Neuropsych

Question 1

Depression Pathophysiology

Answer 1

• All antidepressants effect monoamine system and neurotransmitters (NT)
  
  • Serotonin (5-HT), norepinephrine (NE), and/or dopamine (DA)
• Monoamine Hypothesis: Decrease in function or amount of NT in the brain
  
  • Treatment increases NT immediately, but effects on symptoms are delayed
• Neurotrophic Hypothesis: Adaptive Changes to Amine Receptor Systems
  
  • Desensitization or downregulation of receptors
  • Disrupted Brain-Derived Neurotrophic Factor (BDNF)
    
    • Growth factor protein that regulates differentiation & survival of neurons

Question 2

Antidepressant Classes

Answer 2

• Selective Serotonin Reuptake Inhibitors (SSRI)
  
  • Fluoxetine has the most evidence to support its use in the adolescent population
• Serotonin-Norepinephrine Reuptake Inhibitors (SNRI)
• Tetracyclic and Unicyclic Antidepressants

​

• Not Recommended in children:
  
  • Tricyclic Antidepressants (TCA)
  • Monoamine Oxidase Inhibitors (MAOI)

Question 3

Receptors and Transporters

Answer 3

• ACh M: acetylcholine muscarinic receptor
  
  • Anticholinergic effects (dry)
• H_1: histamine₁ receptor
  
  • ​Sedation, H^OTN, weight gain
• 5-HT_2: serotonin 5-HT2 receptor
  
  • Sedation, H^OTN, sexual dysfunction
  • Bleeding risk – impairment of platelet aggregation with serotonic-affecting agents
• NET: norepinephrine transporter
  
  • NE reuptake inhibition: decreased depression, tremors, tachycardia, sexual dysfunction
• SERT: serotonin transporter
  
  • ​Serotonin reuptake inhibition: decreased depression, anxiety, GI distress, sexual dysfunction

Affinity

• • 0/+, minimal affinity +, mild affinity
• • ++, moderate affinity +++, high affinity

Question 4

SSRI

Answer 4

• MOA - Inhibition of serotonin transporter (SERT)
• Many Treatment Indications - broad spectrum of use
  
  • First line treatment option
  • Safe in overdose
    
    • Relative tolerability
    • Consider variability within class
    • Consider Drug Interactions
• Enhance serotonergic activity
  • GI – n/v/d/GI issues (start early and improve with time)
  • Diminished sexual function and interest
    
    • 30-40% loss of libido, delayed orgasm, diminished arousal
    • Headaches
    • Insomnia, hypersomnia
      
      • Excessive sleepiness or trouble staying awake during the day; can fall asleep at any time
    • Weight gain (especially paroxetine)
    • “Disinhibition” (risk-taking behaviors, increased impulsivity)
    • Increase risk of bleeding
    • Citalopram/Escitalopram – prolong QT interval
    • SIADH and hyponatremia (Age, volume depletion, diuretic use)
• Prozac t1/2 48-72h; active metabolites t1/2 180 hours – longest
• Paxil t1/2 20-23h – shortest

Question 5

Serotonin-Norepinephrine Reuptake Inhibitors (SNRI)

Answer 5

• Similar serotonergic effects to SSRIs
  
  • Increased risk of bleeding
• Noradrenergic effects: Dose-related hypertension; tachycardia
• CNS activation: insomnia, anxiety, agitation
• Increased sweating and urinary retention
• SIADH and hyponatremia (Risk factors - volume depletion, diuretic use)
• Increase risk of seizures
• Duloxetine
  
  • Hepatotoxicity; Hyperglycemia
• Venlafaxine
  
  • Dyslipidemia (Total cholesterol, TG)

Question 6

Tetracyclic and unicyclic

Answer 6

Tetracyclic & Unicyclic Adverse Reactions

• Bupropion
  
  • Improves sexual dysfunction; not sedating; no weight gain
  • Agitation, insomnia, anorexia; hypertension
  • Seizure risk especially in overdose
  • Contraindicated in patients with seizure disorders & eating disorders
• Mirtazapine
  
  • Sedative effect; weight gain; sexual dysfunction
  • Anticholinergic effects (dry mouth, constipation, orthostatic hypotension)
  • Increased arrhythmias (QT prolongation, V Fib)
  • Hyperlipidemia; hyponatremia

Question 7

Serotonin Syndrome

Answer 7

• Overstimulation of 5-HT receptors
  
  • Serotonin antidepressant + other serotonin medications
  • (Linezolid; dextromethorphan, sumatriptan, tramadol, methadone, St. John’s wort)
• Triad of Symptoms
  
  • Cognitive (delirium, coma) +
• Autonomic (hypertension, tachycardia, diaphoresis) +
• Somatic (myoclonus, hyperreflexia, tremor)
• Caution when switching from one serotonin antidepressant to another, especially Fluoxetine with longer t 1⁄2; allow 1-2 weeks washout period

Question 8

Antidepressant Discontinuation Syndrome/Withdrawal Syndrome

Answer 8

• Avoid abrupt discontinuation of antidepressant therapy
• Taper dose over several weeks with consideration to half-life
  
  • Reduce dose every 5-7 days
  • Longer duration for medications with shorter t1⁄2 • Fluoxetine taper may be unnecessary
• Long term therapy - taper over 4-6 months
• If symptoms occur during taper, restart at the original dose taper slower
• Especially if short half-lives; case reports with all drugs
• Differentiate from relapse of depression or other psychiatric/medical conditions
• F.I.N.I.S.H. Mnemonic for recognition of symptoms
  
  • Flu-like symptoms (general malaise, muscle ache, headaches)
  • Insomnia
  • Nausea - GI disturbances
  • Imbalance - Dizziness/lightheadedness, vertigo
  • Sensory disturbances - paresthesia, visual disturbance
  • Hyperarousal - anxiety, agitation
• Symptoms resolve within 1-2 weeks; Not life-threatening

Question 9

AAP Recommendations – Selecting Therapy

Answer 9

First Line – SSRI

• Base selection on optimum combination of safety and efficacy data including drug interactions
• Deliberate self-harm and/or suicide risk is more likely if SSRI started at higher doses
• Only fluoxetine FDA approval ≥6yo for depression
  
  • Also approved for depressive episodes associated with bipolar I disorder (in combo w/ olanzapine ≥ 10yo); and OCD ages ≥7yo
• Escitalopram only FDA approved >12yo for depression
• *Sertraline FDA approved ≥ 6yo for OCD
• Details regarding initial selection of specific SSRI and possible reasons for initial drug choice in GLAD-PC toolkit

Question 10

Selecting between SSRIs

Answer 10

• FDA approval for adolescents
• If no contraindications, fluoxetine recommended as first-choice • Success of prior medication trials
• SSRI half-life
• Interactions with other medications
• Side effect profiles of different medications
• Family history of successful medication treatment
• Patient’s medical issues

Question 11

AAP Recommendations – During Treatment

Answer 11

• Delayed improvements in symptoms
  
  • Consider titrating dose after 2-3 weeks if no positive response noticed
  • Reassess diagnosis/ initial treatment if no improvement noted after 6 to 8 weeks and consider mental health consultation
  • < 50% of patients respond to 1^st line therapy
• Maintain therapy for 6 to 12 months after full resolution of depressive symptoms
  
  • Regardless of length of treatment, monitor all patients on a monthly basis for 6 to 12 months after full resolution of symptoms
• If patient experiences a recurrence, clinicians are encouraged to monitor patients for up to 2 years given high rates of recurrence
• Switch within a class before switching to another class

Question 12

ADHD

Answer 12

• Eval for ADHD for any child 4-18yo presenting with academic or behavioral problems and symptoms of inattention, hyperactivity, or impulsivity
  
  • Pre-school: EBP behavior therapy first; methylphenidate if not improved
  • Elementary: drug and/or behavior therapy, preferably both
    
    • Evidence stronger for stimulant medications and sufficient but less strong for atomoxetine, extended release guanfacine, and extended release clonidine (in that order)
  • Adolescent: drug and/or behavior therapy, preferably both
• ER formulations more expensive, but benefits of consistent & sustained coverage with fewer administrations, better adherence
  
  • Some adolescents, might require > 12 hours of coverage: utilize a short-acting might be used in addition to long-acting
• Identify risk factors for Stimulant Medications
  
  • History of cardiac symptoms; cardiac family history (arrhythmias, sudden death, death at young age from cardiac conditions); vital signs, cardiac physical examination
  • Presence of tic disorder: affects ~20% of patients with ADHD
    
    • Stimulant medication does not clearly worsen tics, may do so in individual cases. Atomoxetine or alpha-agonist may lessen comorbid tics.
  • Minimization of adverse effects
    
    • Affect on sleep initiation
    • Risk status for drug use/abuse

Question 13

AAP Recommendations – Initiating ADHD Therapy

Answer 13

• Begin with low dose and titrate to dose that provides maximum benefit and minimal adverse effects
  
  • During 1^st mo of trx, titrate weekly/biweekly via discussions w parents
  • Stimulant medications can be effectively titrated on a 3 to 7 day basis
  • In-person follow up recommended by 4th week of therapy
• Initially, core symptom reduction is more likely to indicate medication effects
• Effects of improvement in function require more extended time period
• If max dose reached without satisfactory results or intolerable effects, switch to another stimulant before attempting non-stimulant

Question 14

Stimulant Medications

Answer 14

Methylphenidate or amphetamine compounds

• MOA: Affect CNS dopaminergic pathways
• First choice of treatment
  
  • > 70% of children and youth with ADHD respond to 1st stimulants at an optimal dose; 90-95% respond to 2nd stimulant
  • Highly effective for most children in reducing core sx of ADHD
• ADME Consideration:
  
  • Children 4-5 years of age have slower rates of metabolizing methylphenidate, initiate a lower dose and increase in smaller increments
• AE: generally dose dependent
• Most Common AE
  
  • Appetite loss, abdominal pain, headaches, and sleep disturbances
• Decreases growth velocity (~1-2 cm)
  
  • Esp in higher, consistently administered doses
  • Effects decrease by 3rd year of trx
• Uncommon: hallucinations and or psychotic symptoms
• Rare occurrence of sudden cardiac death; depression, suicidal ideation
• AE in preschool-age children – increased mood lability and dysphoria

Question 15

Non-stimulant Medications for ADHD

Answer 15

• First choice of treatment if concerns about possible abuse/diversion or strong family preference against stimulant medication
  
  • Take longer to reach efficacy

Atomoxetine

• May also be effective for comorbid mood or anxiety disorders and has no abuse risk

Guanfacine and Clonidine

• Also beneficial as alternatives or adjuncts to stimulant treatment
• Useful in combination with stimulants for comorbid sleep problems, tics, or Tourette syndrome
• Potential advantages of guanfacine over clonidine include fewer sedative and hypotensive effects

Question 16

Atomoxetine

Answer 16

• MOA: Selective norepinephrine-reuptake inhibitor
• Maximum response may take ~4 to 6 weeks
• BB Warning on possibility of suicidal ideation when initiating medication management
  
  • Early symptoms of suicidal ideation might include thinking about self harm and increasing agitation
• AE
• Initially - GI symptoms and sedation (initiated at 50% of dose in 1st week)
• Appetite suppression
• Rare: hepatitis

Question 17

Guanfacine and Clonidine

Answer 17

• Available: Extended-release guanfacine; extended-release clonidine
• MOA: Selective α_2A-adrenergic agonists
• Maximum response may take ~2-4 week
• Qday or BID
• AE
  
  • Somnolence and dry mouth
  • Taper when discontinue to prevent rebound hypertension

Question 18

Epilepsy: Initiating Antiepileptic Therapy

Answer 18

• Will always involve neurology
• Considers
  
  • Seizure type
  • Adverse Reaction profile
  • Drug interactions and Comorbidities
  • Cost and ease of use; patient factors
• Initiate single agent; titrate to efficacy or intolerable SE
• Switch to another agent; titrate to efficacy or intolerable SE
• Attempt dual therapy if monotherapy not effective
• Withdrawal of therapy
  
  • Do not discontinue abruptly
  • Gradually taper dose down

Non-epilepsy indications:

• Mood disorders
• Refractory pain syndromes
• Trigeminal neuralgia
• Migraine headaches
• Drug withdrawal syndromes
• Social phobias

Question 19

First Generation – Older Agents

Answer 19

• Phenobarbital
• Phenytoin (Dilantin®)
• Carbamazepine
  
  • Oral – Carbatrol®, Tegretol®)
  • New IV - Carnexiv®
• Valproic Acid
  
  • Valproic Acid (Depakene®)
  • Valproate (Depacon®)
  • Divalproex (Depakote®)
• Absence Seizures
  
  • Ethosuximide (Zarontin®)
• Adjunctive Therapy
  
  • Acetazolamide (Diamox®)

Question 20

Second Generation – Newer Agents

Answer 20

• Felbamate (Felbatol®)
• Lamotrigine (Lamictal®)
• Topiramate (Topamax®)
• Levetiracetam (Keppra®)
• Oxcarbazepine (Trileptal®)
• Zonisamide (Zonegran®)
• Lacosamide (Vimpat®)
• Rufinamide (Banzel®)
• Vigabatrin (Sabril®)*REMS
• Ezogabine (Potiga®)
• Perampanel (Fycompa®)
• Brivaracetam (Briviact®)
• Eslicarbazepine (Apiom®)

Question 21

Other therapies for Epilepsy

Answer 21

• Benzodiazepines for Status Epilepticus
  
  • Diazepam; Midazolam; Lorazepam
• Benzodiazepines for Adjunctive Therapy
  
  • Clonazepam (Klonopin®)
  • Clorazepate (Tranxene®)
  • Clobazam (Onfi®) – 2011
    
    • Adjunctive therapy for Lennox-Gastaut Syndrome
• Cannabinoids
  
  • Cannabidiol (Epidiolex®) - Approved June 2018
    
    • Lennox-Gastaut Syndrome or Dravet Syndrome
    • C-V status
  • CBDV (GWP42006) in the pipeline – Phase 2

Question 22

MOA of Neurotransmitters

Answer 22

Excitatory Neurotransmitters

• Glutamine
• Glutamate

Inhibitory Neurotransmitters

• GABA
• Glycine

Goal: Limit sustained repetitive firing & Increase Inhibitory; Decrease Excitatory

• Stabilization of cell membrane
• Prevention of further depolarization
• Decrease impulse transmission
• Increase seizure threshold
• Targets at Inhibitory, GABAergic Synapse
  
  • GOAL: Increase GABA concentrations
    
    • Enhance synaptic release
    • Increase GABA receptor activation
    • Block GABA reuptake
    • Inhibit GABA transaminase mediated metabolism
• Targets at Excitatory, Glutamatergic Synapses
  
  • GOAL: Decrease circulating glutamate
    
    • Blocking voltage-gated sodium channels **
    • Inhibiting voltage-gated calcium channels
    • Inhibiting voltage-gated potassium channels
• Sometimes mechanism of action still unclear….

Question 23

Carbonic Anhydrase Inhibitors

Answer 23

• MOA: inhibit membrane-bound and cytoplasmic forms of carbonic anhydrase
  
  • Carbonic anhydrases are enzymes that catalyze the conversion between CO2 and bicarbonate
  • Inhibition of specific carbonic anhydrases (CA II, CA VII) exhibit anti-seizure activity
    
    • Prevents replenishment of intracellular bicarbonate and depresses the depolarizing action of bicarbonate through GABAA receptors
• Examples: Acetazolamide, Topiramate, Zonisamide

Question 24

First Gen - Older Agents

Answer 24

Carbamazepine (Tegretol®)

• PK: Metabolized to carbamazepine-10,11-epoxide
  
  • Active metabolite w/increases in side effect
  • Auto-inducer
  • Broad-spectrum inducer
• Avoid use in patients carrying HLA-B*1502 allele (Asian descent) (BBW)
  
  • Screened prior to initiating therapy
  • Increased risk of developing SJS/TENS

Phenobarbital

• Metabolism
  
  • Substrate of CYP450 2C19
  • Broad-spectrum inducer
• MOA: Binds to GABAA Receptors
  
  • Increase the duration of the GABA-gated channel openings
  • Less selective actions
    
    • Increases GABA Activity
    • Decreases Glutamic Acid Activity – Binds to AMPA receptor

Phenytoin/Fosphenytoin

• Phenytoin (Dilantin®)
  
  • IV Phenytoin must be administered slowly (50 mg/min)
  • BBW with IV administration:
    
    • Hypotension & severe cardiac arrhythmias (heart block, ventricular tachycardia/fibrillation)
    • “Purple glove syndrome” - discoloration w/edema & limb pain

Fosphenytoin (Cerebyx®) – IV Only

• Prodrug: more soluble form of phenytoin w/less infusion related reactions; Administer more rapidly (150 mg PE/min)
• General PK: Highly protein bound to plasma proteins (albumin)
  
  • Broad-spectrum inducer

Valproic Acid and derivatives

• PK: 90% protein bound
• Displaces other drugs from proteins
• Broad-spectrum inhibitor

Question 25

Metabolism – Newer Agents

Answer 25

Metabolism * Primarily liver metabolized * Mixed (liver & kidneys) – *Felbamate, Topiramate, Levetiracetam* * Oxcarbazepine (Trileptal®) * CBZ benefits without auto-induction & drug interaction profile * Highly protein bound * Brivaracetam (Briviact®) * Analog of levetiracetam Adverse Reactions * GI Symptoms – N/V; weight gain * CNS - Most *common*: ataxia, lethargy, sedation, headaches * Most severe - CNS depression, seizures, death * ***Seizures more common with carbamazepine, lamotrigine*** * Respiratory Depression * CV - Sinus tachycardia, dysrhythmias, hypotension * ***QRS prolongation more common with carbamazepine, lamotrigine, topiramate, lacosamide*** * Suicidality - Increased risk of suicidal thoughts/behavior * Vision – diplopia, nystagmus * Blood dyscrasias – thrombocytopenia, anemia, leukopenia

Question 27

Vigabatrin (Sabril®)

Answer 27

* **FDA approval finally in 2009 (delayed from 1993)\*\*** * Indications * Effective for infantile spasms (West’s Syndrome) * *\*\*Why delayed approval:* * Visual field constriction in ~40% patients * Mostly asymptomatically affects peripheral fields – does not impair central visual acuity * Irreversible or incompletely reversible after discontinue * ***SHARE Rems Program***

Question 28

Serious Cutaneous Adverse Reactions (SCARs)

Answer 28

* Result from immunologic reactions * Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) * Drug Rash with Eosinophilia and Systemic Symptoms * Triad of rash, eosinophilia, and internal organ involvement • Cutaneous drug eruption (usually diffuse maculopapular rash accompanied by facial and neck edema) * Hematologic abnormalities including eosinophilia \> 1,500 cells/mm3 or presence of atypical lymphocytes * Systemic involvement including adenopathies \> 2 cm in diameter, hepatitis, interstitial nephritis, interstitial pneumonia, or carditis * Delayed onset ranging from 3 to 8 weeks * Mortality rate ~10% * Treat with systemic corticosteroids * Discontinue causative drug, normalize over 4 to 8 weeks * Mucocutaneous disorders - Erythema multiforme * Stevens–Johnson’s syndrome (SJS) * Toxic Epidermal Necrolysis (TENS) * Common with antiepileptic agents * Anticonvulsant hypersensitivity syndrome

Question 29

CYP450 Drug Interactions

Answer 29

**Inhibitors** * **CYP2C19** * *Felbamate* * *Topiramate* * Broad Spectrum weak Inhibitor -- Valproic acid *​***Inducers** * **CYP3A4** * *Felbamate* * Broad Spectrum Inducers -- * Carbamazepine * Phenytoin * Phenobarbital ^{**Many AEDs interact with rifampin (broad spectrum inducer) **Remember albumin related interactions}

Question 30

Lamotrigine (Lamictal®)

Answer 30

* **Significant Drug Interactions** * VPA inhibits LTG metabolism * **A dosage reduction of 50% or more is needed** * Inducing agents induce LTG metabolism * **A dosage increase of 20-100% is needed** * **Half Life** * T_1⁄2 ~24 hours (not on VPA or inducing agents) * T_1⁄2 ~12 hours (not on VPA, w/ inducing agents) * T_1⁄2 ~48-60 hours (on VPA) * T_1⁄2 for children are slightly faster in each case

Question 31

AEDs and Pregnancy

Answer 31

* Teratogenicity (especially older agents) * Fetal hydantoin syndrome * Neural tube defects - initiate folic acid * Cardiac & limb malformations, oral cleft defects * Enzyme inducing agents * Increased neonatal hemorrhage due to vitamin k deficiency * AED Pregnancy Registry – www.aedpregnancyregistry.org

Question 32

Status Epilepticus

Answer 32

**Step 1 – Assessment** 1. Stabilize patient (ABC, disability - neurologic exam) 2. Time seizure from its onset, monitor vital signs 3. Assess oxygenation, give oxygen via nasal cannula/mask, consider intubation if respiratory assistance needed 4. Initiate ECG monitoring 5. Collect finger stick blood glucose; If glucose \< 60 mg/dl treat 6. Attempt IV access and collect electrolytes, hematology, toxicology screen, (if appropriate) anticonvulsant drug levels **Step 2 - Benzodiazepine for initial therapy of choice:** * Choose one of the following 3 equivalent first line options: * IM midazolam (10 mg for \> 40 kg, 5 mg for 13-40 kg, single dose) * **OR** IV lorazepam (0.1 mg/kg/dose, max: 4 mg/dose, may repeat once) * **OR** IV diazepam (0.15-0.2 mg/kg/dose, max: 10 mg/dose, may repeat once) * If none of 3 options above are available, choose one of the following: * IV phenobarbital (15 mg/kg/dose, single dose) * **OR** rectal diazepam (0.2-0.5 mg/kg, max: 20 mg/dose, single dose) * **OR** intranasal or buccal midazolam **Step 3 - Second therapy of choice:** * Choose one of the following second line options as a single dose * IV fosphenytoin (20 mg PE/kg, max: 1500 mg PE/dose, single dose) OR * IV valproic acid (40 mg/kg, max: 3000 mg/dose, single dose) OR * IV levetiracetam (60 mg/kg, max: 4500 mg/dose, single dose) * If none of options above are available, give IV phenobarbital (15 mg/kg, single dose) if not given already **Step 4 – Last resort options:** * Choices include: repeat second line therapy or anesthetic doses of either thiopental, midazolam, pentobarbital, or propofol *(all with continuous EEG monitoring and possible inotropic agent for hypotension)*