Although some positive aspects were reported during the pandemic, it remains unclear how COVID-19 qualitatively influences their living context; (2) Methods: this study employed interviews with four participants with ADHD during the declaration of emergency issued in Japan. The study was a part of ongoing coaching as a psychosocial intervention for ADHD, which was initiated long before the pandemic. The data were the answers to the question: “how are things going with participants during this pandemic?”. In a qualitative analysis, the researchers coded the data to identify different themes and sub-themes; (3) Results and Discussion: the qualitative data analysis yielded five themes: (1) Terrible feeling caused by frustration, stress, and anger; (2) Closeness due to the internal difficulties and conflict; (3) Deteriorating ADHD symptoms and executive function related matters; (4) Condition is the same as usual; and (5) Positive aspects associated with the self-lockdown. As a whole, these results show that the COVID-19 pandemic could be a factor in inducing psychological distress in the participants who adjust relatively better at work/school but did not do well at home before the pandemic; (4) Conclusions: this study indicates the need for special support for individuals with ADHD, especially those who originally had difficulties at home. In September 2020, more than a thousand people in Japan suffered from the COVID-19 disease due to the worldwide pandemic. According to the Ministry of Health, Labor and Welfare, as of 22 April 2020, the number of newly confirmed cases of COVID-19 was 420, and the cumulative number of confirmed cases of COVID-19, and the Coronavirus death tool were 11,919 and 287, respectively. Like other developed countries, although the number of patients was relatively low, the Japanese government issued a declaration of emergency on 7 April 2020. The uniqueness of this was that the declaration of emergency was not so restrictive. To prevent the spread of the virus, the Japanese people were “requested and encouraged” to maintain proper social distancing and to avoid the three Cs: “Closed spaces” with poor ventilation, “Crowded places” with many people nearby, and “Close-contact settings”, such as close-range conversations. With loose Japanese implementation for avoiding the occurrence of clusters, the reason for the low morbidity and mortality rate shown in Japan is still unknown, as is its impact on the people of Japan. This declaration of emergency had never been issued before in Japan, not even during the World War.While the emergence of this pandemic has had a tremendous influence on individuals, it might be especially so for patients who have mental health problems, such as schizophrenia , as theyThese types of concerns are additionally represented in the following statements. The Canadian ADHD Resource Alliance (CADDRA) (2000) stated that this worldwide emergency has increased isolation and difficulties in personal communication . SimilarLosing environmental structure and daily routine can make individuals with ADHD more difficult , and theThese findings indicate that, while staying home may have a negative impact on multiple factors, such as inattention, it may have positive aspects as well. However, the qualitative impact of COVID-19 on ADHD symptoms is unclear. Additionally, since the existing studies employed a retrospective design, uncertainty remains because individuals with ADHD were required to recall their experiences. Moreover, there are no studies on, in ongoing interactions, how individuals with ADHD experience their lives in detail when they engage in self-lockdown. Therefore, this study aims to qualitatively analyze the psychosocial and behavioral impact during Japan’s unique policy of self-lockdown, and reveal how environmental change affects the lives of individuals with ADHD symptoms.Based on an interpretive approach, this qualitative study was implemented as part of an ongoing coaching intervention for adults with ADHD; interviews were used to explore how these clients spent their time during self-lockdown. For this intervention, many of the cases received a combination of face-to-face and e-mail support; however, the coaching was changed to use a teleconference style instead of face-to-face contact. The first author conducted the interviews during the course of the coaching  and ADHD symptoms by Conners’ adult ADHD rating scale (CAARSTM)  participated, with their permission, in this study. No incentives or compensation were offered. The clients’ demographic data included age, sex, current employment, and residence. Their intellectual abilities were ascertained using the Wechsler adult intelligence scale (WAISCAARSTM) . A is a Coaching is a psychosocial intervention that supports by putting emphasis on the client’s autonomy and subjectivity. In coaching, a coach, as a supporter, helps clients to attain their goals by exchanging discourses that mainly consist of questions.In this study, coaching was administered according to the method described in the papers on coaching ,10,11. UAt the beginning of the session in the counseling room, informed consent was obtained from each client regarding protecting personal information and the possibility of using the session data for academic studies. Ethical review and approval were waived for this study, due to written consent being obtained at the Center for Counseling and Development Support Services, University of Tsukuba.In this study, data was derived from conversations relating to the clients’ experience regarding situations during the declaration of emergency. More concretely, the data was the content of the answers when the clients were asked, “How are things going with you during this pandemic?” The intervener encouraged the clients to answer on their general impressions, and on the good and bad points of their lives during the pandemic. Conversations relevant to the study were derived from the first and second study-related sessions.®, Tokyo, Japan). The coding from the two interviews was compared. Page-by-page comparisons were conducted, and the research team discussed the differences in the application or new code development until a consensus was reached. Modifications were made to the final codebook. One researcher used it to code all interviews. A sub-theme within each code was developed based on interview quotes. Finally, matrices were developed to explore responses across sites and compare relationships, repetition of themes within an interview and across interviews, patterns of responses across participants, and differences in responses.Guided by the aims of the research, the first author developed a preliminary codebook that best represented the coachees’ reported experiences. Two other researchers experienced in qualitative studies independently coded two interviews using the preliminary codebook, and developed additional codes based on emergent themes using the qualitative data analysis software MAXQDA “I could not make a noise because my husband work at home. I love to quip a comedy on TV, using sewing machine, and so on. I need to be patient for so many things.”(Participant D)While in self-lockdown, the participants who had hyperactivity could not release their energy and had difficulty in being quiet for the family members who worked at home. The clients were also sometimes frustrated by difficulties in communication with others. One participant stated that she lost her temper more easily than normal under the COVID-19 pandemic.This theme includes the participants’ internal difficulties and conflict. They experienced boredom, hardship, concerns, and worries during self-lockdown. “Boring, unexciting, a sense of despair, and depressive feeling. I have been so frustrated, for long period of time, and it has been so hard that I feel this has never ended. I cannot go shopping, to the library, massage, and so on. I cannot do anything I want to. I do these things to avoid too much work.”(Participant D)When this participant has hyperactivity, it is more difficult to deal with the stay-home situation. Under the normal situation, she goes out for social interactions with others to enjoy herself and to release her energy. Participants experience deteriorating inattention, hyperactivity, impulsivity, and executive dysfunction. This includes increasing difficulties in managing their behavior and controlling their motivation under the emergent situation. “It has been so long since I could manage fire in the kitchen, but I left to put a pan into the fire and I totally forgot about it. It might happen because I had something on my mind. I lost myself in thought if the grocery store is open, then if it opens as usual, I should wear the plastic gloves, and so on.”(Participant D)“It is unable to manage time of my family members at home while I am not good at time management.”(Participant B)As with this participant, deteriorating ADHD symptoms are described in various ways. They experienced making careless mistakes due to the situation being different from the normal. Moreover, participants described it being difficult to manage their schedule, because people frequently ask to change the schedule and sometimes they do so the day before the events. For this theme, the participants described their experiences as the same as usual: There was nothing in particular that had changed in a negative or a positive sense.“I feel good about the cadences of my daily life.”(Participant C)This participant described their situation under self-lockdown as the same as normal in both family and work. There were no influences due to self-lockdown and the spread of COVID-19. Some stated that remote work had already started at a certain setting, and therefore they were not affected by a change in working style.Some participants mentioned the positive aspects of the self-lockdown. This included how their lives turned out to be easier and more comfortable than normal in some aspects, such as their daily routine, sleep duration, and task management. “Surprisingly, I can lead a regulated life!”(Participant A)“I am a repeater mainly due to the failure turning in my papers, but since staying home, I have been able to hand them in for 100%, which is unbelievable. I can proceed my assignment because the professors send the title and contents of the assignment clearly on the portal, so I do not miss them. It is so nice to work at my own pace.”(Participant C)These participants stated that they could keep their own pace because they did not need to pay attention to others to keep from missing anything at work. In addition, since they did not need to pay attention to others, it was very easy for them to escape from the social orders and rules in Japan. They did not need to get prepared for work and school, which usually requires their energy not to be late, and to bring everything that they need for work or school. Moreover, since they are surrounded with their favorite things in their own room, many things inspire them with new ideas, and they have become more creative with work.This qualitative study was conducted to elucidate the situation of adults with ADHD during the self-restraint period in response to the COVID-19 epidemic. The patients were asked how they were doing during this period, and their narratives were analyzed qualitatively. Although some were shown to have had a more difficult time due to a deterioration in their executive functions, others had an easier time in comparison. Previous studies revealed that some symptoms of ADHD became worse, while others did not, and some even improved . This stThe first theme, “Terrible feeling caused by frustration, stress, and anger,” pertains to the negative emotions during the self-restraint period. Although most people were experiencing these negative emotions, more or less, including frustration and anger, during the period, our study showed that the negative emotions were exacerbated by difficulties in time management and confinement in the home in adults with ADHD. These negative emotions, such as irritation, have a subsequent negative affect on their communication.Temporal disorganization is one of the main difficulties of executive functioning in ADHD. While every family member stays home during the pandemic, parents with ADHD have to manage their own time as well as that of their children. McGrath (2020) and Zhang (2020) reported that parents of ADHD children favorably rated their children’s behavioral problems during the temporary closure of the schools ,8. HowevDue to their own deficit in time management skills, parents with ADHD have a much more difficult time in managing their children’s activities . In geneThe theme “Deteriorating ADHD symptoms and executive function-related matters” includes problems in managing time and money, exacerbating inattention, and maintenance of one’s routine. The sudden onset of unfamiliar daily routines made adults with ADHD think about many issues simultaneously; consequently, both their inattention and their distractibility became worse, as Zhang (2020) has already pointed out . Financial management became less efficient during the self-restrained period. This condition could be related to abuse/dependency. Compulsive buying, which is not yet included in DSM or ICD diagnoses, is a psychosocial problem, and it should be confronted as an important mental health issue. Compulsive buying is frequently comorbid with anxiety disorders and eating disorders and, as some have pointed out, has some commonality with impulsivity ,17. In aThe unclear future could have posed ADHD patients difficulties in making a new daily routine according to the new situation. Originally, it was often pointed out that individuals with ADHD have difficulty in making and keeping a daily routine . To compWhile some reported a more difficult time during the self-restraint, it cannot be overlooked that there were also themes including “Condition is the same as usual” and “Positive aspects associated with the self-lockdown.” The remarks that individuals with developmental disorders are vulnerable to unusual situations such as the COVID-19 pandemic is important; however, it could be equally important to shed light on the positive side of this pandemic, which they enjoy. According to a recent report, compared to adults with typical development, who had no change in daily difficulties in their lives, adults with high-functioning autism marked a drastic decline in daily difficulties in their lives . It is hIn this study, one patient reported that he could hand in papers during the pandemic better than during ordinary times. Due to executive disfunction, many people with ADHD struggle with their homework assignments because it requires skills to manage many steps to complete their assignment at home. Langberg et al. (2020) showed nine steps for a homework assignment . HoweverWhile some have difficulty in keeping routines in this extraordinary situation, others reported improvement in their daily rhythm, which reveals their poor time management skill during ordinary times. During the self-restraint period, time and effort is saved both from commuting to the workplace and from the morning routines, such as changing clothes. This has three major merits for ADHD patients. First, they have more free time than usual. Some adults with ADHD could take advantage of a few hours of bonus time during the pandemic. In particular, since ADHD is often comorbid with sleep problems , this exIn this study, for a female participant with ADHD who originally had difficulties in her home with taking care of the home and children, working outside would provide her with a shelter from hardship in the home. However, during the pandemic, she was not allowed to go outside without essential reasons during the self-lockdown. As a result, staying home for a long time would deteriorate her mental health. In Japanese society, where women mainly take care of the home and children, women with ADHD would be easily overwhelmed by their dual task  during the pandemic. In this respect, a considerable portion of women with ADHD would need some kind of support during emergency situations. In comparison, for individuals who are originally doing well at their home but have struggled to deal with something outside, staying home can have a minimum negative impact or even positive impact on their lives See . This study has limitations in terms of credibility and reliability. It analyzed narratives of clients with whom there was an established coaching rapport. Therefore, without any hesitation in speaking frankly, their narratives may reflect their actual situation during the self-restraint. However, given the possibility that their narratives mainly reflect what happened just before the interview, there is no guarantee that their narratives perfectly reveal their whole experiences during the pandemic. The benefit of a qualitative study is to pick up individuals’ detailed experiences, which a quantitative study may overlook. Although individual experiences cannot be easily generalized, personal experiences must be analyzed in both a quantitative and a qualitative manner to better understand the experiences more deeply and utilize them to help or support clients.The influences of the self-restraint situation on adults with ADHD were qualitatively analyzed. They varied among the clients. While the situation negatively affected some clients’ lives, it positively affected or had little impact on the lives of others. The positive experiences of adults with ADHD during the declaration of emergency elucidated the difficult times that they were experiencing during ordinary times. Some patients showed a negative change in their emotions and behavior due to worsened ADHD symptoms during the pandemic. Tailor-made support or intervention should be implemented considering individual circumstances and characteristics, including the heterogeneity of ADHD symptoms.


Double-blind placebo-controlled studies investigating the effect of a few-foods diet (FFD) on attention-deficit/hyperactivity disorder (ADHD) have provided consistent evidence that ADHD can be triggered by foods, indicating the existence of a food-induced ADHD subtype. In 2001 the “few-foods” approach was included in an ADHD treatment protocol. This approach consists of (a) determining, by means of an FFD, whether food is a trigger of ADHD; (b) reintroducing, in FFD responders, foods to assess which foods are incriminated; (c) finally composing a personalised diet eliminating the involved foods only. In the Netherlands the few-foods approach is applied in practice. We aimed to retrospectively assess its effectiveness on ADHD and oppositional defiant disorder (ODD) in real life.Data from all children who started the few-foods approach in three specialised healthcare facilities during three consecutive months were included. Behavior was assessed at start and end of the 5-week FFD, using the ADHD Rating Scale and a structured psychiatric interview. Clinical responders  proceeded with the reintroduction phase.Data of 57 children, 27 taking medication and 15 following some elimination diet at start, were available. No differences were noted between parental scores of children with and without medication or some elimination diet at start. 21/27 (78%) children stopped taking medication during the FFD. 34/57 (60%) children were ADHD responders, 20/29 (65%) children meeting ODD criteria were ODD responders. 26/34 (76%) ADHD responders started the reintroduction phase; 14/26 (54%) still participated at six months. Teacher data were available of 18/57 (32%) children. 9/18 (50%) children were ADHD responders.The FFD, if applied by trained specialists, may lead to clinically relevant reduction of ADHD and ODD symptoms in general practice, and a concomitant decrease of ADHD medication. These results corroborate the existence of an ADHD subgroup with food-induced ADHD. Defining and eliminating the incriminated foods, i.e. the underlying causal triggers, may result in secondary prevention of food-induced ADHD. Research into underlying mechanism(s) is of vital importance: finding an easier method or biomarkers for diagnosing food-induced ADHD and ascertaining the incriminated foods may lead to redundancy of the few-foods approach. Attention-deficit/hyperactivity disorder (ADHD), a mental disorder with a worldwide prevalence estimate of 5–7% , is charDiet has been an environmental factor of long-standing interest in ADHD. Diet research has predominantly focussed on food additives, fish oil and on the few-foods diet (FFD), a very restricted elimination diet consisting of a few foods only. Meta-analyses including double-blind placebo-controlled (DBPC) studies only showed that the clinical effects of fish oil and food additives were negligible to modest, while the effects of the FFD on ADHD were substantial , pointinIn 2001 the “few-foods” approach—a diagnostic procedure to define whether or not food is a trigger of ADHD by means of an individually composed FFD to be followed during several weeks—was included in an ADHD treatment protocol . For dieThe current Retrospective Outcome Monitoring of ADHD and Nutrition (ROMAN) study is a post-RCT study to evaluate and compare the effectiveness of the FFD in three general practices applying the few-foods approach. We aim to investigate whether the results of RCT’s applying an FFD in selected groups of children with ADHD can be obtained in a heterogeneous sample of children with ADHD reflecting the real-life situation. We also made an inventory of the number of children still participating in the reintroduction period after 6 months. To the best of our knowledge this is the first multi-centre effectiveness study reporting the effect of an FFD on ADHD, meticulously describing the few-foods approach in practice.viawww.redcentrum.nl. Criteria to start the few-foods approach in practice are (1) long-term and substantial behavioral problems hampering the child’s development according to the parents and/or meeting the DSM-IV criteria for ADHD or ODD; (2) child’s age 2–16 years; (3) Dutch speaking parents; (4) at least average family structure and parenting consistency, based on parental report; (5) commitment of both parents and child. To establish family commitment parents are asked to discuss the impact of the 5-week FFD on family life prior to starting the few-foods approach and children ≥8 years old must give verbal informed assent. In real-life many children with ADHD suffer from comorbid psychiatric disorders, are taking ADHD medication or follow a variety of elimination diets, not based on the few-foods approach. These conditions are no reason for not starting the few-foods approach.In the Netherlands, the few-foods approach is implemented in practice by trained health care professionals working in specialised centres. Parents wishing to explore the impact of food on ADHD may register their child The Dutch few-foods approach in general practice adheres to a stringent protocol and data are collected in accordance with the Declaration of Helsinki. The procedure starts with assessing whether family and child meet the inclusion criteria, followed by an inventory of family history and situation, the child’s medical background and baseline assessments (T0) of the child’s behavior. Subsequently a two-week baseline period follows during which the child adheres to its usual diet and parents keep a one-week extended diary, closely recording the child’s daily activities, eating habits, medication and behavior. Supplements  but not psychoactive drugs, if any, have to be discontinued. At the end of the baseline period the behavioral measurements are repeated (T1) and parents receive elaborate feedback concerning potential pitfalls for adhering to the FFD, based on the information that has been provided through the diary. Then the FFD—in the Netherlands and in some studies synonymously denominated “Restricted Elimination Diet” (RED)—is explained, after which the child starts the 5-week FFD preceded by a transitional week during which the diet is gradually adapted. Parents are urgently requested to support their child optimally by adhering to the FFD as well and to remove all foods that are not allowed during the FFD.During the first 2 weeks a slightly extended FFD is followed, consistent with the few-foods diet procedure applied in previous RCTs , 11: in The further procedure depends on the child’s response to the diet: (1) Children not taking medication at start, not responding favourably to the medication or in whom medication cannot be suspended during the FFD are designated clinical responders when showing behavioral improvements of at least 40% on either the ACS or the ARS at T2 compared to T1. (2) Children taking medication at start and responding favourably, i.e., not showing ADHD behavior at start, are considered clinical responders when at T2 (a) measurements are without medication, (b) children do not meet the DSM-IV ADHD criteria, and (c) the ARS total score is below the 80th percentile .Clinical responders, i.e., children with food-induced ADHD, may start the reintroduction phase to define the incriminated foods. Generally, only children showing behavioral improvements of 40% or more at T2 proceed with the reintroduction phase, although some families do not continue due to the strenuous prospects and the lengthy reintroduction procedure. Conversely, some children showing less improvements sometimes proceed if their parents consider the beneficial effect worthwhile. Foods the child missed the most are added first, according to an introduction schedule based on the DBPC studies’ procedures, i.e., one food at a time during a period of one week and at least full servings on day 4–7 , 15. TheAn inventory of the child’s behavior is made using three questionnaires; the Abbreviated Conners’ Scale (ACS) and the ADHD Rating Scale (ARS) at T0, T1, and T2, and a DSM-IV-based structured psychiatric interview to assess Oppositional Defiant Disorder (ODD) at T1 and T2. The questionnaires, which have been described elsewhere , use a fIn this retrospective study, anonymised data of all children who started the FFD during three consecutive months  in three health care centres were included, provided that parents had given written informed consent for retrospective use of the anonymised data. According to the Dutch central committee on research involving human subjects, retrospective studies do not need approval of a medical ethical committee since the data are already available.rd grade  and SPSS version 15 (LP) were used. Practices were compared regarding the baseline characteristics using Fisher’s exact test for categorical data and F-test for continuous data. To assess the number of children diagnosed with ADHD previous to the start of the few-foods approach children were divided in two age categories, i.e. younger than 8 years old or 8 years and older, since in The Netherlands ADHD research often starts at age of 7, in the 3rd grade . All anaConsidering that in real-life many children with ADHD are taking medication or following some elimination diet and that both medication and dietary eliminations may affect the child’s behavior, differences between groups of children either or not taking medication and either or not following an elimination diet at start were evaluated in both parents’ and teacher’s outcomes, using a paired t-test. Responder versus non-responder and characteristics at start versus diet response or dropout rate analyses were per-protocol and evaluated using Fisher’s exact test.The effect of health care practice on parental and teacher behavioral outcome scores at T2 , were based on the likelihood ratio test using a general linear model with score at T1 as covariate and with or without practice as independent variable. Fit of these models was evaluated with the link test command of STATA .During three consecutive months 61 children started the few-foods approach in three healthcare centres. Parents of four children did not give informed consent, thus the study cohort included 57 children (At start of the few-foods approach 27/57 (47%) children were taking psychoactive drugs, while 15/57 (26%) children followed some elimination diet at start, varying from eliminating additives and sugar to eliminating gluten, allergenic foods and/or foods high in histamine. No significant differences were noted between parental behavioral scores of children with and without some elimination diet or medication at start. Significant differences were observed between all teacher’s behavioral scores of children with and without medication at start, e.g. the difference in the ARS total score was -20.7   stopped medication during the FFD . In children without medication at start, ARS scores decreased significantly   was applied, because parental behavioral scores of children taking ADHD-medication or following some elimination diet at T1 were commensurable to the scores of children not taking ADHD-medication or an elimination diet at T1  children were clinical responders: 5/8 (63%) children taking medication at start and 4/10 (40%) children without medication at start . All 5 responders taking medication at start stopped taking medication during the FFD, consequently the end measurements of all responders were without medication.In 25/34 (74%) responders good family structure was reported. The remaining 9 families had an average family structure; all nine either did not start the reintroduction phase (n=5) or stopped within 6 months (n=4). 26/34 (76%) responders (22 with good and 4 with average family structure) continued with the reintroduction phase; 14/26 (54%) responders, all reporting a good family structure, still participated at the 6-months’ inventory. Four other families, three with good family structure and one with average structure, stopped supervision within 6 months with the intention to proceed the introductions without supervision. Parental education level had no significant relation with family structure, FFD response or the 6-months’ reintroduction participation. No significant effect (likelihood ratio test) of practice on ACS, ARS and ODD scores at start and end (last observation carried forward) was present. None of the parents or children reported adverse effects during the 5-week FFD or the reintroduction phase. All parents of responders, though relieved by the child’s behavioral improvements and the corresponding amelioration in family life, complained about the long-standing and burdensome reintroduction phase.The ROMAN study data show that the FFD, applied in general practice by trained physicians, may significantly reduce ADHD and ODD symptoms in children either or not taking medication or following some elimination diet at start. 34/57 (60%) children (parent scores) and 9/18 (50%) children (teacher scores) were ADHD responders. At start 29/57 (51%) children met the criteria for ODD as well: 20/29 (69%) children were ODD responders, 16/20 (80%) children were both ADHD and ODD responder (parent scores).Children taking medication at start showed significantly less ADHD symptoms at school compared to children not taking medication, while parent scores with and without medication at start were comparable  children took ADHD medication at start of the few-foods approach. However, during the FFD the behavioral improvements were to such an extent that in 12/13  and 5/5  responders, medication was stopped. FFD responders, including the 12/27 (44%) responders who took medication at T1 but not at T2, showed behavioral improvements of 72%  children completed the FFD, which is a considerable number taking the impact of the intervention into account. The low attrition rate might be due to the FFD procedure, allowing some additional foods in the first weeks. Gradually restricting the diet is an important strategic move to help families to persevere when being faced with the immense difference between their regular diet and the FFD. The low attrition rate might also be attributable to the personalised support during the 5-week FFD, based on potential pitfalls recognised in the baseline diary provided by the parents. Although otherwise suggested in ADHD guidelines, see er 1.6.3 , there iNo differences were found between practices, which may be attributable to the protocol that had to be meticulously followed: research has shown that adherence to protocols may improve clinical outcomes , while dIn general practice, family structure is not assessed through questionnaires when applying the few-foods approach but is based on a parent-reported reflection on their parenting quality. Parenting may be qualified as “good” (i.e. most of the time consistent parenting and compliance with family rules) or “average” (some difficulties with consistent parenting and compliance with the family rules). It has been suggested that a stringent diet might affect family structure , thus unThe few-foods diet is designed as a short-term diagnostic procedure to investigate whether or not food is a trigger of ADHD or ODD. It is a too restrictive diet to be used as a long-term intervention. The long-term effect of food has been investigated in previous studies applying the few-foods approach , 15: FFDIn the ROMAN study, 14 of 26 FFD responders who proceeded with the reintroduction phase still participated at 6 months, while 4 of 26 responders proceeded the introductions without expert supervision. All parents complained about the aggravating recurrence of behavioral problems during the reintroduction phase, inevitably leading to the re-elimination of the incriminated food, emphasizing the necessity for further research into the mechanisms of food in children with food-induced ADHD. Further research is especially important considering the substantial effect size, the applicability in practice, and the knowledge that research into the long-term effect of the most applied ADHD therapy to date, i.e., medication, showed disappointing results . FindingGiven the evidence for a microbiota-gut-brain interaction , furtherIn sum, the ROMAN results confirm the results of scientific research into the effect of the FFD and corroborate the existence of an ADHD subgroup with food-induced ADHD. Consequently, the few-foods approach has great potential for ADHD treatment: after defining whether a child belongs to the food-induced ADHD subgroup, the underlying triggers can be established and eliminated in FFD responders. Ultimately this approach may result in secondary prevention of ADHD. Considering the major impact of the FFD in children with ADHD it is timely to abandon the traditional viewpoint that ADHD is a single, symptom-based, diagnosis, and to include the FFD in both guidelines and diagnostic procedures. Stratifying between either “food-induced” or “classic” ADHD may result in personalized ADHD treatment, may improve ADHD health care and may lead to a decrease of medication use. In addition, acknowledgement and inclusion of the food-induced ADHD subgroup in future research into genetic background, phenotypes, endotypes, and/or prevention of ADHD may open a window of opportunity for children with ADHD.Our study shows that an FFD, applied in general practice by trained physicians, may have clinically relevant effects on ADHD and ODD, both in children with and without ADHD-medication or some elimination diet at start. Medication use decreased significantly in FFD responders. Applying the few-foods approach in practice may result in secondary prevention of ADHD. Further research into the mechanism(s) of food-induced ADHD is of vital importance to facilitate the few-foods approach or to replace this approach by an easier to apply intervention.The strengths of this study are the real-life setting, the data collection by different health care professionals (two physicians and one scientist practitioner) working in different practices, and the 6-months follow-up. A limitation is that no inventory was made of physical complaints, often co-occurring in children with ADHD, at start and end of the FFD. Another limitation is that this study is not a randomised controlled trial but an open study, which may lead to bias. However, post-RCT naturalistic studies in a heterogeneous population are important as well, in order to reflect on treatment management in clinical practice .https://dans.knaw.nl/nl, doi: 10.17026/dans-xn4-6pjh.The datasets generated for this study are available at Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.Data was entered by each health care practice. LP and KF wrote the first draft of the manuscript. KF undertook the data analysis. LP, KF, JT and RRP contributed to the literature search, the interpretation of the data and the writing of the manuscript. All authors had full access to the data, approved the final version of the manuscript and decided to submit for publication.LP has received honoraria for applying the FFD-approach in practice.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Gene-set enrichment analyses were used to identify common pathways underlying these disorders. Narcolepsy PRS were significantly associated with ADHD traits both in the hyperactivity domain  and inattention domain . However, EHS PRS was not significantly associated with either domain of ADHD traits. Gene-set enrichment analyses revealed that pathways related to dopaminergic signaling, immune systems, iron metabolism, and glial cell function involved in both ADHD and narcolepsy. Findings indicate that ADHD and narcolepsy are genetically related, and there are possible common underlying biological mechanisms for this relationship. Future studies replicating these findings would be warranted to elucidate the genetic vulnerability for daytime sleepiness in individuals with ADHD.Attention deficit hyperactive disorder (ADHD) is a highly heritable neurodevelopmental disorder, and excessive daytime sleepiness is frequently observed in ADHD patients. Excessive daytime sleepiness is also a core symptom of narcolepsy and essential hypersomnia (EHS), which are also heritable conditions. Psychostimulants are effective for the symptomatic control of ADHD (primary recommended intervention) and the two sleep disorders (frequent off-label use). However, the common biological mechanism for these disorders has not been well understood. Using a previously collected genome-wide association study of narcolepsy and EHS, we calculated polygenic risk scores (PRS) for each individual. We investigated a possible genetic association between ADHD and narcolepsy traits in the Hamamatsu Birth Cohort for mothers and children (HBC study) ( Both rare and common genetic variants have been associated with ADHD. Recent genome-wide association studies (GWAS) have identified several genomic regions associated with ADHD, with a modest contribution of common variants to its development2.Attention deficit hyperactive disorder (ADHD) is a common neurodevelopmental disorder with onset occurring in childhood. Genetic factors play an important role in the development of ADHD, with a heritability of up to 75%3. PRS can also be used to examine the genetic association between two different diseases or phenotypes. To date, the association of ADHD PRS has been reported with depressive symptoms4, body mass index5, substance use disorder6, and educational attainment7, but no examination has thus far been conducted with sleep disorders. Nevertheless, patients with ADHD frequently show excessive daytime sleepiness (EDS)8. Narcolepsy is characterized by EDS with or without cataplexy , hypnagogic hallucinations, and sleep paralysis , and disturbed nocturnal sleep. The prevalence of ADHD in individuals with narcolepsy is (~35%)9 higher than in the general population (~5%)10. Furthermore, psychostimulants, such as methylphenidate, are effective for controlling symptoms of ADHD (first-line approved treatment) and narcolepsy11 (frequently used off-line with good effects). However, the nature of the relationship between the two conditions and the possibility that underlying biological mechanisms connect the two have not been elucidated yet.Recently, based on a polygenic model for complex disorders, polygenic risk scores (PRS) have been calculated and widely used to explain the genetic liability of individuals for certain diseases or phenotypes, using common genetic variants tested in GWAS12. Of note, the HLA DQB1*15:01 and DQB1*06:02 genes have been shown to be associated with narcolepsy, and additional genes may be involved13. Another recent GWAS study, using Japanese individuals, identified some genomic loci related to narcolepsy outside of the major histocompatibility complex (MHC) region, such as CPT1B, TCRA, and P2RY1112. Capitalizing on the much higher prevalence of narcolepsy in the Japanese population (0.16–0.18%)14 compared to the Caucasian population (0.02–0.06%)15, and using the previous Japanese GWAS study of narcolepsy as a discovery cohort, we investigated a possible genetic association between ADHD traits and narcolepsy in our birth cohort sample from the HBC study. We also conducted a polygenic risk analysis of ADHD traits using a summary from the previous GWAS study of essential hypersomnia (EHS), another highly heritable sleep disorder16, conducted in a Japanese population17. They identified genome-wide significance in single nucleotide polymorphism (SNP) on the CRAT gene located in 9q34.1117. Although there has been no direct evidence showing the high-concordance rate in twins and familial accumulation of EHS and narcolepsy, it has been reported that these disorders share several susceptibility genes16, and ~40% of the heritability of EHS was explained by the genetic background of narcolepsy12.One recent study conducted in Japan demonstrated that the relative risk of narcolepsy in affected first-degree family members is 10- to 40-fold higher than in the general population, suggesting that genetic factors play an important role in this diseaseFurthermore, in order to learn more about the common biological mechanisms underlying ADHD and narcolepsy, a gene-set enrichment analysis was performed.https://biosciencedbc.jp/en/). The target population from the HBC study included infants (n = 876) born between December 2007 and June 2011. Recruitment procedures are fully described elsewhere18. The study procedures were approved by the Hamamatsu University School of Medicine and the University Hospital Ethics Committee (research ID:17-037 and 19-145). Written informed consent was obtained from each caregiver for his/her infant’s participation. Individuals with intellectual disability , measured by Wechsler Preschool and Primary Scale of Intelligence (WPPSI), were excluded from the analysis. Also, individuals with parents of non-Japanese descent (n = 8) were removed from the study to minimize the effect of population stratification. This study followed the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) reporting guideline.The discovery cohort for narcolepsy consisted of 409 patients with narcolepsy-cataplexy (narcolepsy type 1: NT1) and 1562 healthy controls. The discovery cohort for EHS was 125 EHS patients without HLA-DQB1*06:02 and 562 controls without HLA-DQB1*06:02. Details are available on the NBDC Human Database  and hyperactivity-impulsivity (nine items). Each item was rated from 0 (never or rarely) to 3 (very often). The sum of raw scores for inattention, hyperactivity-impulsivity domains, and total scores were converted to percentile scores using the scoring procedure provided in the manufacture’s manual20. Full-scale IQ was measured using the Japanese version of the WPPSI, a reliable and child-friendly measure of cognitive development, administered at age 4. All psychological evaluations were conducted by trained psychologists.ADHD traits were ascertained by interview at age 8 using the Japanese version of the ADHD-RS, previously confirmed for its validity and reliability21. In brief, the quality controls for retaining SNPs and individuals were as follows: missing data for SNP < 0.02, Pi-hat calculated by pairwise identify-by-descent (IBD) analysis <0.2, SNP Hardy Weinberg equilibrium of p > 10−6, and minor allele frequency > 0.01. Seventy-six individuals were removed from the analysis as “related individuals” by IBD analysis. Genotyping imputation was performed using BEAGLE 5.0 to the 1000 Genome Project reference panel phase 3 of the Japanese population22. SNPs with an imputation INFO score <0.8 were excluded. We also excluded SNPs located within the MHC region because of high linkage equilibrium in this region. The number of SNPs analyzed for PRS was 5,606,655.Genotyping was conducted using Japonica array, designed specifically for 650,000 SNP for a Japanese population23. The summary GWAS data used to determine the PRS for narcolepsy and EHS was obtained from the NBDC Human Database (https://humandbs.biosciencedbc.jp/en/). To account for population stratification, we included four principle components (PCs). The PCs were calculated based on the pruned data with PLINK 1.924. The criteria for SNP clumping was pairwise LD r2 < 0.1 within the 1 Mb window. PRSs were calculated with different P-value thresholds at 0.05, 0.05, 0.1, 0.5, and 1. Standardized PRS scores (mean = 0 and standard deviation = 1) were used for the analyses.We used PRSice-2 to generate PRS, according to the developers’ protocol23. Gene-sets collections were obtained from the MSigDB database, and GO gene sets (c5) were used for the analyses (http://software.broadinstitute.org/gsea/msigdb/index.jsp). A total GO gene sets used for analysis was 7350. The P-value threshold for PRSet was set at 1 since gene-set PRSs containing a small portion of SNPs may be unrepresentative of the whole gene-sets25. The obtained P-value was corrected for 10,000 permutation tests, and the significance was set at 0.05.Gene-set enrichment analyses were conducted using PRSet implemented in PRSice-2 softwareg) between narcolepsy and EHS were calculated using LD (linkage disequilibrium) Score regression26. Pre-computed LD scores for the East Asian population from the 1000 Genomes Project were used in the analysis (LD scores available on https://github.com/bulik/ldsc) and the summary statistics from the NBDC Human Database was used. Genetic correlation between ADHD and narcolepsy was analyzed using the recent large ADHD GWAS study2. Since the difference in the ethnic population between ADHD and narcolepsy GWAS study, we utilized the “Popcorn” program, which can calculate trans-ethnic genetic correlation27.Genetic correlations , inattentive domains  and total score  , in the hyperactivity domain  and inattentive domain ; total score  (Table Participant characteristics are summarized in Table 1) Table . EHS PRSβ [SE], −5.680 [1.872]; P = 0.0034) and “interleukin 6 production” , were associated with hyperactivity traits and narcolepsy  and “positive regulation of glial cell differentiation”  were significantly associated with both inattention traits and narcolepsy  indicated that several compounds, including N-acetylcysteine, baicalein, and fatty acids, were modulators for hyperactivity-related gene ontologies, and dextroamphetamine was a modulator for inattention-related gene-sets.Exploratory analysis using the Comparative Toxicogenomics Database . Genetic correlation analysis using summary data of Japanese narcolepsy GWAS and ADHD GWAS conducted by psychiatric genomics consortium showed that these disorders were also positively correlated .LD score regression analysis using summary data of previous GWAS studies of narcolepsy and EHS showed that these disorders were positively correlated  was shown to be more prevalent in subjects with narcolepsy compared to general population41. The exact pathophysiology of RLS is still unclear. However, it has been repeatedly reported that RLS is also common in ADHD subjects42, and iron homeostasis and dopamine signaling have been implicated in the development of this condition43. These gene-set enrichment analyses suggest that ADHD traits and narcolepsy share common biological mechanisms such as dopamine signaling, immune system regulation, glial cell function, and iron homeostasis.Interestingly, we identified pathways related to common molecular mechanisms underlying ADHD traits and narcolepsy. Several gene-sets were identified as having an association with ADHD symptoms and narcolepsy in the gene-set enrichment analysis. The results are intriguing and bear further study. Notably, gene-sets relevant to dopaminergic signaling were associated with both disorders, consistent with the recognition that most medications currently used for ADHD, narcolepsy and EHS are thought to increase synaptic dopamineWe did not find a significant association between EHS PRS and ADHD traits, although genetic correlation analysis showed that narcolepsy and EHS were genetically correlated. One possible explanation for this is that the sample size of the discovery cohort of EHS  was smaller than that of narcolepsy . Thus the calculated EHS PRS did not have adequate power for detecting association with ADHD traits in this study.45. N-acetylcysteine has also been shown to be protective for dopamine neurons46. Baicalein is a flavonoid purified from the plant Scutellaria baicalensis. A recent study using an animal model of ADHD demonstrated the efficacy of core ADHD symptoms by regulating dopaminergic signaling in the brain47. More recently, the reduction of fatty acids in the blood48 among children and adolescents with ADHD, and similarly, the efficacy of a high dose of eicosapentaenoic acid (EPA) for ADHD symptoms have been reported49. Future clinical trials using both existing and novel compounds for ADHD and narcolepsy are warranted.Our exploratory analysis using gene-sets enriched in ADHD traits and narcolepsy suggests that medications currently used for ADHD and narcolepsy, such as the psychostimulants, target common biological pathways underlying both disorders. We also found that N-acetylcysteine, baicalein, and fatty acid could be investigated as novel therapeutic agents for both ADHD and narcolepsy symptoms. Although very preliminary, reports suggest the efficacy of N-acetylcysteine for both hyperactivity and inattention symptoms of ADHDThere are some limitations to this study. First, we targeted a general population, leveraging our longitudinal birth cohort HBC. The cohort is representative of the general population, and thus caution is needed when applying the findings to clinically diagnosed ADHD patients. Second, the original GWAS study of narcolepsy included individuals only with NT1, but not narcolepsy type 2 (NT2), which lacks cataplexy. It is unknown whether the genetic architectures of NT1 and NT2 are the same. Thus, a future GWAS study using NT2 is needed. Third, the prevalence of narcolepsy is known to be higher in the Japanese than the Caucasian population, and future studies using different ethnic populations are needed to replicate these findings.In this study, using PRS analysis, we found that genetic risk factors for narcolepsy contribute to ADHD traits in the general Japanese population, and identified common molecular pathways in these conditions. We hope that this discovery will be replicated and lead to an understanding that EDS in ADHD might have a biological foundation.Supplementary figure


Evidence on the effect of interpregnancy interval (IPI) on low birth weight (LBW) births is limited in developing countries including India. Our study aims to examine association between IPI and LBW births in India. We used data from the fourth round of the National Family Health Survey (NFHS-4) conducted in 2015–16 with a representative sample of 52,825 most recent births for examining the association between IPI and LBW. IPI is defined as the gap between the first month in which the index pregnancy was reported in the reproductive calendar (referred to as the month of conception) and the month of pregnancy outcome (including live births and terminations) of preceding pregnancy. Reproductive calendar data were used to estimate IPI. Association between IPI and LBW were examined using multivariable binary logistic regressions. Seventeen percent of the births in our sample were LBW, and more than half (57.6%) of these were accompanied with IPI less than 18 months. Prevalence of LBW births was highest among mother's who had IPI less than six months (19.4%). Regression results, adjusted for control variables, indicate that the risk of LBW was significantly higher among births whose mothers had IPI less than six months  compared with those whose mothers had IPI between 18 and 23 months. This study provides additional evidence on the association between short IPI (<6 months) and LBW births in India. Promoting spacing methods of family planning is an option that India may consider for increasing the IPI and thereby reducing LBW births. Ensuring recommended iron and folic acid tablets/equivalent syrup and TT injections for every pregnant woman may offset the adverse consequences of shorter IPI. •12% of the LBW births were accompanied with IPI <6 months, 20% between 6 and 11 months, and 25% between 12 and 17 months.•The risk of LBW births is higher among mothers having an IPI of <6 months compared with mothers having an IPI of 18–23 months.•Promoting spacing methods of family planning may consider for increasing the IPI and thereby reducing LBW births in India.•Promoting recommended TT injections and iron-folic acid supplements may offset the adverse consequences of short IPI. StudiesRecent estimates from the World Health Organization suggest that about 15–20% of all births worldwide are LBW, representing more than 20 million births in a year. Of these, almost 28% belong to South Asian countries . India aPast studies have used a number of indicators related to spacing between pregnancies or births – interbirth intervals (IBI), interpregnancy intervals (IPI), inter-outcome intervals (IOI) - to explain adverse pregnancy outcomes. IPI is defined as the gap between the first month the index pregnancy was reported in the reproductive calendar (referred to as the month of conception) and the month of pregnancy outcome (including live births and terminations) for the second-most-recent pregnancy . On the Although the prevalence of LBW births is considerable in India, the causes of LBW births are not fully understood. There are a range of sociodemographic factors and health care utilization measures that are associated with LBW births. Some of the sociodemographic and health care utilization factors associated with LBW births in India are lower maternal age, poor maternal nutrition, lower maternal height, lower socioeconomic status, exposure to passive smoking, late registration for antenatal care, lack of recommended antenatal visits, etc. . Higher Having identified the afore-mentioned gaps in the literature, our study examines the association between IPI and LBW births in India, a large and diverse country, using reproductive calendar data collected in the most recent round of National Family Health Survey 2015-16, henceforth referred to as NFHS-4.22.1We used data from NFHS-4 conducted in 29 states and 7 Union Territories (UTs) of India. NFHS-4 provides information on maternal and child health, family planning, other reproductive health indicators as well as sexual behavior; HIV/AIDS knowledge, attitudes, and behavior; and domestic violence . A total2.1.1We used reproductive calendar collected in NFHS-4 to calculate the IPI. The reproductive calendar includes a monthly history of key events such as births, pregnancies, pregnancy terminations, contraceptive use, and reasons for discontinuation of contraception use for a period going back 60 months before the survey. We restricted our sample to those women who had reported at least two pregnancies in the reproductive calendar, with the most recent of those births having occurred in five years preceding the survey. This time frame was necessary as information on birth weight is available for only those births that occurred in five years preceeding the survey. Of the total 699,686 women interviewed in NFHS-4, 83,166 women reported at least two pregnancies in the reproductive calendar. Of these, we excluded 10,096 women who reported non-live births for their most recent pregnancy. We excluded an additional 21 women who reported pregnancies with durations greater than 10 months. Moreover, 19,789 births were excluded because of the unavailability of birthweight. Finally, 435 twin births were excluded from the sample. Following these inclusion and exclusion criteria, our analytical sample is limited to 52,825 most recent singleton births. Notably, our unit of analysis is the most recent birth within the past five years, because information on antenatal visits, TT injections, and IFA tablets/equivalent syrup were collected only in reference to the most recent birth. Therefore, each woman in our sample contributes only one IPI. Hence number of women and children are same in our sample.2.1.2The dependent variable used in this analysis is LBW, defined as weight below 2500 g at birth.1)“Was (NAME) weighed at birth?” if “Yes” then2)(a) “How much did (NAME) weigh?” and have (b) “Record weight in kilograms from health card, if available.” If the health card was not available, birth weight was recorded as per mother's recall.Information on birth weight was collected by asking the following questions to recent mothers:Children who weighed less than 2500 g at birth were coded as LBW (‘1’) and remaining were coded as normal birth weight (‘0’).2.1.3The key independent variable of interest is IPI which is defined as the gap between the first month the index pregnancy was reported in the reproductive calendar (referred to as the month of conception) and the month of pregnancy outcome (including live births and terminations) of the preceding pregnancy . IPI was2.1.4Based on previous studies on LBW births in India and abroad, a number of maternal-level, child-level, maternal and child-care program-level and household-level variables were included. Maternal-level variables are: mother's age at marriage , mother's age at conception , mother's height , mother's schooling , mother smokes tobacco , outcome of previous pregnancy , postpartum contraceptive use after previous pregnancy outcome . Child-level variables include: birth order , index birth wanted , index birth preterm . Maternal and child care program variables include: ≥4 antenatal care (ANC) visits , ≥2 Tetanus Toxoid (TT) injections , consumed ≥100 Iron Folic Acid (IFA) tablets/equivalent syrup . Household-level variables include: wealth quintiles , religion , caste , geographical region , urban-rural residence .Postpartum contraceptive use refers to the use of contraceptive methods between outcome of previous pregnancy and the next pregnancy. Reproductive calendar records monthly information of the use of contraceptive method used by women. Women who reported using any method were coded as ‘yes’ and rest were coded as ‘no’.Index birth wanted was created using the following two questions canvassed in NFHS-4:When you got pregnant with (Name), did you want to get pregnant at that time? .If the women answered no, then NFHS-4 further asked.Did you want to have a baby later on, or did you not want any (more) children?  Births for whom the mothers answered ‘no more’ were coded as not wanted. Rest of the births were coded as wanted.NFHS-4 also collected information on antenatal care received in reference to the most recent birth. NFHS-4 asked women.During this pregnancy, were you given or did you buy any iron folic acid tablets or syrup? .If the women reported yes, then NFHS-4 further asked.During the whole pregnancy, for how many days did you take the tablets or syrup?Mothers who reported taking tablets/syrup for 100 or more days were coded as consumed ≥100 IFA tablets/syrup and rest were coded as not consumed ≥100 IFA tablets/syrup.NFHS-4 also collected information on TT injections received by women during their last pregnancy. Women who received 2 or more TT injections were coded as having received 2 or more TT injections and rest were coded as not having received 2 or more TT injections.2.2As the dependent variable is binary, we used a multivariable binary logistic regression model to examine the association between IPI and LBW adjusting for other variables listed in the previous section. We estimated a series of regression models to examine the association between IPI and LBW in India. In model-1, we regressed LBW on IPI. In model 2, we added maternal-level variables along with IPI. In model 3, we added child-level variables along with independent variables included in model 2. Similarly, we added maternal and child care program related variables in model 4 and household-level variables in model 5. Odds ratios and 95% confidence intervals were reported. We also tested for interactions between education and other strongly associated covariates (e.g. interaction of education with TT and IFA tablets/syrup). However, as the results did not change, we opted to not include interactions in the final models. Since NFHS-4 used a multistage sampling design, appropriate sampling weights were used in estimations. The details of the sampling weights are given in the NFHS-4 report . Appropr33.1Seventeen percent of the most recent births in our sample were LBW. More than half of these births (57.6%) were accompanied with IPI less than 18 months . Of thesThe prevalence of LBW was highest among births whose mothers had IPI less six months (19.4%) followed by births whose mothers had IPI more than 48 months (18.5%) . Prevale3.2Results of logistic regression models to examine the association between IPI and LBW are shown in A number of control variables were also associated with LBW. The risk of LBW was higher among births of shorter mothers compared with taller mothers . The risk of LBW was also significantly higher among births whose mothers had schooling up to secondary compared with births among mothers who had higher schooling. Preterm births were 2.16 (95% CI:1.92 to 2.42) times as likely as other births to be LBW in our study. Births to mothers who consumed less than 100 IFA tablets/equivalent syrup and received less than 2 TT injections were 1.18 (95% CI: 1.09 to 1.29) times and 1.20 (95% CI: 1.11 to 1.31) times more likely to be LBW compared with their counterparts respectively. Compared to the south, risk of LBW babies was higher in the north, central, and west regions of India, and lower in the east and northeast regions.To examine the differential effect of IPI across birth order, mother's schooling, TT injections, and consumption of IFA tablets/syrup, stratified analyses were carried out . In the 4Using data on 52,825 most recent births record as part of NFHS-4, our study findings indicate that short IPI (<6 months) is associated with a higher risk of LBW births in India. This finding holds even after adjusting for the well-known confounding factors such as components of ANC, preterm birth, parity, wantedness of birth, outcome of previous pregnancy, mother's tobacco consumption, etc. This finding is important given that 12% of recent births in India are accompanied with an IPI of less than 6 months. This means that about 3.2 million births in India are accompanied with an IPI of less than 6 months annually. The findings also indicate that the association between shorter IPI and LBW births is stronger among higher order births and mothers having no schooling or up to primary schooling. There is therefore a clear need to focus on women with shorter IPIs.The association between short IPI and LBW in our study is in line with other research from diverse settings including the USA, Canada, Poland, Brazil, and Uruguay, which was conducted using live birth certificates, vital statistics and birth registries . Our stuWe also find significant association between the mothers’ recommended consumption of IFA tablets/equivalent syrup and LBW births. This finding is in line with the only study from India that, using pooled data from NFHS 1998-99 (NFHS-2) and NFHS 2005-06 (NFHS-3), also found significant association between consumption of IFA tablets/equivalent syrup and LBW births in India . This isAnother finding that deserves mention is the relationship between short maternal height and higher risk of LBW births. The relationship between maternal height and the risk of LBW births shows an intergenerational effect of mother's nutritional status. Short stature of mother reflects on the poor nutritional status of mother during childhood and adolescence . A numbeOur study has a number of strengths. A key strength of our study is the estimation and use of IPI in explaining LBW births in India. A majority of the previous studies from India have examined the effect of birth interval on LBW births . Such a Limitations of our study may be noted. First, a selection bias may arise in our analysis due to the unavailability of reports of birthweight for about 22% of the recent births . ChildreAdditionally, only about 55% of the available birthweights were recorded from the health card; the remaining 45% were based on mothers' recall. Therefore, there is a possibility of recall bias in 45% of the cases, though many studies rely on recall birthweight in a number of developing as well as developed countries . To testAs our analysis is based on only those pregnancies that resulted in live births there is a possibility of selection bias, particularly given that short IPI is significantly associated with adverse pregnancy outcomes. Hence, excluding those pregnancies that resulted in non-live births may selectively reduce the population at risk of LBW in our sample, though as with missing birthweights, this bias will tend to make our estimates more conservative. We cannot rule out the possibility of recall bias in the reproductive calendar. Another limitation with the DHS reproductive calendar is that it provides the occurrence of an event in a particular month. However, event may occur at any date in the month. For example, if a pregnancy is terminated in the month of January and a woman becomes pregnant in the month of July, the IPI is 6 months. However, it is possible that the pregnancy was terminated on 31st January and woman became pregnant on 1st July, in which case the IPI would actually be 5 months. While we cannot rule out the possible effects of the absence of specific date reporting in the NFHS-4 reproductive calendar, we believe that the accuracy of this information would be overly compromised by recall bias over a five-year period. Due to the cross-sectional nature of the data we are unable to establish a causal relationship between IPI and LBW births.Our findings provide compelling evidence on the association between short IPI and LBW births in India. Given the considerable prevalence of LBW births in India, there is an urgent need to increase the conception period following a live birth. Note that the mean and median IPI in India has not changed in the 10 years between NFHS-3 (2005-06) and NFHS-4 (2015-16). Focussing on promotion of spacing methods of family planning is an important strategy that India may consider. India's family planning programme has been a female sterilization driven programme, and the use of spacing methods has been limited. India was the first country in the world to launch an official family planning programme in 1952 . Althoughttps://www.dhsprogram.com/what-we-do/survey/survey-display-355.cfm.Our analysis is based on a publicly available dataset with no identifiable information in place. These data can be downloaded freely for research purposes from the MEASURE DHS website Ajit Kumar Kannaujiya (AKK) and Kaushalendra Kumar (KK) conceptualized the analysis; AKK and Ashish Kumar Upadhyay (AKU) conducted data analysis; Abhishek Singh (AS), KK and Lotus McDougal (LM) supervised the data analysis; AKK, AKU and KK wrote the first draft; AS and Anita Raj (AR) reviewed the first draft and edited the paper.None declared.


Objectives: In two studies of adult attention-deficit/hyperactivity disorder (ADHD), SHP465 mixed amphetamine salts (MAS) extended-release significantly reduced ADHD-Rating Scale, 4th Edition total score (ADHD-RS-IV-TS) versus placebo (PBO). This report describes post hoc analyses of SHP465 MAS treatment response and remission rates from those studies.Methods: Adults with Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision–defined ADHD were randomized to SHP465 MAS (12.5–75 mg) or PBO in a 7-week dose-optimization study and to SHP465 MAS  or PBO in a 6-week fixed-dose study. Response was examined using three definitions . Remission was defined as ADHD-RS-IV-TS ≤12. The Kaplan–Meier analyses assessed time to response or remission.Results: The intent-to-treat populations included 136 SHP465 MAS and 132 PBO participants in the dose-optimization study and 302 SHP465 MAS and 103 PBO participants in the fixed-dose study. Percentages of participants meeting response criteria (SHP465 MAS vs. PBO) at the final treatment week in the dose-optimization and fixed-dose studies, respectively, were 66.0% versus 31.6% and 72.7% versus 28.3% (definition 1); 47.9% versus 27.6% and 60.6% versus 16.7% (definition 2); and 54.3% versus 30.3% and 52.6% versus 18.3% (definition 3). The remission criterion (SHP465 MAS vs. PBO) at the final treatment week was met by 37.2% versus 19.7% of participants in the dose-optimization study and 39.7% versus 10.0% of participants in the fixed-dose study. Times to response and remission favored SHP465 MAS over PBO in both studies .Conclusion: These post hoc analyses indicate that SHP465 MAS was associated with greater response and remission rates than PBO in adults with ADHD, with times to response and remission also nominally favoring SHP465 MAS. Each SHP465 MAS capsule contains three types of drug-releasing beads (an immediate-release [IR] bead and two different types of delayed-release beads) that contain equal amounts by weight of four salts , resulting in a 3:1 mixture of dextroamphetamine (d-amphetamine)-to-levoamphetamine (l-amphetamine) base equivalent.SHP465 In three short-term efficacy studies in adults with ADHD, SHP465 MAS produced significantly greater reductions from baseline in ADHD-Rating Scale, 4th Edition total score (ADHD-RS-IV-TS)  have been proposed for ADHD , was a phase 3, randomized, double-blind, PBO-controlled study in which participants were randomized to SHP465 MAS (12.5–75 mg) or PBO for 7 weeks , was a phase 3, randomized, PBO-controlled, double-blind study in which participants were randomized to SHP465 MAS  or PBO for 6 weeks  who met Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision  diagnostic criteria for ADHD. Participants were required to have baseline ADHD-RS-IV-TS ≥24 in the dose-optimization study and ≥32 in the fixed-dose study, and to have had satisfactory medical assessments with no clinically relevant abnormalities based on medical history, physical examinations, or clinical and laboratory evaluations. All participants provided written informed consent before any study-related procedures were conducted. Informed consent documents were written in accordance with Good Clinical Practice Guidelines of the Health Insurance Portability and Accountability Act of 1996.For both studies, key exclusion criteria included having a comorbid psychiatric diagnosis controlled with a prohibited medication or uncontrolled and associated with clinically relevant symptoms that contraindicate SHP465 MAS use or could confound study assessments; structural cardiac, electrocardiogram, or laboratory anomalies at screening or baseline, a history of hypertension, resting systolic blood pressure >139 mmHg, or resting diastolic blood pressure >89 mmHg; a history (within 6 months before screening) of drug dependence or substance use disorder according to DSM-IV-TR criteria (excluding nicotine); or a documented allergy to, intolerance of, or documented history of nonresponsivity to methylphenidate (MPH) or amphetamines.The primary efficacy measure in both studies was the ADHD-RS-IV scale. The ADHD-RS-IV is an 18-item, clinician-administered scale  population .Findings for the prespecified primary efficacy (change in ADHD-RS-IV-TS from baseline to study endpoint) and key secondary (improvement on the dichotomized CGI-I) analyses have been described previously  and at endpoint (response definition 3 [ADHD-RS-IV-TS ≤18] and remission). Endpoint was defined as the average of the last 3 weeks of treatment or the last postbaseline assessment if the last 3 weeks of treatment were missing. In addition, to examine factors that potentially influence remission, subgroup analyses were conducted at endpoint based on sex (men vs. women), age , and baseline symptom count . Kaplan–Meier analyses were used to examine time to response or remission. Because the studies were not powered for these n = 136; PBO, n = 132) and 405  participants. Baseline demographic and clinical characteristics were generally comparable between the SHP465 MAS and PBO treatment groups in both studies  of participants with a ≥50% ADHD-RS-IV-TS reduction + CGI-I rating of 1 or 2 (definition 2) at the final treatment week were 47.9% (37.8–58.0) in the SHP465 MAS group and 27.6% (17.6–37.7) in the PBO group in the dose-optimization study , and werp < 0.0001; The percentages (95% CI) of participants with ADHD-RS-IV-TS ≤18 (definition 3) at week 7 and endpoint, respectively, were 54.3% (44.2–64.3) and 41.9% (33.6–50.2) in the SHP465 MAS group, and 30.3% (19.9–40.6) and 17.4% (11.0–23.9) in the PBO group in the dose-optimization study . The perp < 0.0001; In both studies, numerically greater percentages of participants met the remission criterion with SHP465 MAS than PBO group . In the Remission rates at endpoint based on sex, age, and baseline symptom count are summarized in post hoc analyses of data from two previously published SHP465 MAS clinical studies in adults diagnosed with ADHD  were 76.2% (16/21) and 82.6% (19/23) with MAS IR and LDX, respectively, after 5 weeks of treatment , but remission rates tended to be lower in the dose-optimization study relative to the fixed-dose study . The reasons for the discrepancy between the within-study analysis of remission based on baseline symptom count and the comparison of remission rates and mean ADHD-RS-IV-TS at baseline between studies are not known.Times to response and remission favored SHP465 MAS over PBO in both studies, with separation from PBO being observed after 1–2 weeks of treatment for response and after 2–3 weeks of treatment for remission. These findings are consistent with those of previous studies of LDX , it is more likely related to the fact that the remission criterion is more stringent than the response criteria. As such, attaining remission  likely requires a higher magnitude score reduction from baseline than does attaining ≤30% or ≤50% reductions in ADHD-RS-IV-TS. The ∼1-week delay in meeting the remission criterion may represent the additional time required to attain these higher magnitude score reductions. Furthermore, while some ADHD symptoms may remit quickly after the initiation of stimulant pharmacotherapy, others may take longer to respond to treatment. For example, in regard to misplacing items, even though attention and focus may improve rapidly, it may take some time for individuals with ADHD to improve their organizational skills to the point that items are no longer misplaced.The concepts of treatment response and symptomatic remission explored in these analyses are both important from a clinical perspective. Treatment response criteria can be used by clinicians during the titration of pharmacotherapy to ensure effective doses are utilized. Remission criteria can be used to determine if ADHD symptom levels are reduced to a level associated with a lack of ADHD-associated impairment. Importantly, the definitions of response and remission utilized in these analyses are indicative of clinically relevant reductions in ADHD symptoms. Based on analyses conducted by Goodman et al. , ADHD-RSpost hoc analyses. Therefore, all reported p values are nominal and descriptive. Second, the study population was predominantly white and had the combined ADHD subtype. Therefore, it is not known whether these data would generalize to a more heterogeneous population of adults with ADHD. Finally, data are not currently available linking the treatment response and remission criteria described in this report to improvement in specific aspects of functioning. Further research in this area is recommended to provide additional insight into the clinical and functional meaningfulness of the criteria used in these analyses.When considering these data, several limitations should be considered. First, the study was not powered for these post hoc analyses demonstrate that SHP465 MAS was associated with response and remission rates, respectively, that were 1.7–3.6 times and 1.9–5.9 times greater than PBO. Importantly, even though a conservative definition of remission was used, a substantial percentage of participants (∼30%–40%) met remission criteria at the final visit and/or study endpoint. Times to response and remission also nominally favored SHP465 MAS over PBO, with separation from PBO being observed after 1–2 weeks for response and after 2–3 weeks for remission. Taken together, these findings further indicate that ADHD symptom improvement with SHP465 MAS is associated with a substantial proportion of study participants meeting criteria for clinically relevant treatment response and remission of ADHD symptoms.These post hoc analyses demonstrate that rates of treatment response and remission with SHP465 MAS exceed those observed with PBO, and that the time to response and remission nominally favors SHP465 MAS over PBO, with separation from PBO being observed after 1–2 weeks of treatment for response and after 2–3 weeks of treatment for remission. These findings further emphasize the efficacy of SHP465 MAS versus PBO in reducing the symptoms of ADHD in adults.SHP465 MAS extended-release is a once-daily oral psychostimulant approved for the treatment of ADHD in individuals aged ≥13 years. In two studies, SHP465 MAS significantly reduced ADHD symptoms versus PBO, as measured by ADHD-Rating Scale, 4th Edition total score in adults diagnosed with ADHD. These


Background: While a large amount of medical literature has explored the association between Attention Deficit/Hyperactivity Disorder (ADHD) and Substance Use Disorders (SUDs), less attention has been dedicated to the typologies of SUD and their relationships with ADHD-specific symptomatology and general psychopathology in dual disorder patients. Methods: We selected 72 patients (aged 18–65) with a concomitant SUD out of 120 adults with ADHD (A-ADHD). Assessment instruments included the Diagnostic Interview for ADHD in adults (DIVA 2.0), Conner’s Adult ADHD Rating Scales–Observer (CAARS-O:S): Short Version, the Structured Clinical Interview for Axis I and II Disorders (SCID-I), the Barratt Impulsiveness Scale (BIS-11), the Brief Psychiatric rating scale (BPRS), the Reactivity Intensity Polarity Stability Questionnaire (RIPoSt-40), the World Health Organization Disability Assessment Schedule (WHODAS 2.0) and the Morningness-Eveningness Questionnaire (MEQ). A factorial analysis was performed to group our patients by clusters in different typologies of substance use and correlations between SUDs, as made evident by their typological and diagnostic features; in addition, specific ADHD symptoms, severity of general psychopathology and patients’ functionality were assessed. Results: Two patterns of substance use were identified: the first (type 1) characterized by stimulants/alcohol and the second (type 2) by the use of cannabinoids (THC). Type 1 users were significantly younger and had more legal problems. The two patterns were similar in terms of ADHD-specific symptomatology and its severity at treatment entry. No differences were found regarding the other scales assessed, except for lower scores at MEQ in type 1 users. Conclusions: At treatment entry, the presence of different comorbid SUD clusters do not affect ADHD-specific symptomatology or severity. Attention Deficit Hyperactive Disorder (ADHD) and Substance Use Disorder (SUD) are two disorders that are mutually interconnected, as demonstrated by many studies in the literature. About 15% of young adults with ADHD (A-ADHD) have a comorbid SUD . GeneralSeveral hypotheses have been proposed to explain the strong association between SUD and ADHD. Familial studies confirmed a common genetic matrix between ADHD and SUD; indeed, the prevalence of SUD seems higher in the parents of ADHD children and in the first-degree relatives of ADHD subjects compared with healthy controls. Similarly, ADHD prevalence is higher in children of parents with SUD. All of these data suggest a common familial and genetic substrate for ADHD and SUD ,7,8. KnoFurthermore, many patients report the use of drugs as a way to suppress ADHD symptoms, following the self-medication hypothesis ; accordiIn summary, A-ADHD/SUD comorbidity has frequently been reported in the literature but, despite the self-medication hypothesis, these patients are using various substances that have opposite effects. What is more, studies about the influence of these substances on the clinical picture are lacking. Official statements go no further than declaring that comorbid patients have a more severe illness with a worse outcome.The main purpose of the current study has been to explore substance use patterns among A-ADHD patients while comparing the demographic, clinical and functional features occurring in the different patterns found for substance use. To the best of our knowledge this is the first study ever conducted on a sample of A-ADHD patients never treated with specific ADHD medications that explores patterns of substance use and their clinical correlations at treatment entry.This is an observational, cross-sectional, non-interventional study based on a single evaluation of adult patients admitted between 2016 and 2019 to the Outpatient Unit of the Second Psychiatric Unit of the University of Pisa. All the patients recruited in the study were evaluated by clinical interview and specific diagnostic tests by residents of the Department of Clinical and Experimental Medicine, School of Psychiatry, of the University of Pisa, under the supervision of senior psychiatrists of the ADHD research group.This study was conducted according to the WMA Declaration of Helsinki—Ethical Principles for Medical Research Involving Human Subjects. All subjects examined filled out and signed an informed consent document to qualify for participation in this study. Both the consent form and the experimental procedures were approved by the ethics committee of the University of Pisa , in accordance with internationally accepted criteria for ethical research.At the treatment entry we consecutively recruited 120 patients with A-ADHD; among these we selected 72 individuals who also met DSM-5 criteria for a Substance Use Disorder. All the recruited patients were diagnosed and treated for the first time after reaching the age of 18.The diagnosis of ADHD was made according to DSM-5 criteria and confirmed using the semi-structured, clinician-administered Diagnostic Interview for ADHD in adults (DIVA 2.0).Conner’s Adult ADHD Rating Scales-Observer: Short Version (CAARS-O:S) is a 26-item questionnaire completed by a designated person in order to assess DSM-IV Inattentive Symptoms, DSM-IV Hyperactive-Impulsive Symptoms, DSM-IV Total ADHD Symptoms and the ADHD Index; high scores of items in the ADHD Index suggest clinically significant levels of ADHD symptoms. An anamnestic scale was used to assess patients’ demographic and retrospective clinical data. The Structured Clinical Interview for Axis I Disorders (SCID-I) was used for the assessment of any other psychiatric diagnosis, according to DSM-5. For each patient the clinician completed the 18-item version of the Brief Psychiatric Rating Scale (BPRS), a tool commonly used to assess current psychopathology and severity of symptoms. The Hypomania Checklist (HCL-32) questionnaire was used for lifetime history of hypomanic symptoms. The Barratt Impulsiveness Scale (BIS-11) is a 30-item questionnaire used to assess the impulsiveness construct, which is subdivided into three second order domains named Attentional, Motor and Non-Planning Impulsivity. The Reactivity Intensity Polarity Stability Questionnaire (RIPoSt-40) is a self-report questionnaire of 40 items used to measure Emotional Dysregulation (ED) that could be further subdivided into four subscales known as Emotional Impulsivity, Positive Emotionality, Negative Emotionality and Affective Instability. The World Health Organization Disability Assessment Schedule (WHODAS 2.0), developed by the World Health Organization, is a 36-item self-administered questionnaire used to explore functioning and disability in major life domains. The 19-item Morningness-Eveningness Questionnaire (MEQ) was used to assess patients’ chronotype: a total score of 41 or below indicates an “evening chronotype” while a score of 59 or above indicates a “morning chronotype”.In order to group our patients by clusters in different typologies of substance use we used the following procedure. We scaled the use of each substance by 4 ordinal levels: 0 = no life-time use; 1 = past use; 2 = current (previous 6 months) use; 3 = past and current use. A factorial analysis was performed on the substances investigated (cannabinoids (THC), cocaine, amphetamines, 3,4-metilenediossimetanfetamina (MDMA), opiates, alcohol, illegal benzodiazepines) in A-ADHD patients in order to identify possible composite dimensions. The initials factors were extracted by means of principal component analysis (PCA-type 2) and then rotated according to Varimax criteria in order to achieve a simple structure. This simplification is equivalent to maximizing the variance of the squared loading in each column. The criterion used to select the number of factors was an eigenvalue >1. Items loading with absolute values >0.40 were used to describe the factors. This procedure makes it possible to minimize the correlations between the factors, so allowing their optimization as classificatory tools for each subject. The factor scores were then standardized as z-scores to facilitate the comparison of scores occurring among the factorial measures. All the subjects were then grouped into different subtypes on the basis of the highest z-scores obtained for each factor. This procedure gave the opportunity to classify groups of subjects on the basis of the most statistically abnormal substance use cluster. In this way it became possible to resolve the problem of identifying a cut-off for the inclusion of patients in different identified clusters. In this case, to cluster patients in groups, we used correlations between the substances used.Diagnostic features, specific ADHD symptoms, severity of general psychopathology and patients’ functionality were compared according to the SUD evidenced typology using Student’s T-test for metric and Pearson’s Chi-squared Test for categorial variables.We selected 72 patients with an A-ADHD comorbidity with SUD, of which 52 (72.2%) were males and 20 (27.8%) females . Among these subjects 22 (31.9 %) were students, 27 (39.1%) were unemployed, 13 (18.8%) were employed, 6 (8.7%) were freelances and 1 (1.4%) was a housewife. Regarding marital status, most of these subjects—61 (87.1%)—were single, 5 (7.1%) were married and 3 (4.3%) divorced. 16 (22.9 %) subjects had legal problems. Regarding psychiatric comorbidities: 10 patients (13.9%) had comorbid Bipolar I Disorder, 26 (36.1%) Bipolar II Disorder, 1(1.4%) Major Depressive Disorder; 25 (34.7%) had comorbid Borderline Personality Disorder, 12 (16.7%) Cyclothymic Disorder and 7 (9.7%) Antisocial Personality Disorder; 20 (27.8%) presented comorbid Generalized Anxiety Disorder, 7 (9.7%) Panic Attack Disorder and 2 (2.8%) subjects had Social Phobia; 13 (18.1 %) had Specific Comorbid Learning Disabilities (DSA), 7 (9.7%) Tic Disorders, and 2 (2.8%) Autism Spectrum Disorder. Three patients (4.2%) had comorbid Anorexia Nervosa, 2 (2.8%) Bulimia Nervosa, and 7 (9.7%) were affected by comorbid Binge Eating Disorder.Results of factorial analysis  revealedp = 0.933), legal problems effects  and group-legal problems effects , regarding all the symptomatological rating scales that were used.Turning now to demographics, no differences were found between Type 1 and Type 2 substance use regarding gender, marital status or work. Age was higher in Type 2 patients compared with Type 1. Legal problems were significantly higher in the Type 1 group. At multivariate level, two-factor ANOVA analysis , did not show any significant group effects , and we should use anti-craving medications for cocaine only if the cessation of cocaine use is still incomplete. Conversely, if type 2 is dominant, we should use anti-craving medications for THC, and, unfortunately, given the scarcity of scientific evidence in this kind of treatment, we shouldn’t expect any important positive pharmacological outcome, especially in dual disorder patients. Our clinical experience usually limits us to combating the psychiatric complications of the THC use. Regarding dominant type 2 A-ADHD patients, there is also the risk of a frequency increase as a result of the new leniency and legal innovations associated with cannabis procurement and use. Nevertheless, cannabis had not been legalized, in Italy, for the time being.Limitations: Several limitations should be noted in the present study. First, our sample size was small, a datum that limits the generalizability of our results and the power of the study. Indeed, the patients recruited came to our attention as ADHD treatment naïve patients, neither diagnosed nor treated before adulthood. Many patients with ADHD are often misdiagnosed and reached our attention only when the clinical picture was severe and had been complicated by other comorbidities. Consequently, to confirm our hypothesis, more adult ADHD patients with or without a dual disorder need to be enrolled.Secondly, some of the features assessed, such as impulsiveness, emotional dysregulation and overall functioning, were determined by the answers given to self-report questionnaires, so raising the danger of reporting biases. However, all participants completed the reports under the supervision of a psychiatrist who evaluated them clinically and conducted other valid interviews.Thirdly, our findings showed a preliminary baseline evaluation of A-ADHD patients at treatment entry, without including a control group. Indeed, this cross-sectional picture is a part of a longitudinal study with multiple follow-up steps that facilitated the evaluation of the trajectories of Substance Use Disorders in A-ADHD patients and helped to make clear how the two disorders are influenced by different psychopharmacological treatments. Moreover, besides SUD typology comparisons, we are also analyzing both similarities and differences in A-ADHD patients with and without a dual disorder at treatment entry.In conclusion, another significant limitation is the use of a non-random sample. Our hospital is located in Central Italy, which exerts a specific nationwide attraction on patients who have a dual disorder with predominantly psychopathological aspects. Besides, Italian legislation lists centers of excellence for the treatment of adult ADHD in various areas of Italy, and patients typically apply for treatment to the nearest one. So, a bias in favor of the closest officially recommended area cannot be excluded. The risk of a self-selection bias is related to the type of treatment we offer (stimulant medications). So, only patients interested in this kind of medicine may have requested treatment. Finally, our sample did not include patients who choose an “addiction unit” for their treatment; this applied, specially, to those currently using opioids, who, in fact, were only minimally represented in our sample. In Italy, psychiatric units and addiction units work independently, the result being that the level of communication between them is poor. These sample selection biases limit the generalization of our data.In our dual disorder (A-ADHD/SUD) patients, those who prevalently use cocaine/alcohol are younger and have more legal issues; patients who only use THC go to bed earlier. Despite these minor differences, our findings show a similar presentation of ADHD symptomatology and severity at treatment entry, independently of substance use typology, so suggesting that differences in the clusters of substances used do not affect the clinical manifestation of A-ADHD at treatment entry.