Amphetamine use disorder (AMPH) and attention deficit-hyperactivity disorder (ADHD) often co-occur and are associated with poor treatment outcomes. Elevated impulsivity is a core feature in both disorders. Little is known however about the specific neurocognitive profile regarding different facets of impulsivity, and specifically impulsive choice, in comorbid populations.Three groups ) were assessed with self-reported impulsivity and cognitive tasks of impulsive choice, operationalized as delay aversion (DA) and reflection impulsivity.Twenty-nine participants with comorbid ADHD + AMPH, 25 participants with ADHD only and 116 HC completed screening, including self-rating scales, and cognitive testing. 20, 16 and 114 participants completed computerized cognitive tasks in the ADHD + AMPH group, ADHD group and HC group, respectively. The ADHD + AMPH group reported significantly higher motor, attentional and non-planning impulsiveness, and showed a significantly higher degree of impulsive choice, compared to both groups. There were no differences in task-related impulsiveness between ADHD only and HC.The current findings suggest that individuals with ADHD + AMPH have overall elevated levels of impulsivity compared to individuals with ADHD only. In addition, that ADHD + AMPH is specifically associated with impairments in task-related impulsive choice, which was not found in ADHD only compared to HC. The neurocognitive profile in this specific patient group may represent a need for more systematic screening within healthcare settings in order to develop effective and targeted treatment for comorbid patients.EudraCT, 2012–004298-20.The online version contains supplementary material available at 10.1186/s12888-023-05034-x. Substance Use Disorder (SUD) and Attention Deficit/Hyperactivity Disorder (ADHD) often co-occur , 2 and sElevated impulsiveness is a core feature in both ADHD and SUD, which in itself has been shown to predict relapse and poor SUD treatment outcomes . A commoThe current paper has a focus on impulsive choice, which is considered to reflect impulsive behavior as a result of delayed discounting (DD) and/or reflection impulsivity. Where DD is the tendency of devaluating delayed greater rewards in favor of immediate smaller rewards, and reflection impulsivity is the tendency to not collect enough information prior to a decision. Related to, but distinguished from DD, is delay aversion (DA) which refers to the avoidance of delays as a consequence of a negative emotional response due to delay overall .There has been extensive research on neurocognitive functioning in both ADHD and SUD populations during the last decades and impulsive choice have been found to be associated with both disorders . SpecifiOnly a few studies regarding impulsive choice have been conducted in a controlled human laboratory setting, in ADHD/SUD comorbid populations. One study found steeper DD in individuals with comorbid cocaine use disorder (CUD) and ADHD, compared to individuals with ADHD only . This isThe overall aim of the current study was to examine different aspects of impulsive choice in individuals with comorbid AMPH + ADHD compared to ADHD only. We hypothesized that individuals with AMPH + ADHD would have higher 1) DA and 2) impaired reflection impulsivity, as measured by Cambridge Gambling Task (CGT)  and InfoAdult (> 18 years old) males and females were recruited through public advertising and active recruitment from substance dependence treatment services in the Stockholm region, from August 2015 to December 2019. The patients were recruited to a clinical trial (unpublished)investigating the dose-dependent response of methylphenidate in comorbid SUD/AUD . The study was approved by the Swedish Ethical Review Authority (DNR 2012/1407–31/1) and participants provided their consent following oral and written information.Three groups were recruited: 1) participants with comorbid AMPH/ADHD; 2) ADHD only and 3) HC. Participants were assessed for medical and psychiatric disorders by a designated study physician, including physical examination, pregnancy test, alcohol breathalyzer test, urine toxicology, blood analysis , blood pressure, heart rate and ECG. The presence of ADHD was assessed in accordance with national guidelines including the Diagnostic Interview for ADHD in Adults (DIVA 2.0) , a shortMain inclusion criteria were moderate to severe AMPH and/or ADHD according to DSM-5 . For AMPMain exclusion criteria were presence of severe somatic disorder, pregnancy, other major psychiatric disorders , severe SUD except nicotine- and amphetamine use disorder, use of psychoactive substances during the last seven days, or any pharmacological ADHD treatment during the last 14 days, preceding enrollment. Additionally, participants in the ADHD only group and HC, were excluded if they had a history of SUD (excluding nicotine).Participants in the ADHD + AMPH and ADHD groups were assessed with self-rating scales, including BIS-11, at screening, regardless of current substance use and/or pharmacological treatment. Cognitive tasks were conducted at a later date to ensure the mandatory wash-out period of 7 days from illicit substances and 14 days from pharmacological ADHD treatment.Participants were assessed for substance use via the Time-Line Follow Back interview (TLFB)  and a stCGT and IST from the Cambridge Neuropsychological Test Automated Battery (CANTAB®), were administered using a touch-screen tablet PC (MOTION J3500-i7B) and a press pad from Cambridge Cognition Ltd.Self-reported impulsive behavior was assessed via the Barratt Impulsiveness Scale, a widely used self-report measure of trait impulsivity. In this study, we utilized a validated Swedish translation of the BIS-11. The main subscales measure attentional, motor and non-planning impulsiveness.IST is a task of reflection impulsivity with an administration time of approximately 15 min. The test is constructed as a game in which the participant is presented with a 5 × 5 grid of gray boxes and two larger colored panels below this grid. The purpose of the game is to correctly guess which color the majority of the boxes have under the gray layer (yellow or green). Participants are free to show the underlying color of the boxes one by one. In the Fixed Win condition, no penalty is given for showing the color of the boxes and 100 points is given for a correct guess. In the Decreasing Win condition, the number of points that the participant can win is 250 but decreases by 10 points for every box that the participant shows the color of. There is a fixed time between each trial, meaning that participants will have to wait longer before next trial if they guess quickly, i.e. there is no gain in the time it takes to complete the task by guessing quickly. The key outcome measures of the IST reflect the tendency, or lack thereof, to collect information prior to making decisions.The Cambridge Gambling Task is a computerized test aimed at evaluating quality of decision-making and risk taking. The participant is presented with ten boxes which are either red or blue. The ratio of red:blue boxes varies between trials. The participant is informed that a token is hidden in one of the boxes and that they must make a guess whether the token is in a red or a blue box. The participant then has to place points stake on their guess. If the guess is correct points get added to the participant’s total score and points are deducted if the guess is wrong. The participant is free to choose from a range of bets which are presented sequentially, ranging from a small to a large percentage of the participants current score. The game is performed in two conditions. In one condition of the test, the bets are presented in ascending order with the bets getting larger and larger. In the other condition the bets are getting smaller and smaller.Key outcome measures of CGT reflect the tendency to adjust decisions according to risk and DA.Data was processed and analyzed using R Studio software, version 2021.09.0. Further details on R packages and code are found in A total of 170 participants were recruited and divided into three different groups. Twenty-nine participants with comorbid ADHD + AMPH, 25 participants with ADHD only and 116 HC completed screening, including BIS-11, and cognitive testing. 20, 16 and 114 participants completed computerized cognitive tasks in the ADHD/AMPH group, ADHD group and HC group, respectively. Sociodemographic and clinical data are presented in Tables The ADHD + AMPH group presented with significantly higher self-reported impulsive behavior and showed greater impaired task-related delay aversion and reflection impulsivity compared to ADHD only and HC. Results from cognitive assessments are presented in Table For many of the outcomes data was not normally distributed or homogeneity of variance was not met, or there were some outliers. However, when performing the non-parametric tests described above the results were always identical (or very similar), with one exception, to the main ANOVA analysis and therefore we report only the ANOVA results to facilitate the interpretation of the results. For the outcome “Quality of Decision Making” in the CGT, the non-parametric results are presented. Sensitivity analysis with adjustment for multiple comparisons yielded similar results, which did not affect the overall conclusions  and HC (p < 0.01), indicating that the ADHD/AMPH group were more unwilling and/or unable to wait prior to making decisions. There was no significant difference between ADHD and HC (p = 0.86).The comorbid (ADHD + AMPH) group demonstrated a significantly higher DA score compared to individuals with ADHD only (p < 0.01) and HC (p < 0.01), indicating less adjustment of betting behavior according to risk. There was no significant difference between ADHD and HC (p = 0.79).The ADHD + AMPH group had a significantly lower score of Risk Adjustment, compared to the ADHD group (p = 0.75). The ADHD + AMPH group had a significantly lower Quality of Decision Making compared to the HC group (p = 0.004), while there were no significant differences between ADHD + AMPH and the ADHD only group, nor between ADHD only and HC. There were no significant differences between groups on Overall Proportion Bet (p = 0.95).There was no significant difference between groups on Risk Taking (p = 0.03) group and HC (p < 0.01), the ADHD + AMPH group opened significantly fewer boxes prior to their decision in the decreasing win condition, indicating impairment in reflection impulsivity. There was no significant difference between ADHD and HC (p = 0.50).Compared to the ADHD only (p < 0.01) group and HC (p < 0.01), the ADHD + AMPH group opened significantly fewer boxes prior to their decision in the fixed win condition, indicating impairment in reflection impulsivity. There was no significant difference between ADHD and HC (p = 0.10).Compared to the ADHD only (p < 0.01) and HC (p < 0.01), indicating impairment in reflection impulsivity. There was no significant difference between ADHD and HC (p = 0.84).The ADHD + AMPH group had a significantly lower mean probability of making a correct choice at the point of decision, in the decreasing win condition, compared to the ADHD only group (p < 0.01) and HC (p < 0.01), indicating impairment in reflection impulsivity. There was no significant difference between ADHD and HC (p = 0.26).The ADHD + AMPH group had a significantly lower mean probability of making a correct choice at the point of decision, in the fixed win condition, compared to the ADHD only group (p < 0.01) and HC (p < 0.01). The ADHD group had a significantly higher mean score than the HC (p < 0.01).The ADHD + AMPH group had a significantly higher total mean score of self-reported trait impulsiveness compared to the ADHD only group (p < 0.01) and HC (p < 0.01). The ADHD group had a significantly higher mean score than the HC (p < 0.01).The ADHD + AMPH group scored significantly higher on the motor impulsivity BIS-11 subscale compared to the ADHD only group (p < 0.01) and HC (p < 0.01). The ADHD group had a significantly higher mean score than the HC (p < 0.01).The ADHD + AMPH group scored significantly higher on the attentional impulsivity BIS-11 subscale compared to the ADHD only group (p < 0.01) and HC (p < 0.01). The ADHD group had a significantly higher mean score than the HC (p < 0.01).The ADHD + AMPH group scored significantly higher on the non-planning impulsivity BIS-11 subscale compared to the ADHD only group  and reflection impulsivity, in individuals with comorbid ADHD + AMPH, compared to individuals with ADHD only and HC. The ADHD + AMPH group demonstrated significantly higher levels of impulsiveness compared to the ADHD only group and HC’s, both in regard to self-reported impulsivity and as measured by cognitive tasks. Although the ADHD only group had significantly higher self-reported impulsiveness, compared to HC, there were no differences between the two control groups on task-performance.Specifically, the ADHD + AMPH group, compared to the control groups, showed more pronounced delay aversion (DA), i.e., they were significantly less able/willing to withstand delay prior to making decisions, and showed a significantly smaller tendency towards risk adjustment . Moreover, they collected significantly less information prior to decisions, indicating impaired reflection impulsivity. These findings are in line with previous research on individuals with comorbid cocaine use disorder and ADHD , 6. HoweA previous study that investigated impulsiveness in CUD/ADHD, found steeper delay discounting (DD) in the comorbid group, compared to ADHD only, but found no significant difference on any of the three subscales of BIS-11 . This isThe study found no evidence supporting any differences in performance on tasks of DA, risk adjustment and reflection impulsivity between the ADHD only group and HC. This is in accordance with the findings of two previous studies , 15, demThere are some important limitations in the current study, of which the main one being the small sample size. Another limitation is that both the ADHD + AMPH and ADHD only groups, respectively, were recruited from participants in a clinical trial that excluded several other comorbidities and required the participants to be drug negative. This limits the external validity of the findings, and they may therefore not be representative of a broader clinical population. For instance, individuals with more severe symptoms, and other concurrent SUD,’s might not have been able to succeed with the mandatory detoxification prior to enrollment. On the other hand, the exclusion of patients with other major psychiatric comorbidities and/or current use of psychoactive substances could be viewed as a strength as it, might have confounded the results, and thus adds to the internal validity. Additionally, detailed life-time data on other illicit substances (than amphetamine) was not collected, which theoretically might have confounded results. On the other hand, no participants fulfilled DSM V criteria for any other moderate to severe SUD, other than amphetamine use disorder, during the 12 months preceding inclusion. Significantly higher degree of depressive symptoms in the ADHD groups, and the significant differences in nicotine use and sociodemographic data, might also have confounded results. Specifically, nicotine has been found to both be an enhancer of some aspects of cognition short term, while heavy smoking is associated with impairment . AnotherTheoretically, there may also be an overlap between performance on the two tasks utilized. Whereas IST is operationalized to measure reflection impulsivity, and CGT to reflect delay aversion, one cannot rule out that delay aversion to some extent also influences the performance on IST. On the other hand, the IST utilized is designed in such a way that there is no gain in delay by choosing quickly . In addition, it should be noted that even though impulsivity is viewed as a multidimensional construct, there is currently no consensus on the underlying dimensions of impulsivity. On the other hand, impulsive choice specifically, is by many authors viewed as a separate dimension of impulsivity , 11. MorPrevious research suggests that impairments in impulsive choice may contribute to the development of SUD and vice versa , howeverThe findings in this study have important clinical implications and possibly contribute to the understanding of the observed weaker pharmacological effect on ADHD symptoms in comorbid populations . AlthougThe current findings suggest that individuals with ADHD + AMPH have overall elevated levels of impulsivity compared to individuals with ADHD only. In addition, that ADHD + AMPH is specifically associated with impairments in task-related impulsive choice, which was not found in ADHD only compared to HC. The neurocognitive profile in this specific patient group may represent a need for more systematic screening within healthcare settings in order to develop effective and targeted treatment for comorbid patients.Additional file 1.


Introduction: Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental disorders, characterized by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), which is marked by symptoms such as inappropriate levels of inattention, hyperactivity, and impulsivity that can affect academic, social, and personal functioning in children and adolescents. This review summarizes clinical trials demonstrating the effectiveness of Alpha-2 agonists in reducing symptoms of inattention, hyperactivity, and impulsivity in children with ADHD. Studies were identified through a systematic search of PubMed and Cochrane databases. However, these medications’ long-term safety and efficacy remain uncertain, with a lack of data on their effects on growth, cardiovascular function, and other adverse events. Further studies are required to determine these medications’ optimal dose and treatment duration. Methods: Medications that target the noradrenergic system, such as Alpha-2 agonists, have been increasingly used as a treatment option for ADHD, with guanfacine and clonidine being two of the most commonly used medications. They function by selectively targeting Alpha-2 adrenergic receptors in the brain leading to improved attention and reduced hyperactivity and impulsivity symptoms in children with ADHD. Results: Clinical trials have demonstrated the effectiveness of Alpha-2 agonists in treating ADHD in children by reducing symptoms of inattention, hyperactivity, and impulsivity. However, these medications’ long-term safety and efficacy still need to be completely understood. Due to a lack of information on the effects of Alpha-2 agonists on growth, cardiovascular function, and other long-term adverse events, more studies must investigate the optimal dose and treatment duration for these medications. Conclusions: Despite these concerns, Alpha-2 agonists remain a valuable treatment option for ADHD in children, especially those unable to tolerate stimulant medications or who have coexisting conditions such as tic disorders. Future research should continue to explore the safety and efficacy of Alpha-2 agonists in the long term. In conclusion, Alpha-2 agonists show promise as a treatment for ADHD in children; however, the safety and efficacy of these drugs in the long term are not yet completely understood. Additional studies are required to investigate the optimal dose and treatment duration for these medications in their use as a treatment for this debilitating disease. Attention deficit hyperactivity disorder (ADHD) is one of the most common mental diseases affecting children and adolescents. The main features of ADHD include difficulty with attention and concentration, impulsivity, and hyperactivity. These symptoms can significantly impact a child’s academic and social functioning . ADHD isDespite the potential benefits of Alpha-2 agonists, their use has some limitations. One of the major restrictions is that they may not be as functional as stimulant medications in treating the core symptoms of ADHD, particularly hyperactivity. Another limitation is that they may cause sedation, which can interfere with academic and social functioning. Also, Alpha-2 agonists may have cardiovascular side effects including reduced blood pressure and heart rate, which require monitoring .Recent studies have explained that ADHD is not a homogeneous disorder, and there is considerable variability in treatment response among individuals . GeneticOverall, Alpha-2 agonists have emerged as a promising treatment option for ADHD in children. They have a different action mechanism than traditional medications and may have fewer side effects. However, more research is required to investigate their long-term efficacy and safety, particularly in comparison to stimulant medications. Clinicians should consider each child’s needs and characteristics when making treatment decisions for ADHD, and Alpha-2 agonists may be a useful addition to the treatment arsenal for some children with ADHD.The focus of this paper is to go through the current evidence regarding the use of Alpha-2 agonists for ADHD in children and adolescents. Specifically, we aim to assess the efficacy and safety of these medications, compare them to traditional medications such as stimulants and non-stimulants, and identify predictors of treatment response. Additionally, we aim to provide recommendations for clinicians regarding the use of Alpha-2 agonists in the treatment of ADHD in children.We are revising the topic of Alpha-2 agonists because they have emerged as a promising treatment option for ADHD in children, and there is a requirement for a comprehensive review of the current evidence regarding their use. In addition, with the variability in treatment response among individuals and the potential for adverse effects related to traditional medications, it is important to explore alternative treatment options, such as Alpha-2 agonists to provide personalized and effective care for children with ADHD.Alpha-2 agonists stimulate alpha-2 receptors, most predominantly in the prefrontal cortex. The most used agents for ADHD are clonidine and guanfacine. Clonidine stimulates Alpha-2A, Alpha-2B, and Alpha2C, whereas guanfacine stimulates the Alpha-2A receptors in the prefrontal cortex. These actions on both the pre-and post-synaptic membrane alter arousal and cognitive processes that are implicated in ADHD. The most prominent side effect of both drugs is sedation and orthostatic hypotension. Sudden discontinuation of these drugs could also result in rebound hypertension. However, it has milder side effects than clonidine due to the longer duration of action of guanfacine’s longer duration of action .Alpha-2 agonists are second-line agents to stimulants. They were originally administered simultaneously to extend the duration of action of stimulants. Some data showed that doing this allowed for equal efficacy while using a smaller dose of stimulant. Also, patients with ADHD are prone to sleep disorders that can be worsened with use of stimulants. Due to the sedative side effects of Alpha-2 agonists, especially clonidine, they can be advantageous in patients experiencing insomnia. Now that there are long-action formulations of stimulants, this is no longer indicated unless additional therapy is required for complex ADHD. Examples are when a patient suffers from comorbid conditions such as Tourette syndrome, oppositional defiant disorder, or aggressive/impulsive behavior . These cMonotherapy of Alpha-2agonists for ADHD is currently being researched. It is currently thought that they are effective in treating the hyperactivity and impulsivity of ADHD but not in improving inattention. Also, current formulations do not maintain adequate plasma concentrations without causing significant side effects. There are currently phase 3 trials underway on sustained-release formulations of clonidine, but Alpha-2 agonist monotherapy for ADHD is considered off-label .Recent studies have also investigated the potential use of Alpha-2 agonists as a monotherapy for ADHD in children ,13. HoweGuanabenz, guanfacine, clonidine, tizanidine, medetomidine, and dexmedetomidine are all α-2 agonists that vary in their potency and affinities for the various α-2 receptor subtypes. Clonidine, tizanidine, and dexmedetomidine are metabolized in the liver have received the greatest clinical use . Clonidi2A-adrenoceptor agonist, is an effective treatment for ADHD treatment in children and adolescents. These trials primarily focused on the combined ADHD subgroup, which includes both hyperactive/impulsive and inattentive symptoms [Clinical trials have demonstrated that guanfacine, a preferential αsymptoms . Neverthsymptoms . Adversesymptoms . Unlike symptoms . The stusymptoms .Over 13 weeks, a randomized, placebo-controlled trial was performed to determine the safety and efficacy of guanfacine extended release (GXR) in adolescents with ADHD. Most participants received optimal doses of 3, 4, 5, or 6 mg, with 46.5% receiving optimal dose in excess of the currently permitted maximum of 4 mg. Most treatment-emergent adverse events were mild to moderate in severity, with sedation-related events being the most frequently reported .Clonidine and guanfacine are Alpha-2 agonist drugs, that can be administered through oral, transdermal, intravenous, or epidural routes . ClonidiFor clonidine’s oral dosage form (extended-release tablets), the initial dosing for teenagers and children aged six years and older is 0.1 milligram (mg) once a day, given at bedtime .For guanfacine’s oral dosage form (extended-release tablets), the initial dosing for adults and children aged six years and older is 1 mg once a day, either in the morning or evening, at the same time each day. The doctor may adjust the dose using increasing increments (not exceeding 1 mg/wk). The recommended target dose range, based on clinical response and tolerability, is 0.05–0.12 mg/kg/day PO initially. For children aged 6–12 years, doses >4 mg/day have not been evaluated, while for those aged 13–17 years, doses >7 mg/day have not been evaluated . In a raOptimal dosing and duration of treatment for Alpha-2 agonists, such as clonidine and guanfacine, must be individualized to the patient’s needs and response. While there are general dosing guidelines for these medications, the optimal dose may vary depending on the patient’s age, weight, and comorbidities. For example, renal or hepatic impairment patients may require lower doses of these medications to avoid potential toxicity . AdditioPatients may require different dosages and treatment durations to attain the desired therapeutic effect. In addition, these medications can cause adverse effects, so patients should be closely monitored to make sure that the profits of treatment outweigh the risks.Current clinical practice guidelines for treating ADHD in elementary school-aged children rate stimulants, atomoxetine, extended-release guanfacine, and extended-release clonidine as most effective (in that order), with an effect size of 1 for stimulants and 0.7 for non-stimulants . In metaBecause not all children are candidates for treatment with the first-line choice stimulants, and some may not be fully treated with stimulant monotherapy, alpha 2 agonists represent a potentially useful alternative monotherapy or adjunctive therapy to traditional stimulants. Also, alpha 2 agonists, such as guanfacine and clonidine, may have a more favorable side effect profile . Side efIn randomized control trials examining alpha 2 agonist guanfacine as a monotherapy in children with ADHD, somnolence, headache, and fatigue were observed as adverse effects in a cohort consisting of 6–17-year-old patients . This stGuanfacine may have unique utility in children with ADHD with other comorbidities. In a randomized control trial of children with autism, Guanfacine was superior to a placebo, and showed efficacy in reducing hyperactivity and impulsiveness, with lower discontinuation rates than traditional stimulant methylphenidate . GuanfacClonidine, another centrally acting alpha 2 agonist, has been used off-label for years in treating ADHD . AlthougThe screening and selection process for this paper, “The Role of Alpha-2 agonists for Attention Deficit Hyperactivity Disorder in Children” involved a comprehensive search of electronic databases, including PubMed and Cochrane. The search was restricted to papers published in English between 2000 and 2023. The initial search yielded around 300 articles of which hundred were duplicates. The remaining articles were screened according to their topics and abstracts, and around 50 were deemed potentially relevant.The selected articles included randomized controlled trials, observational studies, meta-analyses, and systematic reviews that investigated the use of Alpha-2 agonists in treating ADHD in children.Overall, the review aimed to provide a comprehensive and up-to-date summary of the role of Alpha-2 agonists in treating ADHD in children according to the best available evidence from the literature.Several studies have shown that children with ADHD exhibit specific deficiencies in cognitive and emotional/behavioral domains compared to typically developing children. In particular, deficits in attention, executive function, and working memory have been consistently reported in the literature  ,49 EmotiThe use of Alpha-2 agonists, such as guanfacine and clonidine, effectively reduces symptoms of inattention, hyperactivity, and impulsivity in children with ADHD . The prIn summary, the use of Alpha-2 agonists in the treatment of ADHD in children may not only reduce symptoms of inattention, hyperactivity, and impulsivity but may also improve cognitive functioning and reduce parental stress levels. However, further research is essential to assess better the mechanisms underlying these effects and to identify optimal dose and treatment durations.Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disease affecting children and adults and it can interfere with daily functioning and quality of life. The causes of ADHD are not fully understood, but genetic, environmental, and neurobiological factors are believed to contribute to its development .Managing ADHD can be challenging, particularly in children who may struggle with academic and social demands in addition to their symptoms. The primary treatments for ADHD are medication and behavioral therapies and Alpha-2 agonists have emerged as a promising option for treating ADHD in children . GuanfacIn summary, Alpha-2 agonists are a promising addition to the treatment options for ADHD in children. While they have potential side effects and interactions, they offer healthcare professionals and parents/caregivers another option for managing ADHD in children. By working closely with healthcare providers and carefully monitoring their children’s treatment, parents and caregivers can help ensure the best outcomes for children with ADHD.


Previous observational studies have reported potential associations among attention-deficit/hyperactivity disorder (ADHD), obesity, and diabetes (including type 1 and type 2 diabetes mellitus [T1DM/T2DM]). However, whether the association between ADHD and diabetes is mediated by obesity is unknown.With two-sample Mendelian randomization, we analysed the causal effect of ADHD on T1DM and T2DM and six obesity-related traits  and the causal effect of these obesity-related traits on T1DM/T2DM. Finally, with multivariable Mendelian randomization, we explored and quantified the possible mediation effects of obesity-related traits on the causal effect of ADHD on T1DM/T2DM.P = 0.433.). In addition, ADHD had a 6.1% increased causal effect on high WC  and an 8.2% increased causal effect on high WHR . In addition, a causal effect of genetically predicted high WC  on a higher risk of T2DM was found. In further analysis, WC mediated approximately 26.75% (95% CI = 24.20%–29.30%) of the causal association between ADHD and T2DM.Our results showed that ADHD increased the risk of T2DM by 14%  but with no evidence of an effect on T1DM (OR = 0.916, 95% CI = 0.735–1.141, WC mediates a substantial proportion of the causal effect of ADHD on the risk of T2DM, which indicated that the risk of T2DM induced by ADHD could be indirectly reduced by controlling WC as a main risk factor. Recently, an increasing number of studies have shown that individuals with ADHD have a higher risk of developing endocrine and metabolic disorders, and diabetes mellitus (DM) is one of the most common of these disorders  is a newly emerged genetic epidemiological method that uses genetic variants as instruments to estimate the effect of an exposure on an outcome of interest. In addition, MR can be extended to estimate direct effects, indirect effects and proportions mediated. Unlike traditional observational mediation analysis approaches, MR estimates are robust to violations of the often untestable assumptions of the noninstrumental variable between an exposure, mediator or outcome, including unmeasured confounding and measurement error . Most of the previous research used body mass index (BMI) as an obesity marker. However, given that a recent study proposed that BMI alone cannot help adequately assess and manage all obesity-related health risks  dataset was available in the database, we chose the largest or the newest one with detailed publication information (including authors and year of publication) for further analysis. The characteristics of the included studies are shown in et al., https://gwas.mrcieu.ac.uk/datasets/ieu-a-1183/.The genetic variants for ADHD were obtained from the Psychiatric Genomics Consortium, which consists of 8,047,420 genetic variants of European ancestry and includes 20,183 cases and 35,191 controls  in each respective cohort study; (2) to avoid offsets caused by linkage disequilibrium (LD), SNPs had to be independent of each other by satisfying the LD of SNPs associated with ADHD, obesity-related traits or T1DM/T2DM with a threshold of r2 < 0.001 and window size = 10,000 kb. The LD levels were calculated based on the 1000 Genomes Project of European samples  the SNPs were significantly associated with ADHD, obesity-related traits and T1DM/T2DM with genome-wide significance  was considered the most effective method  , MR‒Egger and weighted median methods (similar estimation with IVW) with no significant directional pleiotropic effects (P > 0.05) suggested a causal effect of ADHD on obesity-related traits and DM. The odds ratio (OR) and 95% confidence interval (CI) were used to display our results.The pleiotropic effects can be estimated by the intercept of MR‒Egger. The MR‒Egger intercept test showed no significant difference from zero with a https://gwas.mrcieu.ac.uk) and MR-PRESSO (version 1.0) of R version 3.6.0 (2019-04-26). The data and codes for this study can be obtained from the corresponding author on reasonable request.Our MR analysis was performed by the TwoSampleMR package  was used. A P value of 0.008 ≤ P < 0.05 was regarded as a suggestive finding.To account for multiple testing in our primary analyses of the six obesity-related traits, a Bonferroni-corrected threshold of et al., The estimates of the effects of obesity-related traits on T1DM/T2DM were obtained by regression-based MVMR .The characteristics of SNPs are shown in the Supplementary materials. All the IVs associated with ADHD or obesity-related traits are significant with reference to a level of genome-wide significance .Genetically predicted ADHD was causally associated with a higher risk of T2DM  and an 8.2% increased causal effect on high WHR   .P < 0.001; P < 0.001; P = 0.003; There was a causal effect of genetically predicted high BMI . Data from the International Diabetes Federation reveal that 537 million adults are living with DM globally, and the number is projected to increase to 783 million by 2045 . WC is one of the indices reflecting obesity and seems to be a less important indicator than BMI. However, a growing number of studies are beginning to recognize its importance. One study included 11,666 respondents and found a linear association between the number of inattentive and hyperactive/impulsive symptoms in adolescence and WC (Fuemmeler et al., As far as we know, this study is the first two-sample MR study to identify the mediation effects of obesity on the causal effect of ADHD on DM. To minimize bias from horizontal pleiotropy, we applied different MR sensitivity analyses, which produced consistent results with those from the main MR analyses. However, this paper still has some potential weaknesses. First, the data were mainly constrained to European populations, which might potentially limit the generalizability of our results to other populations and ethnicities. In addition, the genetic variants associated with ADHD were from a GWAS where ADHD was considered a binary trait, representing the average causal effect in “compliers” in MR analysis (Burgess and Labrecque, By using distinct analytical methods, including genetic approaches that can draw a causal inference, our results confirmed for the first time that ADHD was associated with significantly higher odds of T2DM than T1DM. WC, which is one of the indices reflecting obesity that is often overlooked by policy-makers and researchers, mediates a large proportion of the association. Our study indicated that T2DM should be carefully considered in patients with ADHD, and controlling WC could help to reduce the risk of T2DM induced by ADHD.


Adult ADHD diagnosis sometimes represents a challenge for the clinician, due to the comorbid psychiatric diseases that are often associated and which complicate de recognition of the primary symptoms of ADHD. The prevalence of ADHD in adult populations is 2’5% and it is a relevant cause of functional impairment.Presentation of a clinical case of a male cocaine user diagnosed with adult ADHD.Literature review on adult ADHD and comorbid substance abuse.A 43-year-old male who consulted in the Emergency Department due to auditory hallucinosis in the context of an increase in his daily cocaine use. There were not delusional symptoms associated and judgment of reality was preserved. Treatment with olanzapine was started and the patient was referred for consultation. In psychiatry consultations, he did not refer sensory-perceptual alterations anymore, nor appeared any signals to suspect so, and he was willing to abandon cocaine use after a few appointments. He expressed some work concerns, highlighting that in recent months, in the context of a greater workload, he had been given several traffic tickets for “distractions.” His wife explained that he had always been a inattentive person (he forgets important dates or appointments) and impulsive, sometimes interrupting conversations. In the Barkley Adult ADHD Rating Scale he scored 32 points.He was diagnosed with adult ADHD and treatment with extended-release methylphenidate was started with good tolerance and evolution, with improvement in adaptation to his job and social environment. Since then, the patient has moderately reduced the consumption of drugs, although he continues to use cocaine very sporadically.Early detection of ADHD and its comorbidities has the potential to change the course of the disorder and the morbidity that will occur later in adults. Comorbidity in adult ADHD is rather the norm than the exception, and it renders diagnosis more difficult. The most frequent comorbidities are usually mood disorders, substance use disorders, and personality disorders. Treatment of adult ADHD consists mainly of pharmacotherapy supported by behavioral interventions. When ADHD coexists with another disorder, the one that most compromises functionality will be treated first and they can be treated simultaneously. The individual characteristics of each patient must be taken into account to choose the optimal treatment.None Declared


Background: Attention-deficit–hyperactivity disorder (ADHD) is a neurodevelopmental disorder neurobiologically conceptualized as a network disorder in white and gray matter. A relatively new branch in ADHD research is sensory processing. Here, altered sensory processing i.e., sensory hypersensitivity, is reported, especially in the auditory domain. However, our perception is driven by a complex interplay across different sensory modalities. Our brain is specialized in binding those different sensory modalities to a unified percept—a process called multisensory integration (MI) that is mediated through fronto-temporal and fronto-parietal networks. MI has been recently described to be impaired for complex stimuli in adult patients with ADHD. The current study relates MI in adult ADHD with diffusion-weighted imaging. Connectome-based and graph-theoretic analysis was applied to investigate a possible relationship between the ability to integrate multimodal input and network-based ADHD pathophysiology. Methods: Multishell, high-angular resolution diffusion-weighted imaging was performed on twenty-five patients with ADHD  years) and twenty-four healthy controls  years). Structural connectome was created and graph theory was applied to investigate ADHD pathophysiology. Additionally, MI scores, i.e., the percentage of successful multisensory integration derived from the McGurk paradigm, were groupwise correlated with the structural connectome. Results: Structural connectivity was elevated in patients with ADHD in network hubs mirroring altered default-mode network activity typically reported for patients with ADHD. Compared to controls, MI was associated with higher connectivity in ADHD between Heschl’s gyrus and auditory parabelt regions along with altered fronto-temporal network integrity. Conclusion: Alterations in structural network integrity in adult ADHD can be extended to multisensory behavior. MI and the respective network integration in ADHD might represent the maturational cortical delay that extends to adulthood with respect to sensory processing. Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with core symptoms of inattention, hyperactivity, and/or impulsivity . Over thAs described in our previous work , we recr3, sagittal slice orientation, slice-parallel imaging acceleration factor 3, CAIPI shift 1, Turbofactor 192) [2; voxel size = 2.0 × 2.0 × 2.0 mm3; matrix size = 104 × 104 × 72 acquisition time = 11:26 min. In addition, five non-DW images were collected with reversed phase-encoding blips for the purpose of correcting susceptibility-induced distortions.MR images were acquired on a 3 T MRI scanner  using a 32-channel head coil for signal reception. Magnetization-prepared rapid gradient echo (MP-RAGE) T1-weighted images were acquired with an acquisition time of 2 min 40 s using controlled aliasing in parallel imaging results in higher acceleration (CAIPIRINHA) and elliptical sampling (repetition time (TR) = 2500 ms, echo time (TE) = 3.55 ms, inversion time = 1100 ms, flip angle = 7°, matrix size = 256 × 256 × 176, voxel size = 1.0 × 1.0 × 1.0 mmtor 192) . Multishtor 192) . The prohttps://surfer.nmr.mgh.harvard.edu/); (x) whole-brain anatomically constrained tractography (ACT) [The software package MRtrix3 was used to perform fiber tractography based on the multishell, multitissue constrained spherical deconvolution approach (MSMT-CSD)  via the hy (ACT)  using thhy (ACT)  with thep-values [Statistically, group comparisons were performed at the edge-level using nonparametric permutation testing (n = 5000). Here, threshold-free network-based statistics were applied with familywise error-corrected p-values . In a sep = 0.005) two-tailed t-test between ADHD and controls.Local and global measures of brain networks can be analyzed with respect to graph theory. Here, a brain network is represented as a graph with its respective number of nodes and edges . ImplemeFor a complete sample description, please refer to our previous publication . There was no difference in terms of age and gender.ADHD = 18.01% (SD = 2.5), MeanControls = 45.9% (SD = 3.7), U= 160.5, p = 0.002; The Mann–Whitney U test indicated that patients with ADHD integrated significantly less compared to healthy controls (Meanp = 0.05) in ADHD compared to controls was found in the following networks: right entorhinal cortex and right insula, left entorhinal cortex and right cerebellum, right superiortemporal cortex and left Heschl gyrus, right putamen and right precuneus, and left parsopercularis and right precuneus. Detailed network information can be found in Higher network connectivity  and left anteriorcingulate cortex , right superiortemporal gyrus (STG) and right inferiorparietal gyrus (IPG), left inferiortemporal gyrus (ITG) and left supramarginal gyrus (SMG), and right Heschl gyrus and right inferiorparietal gyrus (IPG). Detailed network information can be found in MCG-scores in healthy controls were significantly associated with network connectivity between the left caudate and left supramarginal gyrus (SMG), right thalamus and left supramarginal gyrus (SMG), left supramarginal gyrus and left superiorfrontal gyrus (SFG), right superiortemporal gyrus (STG) and right anterior cingulate cortex and right precuneus and left superior temporal sulcus (STS), and left Heschl gyrus and left superior frontal gyrus (SFG). Detailed network information can be found in Global efficiency and shortest path length yielded no significant results. Patients with ADHD showed higher nodal local efficiency for left isthmuscingulate, left/right lateral occipital cortex, left pericalcarine fissure, and right inferiorparietal gyrus. Degree centrality was elevated in ADHD for the left postcentral gyrus compared to controls. Further, patients showed a higher clustering coefficient in the right lateraloccipital cortex see .To the best of our knowledge, this is the first study investigating the relationship between multisensory integration and structural connectivity in an adult ADHD sample compared to a healthy control group. Connectivity measures were calculated based on diffusion MRI-based structural connectome analyses and graph–theoretical approaches and correlated to fused MI performance. In ADHD, MI was significantly associated with network connectivity between Heschl gyrus and IPG along with connectivity within ACC and between IPG and SMG. MI in controls was significantly associated with network connectivity between thalamus and SMG, Heschl gyrus, and the precuneus, STG, and ACC. Overall, compared to controls, patients with ADHD elicited higher network integrity within temporal and occipital networks, while controls showed higher global connectivity in fronto-temporal, fronto-limbic, and fronto-insular networks. In children with ADHD, sensory-processing deficits have been reported across the senses, i.e., visual, auditory, touch, and smell ,42,43. TFurthermore, ADHD pathophysiology has been strongly associated to dysfunctional resting-state connectivity and regional brain abnormalities . In partWe demonstrated that the ability to integrate top–down multisensory information in patients with ADHD is associated with bottom–up networks. Missing top–down network involvement for complex stimuli integration might represent the maturational cortical delay in ADHD that extends to adulthood with respect to sensory processing.


Emerging research suggests that attention-deficit/hyperactivity disorder (ADHD) increases the risk for cardiovascular (CVDs) and metabolic disorders  in adulthood. Yet, available studies are scarce and have mainly been focused on individuals receiving clinical ADHD diagnoses. We aimed to investigate the prospective associations of ADHD symptoms in young and mid-adulthood with subsequent cardiometabolic disorders and the underlying mechanisms.We studied 10,394 twins from the Swedish Twin Registry (STR), born between 1958 and 1985 without previous medical history of cardiometabolic disorders. They provided self-assessment of ADHD symptoms (score range 0–36) via a validated, DSM-IV-based scale in a web-based questionnaire/telephone interview within the Study of Twin Adults: Genes and Environment (STAGE), in 2005–2006 (aged 19–47 years), and were followed until the end of 2018 (33–59 years) to identify incident clinical diagnoses/medication prescriptions for cardiometabolic disorders acquired from Swedish national registers. We used Cox regression models to investigate the associations between ADHD symptoms score and cardiometabolic outcomes, with and without adjustment for relevant covariates, and a co-twin control design to study familial confounding.A one-unit increase in the level of ADHD symptoms was associated with a 2% increase in the rate of CVDs  and a 3% increase in the rate of metabolic disorders , after adjusting for birth year and sex. The associations were no longer significant after adjusting for educational attainment, lifestyle factors, and comorbid psychiatric disorders. The associations remained significant after adjusting for familial factors shared by dizygotic twin pairs but became nonsignificant after adjusting for factors shared by monozygotic twin pairs. However, the strength of the associations attenuated significantly in monozygotic twins compared to dizygotic twins for CVDs only, suggesting genetic confounding.ADHD symptom score is associated with a higher risk for cardiometabolic disorders, which may be explained by lower educational attainment, adverse lifestyle factors, and psychiatric comorbidities. Moreover, the associations appear to be partly confounded by shared genetic factors, especially for CVDs. Further research is needed to investigate the identified associations at the level of individual cardiometabolic disorders and to follow-up participants until a more advanced older age.The online version contains supplementary material available at 10.1186/s12916-023-03174-1. Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental condition that typically emerges in childhood and is characterized by inattentive and/or hyperactive symptoms that often persist well into adulthood , 2. WhilEmerging research has reported significant associations of ADHD with increased risk for a range of CVDs and metabolic disorders , both in children  and adulThere is also a scarcity of research investigating the underlying mechanisms of the potential associations between ADHD and cardiometabolic disorders. Two potential mechanisms have been proposed. First, ADHD is associated with several adverse life-course outcomes, such as lower socioeconomic status, lifestyle factors, and comorbid psychiatric disorders, which are also risk factors for cardiometabolic disorders , 20. IndIn this study, we employed a longitudinal population-based study to investigate the associations of ADHD symptoms severity in young- and mid-adulthood with subsequent cardiometabolic disorders in later life. We further investigated whether any identified associations were explained by educational attainment, lifestyle factors, and comorbid psychiatric disorders or confounded by familial factors , using a genetically informed co-twin control approach.A total of 42,582 twins born in Sweden between 1959 and 1985 who survived their first birthday were identified from the population-based Swedish Twin Registry . Out of N = 7366) were men [α of 0.79 for inattention and 0.77 for hyperactivity/impulsivity. In case there were more than two missing items for either of the two subscales, a participant would be deleted from the analysis, and when there were two or fewer missing values, missing items were replaced with a mean score for this subscale  or dispensed medication prescriptions from the Prescribed Drug Register (PDR) and coded according to the Anatomical Therapeutic Classification (ATC) system  based on self-reported weight and height and classified in accordance with the WHO criteria into four categories: underweight (< 18.5 kg/m2), normal weight (18.5–24.9 kg/m2), overweight (25.0–29.9 kg/m2), and obese (≥30 kg/m2) [The following variables, previously reported to be associated with ADHD  and card0 kg/m2) . Partici0 kg/m2) .Criteria based on the Diagnostic and Statistical Manual of Mental Disorders, fourth revision (DSM-IV), were used for self-reported symptoms of major depression, generalized anxiety disorder, and alcohol dependence . DetaileWe used Cox proportional hazards models to assess the associations between ADHD symptoms and subsequent CVDs and metabolic disorders during the follow-up, with attained age as the underlying time scale. Associations were presented as hazard ratios (HRs) with 95% confidence intervals (CIs). The follow-up period started at the time of the interview/questionnaire completion and ended at either a diagnosis/dispensed medication prescription of the outcome of interest, death, or December 31, 2018. A cluster robust sandwich estimator was used to remove distributional assumptions and correct CIs for dependence on family data. The analysis was adjusted for sex and birth year in the first step, and then additionally adjusted for educational attainment, lifestyle factors, and comorbid psychiatric disorders in the second step.χ2 test statistic [The co-twin control design was used to investigate whether ADHD is directly associated with CVDs and metabolic disorders after accounting for familial  factors. To control for unmeasured familial confounding, we applied a stratified Cox regression model with each twin pair being entered as a separate stratum. By using this model, we analyzed the correlation between the difference in ADHD symptoms within a twin pair and the difference in subsequent cardiometabolic outcomes within the same pair . We modetatistic . Due to We conducted five sensitivity analyses. First, we investigated the patterns of associations with cardiometabolic outcomes when we consider the scores on the two ADHD subscales, separately: the inattention and hyperactivity/impulsivity subscale. Second, we explored whether the associations remain the same depending on the definition of ADHD, using clinical and research-based diagnoses. Clinical diagnoses of ADHD were based on ICD codes obtained from the NPR , established at any time point, since we assumed that individuals with ADHD diagnoses had childhood-onset of symptoms, in line with the DSM-IV diagnostic criteria. Research diagnoses of ADHD were obtained using the norm-based criteria : the priData management and analysis was done using SAS V.9.4 (SAS Institute) and R version 4.1.0.p < 0.010) and significantly correlated with age , sex, cardiometabolic outcomes, and all considered covariates . The mean age at the time of STAGE interviews was 33.30 years , and at the end of the follow-up, it was 46.28 years . There were 4766 monozygotic and 5618 dizygotic twins with 2962 individuals from same-sex twin pairs. During the follow-up period, 1313 (12.6%) individuals had an incident diagnosis or dispensed medication prescription for any CVD and 728 (7%) for any metabolic disorder  and a 3% increase in the rate of metabolic disorders , after adjusting for birth year and sex .An increase of one unit in the level of ADHD symptoms (score range 0–36) was associated with a 2% increase in the rate of CVDs  and metabolic disorders  remained statistically significant (Table p = 0.968) and metabolic disorders  were no longer statistically significant. The difference in estimates between monozygotic and dizygotic twins was statistically significant for CVDs (p = 0.045), but not for metabolic disorders (p = 0.839) ; this association was similar in magnitude to the association observed for dizygotic twins .When examining the ADHD subscales separately, we found significant associations of both inattention and hyperactivity/impulsivity subscale with CVDs and metabolic disorders, which attenuated and were no longer significant after adjustments for covariates . The associations remained significant after adjustments for familial factors shared between dizygotic twins across both inattention and hyperactivity/impulsivity subscales, except for the association of the inattention subscale and metabolic disorders, with HR = 1.05, 95% CI = 1.00–1.11, We also considered different definitions of ADHD, using a clinical and research diagnosis of ADHD. There were 79 (0.76%) individuals with a clinical diagnosis of ADHD and 311 (2.99%) with a research diagnosis of any ADHD subtype , and comorbid psychiatric disorders . This indicates that the risk of cardiometabolic disorders associated with ADHD symptoms is at least partly explained by adverse socioeconomic factors, lifestyle, and psychiatric health outcomes , 13, 14.Furthermore, we cannot rule out the additional effects of other potentially relevant early-life factors  or lifestyle factors such as sleep disorders and nutrition , 19, 20.Additionally, the associations between ADHD symptoms and CVDs seemed to be confounded by familial factors. Our findings also suggested that these familial factors might be, at least to some extent, driven by shared genetic factors that influence both ADHD symptoms and CVDs, as evidenced by the significantly stronger attenuation of the association when controlling for familial factors shared by monozygotic twins compared to dizygotic twins. This is largely in line with a previous register-based sibling study that reported that shared familial factors partly explained the association between ADHD and CVDs . Yet, thFor metabolic disorders, on the other hand, our results suggested potential familial confounding of the associations with ADHD, but not strong evidence for genetic confounding, in contrast to previous research , 23. OneWhen examining the two ADHD subscales separately, we found that hyperactivity/impulsivity symptoms were significantly associated with metabolic disorders within monozygotic twin pairs, which indicates direct effects via non-shared environmental influences. These findings suggest that symptoms of hyperactivity/impulsivity may lead to cumulative, health-adverse effects throughout adulthood resulting in metabolic disorders. Indeed, it has been argued that hyperactive and impulsive symptoms may lead to abnormal eating behaviors and binge eating, which in turn may lead to obesity and other metabolic disorders . Also, iOverall, we showed that the associations of ADHD with cardiometabolic disorders were mostly independent of the ADHD subscale used , definition of ADHD, and sex, and they remained consistent when we limited the analysis to same-sex dizygotic twin pairs.The results of the current study need to be considered in light of several potential study limitations. Namely, the utilized ADHD scale covered only currently present symptoms, without addressing whether ADHD symptoms were present since childhood and whether they were accompanied by functional impairments, which are also required as diagnostic criteria by the DSM-IV. This is important, as in adults, ADHD symptoms may resemble the symptoms of other psychiatric disorders, such as anxiety or depression , or neurFurthermore, it may be difficult to discern the effects of ADHD symptoms and ADHD medications in relation to the risk of CVDs. ADHD stimulant medications have been shown to affect blood pressure and heart rate and they are prescribed with clinical precautions regarding the cardiovascular risks . HoweverFurthermore, all variables assessed using the STAGE interview/questionnaire were based on self-assessment. There are clear advantages to this approach. It allows assessment of large study populations at lower costs than assessment by trained professionals and provides wider coverage of affected individuals compared to using data from electronic health registers, which only capture individuals who receive a formal diagnosis and in Sweden only cover specialist healthcare visits . Furthermore, there is very poor coverage of lifestyle factors in electronic health registers, such as obesity, smoking, and physical activity. Finally, using continuous scales of ADHD symptoms rather than clinical diagnoses allows for more detailed data and in turn provides greater statistical power, which is needed in within-twin analyses. On the other hand, measurements of health-related variables based on self-assessment may arguably be unreliable . For insFurthermore, about 5% of the study population had self-reported BMI categorized as obese at the time of STAGE, although only 1.9% received a clinical diagnosis of obesity during the follow-up. Thus, individuals diagnosed with obesity were likely already obese at the start of the follow-up and probably only those with associated health problems sought health care and received a diagnosis of obesity. Consequently, the outcome of obesity in the current study probably covers individuals with the most severe clinical presentations of the condition.In the current paper, the included covariates may likely have mediated the association between ADHD symptoms and cardiometabolic disorders. However, the covariates were assessed at the same time as the exposure , and we only adjusted our analyses for these covariates to observe whether the associations changed after their inclusion in the model. To more thoroughly investigate whether they have the role of mediators and to provide estimates of the presumed mediators’ effects on the associations, future studies need to consider assessing these variables after the assessment of ADHD symptoms, as well as conducting a formal mediation analysis, such as the causal mediation analysis .Additionally, the oldest individuals in our cohort were only 59 years old at the end of follow-up . The incidence of cardiometabolic disorders peaks after the age of 60–65 , 51, andFinally, due to the discrepancies in the analytical sample sizes for the analysis at the whole study population level, after adjustments for covariates, and within dizygotic/monozygotic twins and considering the overall small effect sizes of the associations with overlapping confidence intervals across analyses, we cannot rule out that the attenuation of the associations after the adjustments for covariates and for familial factors shared between monozygotic twins may be partially due to the loss of statistical power. Nevertheless, when it comes to the associations between ADHD symptoms and CVDs, we found a more pronounced and statistically significant attenuation in the strength of the association within monozygotic twins compared to the analysis within dizygotic twins. This was not the case for the associations with metabolic disorders, although the decrease in the number of individuals with disease outcomes was equivalent for the analyses with both CVDs and metabolic disorders. Thus, our results may indicate genetic confounding of the association between ADHD symptoms and CVDs.Using a longitudinal population-based study design, we found that ADHD symptom score is associated with a subsequent increased risk of both CVDs and metabolic disorders. Our findings also suggest that this risk may be explained by adverse life-course factors associated with ADHD—inadequate educational attainment, unhealthy lifestyle factors, and comorbid psychiatric disorders. Thus, it may be beneficial for future prevention programs to target these potentially modifiable risk factors in adults with ADHD. Additionally, our findings indicated that the association between ADHD symptoms and the risk of CVDs might be confounded by genetic factors to some extent. Yet, we did not find as strong evidence for shared genetic factors explaining the association with metabolic disorders. Future studies are needed to investigate the identified associations at the level of individual cardiometabolic disorder categories, with longer follow-up of potential mediators and cardiometabolic outcomes to a more advanced older age.Additional file 1: Table S1. Diagnostic codes for the cardiovascular and metabolic disorders included in the study, according to the International Classification of Diseases 10th revisions (ICD-10) and medication prescriptions coded according to the Anatomical Therapeutic Classification (ATC). Table S2. Incidence of clinical diagnoses/dispensed medication prescriptions for cardiovascular and metabolic disorders as distinct categories, and associations with ADHD score, expressed as hazard ratios (HR) with 95% confidence intervals (CI), adjusted for birth year and sex. Table S3. Associations of scores on the inattention (IA) and hyperactivity/impulsivity (HI) subscales, with cardiovascular (CVD) and metabolic disorders, presented as hazard ratios (HR) with 95% confidence intervals (CI). Table S4. Frequencies for clinically diagnosed individuals and individuals with research diagnosis of ADHD. Table S5. Associations of ADHD score with cardiovascular disorders (CVDs) and metabolic disorders, as hazard ratios with 95% confidence intervals for men. Table S6. Associations of ADHD score with cardiovascular disorders (CVDs) and metabolic disorders, as hazard ratios with 95% confidence intervals for women. Table S7. Associations of ADHD score with cardiovascular disorders (CVDs) and metabolic disorders, as hazard ratios with 95% confidence intervals (CI) for monozygotic (MZ) twin pairs, and dizygotic (DZ) twin pairs with the same-sex female/male twin pairs. Supplementary methods. Description of DSM-IV criteria for psychiatric comorbidities. Fig. S1-S6. Natural cubic spline function to model non-linear associations between ADHD symptoms and cardiometabolic disorders. Table S8. Associations between quartiles, the 90th and 99th percentile of ADHD scores and the risk of cardiometabolic outcomes.


Adolescents and adults with attention-deficit/hyperactivity disorder (ADHD) are at increased risk of suicidal spectrum behaviors (SSBs). However, there is limited knowledge about risk factors triggering SSBs in this group of people.To explore published literature concerning factors that may increase the risk of SSBs in adults and adolescents with ADHD.nd of February 2022 using the Ovid MEDLINE and Web of Science databases. Three categories of search terms were used: (1) self-harm, self-injury, self-mutilation, suicide, self-poisoning; (2) adults, adolescents; and (3) attention-deficit hyperactivity disorder/ADHD. Studies with data concerning mediating factors of SSBs in relation to a clinical diagnosis of ADHD in participants above 16 years of age were included.A systematic literature search following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted on 22The literature search identified 604 articles, of which 40 were included in the final study selection. Factors found to increase the likelihood of SSBs included ADHD symptom severity and persistence, female gender, family history of ADHD, childhood and parental influences, and social functioning. Even when adjusting for psychiatric comorbidities, most studies showed that adults and adolescents with ADHD have an elevated risk of SSBs.This systematic review has documented that several demographic and clinical features are associated with an increased risk of SSBs in adolescents and adults with ADHD. Notably, ADHD emerges as an independent risk factor for SSBs. This information ought to have clinical implications in terms of screening and suicide prevention strategies. Further longitudinal studies are needed to investigate the outcome of preventive strategies in individuals along the full spectrum of ADHD symptom severity.The online version contains supplementary material available at 10.1186/s12888-023-05099-8. Suicide is a major cause of death, and suicidal spectrum behaviors (SSBs) are mental health problems causing harm at all societal levels . SeveralADHD is a common neurodevelopmental disorder, with an estimated global prevalence of 5.6% in school children and 2.6% in adults , 8. InatSSBs range from self-harm behaviors, suicidal thoughts and suicidal ideation (SI) to suicide attempts (SA) and completed suicides . Self-haThe risk of SSBs and increased morbidity have mainly been related to the high frequency of comorbid mood and anxiety disorders, substance use disorders and personality disorders among adults with ADHD , 14. ThePrevious reviews have mainly focused on the prevalence of SBBs , 13, 18,To that end, a systematic literature review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted, focusing on factors contributing to increased risk of SSBs in adolescents and adults with ADHD. Ultimately, this information can be used to identify, prevent, and treat SSBs in individuals with ADHD.The primary literature search was conducted on the 22nd of February 2022, with the purpose of finding articles that examined the association between ADHD and SSBs in adults and adolescents. OVID Medline was chosen as the primary database and was accessed through the Norwegian Electronic Health Database.The following search criteria was entered: ("self harm" OR self-harm OR self-injur* OR "self injur*" OR suicid* OR self-mutilat* OR "self mutilat*" OR "self poison*" OR self-poison*) AND (adult* OR adolescen*) AND (ADHD OR "attention-deficit/hyperactivity" OR "attention-deficit hyperactivity" OR hyperkinetic).OVID Medline returned a total of 604 articles Fig. . In the An additional literature search was done the 13th of March 2022 on Web of Science, to examine any other relevant papers not included in the primary search. The same search criteria were used as in the previous literature search. This returned a total of 418 papers, and the references were screened by both authors. OVID Medline was repeatedly searched until the screening process was complete on the 27th of July 2022, to ensure that recently published papers could be included in the review.In addition, all references from selected articles related to comorbid psychiatric disorders were searched to examine additional relevant results not included in the initial search. The same procedure was also done for all recent systematic reviews on the subject of ADHD and SSBs –6, 13.The screening process is described in Fig. Papers written in EnglishStudy population with a mean age above 16, either at baseline or at assessment for SSBsInclusion of an ADHD sample with a diagnosis according to DSM  or ICD  criteriaData on factors associated with ADHD that mediate the risk of SSBsReviews, meta-analyses, comments, letters, editorials, case-reports, and protocolsNot in the field of psychology or psychiatryStudies investigating treatment- and diagnostic methodsStudies investigating efficiency of pharmacological treatmentA clinical diagnosis of ADHD was required to ensure validity. Articles only reporting ADHD symptoms or diagnoses solely based on self-report questionnaires, such as the Adult ADHD Self-Report Scale (ASRS) or Wender Utah Rating Scale (WURS), were thus excluded. We included studies with a clinical ADHD diagnosis collected from registers or medical prescriptions indicating ADHD. Studies comparing comorbid psychiatric disorders with and without ADHD were included , while studies without a clear differentiation between diagnoses were excluded.The literature search returned a total of 604 papers, including three duplicates Fig. . One papThe majority of the studies 23/40) were published between 2017 and 2022 . The stu/40 were In total, the papers investigated 15 million individuals, of which there were 626 663 individuals diagnosed with ADHD. This number was reached after excluding papers that most likely used the same study populations. Thirty-seven articles included information about number of participants, of which 52% were males. Thirty-four articles also reported the number of included participants with ADHD, with an estimated percentage of males at 62%.Different instruments were used for assessing and establishing an ADHD diagnosis, including clinical interviews, national registers, or databases. All methods followed the ICD- or DSM-diagnostic criteria. See Table Since SSBs are a broad concept, several studies have investigated more than one aspect of SSBs. This accounts for 14 of the studies included in the review –46, 49.A wide range of definitions of self-injurious or suicidal behaviors are used in the final selection of studies. The majority, which accounts for 35 of 40 articles, focused on suicide as one of their outcomes. SA or acts are the most common behavior investigated. We identified 12 studies that investigated SI or thoughts as one of their outcomes , 43, 45,Of the included studies, thirteen investigated the prevalence and impact of an ADHD diagnosis on SSBs among adolescents and adults , 48, 50.p < 0.001) ) to 8.48 (95%CI [1.00–74.07]) , 39. Par< 0.001) .. ) .In the same study, female gender was significantly associated with a higher likelihood of SA  . A studyp < 0.001) than males without ADHD. Males with ADHD had 3.38-fold higher rate than those without ADHD  ) .. found no significant differences between those with and without comorbid psychiatric disorders regarding the risk of SI ), compared to a parent without a registered psychiatric disorder with IRRs of 4.85 (95% CI [4.40–5.35]). The same was found for parental history of suicidal behavior, with IRRs of 3.87 (95% CI [3.9–4.68]) and 2.99 (95% CI [2.75–3.25]), respectively .. [In the BGALS sample, adverse childhood experiences (ACE) correlated significantly with lifetime SA in females with ADHD . Further. .. investigated social preference, peer victimization, and perceived self-competence in relation to SSBs in the BGALS sample [(p = 0.007) [p = 0.057) [Meza et alS sample , 45. SocS sample , 45. Per= 0.007) . Self-re= 0.007) , 45. For= 0.057) . In thei. evaluated ADHD subtypes in connection to thwarted belongingness, perceived burdensomeness, and acquired capability for suicide. Neither adults with predominantly hyperactive/impulsive presentation (ADHD-HI), nor ADHD-I were positively associated with suicide, but rather significantly negatively correlated with thwarted belongingness (p < 0.005) and perceived burdensomeness (p < 0.05) [Exploring the Interpersonal Theory of Suicide, Silva et al < 0.05) . ADHD wa < 0.05) .. investigated the impact of financial distress on the association between ADHD and suicide in a Swedish population-based study. Individuals with ADHD who were in the highest default risk bins had a three-fold higher suicide rate than those with ADHD in the lowest default bins [. found that those who were post-secondary graduates had 64% lower likelihood of having ever attempted suicide in comparison to those who had not finished high school [Beauchaine et alult bins . When exh school .Overall, the present review supports the strong association between risk of SSBs and having a diagnosis of ADHD reported in previous reviews and meta-analyses , 13, 18.The importance of ADHD-C as a risk factor of SSBs was confirmed by most studies investigating subtypes of ADHD , 47, 49.., state that “our previous reports revealed extremely few differences by subtype” [. proposed dimensional modifiers reflecting the number of hyperactivity-impulsivity and inattention symptoms at the time of assessment [However, there is an ongoing discussion regarding distinctions between ADHD subtypes. For instance, Owens et alsubtype” . The dissubtype” , 60. Wilsessment , supportConsidering the unstable nature of ADHD symptomatology and the heterogenous nature of the disorder , 37, botThe expression of ADHD, as well as its development over time, should therefore be considered when determining the risk for SSBs, and this information should be included in prevention strategies from patients’ early age. It should be noted that studies have shown persistent ADHD is associated with severe emotionally impulsive symptoms leading to increased impairments in daily life, and that emotional problems in ADHD tend to increase in adulthood , 61.This review finds various aspects of impulsivity, executive functioning and internalizing and externalizing pathology to play a significant role in the risk for SSBs , 46, 49.. hypothesized that impulsivity is the driving force of SSBs [A pioneering review on the subject by James et al of SSBs . The imp of SSBs , and tha of SSBs , 63.In the present review, there are some conflicting results. Although one study suggested significant correlations between hyperactivity/impulsivity symptom severity scores measured in childhood and both NSSI and SA in adolescence and adulthood , impulsiIn a recent review, key findings point to predominant inattention symptoms and internalizing problems in females, while males are more likely to display hyperactive-impulsive symptoms together with externalizing psychopathology . AlthougOverall, our findings support that dimensions of emotional dysregulation are an important risk factor of SSBs, and that externalizing and internalizing psychopathology can arise as different symptom expressions of ADHD. Emotional dysregulation can increase symptom severity of ADHD, and lead to increased presence of comorbid disorders and problems with activities in daily life . Our finThis review included a total of 25 articles investigating the role of psychiatric comorbidities. Articles included in the review showed an elevated risk of SSBs in those with comorbid psychiatric disorders , 40. Wheconfounding but not responsible” of the ADHD-SSBs relationship [As far as we know, the present review is the first systematic review that thoroughly assesses the role of psychiatric comorbidity in adults and adolescents with ADHD in relation to SSB. With the use of various methods in the included studies, our findings can be considered robust and in line with Septier and Stordeur who hypothesized that psychiatric comorbidities are “tionship . RegardlThe results further indicated that having comorbid externalizing disorders, such as SUDs, as well as internalizing disorders, such as depression and anxiety, are conditions that increase the risk of SSBs in individuals with ADHD. In addition, difficulties in emotional regulation can be viewed as cardinal symptoms in many psychiatric disorders. Various expressions of symptoms and comorbid disorders thus strengthen the hypothesis of emotional dysregulation being a significant potential mediating factor contributing to a higher risk of SSBs in adolescents and adults with ADHD. An important aspect of these disorders is that symptom expression differs between males and females, something that should be taken into consideration in risk estimates of SSBs.This review includes six studies investigating gender differences related to SSBs in individuals with ADHD. All studies showed that females have a higher likelihood of SSB than males , 36, 50.Poor social functioning is presented as an important mediating factor between ADHD and SSBs in studies including only females , 45. KakThe field of study for both ADHD and SSBs are associated with what can be called a “gender paradox”. It is important to consider that 48% of the total study population of this review are females. The fairly equal gender distribution is a strength of the current review, considering that more males than females are diagnosed with ADHD, at least in childhood . Self-haTwo population studies reported increased risk of suicidal behavior among close family members of individuals with ADHD , and thaStudies included in this review indicate that adverse childhood experiences, including negative parenting, should be considered as significant mediators of the association between ADHD and SSBs , 34. ResTo understand associations between ADHD and SSBs, one should take the bidirectional link between genetic and environmental factors into account. This is in line with the stress-diathesis model, that points to an interaction between environmental stressors and heritable trait susceptibility of SSBs, independent of psychiatric disorders . Both paSeveral limitations need to be considered before making robust conclusions. First, some of the presented risk factors are supported by only a few studies. Some studies are also limited by small sample sizes, and imbalances regarding gender and geographical origins. Together, these limitations restrict the representativeness of the included findings.Meta-analyses of the findings would have provided more precise risk estimates. However, we found it challenging to conduct reliable meta-analyses due to the variety of methods used to measure and analyze outcomes, as well as the different terminology regarding SSBs. As more data are generated on the association between ADHD and SSBs, future meta-analyses are called for, especially regarding the relative importance of different psychiatric comorbidities.Considering that ADHD symptom expression seem to be related to a wide range of familial and environmental factors, further studies on risk factors associated with SSBs and ADHD should consider inclusion of symptoms at a dimensional rather than diagnostic level. The factors found in this review are also likely to interact with each other, making it challenging to establish independent effects. Due to symptom overlap, it may also be challenging to differentiate ADHD from disorders such as BD and PDs. Since all papers specifically assessing drug efficiency or treatment were excluded, medication use could be a potential confounding or mediating factor that has not been accounted for in this review.This is the first systematic PRISMA review investigating a broad range of risk factors triggering SSBs in adolescents and adults with a clinical diagnosis of ADHD. By this, the review expands on findings reported in previous reviews.Factors found to increase the risk of SSBs include ADHD symptom severity and persistence, gender, family history of ADHD, childhood and parental influences, and social functioning. When adjusting for psychiatric comorbidities, adolescents and adults with ADHD still had an increased risk of SSBs.Overall, ADHD emerges as an independent risk factor for SSBs. Awareness of psychiatric comorbidities, symptom expression, and other risk factors associated to SSBs should have clinical implications in terms of screening and suicide prevention strategies in adolescents and adults with ADHD. Future longitudinal studies investigating the relative strengths of the risk factors reported in the present study and the impact of preventive strategies on the life of individuals along the full spectrum of ADHD symptom severity are called for.The review protocol was not registered prior to conducting the literature search.Additional file 1.


Pregnancy is an important life event, involving body and mind transformation as well as brain reorganization. ADHD dimension is an additional aggravating factor, albeit poorly studied in the literature, in patients with mental health disorders in the peripartum.The purpose of this study was to evaluate the correlation among ADHD dimension, trauma in childhood, and anxiety-depressive symptomatology to assess whether the ADHD dimension may affect the quality of life of peripartum patients, and to identify vulnerability factors and self-harmrisk.The sample included 74 women aged 21-46 years, recruited from Sant’Andrea Hospital in Rome between 2015 and 2019. All recruited women were administered the following scales: Adult ADHD Self Report Scale (ASRS), Edinburgh Postnatal Depression Scale (EPDS); Childhood Trauma Questionnaire (CTQ), Perceived Stress Scale (PSS); Minnesota Multiphasic Personality Inventory (MMPI). Statistical analysis was performed by Pearson’s correlation with SPSS software to verify the presence of linear relationships (p<0.05) among theADHD dimension, assessed by the ASRS scale, and the other psychopathological dimensions.The sample was divided into two groups depending on the results of ASRS: 26 patients were positive for at least one of the ASRS scale items, while 48 patients were negative. The groups did not statistically differ in socio-demographic variables examined. The medium score at EPDS was 15,11 . It was found that the severity of ADHD dimension directly correlated with the duration of mental symptoms in peripartum , with the total CTQ scale score , with emotional abuse detected by CTQ , with emotional neglect detected by CTQ  and with perceived stress detected by PSS scale . Furthermore, we identified a correlation between self-injurious ideation and ADHD symptomatology  evaluating the item 10 of EPDS.The severity of ADHD traits directly correlates with the symptomatology and duration of mental disorder in peripartum. Specifically, ADHD patients who develop anxious-depressive symptoms are more likely to have experienced emotional abuse and emotional neglect in childhood.None Declared