CNS 33: Psychopharmacology in Children and Adolescents

In this discussion, we will go over common pediatric mental health conditions as well as the pharmacologic agents.

Introduction to Psychopharmacology in Children and Adolescents

Many psychiatric disorders in children stemmed from family background and their environment. Children who have strong social support, even temperament, and high intelligence tend to be resilient to having disorders, and those who live in poverty or have a history of violence, abuse, or neglect tend to be at risk of having these disorders.

When considering treatments in children, we must carefully weigh the risks and benefits ratio and consider what we need to do now in order to prevent potential impact in the future.

Pharmacokinetics in Pediatrics

There are several factors that we need to consider due to the pharmacokinetic differences seen in pediatric patients.

  • Total percentage of total body fat: Children tend to have more body fat than adults. Since most psychotropic medications are highly lipophilic, we have to be careful when using them.
  • Liver: Children’s metabolism is much faster than adults and may eliminate medications at a much quicker rate than adults
  • Metabolizing Enzymes: During infancy, children do not have phase II enzymes or many of the CYP450 enzymes
  • Renal: Same as liver clearance. Children can eliminate medications renally faster than adults can

This is why some medications may be effective in adults, but not in children, such as tricyclic antidepressants. Children are also more susceptible to metabolic side effects, such as those from antipsychotics.

Remember that efficacy is therapeutic benefit in a controlled setting, such as Randomnized Controlled Trial, and effectiveness is therapeutic benefit in a non-controlled setting.

Attention Deficit Hyperactivity Disorder (ADHD)

In order for a child to be diagnosed with ADHD, they must have symptoms before 12 years of age and display maladaptive behaviors in two environments (home and school. If there is only a maladaptive behavior in one setting, it’s treated as a behavioral issue.

There is a genetic component to ADHD that children tend to inherit from parents, typically fathers. Some associations have been made with prenatal alcohol and drug exposure as well.

Males are diagnosed with ADHD more often than females.

The prevalence of ADHD is not increasing, but the number of diagnoses is.

In the past 20 years, there have been increased rates of prescribing ADHD medications to adults. While most children do not need to remain on their ADHD treatment lifelong, there are a number of adults who can never adapt and require medications.

ADHD Presentation Type

There are two types of ADHD presentations: Inattentive and Hyperactive/impulsive type

  • Inattentive ADHD is more common in females than males
  • Hyperactive/Impulsivity ADHD is more common in males than females

DSM-5 Criteria

  • A minimum of 6 months of a persistent pattern
  • Having greater than 6 symptoms of either hyperactivity or inattention
  • Symptoms present before the age of 12
  • Occur in more than 2 environments
  • Not due to other medications or psychiatric disorders

Pathophysiology

In these patients, there is a deficit of dopamine in the dopamine pathway, which makes it hard for the individual to maintain attention or arousal. This system also helps resists distraction. There is also a deficit in norepinephrine, which plays a crucial role in modulating attention.

There are many co-morbidities that can happen with ADHD. It is a huge cost to the community, and treatment should be made based on these comorbidities. These comorbidities may also present similarly to ADHD presentation, as such, it is important to rule them out:

  • Inattention –> anxiety, mood, substance abuse disorder, maladjustment, depressive symptoms
  • Hyperactivity-impulsivity –> ODD, CD, SUD

Generally, the treatment course should first treat 1) substance abuse, then 2) mood disorders, then 3) anxiety disorders, then 4) ADHD, and then 5) nicotine dependence.

Unfortunately, many adult treatments end in anxiety disorders and never got to the ADHD diagnosis.

Pharmacologic Treatment Guidelines

  • 1st-line:
    • Age 4-5 years: behavior therapy
    • Age 6-18 years: amphetamines or methylphenidates
  • 2nd-line
    • Age 6-18 years: atomoxetine, alpha-2-agonists (ER)
  • 3rd-line (co-morbid depression)
    • Bupropion
    • Tricyclic Antidepressant

Introduction to Stimulants

Due to the deficits in DA and NE seen in ADHD, medications used to treat ADHD (stimulants) target these agents to increase NE and DA signaling in the prefrontal cortex.

Amphetamine: Competitively inhibits DAT and disrupts presynaptic vesicles, leading to an increase in both DA and NE. These include amphetamine salts and dextroamphetamine.

Methylphenidate: Competitively inhibits DAT and disrupts presynaptic reuptake of DA and NE (DA>NE). These include methylphenidate and dexmethylphenidate.

Both inhibit MAO with amphetamine having a greater affinity than methylphenidate

Common adverse effects: New-onset tics, GI upset, decreased appetite, insomnia, blood pressure change (usually 1-2 mmHg), and heart rate change. Psychiatric disorders and seizures may also happen.

BBW: abuse, drug dependence which can lead to cardiac death/serious CV events

Contraindication: hyperthyroidism, thyrotoxicosis, glaucoma, agitated states, history of drug abuse, within 14 days of administration.

Long-term use caution: Individuals typically experience growth retardation of 1.5 cm a year. This is due to a combination of appetite suppression and the medication itself. Modifying household meals may be effective.

It is recommended to start the patient on IR formulation to determine appropriate dosing and assess efficacy. Both amphetamine and methylphenidate are equally efficacious. If one stimulant fails, it is reasonable to switch to the other class.

Amphetamine Containing Products

  • Short-Acting
    • Adderall (mixed AMP salts), Dextrostat (d-AMP), Procentra (d-AMP liquid)
    • Peak: 3-4 hours
    • Duration: 4-5 hours
    • Due to their short duration, these medications often require BID-TID dosing. If the dose is taken late in the day, it can precipitate insomnia.
  • Intermediate-Acting
    • Dexedrine Spansules (d-AMP)
    • Peak: 6-8 hours
    • Duration: 8 hours
    • This medication can be taken once daily in the morning or twice daily.
    • The Spansules contain 50:50 IR: DR formulation
  • Long-Acting (The most common)
    • Adderall XR (mixed AMP salts), Vyvanse (lisdexamfetamine)
    • Peak: 7 hours for Adderall XR and 3-4 hours for Vyvanse
    • Duration: 10 hours
    • Adderall XR is similar to Dexedrine Spansules in that it also contains a 50:50 mix of IR and DR.
    • Vyvanse is a prodrug of dextroamphetamine. It is activated in the gut (cannot be snorted.)
    • Both of these agents are once-daily agents

Methylphenidate Containing Products

  • Short-Acting
    • Ritalin (MPH), Focalin (d-MPH)
    • Peak: 1-3 hours
    • Duration: 4 hours
    • Like AMP short-acting agents, they require BID-TID dosing. If taken late, they can precipitate insomnia. MPH also comes as a solution or chewable.
  • Intermediate-Acting
    • Ritalin SR (MPH), Metadate ER (MPH)
    • Peak: 4-5 hours
    • Duration 6-8 hours
    • The delayed release action comes from a wax-based matrix
    • Typically dose BID
  • Long-Acting
    • Ritalin LA (MPH)
      • Once-daily capsule
      • 50:50 mix of IR and DR
      • Peaks: 1-3 hours and 5-6 hours
      • Duration: 8-12 hours
    • Metadate CD (MPH)
      • Once daily capsule
      • 30:70 mix of IR and DR (good option for worsened afternoon symptoms)
      • Peaks: 1-3 hours and 5-6 hours
      • Duration 8-12 hours
    • Quillivant XR (MPH-XR suspension)
      • Solution
      • 20:80 mix of IR and DR
      • Peak: 4 hours
      • Duration: 12 hours
    • Aptensio XR (MPH-MLR)
    • Concerta (MPH)
      • Once daily OROS
      • Ghost tablet in feces
      • Avoid those with bowel obstruction
      • Peak: 2 hours, then 3-4 hours, and then slowly release phase
      • Duration: 8-12 hours
    • Focalin XR (d-MPH)
      • 50:50 mix of IR and DR
      • Peak: 1.5 hours then 6 hours
      • Duration: 10 hours
    • Daytrana (MPH)
      • Delayed onset of 2 hours
      • Duration: 8 hours
      • Remove after 9 hours, but the effect lasts another 3 hours post-removal.
      • Must be careful with the disposal
      • A patch can cause discoloration of the skin about one month after usage
      • Usually put on the lower abdomen, but not at the waistline (avoid rubbing)

These medications (AMP and MPH) can be titrated weekly.

Other Pharmacologic Options

Atomoxetine (Strattera)

  • Not as effective
  • Only hit NE with no DA (no mood regulation)
  • This is a great option for those who don’t want to take stimulants.
  • Takes 4 weeks to see the effect
  • Concerns with CYP2D6 metabolism
  • Doesn’t work with a tic disorder, substance use disorder, and comorbid anxiety disorder
  • BBW: increased suicidality, especially in combination with SSRIs.
  • Severe liver injury.

BID dosing can help decrease ADRs.

Alpha-2 Agonist (ER) (Clonidine/Catapres and guanfacine/Intuniv)

  • Primarily work through NE as well
  • Use for tic disorder
  • Hypotension tends to be the dose-limiting factor
  • Must be titrated to effective dose and taper to discontinue due to rebound hypertension
  • Take 2-4 weeks for effect

This is not a 1:1 conversion between IR and ER

Alternative Agents (Bupropion, TCAs, and Modafanil)

Bupropion is usually only used with concurrent depression and nicotine dependence. Among TCAs, only imipramine, desipramine, and nortriptyline have sufficient data for recommendation. Modafanil only shows modest efficacy and put the patients at risk for SJS and psychosis exacerbations.

Natural Products

Omega-3 and omega-6 have not really shown efficacy.

Iron may work in children at risk for iron deficiency.

Pharmacotherapy for ADHD

The treatment duration varies patient to patient. It’s generally recommended that if the patient has been symptom-free for at least 1 year, the need for medication should be re-assessed. If after discontinuation the symptoms worsen, the medications may be restarted.

These medications should be avoided in pregnancy because they have been associated with premature birth and low birth weight.

Similarly with lactation, if the medication cannot be discontinue, the patient should consider pumping and dumping. Otherwise, a switch to bupropion is recommended.

Depression

SSRIs are recommended for pediatric depression. Generally pharmacologic treatment does not start until 8 years of age. Only fluoxetine, citalopram, escitalopram, and sertraline are approved, but start with fluoxetine first.

DO NOT use paroxetine due to adverse reaction effects.

The patients should be reminded that SSRIs can take 4-6 weeks to see the effect. Patients should also be started on psychotherapy along with the pharmacologic agent.

Two guidelines can be used to guide the treatment: NICE and AAP Guidelines

Anxiety Disorders (10-20%)

Only OCD have approved indication in pediatrics. The approved medications are clomipramine (10+ years), fluvoxamine (8+), sertraline (6+), and fluoxetine (7+). These medications have been shown to help with compulsion.

Because these agents can take several weeks to work, clonazepam can be used to bridge the gap.

The CAM study was done on 100-150mg of sertraline per week.

Suicide is the third leading cause of death in children. 90% of these are due to untreated psychological illness. Children are most susceptible during care initiation. More youth on medications spontaneously reported suicidality than youth on placebo.

This increased in suicidality though leads to the box warning of SSRI. During week 1-4: the child to be monitored weekly. Week 5-12: every other week.

Autism/Asperger’s

These are a spectrum of poor socializing ability. Many patients display insistent on sameness. Severity is assessed using scales, such as the Clinical Global Impression Scale, Aberrant behavior checklist, and childhood autism rating scale.

Medications often required to treat related symptoms of depression, anxiety, aggressiveness, and hyperactivity.

Depression: Fluoxetine, sertraline, escitalopram

Anxiety: VPA helps with mood stabilization

Aggression: Risperidone

Insistent on Sameness: Escitalopram

Repetitive behaviors: Risperidone, aripriprazole, and TCAs (maybe)

Eating Disorders

There are two major eating disorders: anorexia and bulimia. Anorexia, typically, requires a lot more medications because we need to treat other factors as well.

Anorexia: SSRI, antipsychotics, cyproheptadine, hormones, and zinc

Bulimia: Fluoxetine, bupropion, venlafaxine, fluvoxamine

When using bupropion, we must be careful of seizure if the patient is still actively throwing up. This is due to electrolyte imbalance.

Substance Abuse

The rate of substance abuse in youth has declined in the past 15 years, but there is an increased in vaping. It is typically associated with poor family relationships and poor parental supervision.

Pediatric Bipolar Disorder

This is a controversial diagnosis. Typically, the youngest age for diagnosis is 10 years old.

Risperidone is the top agent. If risperidone cannot be used, aripiprazole or olanzapine (13 years and older) can be used.

Never use topiramate and oxcarbazepine in kids due to significant ADRs.

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