PSY10 ADHD

Epidemiology of ADHD • Historically viewed as a childhood disorder only but that’s changed with [blank_start]3-7%[blank_end] of school age children diagnosed globally, in adults ~ half that • Increased incidence of [blank_start]depression[blank_end], ~14% of those who are 6-17 years old, some studies demonstrated in up to 50% of adolescents • Adults with ADHD also show early onset of depression, increased [blank_start]morbidity[blank_end] and severity plus a higher [blank_start]suicide[blank_end] rate compared to adults without ADHD • Treatment of depression with comorbid ADHD generally more [blank_start]difficult[blank_end], treatment-resistance is more common • Childhood ADHD is sometimes the early expression of an emergent [blank_start]bipolar disorder[blank_end] • 10 - 20% of adults with bipolar disorder have comorbid [blank_start]ADHD[blank_end]

Children and adolescents: Easy to diagnose, [blank_start]High[blank_end] levels of identification, and Tx > 50%, stimulants used [blank_start]first and second[blank_end] line Adults: Hard to diagnose (inaccurate retrospective recall of [blank_start]onset[blank_end]). Late onset, same [blank_start]genetics, comorbidity and impairments[blank_end]. [blank_start]Low[blank_end] levels of identification, and Tx < 20%. Stimulants [blank_start]not[blank_end] first line.

DSM-V Diagnosis Noted trio of symptoms i.e. inattention (selective and sustained), hyperactivity and impulsivity. - Inattention: -- Sustained attention: Hypothetically modulated by connections between the [blank_start]dorsolateral prefrontal cortex (DLPFC)[blank_end] projecting to the striatal complex, the thalamus and back. Inefficient activation leads to difficulty following through/[blank_start]finishing[blank_end] tasks, dis[blank_start]organization[blank_end] and trouble sustaining mental [blank_start]effort[blank_end]. -- Selective attention: Hypothetically modulated by connections between the [blank_start]dorsal anterior cingulate cortex (dACC)[blank_end] which projects to the striatal complex, then thalamus and back to the dACC. Inefficient activation of the [blank_start]dACC[blank_end] results in symptoms such as decreased attention to [blank_start]detail[blank_end], careless mistakes, not listening, [blank_start]losing[blank_end]things, being [blank_start]distracted[blank_end] and forgetting. - Hyperactivity and impulsivity Often fidgets, squirm, is restless, can't stay [blank_start]seated[blank_end], difficulty playing [blank_start]quietly[blank_end], [blank_start]interrupts[blank_end] or intrudes on others; may take over what others are doing • [blank_start]Six[blank_end] or more symptoms must be present for at least 6 [blank_start]months[blank_end]; [blank_start]five[blank_end] symptoms required in older adolescents and adults (> 17 years of age) • Significant impairment must be seen in two or more settings (e.g. home and school); symptoms must be documented by parent, teacher, and clinician.

Match the symptoms to the regions: Dorsal ACC - [blank_start]selective attention[blank_end] Prefrontal cortex (PFC) - [blank_start]hyperactivity[blank_end] Dorsolateral prefrontal cortex (DLPFC) - [blank_start]sustained attention[blank_end] Orbitofrontal cortex - [blank_start]impulsivity[blank_end]

Causes? • Familial and [blank_start]genetic[blank_end] association • Synaptogenesis in [blank_start]PFC[blank_end] might be responsible... -At 6-7 years, [blank_start]sustained[blank_end] attention and planning begin to develop. This age is characterized by “[blank_start]synaptic pruning,[blank_end]” i.e. overproduced or “weak” synapses are “weeded out,” which allows [blank_start]cognitive intelligence[blank_end] to mature. Errors in this [blank_start]process[blank_end] could hypothetically affect further development of executive function and could be a cause of ADHD. ADHD symptoms in children often appear around [blank_start]6[blank_end] years of age.

Hyperactivity and impulsivity are key symptoms in childhood, while inattention becomes prevalent with age.

Impulsivity • Associated with reciprocal connections between the [blank_start]orbitofrontal cortex (OFC)[blank_end], the striatal complex, and the thalamus. Hyperactivity and psychomotor agitation/retardation • Modulated by cortico-striato-thalamo-cortical ([blank_start]CSTC[blank_end]) loop from the [blank_start]PFC[blank_end] to the [blank_start]lateral[blank_end] striatum, to the thalamus and back to the PFC.

Choose the correct statement.

Comorbidities • Result of [blank_start]similar or additional[blank_end] deficits within the ventromedial prefrontal cortex – [blank_start]limbic[blank_end] system • Many [blank_start]mood[blank_end] disorders comorbid with ADHD in children and adults • Symptoms in adults more disabling if comorbidities were already present in the [blank_start]child[blank_end]. Reinforces the importance of treating all symptoms in young patients to maximize their chances of a “regular” adult life • Oppositional defiant or [blank_start]Conduct[blank_end] disorder occur in 30-[blank_start]60[blank_end]% of youth diagnosed with ADHD • Childhood comorbidities include depression, [blank_start]Autism[blank_end] spectrum disorders, childhood [blank_start]bipolar[blank_end] disorder

As deficient [blank_start]arousal in the PRC[blank_end] is the main problem in ADHD, drugs to treat it either: 1. increase the [blank_start]release of DA and NA[blank_end] or 2. increase tonic [blank_start]firing of the neurons[blank_end] increases prefrontal activity to an optimal level Hypothetically, if DA and NA levels are to low, low [blank_start]NA[blank_end] causes reduced '[blank_start]signal[blank_end]' and low [blank_start]DA[blank_end] causes increased '[blank_start]noise[blank_end]'. Inability to sit still and focus are manifestations of the imbalanced signal-to-noise ratio. Treatment increases [blank_start]signal strength output[blank_end] by increasing the [blank_start]concentration[blank_end] of both DA and NA until they reach the optimal dose.

Methylphenidate(stimulant) / Vitamin R: - increase release of DA in the [blank_start]NAc[blank_end] (nucleus accumbens) and - increase release of NA and DA in the [blank_start]PFC[blank_end] by [blank_start]blocking blocking[blank_end] reuptake pumps (NAT and DAT). Unlike amphetamine, [blank_start]methylphenidate[blank_end] is not taken up into the [blank_start]DA terminal[blank_end] via the transporter and is not a [blank_start]competitive[blank_end] inhibitor.

Amphetamine: Competitive inhibitor- 1) at [blank_start]DAT[blank_end] which competes with DA 2) at [blank_start]NAT[blank_end] which competes with NA Also competitive inhibitor of the [blank_start]VMAT[blank_end] (methylphenidate is [blank_start]not[blank_end]) = taken into the [blank_start]DA terminal[blank_end] via the DAT, where it's packaged into [blank_start]vesicles[blank_end]. At [blank_start]high[blank_end] levels, it also [blank_start]displaces[blank_end] DA from the vesicles into the terminal. Once a critical [blank_start]threshold[blank_end] of DA is reached, DA is expelled from terminaml by opening [blank_start]channels[blank_end] to allow [blank_start]large[blank_end] scale release into the [blank_start]synapse[blank_end] and reversal of the [blank_start]DAT[blank_end]! This rapid release of DA leads to the [blank_start]euphoria[blank_end] experienced by amphetamine users.

Dexamphetamine • Competitive inhibitor at [blank_start]DAT, NET,[blank_end] and the [blank_start]Vesicular Monoamine Transporter[blank_end] (VMAT) - competes with Da and NA • Unlike methylphenidate, which is not taken [blank_start]into the cell[blank_end] • [blank_start]d-isomer[blank_end] more effective than [blank_start]l-isomer[blank_end] for DAT binding • d- and l-isomers are equipotent for [blank_start]NAT[blank_end] binding

Common Stimulant Adverse effects: 1. [blank_start]Reduced appetite, weight loss[blank_end] Have a high-calorie meal when stimulant effects are low (at breakfast or at bedtime), or consider cyproheptadine (antihistamine) at bedtime 2. [blank_start]Stomach-ache[blank_end] Give on a full stomach; lower dose if possible 3. [blank_start]Insomnia[blank_end] Give earlier in the day; decrease last dose of the day, consider a hypnotic at bedtime e.g. clonidine, melatonin, or cyproheptadine. 4. [blank_start]Headache[blank_end] Divide dose, give with food, or give analgesic 5. [blank_start]Rebound symptoms[blank_end] Consider longer-acting stimulant trial, atomoxetine, or antidepressant 6. [blank_start]Irritability/jitteriness[blank_end] Assess for comorbid condition e.g. bipolar disorder; reduce dose; consider mood stabilizer or atypical antipsychotic

Atomoxetine • Selective [blank_start]NA reuptake inhibitor (NRI)[blank_end], also an antidepressant • Since the PFC lacks [blank_start]high[blank_end] concentrations of the DAT, [blank_start]DA[blank_end] is inactivated there by the [blank_start]NAT[blank_end] (promiscuous). So, blocking NAT will increase [blank_start]both DA and NA[blank_end] levels in the PFC • The relative [blank_start]lack[blank_end] of NAT in the [blank_start]NAc[blank_end] prevents atomoxetine from [blank_start]increasing[blank_end] NA or DA levels in that region → reduced risk of [blank_start]abuse[blank_end] Bupropion - Not selective, is a [blank_start]noradrenaline - dopamine[blank_end] reuptake inhibitor or [blank_start]NDRI[blank_end] - Effective for the treatment of ADHD and depression - Preferred for [blank_start]older[blank_end] patients due to comorbid substance abuse or depression

Relative effects • [blank_start]Atomoxetine[blank_end] - slower onset than stimulants - 2–4 weeks v’s 1–2 hours, full benefit might take [blank_start]6-12 weeks[blank_end] • Gender - males having increased [blank_start]methylphenidate bioavailability[blank_end] compared to females • Dose [blank_start]variability[blank_end] for all of mentioned meds, can be due to inter-individual variability in plasma concentration. • All metabolized by CYP2D6 so [blank_start]bupropion, fluoxetine, or paroxetine[blank_end] can increase biavailability by [blank_start]4-8[blank_end] times • Atomoxetine - [blank_start]CYP2D6 poor metabolizers[blank_end] may experience more insomnia, weight loss, increased HR and BP constipation and depression compared to extensive metabolizers BUT might also have [blank_start]better[blank_end] therapeutic benefit • Small increase in [blank_start]HR and BP[blank_end] on 1-2% of children • No effect on liability for substance abuse with increasing age, possibly [blank_start]protective[blank_end] if started < [blank_start]8[blank_end] years of age