Psychiatric Drugs and The Brain - Planning

Aimee Lowth z3330151
Fiona Hart z3253251
Madelyne Bisby z3415450
Ashton Curry-Hyde z3360668


Psychiatric Disorders, Drugs and the Brain





Introduction

David Anderson’s TED talk “Your Brain is More Than a Bag of Chemicals”, is based on his research, “Drugs, Dopamine and Drosophila – a Fly Model for ADHD”. Anderson explains the effects of current drug treatments used in treating mental illness and the limitations of a chemically-based perspective of the brain. Using his own research on Attention Deficit Hyperactivity Disorder (ADHD) in Drosophila melanogaster, Anderson provides insight into the neuronal basis of the brain and potential new drug treatments for mental illness, such as ADHD, with reduced aversive side effects.

In ADHD, the individual normally displays levels of hyperactivity, attention and impulsivity which are typically inappropriate for their age. ADHD is classically diagnosed in childhood with a point prevalence of 3-7% at 7 years (Ebejer et al, 2012; Manos, 2010). Common risk factors for ADHD include low birth weight, negative attention from parents and physical and emotional neglect (Ebejer et al, 2012).

While there are several studies that indicate disruptions in the frontocerebellar circuits and frontostriatal circuits are the cause for several symptoms related to ADHD (Nigg, J., et al. 2005; Krain et al. 2006; Swanson et al. 2002; Durston et al, 2003), an in depth analysis of the genetic inheritance of several factors corresponding to ADHD by Faraone et al, 2005, indicates that the genetic inheritance of several mutations, and the resulting susceptibility to ADHD, is the prime component in understanding ADHD as a mental illness, as a result of genetic mutations and the subsequent chemical imbalances experienced in the brain.

Anderson’s research into ADHD in Drosophila melanogaster, and the correlation to ADHD in humans is an incredibly intriguing topic of research. Anderson’s passionate expression of his alternative views towards a controversial topic such as the chemistry of the human brain, and his subsequent work in this field, provided a fantastic research opportunity. All of these factors provided us with an interest to read further into an area of research that we could learn a lot from, and hence, begin to understand further, a disease that affects so many of the population.


Neuroscientific Context


Attention Deficit Hyperactivity Disorder (ADHD)


Behaviours and symptoms

Within the diagnosis of ADHD, patient behaviours are characterised by impairment in multiple functional domains, such as memory, attention and organisation. The DSM-IV defines ADHD as a cluster of symptoms within two dimensions: hyperactivity and impulsivity, which have to be consistent to a degree that is maladaptive and inconsistent with developmental levels (Ghanizadeh, 2012; Steinau, 2013). Dependent on the dimensions within which the participant corresponds to, there are three nominal sub-types of ADHD: predominately hyperactive-impulsive (ADHD-H), predominately inattentive type (ADHD-I) and combined type (ADHD-C). Comprehensive reviews of the DSM-IV criterion suggest that these dimensions accurately represent functional and behavioural correlates of inattention and hyperactivity-impulsivity however lack long-term stability of sub-types (Willcutt et al, 2012). The DSM-V, released in 2013, retained the DSM-IV wording of all 18 symptoms but has increased the prevalence of ADHD by revising criterion to increase relevance for children, adolescents and adults (Steinau, 2013; Dalsgaard, 2013).

Children affected by ADHD typically suffer from reading difficulties, poor social interaction and emotional regulation and impaired motor performance (Ebejer et al, 2012). Only 66% of children diagnosed with ADHD continue to exhibit symptoms in adulthood and continue to meet DSM-IV criteria (Durell et al, 2013). Adults with ADHD commonly exhibit lower educational attainment, poor relationship quality and high rates of unemployment. In addition, adults with ADHD have higher incidences of co-morbid psychiatric disorders, such as conduct disorder, mood disorders, anxiety and substance disorders (Ebejer et al, 2012; Manos, 2010).

Causes of ADHD

The prefrontal cortex and striatum are key areas involved in understanding ADHD. The prefrontal cortex controls attention, planning and impulse control including the inhibition of inappropriate actions (Arnsten A, 2006). The striatum plays a role in planning and modulation of movement pathways as well as other cognitive processes involving executive function (Rolls E, 1994; Voytek & Knight, 2010). These structures can be seen in Figure 1 below.

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Figure 1. Key Brain Areas in ADHD (Source: Henkel, J. 2009. Food and Drug Administration)

Recent studies, such as Crosbie and Schachner, 2001, have shown that there is a significant genetic component to the cause of ADHD. Their research concluded that children with a first-degree relative with ADHD were more likely to display poor response inhibition than children who did not have this family history. Response inhibition is critical, as it is considered a primary marker in the diagnosis of ADHD.

A study conducted by Steven Faraone et al, 2005, attained a heritability estimate of 76% for ADHD in monozygotic twins. Despite such a high genetic estimate, Faraone et al. notes the need for further studies examining the interacting roles of genes and the environment in forming ADHD behavioural phenotypes (Faraone et al, 2005).

Such gene polymorphisms have corresponding chemical factors and phenotypic dysfunctions. The neuroimaging analysis by Nigg and Casey, 2005, indicated that an independent or combined disruption in the frontocerebellar circuits and frontostriatal circuits resulted in an inability to maintain and adjust behaviours according to social setting and was related to the input of the prefrontal cortex (Nigg, J., Casey, B. 2005). This was supported by further neuroimaging findings on these circuits and their role in ADHD by Krain and Castellanos, 2006, Swanson and Castellanos, 2002 and Durston et al., 2003. Contrastingly, it was found that the dopamine transporter gene, DAT1, could be responsible for the short attention span issues associated with ADHD (Bellgrove et al., 2005). Although unclear, mutations of the DAT1, SLC6A3 gene is thought to potentially affect DAT1 expression, and thus lead to a deregulated DAT and thus impaired dopaminergic transmission. Currently only examined in animal models, a mutation of the DAT, SLC6A3 gene is associated with increased striatal DAT activity, decreased dopaminergic tone and deficits in inhibitory behaviour (Gainetdinov et al, 1999).


The Dopamine Neurotransmitter


As supported by the research of Faraone et al, 2005, an understanding of the neurotransmitter dopamine is crucial in understanding ADHD. Dopamine is associated with altering attention, arousal, motor control and reward motivated behaviours. It also controls the release of certain hormones, such as noradrenaline (Missale, et al).

Dopamine receptors play a critical role in the mediation of the HPA axis in both a pathological and physiological sense (Pivonello, 2007). Dopamine receptors have two forms: D1-like receptors and D2-like receptors. Although each type is situated in differing parts of the brain and perform different functions, both receptor types change cAMP concentration. Changing cAMP concentration affects the accumulation of regulation protein kinase A activity which in turn affects multiple downstream effectors via phosphorylation or dephosphorylation (activation or inactivation) (Vallone, 2000).

D1-like receptors couple with G proteins and activate adenylyl cyclase which catalyses the conversion of ATP to cAMP and pyrophosphate, which serve as a regulatory signal to activate various other molecules. This action can be seen in Figure 2. The D1-like receptor family includes dopamine receptor D1 (DRD1) and dopamine receptor D5 (DRD5). DRD1 is highly expressed in the prefrontal cortex and striatum. Studies on mice have shown that decreasing DRD1 receptors decreases striatum volume, increases locomotor activity (hyperactivity), and results in the lack of stimulant effects of cocaine and amphetamine, poor performance and slower learning ability, which is reflected in the symptoms of ADHD in humans.

D2-like receptors also couple with G proteins but act in inhibiting adenylyl cyclase (Sibley, 1992), as demonstrated in Figure 2. The D2-like receptor family includes dopamine receptors D2, D3 and D4. Furthermore, Maldonado, 1997, found that hyperactivity and highly increased reward behaviour in mice resulted from a deletion of DRD2 polymorphism (Maldonado, 1997). DRD3 plays a major role in the reward process of addictive behaviours and incentive-based learning (motivation and motor behaviour), and a relationship between manifestation of impulsive and hyperactive symptoms of ADHD has been revealed (Davis, 2009). DRD4 is the most widely expressed receptor of the D2-like receptor family, and is especially present in the hippocampus. It plays a major role in the processes important for synaptic strength and modulation of neuronal firing activity, which are impaired in ADHD patients.
dopamine_receptor_signalling.png
Figure 2. Dopamine Receptor Signalling (Source: A Finch, 2013)


The actions of both dopamine receptor families mediate cognition, emotion, vascular function, neuronal control and event prediction (Beninger, 1998). It has been hypothesised that the disequilibrium of D1-like and D2-like receptors results in a disturbed dopaminergic system and therefore are crucial in the pathogenesis of ADHD-like symptoms during brain development and maturation.

Current Drug Treatments

Current drug treatments for ADHD are used to manage the symptoms of the disorder, not to cure it. Medications for this disorder work differently in different patients and are not always effective. Pharmacological treatments focus on balancing neurotransmitters in the brain, specifically dopamine and to a lesser extent, noradrenaline, primarily within the prefrontal cortex and also the striatum.

Methylphenidate, otherwise known as Ritalin acts as a stimulant, the chemical structure for which can be seen in Figure 3 below. Stimulants are the most common medication in use for ADHD management and the medications are available in the form of pills, powders or patches (Bidwell et al, 2011). Each medication differs in the duration of their effect on the brain. Although these drugs do cause minor side effects, in most cases these can be reduced with a lower dosage.
Figure 3. Chemical Structure: Methylphenidate (Source: Axten et al. 1998)
Figure 3. Chemical Structure: Methylphenidate (Source: Axten et al. 1998)

Non-stimulant medications for ADHD, such as atomexotine, otherwise known as Strattera, have also been introduced and approved by the FDA (Gibson et al, 2006). Despite approval, these are not a first-line medication option and are used most commonly in patients who are refractory to other medications.

Stimulants: Method of Action

Stimulants act as indirect agonists of adrenoreceptors and dopaminergic receptors by blocking the reuptake of noradrenaline and dopamine in neuronal synapses. Consequently, the duration of the neurotransmitters are extended and the actions of these neurotransmitters are enhanced (Wilens TE, 2008).

Stimulants increase the availability of neurotransmitters dopamine and noradrenaline in the prefrontal cortex which enhances the efficiency of processing at pyramidal neurons, resulting in a reduction of ADHD symptoms. These neurotransmitters work together to increase signal-to-noise ratio in pyramidal neurons of the brain, such that noradrenaline acts to increase the signal strength and dopamine acts to decrease noise (Stahl S, 2010). Perhaps the most significant effect of these neurotransmitters is in the prefrontal cortex, in comparison to the neurotransmitters' minor effects in the striatum and nucleus accumbens. The prefrontal cortex is known to regulate behaviour and attention and low doses of stimulants have been seen to improve executive function in both 'normal' patients and patients with ADHD. While low and moderate levels of stimulants result in improvement of ADHD symptoms, high levels of stimulants have been seen to impair prefrontal regulation (Arnsten A, 2006).

Methylphenidate (Ritalin) in particular studies in rats has shown an increase in levels of dopamine primarily in the prefrontal cortex but also in the nucleus accumbens and striatum as well as an increase in noradrenaline in the prefrontal cortex alone. In the striatum, the actions of methylphenidate have been seen to modulate neuronal activity during stimulus-controlled tasks involving motor inhibition (Wilens TE, 2008).

Stimulants: Side Effects
Stimulant medications have been known to cause appetite suppression and weight loss in addition to an increased risk of depression and anxiety. Children taking stimulant medications for ADHD are seen to engage in less physical activity and organised sport as well as pleasure reading (Kim and Mutyala et al., 2011). Side effects as a result of taking Ritalin are demonstrated in Figure 4.

In a study by Toomey and Sox et al. in 2012, 71% of parents spoken to reported at least one side effect in their children taking stimulant medication for ADHD and 21% reported that they had chosen to discontinue their children's medication. Of the group that discontinued the medication, 62% reported that they made the decision to discontinue due to side effects experienced by their child. The most common side effects reported were loss of appetite (42%), sleep problems (40%), mood changes (23%), headache (13%), and stomach ache (12%) (Toomey and Sox et al., 2012).

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Figure 4. Summary of the actions of Ritalin. (Source: Aimee Lowth. 2013)

Drosophila Disease Model

The use of Drosophila melanogaster as a human neurodegenerative disease model has become more popular in recent years though not too much work has been done and published using this model. As an animal model, the common fruit fly provides a simple reductionist model for the human brain. The central nervous system in the Drosophila is derived from an evolutionary origin that is common to both fly and human with several similar neurobiological processes including membrane excitability, neuronal signalling and shared classes of neurotransmitters. In addition, 75% of human genes have a recognisable match in Drosophila (van Alphen and van Swinderen, 2011), as demonstrated in Figure 5.

fig5.png
Figure 5. Classification of 714 Clear-Hit Drosophila Genes According to Human Disease Phenotypes (Source: Reiter & Potocki et al., 2001)

A study by van Swinderen and Brembs in 2010 presented ADHD-like behaviour in a Drosophila mutant. This fly showed increased hyperactivity and distractibility compared to the wild-type Drosophila. With administration of Methylphenidate some of the behaviours in the mutant Drosophila returned to wild type level showing support for this model in the study of ADHD and its treatment.

Analysis

TED is an acronym for ‘Technology, Entertainment and Design’. TED Talks began as an initial attempt to share the talks from the TED Conference. However, in an expression of the global populations’ endearment towards knowledge and controversial topics of interest, TED Talks became the idea behind the axiom of TED Conference of “ideas worth spreading”. This TED talk is globally available and as such, Anderson has made the content rather simplified and easy to understand for a wide audience. However, the talk could also be used as a platform for further discussion on this topic by neuroscientists in a more advanced scientific context.

TED Talks are designed for experts in research from diverse fields to talk about a topic they are passionate about. In this way, David Anderson is predisposed to present a subjective view which best corresponds to his research perspective. Despite this, his view is scientifically supported by the research and publications of many different scientists within the field of neuroscience. The methods and research models he describes are considered accurate and well respected and relevant to current neuroscientific practice. Anderson, as a neurobiologist, exhibited clear bias towards the neurological basis of psychiatric disorders and the importance of recognising the emotional consequences of chemical imbalances at specific neuronal sites in contrast to the broader chemical imbalance theories. However, TED Talks are strictly limited to 18 minutes and do not allow for an equally informative discussion of both perspectives.
This talk is significantly linked to the future development of highly specific and targeted pharmacological treatments for mental illness. The creation of a medication with very specific receptor targets would revolutionise the treatment of many diseases including ADHD as well as reducing the discomfort of on- and off-target side effects seen in current medications.

Anderson foregrounds the need to target specific neurons, receptors and regions of the brain depending on those involved in the psychiatric disorder, which is in contrast to the previous method of 'washing' the brain with drugs. Specifically considering ADHD, this method would appear to be more beneficial, targeting DR1- and DR2-like families so as to specifically address those neurons and receptors involved in the disorder and potentially decreasing negative side effects.
It is understandable why Anderson made a correlation between the study on Drosophila and humans, and how this research may help future researchers with drug treatments for ADHD. The correlation between humans and Drosophila makes this an ideal animal model for the study of human disease and behaviours. For example, although not anatomically the same, the location and function of the D1-like receptor family could be compared to that of the mushroom body of the Drosophila. Similarities such as this make it evident that such a study would prove relevant to future studies in the treatment for ADHD. However, further research into the behavioural attributes of Drosophila is needed to ensure this particular model is viable as a method of exploring human neurodegenerative disease.

Appendix

Search and Selection Strategy

In our research into the neuroscientific context of this talk we have found a large volume of studies and research papers which explore content related to the subject of Anderson's talk and support the conclusions and findings presented in this video. In attempting to find articles for the project, our main search engine was Siris. Upon finding relevant research papers using specific search terms (e.g. ADHD, dopamine, etc.), we took appropriate references sited in these papers to further increase our knowledge. It was crucial to find research papers which were as recent as possible due to the changing nature of the neuroscientific field.

Analysis of Reviewer's Comments

In response to the reviewer comments, several significant changes were made to the Wiki. In doing so, we hoped to make the wiki more cohesive and accessible to the reader. The majority of the reviewer comments surrounded the incomplete nature of the wiki and draft format. Following revision of the wiki post-review, the draft titles, individual word counts and topic divisions were removed to create a cohesive wiki. Linking sentences and relevant sub-headings were included in an attempt to link the separate nature of several of the topics.
The word count was a significant consideration in the creation of this wiki. Some of the reviewer comments mentioned the addition of relevant information to broaden understanding and relevance, such as a discussion on autism spectrum in the context of ADHD. These additions could not be included as the word limit was already constrained. In addition, sentence structure and paragraphs were reviewed to make the wiki more concise, clear and reduce the word count.

The reviewers contributed insight in to the content of the wiki and these comments were taken in to consideration. The bias of the TED talk was reworded and considered the one-sided nature of the TED talks themselves. Another example is the inclusion of a diagram about the D1/ D2 receptor processes. Not all reviewer contributions resulted in changes in the wiki, such as the concept of summarising the current drug treatments in to a table as the nature of the content did not allow for this.

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