Stimulants, headache and bipolar

Bipolar Disorder

• [Is there a genetic component?] 

• Genetic -- 80-90% of patients have 1st relative with mood disorder 

Comorbidities of ADHD

• [...] 
  

  • Alpha-2 agonist

• Tourette disorder 

Non-Stimulant Agents 

• Clonidine Extended Release (Kapvay)
  

  • Clinical Pearls 
    

    • Less effective than stimulants but can be used in combination 

    • May be preferred if:

      • patient has active substance abuse problem, comorbid anxiety, tics, Tourette

      • OR has intolerable side effects to stimulants 

    • More sedation than stimulants and atomoxetine 

    • Better at ↓ [...] than [...] 

    • May ↓ [...] 

    • Monotherapy or with stimulants

• hyperactivity

• inattention

• severity of tics 

Non-Stimulant Agents 

• [...] 
  

  • Mechanism: 

    • unknown 

    • Possibly:

      • postsynaptic alpha₂ agonist stimulation

      • regulation of subcortical activity in the prefrontal cortex 

  • PK/PD 

    • Onset: up to 2 weeks 

    • Duration: 10-12 hours 

  • Not a controlled substance 

  • Adverse Effects: 

    • sedation

    • bradycardia

    • hypotension

    • headache 

  • Rebound HTN if stopped abruptly

• Clonidine Extended Release (Kapvay) 

Non-Stimulant Agents 

• Clonidine Extended Release (Kapvay) 
  

  • Mechanism: 

    • unknown 

    • Possibly:

      • postsynaptic [...] agonist stimulation

      • regulation of subcortical activity in the prefrontal cortex 

  • PK/PD 

    • Onset: up to 2 weeks 

    • Duration: 10-12 hours 

  • Not a controlled substance 

  • Adverse Effects: 

    • sedation

    • bradycardia

    • hypotension

    • headache 

  • Rebound HTN if stopped abruptly

alpha₂

Non-Stimulant Agents 

• Clonidine Extended Release (Kapvay) 
  

  • Mechanism: 

    • unknown 

    • Possibly:

      • postsynaptic alpha₂ agonist stimulation

      • regulation of subcortical activity in the prefrontal cortex 

  • PK/PD 

    • Onset: up to 2 weeks 

    • Duration: 10-12 hours 

  • Not a controlled substance 

  • Adverse Effects: 

    • [does it make you drowsy?]

    • [brady or tachy]cardia

    • [hypo or hyper]tension

    • headache 

  • Rebound HTN if stopped abruptly

• sedation

• brady

• hypo

Non-Stimulant Agents 

• Clonidine Extended Release (Kapvay) 
  

  • Mechanism: 

    • unknown 

    • Possibly:

      • postsynaptic alpha₂ agonist stimulation

      • regulation of subcortical activity in the prefrontal cortex 

  • PK/PD 

    • Onset: up to 2 weeks 

    • Duration: 10-12 hours 

  • Not a controlled substance 

  • Adverse Effects: 

    • sedation

    • bradycardia

    • hypotension

Rebound HTN

Non-Stimulant Agents 

• Atomoxetine (Strattera)
  

  • Adverse effects 

    • CNS: 

      • Dizziness

      • fatigue

      • drowsiness 

    • Dermatologic

      • hyperhidrosis = abnormally excessive sweating

    • GI: 

      • anorexia

      • upset stomach

      • nausea 

    • CV: hypertension

  • Warnings 

    • Cardiovascular events, including sudden death (same as stimulants) 

    • May increase [...] 

  • Contraindications 
    

    • [...] 

    • Severe cardiac disorders 

    • Moderate-severe HTN 

    • Use with or within 14 days of MAO inhibitors 

    • Uncontrolled hyperthyroidism

• suicidal ideation 

• Glaucoma

Non-Stimulant Agents 

• [...] 
  

  • Mechanism: 

    • selective norepinephrine reuptake inhibitor 

  • PK/PD 

    • Onset of action: 2-4 weeks 

    • Duration: 10-12 hours 

    • Takes 6-12 weeks for max effect 

    • May be used with stimulants

• Atomoxetine (Strattera) 

Non-Stimulant Agents 

• Atomoxetine (Strattera) 
  

  • Mechanism: 

    • [...] 

  • PK/PD 

    • Onset of action: 2-4 weeks 

    • Duration: 10-12 hours 

    • Takes 6-12 weeks for max effect 

    • May be used with stimulants

• selective norepinephrine reuptake inhibitor 

• Adverse effects 

  • CNS: Dizziness, fatigue, drowsiness 

  • Dermatologic: hyperhidrosis 

  • GI: anorexia, upset stomach, nausea 

  • CV: hypertension

• Warnings 

  • Cardiovascular events, including sudden death (same as stimulants) 

  • May increase suicidal ideation 

• Contraindications 
  

  • Glaucoma 

  • Severe cardiac disorders 

  • Moderate-severe HTN 

  • Use with or within 14 days of MAO inhibitors 

  • Uncontrolled hyperthyroidism

Non-Stimulant Agents 

• [...]
  

  • Clinical Pearls 

    • Less effective than stimulants 

    • Option if patient has active substance abuse problem, anxiety, tics OR has intolerable side effects to stimulants 

    • Less growth suppression than stimulants 

• Atomoxetine (Strattera)

Non-Stimulant Agents 

• [...] 
  

  • Mechanism: 

    • unknown 

    • Possibly:

      • preferentially binds postsynaptic alpha_2A-adrenoreceptors in prefrontal cortex 

      • delays firing of prefrontal cortex neurons 

  • PK/PD 

    • Onset: up to 2 weeks 

    • Duration: 18 hours 

  • Dosed once daily

  • Clinical Pearls

    • Same as clonidine 

    • Longer-acting than clonidine 

    • AE: same as clonidine 

    • Rebound HTN if stopped abruptly

• Guanfacine ER (Intuniv) 

Non-Stimulant Agents 

• Guanfacine ER (Intuniv) 
  

  • Mechanism: 

    • unknown 

    • Possibly:

      • preferentially binds postsynaptic [...] in prefrontal cortex 

      • delays firing of prefrontal cortex neurons 

  • PK/PD 

    • Onset: up to 2 weeks 

    • Duration: 18 hours 

  • Dosed once daily

  • Clinical Pearls

    • Same as clonidine 

    • Longer-acting than clonidine 

    • AE: same as clonidine 

    • Rebound HTN if stopped abruptly

alpha_2A-adrenoreceptors

Non-Stimulant Agents 

• Guanfacine ER (Intuniv) 
  

  • Mechanism: 

    • unknown 

    • Possibly:

      • preferentially binds postsynaptic alpha_2A-adrenoreceptors in prefrontal cortex 

      • delays firing of prefrontal cortex neurons 

  • PK/PD 

    • Onset: up to 2 weeks 

    • Duration: 18 hours 

  • Dosed once daily

  • Clinical Pearls

    • Same as clonidine 

    • [Shorter or Longer]-acting than clonidine 

    • AE: same as clonidine 

    • [...] if stopped abruptly

• Longer

• Rebound HTN

44-87% of children with ADHD have at least one other disorder such as:

1. [...]

2. [...]

3. [...] 

1. Oppositional defiant disorder (ODD)

2. Anxiety disorder

3. Tics and Tourette Disorders 

• ODD = people who yell out, act out against their parents, etc 

• Tics = repeated motion
  

• Anxiety, social anxiety disorder, etc are more prevalent in these patients -tend to act out more, deviant behavior

• -90% of patients with terrets will have ADHD too 

Migraine Medications: Prophylaxis

• Anticonvulsants 

  • Increases GABA (inhibitory neurotransmitter) to brain neurons and may enhance GABA at postsynaptic receptor sites 

  • Many potential side effects; both are teratogenic! 

  • Preferred in [...] or [...]

  • Drug of choice 

    • [...] 

    • [...] 

• seizure disorder or bipolar illness

• Divalproex 

• Topiramate 

Migraine Medications: Prophylaxis

• Beta-Blockers and Verapamil 

  • Reduces frequency ~50% in more than half of patients 

  • Modulates adrenergic and serotonergic tone making patients less susceptible to migraines 

    • Preferred in [...] or [...] 

    • Drug of choice: [...]

• HTN or angina 

• Propranolol

Typically takes 2-3 months to determine effectiveness 

Continue for 6-12 months after improvement is seen 

May taper and discontinue

Migraine Medications: Prophylaxis

• New Drugs – Migraine Prophylaxis 

  • Galcanez[...] (Emgality) 

  • Epitinez[...] (Vyepti) 

  • Eren[...] (Almovig) 

  • Fremanez[...]-vfm (Ajovy)

  • Mechanism 

    • Binds to calcitonin-gene related peptide (CGRP) 

    • modulates trigeminovascular pain transmission

• umab

• umab

• umab

• umab

Migraine Medications: Prophylaxis

• New Drugs – Migraine Prophylaxis 

  • Galcanezumab (Emgality) 

  • Epitinezumab (Vyepti) 

  • Erenumab (Almovig) 

  • Fremanezumab-vfm (Ajovy)

  • Mechanism 

    • Binds to [...] 

    • modulates [...] pain transmission

• calcitonin-gene related peptide (CGRP) 

• trigeminovascular

Migraine Medications: Prophylaxis

• NSAIDs 

  • Used sparingly due to a risk of rebound 

  • For [...] 

    • e.g. [...]

    • Initiate 1-2 days prior to onset 

      • Before headache is expected to occur 

    • Discontinue when high risk period is over

• recurrent, predictable migraines 

• menstrual associated migraines

Migraine Medications: Prophylaxis

• Options -- [...] will help determine choice
  

  • Beta-blockers 

  • Tricyclic antidepressants 

  • Anticonvulsants 

  • NSAIDs 

Typically takes 2-3 months to determine effectiveness 

Continue for 6-12 months after improvement is seen 

May taper and discontinue

Co-morbidities

Migraine Medications: Prophylaxis

• Options -- Co-morbidities will help determine choice
  

  • [...] 

  • [...] 

  • [...] 

  • [...] 

Typically takes 2-3 months to determine effectiveness 

Continue for 6-12 months after improvement is seen 

May taper and discontinue

• Beta-blockers 

• Tricyclic antidepressants 

• Anticonvulsants 

• NSAIDs 

Migraine Medications: Prophylaxis

• Tricyclic Antidepressants 

  • Down regulates serotonin and NE receptors – exact mechanism unknown 

  • TCAs are associated with more side effects therefore tolerability may prevent use 

  • Preferred if patient has [...] or [...] 

  • Drug of choice: [...]

• depression

• insomnia

• Amitriptyline

Migraine Medications: Prophylaxis

• Cluster Headache: Treatment and Prophylaxis 

  • Treatment 

    • [...] (relieves pain in 50-85% of patients) 

    • Triptans: 

      • SQ and intranasal sumatriptan and intranasal zolmitriptan may also effective

100% Oxygen

Migraine Medications: Prophylaxis

• [For what type of headache]: Treatment and Prophylaxis 

  • Treatment 

    • 100% Oxygen (relieves pain in 50-85% of patients) 

    • Triptans: 

      • SQ and intranasal sumatriptan and intranasal zolmitriptan may also effective

Cluster Headache

Migraine Medications: [...]

• Scheduled medication to decreased frequency, severity and duration of migraines 

• May improve response to acute therapy

• When to use 
  

  • 4 or more attacks per month

• Intermittent use for predictable pattern such as in:

  • Menstrual migraine 

  • Exercise induced migraine

Prophylaxis

Migraine Medications: Prophylaxis

• Scheduled medication to decreased frequency, severity and duration of migraines 

• May improve response to acute therapy

• When to use 
  

  • 4 or more attacks per month

• Intermittent use for predictable pattern such as in:

  • [...] 

  • [...]

Typically takes 2-3 months to determine effectiveness 

Continue for 6-12 months after improvement is seen 

May taper and discontinue

• Menstrual migraine 

• Exercise induced migraine

[...]

• Chronic illness that causes periodic shifts in mood through episodes of dysthymia, depression, hypomania, and mania 
  

  • Not from substance use 

  • Not caused by another medical condition 

• Symptoms typically presents in early adulthood 
  

  • Rare before puberty and after 65 

  • Usual age range of onset 18-44 years 

• No predilection for race, sex, or ethnicity 

• 1/3 attempt suicide

Bipolar Disorder

Bipolar Disorder

• Chronic illness that causes periodic shifts in mood through episodes of dysthymia, depression, hypomania, and mania 
  

  • Not from substance use 

  • Not caused by another medical condition 

• Symptoms typically presents in early adulthood 
  

  • [Is it common] before puberty and after 65 

  • Usual age range of onset 18-44 years 

• No predilection for race, sex, or ethnicity 

• 1/3 attempt suicide

Rare

Amphetamines 

• Formulations

  • All available as [which formulation?] 

  • Onset of action ≤ 60 mins; variable with formulation 

  • Duration 

    • Short-acting (6 hrs.) → 1-2 doses per day 

      • Mixed amphetamine salts (Adderall) 

    • Long-acting (10-12 hours) 

      • Mixed amphetamine salts extended-release (Adderall ER) 

      • Lis-dexamphetamine (Vyvanse)

        • Lysine bound to amphetamine in order to prevent degradation 

oral

Amphetamines 

• Formulations

  • All available as oral 

  • Onset of action ≤ 60 mins; variable with formulation 

  • Duration 

    • Short-acting (6 hrs.) → 1-2 doses per day 

      • Mixed amphetamine salts ([...]) 

    • Long-acting (10-12 hours) 

      • Mixed amphetamine salts extended-release ([...]) 

      • Lis-dexamphetamine ([...])

        • Lysine bound to amphetamine in order to prevent degradation 

• Adderall

• Adderall ER

• Vyvanse

Amphetamines 

• Mechanism of action 
  

  • [...] 

  • Minor pathway: [...] 

• Formulations 
  

  • Amphetamine 

  • Dextroamphetamine 

  • Mixed salts – d-amphetamine and l-amphetamine (3:1) 

  • Lis-dexamphetamine (lysine-bound)

• Promote release of dopamine and norepinephrine from their storage sites in the presynaptic nerve terminals

• blocks reuptake 

Amphetamines 

• Metabolism 
  

  • [...] via:

    • oxidation

    • deamination

    • CYP2D6 

  • Various active metabolites 

• Elimination 

  • via [...]

• Hepatic

• urine

Bipolar Disorder Medications 

• Anticonvulsants

  • Carbamazepine

    • [Why is this drug notorious for drug-drug interactions?]

    • Also is a 3A4 substrate!

    • Black Box Warnings

      • Stevens-Johnson syndrome (SJS) 

      • Toxic Epidermal Necrosis Syndrome (TENS) (HLA-B*1502) 

      • Aplastic anemia and agranulocytosis

• Strong CYP3A4 INDUCER

Carbamazepine -- has three a's 

• aplastic anemia 

• agranulocytosis 

Bipolar Disorder Medications 

• Anticonvulsants

  • Carbamazepine

    • Strong CYP3A4 INDUCER

    • Also is a 3A4 substrate!

    • Black Box Warnings

      • [...] 

      • [...] 

      • [...] and [...]

• Stevens-Johnson syndrome (SJS) 

• Toxic Epidermal Necrosis Syndrome (TENS) (HLA-B*1502) 

• Aplastic anemia and agranulocytosis

Bipolar Disorder Medications 

• Anticonvulsants

  • Divalproex -- anti-epilectic drug

    • Black Box warnings

      • [...]

      • [...]

      • [...]

• Hepatotoxicity

• Pancreatitis

• Teratogenicity

Bipolar Disorder Medications 

• Anticonvulsants

  • Lamotrigine

    • Black Box Warnings 

      • [...] 

      • [...] 

only two L's in LLama --> two black box warnings

• Stevens-Johnson syndrome (SJS) 

• Toxic Epidermal Necrosis Syndrome (TENS) 

Bipolar Disorder Medications 

• Lithium
  

  • Adverse Effects -- LITHIUM
    

    • L -- [...] 

    • I -- [...] 

    • T -- [...] 

    • H-- [...] 

    • I -- [...] 

    • U -- [...] 

    • M -- [...]

• Leukocytosis

• Insipidus

• Tremor, teratogen 

• Hypothyroidism

• Increased weight 

• Ugh…nausea and vomiting 

• Misc. CNS, cardia

Bipolar Disorder Medications 

• Lithium
  

  • Conditions causing Li toxicity 
    

    • Sodium restriction 

    • Activities that cause you to be [...]

      • Dehydration 

      • Vomiting/diarrhea 

      • Heart failure 

      • Heavy exercise 

      • Sauna baths, hot weather, fever 

      • Medical illnesses prone to dehydration

dyhydrated

Bipolar Disorder Medications 

• Lithium
  

  • Drug Interactions and Pregnancy 
    

    • Several drug interactions 
      

      • [Increases or decreases] serum lithium & [Increases or decreases] renal elimination
        

        • Diuretics 

        • ACE-inhibitors 

        • NSAIDs 

      • [Increases or decreases] serum lithium & [Increases or decreases] renal elimination
        

        • Theophylline 

        • Caffeine 

        • Pregnancy

• Increases

• decreases

• decreases

• increases

Bipolar Disorder Medications 

• Lithium
  

  • Drug Interactions and Pregnancy 
    

    • Several drug interactions 
      

      • Increases serum lithium & decreases renal elimination
        

        • [...] 

        • [...]

        • [...] 

      • Decreases serum lithium & increases renal elimination
        

        • Theophylline 

        • Caffeine 

        • Pregnancy

• Diuretics 

• ACE-inhibitors 

• NSAIDs 

Bipolar Disorder Medications 

• Lithium
  

  • Indications: 

    • Acute [...] 

    • Acute [...] 

    • Maintenance of [...] 

  • First line agent 

    • Monotherapy or in combination with anticonvulsants or antipsychotics 

    • Seems to work best for bipolar I

  • Efficacious (50%-70% response)

    • decreases the frequency and severity of both manic and depressive attacks 

  • Use is limited by tolerability and safety 

  • Requires close monitoring 

    • Therapeutic level 

    • Safety monitoring 

• mania

• bipolar depression 

• bipolar I and II 

Bipolar Disorder Medications 

• Lithium
  

  • Indications: 

    • Acute mania 

    • Acute bipolar depression 

    • Maintenance of bipolar I and II 

  • [What line of therapy] 

    • Monotherapy or in combination with anticonvulsants or antipsychotics 

    • Seems to work best for bipolar I

  • Efficacious (50%-70% response)

    • decreases the frequency and severity of both manic and depressive attacks 

  • Use is limited by tolerability and safety 

  • Requires close monitoring 

    • Therapeutic level 

    • Safety monitoring 

• First line agent 

Bipolar Disorder Medications 

• Lithium
  

  • Lithium-associated [...] 
    

    • Lithium interferes with action of antidiuretic hormone (ADH) 
      

      • ADH is responsible for free water reabsorption in the collecting tubule 

    • Usually reversible but can be irreversible with long- term use 

    • 30-50% of patient develop DI 

    • Management 
      

      • Amiloride (potassium-sparing diuretic) -- if lithium cannot be stopped 

      • Decreases lithium concentration at the collecting ducts

Diabetes Insipidus 

Bipolar Disorder Medications 

• Lithium
  

  • Lithium-associated Diabetes Insipidus 
    

    • Lithium interferes with action of antidiuretic hormone (ADH) 
      

      • ADH is responsible for free water reabsorption in the collecting tubule 

    • Usually reversible but can be irreversible with long- term use 

    • 30-50% of patient develop DI 

    • Management 
      

      • [...] (potassium-sparing diuretic) -- if lithium cannot be stopped 

      • Decreases lithium concentration at the collecting ducts

Amiloride

Bipolar Disorder Medications 

• Lithium
  

  • Lithium-associated Diabetes Insipidus 
    

    • Lithium interferes with action of [...] 
      

      • [...] is responsible for free water reabsorption in the collecting tubule 

    • Usually reversible but can be irreversible with long- term use 

    • 30-50% of patient develop DI 

    • Management 
      

      • Amiloride (potassium-sparing diuretic) -- if lithium cannot be stopped 

      • Decreases lithium concentration at the collecting ducts

• antidiuretic hormone (ADH) 

• ADH

Bipolar Disorder Medications 

• Lithium
  

  • Mechanism: 
    

    • exact mechanism unknown -- Mood stabilizing effects 

    • Appears to be neuroprotective:
      

      • decreasing [...]

      • enhancing [...], etc

• glutamate

• neurotropic factors

Glutamate is the main excitatory neurotransmitter of the CNS 

Bipolar Disorder Medications 

• Lithium
  

  • Monitoring 
    

    • Therapeutic levels 
      

      • Acute mania [...] to [...] mEq/L 

      • Maintenance: [...] to [...] mEq/L 

    • Toxic Concentrations 
      

      • >1.5 mEq/L 
        

        • tremor, N/V, blurred vision, vertigo, confusion, decreased deep tendon reflexes 

      • >2.5 mEq/L
        

        • seizures, coma, cardiac dysrhythmia, permanent neurological impairment 

      • >3.5 mEq/L 
        

        • potentially fatal 

    • Baseline and periodically: 
      

      • BMP, CBC, renal, thyroid function, urinalysis, electrocardiogram 

    • Pregnancy test for all females -- because it is highly teratogenic 

• 0.5

• 1.2

• 0.6

• 1

Bipolar Disorder Medications 

• Lithium
  

  • Monitoring 
    

    • Therapeutic levels 
      

      • Acute mania 0.5 to 1.2 mEq/L 

      • Maintenance: 0.6 to 1 mEq/L 

    • Toxic Concentrations 
      

      • [...] mEq/L 
        

        • tremor, N/V, blurred vision, vertigo, confusion, decreased deep tendon reflexes 

      • [...] mEq/L
        

        • seizures, coma, cardiac dysrhythmia, permanent neurological impairment 

      • [...] mEq/L 
        

        • potentially fatal 

    • Baseline and periodically: 
      

      • BMP, CBC, renal, thyroid function, urinalysis, electrocardiogram 

    • Pregnancy test for all females -- because it is highly teratogenic 

• >1.5

• >2.5

• >3.5

Bipolar Disorder Medications 

• Lithium
  

  • Monitoring 
    

    • Therapeutic levels 
      

      • Acute mania 0.5 to 1.2 mEq/L 

      • Maintenance: 0.6 to 1 mEq/L 

    • Toxic Concentrations 
      

      • >1.5 mEq/L 
        

        • tremor, N/V, blurred vision, vertigo, confusion, decreased deep tendon reflexes 

      • >2.5 mEq/L
        

        • seizures, coma, cardiac dysrhythmia, permanent neurological impairment 

      • >3.5 mEq/L 
        

        • potentially fatal 

    • Baseline and periodically: 
      

      • BMP, CBC, renal, thyroid function, urinalysis, electrocardiogram 

    • [should females take special precautions?] 

• Pregnancy test for all females -- because it is highly teratogenic 

Bipolar Disorder Medications 

• Lithium
  

  • PK 
    

    • High absorption from GI tract (80-100% bioavailable) 

    • No protein binding, no metabolization 

    • 95% of a single dose is eliminated via urine 

    • Half-life ~ 24 hours 
      

      • Steady state ~5 days; onset of action takes more time! 

    • Elimination via [...] 
      

      • Li+ competes with Na+ for [...] 

      • Li+ retention can be [increased or decreased] by Na+ loss
        

        • Example of Na+ loss: sweating! 

• kidneys

• tubular

• reabsorption

• increased

Bipolar Disorder Medications 

• Lithium
  

  • PK 
    

    • High absorption from GI tract (80-100% bioavailable) 

    • No protein binding, no metabolization 

    • 95% of a single dose is eliminated via urine 

    • Half-life ~ 24 hours 
      

      • Steady state ~5 days; onset of action takes more time! 

    • Elimination via kidneys 
      

      • Li+ competes with Na+ for tubular reabsorption 

      • Li+ retention can be increased by Na+ loss
        

        • Example of Na+ loss: [...]! 

sweating

Bipolar Disorder Medications 

• Lithium
  

  • Treatment 
    

    • Ideally, use in patients with normal cardiac and renal function 

    • Therapeutic levels must be maintained 

    • Compliance is challenging 

    • May take 1-2 weeks for [...] effects 
      

      • Antipsychotics and benzodiazepines used as adjuncts to “bridge” 

    • May take 6-8 weeks for [...] effects

• antimanic

• antidepressant

Bipolar Disorder Medications 

• Main 3 Classes
  

  • [...] 

    • Carbonate 

    • Citrate 

  • [...] 

    • Divalproex

    • Carbamazepine

    • Lamotrigine 

  • [...] 

    • Aripiprazole

    • Olanzapine

    • Quetiapine

    • Lurasidone, etc. 

• Adjunct Therapy 
  

  • Benzodiazepines 

  • Antidepressants

• Lithium

• Anticonvulsants

• Antipsychotics

Bipolar Disorder Medications 

• Main 3 Classes
  

  • Lithium 

    • Carbonate 

    • Citrate 

  • Anticonvulsants 

    • Divalproex

    • Carbamazepine

    • Lamotrigine 

  • Antipsychotics 

    • Aripiprazole

    • Olanzapine

    • Quetiapine

    • Lurasidone, etc. 

• Adjunct Therapy 
  

  • [...] 

  • [...]

• Benzodiazepines 

• Antidepressants

Bipolar Disorder Medications 

• [...] 

  • mood-stabilizing drugs that reduce manic and depressive episodes 

  • Monotherapy or adjunct 

    • Can be used in combination +/- lithium +/- antipsychotic

  • Drugs 

    1. Divalproex 

    2. Carbamazepine 

    3. Lamotrigine 

Anticonvulsants

Bipolar Disorder Medications 

• Anticonvulsants 

  • mood-stabilizing drugs that reduce manic and depressive episodes 

  • Monotherapy or adjunct 

    • Can be used in combination +/- lithium +/- antipsychotic

  • Drugs 

    1. [...] 

    2. [...] 

    3. [...] 

1. Divalproex 

2. Carbamazepine 

3. Lamotrigine 

Bipolar Disorder Medications

• Antipsychotics 
  

  • Antidepressants 

    • Controversial

      • [why?] 

    • Not to be used as monotherapy 
      

      • Used in combination with mood stabilizer

    • Considered “3rd line” 

    • If used, SSRIs and bupropion are preferred

• potential for switching to manic phase (especially in bipolar I) 

Bipolar Disorder Medications

• Antipsychotics 
  

  • Antidepressants 

    • Controversial

      • potential for switching to manic phase (especially in bipolar I) 

    • Not to be used as monotherapy 
      

      • Used in combination with mood stabilizer

    • [what line of therapy?] 

    • If used, SSRIs and bupropion are preferred

• Considered “3rd line” 

Bipolar Disorder Medications

• Antipsychotics 
  

  • Bipolar depression Drugs

    • [...] 

    • [...]

    • [...] 

  • MOA: 
    

    • blockade of D2 receptors in CNS

• Quetiapine (Seroquel) 

• Olanzapine-fluoxetine (Symbyax)

• Lurasidone (Latuda) 

for acute and mixed mania

Bipolar Disorder Medications

• Antipsychotics 
  

  • Bipolar depression Drugs

    • Quetiapine (Seroquel) 

    • Olanzapine-fluoxetine (Symbyax)

    • Lurasidone (Latuda) 

  • MOA: 
    

    • [...]

• blockade of D2 receptors in CNS

for acute and mixed mania

Bipolar Disorder Medications

• Antipsychotics 
  

  • Useful for [...] or [...] episodes 

  • Monotherapy or +/- mood stabilizer +/- BZD 

  • Quick onset, making it useful as bridge therapy 

  • Often used in combination regimens for acute treatment of mania

acute or mixed mania

Bipolar Disorder Medications

• Antipsychotics 
  

  • [...] 

    • Useful for acute treatment of mania/hypomania 

    • Used in combination with mood stabilizer or antipsychotic 

    • Helpful for agitation, insomnia, hyperactivity 

    • Not effective at core symptoms or prevention of relapse 

    • Long-term therapy is not recommended

Benzodiazepines

adjunt therapy -- used to bridge the gap between anti-maniac and anti-depression effects of Lithium

Bipolar Disorder Medications

• Antipsychotics 
  

  • Benzodiazepines 

    • Useful for acute treatment of mania/hypomania 

    • Used in combination with mood stabilizer or antipsychotic 

    • Helpful for agitation, insomnia, hyperactivity 

    • Not effective at core symptoms or prevention of relapse 

    • [Is Long-term therapy recommended?]

• Long-term therapy is not recommended

adjunt therapy -- used to bridge the gap between anti-maniac and anti-depression effects of Lithium

Bipolar Disorder: Definitions 

• [...]: 

  • At least one manic episode, which may have been preceded by and may be followed by hypomanic or major depressive episode(s) 

• Bipolar I disorder

Bipolar Disorder: Definitions 

• [...]: 

  • At least one hypomanic episode and a current or past major depressive episode 

Bipolar II disorder

Bipolar Disorder: Definitions 

• [...]: 

  • Chronic fluctuations between mild depression and hypomania, none of which meet the criteria for mania or major depressive episode 

Cyclothymic disorder

Bipolar Disorder: Definitions 

• [...] 

  • A distinct period of persistently elevated, expansive, or irritable mood, lasting throughout at least 4 days, that is clearly different from the usual nondepressed mood 

    • Inflated self-esteem or grandiosity 

    • Decreased need for sleep 

    • More talkative than usual or pressure to keep talking 

    • Flight of ideas or racing thoughts 

    • Distractibility 

    • Increase in goal-directed activity or psychomotor agitation 

    • Excessive involvement in pleasurable activities that have high potential for painful consequences

• Hypomanic Episode 

Bipolar Disorder: Definitions 

• Hypomanic Episode 

  • A distinct period of persistently elevated, expansive, or irritable mood, lasting throughout [for how long], that is clearly different from the usual nondepressed mood 

    • Inflated self-esteem or grandiosity 

    • Decreased need for sleep 

    • More talkative than usual or pressure to keep talking 

    • Flight of ideas or racing thoughts 

    • Distractibility 

    • Increase in goal-directed activity or psychomotor agitation 

    • Excessive involvement in pleasurable activities that have high potential for painful consequences

at least 4 days

Bipolar Disorder: Definitions 

• [...] 

  • 5 or more of the following in same 2-week period 

  • Several other symptoms need to be present for diagnosis

    • Depressed mood 

    • Diminished interest/pleasure in most/all activities 

    • Significant weight change 

    • Feelings of worthlessness 

    • Psychomotor agitation or retardation 

    • Insomnia or hypersomnia 

    • Fatigue 

    • Diminished ability to think 

    • Recurrent thoughts of death

• Major Depressive Disorder 

Bipolar Disorder: Definitions 

• [...] 

  • Distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary) 

    • Inflated self-esteem or grandiosity 

    • Decreased need for sleep 

    • More talkative than usual or pressure to keep talking 

    • Flight of ideas or racing thoughts 

    • Distractibility 

    • Increase in goal-directed activity or psychomotor agitation 

    • Excessive involvement in pleasurable activities that have high potential for painful consequences

• Manic Episode 

Bipolar Disorder: Definitions 

• Manic Episode 

  • Distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting [how long] (or any duration if hospitalization is necessary) 

    • Inflated self-esteem or grandiosity 

    • Decreased need for sleep 

    • More talkative than usual or pressure to keep talking 

    • Flight of ideas or racing thoughts 

    • Distractibility 

    • Increase in goal-directed activity or psychomotor agitation 

    • Excessive involvement in pleasurable activities that have high potential for painful consequences

at least 1 week

Bipolar Disorder: Definitions 

• [...]: 

  • concurrent features of mania and depression

Mixed Episode

Methylphenidate 

• Formulations

  • [...]

    • Onset of action: 

      • ≤ 60 mins

      • except Ritalin SR, 1-3 hrs 

    • Duration 

      • Short-acting (3-5 hrs.) → 2-3 doses per day

      • Intermediate (6-8hrs.) → 1dose per day

      • Long-acting (8-12 hrs.) → 1 dose per day 

  • [...]

    • Can be placed on the hip for up to 9 hours 

      • Effects last ~12 hours 

    • Onset of action: 1-2 hours 

    • Adverse reactions 

      • Same as oral 

      • Skin reactions e.g. contact sensitization 

      • Excessive absorption exposed to heat

• Oral

• Transdermal (Daytrana)

Methylphenidate 

• Formulations

  • Oral

    • Onset of action: 

      • ≤ 60 mins

      • except Ritalin SR, 1-3 hrs 

    • Duration 

      • [...] (3-5 hrs.) → 2-3 doses per day

      • [...] (6-8hrs.) → 1dose per day

      • [...] (8-12 hrs.) → 1 dose per day 

  • Transdermal (Daytrana)

    • Can be placed on the hip for up to 9 hours 

      • Effects last ~12 hours 

    • Onset of action: 1-2 hours 

    • Adverse reactions 

      • Same as oral 

      • Skin reactions e.g. contact sensitization 

      • Excessive absorption exposed to heat

• Short-acting

• Intermediate

• Long-acting

Methylphenidate 

• Formulations

  • Oral

    • Onset of action: 

      • ≤ 60 mins

      • except Ritalin SR, 1-3 hrs 

    • Duration 

      • Short-acting (3-5 hrs.) → 2-3 doses per day

      • Intermediate (6-8hrs.) → 1dose per day

      • Long-acting (8-12 hrs.) → 1 dose per day 

  • Transdermal (Daytrana)

    • Can be placed on the hip for [how long? Is it longer than the oral?] 

      • Effects last ~12 hours 

    • Onset of action: 1-2 hours 

    • Adverse reactions 

      • Same as oral 

      • Skin reactions e.g. contact sensitization 

      • Excessive absorption exposed to heat

up to 9 hours

Methylphenidate 

• [What] line therapy 

• Mechanism of action
  

  • [...]

• Metabolism 
  

  • Hepatic 

• Elimination 
  

  • 78%-97% eliminated via urine as inactive metabolites

• First

• Blocks the reuptake of norepinephrine and dopamine into presynaptic neurons

Concentrates in brain more than plasma

Methylphenidate 

• First line therapy 

• Mechanism of action
  

  • Blocks the reuptake of norepinephrine and dopamine into presynaptic neurons

• Metabolism 
  

  • [...] 

• Elimination 
  

  • [...]

• Hepatic

• 78%-97% eliminated via urine as inactive metabolites

Concentrates in brain more than plasma

Non-Stimulants 

• [...] and [...] 

• [...] 

• Options if: 
  

  • Stimulants caused intolerable side effects 

  • Contraindications to stimulants 

  • Stimulants failed or inadequate response 

  • Abuse/dependence issues with stimulants

• Clonidine

• guanfacine

• Atomoxetine

Stimulants Warnings 

• [What scheudle is it?]: 

  • High potential for abuse and dependence. 

C-II

• Administration for prolonged periods may lead to drug dependence

• Assess the risk of abuse prior to prescribing and monitor for signs of abuse and dependence while on therapy

Stimulants Warnings 

• [...] 
  

  • Prolonged (>4 hrs) erection 

  • Often painful 

  • Surgical intervention may be necessary

Priapism

Stimulants Warnings 

• [...]
  

  • Peripheral vasculopathy 

  • Typically mild and intermittent 

  • Rare: digital ulceration and/or soft tissue breakdown 

• Raynaud phenomenon 

Stimulants: Adverse Effects

• In general:

  • Poor growth

  • weight loss

  • decreased appetite

• CNS: 
  

  • Jitteriness 

  • Sleep disturbance 

  • Irritability 

  • Headache 

  • Rare: psychosis

• CV: 
  

  • Tachycardia 

  • Palpitations 

  • Increased BP and HR

• GI 
  

  • [...] 

  • [...] -- dry mouth

  • Upset stomach and nausea

• Anorexia

• Xerostomia

Stimulants: Contraindications 

• Symptomatic cardiovascular disease 

• Moderate to severe [hypo or hyper]tension 

• [hypo or hyper]thyroidism 

• Known hypersensitivity or idiosyncrasy to sympathomimetic amines 

• [specific disease?] 

• Marked anxiety, tension and agitation 

• History of drug abuse 

• Concurrent use or use within 14 days of the administration of [...]

• hyper

• hyper

• Glaucoma

• monoamine oxidase inhibitors

[...]

• Characterized by a considerable degree of inattentiveness, distractibility, impulsivity, and often hyperactivity 

ADHD

Adults must have childhood-onset, persistent, and current symptoms of ADHD to be diagnosed 

Headaches: General Principles

• Primary headaches

  • [...] 

• Secondary headaches 

  • [...] 

• recurrent, not caused by underlying disease 

• caused by underlying disease 

Migraine Medications: Acute Treatment 

• Simple Analgesics 
  

  • Used for: 

    • [...] 

    • [...] 

  • Choices:

    • Acetaminophen 

      • Combination 

        • Acetaminophen (APAP), aspirin, caffeine 

  • MOA 

    • APAP: 

      • not completely understood

      • may activate descending serotonergic inhibitory pathways in the CNS 

    • Caffeine: 

      • CNS stimulant

      • vasoconstrictor on cerebral vessels 

    • Aspirin: 

      • inhibits prostaglandin synthesis in CNS

• Mild-moderate migraines 

• tension headaches 

Migraine Medications: Acute Treatment 

• Simple Analgesics 
  

  • Used for: 

    • Mild-moderate migraines 

    • tension headaches 

  • Choices:

    • Acetaminophen 

      • Combination 

        • Acetaminophen (APAP), aspirin, caffeine 

  • MOA 

    • APAP: 

      • not completely understood

      • may activate [...] pathways in the CNS 

    • Caffeine: 

      • CNS stimulant

      • vaso[dilator or constrictor] on cerebral vessels 

    • Aspirin: 

      • inhibits [...] in CNS

• descending serotonergic inhibitory

• constrictor

• prostaglandin synthesis

Migraine Medications: Acute Treatment 

• Treatment options
  

  • [...]

  • [...]

  • [...]

  • Misc. agents 

    • oxygen -- used primarily for [...] 

• Simple analgesics

• Triptans

• Ergot alkaloids

• cluser headaches 

Migraine Medications: Acute Treatment 

• Ergot Alkaloids
  

  • Adverse Effects 

    • [...] (common) 

      • Worse with ergotamine 

      • Administer with an antiemetic 

    • Paresthesia 

    • Weakness and fatigue 

    • Abdominal pain 

    • Chest tightness 

    • Peripheral ischemia and painful extremities (rare)

Nausea and vomiting

Migraine Medications: Acute Treatment 

• Ergot Alkaloids
  

  • Adverse Effects 

    • Nausea and vomiting (common) 

      • Worse with [which ergot type?] 

      • Administer with an [...] 

    • Paresthesia 

    • Weakness and fatigue 

    • Abdominal pain 

    • Chest tightness 

    • Peripheral ischemia and painful extremities (rare)

• ergotamine

• antiemetic

Migraine Medications: Acute Treatment 

• Ergot Alkaloids
  

  • Contraindications 

    • [...] 

    • Use of [...] with 24 hours 

    • Use with [...]

    • Hepatic dysfunction 

    • Renal dysfunction 

    • Coronary artery disease 

    • Cerebrovascular disease 

    • Peripheral vascular disease 

• Pregnancy/lactation (category X) 

• triptan

• a strong CYP3A4 inhibitor

Migraine Medications: Acute Treatment 

• Ergot Alkaloids
  

  • Mechanism: 

    • migraine effects due to:

      • vaso[constriction or dilation] via [...]

      • inhibition of [...] --> preventing inflammation

    • Also [...] vaso[constriction or dilation]

• constriction

• 5-HT1B/1D receptor

• vasoactive peptide release

• alpha-1

• constriction

Migraine Medications: Acute Treatment 

• Ergot Alkaloids
  

  • Types of Ergots

    • [...] 

      • Sublingual and rectal suppository 

    • [...] 

      • Better tolerated than above 

      • Intranasal, IV/IM/SC 

    • Start ASAP at onset of migraine attack 

    • Can be combined with caffeine or simple analgesics 

    • Triptans contraindicated within 24 hours of an ergot 

    • PK: 

      • hepatically metabolized and eliminated via bile

• Contraindications 

  • Pregnancy/lactation (category X) 

  • Hepatic dysfunction 

  • Renal dysfunction 

  • Coronary artery disease 

  • Cerebrovascular disease 

  • Peripheral vascular disease 

  • Use of triptan with 24 hours 

  • Use with a strong CYP3A4 inhibitor

• Ergotamine

• Dihydroergotamine (DHE 45) 

Migraine Medications: Acute Treatment 

• Ergot Alkaloids
  

  • Types of Ergots

    • Ergotamine 

      • Sublingual and rectal suppository 

    • Dihydroergotamine (DHE 45) 

      • [Better or worse] tolerated than above 

      • Intranasal, IV/IM/SC 

    • Start ASAP at onset of migraine attack 

    • Can be combined with caffeine or simple analgesics 

    • Triptans contraindicated within 24 hours of an ergot 

    • PK: 

      • hepatically metabolized and eliminated via bile

Better

Migraine Medications: Acute Treatment 

• Ergot Alkaloids
  

  • Types of Ergots

    • Ergotamine 

      • Sublingual and rectal suppository 

    • Dihydroergotamine (DHE 45) 

      • Better tolerated than above 

      • Intranasal, IV/IM/SC 

    • Start ASAP at onset of migraine attack 

    • Can be combined with caffeine or simple analgesics 

    • [...] contraindicated within 24 hours of an ergot 

    • PK: 

      • hepatically metabolized and eliminated via bile

Triptans

Migraine Medications: Acute Treatment 

• Ergot Alkaloids
  

  • Types of Ergots

    • Ergotamine 

      • Sublingual and rectal suppository 

    • Dihydroergotamine (DHE 45) 

      • Better tolerated than above 

      • Intranasal, IV/IM/SC 

    • Start ASAP at onset of migraine attack 

    • Can be combined with caffeine or simple analgesics 

    • Triptans contraindicated within 24 hours of an ergot 

    • PK: 

      • [...] metabolized and eliminated via [...]

• hepatically

• bile

Migraine Medications: Acute Treatment 

• Ergot Alkaloids
  

  • Warnings 

    • Cardiovascular 

      • [...] due to vasospastic reactions 

      • [...] 

      • Evaluate patients that complain of [...] 

      • Watch out for signs of decreased arterial flow such as in:

        • [...]

        • [...]

    • Cerebrovascular events have occurred (rarely) after injection 

    • Avoid concurrent use with strong CYP3A4 inhibitors 

      • Increases vasospasms

      • will be on exam

• Peripheral ischemia

• Myocardial ischemia 

• angina

• Raynaud syndrome

• Ischemic bowel

Migraine Medications: Acute Treatment 

• Ergot Alkaloids
  

  • Warnings 

    • Cardiovascular 

      • Peripheral ischemia due to vasospastic reactions 

      • Myocardial ischemia 

      • Evaluate patients that complain of angina 

      • Watch out for signs of decreased arterial flow such as in:

        • Raynaud syndrome

        • Ischemic bowel

    • Cerebrovascular events have occurred (rarely) after injection 

    • Avoid concurrent use with [...] 

      • Increases vasospasms

      • will be on exam

strong CYP3A4 inhibitors 

Migraine Medications: Acute Treatment 

• Opioids and Barbiturates
  

  • [What line of option?]

  • Lack of quality evidence 

  • Potential for abuse, tolerance, dependence, addiction, overdose

  • Relevant Drug

    • Fioricet (includes butalbital, APAP, caffeine) 

      • Indicated for tension headaches 

      • Prone to overuse headache 

      • Limited data to support efficacy 

      • Schedule III (butalbital)

• Last-line options (“rescue”)