Epidemiology of ADHD
• Historically viewed as a childhood disorder only but that’s changed with ❌ of school age children diagnosed globally, in adults ~ half that
• Increased incidence of ❌, ~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 ❌ and severity plus a higher ❌ rate compared to adults without ADHD
• Treatment of depression with comorbid ADHD generally more ❌, treatment-resistance is more common
• Childhood ADHD is sometimes the early expression of an emergent ❌
• 10 - 20% of adults with bipolar disorder have comorbid ❌

Children and adolescents: Easy to diagnose, ❌ levels of identification, and Tx > 50%, stimulants used ❌ line
Adults: Hard to diagnose (inaccurate retrospective recall of ❌). Late onset, same ❌. ❌ levels of identification, and Tx < 20%. Stimulants ❌ 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 ❌ projecting to the striatal complex, the thalamus and back. Inefficient activation leads to difficulty following through/❌ tasks, dis❌ and trouble sustaining mental ❌.
-- Selective attention: Hypothetically modulated by connections between the ❌ which projects to the striatal complex, then thalamus and back to the dACC. Inefficient activation of the ❌ results in
symptoms such as decreased attention to ❌, careless mistakes, not listening, ❌things, being ❌ and forgetting.
- Hyperactivity and impulsivity
Often fidgets, squirm, is restless, can't stay ❌, difficulty playing ❌, ❌ or intrudes on others; may take over what others are doing

• ❌ or more symptoms must be present for at least 6 ❌; ❌ 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 - ❌
Prefrontal cortex (PFC) - ❌
Dorsolateral prefrontal cortex (DLPFC) - ❌
Orbitofrontal cortex - ❌

Causes?
• Familial and ❌ association
• Synaptogenesis in ❌ might be responsible...
-At 6-7 years, ❌ attention and planning begin to develop. This age is characterized by “❌” i.e. overproduced or “weak” synapses are “weeded out,” which allows ❌ to mature.

Errors in this ❌ could hypothetically affect further development of executive function and could be a cause of ADHD.
ADHD symptoms in children often appear around ❌ years of age.

Impulsivity
• Associated with reciprocal connections between the ❌, the striatal complex, and the thalamus.
Hyperactivity and psychomotor agitation/retardation
• Modulated by cortico-striato-thalamo-cortical (❌) loop from the ❌ to the ❌ striatum, to the thalamus and back to the PFC.

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

As deficient ❌ is the main problem in ADHD, drugs to treat it either:
1. increase the ❌
or
2. increase tonic ❌ increases prefrontal activity to an optimal level

Hypothetically, if DA and NA levels are to low, low ❌ causes reduced '❌' and low ❌ causes increased '❌'. Inability to sit still and focus are manifestations of the imbalanced signal-to-noise ratio.
Treatment increases ❌ by increasing the ❌ of both DA and NA until they reach the optimal dose.

Methylphenidate(stimulant) / Vitamin R:
- increase release of DA in the ❌ (nucleus accumbens)
and
- increase release of NA and DA in the ❌
by ❌ reuptake pumps (NAT and DAT).

Unlike amphetamine, ❌ is not taken up into the ❌ via the transporter and is not a ❌ inhibitor.

Amphetamine:
Competitive inhibitor-
1) at ❌ which competes with DA
2) at ❌ which competes with NA

Also competitive inhibitor of the ❌ (methylphenidate is ❌) = taken into the ❌ via the DAT, where it's packaged into ❌.

At ❌ levels, it also ❌ DA from the vesicles into the terminal.

Once a critical ❌ of DA is reached, DA is expelled from terminaml by opening ❌ to allow ❌ scale release into the ❌ and reversal of the ❌! This rapid release of DA leads to the ❌ experienced by amphetamine users.

Dexamphetamine
• Competitive inhibitor at ❌ and the ❌ (VMAT) - competes with Da and NA
• Unlike methylphenidate, which is not taken ❌
• ❌ more effective than ❌ for DAT binding
• d- and l-isomers are equipotent for ❌ binding

Common Stimulant Adverse effects:
1. ❌
Have a high-calorie meal when stimulant effects are low (at breakfast or at bedtime), or consider cyproheptadine (antihistamine) at bedtime

2. ❌
Give on a full stomach; lower dose if possible

3. ❌
Give earlier in the day; decrease last dose of the day, consider a hypnotic at bedtime e.g. clonidine, melatonin, or cyproheptadine.

4. ❌
Divide dose, give with food, or give analgesic

5. ❌
Consider longer-acting stimulant trial, atomoxetine, or antidepressant

6. ❌
Assess for comorbid condition e.g. bipolar disorder; reduce dose; consider mood stabilizer or atypical antipsychotic

Atomoxetine
• Selective ❌, also an antidepressant
• Since the PFC lacks ❌ concentrations of the DAT, ❌ is inactivated there by the ❌ (promiscuous). So, blocking NAT will increase ❌ levels in the PFC
• The relative ❌ of NAT in the ❌ prevents atomoxetine from ❌ NA or DA levels in that region → reduced risk of ❌

Bupropion
- Not selective, is a ❌ reuptake inhibitor or ❌
- Effective for the treatment of ADHD and depression
- Preferred for ❌ patients due to comorbid substance abuse or depression

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