Addressing Emotional Dysregulation and Potential Pharmacogenetic Implication of 5-HTTLPR Genotype in Attention Deficit Hyperactivity Disorder Free

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with delayed development of brain structures, particularly the prefrontal cortex which is responsible for executive function (EF) [1]. EF is constituted as the highest mental ability in humanity for self-regulation which consists of two dimensions: metacognition and inhibition [2‒5]. Individuals with ADHD will present with inattentive, impulsive, and hyperactive behaviors as described in the Diagnostic and Statistical Manual of Mental Disorders (DSM–5) of ADHD diagnostic criteria [6] due to executive developmental delay [1] of the metacognition and inhibition domains [7, 8]. The neurophysiology and neurogenetics of EF in ADHD amalgamate the observable psychophysiological manifestation of externalizing behaviors. The complexity of cross-disciplinary and interdisciplinary issues of interest is dissected and clarified in this review. Hopefully this review could provide some insights into the current mental health field which was ambushed by a problem that needs to be combated. The majority of the studies on ADHD investigated adolescent subpopulation concurrently with child subpopulation, resulting in under-revelation of the issue that had been described in the main text. The novel approach to ADHD in this review hopefully compensates for the limitation of current scientific literature from the methodological point of view. The revealed concerning issue is the suboptimal ADHD management outcomes during the developmental progression into adolescence and adulthood in relation to the under-managed emotional dysregulation in childhood.

The association between executive dysfunction and emotion dysregulation in ADHD can be explained from a psychophysiological perspective. As illustrated in Figure 1, impairment in cognitive dimensions of metacognition and inhibition under the EFs domain results in externalizing behaviors, such as hostility and defiance. Metacognition affects cognition of working memory use which is important for self-restraint. Behavioral manifestations of executive dysfunction such as inattention, distractibility, restlessness, psychomotor agitation, hyperactivity, hyperkinesis, impulsivity, and emotional dysregulation are the factors that lead to the development of comorbidities and functional impairments in adolescents and adults with ADHD as compared with children with ADHD [9‒12]. Figure 2 illustrates that the EF bifactor model structures the psychopathology of ADHD into an EF view.

According to Barkley (1997), teenage drivers with ADHD are 4 times more likely to be involved in automobile accidents at their fault and causing associated injuries compared with other adolescents [13]. In addition, adolescents with ADHD are more likely to have risky sexual behavior; they have 3 times more sexual partners and 4 times higher rate of sexually transmitted disease as compared to the controlled group [14]. Untreated ADHD in adolescents leads to limited educational success [15], peer relationship problems [16‒18], and substance use disorders [19].

These unresolved problems during adolescent ADHD have the potential to propagate further impairment into adulthood, as 75% of adolescents continue to have ADHD into adulthood [20]. Therefore, it is not surprising that over 80% of adults with ADHD have additional mental health comorbidities, such as depression (another comorbidity) [21]. With the presence of psychiatric comorbidities, ADHD adults are 7 times more likely to attempt suicide and 10 times more likely to die by suicide compared to adults without ADHD [22]. Furthermore, antisocial behavior and actions that break the law are common as evidenced by statistics from a Malaysian forensic hospital (Hospital Bahagia Ulu Kinta), showing that 25% of the 120 admitted patients had a history of childhood ADHD, and the prevalence of adult ADHD was 15.8% [23].

The bifactor model of EF informs us that metacognition and inhibition dimensions of EF require activation before an individual starts a task. This requires working memory under the metacognition dimension in order to organize the materials needed and estimating the time needed in order to complete the task. At the same time, effort and focus need to be sustained by managing frustration and modulating feelings in the process of doing the task in order to keep motivated to accomplish the task. These are also under the control of metacognition. The inhibition dimension of EF enables an individual to give up immediate consequences in order to pursue delayed gratification, a very important component for social and occupational success. Impairment in these two dimensions of metacognition and inhibition will result in social and occupational impairments for individuals [24, 25].

Executive dysfunction in adults and adolescents with ADHD are associated with decreased intentional cognitive control to deactivate the default mode networks (DNMs) due to set-shifting impairment [26, 27]. Mood disorders among individuals with ADHD are due to overactive DNMs. EF is required to switch off the default mode network, so that the individual is able to engage in the focus mode network. The disinhibited DNMs result in the tendency to develop psychopathology of mood disorders [28, 29]. Many reports have revealed that those with DNM are predisposed to develop addiction issues, such as substance use-related disorders or extreme social media engagement [30, 31]. This is due to the default response disinhibition [32‒34], which is also associated with Cluster B personality disorder [35].

In order to identify ADHD comorbidities and their prevalence, a search was done to identify publications over the past 10 years (2011–2021) from Ovid MEDLINE, PubMed, and PsychINFO with additional search limits to locate English language written publications over the past 10 years (2011–2021).

In the first stage of the screening process, the keywords included comorbidities (“mood disorder*” OR “anxiety disorder*” OR “impulse control disorder*” OR “intermittent explosive disorder*” OR “conduct disorder” OR “oppositional defiant disorder” OR “Attention Deficit and Disruptive Behavior Disorder” OR “substance” OR “Substance-Related Disorder” OR “eating disorder*” OR “Feeding and Eating Disorders” OR “sleep disorder*” OR “Sleep Wake Disorder*” OR “personality disorder*” OR “Antisocial Personality Disorder” OR “Borderline Personality Disorder”), social problems (Driving OR “risk-taking” OR “driving related-risks” OR “Suicide” OR “Suicid*” OR “completed suicide” OR “attempted suicide” OR “self harm” OR “Self-Injurious Behavior” OR Criminality OR “legal offen*” OR “Sexual Behavior” OR “Family Conflict” OR “Family Relation*”), and Quality of Life (QoL) (“Quality of Life” OR “Burden of Disease” OR “Global Burden of Disease” OR “Caregiver Burden” OR “Burden”). (Refer to online supplementary material at www.karger.com/doi/10.1159/000529732 for a complete set of search terms used).

The titles and abstracts of identified publications were screened. References cited/papers reviewed only included studies on adolescents with ADHD (10–19 years) and adults with ADHD (>19 years) with impaired quality of social, academic, or occupational functioning, with adequate information to allow for the estimation of at least one relevant outcome as outlined above. Interventional studies or publications which reported on pediatric participants (0–9 years old), other diseases (not ADHD), and involving nonhuman participants were excluded.

For the second stage of screening, full texts of the publications were extracted and assessed. Only publications with correlational designs, observational studies, retrospective cohort studies, case-control studies, cross-sectional studies, and literature review (qualitative or quantitative) were included.

Data were extracted from included studies using available data extraction forms/tools according to the selection criteria. Information was collected on general details (title, authors, reference/source, country, year of publication, setting), participants (age and gender), and results (the identified ADHD burdens/impairment). Data were presented in summary form and descriptively in table form for general details (title, authors, reference/source, country, year of publication, setting), participants (age and gender), and results (the identified ADHD burdens/impairment and the efficacy of pharmacological intervention in reducing ADHD impairment) (refer to online supplementary material). A narrative synthesis was performed for the comparison of the identified burden/impairment of ADHD in both ADHD adolescent group and ADHD adults’ group.

The literature review was undertaken using the criteria described above, with each of the relevant search terms entered concurrently. The first stage screening process involved a screening of 3,399 articles (21 from PubMed, 45 from Ovid, and 3,335 from PsychINFO) identified using the search terms included in online supplementary material. A total of 2,484 studies were retrieved from PsychINFO for analysis after applying the further search limits to exclusively select English publications from 2011 to 2021. Publications with irrelevant study designs have to be excluded manually because these were unable to be technically filtered out through search limits using Ovid MEDLINE and PubMed at stage 2 screening level (Fig. 3).

After removing the duplicates using Zotero software, 92 publications were identified, of which 42 were removed due to the title and abstract mismatch. The full texts of the remaining 50 publications were reviewed. After excluding the studies with irrelevant study designs, only 24 eligible publications were included for the final review (Fig. 4). These are from 11 different “Western” countries (Canada, Sweden, Spain, the UK, Germany, the Netherlands, Belgium, the USA, Switzerland, France, and Norway) and 3 different “Eastern” countries (Korea, Taiwan, and Japan) as well as 1 publication from Nigeria. The review (Table 1, Table 2; Fig. 5) of recent ADHD literature as described above incorporated the following elements in order to provide a more comprehensive understanding of the burdens according to the bifactor model of EF: (a) rate of comorbidities with externalizing behavior reported from Western countries (26.7%) is more prevalent than the reported rate from Eastern countries (18.1%) [33‒38], (b) rate of comorbidities with internalizing behavior reported from Eastern countries’ publications (36.5%) is more prevalent than the reported rate from Western countries (20%) [39‒45], (c) similar rates of comorbidities with both externalizing and internalizing behavior reported are from Eastern countries (27.2%) and Western countries (27.6%) publications [34, 36‒42].

Suicide rates reported from Eastern countries was 36.5% [34, 43‒45], almost twice the rate of the reported suicide rate in Western countries at approximately 20% [46‒48].

Burden addiction including substance abuse, pathological gambling, and internet addiction in Western countries was 40% [29, 33, 35, 37, 45, 47, 48] almost twice the reported rate in Eastern countries at 18% [38, 45].

It has been reported that Wender Utah Rating Scale (WURS) is one of the validated rating scales suitable to assess behavioral manifestations of executive dysfunction which are symptoms of inattention, restlessness, and impulsivity in ADHD in bipolar type II disorder patients [49]. Aggression tendency and social problems assessed using WURS are targeted core issues that result in ADHD impairment. Unaddressed emotional dysregulation in ADHD can be manifested as aggressiveness which subsequently affects social functioning [49‒52]. The potential genetic role of the 5-HTTLPR (serotonin-transporter-linked promoter region) genotype in manifesting the emotional impulsivity phenotype in bipolar type II disorder, but not in other mood disorders like bipolar type I disorder or major depressive disorder. An interesting study also reported that the 5-HTTLPR genotype was significantly associated with the total WURS score and linked with the impulsivity factor of the rating scale in bipolar type II disorder patients. There is strong evidence of a potential role of the 5-HTTLPR genotype in manifesting the phenotype of childhood ADHD impulsivity [53].

Among the regulating mechanisms of serotonin in the synapse of neurons is the serotonin transporter. It primarily does this by removing serotonin from the synapse and then returning it to the presynaptic neuron to be degraded or re-released in the future [54]. The serotonin transporter is also known as the solute carrier family 6 member 4 (SLC6A4) protein. The serotonin transporter gene (SLC6A4) is located on chromosome 17q11.1–q12 [55]. The SLC6A4 is upregulated, thereby increasing the availability of the serotonin transporter protein by various mechanisms [56]. The serotonin-transporter-linked promoter region (5-HTTLPR) is involved in upregulation of SLC6A4 [56].

The 5-HTTLPR is 20–23 base pairs long and consists of repetitive GC-rich elements. A deletion/insertion in the 5-HTTLPR was first reported to create a short (S) allele and a long (L) allele (14- and 16-repeats, respectively) [55]. There are at least 14 alleles of the 5-HTTLPR [55], which are named and categorized into either short (s) or long (l) alleles based on the number of tandem repeats:

• • Short alleles, s (4 alleles: 14-A, 14-B, 14-C, 14-D)

• • Long alleles, l (6 alleles: 16-A, 16-B, 16-C, 16-D, 16-E, 16-F)

• • Other alleles (4 alleles: 15, 19, 20, 22)

There are 3 possible genotypes, s/s, s/l, and l/l, which indicate that a person has either 2 short alleles, 1 short and 1 long allele, or 2 long alleles, respectively [57]. In general, the short allele (s) is associated with less efficient transcription than the long allele (l) [54]. Hence, it is expected that the short allele (s) will be associated with a decrease in the availability of the serotonin transporter protein, thus resulting in decreased levels of serotonin reuptake from the synapse. Several studies show the short allele (s) is associated with greater sensitivity to stress [54]. A meta-analysis of 54 studies and 40,749 subjects found a relationship between stress and depression, with the s allele associated with an increased risk of developing depression under stress (p = 0.00002) [54]. The associations of 5-HTTLPR with the phenotypes are shown in Table 3.

The 5-HTTLPR variant of interest was significantly associated with impulsivity, precisely the ll genotype. The degree of impulsivity was dependent on the number of l alleles in the 5-HTTLPR genotype, with ll genotype individuals displaying the highest degree of impulsivity while the other genotypes ls and ss showed milder degrees of impulsivity. The 5-HTTLPR genotype may confer a vulnerability to environmental stress-induced depression and emotional impulsivity and is the manifestation genotype [53].

The finding of a meta-analysis further supported the association of the 5-HTTLPR I allele with depression, but one-third of the included studies in the meta-analysis had shown that there is no association between s allele and environmental stress-induced depression [58]. However, another meta-analysis [54] revealed that the s allele was related to genetic vulnerability of environmental stress-induced depression, although the association between the s allele of the 5-HTTLPR and environmental stress-induced depression is not unequivocal from these two meta-analyses [54, 58].

For the purposes of this review, the ll genotype will be termed “externalizing serotonergic genes” and the ss genotype will be named “internalizing serotonergic genes” in this review to further illustrate the potential and subtle confounding impact of 5-HTTLPR genotype on the development of burdens in adolescents and adults with ADHD. According to Barkley [5, 8], two-thirds of ADHD’s executive dysfunction is associated with neurogenetic deficit which is extremely heritable at 99%. The neurogenetic factor is associated with emotional, arousal genetic liability in ADHD [59‒61]. The neurogenetic deficit in ADHD is also associated with “externalizing serotonergic genes” [56, 57, 62‒64] and externalizing factors [65‒67]. Expression of “externalizing serotonergic genes” affects the metabolic pathway of serotonin [68‒71] and has been linked to emotional impulsivity behaviors, such as anger, hostility, impatience, frustration.

The study from Puerto Rico on the significance of childhood ADHD included WURS in the process of data collection [72]. Coincidentally, the same rating scale was used by two of the reviewed publications to assess the similarities between emotional dysregulation in children and adults suffering from ADHD and mood disorders [53, 73]. WURS is associated with the 5-HTTLPR genotype and the impulsivity phenotype in childhood ADHD features [53]. The application of WURS, the psychological phenotype of heightened emotional intensity in adult ADHD subjects, was detected. This was distinct from the mood presentation in subjects with other mood disorders that displayed lower emotional intensity [73]. The synchronicity of the screening tool used in these three studies suggests that the 5-HTTLPR genotype of interest could play a potential genetic role in behavioral manifestation of emotional impulsivity. Perhaps it may be a possible confounding factor for emergence of criminal behavior in adulthood that is progression from unresolved emotional impulsivity manifest in childhood.

Prolonged response inhibition time is a potential ADHD neurocognitive endophenotype [74, 75] that arises from complex allelic interaction and environmental factors. ADHD endophenotype with prolonged and inconsistent reaction times predisposes individuals to anger, hostility, impatience, and frustration. These kinds of behavior also can be seen in oppositional defiant disorder (ODD) and antisocial personality disorder (ASPD) which are behavioral disorders with underlying executive dysfunction [76, 77]. Therefore, the potential role of the 5-HTTLPR genotype could be associated with ADHD neurocognitive endophenotype [78]. The relationship between 5-HTTLPR and certain psychiatric phenotypes and ADHD symptoms is shown in Table 3.

Metacognition impairment can result in a weak ‘self-awareness cognitive radar’ to detect the arising primitive reaction toward stimulus. This may lead to uninhibited expression in verbal or/and motor reaction. These primitives driven behaviors are the impulsive behavioral manifestation in ADHD. Adolescents and adults with ADHD express forms of cognitive impulsivity, emotional impulsivity, and motivational impulsivity. These can be more subtle as compared with impulsivity behavior presented in children where more obvious forms of motor impulsivity and verbal impulsivity are demonstrated. The subtle impulsivity in adolescents and adults with ADHD manifest as externalizing behavior that subsequently causes functioning impairment.

Executive dysfunction results in communication and interpersonal relationship challenges in establishing adaptive social engagement [79]. It has been reported that subjects with adult ADHD showed more intense emotional reaction than subjects with bipolar disorder and subjects in the control group [73]. Emotional impulsivity as a result of response disinhibition [2, 80, 81] in ADHD causes individuals to overstep or ignore appropriate social boundaries. These actions may be viewed by others including partners as disrespect which can lead to interpersonal relationship problems [65‒67]. Therefore, it is not surprising that there is a higher divorce rate among adults with ADHD due to the significant difference in the displayed emotional intensity compared to adults with bipolar disorder and controls [73]. Self-awareness in adults and adolescents with ADHD contributes to this poor awareness of social cues and trouble processing social details. Impairment in social functioning [36, 41, 42, 82‒84] among adolescents and adults with ADHD can be explained by emotional impulsivity deficiencies in EF components. All this impacts their interpersonal relationships in a negative manner [73].

Executive dysfunctions directly impact social and occupational functioning. Several studies showed that adults with ADHD have more difficulty adapting to the executive demands in the workplace [48, 85, 86]. Interpersonal relationship issues that are affected by executive dysfunction also have a direct impact on occupational functioning [36, 85].

Metacognition deficit alone will lead to comorbidities with internalizing behaviors, such as anxiety and depression. Metacognition deficit due to anxiety is learned or acquired from the environment. In both these ADHD populations of concern, self-awareness under the metacognition dimension is overloaded with perceived fear and triggers the fight-or-flight psychophysiological response that impairs the prefrontal cortex function. This impairs working memory and proactive control which reduce the cognitive capacity for problem solving and decision making [87].

Executive dysfunction in adults and adolescents with ADHD is associated with decreased intentional cognitive control to deactivate the default mode networks due to set-shifting impairment [56, 57]. Mood disorders among individuals with ADHD are due to overactivated DNMs. Executive function is required to piston off the DNM so that the individual is able to engage in the focus mode network. The disinhibited DNMs result in the tendency to develop psychopathology of mood disorders [58, 59]. Substance use-related disorders are particularly more prevalent in the Western countries than the Eastern countries [36‒38, 40, 72, 88, 89]. DNM associated with hedonic adaptation [90] in ADHD leads to behaviors such as emotional eating that result in obesity and harms physical health. Novelty or danger-seeking behaviors in ADHD like violating traffic regulation and unprotected sex further jeopardize physical health [73, 91‒93].

Emotional impulsivity, motivational impulsivity, and cognitive impulsivity contribute to high-risk behavior [36‒38, 40, 72, 88, 89] and criminal offenses [42, 72]. According to previous reports, the psychiatric disorders which present with externalizing behavior are ODD, borderline personality disorder [94], and ASPD. There is an association between childhood ADHD diagnosis, conduct disorder (CD), and ASPD. One of the reviewed publications stated that 75% of the patients with childhood ADHD diagnosis with or without persistence into adulthood had comorbid CD [43].

The association among ADHD, CD, and ASPD is further strengthened by logistic regression and personality disorder screening scores. According to the review, severity of CD is directly proportional to coexisting antisocial personality disorder risk. ADHD with the presence of a CD diagnosis further increases the risk of coexisting ASPD. As highlighted by several studies, all participants with ADHD and comorbid CD had positive scores on the personality disorder screening. ADHD with comorbid CD is seen as a distinct subtype that should be classified independently from ADHD and CD alone [95].

Legal issues and substance-related problems are prevalent among individuals with Cluster B personality traits which are associated with ADHD neurogenetic factors [53, 73]. Cluster B personality traits link ADHD and ODD to a common genetic liability we called externalizing factor which is dominantly dopaminergic regulated [96] and associated with both metacognition and inhibition dimension impairment or inhibition dimensions alone.

A review of recent ADHD literature to provide a more comprehensive understanding of the burdens according to the bifactor model of EF was performed [17, 18] (Table 1; Fig. 5). Rates of comorbidities with externalizing behavior reported from Western countries [26.7%] are more prevalent than the reported rate from Eastern countries [18.1%] [43, 44, 46, 53, 72, 88]. Rates of comorbidities with internalizing behavior reported from Eastern countries’ publications [36.5%] are more prevalent than the reported rate from Western countries [20%] [36‒38, 45, 47, 48, 85]. Similar rates of comorbidities with both externalizing and internalizing behavior reported are from Eastern countries [27.2%] and Western countries [27.6%] publications [39‒42, 46, 73, 82, 97]. Suicide rates reported from 36.5% Eastern countries [36, 45, 46, 85] was almost twice the rate of the reported suicide rate in Western countries ranging from 20% [37, 38, 44]. Addictions include substance abuse, pathological gambling, and internet addiction in Western countries ranging from 40% [36‒38, 40, 72, 88, 89] are almost twice the reported rate in Eastern countries ranging from 18% [36, 41]. The trending issues in Eastern countries are occupational impairment [98‒101], mental health issues, and suicidal behavior [102]. While the trending issues in Western countries are substance use disorders [101], physical health issues, and legal issues [103].

The molecular pathophysiology of 5-HTTLPR variation can be explained. The l allele is more receptive to stimulant pharmacological intervention by acting on the raphe nuclei located in the median column of the reticular formation which is important in regulating arousal and attention [104‒106]. This affects the trigeminal cardiac reflex which can have either parasympathetic or sympathetic effect on the cardiovascular physiology. The afferent signal conducted by the trigeminal nerve is relayed to the autonomic nervous system-modulated efferent pathways through the short internuncial fibers in the reticular formation. For sympathetic effect, the efferent signal is transmitted to the trigeminal nucleus caudalis and the parabrachial nucleus to exert sympathetic response on the cardiovascular system [107‒111]. The role of the trigeminal system in regulating the autonomic nervous system that affects heart rate variability [107, 112] has a major influence on brain activity. The sympathetic efferent physiological reaction is followed by parasympathetic efferent-induced physiological effect which involves the vagus nerve. Through the myelinated ventral vagal complex [113], nitric oxide is released to depolarize an adjacent neuron through excitatory postsynaptic potential for dopamine synthesis and ends with a reverse process due to an inhibitory response through inhibitory postsynaptic potential [114]. Nitric oxide-mediated latent vasodilation [112] reduces cerebral blood flow [115] and oxygen metabolism in the brain [116] due to its lipid-soluble properties [117]. However, interestingly, there is a greater proportion of cerebral blood flow directed to the gray matter than the amount of cerebral blood flow to other parts of the brain structure [115]. This explanation provides a potential implication to accelerate the brain development in ADHD up to the normal prefrontal cortex and EFs development [118] if the patient stays on treatment long enough.

Stimulant medication acts as a dopaminergic neurogenetic treatment by crossing the blood-brain barrier to alter the expression of the “externalizing serotonergic genes” in order to temporarily improve the ADHD behavior like inattention and hyperactivity. At the same time, dopaminergic emotions also can be reduced as the medication downregulates the externalizing factor which is associated with “externalizing serotonergic genes” [56, 57, 62‒64]. Stimulant medication has the potential to permanently alter the expression of serotonin reuptake transporter which is associated with “externalizing serotonergic genes” [56, 57, 62‒64]. The externalizing behavior is due to the ADHD neurogenetic executive dysfunction to regulate internalizing negative emotion. Therefore, treating ADHD with stimulant medication may result in improvement in externalizing behavior [119‒122] and managing ADHD symptoms [123]. The mechanism of action to understand the influence of polymorphisms on pharmacodynamics and symptom control is explained in Fig. 6a, b and Table 4.

The 5-HTTLPR variants with s allele are more receptive to non-stimulant. Sympathomimetic pharmacological agents (non-stimulant) like clonidine and guanfacine are alpha agonists that act similarly as stimulant pharmacological agents on the central nervous system. Research evidence regarding the mechanism of action on biomolecular level is well established for clonidine and guanfacine [124‒126]. However, research evidence regarding the mechanism of action on psychophysiology level is less established for both respective pharmacological agents. Stimulation of adrenergic receptors on the afferent vagus nerve [127] that is relayed to the hypothalamus is associated with such neurophysiological changes [128, 129] on the cognitive level [114, 130]. The mechanism of action to understand the influence of polymorphisms on pharmacodynamics and symptom control is explained in Figure 7 and Table 4.

In terms of the accuracy and specificity of prevalence data, some of the references used were older than 10 years, which were not as current as we would have liked. Some publications after 2015 cited prevalence data from before 2003. However, they were used because they provided the most reliable and widely used prevalence rates in the absence of more recent information. [40, 131‒137].

The review that has been undertaken allows us to draw two conclusions. First, the Wender Utah Rating Scale (WURS) is a better and more comprehensive tool to assess the significance of impairment in adults and adolescents with ADHD. Second, the 5-HTTLPR genotypes in relation to ADHD neurocognitive endophenotype present a potential for pharmacogenetic intervention. The additional information presented in this review hopefully informs future ADHD genetics studies investigating neurocognitive endophenotype that is associated with emotional dysregulation.

No funding sources to be declared.

No conflict of interest to be declared.

Tan Hao Xuan determined the documentative research topic, performed the literature review, and drafted the manuscript. Adam Harish reviewed the prevalence section and the associations of 5-HTTLPR genotypes. Sivakumar Thurairajasingam provided co-supervision and insight into aspects of psychological medicine. Maude Elvira Phipps provided main supervision throughout the scholarly intensive project that led to this work and edited the manuscript.