity BioBank revealed distinct correlations of CKB with the other two genes in omental visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (SAT). Furthermore, between-subject comparisons of gene expression levels showed generally higher expressions of all three genes of interest in VAT than in SAT. Future in vitro analyses are needed to assess the functional implications of these findings.

The role of leptin in rodent and human sleep: A transdiagnostic approach with a particular focus on anorexia nervosa.

This narrative review addressed to both clinicians and researchers aims to assess the role of hypoleptinemia in disordered sleep with a particular focus on patients with anorexia nervosa (AN). After introducing circadian rhythms and the regulation of circulating leptin, we summarize the literature on disordered sleep in patients with AN and in fasting subjects in general. We highlight novel single-case reports of substantially improved sleep within days after initiation of off-label metreleptin treatment. These beneficial effects are set in relationship to current knowledge of disordered sleep in animal models of an impaired leptin signaling. Specifically, both absolute and relative hypoleptinemia play a major role in animal models for insomnia, obstructive sleep apnea and obesity hypoventilation syndrome. We pinpoint future research required to complement our understanding of the role of leptin in sleep in patients with acute AN. Moreover, within the section clinical applications we speculate that human recombinant leptin may be useful for the treatment of treatment-resistant sleep-wake disorders, which are associated with (relative) hypoleptinemia. Overall, we stress the role of the hormone leptin in sleep.

Lipocalin 2 - mutation screen and serum levels in patients with anorexia nervosa or obesity and in lean individuals.

Context: The bone-derived adipokine lipocalin-2 is relevant for body weight regulation by stimulating the leptin-melanocortin pathway. Objective: We aimed to (i) detect variants in the lipocalin-2 gene (LCN2) which are relevant for body weight regulation and/or anorexia nervosa (AN); (ii) describe and characterize the impact of LCN2 and MC4R variants on circulating lipocalin-2 level. Methods: Sanger sequencing of the coding region of LCN2 in 284 children and adolescents with severe obesity or 287 patients with anorexia nervosa. In-silico analyses to evaluate functional implications of detected LCN2 variants. TaqMan assays for rare non-synonymous variants (NSVs) in additional independent study groups. Serum levels of lipocalin-2 were measured by ELISA in 35 females with NSVs in either LCN2 or MC4R, and 33 matched controls without NSVs in the two genes. Results: Fourteen LCN2-variants (five NSVs) were detected. LCN2-p.Leu6Pro and p.Gly9Val located in the highly conserved signal peptide region may induce functional consequences. The secondary structure change of lipocalin-2 due to LCN2-p.Val89Ile may decrease solubility and results in a low lipocalin-2 level in a heterozygotes carrier (female recovered from AN). Lean individuals had lower lipocalin-2 levels compared to patients with obesity (p = 0.033). Conclusion: Lipocalin-2 levels are positively associated with body mass index (BMI). Single LCN2-variants might have a profound effect on lipocalin-2 levels.

Rapid Emergence of Appetite and Hunger Resulting in Weight Gain and Improvement of Eating Disorder Symptomatology during and after Short-Term Off-Label Metreleptin Treatment of a Patient with Anorexia Nervosa.

Off-label treatment of a 15-year-old female patient with anorexia nervosa (AN) with human recombinant leptin (metreleptin) for nine days was associated with self-reported increments of appetite and hunger resulting in rapid weight gain and substantial improvement of eating disorder cognitions and of depression. The results further substantiate the effects of metreleptin on both AN and depression. We contrast these results with the widespread view that leptin is an anorexigenic hormone. Randomized controlled trials are warranted to confirm the described effects.

Perceived impact of the COVID-19 pandemic on child and adolescent psychiatric services after 1 year (February/March 2021): ESCAP CovCAP survey.

In April 2020, the European Society for Child and Adolescent Psychiatry (ESCAP) Research Academy and the ESCAP Board launched the first questionnaire of the CovCAP longitudinal survey to estimate the impact of COVID-19 on child and adolescent psychiatry (CAP) services in Europe. In this brief report, we present the main findings from the second questionnaire of the survey, one year after the COVID-19 pandemic began to hit Europe (i.e., February/March 2021). While service delivery to patients and their families was affected in a major way (reported by 68%) at the beginning of the pandemic, the majority of respondents (59%) in this second survey only reported a minor impact on care delivery. The use of telemedicine remained widespread (91%) but the proportion of CAP services partially closed or transformed to accommodate COVID-19 patients (59% in 2020) dropped to 20%. On the other hand, the perceived impact on the mental health and psychopathology of children and adolescents dramatically increased from "medium" (> 50%) in 2020 to "strong" or "extreme" (80%) in 2021. Four nosographic entities were particularly impacted: suicidal crises, anxiety disorders, eating disorders and major depressive episodes. Accordingly, this was associated with a substantial increase in the number of referrals or requests for assessments (91% reported an increase in 2021 while 61% reported a decrease in 2020). Finally, heads of the CAP departments expressed strong concerns regarding the management of the long-term consequences of this crisis, especially regarding the provision of care in light of the perceived increase in referrals.