Table of Contents
Introduction
Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder affecting approximately 6.1 million children. It is characterized by impulsivity, inattention, and hyperactivity. Impulsivity is characterized by recklessness and impatience. Inattention is defined as an inability to finish one task without becoming distracted by another. Hyperactivity is simply increased motor activity, which can present as fidgeting, excessive talking, or difficulty engaging in leisure activities. This can lead to issues with academic, occupational, and social functioning.
ADHD begins in childhood and often persists into adulthood, leading to consequences including anxiety, depression, delinquency, and drug abuse. ADHD results from a multitude of genetic and environmental risk factors, and it is considered to be a heterogeneous disorder, meaning that each individual experiences variations in symptoms as well as differing severity of symptoms. Despite this, patients with ADHD are clustered into three groups: predominantly inattentive (ADHD-PI), predominantly hyperactive-impulsive (ADHD-HI), and combined (ADHD-C).
It is known that ADHD is associated with dysregulated frontal subcortical cerebellar pathways which module reward response, attention, inhibitory control, and motor behavior. In particular ADHD impacts the prefrontal cortex, basal ganglia, limbic system, and reticular activating system. The prefrontal cortex is involved in decision making, planning, and social behavior. The limbic system, located around the thalamus, regulates basic emotions, motivation, learning, and memory. The reticular activating system mediates attention. Patients with ADHD have also been documented to have smaller prefrontal cortexes, cerebellums, corpus callosums, and basal ganglia.
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Currently, well-studied animal models fall into one of two categories: genetically induced and environmentally induced. Transgenic rodent models include the dopamine transporter knock out mice, dopamine receptor knock-out mice, thyroid hormone receptor transgenic mice, the coloboma mutant mouse model, and spontaneously hypertensive rats. Environmentally induced rodent models include the ethanol exposure mouse model and the nicotine exposure mouse model.
Each model will be assessed for its face, construct, and predictive validity. A model with face validity will mimic the symptoms and behavioral characteristics of ADHD. Capturing the ADHD symptoms in an animal model is a difficult, as many models only possess two of the three ADHD hallmarks. A model with construct validity will possess similar underlying mechanisms to ADHD, which is also difficult because it is known that ADHD results from a wide variety of genetic abnormalities. Finally, a model with predictive validity will have its symptoms relived via administration of methylphenidate or other drug used to successfully treat ADHD.
Risk Factors
Genetic components of ADHD were traditionally studied utilizing twin and family studies. These studies often rely on maternal or a teacher’s assessment of symptoms present and severity. While it is possible that mothers or teachers do not properly assess the child’s symptom severity, it has been shown that both parties produce similar assessments. These studies have shown strong inheritable components of ADHD, but issues arise regarding separating genetics and environment for twins sharing the same environment and being exposed to the same environmental influences, creating a need for genetic studies.
Identifying specific genes associated with ADHD has been completed by three major strategies: genotyping many genetic markers in families where pairs of siblings have been diagnosed with ADHD, comparing allele frequencies between ADHD patients and non-ADHD patients, and Genome Wide Association studies.
Genome Wide Association Studies have shown comorbidity of ADHD with depression, bipolar disorder, autism spectrum disorders, dyslexia, conduct disorder, tic disorders, and schizophrenia due to 4 key loci shared. Additionally, common genetic variants were found to attribute to 40% of ADHD’s heritability, however, other studies have reported ADHD is 60% to 80% heritable. Genes associated with ADHD include those than encode for sodium dependent dopamine transporters, dopamine receptors 4 and 5, the serotonin 1B receptor, the 5-HTT serotonin receptor, norepinephrine transporters, and SNAP-25. Dopamine transporters are responsible for reuptake of dopamine from the synaptic cleft so dopamine can reenter the cytosol to be packaged into vesicles.
The D4 dopamine receptor gene (DRD4), highly expressed in the prefrontal cortex, is one of the genes most strongly linked to ADHD. The D4 receptor is inhibitory G protein coupled receptor, downregulating production of cAMP. The D5 dopamine receptor is also a G protein coupled receptor, but it is excitatory and promotes the production of cAMP. The serotonin 1B receptor is a type of autoreceptor, known to play a role in Obsessive Compulsive Disorder (OCD). The norepinephrine transporter is responsible for uptake of norepinephrine into the synaptic cleft. SNAP-25 is a type of transmembrane snare protein, assisting in vesicle fusion and exocytosis. Catechol O Methyltransferase (COMT) is an enzyme involved in dopamine breakdown. Numerous studies of the gene encoding this enzyme have found contradictory findings regarding its potential link to ADHD.
- ADHD and depression are often comorbid. Studies have found those with ADHD are three times more likely to report depression. It can be difficult to separate ADHD from depression because both disorders impact mood, concentration, sleep, and motivation, but depression does not usually present until adolescence.
- ADHD and bipolar disorder can also occur together, as approximately 20% of ADHD patients are also diagnosed with bipolar disorder. Both of these disorders can affect mood, sleep, concentration, and reported energy levels. One key difference is that a severe mood change in a person with ADHD is often triggered by a particular event, while bipolar patients report manic or depressive episodes lacking any particular trigger. Interestingly, the majority of patients with ADHD and bipolar disorder are male.
- ADHD and autism spectrum disorders both impact relationship formation. A major difference is that children with ADHD are usually aware of social rules, they are simply unable to follow them due to being impulsive and inattentive, unlike children on the autism spectrum that are often simply unaware of the rules. It is estimated that 10% of children with ADHD are also diagnosed with autism spectrum disorders.
It is estimated that approximately 55% of ADHD patients also have a learning disability, most commonly dyslexia, a heritable disorder that impacts learning. Patients with dyslexia often struggle with recalling words as well as phonemic awareness, which makes reading and speaking difficult. It is common that a dyslexia diagnosis is not considered because the child’s doctor or parents assume reading and speaking is challenging due to the child’s inability to focus.
More often than not, tic disorders are comorbid with another disorder such as OCD, major depressive disorder, and ADHD. Tics can be vocal or motor, and categories of tic disorders include: transient tic disorders, chronic tic disorders, and Tourette syndrome. ADHD and tic disorders are linked because it has been documented that taking ADHD medications can result in tics, but it is believed that those with tic disorders were genetically predisposed to begin with, and ADHD medications do not necessarily cause tics.
ADHD and schizophrenia can both impact attention and impulsivity. One study found that 24% to 47% of schizophrenia patients reported attention deficits in childhood. In a much larger study it was found that schizophrenia patients are twice as likely to report attention deficits in childhood. Another study found that 58% of patients that exhibited attention deficits in childhood were diagnosed with schizophrenia in adulthood, indicating attention deficit as a potential predictor of psychosis or schizophrenia.
ADHD and oppositional defiant disorder, conduct disorder, and antisocial personality disorder are commonly comorbid. Those with oppositional defiant disorder often possess the following traits: aggressive tendencies, lack of patience, lack of empathy, deceitfulness, and a general lack of concern for and resistance towards rules and social norms. Oppositional defiant disorder often begins in childhood, and progresses into conduct disorder in adolescence. It has been found that both ADHD and conduct disorder are associated with a serotonin transporter gene. It has also been documented in family studies that conduct disorder and ADHD together create an even stronger line of evidence for inheritance than ADHD alone. A diagnosis of conduct disorder in adolescence often leads to antisocial personality disorder in adulthood. It is unknown if ADHD increases the risk for antisocial personality disorder in adulthood, or if a conduct disorder diagnosis in adolescence is the main contributor.
Gender Differences in ADHD
Although it is believed that genetic factors account for the majority of ADHD heritability, environmental factors may still play an important role in ADHD. Factors such as prenatal exposure to nicotine, cocaine, alcohol, caffeine, and antidepressants have been documented to influence ADHD, as well as maternal stress and depression. Low birth weight and premature birth have also been correlated with ADHD.
Interestingly, ADHD is more common in males than females, for reasons yet to be uncovered. Females with ADHD are more likely to be grouped as predominantly inattentive than males. Though ADHD manifests into different symptoms for males and females, family and twin studies agree that ADHD in males and females is equally inherited, disagreeing with the hypothesis that each gender possesses unique genetic risk factors.
Treatment
Methylphenidate, also known as Ritalin, is a stimulant and the current treatment of choice for ADHD. It functions by blocking sodium dependent dopamine transporters. Methylphenidate increases extracellular dopamine levels and activates post synaptic dopamine receptors. However, impaired dopamine receptor signaling as well as sensitization to dopaminergic stimulants is known to increase the risk of drug addiction (Robinson and Berridge, 1993; Milberger et al., 1997), so there is concern regarding its safety.
Like methylphenidate, cocaine blocks the dopamine transporter and elevates extracellular dopamine levels (Jones et al., 2000). Cocaine is highly addictive and it has been found that non-human primates will self-administer cocaine, which is a typical characteristic of addiction (Johanson and Schuster, 1975; Bergman et al., 1989). Due to the similar mechanisms of methylphenidate and cocaine, there is concern that methylphenidate is equally addictive (Vastag, 2001). It is difficult to study methylphenidate’s addictive potential and ADHD as a whole because most animal models only possess one or two of the three hallmarks of ADHD, particularly hyperactivity.
Studies currently published regarding the addictive potential of methylphenidate are conflicting. Some studies correlate methylphenidate use with an increased risk for addiction (Brandon et al., 2001; Achat-Mendes et al., 2003), while others disagree (Andersen et al., 2002b; Augustyniak et al., 2006; Guerriero et al., 2006; Thanos et al., 2007). Some of the contrasting results can be explained by varying dosages, administration route, tests used to assess addictive potential, and the developmental stage when methylphenidate administration started.
