ADHD Pharmacology V1 PDF

Attention-deficit hyperactivity disorder (ADHD) Dr. Valeria Parlatini MD, PhD, AFHEA, MRCPsych Associate Professor and honorary Consultant in Child and Adolescent Psychiatry  Outline ADHD: clinical presentation Catecholaminergic neurotransmission, a recap Catecholaminergic dysfuncti...

Attention-deficit hyperactivity disorder (ADHD) Dr. Valeria Parlatini MD, PhD, AFHEA, MRCPsych Associate Professor and honorary Consultant in Child and Adolescent Psychiatry  Outline ADHD: clinical presentation Catecholaminergic neurotransmission, a recap Catecholaminergic dysfunction in ADHD ADHD: management Stimulant mechanisms of action Stimulant effects on the brain Non-stimulants Predicting treatment response What is ADHD? Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by impairing levels of inattention, impulsiveness and hyperactivity (DSM 5-TR, APA 2022). …in practice? Inattentive symptoms (at least 6/9 in childhood; 5/9 in adulthood) often fails to pay attention to details or makes careless mistakes often has difficulty concentrating (e.g. movies, books) often does not seem to listen when spoken to directly often does not follow through on instructions and fails to finish tasks often has difficulty organising his daily activities tends to procrastinate, especially tasks that require mental effort often loses things is often easily distracted by external stimuli if often forgetful in daily activities Impulsivity-hyperactivity symptoms (at least 6/9 in childhood; 5/9 in adulthood) often fidgets cannot stay seated for long feels restless tends to be laud talks excessively has more energy than other people often has difficulty awaiting turn often says things without thinking often interrupts others …consequences?  Prevalence & Demographic differences 4-6% of children and 2-3% of adults 2.5/1 M/F ratio in CYP [Referral bias] No significant differences between LMIC and HIC ADHD often persists in adolescence (50-80%) and adulthood (30-50%) [different symptomatology] Cortese et al., 2023 ADULT LIFE Faraone et al., 2015  CLINICAL CASES A. is a 5y old girl referred for hyperactivity and challenging behaviour. She is often running away and climbing on furniture, with no sense of danger. She often gets into trouble in school for talking inappropriately and getting into fights. C. is a 12y old girl referred for hyperactivity and inattention problems, who is struggling with making and keeping friends. On assessment, she makes inappropriate comments and struggles to understands others’ emotions and intentions (ADHD + ASD). N. is a 22y old man currently repeating the second year of his engineering course at university, after he had to repeat the first year. He reports that he is under- performing because of his inattentive symptoms, despite having an IQ of 139.  ADHD & everyday life Academic performance and employment. Addictions, unhealthy eating/drinking behaviours, higher risk of physical injury and car accidents. Health problems: obesity, vision disorders, allergies and asthma, diabetes, somatic disorder Quality of life (social/emotional functioning) Emotional and conduct problems (bullying, criminal behaviours) Teen pregnancies Faraone et al., 2021  Diagnosis Age-inappropriate levels of hyperactive-impulsive and/or inattentive symptoms for at least 6 months Symptoms are detected in different settings (e.g., home and school) Symptoms affect everyday life and functioning Some of the symptoms appeared in early to mid-childhood No other disorder better explains the symptoms No objective markers Psychiatric interview (child, parent/caregiver) + collateral information (school). Rating scales (e.g., Conner’s Rating Scales) or neuropsychological tests (e.g., QB-Test) can support the clinician’s judgement  Etiology Liability threshold model: neither genetic or environmental factors are sufficient, per se, to cause ADHD. Genetic and environmental risk factors accumulate and, when a certain threshold is overcome, ADHD symptoms manifest Genetics: polygenic risk (no single gene); familiarity; p factor (both in clinical and general population) Environment: toxins, alcohol and cigarette smoke during pregnancy, nutrient deficiencies, obstetric complications, low birth weight, premature birth, maternal hypertension, maternal obesity, stress, infection, poverty and trauma Neurobiology of ADHD ADHD symptoms have been associated with structural as well as functional differences mainly in fronto-striatal networks but also in parietal and cerebellar connections. Parlatini et al., Mol Psych, 2023 Catecholaminergic pathways Activity within these networks is modulated by dopamine (DA) and norepinephrine (NE). Parlatini et al., Neurosci Biobehav Rev. 2024 Dopamine (DA) is predominantly synthesized from the amino acid L-tyrosine within the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA). DA acts through highly topographically organized projections, such as the nigrostriatal pathway, well known for its role in movement regulation. Mesocortical and mesolimbic dopaminergic pathways are involved in executive functions and affect regulation, through projections to the cortex and limbic structures. Noradrenergic pathways are highly distributed throughout the brain. These originate from the locus coeruleus (LC), which is in the brainstem and is reciprocally connected with cortical regions, such as the PFC. They modulate neural functions according to arousal state and attention.  Cortico-striatal loops Fronto-striatal pathways has been the most investigated in ADHD research GABA-glutamatergic circuits regulated by dopamine They are involved in motor, cognitive and affective regulation by connecting different parts of the Cx to the basal ganglia and thalamus, which in turn project back to the Cx. Motor= sensorimotor Cx-striatum-thal-SMA Motor planning for known movements Cognitive=DLFPC-striatum-thal-premotor Cx/PFC Planning complex movements/learning Limbic=ACC/OFC-n.accumbens (ventral striatum)-thal-Cx Emotional aspects of movements e.g. smiling These circuits contribute to executive functions and affect regulation, which can be impaired in ADHD. Parlatini et al., Neurosci Biobehav Rev. 2024; Catani & Thiebaut de Schotten, OUP, 2008  Cortico-striatal loops DA increases the production of cyclic adenosine monophosphate (cAMP) signaling through D1 receptors, and thus weakens inappropriate connections; NE inhibits cAMP production through α2A receptors, and thus enhances the strength of specific connections. DA and NE optimize PFC function by respectively reducing ‘noise’ and enhancing ‘signal’ within glutamatergic circuits. Parlatini et al., Neurosci Biobehav Rev. 2024 DA and NE critically contribute to optimal frontal brain activity. This is responsible for the regulation of attention, inhibition, motivation and emotion. Task performance DA and NE concentration Both excessive and insufficient catecholamine release negatively impact on PFC functions. (Arnsten 2009, Arnsten & Rubia 2012, da Silva et al 2023). Catecholaminergic dysfunction in ADHD It plays an important role in ADHD pathophysiology. This is supported by: -candidate gene studies (Faraone et al., 2021); -animal models (Rahi & Kumar 2021); -the efficacy of stimulants (Cortese et al., 2018); -PET/SPECT studies (primarily measuring striatal DA transporter (DAT) binding). Studies of DAT binding have yielded inconsistent results A meta-regression based on 9 PET/SPECT studies suggested inconsistencies may be related to the confounding effect of previous treatment. The ADHD group showed 14% greater striatal DAT binding than controls, but the percentage of individuals receiving stimulant treatment was positively associated with higher DAT levels. Possible adaptive response to chronic treatment, which induces persistent DAT blockade. Fusar-Poli et al., Am J Psychiatry 2012  Management of ADHD (NICE) #1 Pre-schoolers (< 5 years) 1. ADHD-focused group parent training 2. If ADHD symptoms still impairing across more than one domain: obtain specialist advice and consider medication  Management of ADHD (NICE) #2 Children and adolescents ≥ 5 years 1. Group-based ADHD-focused support 2. If ADHD symptoms still impairing across more than one domain/context: consider medication (trialled in this order; see Cortese et al., 2018) Methylphenidate (stimulant) Lisdexamfetamine (or dexamphetamine; stimulants) Atomoxetine or guanfacine (non-stimulants) If symptoms of oppositional defiant disorder or conduct disorder co-occur with ADHD: parent- training Adolescents/Young people: Cognitive Behavioral Therapy if symptoms still impairing with medication  Management of ADHD (NICE) #3 Adults 1. Medication (in this order): Methylphenidate, lisdexamfetamine or dexamphetamine Atomoxetine 2. Supportive psychological intervention if patient asks and/or medication is ineffective or not tolerated Indication for ADHD meds - Moderate/severe impairment - Stimulants such as methylphenidate (Ritalin, Concerta) are first line - Other options (lisdexamfetamine, atomoxetine, guanfacine) Cautions/side effects Stimulants may increase blood pressure and heart rate Can decrease appetite Can affect sleep Therefore, before and during treatment we check BP, HR, height and weight. Different formulations Ritalin 8am 12 4pm Concerta 8am 6pm Stimulant mechanism of action MPH exists as two enantiomers (i.e. two compounds with mirrored chemical struc- ture), respectively called d-threo and l-threo- MPH vs amphetamines MPH. Therapeutic effects primarily due to the d-enantiomer. MPH blocks both DA and NE transporters through allosteric binding (i.e. on a different site from that of the endogenous neurotransmitter). AMP also exist as d- and l-isomers but, although the former is more potent for DAT binding, they are equally potent for NET binding. AMP block DAT and NET by binding on the same site of the endogenous neurotransmitter, thus they act as a competitive inhibitor, and can also induce DAT reversal at higher dose. Parlatini et al., Neurosci Biobehav Rev. 2024 Stimulant mechanism of action MPH vs amphetamines lisdexamfetamine is a long- acting d- amphetamine prodrug. It is hydrolyzed into d-amphetamine in the blood and has a different pharmacokinetic profile than short- acting amphetamines, offering the longest therapeutic action among stimulants (up to 13–14 hours). Parlatini et al., Neurosci Biobehav Rev. 2024 Stimulant mechanism of action By acting on the catecholamine transporters, stimulants increase the endogenous DA stimulation of D1-receptors, and Task the NE-dependent activation of post-synaptic α2A-receptors. performance DA and NE concentration Thus they enhance PFC function, by respectively reducing ‘noise’ and enhancing ‘signal’ within glutamatergic circuits (Arnsten and Rubia, 2012). PET/SPECT studies suggested more complex mechanisms: - Support engagement of task-related brain networks, such as the dorsal frontoparietal attentive network - Reduce the activation of the default-mode network (DMN) - Increase the perception of events as salient (DA release is higher during a rewarded task) MPH and amphetamines increase catecholaminergic availability in cortico-striatal regions that are altered in ADHD, and positively affect executive functions, decision making, emotion and reward processing. Parlatini et al., Neurosci Biobehav Rev. 2024 …thus people with ADHD are now able to seat down and focus on task!  Stimulant effects on brain regional structure and function Early structural MRI studies suggested that stimulant treatment is associated with attenuation or absence of some grey matter volumetric alterations often observed in untreated children with ADHD (Frodl and Skokauskas, 2012, Nakao et al., 2011). However, other studies do not support this treatment-related effect (Greven et al., 2015). fMRI studies suggest that a single dose of stimulants modulate brain activity levels in individuals with ADHD towards those of their neurotypical peers, e.g. during attention and response inhibition tasks. Conversely, the few studies that investigated the effect of chronic treatment with MPH reported inconclusive evidence of improvement on brain function after wash-out (Kobel et al., 2009, Konrad et al., 2007, Pliszka et al., 2006).  Stimulant effects on brain structural and functional connectivity A recent systematic review of diffusion imaging studies have provided preliminary evidence of subtle white matter differences between treated vs untreated individuals with ADHD, e.g. in the inferior longitudinal fasciculus, uncinate fasciculus, and posterior corpus callosum (Parlatini et al., 2023a, de Luis-Garcia et al., 2015). However, the meta-regression analysis did not support effect of prolonged stimulant treatment (Parlatini et al., 2023a). Similarly to brain regional fMRI studies, functional connectivity studies showed that an acute dose of stimulants shifts connectivity during tasks or rest towards that of neurotypical peers, e.g. by enhancing connectivity of task-related fronto- striatal/parietal networks and suppressing the DMN. A single dose of stimulants positively affects brain activity/functional connectivity. Prolonged stimulant treatment might not translate into long-lasting changes of brain anatomy/activity, although this may require further investigation. Non-stimulants ATOMOXETINE =selective NE reuptake inhibitor NET mediates both DA and NE reuptake in the PFC, main target of ATX. Lower levels of NET in the n. accumbens, thus safer in addition. GUANFACINE (children only)= selective alpha-2A receptor agonist, which mediates NE effects in the PFC. Weaker sedative and hypotensive effects than non-selective agonist clonidine. PREDICTORS OF TREATMENT RESPONSE IN ADULT ADHD Neuroimaging  A longitudinal placebo-controlled neuroimaging study to Neuroimaging identify biological predictors of treatment response in adults with ADHD 60 adults 20 matched with ADHD controls DAY 1 DAY 2 DD MPH Single dose Placebo Rationale BAARS-IV BAARS-IV QbDD test QbDD test - stimulants, such as MRI scans MRI scans methylphenidate (MPH), are effective in treating ADHD, but Long-acting MPH there is individual variability DD for two months -it is not possible to predict in DAY 3 advance who will respond BAARS-IV DD Qb test -pressure on services with long waiting times DD Responders DD Non-responders  Brain connectivity as a predictor of treatment response in ADHD Variables Assoc. Left SLF I Volume + Baseline symptoms + Medication naivety + Dose - Right handedness + Total IQ + Inattention (baseline) - Impulsivity - (acute dose MPH) Individuals with a smaller left SLF I were less likely to respond to treatment; MPH was less effective in those with more alterations in attentive networks. Parlatini et al., Translational Psychiatry, 2023  Other Thal.R MRI modalities pSTG.L to identify Thal.R pSTG.L predictors Thal.R of treatment response in ADHD pSTG.L Thal.L Thal.L Functional connectivity analysis Structural MRI & virtual histology b) Cluster 2 PostCG.L PreCG.L PreCG.L PostCG.L PreCG.L PostCG.L Ver6 Ver6 Ver6 MPH vs Placebo c) Cluster 3 PreCG.R & L SMA.L Cluster 2: Change in FC and clinical outcome PreCG.L PreCG.R AC PostCG. SMA.L SMA.L Neuroanatomy Gene maps R&L Non-Responders PostCG.L An acute dose PostCG.R Put.L of Put.R Responders Pall.L AC Put.L MPH Put.Rinduces Put. R&L Pall.L functional AC changes PostCG.R & L NRe had more brain alterations than Re. ∆SYMPTOMS in rs-fc, which are PreCG.L PreCG.R t (TFCE) associated with the ADHD vs Controls cortical differences 0 clinical response 5 at 2 were enriched for biologically plausible months. genes (e.g. NA transport). % ∆ FC (res) Pretz*, Parlatini*, Murphy, under review Parlatini et al., Nature Mental Health 2024  A longitudinal placebo-controlled neuroimaging study to identify biological predictors of treatment response in adults with ADHD Machine learning & virtual histology Structural connectivity Parlatini et al., Nature Mental Health 2024 Parlatini et al., Translational Psychiatry 2023 Pre-treatment brain characteristics, at Functional connectivity baseline or under a single dose of MPH, were associated with the clinical response at two months. Combining biological with clinical characteristics helped identify a more accurate profile of factors associated Pretz*, Parlatini*& Murphy, under review with treatment response. Key reading Faraone et al., 2021 Key reading 10.1016/j.neubiorev.2024.105841 Thank you all for your attention! [email protected]