Brain Chemistry and Medication in ADHD

1. Brain Chemistry and Medication in ADHD maurice.place@northumbria.ac.uk

2. Disclosure Member of the speakers panel of AstraZeneca Eli Lilly Janssen Cilag Shire

3. The basic brain chemistry

4. The basic brain chemistry

5. The basic brain chemistry hippocampus plays important roles in short-term and long term memory as well as spatial awareness, and very vulnerable to long term stress corpus callosum links the left & right hemisphere facilitating higher level cognitive function - abnormalities associated with autism Nucleus accumbens important role in pleasure, reinforcement of learning, aggression and addiction. amygdala processes memory and emotional reactions pre-frontal cortex planning complex cognitive behaviour, personality expression, decision making and moderating social behaviour – clear deficits noted in children with ADHD (Shaw et al 2008)

6. Corpus callosum Locus ceruleus

7. The basic brain chemistry "At a purely chemical level, every experience humans find enjoyable - whether listening to music, embracing a lover, or savouring chocolate - amounts to little more than an explosion of dopamine in the nucleus accumbensas exhilarating and ephemeral as a firecracker.“ J Madelaine Nash

8. The prefrontal cortex controls planning, working memory, organization, modulating mood As they mature teenagers can reason better, develop more control over impulses make judgments better The basic brain chemistry

9. The basic brain chemistry The neurone and synapse

10. The basic brain chemistry

11. The basic brain chemistry

12. The basic brain chemistry Transporter return

13. The basic brain chemistry Babies are born with 100 billion neurones. Synapses rise to 18,000 per neurone in first weeks of life The brain more than doubles by 12 months, with 40,000 new synapses being formed every second in the infant’s brain

14. The basic brain chemistry neuro-transmitters of the brain Amino acids: glutamate, γ-aminobutyric acid (GABA) Biogenic amines: dopamine (DA), noradrenaline (norepinephrine)(NA or NE), serotonin (5-HT) Peptides: substance P, opioid peptides, etc.

15. The basic brain chemistry neuro-transmitters of the brain Amino acids: glutamate glutamate - in fast excitatory synapses in the brain and spinal cord. It is also used at most synapses that are "modifiable", i.e. capable of increasing or decreasing in strength. Modifiable synapses are thought to be the main memory-storage elements in the brain

16. The basic brain chemistry neuro-transmitters of the brain Amino acids: glutamate glutamate - in fast excitatory synapses in the brain and spinal cord. It is also used at most synapses that are "modifiable", i.e. capable of increasing or decreasing in strength. Modifiable synapses are thought to be the main memory-storage elements in the brain γ-aminobutyric acid (GABA) GABA - in fast inhibitory synapses of virtually every part of the brain - enhanced by tranquillisers

17. The basic brain chemistry neuro-transmitters of the brain Amino acids: glutamate, γ-aminobutyric acid (GABA) biogenic amines: dopamine (DA) regulation of motor behaviour, pleasures related to motivation and also emotional arousal.

18. The basic brain chemistry neuro-transmitters of the brain Amino acids: glutamate, γ-aminobutyric acid (GABA) biogenic amines: dopamine (DA) regulation of motor behaviour, pleasures related to motivation and also emotional arousal. Only about 400,000 in brain (Shultz 2007) noradrenaline (norepinephrine)(NA or NE) responsible for vigilant concentration and decision making

19. The basic brain chemistry neuro-transmitters of the brain Amino acids: glutamate, γ-aminobutyric acid (GABA) biogenic amines: dopamine (DA) regulation of motor behaviour, pleasures related to motivation and also emotional arousal. Only about 400,000 in brain (Shultz 2007) noradrenaline (norepinephrine)(NA or NE) responsible for vigilant concentration and decision making serotonin (5-HT) Most are in gut - regulates appetite, sleep, memory, learning, mood, and behaviour.

20. The basic brain chemistry neuro-transmitters of the brain Amino acids: glutamate, γ-aminobutyric acid (GABA) biogenic amines: dopamine (DA), noradrenaline (norepinephrine)(NA or NE), serotonin (5-HT) Peptides: substance P, opioid peptides regulate pain control

21. The Nature of ADHD

22. The Nature of ADHD Understanding the neuroanatomy of ADHD

23. The Nature of ADHD the caudate nucleus combines with the putamen and globuspallidus to form the striatum (Vogt & Vogt 1941) prefrontal cortex (brown) globuspallidus (blue) caudate nucleus (green) putamen (red)

24. Cingulate gyrus Locus ceruleus

25. The Nature of ADHD the caudate nucleus combines with the putamen and globuspallidus to form the striatum (Vogt & Vogt 1941) In ADHD there are brain volume changes in the frontal lobe and the caudate nucleus

26. The Nature of ADHD And graymatter reduction in the caudate nucleus (Ellison-Wright et al 2008)

27. The Nature of ADHD fronto-striatal abnormalities also found in: Autism (Takarae et al 2007) Tourettessyndrome (Marsh et al 2008) OCD (Atmaca et al 2007) Anorexia (Kaye 2008) Bulimia (Marsh et al 2009)

28. The Nature of ADHD Understanding the neurophysiology of ADHD

29. The Nature of ADHD Main focus in ADHD to date: biogenic amines – dopamine and noradrenaline (catecholamines) serotonin

30. Cingulate gyrus Locus ceruleus

31. The Nature of ADHD Neurophysiological and brain-imaging studies suggest integration of frontal executive functions with striatal organization and response strategies are disturbed in children with ADHD (Oades, 1998; Rubia et al, 2001)

32. The Nature of ADHD ADHD is not hyper-arousal but weakening of cortical circuits which regulate attention and behaviour.

33. The Nature of ADHD Neurophysiological and brain-imaging studies suggest integration of frontal executive functions with striatal organization and response strategies are disturbed in children with ADHD (Oades, 1998; Rubia et al, 2001) and are controlled by catecholamine transmitters (Sagvolden & Sergeant, 1998; Castellanos & Tannock, 2002).

34. The Nature of ADHD Dopamine is associated with an impulsive style in ADHD children (Langley et al., 2004). AND research points to the altered function of dopamine neurons as the main predisposing factor for ADHD (Sagvoldenet al. , 2004).

35. The Nature of ADHD At its most basic – in ADHD pathways that use dopamine transmission are poorer than the average …

36. The Nature of ADHD The neurotransmission can get upset at various points within the brain …

37. The Nature of ADHD Transporter return

38. The Nature of ADHD • In the prefrontal cortex of the brain • dopamine regulation is controlled • by Catechol O-Methyltransferase (COMT) • this enzyme is responsible for breaking down any free dopamine • (and higher activity in ADHD has been found to have association • with conduct problems – Caspi et al 2008; Langley et al 2010) • In the striatum • it is the dopamine transporter (DAT) proteins • that have this regulatory role • of maintaining dopamine levels.

39. The Nature of ADHD BUT dopamine is also important in other disorders Parkinsonism Schizophrenia Huntington's chorea Tourette’s syndrome Social phobia Drug & alcohol dependence

40. The Nature of ADHD AND LETS NOT FORGET noradrenaline: both dopamine and noradrenaline transporters can clear dopamine that is around the synapse. (Wayment et al. 2001) AND SO changes to noradrenaline transporter changes dopamine levels (De Montis et al. 1990)

41. The Nature of ADHD And in animal studies high levels of dopamine and noradrenaline in the prefrontal cortex are necessary for optimal functioning because deficits affect attention regulation increase immature behaviour produce a lack of restraint and increase motor activity. (Spencer et al 2002)

42. The Nature of ADHD catecholamines have the major role in the cognitive domains and this disturbance is main source of dysfunction in ADHD. WITH modest increases in noradrenaline improving focused attention and decreasing impulsivity and distractibility (Aston-Jones et al 1997).

43. The Nature of ADHD In executive function testing children with ADHD show less activation in a right striatal-parietal network while performing a mental rotation task (Vance et al 2007) less frontal-striatal activation in an executive control task (Konrad et al 2006) an interference suppression task (Vaidya et al 2005) a response inhibition task (Booth et al 2005)

44. The Nature of ADHD Dopamine is associated with an impulsive style in ADHD children (Langley et al., 2004). BUT serotonin (5HT) system is also significant – Changes in the serotonin transporter affinity are related to increases in behavioural & cognitive impulsivity (Oadeset al., 2002).

45. The Nature of ADHD Dopamine is associated with an impulsive style in ADHD children (Langley et al., 2004). ANDpsychostimulant action to improve ability to delay depends on an intact serotonin system (Winstanley et al., 2003).

46. The Nature of ADHD So various brain transmitters can affect the pathway function

47. The Nature of ADHD dopamine receptor DRD4 (7 repeat allele) dopamine transporter gene (DAT1) (10 repeat allele) ...associated with reduced intellectual functioning among children diagnosed as having ADHD …predicts which children with ADHD are at greatest risk for poor adult prognosis. (Mill et al 2006)

48. The Nature of ADHD SO dopamine is main agent but noradrenaline can have similar action and serotonin is needed to facilitate action

49. The Nature of ADHD Gender Issues in ADHD Psychosocial functioning in boys and girls is generally similar, but more externalizing behaviours have been identified in boys (Gershon 2002) Studies suggest sex differences in the physiological response to agents that interact with the dopaminergic system in the brain. (Becker 1999; Munro et al 2006)

50. NB-No medications in the UK are currently licensed to treat ADHD in adults. Atomoxetine may be continued into adulthood in adolescents whose symptoms persist and who have responded favourably