Cocaine dependence is in part genetic, and it shares genetic risk factors with other psychiatric conditions and personality traits.

Cocaine is one of the most used illicit drugs worldwide and its abuse produces serious health problems. In Europe, around 5.2% of adults (from 15 to 64 years old) have tried cocaine, but only 20% will develop addiction. Why? Genetics is part of the answer. Cocaine dependence is a complex psychiatric disorder that results from the interaction of both environmental and genetic risk factors. Twin and adoption studies indicate that genetic alterations contribute substantially to cocaine dependence susceptibility, which has an estimated genetic load (heritability) as high as 65-79%. Although many studies with focus on candidate genes have been performed, only a few risk variants for cocaine dependence have been identified and replicated so far.

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In this study we performed a meta-analysis of genome-wide association studies (GWAS) of cocaine dependence using more than 6,000 European ancestry individuals. This approach allowed us to inspect a huge number of genetic variants distributed all along the genome that are common in the general population. We identified a gene (HIST1H2BD) associated with cocaine dependence that is located in a region on chromosome 6 enriched in genes that encode histones, proteins that combine with DNA, protecting it and contributing to the activation (or inhibition) of genes. Some of these genes have previously been associated with schizophrenia.

Several studies have shown that substance use disorders (SUD), and especially cocaine dependence, co-occur in patients with other psychiatric disorders and personality traits. Such comorbidity is associated with increased severity for all disorders, although it is unclear whether this relationship is causal or the result of shared genetic and/or environmental risk factors. We calculated the shared genetics (genetic correlation) between cocaine dependence and six comorbid conditions. For the first time we found significant genetic correlation with attention deficit/hyperactivity disorder (ADHD), schizophrenia, major depression and risk- taking behavior. We also used another approach (polygenic risk score analysis, PRS) to prove that all tested comorbid conditions are associated with cocaine dependence status, suggesting that cocaine dependence is more likely in individuals that carry genetic risk factors for the tested conditions than in those that do not.

To our knowledge, this is the largest reported GWAS meta-analysis in European-ancestry individuals with cocaine dependence. We identified suggestive risk factors for the disorder in several genomic regions and found evidence for shared genetic risk factors between cocaine dependence and several co-occurring psychiatric traits. However, the size of the sample is still limited and further studies are needed to confirm our results.

Read more at: https://www.sciencedirect.com/science/article/pii/S0278584619301101?via%3Dihub

Judit Cabana-Domínguez and Bru Cormand

Judit Cabana Domínguez is a Postdoctoral researcher at the Genetics, Microbiology and Statistics Department at the University of Barcelona.

Bru Cormand is Full Professor of Genetics at the Genetics, Microbiology and Statistics Department at the University of Barcelona.

ADHD and autism – similar or different disorders?

Have you ever thought that ADHD and autism could perhaps be the same disorder? – Or have you thought that they are way too different, two different planets in the psychiatric universe? Researchers do not agree on this. We know that both ADHD and autism are neurodevelopmental conditions with onset in childhood and that they share some common genetic factors, however, they appear with quite different phenotypical characteristics. We also know that people with ADHD or autism have an increased risk of getting other psychiatric disorders, so-called comorbidities, and smaller studies have shown that individuals with ADHD or autism get different psychiatric disorders, and at a different degree.

How can we utilize this knowledge about different psychiatric comorbidities between ADHD and autism? How can we get closer to an answer to this question; are ADHD and autism similar or different conditions? By using large datasets; unique population-based registries in Norway, we wanted to compare the pattern of psychiatric comorbidities in adults diagnosed with ADHD, autism or both disorders. In addition, we wanted to compare the pattern of genetic correlations between ADHD and autism for the same psychiatric traits, and for this, we exploited summary statistics from relevant genome-wide association studies.

In the registries, we identified 39,000 adults with ADHD, 7,500 adults with autism and 1,500 with both ADHD and autism. We compared these three groups with the remaining population of 1.6 million Norwegian adult inhabitants without either ADHD or autism. The psychiatric disorders we studied were anxiety, bipolar, depression, personality disorder, schizophrenia spectrum (schizophrenia) and substance use disorders (SUD).

Interestingly, we found different patterns of psychiatric comorbidities between ADHD and autism, overall and when stratified by sex (Fig.1). These patterns were also reflected in the genetic correlations, however, only two of the six traits showed a significant difference between ADHD and autism (Fig.2).

Figure 1 - Solberg et al. 2019
Figure 1. Prevalence ratios of psychiatric disorders in adults with ADHD, autism or both ADHD and autism, relative to the remaining population, by sex. As can be seen in the figure, schizophrenia is more frequent in autism or ADHD+autism than ADHD alone, while the reverse is true for substance use disorder. There are also significant differences in prevalence between men and women. Figure from Solberg et al. 2019, CC-BY-NC-ND.

Figure 2. Left: The pattern of prevalence ratios of psychiatric comorbidity in adults with ADHD or autism observed in this study (ADHD; n=38,636, autism; n=7,528). Right: genetic correlations (rg) calculated from genome wide association studies. Psychiatric conditions are highly prevalent in both ADHD and ASD, with schizophrenia being most prevalent in ASD and antisocial personality disorders in ADHD. Genetic correlations are also high with both disorders, with especially high correlations between ADHD and alcohol dependence, smoking behavior and anti-social behavoiur. Major depressive disorder has high genetic correlations with both ADHD and autism. Figure from Solberg et al. 2019, CC-BY-NC-ND.

The most marked differences were found for schizophrenia and SUD. Schizophrenia was more common in adults with autism, and SUD more common in adults with ADHD. Associations with anxiety, bipolar and personality disorders were strongest in adults with both ADHD and autism, indicating that this group of adults suffers from more severe impairments than those with ADHD or autism only. The sex differences in risk of psychiatric comorbidities were also different among adults with ADHD and ASD.

In conclusion, our study provides robust and representative estimates of differences in psychiatric comorbidities between adults diagnosed with ADHD, autism or both ADHD and autism. With the results from analyses of genetic correlations, this finding contributes to our understanding of these disorders as being distinct neurodevelopmental disorders with partly shared common genetic factors.

Clinicians should be aware of the overall high level of comorbidity in adults with ADHD, autism or both ADHD and autism, and the distinct patterns of psychiatric comorbidities to detect these conditions and offer early treatment. It is also important to take into account the observed sex differences. The distinct comorbidity patterns may further provide information to etiologic research on biological mechanisms underlying the pathophysiology of these neurodevelopmental disorders.

This study was done at Stiftelsen Kristian Gerhard Jebsen Centre for Neuropsychiatric disorders, University of Bergen, Norway, and published OnlineOpen in Biological Psychiatry, April 2019, with the title:

“Patterns of psychiatric comorbidity and genetic correlations provide new insights into differences between attention-deficit/hyperactivity disorder and autism spectrum disorder”. https://doi.org/10.1016/j.biopsych.2019.04.021

Figure 1 and 2 are re-printed by permission https://creativecommons.org/licenses/by-nc-nd/4.0/

Berit Skretting Solberg is a PhD-candidate at the Department of Biomedicine/Department of Global Health and Primary Care, University of Bergen, Norway. She is also a child- and adolescent psychiatrist/adult psychiatrist. She is affiliated with the CoCa-project, studying psychiatric comorbidities in adults with ADHD or autism, using unique population-based registries in Norway.

 

ADHD and cannabis use

It is not uncommon for individuals to suffer from two or more psychiatric disorders at the same time. The appearance of these disorders frequently follows a specific order, and one disorder may predispose to others, all of which in combination contribute to the worsening of the quality of life of the individuals who suffer them. This is usually associated with more severe symptoms and worse prognosis. In addition, making a diagnosis and applying personalized treatments becomes more challenging in this context. By investigating the genetic overlap between disorders, we gain better understanding of why the disorders frequently co-occur.

In mental health, substance use disorders often appear when there is another mental condition. This is the case for attention-deficit/hyperactivity disorder (ADHD) and substance use disorder, where individuals with ADHD are more likely to use drugs during their lifetime than individuals who do not have ADHD. In particular, cannabis is the most commonly used substance among individuals with ADHD, which can also lead to the use of other drugs and to the worsening of their symptoms. ADHD is one of the most common neurodevelopmental disorders, affecting around 5% of children and 2.5% of adults, and is characterized by attention deficit, hyperactivity and impulsivity. Both ADHD and cannabis use are conditions determined partly by environmental factors but where genetic factors also play an important role.

We recently investigated the genetic overlap between ADHD and cannabis use, and found that the increased probability of using cannabis in individuals with ADHD, can be, in part, due to a common genetic background between the two conditions. We identified four genetic regions involved in increasing the risk of both ADHD and cannabis use, which could point to potential druggable targets and help to develop new treatments. In addition, we confirmed a causal link between ADHD and cannabis use, and estimated that individuals with ADHD are almost 8 times more likely to consume cannabis than those who do not have ADHD. This evidence goes in line with a temporal relationship, where the ADHD appears in childhood and the use of cannabis during adolescent or adulthood. This suggests that having ADHD increases the risk of using cannabis, and not vice versa.

This research has only been possible thanks to large international collaborations by the Psychiatric Genomics Consortium (PGC), iPSYCH, and the International Cannabis Consortium (ICC), where the genomes of around 85 000 individuals were analysed.

Overall, these results support the idea that psychiatric disorders are not independent, but have a common genetic background, and share biological pathways, which put some individuals at higher risk than others. This will help to overcome the stigma of addiction and mental disorders. In addition, the potential of using genetic information to identify individuals at higher risk will have a strong impact on prevention, early detection and treatment.

Further reading

María Soler Artigas et al. Attention-deficit/hyperactivity disorder and lifetime cannabis use: genetic overlap and causality, Molecular Psychiatry (2019) – https://www.nature.com/articles/s41380-018-0339-3

About the author

María Soler Artigas is postdoctoral researcher at the Psychiatry, Mental Health and Addictions group at Vall d’Hebron Institut de Recerca (VHIR), also part of the Biomedical Research Networking Center in Mental Health (CIBERSAM). Her research is part of the CoCA consortium that investigates comorbid conditions of ADHD.

German study first to show direct medical costs of ADHD and its comorbid conditions across the lifespan

Having ADHD is expensive. A study of German insurance data has shown that the medical costs of a person with ADHD are 1500 euro higher per year, compared to a person without ADHD. But that’s not all; individuals with ADHD are far more likely to suffer from additional conditions such as mood and anxiety problems, substance abuse or obesity. Treatment of these conditions can cost up to an additional 2800 euro per year. As ADHD – especially in adults – is still poorly recognised and diagnosed, these numbers may not reflect the complete picture of ADHD medical costs. Improving diagnosis and adult mental healthcare may prevent mental health problems later in life and actually reduce costs, argue Berit Libutzki and her co-authors.

ADHD (Attention Deficit / Hyperactivity Disorder) is a developmental condition. Symptoms arise before the age of 12 and are characterised by age-inappropriate and impairing behaviour in terms of problems with attention, impulsivity and hyperactivity. World-wide prevalence of children with ADHD is estimated around 5%, while in adults this is around 2.5%. This means that in about half of the children problems do not subside with age. For these people, ADHD is a lifelong condition that often impairs health, career and social life.

To estimate the economical costs of ADHD, Berit Libutzki and her colleagues from HGC Healthcare Consultants GmbH analysed the (anonymised) health insurance data of almost four million Germans. They compared the medical costs of people with an ADHD diagnosis to those of a well-matched group without ADHD.

medical costs per person_figure

The results showed that the medical costs of a person with ADHD are on average 1508 euro higher than those of a person without ADHD. These costs are mainly due to treatments in hospitals and by psychiatrists. ADHD medication itself (such as Methylphenidate) are in third place, contributing to only 11% of the additional costs. Other interesting findings from the study are that medical costs are a bit higher in women compared to men, and that costs are much higher in individuals over 30 years old compared to younger age groups. After the age of 18, the costs of for example ADHD medication drop, while psychiatrist costs and costs for other (non-ADHD) medications increase notably. Also sick payment is high in adult ADHD patients, leading to a significant increase in costs. One of the explanations for these cost increases could be a gap in care after leaving the regular care of a paediatrician at age 18, and the development of disorders that arise in addition to ADHD.

medical costs increase_figure

ADHD plus additional (mental) health problems

It has been shown before that having ADHD puts you at a much higher risk of developing additional (comorbid) disorders. Mood disorders – such as depression – and anxiety are most frequent; in the German data two-thirds of ADHD individuals over 30 had such an additional diagnosis (compared to only a fifth of adults without ADHD). Substance abuse and obesity are more common in people with ADHD as well. These comorbidities should not be underestimated as they add strongly to the burden of disease. The study shows that substance abuse and morbid obesity are even the most costly, especially in adulthood. In total, the surplus costs associated with these conditions are 1420-2715 euro higher for ADHD individuals, compared to individuals who suffer from mood or anxiety disorder, substance abuse, or obesity alone.

comorbid disorders_figure

Scientists think that certain genetic factors that play a role in ADHD also make a person more vulnerable for these comorbid health conditions. Libutzki and her team are part of the European research consortium Comorbid Conditions of ADHD (CoCA) that investigates the shared biological mechanisms of ADHD and these additional disorders. “Through this research we hope to find leads to prevent these disorders from developing, and improve mental health care.”, says the leader of the CoCA consortium Prof. Dr. Andreas Reif of the University Hospital Frankfurt.

“It is intriguing to speculate that these comorbidities, which were shown to be the important cost drivers in adulthood, could be prevented if mental healthcare were provided more constantly over the lifespan” write the authors. “The prevention of the development of comorbidities with age should be the focus of mental health care. Early treatment starting in childhood and continued treatment of adolescents into adulthood seem therefore advisable.”

Improving diagnosis and adult mental health care

There is one caveat in the study by Libutzki, that is also acknowledged by the authors: many people, especially adults, are not diagnosed with ADHD, even though they experience the symptoms. “Our knowledge gap is especially large in adulthood”, says Dr. Catharina Hartman from the University Medical Centre Groningen, The Netherlands. “The prevalence of adult ADHD in the health insurance data was very low (0.2 %). Given that the population prevalence for adult ADHD is 2,5 %, this indicates that many adults with ADHD are currently not diagnosed or treated. They may nonetheless make high direct costs since their ADHD may not be recognised, or they make indirect costs through unemployment or criminality.” This would indicate that the costs reported by the study are underestimated. On the other hand, adults often find out about their ADHD only after consulting a psychiatrist for other mental health problems. This would indicate that estimated costs and prevalence of comorbid disorders with ADHD in adulthood are overestimated, compared to when you were to include also all undiagnosed people with ADHD, and diagnosed persons who do not make costs (i.e. milder cases of ADHD).

The study thus provides a partial view on the costs of ADHD during the lifespan. That said, it is among the first to show in detail the lifespan medical costs of ADHD and comorbid disorders in Germany. These findings are likely to be representative of other western-European countries. Policy makers in these countries are strongly advised to investigate ways to improve the transition from child to adult mental healthcare and increase awareness about adult ADHD. This will not only improve the quality of life of many adults but may also save money.

Further reading

Libutzki, Ludwig, May, Jacobsen, Reif and Hartman (2019). Direct medical costs of ADHD and its comorbid conditions on basis of claims data analysis.  European Psychiatry, 58: 38-44. https://www.europsy-journal.com/article/S0924-9338(19)30019-7/abstract

The findings from this study are also summarised in an infographic: https://my.visme.co/projects/1jok0qg8-medical-costs-adhd

ADHD Is A Risk Factor For Type Two Diabetes And High Blood Pressure, As Well As Other Psychiatric Disorders

All Swedish residents have their health records tracked through unique personal identity numbers. That makes it possible to identify psychiatric and medical disorders with great accuracy across an entire population, in this case encompassing more than five and a half million adults aged 18 to 64. A subgroup of more than 1.6 million persons between the ages of 50 and 64 enabled a separate examination of disorders in older adults.

Slightly over one percent of the entire population (about 61,000) were diagnosed with ADHD at some point as an adult. Individuals with ADHD were nine times as likely to suffer from depression as were adults not diagnosed with ADHD. They were also more than nine times as likely to suffer from anxiety or a substance use disorder, and twenty times as likely to be diagnosed with bipolar disorder.  These findings are very consistent with reports from clinical samples in the USA and Europe.

Adults with ADHD also had elevated levels of metabolic disorders, being almost twice as likely to have high blood pressure, and more than twice as likely to have type 2 diabetes. Persons with ADHD but without psychiatric comorbidities were also almost twice as likely to have high blood pressure, and more than twice as likely to have type 2 diabetes.

Similar patterns were found in men and women with ADHD, although comorbid depression, bipolar disorder, and anxiety were moderately more prevalent in females than in males, whereas substance use disorder, type 2 diabetes, and hypertension were more prevalent in males than in females.

ADHD was less than a third as prevalent in the over-50 population as in the general adult population. Nevertheless, individuals in this older group with ADHD were twelve times as likely to suffer from depression, anxiety, or substance use disorders, and more than 23 times as likely to be diagnosed with bipolar disorder as their non-ADHD peers. They were also 63% more likely to have high blood pressure, and 72% more likely to have type 2 diabetes.

The authors noted, “Although the mechanisms underlying these associations are not well understood, we know from both epidemiologic and molecular genetic studies that a shared genetic predisposition might account for the co­existence of two or more psychiatric conditions. In addition, individuals with ADHD may experience increased difficulties as the demands of life increase, which may contribute to the development of depression and anxiety.” As for associations with hypertension and type 2 diabetes, these “might reflect health ­risk behaviors among adult patients with comorbid ADHD in addition to a shared biological substrate. As others have noted, inattention, disinhibition, and disorganization associated with ADHD could make it difficult for patients to adhere to treatment regimens for metabolic disorders.” They concluded that “Clinicians should remain vigilant for a wide range of psychiatric and metabolic problems in ADHD affected adults of all ages and both sexes.”

Stephen Faraone is distinguished Professor of Psychiatry and of Neuroscience and Physiology at SUNY Upstate Medical University and is working on the H2020-funded project CoCA. 

REFERENCES

Qi Chen, Catharina A. Hartman, Jan Haavik, Jaanus Harro, Kari Klungsøyr, Tor­Arne Hegvik, Rob Wanders, Cæcilie Ottosen, Søren Dalsgaard, Stephen V. Faraone, Henrik Larsson, “Common psychiatric and metabolic comorbidity of adult attention-deficit/hyperactivity disorder: A population-based cross-sectional study,” PLoS ONE (2018), 13(9): e0204516. https://doi.org/10.1371/journal.pone.0204516.

How can we make sense of comorbidity?

Comorbidity, defined as the simultaneous occurrence of more than one disorder in a single patient, is commonplace in psychiatry and somatic medicine. In research, as well as in routine clinical settings.

In March 2016 the new H2020 collaborative project “CoCA” (Comorbidity in adult ADHD) was officially launched, with a 3-day kick-off meeting in Frankfurt, Germany. This ambitious project, which is coordinated by professor Andreas Reif and is co-maintaining this shared blog, will investigate multiple aspects of comorbidity in ADHD.

For instance, CoCA will “identify and validate mechanisms common to the most frequent psychiatric conditions, specifically ADHD, mood and anxiety disorders, and substance use disorders (SUD), as well as a highly prevalent somatic disorder, i.e. obesity”.

As reflected in this bold mission, most scientists trained in the biological sciences agree that studies of overlapping and concurrent phenomena may reveal some underlying common mechanisms, e.g. shared genetic or environmental risk factors.

However, particularly in psychiatry and psychology, the origins of comorbidity have been fiercely debated. Critics have argued that observed comorbidities are “artefacts” of the current diagnostic systems (Maj, Br J Psychiatry, 2005 186: 182–184).

This discussion relates to fundamental questions of how much of our scientific knowledge reflects an independent reality, or is merely a product of our own epistemological traditions. In psychiatry, the DSM and ICD classification systems have been accused of actively producing psychiatric phenomena, including artificial diagnoses and high comorbidity rates, rather than being “true” representations of underlying phenomena.  Thus, the “constructivist” tradition argues that diagnostic systems are projected onto the phenomena of psychiatry, while “realists” acknowledge the presence of an independent reality of psychiatric disorders.

In an attempt to explain these concepts and their implications, psychiatric diagnoses and terminology have been termed “systems of convenience”, rather than phenomena that can be shown to be true or false per se (van Loo and Romeijn, Theor Med Bioeth. 2015, 41-60). It remains to be seen whether such philosophical clarifications will advance the ongoing debate related to the nature of medical diagnoses and their co-occurrence.

CoCA will not resolve these controversies. Neither can we expect that our new data will convince proponents of such opposing perspectives.

It is important to acknowledge the imperfections and limitations of concepts and instruments used in (psychiatric) research.

However, it may provide some comfort that similar fundamental discussions have a long tradition in other scientific disciplines, such as physics and mathematics. Rather  than being portrayed as a weakness or peculiarity of psychiatric research, I consider that an active debate, with questioning and criticism is considered an essential part of a healthy scientific culture.

Hereby, you are invited to join this debate on this blog page!Wooden ruler vector