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Article: Genome Guided Personalized Drug Therapy in Attention Deficit Hyperactivity Disorder.

Haavik, Jan

2022 Volume 13, Page(s) 925442

Abstract: ADHD is a common behavioral syndrome with a heritability of 70-80%. Genome wide sequencing and association studies indicate that ADHD risk variants are distributed across a wide range of allele frequencies and relative risks. Several common single ... ...

Abstract	ADHD is a common behavioral syndrome with a heritability of 70-80%. Genome wide sequencing and association studies indicate that ADHD risk variants are distributed across a wide range of allele frequencies and relative risks. Several common single nucleotide variants (SNPs) have been identified that increase the risk of ADHD with a few percent. Many of the reported risk genes and copy number variants are shared with other neuropsychiatric disorders. Moreover, ADHD often coexists with common or rare somatic diseases, including rare Mendelian neurometabolic diseases that can affect normal brain development and function. Some genetic/metabolic syndromes masquerading as common ADHD may lead to irreversible brain damage if not properly identified and treated during early childhood. As ADHD is such a heterogeneous condition in terms of severity, clinical features and most probably also underlying biology, it is crucial to offer individualized treatments. Recent progress in ADHD genetics is reviewed, prospects of using this information for targeted pharmacotherapy are discussed and critical knowledge gaps are identified. It is suggested that genome guided therapies could be introduced gradually, starting with rare ADHD syndromes with highly penetrant risk genes. Routine diagnostic application of whole exome or whole genome sequencing combined with metabolomic screening, and brain imaging may be needed in cases with suspected neurometabolic disorders. Identification and treatment of ADHD patients with defined neurometabolic aberrations could be a first step toward genome guided personalized treatment of ADHD. Possibly, screening for relevant biomarkers may gradually be implemented to guide treatment choices in larger patient groups.
Language	English
Publishing date	2022-06-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564218-2
ISSN	1664-0640
ISSN	1664-0640
DOI	10.3389/fpsyt.2022.925442
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Article ; Online: Risk factors of suicidal spectrum behaviors in adults and adolescents with attention-deficit / hyperactivity disorder - a systematic review.

Austgulen, Amalie / Skram, Nanna Karen Gilberg / Haavik, Jan / Lundervold, Astri J

BMC psychiatry

2023 Volume 23, Issue 1, Page(s) 612

Abstract: Introduction: 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.: ... ...

Abstract	Introduction: 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. Objective: To explore published literature concerning factors that may increase the risk of SSBs in adults and adolescents with ADHD. Methods: A systematic literature search following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted on 22 Results: The 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. Conclusion: 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.
MeSH term(s)	Humans ; Adolescent ; Adult ; Female ; Child ; Suicidal Ideation ; Attention Deficit Disorder with Hyperactivity/epidemiology ; Suicide ; Self-Injurious Behavior ; Risk Factors
Language	English
Publishing date	2023-08-21
Publishing country	England
Document type	Systematic Review ; Journal Article
ZDB-ID	2050438-X
ISSN	1471-244X ; 1471-244X
ISSN (online)	1471-244X
ISSN	1471-244X
DOI	10.1186/s12888-023-05099-8
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Article ; Online: Use of big data and machine learning algorithms to extract possible treatment targets in neurodevelopmental disorders.

Malik, Muhammad Ammar / Faraone, Stephen V / Michoel, Tom / Haavik, Jan

Pharmacology & therapeutics

2023 Volume 250, Page(s) 108530

Abstract: Neurodevelopmental disorders (NDDs) impact multiple aspects of an individual's functioning, including social interactions, communication, and behaviors. The underlying biological mechanisms of NDDs are not yet fully understood, and pharmacological ... ...

Abstract	Neurodevelopmental disorders (NDDs) impact multiple aspects of an individual's functioning, including social interactions, communication, and behaviors. The underlying biological mechanisms of NDDs are not yet fully understood, and pharmacological treatments have been limited in their effectiveness, in part due to the complex nature of these disorders and the heterogeneity of symptoms across individuals. Identifying genetic loci associated with NDDs can help in understanding biological mechanisms and potentially lead to the development of new treatments. However, the polygenic nature of these complex disorders has made identifying new treatment targets from genome-wide association studies (GWAS) challenging. Recent advances in the fields of big data and high-throughput tools have provided radically new insights into the underlying biological mechanism of NDDs. This paper reviews various big data approaches, including classical and more recent techniques like deep learning, which can identify potential treatment targets from GWAS and other omics data, with a particular emphasis on NDDs. We also emphasize the increasing importance of explainable and causal machine learning (ML) methods that can aid in identifying genes, molecular pathways, and more complex biological processes that may be future targets of intervention in these disorders. We conclude that these new developments in genetics and ML hold promise for advancing our understanding of NDDs and identifying novel treatment targets.
MeSH term(s)	Humans ; Genome-Wide Association Study ; Big Data ; Neurodevelopmental Disorders/drug therapy ; Neurodevelopmental Disorders/genetics ; Algorithms ; Machine Learning
Language	English
Publishing date	2023-09-12
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	194735-7
ISSN	1879-016X ; 0163-7258
ISSN (online)	1879-016X
ISSN	0163-7258
DOI	10.1016/j.pharmthera.2023.108530
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Article ; Online: The effects of phenylalanine and tyrosine levels on dopamine production in rat PC12 cells. Implications for treatment of phenylketonuria, tyrosinemia type 1 and comorbid neurodevelopmental disorders.

Szigetvari, Peter D / Patil, Sudarshan / Birkeland, Even / Kleppe, Rune / Haavik, Jan

Neurochemistry international

2023 Volume 171, Page(s) 105629

Abstract: Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene, resulting in phenylalanine accumulation and impaired tyrosine production. In Tyrosinemia type 1 (TYRSN1) mutations affect ... ...

Abstract	Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene, resulting in phenylalanine accumulation and impaired tyrosine production. In Tyrosinemia type 1 (TYRSN1) mutations affect fumarylacetoacetate hydrolase, leading to accumulation of toxic intermediates of tyrosine catabolism. Treatment of TYRSN1 with nitisinone results in extreme tissue levels of tyrosine. Although PKU and TYRSN1 have opposite effects on tyrosine levels, both conditions have been associated with neuro-psychiatric symptoms typically present in ADHD, possibly indicating an impaired dopamine (DA) synthesis. However, concrete in vivo data on the possible molecular basis for disrupted DA production under disease mimicking conditions have been lacking. In pursuit to uncover associated molecular mechanisms, we exposed an established, DA producing cell line (PC12) to different concentrations of phenylalanine and tyrosine in culture media. We measured the effects on viability, proteomic composition, tyrosine, DA and tyrosine hydroxylase (TH) levels and TH phosphorylation. TH catalyzes the rate-limiting step in DA synthesis. High extracellular levels of phenylalanine depleted cells of intracellular tyrosine and DA. Compared to physiological levels (75 μM), either low (35 μM) or high concentrations of tyrosine (275 or 835 μM) decreased cellular DA, TH protein, and its phosphorylation levels. Using deep proteomic analysis, we identified multiple proteins, biological processes and pathways that were altered, including enzymes and transporters involved in amino acid metabolism. Using this information and published data, we developed a mathematical model to predict how extracellular levels of aromatic amino acids can affect the cellular synthesis of DA via different mechanisms. Together, these data provide new information about the normal regulation of neurotransmitter synthesis and how this may be altered in neurometabolic disorders, such as PKU and TYRSN1, with implications for the treatment of cognitive symptoms resulting from comorbid neurodevelopmental disorders.
MeSH term(s)	Rats ; Animals ; Dopamine/metabolism ; Tyrosine/metabolism ; Tyrosinemias ; Phenylalanine ; PC12 Cells ; Proteomics ; Phenylketonurias/metabolism ; Tyrosine 3-Monooxygenase/metabolism ; Neurodevelopmental Disorders
Chemical Substances	Dopamine (VTD58H1Z2X) ; Tyrosine (42HK56048U) ; Phenylalanine (47E5O17Y3R) ; Tyrosine 3-Monooxygenase (EC 1.14.16.2)
Language	English
Publishing date	2023-10-20
Publishing country	England
Document type	Journal Article
ZDB-ID	283190-9
ISSN	1872-9754 ; 0197-0186
ISSN (online)	1872-9754
ISSN	0197-0186
DOI	10.1016/j.neuint.2023.105629
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Article ; Online: Potassium channels in behavioral brain disorders. Molecular mechanisms and therapeutic potential: A narrative review.

Alam, Kazi Asraful / Svalastoga, Pernille / Martinez, Aurora / Glennon, Jeffrey Colm / Haavik, Jan

Neuroscience and biobehavioral reviews

2023 Volume 152, Page(s) 105301

Abstract: Potassium channels ( ... ...

Abstract	Potassium channels (K
MeSH term(s)	Humans ; Potassium Channels/genetics ; Potassium Channels/metabolism ; Brain Diseases/drug therapy ; Potassium/metabolism
Chemical Substances	Potassium Channels ; Potassium (RWP5GA015D)
Language	English
Publishing date	2023-07-04
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	282464-4
ISSN	1873-7528 ; 0149-7634
ISSN (online)	1873-7528
ISSN	0149-7634
DOI	10.1016/j.neubiorev.2023.105301
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Article ; Online: Synthetic corticosteroids as tryptophan hydroxylase stabilizers.

Betari, Nibal / Teigen, Knut / Sahlholm, Kristoffer / Haavik, Jan

Future medicinal chemistry

2021 Volume 13, Issue 17, Page(s) 1465–1474

Abstract: Background: ...

Abstract	Background:
MeSH term(s)	Adrenal Cortex Hormones/chemical synthesis ; Adrenal Cortex Hormones/chemistry ; Adrenal Cortex Hormones/pharmacology ; Catalytic Domain/drug effects ; Enzyme Stability ; Humans ; Molecular Conformation ; Molecular Docking Simulation ; Tryptophan Hydroxylase/metabolism
Chemical Substances	Adrenal Cortex Hormones ; Tryptophan Hydroxylase (EC 1.14.16.4)
Language	English
Publishing date	2021-07-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1756-8927
ISSN (online)	1756-8927
DOI	10.4155/fmc-2021-0068
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Article: Insomnia, Alcohol Consumption and ADHD Symptoms in Adults.

Lundervold, Astri J / Jensen, Daniel A / Haavik, Jan

Frontiers in psychology

2020 Volume 11, Page(s) 1150

Abstract: Introduction: Substance use disorders and insomnia are common in the general population, and particularly among adults with attention-deficit/hyperactivity disorder (ADHD). Here we investigated the relationship between insomnia, alcohol consumption and ... ...

Abstract	Introduction: Substance use disorders and insomnia are common in the general population, and particularly among adults with attention-deficit/hyperactivity disorder (ADHD). Here we investigated the relationship between insomnia, alcohol consumption and ADHD symptoms. Methods: Adults with an ADHD diagnosis ( Results: Compared to controls, the ADHD group reported a higher frequency of insomnia, a higher quantity of consumed alcohol and a higher frequency of internalizing disorders. Current and childhood ADHD symptoms were more severe in those with than without insomnia. Scores on ADHD symptom scales were explained by the presence of insomnia and internalizing disorders, while the contribution from alcohol consumption was restricted to the control group. Discussion: The high functional impact of insomnia, alcohol misuse and internalizing disorders is well known. The present study contributed by focusing on their relations to ADHD symptoms, and by showing that strong relations were not restricted to adults with a clinical ADHD diagnosis. By this, the results put a critical light on a categorical delineation between adults with an ADHD diagnosis and population selected controls, and call for further studies including dimensional metrics of ADHD symptoms and co-occurring problems.
Language	English
Publishing date	2020-05-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2563826-9
ISSN	1664-1078
ISSN	1664-1078
DOI	10.3389/fpsyg.2020.01150
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Article: Alcohol and drug use disorders in adult attention-deficit/hyperactivity disorder: Prevalence and associations with attention-deficit/hyperactivity disorder symptom severity and emotional dysregulation.

Anker, Espen / Haavik, Jan / Heir, Trond

World journal of psychiatry

2020 Volume 10, Issue 9, Page(s) 202–211

Abstract: Background: High risk of alcohol and drug use disorders in people with attention-deficit/hyperactivity disorder (ADHD) calls for exploratory research of relationships with clinical features of ADHD.: Aim: To estimate prevalence of alcohol/drug use ... ...

Abstract	Background: High risk of alcohol and drug use disorders in people with attention-deficit/hyperactivity disorder (ADHD) calls for exploratory research of relationships with clinical features of ADHD. Aim: To estimate prevalence of alcohol/drug use disorders and associations with ADHD symptom severity and emotional dysregulation, in adults with ADHD. Methods: This observational cross-sectional clinical study consisted of patients admitted to a private psychiatric outpatient clinic in Oslo, Norway (2014-2018). Five-hundred and fifty-eight eligible patients diagnosed with ADHD (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria) agreed to participate. Alcohol and drug use disorders were diagnosed using the Mini International Neuropsychiatric Interview (MINI). Dependence and abuse were merged into "use" disorder as in MINI version 7.0/DSM-5. Questions were related both to lifetime and the past 12-mo. ADHD severity was assessed by the Adult ADHD Self Report Scale (ASRS). Subdivisions of the ASRS questionnaire as inattentive items and hyperactive/impulsivity items were recorded separately. Emotional dysregulation was assessed by the eight-item version of Barkley's Current Behavior Scale - Self Report. Results: The 12-mo prevalence was 5.3% for alcohol use disorder and 13.7% for drug use disorder. The lifetime prevalence was 12.0% for alcohol use disorder and 27.7% for drug use disorder. Men had higher rates of both alcohol use disorder and drug use disorder compared to women. The prevalence of drug use disorder was more than twice that of alcohol use disorder for both sexes. The drugs most participants reported having used were (in descending order): Amphetamine (19.1%), cannabis (17.1%), cocaine or ecstasy (7.4%), benzodiazepines (7.4%), and heroin or other opioids (2.9%). Lifetime drug use disorder was significantly associated with both hyperactivity-impulsivity symptoms and emotional dysregulation symptom severity. Lifetime alcohol use disorder, on the other hand, was not significantly associated with ADHD symptoms or emotional dysregulation when adjusted for gender and age. Conclusion: Patients with ADHD have a high lifetime prevalence of drug use disorder, which is associated with higher levels of hyperactivity-impulsivity symptoms and emotional dysregulation.
Language	English
Publishing date	2020-09-19
Publishing country	United States
Document type	Journal Article
ISSN	2220-3206
ISSN	2220-3206
DOI	10.5498/wjp.v10.i9.202
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Article ; Online: Validity and accuracy of the Adult Attention-Deficit/Hyperactivity Disorder (ADHD) Self-Report Scale (ASRS) and the Wender Utah Rating Scale (WURS) symptom checklists in discriminating between adults with and without ADHD.

Brevik, Erlend Joramo / Lundervold, Astri J / Haavik, Jan / Posserud, Maj-Britt

Brain and behavior

2021 Volume 11, Issue 5, Page(s) e02067

Language	English
Publishing date	2021-03-19
Publishing country	United States
Document type	Published Erratum
ZDB-ID	2623587-0
ISSN	2162-3279 ; 2162-3279
ISSN (online)	2162-3279
ISSN	2162-3279
DOI	10.1002/brb3.2067
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Article ; Online: Goal management training improves executive control in adults with ADHD: an open trial employing attention network theory to examine effects on attention.

Jensen, Daniel A / Lundervold, Astri J / Stubberud, Jan / Halmøy, Anne / Haavik, Jan / Sørensen, Lin

BMC psychology

2022 Volume 10, Issue 1, Page(s) 207

Abstract: Background: Adults with Attention-Deficit/Hyperactivity Disorder (ADHD) typically experience poorer attentional control. According to the attention network theory, attentional control relies on three interacting networks of alerting, orienting, and ... ...

Abstract	Background: Adults with Attention-Deficit/Hyperactivity Disorder (ADHD) typically experience poorer attentional control. According to the attention network theory, attentional control relies on three interacting networks of alerting, orienting, and executive control. In ADHD, it is mainly the alerting and executive control networks that are suggested and found to be compromised. Methods: In the current study, we investigated if a group-based metacognitive remediation program (Goal Management Training [GMT]) in adults with ADHD would enhance attentional control using an experimental measure of the attention network theory. We expected that GMT would specifically enhance the executive control and alerting networks. Results: Data from post- and follow up-assessments of 21 adults (age: 39.05 [11.93]) with ADHD who had completed GMT were included. Linear mixed-effects modeling revealed significant improvements in the functioning of the executive control network for the majority of the participants, although a small subset of participants showed a negative development following the intervention. Results also showed an improvement in the orienting network at follow up, but no change in the alerting network. Conclusion: The results may indicate that improvements in the functioning of the executive control network are central to the positive effects of GMT reported in disorders characterized by impaired attentional control. Trial registration: The study was retrospectively registered in the ISRCTN (Identifier: ISRCTN91988877) on the 18/01/2021.
MeSH term(s)	Adult ; Attention Deficit Disorder with Hyperactivity ; Cognition Disorders ; Executive Function ; Goals ; Humans ; Middle Aged ; Neuropsychological Tests
Language	English
Publishing date	2022-08-26
Publishing country	England
Document type	Clinical Trial ; Journal Article
ZDB-ID	2705921-2
ISSN	2050-7283 ; 2050-7283
ISSN (online)	2050-7283
ISSN	2050-7283
DOI	10.1186/s40359-022-00902-9
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