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1
Update on Newer Psychiatric Medications
Teresa (Tess) Judge-Ellis
DNP, FNP-BC, PMHNP-BC, FAANP Associate Lecturer, Fitzgerald Health Education Associates,
North Andover, MA
Clinical practice, FNP/PMHNP Winfield Community Clinic, Winfield, IA
PMHNP Meadowlark Psychiatric Services, North Liberty, IA
Clinical Associate Professor, University of Iowa College of Nursing, Iowa City, IA
Fitzgerald Health Education Associates 1
Disclosure
• No real or potential conflict of interest to disclose.
• No off-label, experimental or investigational use of drugs or devices will be presented.
Fitzgerald Health Education Associates 2
Objectives
• Upon completion of the learning activity the participant will be able to:
– Recognize clinical scenarios when newer and second line medications should be considered in the management of major depressive disorder (MDD).
Fitzgerald Health Education Associates 3
2
Objectives (continued)
• Upon completion of the learning activity the participant…: (cont.)
– Identify the mechanism of action of newer medication for the treatment of MDD.
– Describe the mechanism of action of newer agents for insomnia.
Fitzgerald Health Education Associates 4
Major Depressive Disorder SIG E CAPS + Mood
DSM-5 criteria
• Sleep
• Interest*
• Guilt
• Energy
*Gateway symptoms
• One must be present + 4 other symptoms present for 2 weeks
• Not due to other psychiatric or medical condition or substance use disorder
Fitzgerald Health Education Associates 5
• Concentration
• Appetite
• Psychomotor
• Suicidal thoughts
• + mood*
Psychotropic Options for Major Depressive Disorder
Fitzgerald Health Education Associates 6
3
Generic Selective Serotonin Reuptake Inhibitors (SSRI)
• The first-line medications for most
mood disorders
– Citalopram (Celexa®)
– Escitalopram (Lexapro®)
– Fluoxetine (Prozac®)
– Fluvoxamine (Luvox®)
– Paroxetine (Paxil®)
– Sertraline (Zoloft®)
Fitzgerald Health Education Associates 7
Serotonin Norepinephrine Reuptake Inhibitors (SNRI)
Generic SNRI
• Venlafaxine (Effexor®)
• Duloxetine (Cymbalta®)
Branded SNRI
• Desvenlafaxine (Pristiq®)
• Levomilnacipran (Fetzima®)
Fitzgerald Health Education Associates 8
Other Antidepressants
Generic
• Norepinephrine-dopamine reuptake inhibitor
–Bupropion (Wellbutrin®)
•Noradrenergic and specific serotonergic antidepressant
–Mirtazapine (Remeron®)
Trade/Branded
•Serotonin modulator and stimulator
−Vortioxetine (Trintellix®)
•Serotonin partial agonist/reuptake inhibitor
−Vilazodone (Viibryd®)
Fitzgerald Health Education Associates 9
4
Newer Antidepressants
Vilazodone (Viibryd®)
Vortioxetine (Trintellix®)
Levomilnacipran (Fetzima®)
Fitzgerald Health Education Associates 10
What do they have in common? Serotonin
Adverse effects and cautions
Attributed to increased
serotonergic activity
Fitzgerald Health Education Associates 11
Adverse Effects and Precaution
Common to all SSRI/SNRI
• Abnormal bleeding
– Caution about increased risk of bleeding with patients on NSAIDs, aspirin, warfarin and other anticoagulants
• Activation of mania/hypomania
– As with all antidepressants
Fitzgerald Health Education Associates 12
5
Adverse Effects and Precaution
Common to all SSRI/SNRI (continued)
• Hyponatremia
– Especially with elderly patients and those on diuretics
• Angle closure glaucoma risk in patients with anatomically narrow angles due to pupillary dilation
Fitzgerald Health Education Associates 13
• Contraindicated due to risk of serotonin syndrome
– With MAOI use and within 14 days of stopping an MAOI
– In patients being treated with linezolid or intravenous methylene blue
Fitzgerald Health Education Associates 14
Adverse Effects and Precaution
Common to all SSRI/SNRI (continued)
• Boxed warning for an increase risk of suicidal thinking and behavior (suicidality) in children, adolescents and young adults (age 18−24 years) with MDD and other psychiatric disorders.
• Pregnancy category C
• Breastfeeding risk: Acceptable for SSRIs
Fitzgerald Health Education Associates 15
Adverse Effects and Precaution
Common to all SSRI/SNRI (continued)
6
Adverse Effects and Precaution Serotonin Syndrome
• What is it? – Over activation of the central and
peripheral serotonin receptors due to high level of serotonin
• Incidence is unknown. – Uncommon with low dose SSRI or SNRI
and occasional use of a triptan
• A diagnosis of exclusion
Fitzgerald Health Education Associates 16
Risk of Serotonin Syndrome (continued)
•Caution with concomitant use of other serotonergic drugs – Examples: Triptans, TCAs, fentanyl, lithium,
tramadol, tryptophan, buspirone, St John’s Wort, antidepressants, MAOIs, SGAs, phentermine
•Alerts
–Chronic pain, migraine history, depression or anxiety, end-stage renal disease
Fitzgerald Health Education Associates 17
Serotonin Syndrome
• Signs and symptoms
– Alteration in mental status
– Neuromuscular abnormalities
– Autonomic hyperactivity
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Boyer E and Shannon M. N Engl J Med 2005;352:1112-1120
Spectrum of Clinical Findings in Serotonin Syndrome
19 Fitzgerald Health Education Associates
Boyer E and Shannon M. N Engl J Med;352:1112-1120
Findings in a Patient with Moderately Severe Serotonin Syndrome
20 Fitzgerald Health Education Associates
Intervention in Serotonin Syndrome
• Mildly ill
– Hyperreflexia, tremor, afebrile
• Supportive care
• Removal of precipitating drugs
• Benzodiazepines – Source: Boyer E and Shannon M. N Engl J Med
2005;352:1112-1120.
Fitzgerald Health Education Associates 21
8
Intervention in Serotonin Syndrome (continued)
• Moderately ill – Aforementioned findings, fever,
cardiorespiratory abnormalities • Aggressive correction of cardiorespiratory
and thermal abnormalities
• Administration of 5-HT2A antagonists such as cyproheptadine (Periactin®) with a dose range=12−32 mg/24h so that up to 95% of serotonin receptor sites are occupied
– Source: Boyer E and Shannon M. N Engl J Med;352:1112-1120.
22 Fitzgerald Health Education Associates
Vilazodone (Viibryd®)
• Indication
– For the treatment of major depressive disorder in adults age ≥18 years
• Mechanism of action
– Increases CNS serotonergic activity
• SSRI
• Partial 5-HT1A receptor agonist
• Cost=$140 per month
Fitzgerald Health Education Associates 23
• How supplied
– 10 mg, 20 mg, and 40 mg tablets
• Recommended daily dose
– Start with an initial dose of 10 mg once daily with food for 7 days
– Then increase to 20 mg once daily with food
– Increase up to 40 mg once daily with food after a minimum of 7 days between doses
Fitzgerald Health Education Associates 24
Vilazodone (Viibryd®) (continued)
9
Vilazodone (Viibryd®) (continued)
• Take with food
– Taking on an empty stomach can decrease availability by 50−60%
Fitzgerald Health Education Associates 25
Vilazodone (Viibryd®) Adverse Effects
•Most common adverse effects
– Diarrhea, nausea, vomiting
– Insomnia
– Headache, dizziness
•No reported weight gain in clinical trials
•Minimal reported sexual adverse reactions
Fitzgerald Health Education Associates 26
Vilazodone (Viibryd®) Niche
Comorbid depression and anxiety
Weight gain worriers
Sexual adverse effect concerns
Fitzgerald Health Education Associates 27
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Case Example
•Mr. R., a 25-year-old graduate student, recently moved to your town to begin graduate studies. He has a history of major depressive disorder and generalized anxiety disorder. His anxiety is worse and he is feeling depressed. His current medication is sertraline 100 mg. PHQ-9=16; GAD-7=12
Fitzgerald Health Education Associates 28
Case Example (continued)
• You increase his sertraline to 150 mg and recommend counseling.
• He returns in 2 months with continued mild depression (PHQ-9=14; GAD-7=12) and worsening anxiety symptoms of rumination, muscle tension and occasional difficulty with middle insomnia.
Fitzgerald Health Education Associates 29
Case Example (continued)
• He is also unhappy with the sexual adverse effects, specifically difficult and delayed orgasm, that he attributes to the sertraline.
• You start vilazodone 10 mg daily with breakfast and reduce the sertraline to 100 mg.
Fitzgerald Health Education Associates 30
11
• During week 2 you reduce the sertraline to 50 mg daily and increase vilazodone to 20 mg daily.
• During week 3 the sertraline was discontinued and the vilazodone was increased to 40 mg daily.
Fitzgerald Health Education Associates 31
Case Example (continued)
• Mr. R. tolerated this transition well. After a month his depression had improved (PHQ-9=10) and his anxiety symptoms were improved (GAD-7=7).
• While he still has some delay to orgasm, this is much improved and he opts to continue on vilazodone (Viibryd®) 40 mg.
Fitzgerald Health Education Associates 32
Case Example (continued)
Vortioxetine (Trintellix®)
• Indication
– For treatment of major depressive disorder in adults age ≥18 years
• Cost
– About $240/month
Fitzgerald Health Education Associates 33
12
Vortioxetine (Trintellix®) September, 2013
• What is it?
– “Multi-modal” antidepressant or a “serotonin modulator and stimulator”
• Selective serotonin reuptake inhibitor (SSRI)
• Serotonin receptor agonist (5-HT1A)
• Partial agonist (5-HT1B)
• Antagonist (5-HT3A, 5HT7, 5-HT1D)
Fitzgerald Health Education Associates 34
Vortioxetine (Trintellix®) (continued)
•How supplied
– 5 mg, 10 mg, 15 mg, and 20 mg tablets
•Recommended daily dose
– 10 mg starting dose without regards to meals
• If 10 mg is tolerated, dosage can be increased to 20 mg/day.
• Consider 5 mg/day for those unable to tolerate higher doses
Fitzgerald Health Education Associates 35
Vortioxetine (Trintellix®) (continued)
• Elderly study
– 155 adults age 64−88 years with MDD
• Diagnosed with MDD recurrent
• No comorbid cognitive impairment; MMSE score>24
– Vortioxetine 5 mg or placebo
– Significant improvement in the HAMD-24
Fitzgerald Health Education Associates 36
13
Vortioxetine (Trintellix®) Adverse Effects and Precaution
• Vortioxetine is metabolized by CYP2D6.
−Reduce vortioxetine dose by 50% when co-administrated with a strong CYP2D6 inhibitor (e.g., bupropion, fluoxetine, paroxetine, quinidine).
−Consider increasing the vortioxetine dose when co-administered with a strong CYP2D6 inducer (e.g., rifampicin, carbamazepine, phenytoin)
Fitzgerald Health Education Associates 37
Vortioxetine (Trintellix®) Adverse Effects and Precaution
(continued)
• Vortioxetine is metabolized by CYP2D6. (cont.)
−Maximum recommended dose of vortioxetine is 10 mg/day in known CYP2D6 poor metabolizers.
Fitzgerald Health Education Associates 38
Vortioxetine (Trintellix®) Adverse Effects and Precaution
• Most common adverse effects
– Nausea, constipation, vomiting, dry mouth
• Dose related
• Mostly in the first week
– Sexual dysfunction/adverse effects
– Dizziness
– Minimal reported weight gain
Fitzgerald Health Education Associates 39
14
Vortioxetine (Trintellix®) Adverse Effects and Precaution
(continued)
• Taper off vortioxetine is recommended to avoid transient discontinuation symptoms of headache and muscle tension.
• Individualize taper- generally 2‒4 weeks
Fitzgerald Health Education Associates 40
Vortioxetine (Trintellix®) Niche
Elderly with depression
Concern will be with insurance coverage.
Depression where cognitive “fog” is a dominant concern
Fitzgerald Health Education Associates 41
Case Example
• Norma is an 82-year-old woman with a history of major depressive disorder. She was hospitalized at age 70 and 76 years. Her symptoms had been managed well with citalopram 60 mg.
Fitzgerald Health Education Associates 42
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Case Example (continued)
• Past psychiatric medication tried and failed: Fluoxetine, citalopram, and bupropion.
• After FDA warnings about prolonged QT interval with citalopram, she was tapered off citalopram and onto sertraline. Currently she is on sertraline 150 mg daily.
Fitzgerald Health Education Associates 43
Case Example (continued)
• Depressive symptoms of decreased interest, lack of motivation and energy remain, which keep her from going out with friends and socializing. PHQ-9=17
Fitzgerald Health Education Associates 44
•Norma agreed to a medication change.
–Week 1: Sertraline 100 mg daily
–Week 2: Sertraline 50 mg and vortioxetine 5 mg
–Week 3: Sertraline 25 mg and vortioxetine 5 mg
–Week 4: Vortioxetine 5 mg
Fitzgerald Health Education Associates 45
Case Example (continued)
16
•She tolerated the switch without difficulty.
•Return visit at 2 months where she reported improvement in interest and “ambition.” PHQ=12
•Vortioxetine is increased to 10 mg. She returns in 6 weeks and feels “back to my old self.” PHQ=8
Fitzgerald Health Education Associates 46
Case Example (continued)
Levomilnacipran (Fetzima®) July, 2013
• Indication
– For the treatment of major depressive disorder in adults age ≥18 years
• Cost
– $200 per month
Fitzgerald Health Education Associates 47
Levomilnacipran (Fetzima®)
•Mechanism of action
–Serotonin and norepinephrine reuptake inhibitor
• Relatively more selective for norepinephrine reuptake inhibition (NRI) compared with serotonin reuptake inhibition (SRI)
–>10-fold greater selectivity for NRI than SRI compared with duloxetine or venlafaxine
Fitzgerald Health Education Associates 48
17
Levomilnacipran (Fetzima®)
•Mechanism of action (cont.)
–Serotonin and norepinephrine...(cont.)
• Relatively more… (cont.)
–Could offer more targeted treatment of NE deficiency MDD symptoms (e.g., concentration, physical slowing, decreased self-care)
• Could be considered a NSRI
Fitzgerald Health Education Associates 49
• How supplied – 20 mg, 40 mg, 80 mg, 120 mg ER capsules
• Recommended daily dose – Start at 20 mg daily, increase to 40 mg
daily after 2 days
– Based on efficacy and tolerability, increase by increments of 40 mg/d every 2 or more days up to a maximum dose of 120 mg daily
• Take with or without food Fitzgerald Health Education Associates 50
Levomilnacipran (Fetzima®) (continued)
Levomilnacipran (Fetzima®) Adverse Effects and Precaution
• Elevated blood pressure and heart rate – Measure blood pressure and pulse prior to
initiating levomilnacipran and periodically throughout treatment. • Mean change from baseline after one year
of levomilnacipran – SBP was 3.9 mm Hg
– DBP was 3.1 mm Hg
– Control pre-existing hypertension before starting levomilnacipran.
Fitzgerald Health Education Associates 51
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Levomilnacipran (Fetzima®) Adverse Effects and Precaution
(continued)
• Urinary hesitancy or retention
– Use with caution in patients prone to obstructive urinary disorders.
– Consider new onset of urinary hesitancy, urinary retention or dysuria a possible drug-related effect.
Fitzgerald Health Education Associates 52
Levomilnacipran (Fetzima®) (continued) • Do not exceed 80 mg once daily when
used with strong CYP3A4 inhibitors. – Ketoconazole, clarithromycin, ritonavir
• Renal dosing – Moderate renal impairment (GFR 30−59
mL/min/1.73 m2) • Dose should not exceed 80 mg once daily
– Severe renal impairment (GFR 15–29 mL/min/1.73 m2) • Dose should not exceed 40 mg once daily
– Not recommended with end-stage renal disease
Fitzgerald Health Education Associates 53
• Most common adverse effects
– Nausea, constipation, vomiting
– Hyperhidrosis
– Heart rate increase, palpitations
– Erectile dysfunction
• Pregnancy category C
• Lactation risk unknown
Fitzgerald Health Education Associates 54
Levomilnacipran (Fetzima®) (continued)
19
Levomilnacipran (Fetzima®)Niche
Comorbid chronic pain and depression
Renal dosing
Fitzgerald Health Education Associates 55
Case Example
•Marjorie, 53-years-old, has fibromyalgia and depression. Her previous antidepressants include fluoxetine, duloxetine, citalopram, and sertraline. She takes nortriptyline 20 mg at bedtime for fibromyalgia and sleep. Some days are better than others with regards to her fibromyalgia.
Fitzgerald Health Education Associates 56
Case Example (continued)
•She has not taken any antidepressants for several years, but would like to restart because of worsening depression symptoms. PHQ was 16.
•You recommend returning to her counselor and starting on levomilnacipran (Fetzima®).
Fitzgerald Health Education Associates 57
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•She starts levomilnacipran 20 mg/d for 2 days, then 40 mg daily for 5 days.
•After one month she returns and her depression is improved but not 100% relieved. PHQ score is 12. She believes her pain is improving.
Fitzgerald Health Education Associates 58
Case Example (continued)
•You increase the levomilnacipran to 80 mg.
•One month later, PHQ is at 8. She feels happier and relates her pain is less of an issue.
Fitzgerald Health Education Associates 59
Case Example (continued)
New Second Generation Antipsychotic Indication for
MDD Augment
Brexpiprazole (Rexulti®)
Fitzgerald Health Education Associates 60
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SGAs for MDD Augment
• Quetiapine XR (Seroquel XR®)
• Aripiprazole (Abilify®)
Fitzgerald Health Education Associates 61
Brexpiprazole (Rexulti®) July, 2015
• Indication
– For schizophrenia and adjunctive treatment for major depressive disorder
• Cost
– $867 per month
Fitzgerald Health Education Associates 62
Brexpiprazole (Rexulti®) (continued)
• Mechanism of action
– 5-HT1A receptor partial agonist
– D2 receptor partial agonist
– 5-HT2A receptor antagonist
– α1A receptor antagonist
– α1D receptor antagonist
Fitzgerald Health Education Associates 63
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• How supplied
– 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg tablets
•Recommended daily dose for MDD augment
– 0.5 mg or 1 mg daily
– Titrate increases at weekly interval to the patient’s clinical response and tolerability
Fitzgerald Health Education Associates 64
Brexpiprazole (Rexulti®) (continued)
•Recommended daily dose for MDD augment (cont.)
– Target dose 2 mg daily; maximum daily dose 3 mg
• Take with or without food
Fitzgerald Health Education Associates 65
Brexpiprazole (Rexulti®) (continued)
• Dose adjustments with moderate to severe hepatic impairment (<2 mg daily)
• Dose adjustments for renal impairment GFR≤60 mL/min/1.73 m2 (2 mg/day)
Fitzgerald Health Education Associates 66
Brexpiprazole (Rexulti®) (continued)
23
• Dosing adjustments recommended
– Patients who are known CYP2D6 poor metabolizers
– Patients taking CYP3A4 inhibitors, or CYP2D6 inhibitors or strong CYP3A4 inducers
Fitzgerald Health Education Associates 67
Brexpiprazole (Rexulti®) (continued)
• In clinical trials, brexpiprazole dosing was not adjusted for strong CYP2D6 inhibitors: Paroxetine, fluoxetine
– However start low, 0.5 mg and wait longer between dosage adjustments
Fitzgerald Health Education Associates 68
Brexpiprazole (Rexulti®) (continued)
Brexpiprazole (Rexulti®) Boxed Warnings
• Increased mortality in elderly patients with dementia-related psychosis
– Common to all SGAs
• Suicidal thoughts and behaviors in children, adolescents, and young adults
– Common to all antidepressants
Fitzgerald Health Education Associates 69
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Brexpiprazole (Rexulti®) Antipsychotic Adverse Effects
• Neuroleptic malignant syndrome
• Tardive dyskinesia
• Extrapyramidal adverse effects
• Metabolic changes
– Hyperglycemia/diabetes, dyslipidemia, weight gain
Fitzgerald Health Education Associates 70
Brexpiprazole (Rexulti®) Antipsychotic Adverse Effects
(continued)
• Leukopenia, neutropenia, agranulocytosis
• Orthostatic hypotension/syncope
• Body temperature dysregulation
• Dysphagia
• Cognitive and motor impairment
Fitzgerald Health Education Associates 71
Brexpiprazole (Rexulti®) Antipsychotic Metabolic Syndrome
Monitoring Recommendations
• Baseline
– BMI, waist circumference, Hgb A1C, fasting plasma glucose, fasting lipid profile
• 1 month
– BMI, waist circumference
• 2 months
– BMI, waist circumference
Fitzgerald Health Education Associates 72
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Brexpiprazole (Rexulti®) Antipsychotic Metabolic Syndrome
Monitoring Recommendations (continued)
• 3 months – BMI, waist circumference, Hgb A1C, fasting
plasma glucose, fasting lipid profile
• 6 months – BMI, waist circumference
• Annually – BMI, waist circumference, Hgb A1C, fasting
plasma glucose, fasting lipid profile
Fitzgerald Health Education Associates 73
Brexpiprazole (Rexulti®) Niche
Recurrent MDD
Adjunctive
System for monitoring
Fitzgerald Health Education Associates 74
Suvorexant (Belsomra®)
Fitzgerald Health Education Associates 75
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Sleep Architecture Naturally Occurring Sleep’s 2 Stages
1. Non-rapid eye movement (NREM)
– Stage 1 − Transitional
– Stage 2 − Light sleep
– Stage 3 − Deep sleep
– Stage 4 − Deepest sleep
2. Rapid eye movement (REM)
Fitzgerald Health Education Associates 76
Non-REM: Stages 1 and 2
• Stage 1
– Easily awakened “muscle jump” (hypnic myoclonia)
• Stage 2
– Heart rate slows, body temperature drops
– 50% of total sleep time
Fitzgerald Health Education Associates 77
Non-REM: Stage 3
• Stage 3
– Delta waves (slow waves)
– Moving to deeper sleep
Fitzgerald Health Education Associates 78
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Stage 4: “Deep Sleep”
•Stage 4 – Delta waves exclusively
• Difficult to arouse • No eye movement or
muscle activities
– When interrupted • “Groggy and disoriented”
– Stage of bedwetting, night terrors or sleep walking occur during deep sleep
Fitzgerald Health Education Associates 79
REM Sleep: 20% of Adult Sleep
• Rapid, irregular and shallow breathing
• Rapid eye jerks in various directions
• Temporary paralysis of limb muscles
• Increased HR, BP
• Penile erections
• Most vivid dreams
Fitzgerald Health Education Associates 80
Sleep Stages Movement Through 5 Stages
• Adults actively move
through the sleep process from NREM stages 1−4 to REM
– Complete cycle typically 90−100 minutes
– Complete 4−5 cycles per night
Fitzgerald Health Education Associates 81
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Sleep Stages
Movement Through 5 Stages (continued)
• Length of REM sleep becomes progressively longer and time in deep sleep decreases throughout the night
Fitzgerald Health Education Associates 82
Potential Influence of Sleep Aids on Sleep Architecture:
Potential Increase in Stage 1, Stage 2, Sleep Potential Reduction in Stage 3,
Stage 4, REM Sleep
Consider as short-term therapy!
Source: http://www.medscape.com/viewarticle
/723907_2
Fitzgerald Health Education Associates 83
Circadian Rhythm
•Biologic “internal clock”
–Housed in suprachiasmatic nucleus in anterior hypothalamus
–Fully developed by age 25 years
– Source: http://www.howsleepworks.com/how_circadian.html
Fitzgerald Health Education Associates 84
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Sleep-Wake Homeostasis
• The pressure to sleep
– Also known as sleep drive
• Unable to overcome
– With use of stimulants, can only mask need to sleep
– With medications, can mildly promote or enhance sleep drive
Fitzgerald Health Education Associates 85
Pharmacology of Insomnia Treatment Therapeutic Approaches
•Stimulate/activate sleep promoting system
– GABA
• Inhibitory neurotransmitter (NT)
• Main hypothalamic NT, projects to several sleep regulating centers of the brain
– Increase in GABA inhibits (“blocks”) the wake-promoting chemicals
– Melatonin
Fitzgerald Health Education Associates 86
Pharmacology of Insomnia Treatment Therapeutic Approaches
(continued)
• Suppress the wake-promoting systems
– Histamine
– Cholinergic
– Serotonin
– Orexin
Fitzgerald Health Education Associates 87
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Suvorexant (Belsomra®) Novel Mechanism of Action
• What is it?
– Orexin-receptor antagonist
• Any drug that occupies a receptor site and prohibits its activation is an antagonist.
• First drug in this class FDA approved to treat insomnia
Fitzgerald Health Education Associates 88
Source of image: https://en.wikipedia.org/wiki/Orexin#/media/File:1CQ0_crystallography.png
Suvorexant (Belsomra®) Mechanism of Action
(continued)
• Blocking the binding of neuropeptides orexin A and orexin B to receptors OX1R and OX2R=Thought to suppress the wake drive
Fitzgerald Health Education Associates 89
Suvorexant (Belsomra®) C-IV
• Indication
– For treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance in adults age ≥18 years
• What would you expect for PK?
Fitzgerald Health Education Associates 90
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Suvorexant (Belsomra®) PK Information
• Peak plasma time
– 2 h post dose
– With high fat meal= 1.5 h delay
• T ½=12 h
– As a result, when taking at 10 PM, 50% of the dose still on board at 10 AM
• Zolpidem (Ambien®)
– T ½=2.6 h
• 2.6 h × 3=7.8 h, take at 10 PM, approx. 12.5% of dose on board at 6 AM
– Time to Cmax=1.6 h
Fitzgerald Health Education Associates 91
Suvorexant (Belsomra®) Recommended Dose
• How supplied
– 5 mg, 10 mg, 15 mg, and 20 mg tablets
• Recommended daily dose
– 10 mg, taken ≥30 mins prior to bedtime, only if ≥7 h of sleep time available, only 1 dose per night
• If 10 mg dose is well-tolerated but not effective, dose can be increased up to a maximum dose of 20 mg daily.
Fitzgerald Health Education Associates 92
Suvorexant (Belsomra®) Precaution Do we have this information on older meds?
• Per FDA required study
– Exposure to suvorexant increased in obese compared to nonobese patients
• AUC and Cmax increased by 46% and 25% respectively compared to nonobese females.
– Women compared to men
• Consistent with warnings about other sleep aids including zolpidem (Ambien®)
Fitzgerald Health Education Associates 93
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Suvorexant (Belsomra®) Adverse Effects and Precaution
(continued)
• Patient advised about these in handout provided with medication.
– CNS depressant effects and daytime impairment
– Abnormal thinking and behavioral changes
– Worsening of depression/suicidal ideation
– Sleep paralysis, hallucinations, cataplexy-like symptoms
Fitzgerald Health Education Associates 94
Newer ADHD Medications
Fitzgerald Health Education Associates 95
ADHD Symptom Clusters DSM-5
• Inattention
– Off task, lacking persistence, difficulty sustaining focused, disorganized
• Hyperactivity
– Excessive motor activity when it is not appropriate, excessive fidgeting, tapping, talkativeness
Fitzgerald Health Education Associates 96
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ADHD Symptom Clusters (continued)
• Impulsivity
– Hasty actions without forethought and with high potential for harm, desire for immediate rewards, inability to delay gratification
Fitzgerald Health Education Associates 97
Stimulants: First-line Medication in the Treatment of ADHD Safe and Effective
• Mechanism of action
– Increased norepinephrine and dopaminergic activity in the prefrontal cortex and other areas in the brain is thought to explain it’s efficacy.
• How they differ?
Fitzgerald Health Education Associates 98
Stimulants: First-line Medication in the Treatment of ADHD Safe and Effective
(continued)
• Methylphenidate (e.g., Ritalin®, Methylin®, Ritalin® LA, Concerta®) – Inhibits the reuptake of dopamine and
norepinephrine
• Amphetamine salts (Adderall®) – Inhibits the reuptake of dopamine and
norepinephrine – Releases dopamine and norepinephrine from
the presynaptic neuron Fitzgerald Health Education Associates 99
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Dopamine and Norepinephrine Pathways and ADHD
Prefrontal cortex –Inhibitory control •Ability to block out irrelevant stimuli to focus on the relevant
Fitzgerald Health Education Associates 100
Dopamine and Norepinephrine Pathways and ADHD
(continued)
Executive function –Relates to task completion – Analyze, plan, organize, develop timelines, adjust or
shift, complete
Fitzgerald Health Education Associates 101
Dorsal striatum and motor response in ADHD –ADHD variable reaction time • Quick motor and long-delayed motor responses • Results in trouble executing motor component of a task
Fitzgerald Health Education Associates 102
Dopamine and Norepinephrine Pathways and ADHD
(continued)
35
Ventral striatum and response to reward in ADHD –ADHD and difficulty with delaying gratification –Arousal adjustment in response to the emotional
Fitzgerald Health Education Associates 103
Dopamine and Norepinephrine Pathways and ADHD
(continued)
Cerebellum and motor timing in ADHD
–Children with ADHD have a difficult time with tasks that require time estimation or time discrimination.
Fitzgerald Health Education Associates 104
Dopamine and Norepinephrine Pathways and ADHD
(continued)
Newest ADHD Medications “Me-too”
Methylphenidate ER (QuilliChew ER®, Quillivant XR®, Aptensio XR®)
Amphetamines (Adzenys XR-ODT®
Dyanavel® XR, Evekeo®)
Fitzgerald Health Education Associates 105
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Methylphenidate Extended-Release All with IR/ER onset of action
Methylphenidate ER
medications with
IR/ER action
Administration
Once daily
Duration of
Action (approx.)
QuilliChew® ER Cherry tablet 8 hours
Quillivant® XR Oral suspention 12 hours Aptensio® XR Whole or sprinkled 12 hours Concerta® Whole 12 hours
Ritalin® LA Whole or sprinkled
on applesauce
6‒9 hours
Metadate® CD Whole or sprinkled
on applesauce
6‒9 hours
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Amphetamines Amphetamines
ER
Administration
Once daily
Duration of
action (approx) Adderall® XR
(mixed
amphetamine
salts)
Whole or
sprinkled on
applesauce
10‒12 hours
Adzenys XR-
ODT®
(amphetamine)
Sublingual
orally
disintegrating
10‒12 hours
Dyanavel XR®
(amphetamine)
Suspension At least 12 hours
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Amphetamines (continued)
Amphetamine Administration
1‒3 times per day
Additional doses at
4‒6 hours
Duration of
action
(approx.)
Adderall® IR
(mixed
amphetamine salts)
Whole 6 hours
Evekeo®
(mixed
amphetamine salts)
Whole At least 9.25
hours
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Decision Making in ADHD Medications
• Choice of medication
– Onset of action
– Duration of action
– Ease of taking medication
– Adverse effects
– Dosing
– Cost
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Fitzgerald Health Education Associates
End of Presentation
Thank you for your time and attention.
Tess Judge-Ellis
DNP, FNP-BC, PMHNP-BC, FAANP
www.fhea.com [email protected]
110
References
• Anderson, S. & VandeGriend, J (2014) Quetiapine for insomnia: A review of the literature. American Journal of Health-Syestem Pharmacists, 71, 394-402
• Coe, H. & Hong, I. (2012). Safety of Low Doses of Quetiapine when Used for Insomnia. The Annals of Pharmacotherapy;46:718-722.
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References (continued)
• Belsomra (suvorexant) Product Insert, http://www.merck.com/product/usa/pi_circulars/b/belsomra/belsomra_pi.pdf
• Brintellix (vortioxetine) Product Insert, http://general.takedapharm.com/content/file.aspx?applicationcode=396066C6-E50F-4113-ABAD-54FE9525BF7E&filetypecode=BRINTELLIXPI&cacheRandomizer=3dae8368-2480-4331-bf59-1fe9c7f9eb54
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References (continued)
• Dopheide, J. & Pliszka, S. (2009) Attention-Deficit-Hyperactivity Disorder: An Update. Pharmacotherapy, 29 (6); 656-679.
• Elmaadawi, A., Singh, N., Reddy, J., Nasr, S., (2015) Prescriber’s guide to using 3 new antidepressants: Vilazodone, levomilnacipran, vortioxetine. Current Psychiatry (2015) 14(2): 28-29, 32-36.
• Fetzima (levomilnacipran) Product Insert, http://www.allergan.com/assets/pdf/fetzima_pi#page=1
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References (continued)
• Prescriber’s Letter; March 2016; Vol: 23. New ADHD Stimulant Formulations
• Prescriber’s Letter; September 2013; ADHD Stimulant FAQs
• Prescriber’s Letter: February 2015; Vol: 31. Role of Suvorexant (Belsomra) for Insomnia.
• Solanto, M. (1998) Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity disorder: a review and integration. Behavioural Brain Research 94 (1998), 127-152
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References (continued)
• Seier, K., Connell, R., Resche, W., Thomas, C. (2013). Recommendations for lab monitoring of atypical antipsychotics. Current Psychiatry, 12(9):51-54.
• http://www.ninds.nih.gov/disorders/brain_basics/understanding_sleep.htm
• http://www.howsleepworks.com/types_rem.html
• Viibryd (vilazodone) Product Insert, http://www.allergan.com/assets/pdf/viibryd_pi
• Volpi-Abadie, J., Kaye, A.M., Kaye, A.D. (2013). Serotonin Syndrome. The Ochsner Journal 13: 533-540
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• Images/Illustrations: Unless otherwise noted, all images/ illustrations are from open sources, such as the CDC or Wikipedia or property of FHEA or author.
• All websites listed active at the time of publication.
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Statement of Liability
• The information in this program has been thoroughly researched and checked for accuracy. However, clinical practice and techniques are a dynamic process and new information becomes available daily. Prudent practice dictates that the clinician consult further sources prior to applying information obtained from this program, whether in printed, visual or verbal form.
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