The Origins of Anxiety Disorders

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As part of the K+ programme, I completed an essay on the genetic and environmental origins of anxiety disorders. It was a great project where I got to learn about mental illnesses through a PhD tutor and develop my independent research skills. Thought it’d be good to share it on here, Enjoy!

Note: endnotes ( for example [1] ) will only work on the individual post’s page. Click on the post title above or ‘continue reading’ at the end.

Why is it important to study the genetic and environmental origins of anxiety disorders?

Anxiety disorders are prominent throughout the world of medicine and the society we live in today. Up to 9.7% of the UK population suffer from mixed depression and anxiety, with Generalised Anxiety Disorder (GAD) accounting for 30% of mental health cases seen by GPs [1]. The act of merely classifying and diagnosing discrete disorders has helped the research field come a long way, but recognising the importance of further research is crucial to continual development. The presence of anxiety disorders is sourced from complex traits; these traits (our phenotypes) are an eventual result of our genotypes. However, this simplistic sequential model undermines the complexity of the brain and the role of the environment. Studying the genetic and environmental origins of anxiety disorders is key to understanding the reciprocal relationship between them.

 

Importance of research:

Studying genetic and environmental origins is important to a wide range of people that may be possibly affected. A consequence of research could mean that the Diagnostic and Statistical Manual (DSM) of Mental Disorders is further edited and improved. Throughout the history of the manual, Post-World War II, several editions have been made which incorporate the latest ideas and suggestions by researchers or physicians. More recently in 2000, research groups began revising specific disorder areas where there were gaps in previous research [2]. This led to the most recent DSM-5 being published in 2013. Continual study of origins of anxiety disorders means that breakthroughs in diagnostic procedures and understanding can be documented in the DSM – allowing it to be a reliable source for mental health professionals and researchers.

Scientists and science in general will also be greatly benefitted by the study of underlying causes of anxiety disorders. It means that the mysteries of the brain are more fully understood, along with detailed neurological systems that may be the source of multiple disorders. Alongside this, it also means that existing treatments can be used to treat new disorders definitively or vice versa – they can be adapted based upon new understanding.

In addition to this, ground-breaking scientific discoveries will inevitably show their effect in society’s perception of mental disorders and affect government regulations. General attitude towards sufferers has improved over time as a result of increased awareness – due to extensive research on subconscious pathways and genetic risk factors. A study [3] by TNS-BMRB revealed that 71% of people agreed that ‘Mental illness is an illness like no other’ in 1994 compared to a higher 77% in 2011. Further neurological research will continue to convey this point to the wider public and show that it is the same as other pathological diseases. Increased awareness also has further implications in terms of amendments to the Mental Health Act 1983; for example, it was revised to include new chapters on human rights and physical healthcare amongst others in April 2015 [4].

Genetic origins of anxiety disorders:

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In an attempt to study the aetiology and narrow the possible causes of anxiety disorders, twin studies have been used as a way to identify genetic origins. In twin studies, pairs of identical and non-identical twins are involved. The idea behind the studies is that, if genetics plays a role in the disease’s development, identical twins will be much more likely to develop the same disease. This is because they share more of their genes (100%) compared to non-identical twins (only 50%). The environment is assumed to be shared and identical. Then, data from the studies can be used to construct a heritability estimate. Heritability is a quantitative method of analysing genetic influences on a trait. Recent studies have shown this figure to be from 30% to 40% [5] in the development of adolescent and childhood anxiety, whilst being 43% for panic disorder and 32% for GAD [6]. These relatively high percentages show that genotypes account for much of the phenotypic variations within the population – being genetically predisposed to a certain disorder is therefore entirely possible. These discoveries are of huge importance to current sufferers, providing them with knowledge that they may pass on their genes unto children. This will still leave them at risk of developing the disease, but tested treatments and precautions can be enforced from a young age.

In the modern era, medical advancements in molecular genetics have allowed us to match specific genes to phenotypes using extracted DNA. Genome-wide Association Studies (GWAS) compare DNA sequences of millions of individuals to find common genes that lead to an associated trait. The studies identify common single-nucleotide polymorphisms (SNPs), a source of genetic variation, within the affected population. These are usually found within introns and indicate that nearby genes may put individuals at risk [7]. In recent GWAS studies on panic disorder, meta-analysis has identified several SNPs which point towards specific genes – such as BDKRB2, MCPH1 and others [8], [9]. Further studies have identified links between various symptoms of anxiety and different genes coding for the production of serotonin and dopamine [10]. Studies like this are important in not only advancing the field of genetics, but opening up larger possibilities in the form of pre-implantation genetic screening.

However, genes involved in complex traits like anxiety disorders are not deterministic; genes individually follow laws of Mendelian inheritance but the complex trait does not. This is unlike other neurodegenerative diseases such as Huntington’s disease. Furthermore, phenotypes may be polygenic, meaning that they are affected by several genes collectively. Genes may also be pleiotropic, and lead to an increased chance of developing multiple disorders at the same time. As for the previously mentioned BDKRB2 gene, recent research has associated the gene to bipolar disorder as well as obsessive-compulsive disorder (OCD). This research has forced the conclusion that the gene confers susceptibility to several psychiatric disorders [11]. This detailed, fundamental understanding would not have been possible without initial studies. It also allows us to potentially consider other variables associated to disorders. Another such variable is the environment, including how increased sensitivity and exposure further heightens the risk of anxiety disorders.

Environmental origins of anxiety disorders:

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Recently, research has linked the cause of OCD to a group of structures in the brain known as the basal ganglia. Mainly a structure that coordinates movement through circuits, it also communicates with other structures such as the orbitofrontal cortex and the anterior cingulate gyrus . This communication is through the limbic loop and one of its functions is to detect errors in day-to-day occurrences [12]. Brain scans in OCD patients showed hyperactivity throughout these loops [13], neurologically explaining some of the symptoms of OCD i.e. intrusive thoughts and the constant feeling that something is wrong. This research not only proves that OCD is a biological disorder, but that it may have environmental origins. Physical damage to the basal ganglia has been linked by the researchers to several environmental causes – such as bacterial infections, hypoxia and neurotoxic agents [14]. The claim of neurotoxins as a possible cause has been supported by a study of several substances on the basal ganglia’s function [15]. Compounds such as carbon monoxide and hydrogen sulphide were shown to inhibit its mitochondrial function along with damaging the pallidum and putamen – two of the constituent parts.

Another study, carried out on mice, indicates that long-term changes in the basal ganglia can be caused by the abuse of psychostimulants such as methamphetamine [16]. Extended research is important to find out if this is the case in humans. In terms of prevention of psychiatric disorders, neuroscience-related research such as this is crucial. Possible causes can be confidently identified and stricter measures enforced on a national level – pertaining to drugs and chemical waste levels for example.

Overall, these studies show that development of anxiety may be sourced from purely environmental factors. However, in reality, anxiety disorders have been shown to be a result of both genetic and environmental factors which interact in complex ways.

Genetic and environmental origins of anxiety disorders:

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There are many logical propositions put forward by researchers to understand the link between genetic and environmental influence. The differential susceptibility hypothesis suggests that some people have a brain which makes them more responsive to their environment compared to others. Recent research has supported this hypothesis in relation to the development of depression through childhood maltreatment [17]. The key determining factor, in this case, was variation found in the serotonin transporter gene (5HTTLPR) which leads to either the short or long allele. Individuals with the short allele report greater depressive symptoms as opposed to those with the long allele, when exposed to recent maltreatment. Similar links have also been made with the polymorphism of the 5HTTLPR gene and anxiety sensitivity [18] – making a subject prone to anxiety disorders. Studying areas such as differential susceptibility brings rise to a wide range of possible treatments and prevention measures. Genetic screening can identify people at risk and therapy, for example, can be offered from a very early stage.

Another area of study that can have similar beneficial consequences is gene-environment correlation (rGE) [19]. One type of this correlation is known as passive. This is when parents create a home environment that is reflective of their own heritable traits (that are sourced from a disorder). If the children further inherit genes that put them at risk, this coupling of environmental and genetic factors will likely lead to development of the disorder. Another type of rGE is known as evocative. This is when a sufferer displays their own heritable traits and influences the environment around them. Over time, the influenced environment will continue to worsen their condition; therefore, leading to further development of their disorder. As an example, recent studies have shown that children reporting high levels of anxiety elicit more extreme maternal control [20]. This extreme maternal control is likely to evoke further anxiety amongst children.

The last type of rGE is known as active – where the sufferer actively seeks out environments which suit their heritable traits. For example, introverts may seek quiet environments which do not aid their recovery from a disorder. Studying these types of correlation allows psychiatrists and other professionals to understand how past history affects a person’s current condition – a critical skill in the process of diagnosing and dealing with mental health patients.

Treatment of anxiety disorders:

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The end-goal of all research into the origins of anxiety disorders is to potentially find treatments for them. Selective serotonin reuptake inhibitors (SSRIs) have been developed as a form of treatment for mental health illnesses such as GAD, OCD and panic disorder. Brand name examples include Prozac, Paxil and Zoloft. They work by blocking reuptake of serotonin into nerve cells, allowing higher levels of the neurotransmitter to pass through the brain. This has a good influence on mood and emotion along with increasing sensitivity to other treatment such as Cognitive Behavioural Therapy – a widely used and effective therapy for sufferers of anxiety.

Promising neurosurgical options such as Deep Brain Stimulation (DBS) have also been touted as a future treatment for OCD. In DBS, electrodes are implanted within the basal ganglia and the activity of neurons can be controlled externally. Essentially, the hyperactivity is corrected and the extent of changes can be tuned for every individual – implanting electrodes has no initial effect. Encouraging results have been seen in trial patients who express great satisfaction [21], [13].

In conclusion, past efforts to delve into the inner mechanisms of anxiety disorders have yielded results – the beneficial effects of which have propagated throughout society. As a consequence, studies have led to improvements in diagnostic procedures, treatment methods and advancements in science as a whole. They also have a pivotal role in attitudes towards mental illness, when coupled with other public awareness organisations. An example of this is Time-To-Change’s anti-stigma campaign which was found to positively influence attitudes in recent studies [22]. The sharing of individual experiences can also have an impact, through social media and blogs – such as Zoella [23] and the “I am living with anxiety” blog [24]. Further study will support these campaigns through scientific knowledge and pave the way for definitive treatments.

Thanks for reading. Click below to see sources.

Sources:

[1] Mentalhealth.org.uk, (2015). Mental Health Statistics: Anxiety. [online] Available at: https://www.mentalhealth.org.uk/help-information/mental-health-statistics/anxiety-statistics/ [Accessed 30 Aug. 2015].

[2] American Psychiatric Association, (2015). History of the DSM. [online] Available at: https://psychiatry.org/psychiatrists/practice/dsm/history [Accessed 30 Aug. 2015].

[3] Rethink.org, (2013). Report: Attitudes to Mental Illness. [online] Available at: https://www.rethink.org/news-views/2013/11/attitudes-to-mental-illness [Accessed 30 Aug. 2015].

[4] Gov.UK, (2015). New Mental Health Act code of practice – News stories. [online] Available at: https://www.gov.uk/government/news/new-mental-health-act-code-of-practice [Accessed 30 Aug. 2015].

[5] Rice, F. and Thapar, A. (2009). Depression and Anxiety in Childhood and Adolescence: Developmental Pathways, Genes and Environment. Handbook of Behavior Genetics, pp.379-396.

[6] Hettema, J., Neale, M. and Kendler, K. (2001). A Review and Meta-Analysis of the Genetic Epidemiology of Anxiety Disorders. American Journal of Psychiatry, 158(10), pp.1568-1578.

[7] Genetics Home Reference, (2015). What are single nucleotide polymorphisms (SNPs)?. [online] Available at: https://ghr.nlm.nih.gov/handbook/genomicresearch/snp [Accessed 31 Aug. 2015].

[8] Otowa, T., Kawamura, Y., Nishida, N., Sugaya, N. et al (2012). Meta-analysis of genome-wide association studies for panic disorder in the Japanese population. Translational Psychiatry, 2(11), p.e186.

[9] Nature.com, (2015). Translational Psychiatry – Table 2 for article: Meta-analysis of genome-wide association studies for panic disorder in the Japanese population. [online] Available at: https://www.nature.com/tp/journal/v2/n11/fig_tab/tp201289t2.html [Accessed 31 Aug. 2015].

[10] Smoller, J., Block, S. and Young, M. (2009). Genetics of anxiety disorders: the complex road from DSM to DNA. Depression and Anxiety, 26(11), pp.965-975.

[11] Gratacòs, M., Costas, J., de Cid, R. Bayés, M., et al (2009). Identification of new putative susceptibility genes for several psychiatric disorders by association analysis of regulatory and non-synonymous SNPs of 306 genes involved in neurotransmission and neurodevelopment. Am. J. Med. Genet., 150B(6), pp.808-816.

[12] Fitzgerald KD, e. (2015). Error-related hyperactivity of the anterior cingulate cortex in obsessive-compulsive disorder. [online] Available at: https://www.ncbi.nlm.nih.gov/pubmed/15691530/ [Accessed 31 Aug. 2015].

[13] BBC Horizon, (2015). OCD: A Monster in my Mind 24-30minutes. Available at: https://www.bbc.co.uk/iplayer/episode/b06874cc/horizon-20142015-16-ocd-a-monster-in-my-mind [Accessed 31 Aug. 2015].

[14] Hope4ocd.com, (2015). Neurobiology. [online] Available at: https://www.hope4ocd.com/neurobiology.php [Accessed 31 Aug. 2015].

[15] Albin, R. (2000). BASAL GANGLIA NEUROTOXINS. Neurologic Clinics, 18(3), pp.665-680.

[16] Chapman, D.E., Hanson, G.R., Kesner, R.P., and Keefe, K.A.  (2001) Long-term changes in basal ganglia function after a neurotoxic regimen of methamphetamine. J. Pharmacol. and Exper. Ther,  pp. 520-527.

[17] Karg, K., Burmeister, M., Shedden, K. and Sen, S. (2011). The Serotonin Transporter Promoter Variant (5-HTTLPR), Stress, and Depression Meta-analysis Revisited. Arch Gen Psychiatry, 68(5), p.444.

[18] Stein, M., Schork, N. and Gelernter, J. (2007). Gene-by-Environment (Serotonin Transporter and Childhood Maltreatment) Interaction for Anxiety Sensitivity, an Intermediate Phenotype for Anxiety Disorders. Neuropsychopharmacology, 33(2), pp.312-319.

[19] Jaffee, S. and Price, T. (2008). Genotype–environment correlations: implications for determining the relationship between environmental exposures and psychiatric illness. Psychiatry, 7(12), pp.496-499.

[20] Eley, T., Napolitano, M., Lau, J. and Gregory, A. (2010). Does childhood anxiety evoke maternal control? A genetically informed study. Journal of Child Psychology and Psychiatry, 51(7), pp.772-779.

[21] Ocduk.org, (2015). Deep Brain Stimulation (DBS). [online] Available at: https://www.ocduk.org/deep-brain-stimulation [Accessed 31 Aug. 2015].

[22] Evans-Lacko, S., Corker, E., Williams, P., Henderson, C. and Thornicroft, G. (2014). Effect of the Time to Change anti-stigma campaign on trends in mental-illness-related public stigma among the English population in 2003–13: an analysis of survey data. The Lancet Psychiatry, 1(2), pp.121-128.

[23] Zoella.co.uk, (2011). Zoella | Beauty, Fashion & Lifestyle Blog: Panic Attacks.. [online] Available at: https://www.zoella.co.uk/2011/12/panic-attacks.html [Accessed 1 Sep. 2015].

[24] Iamlivingwithanxiety.blogspot.co.uk, (2015). I am living with anxiety. [online] Available at: https://iamlivingwithanxiety.blogspot.co.uk/ [Accessed 1 Sep. 2015].

About the author

Medical student at University College London (1st Year). Passionate about science, design and photography.

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