Upload
others
View
11
Download
1
Embed Size (px)
Citation preview
7/14/2019
1
#FSHP2019
Treatment Resistant DepressionTreatment Resistant DepressionSamantha Themas, PharmD, BCPPClinical Pharmacy Specialist – Psychiatry Memorial Regional [email protected]
#FSHP2019DisclosureDisclosureI do not have (nor does any immediate family member have):
– a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity
– any affiliation with an organization whose philosophy could potentially bias my presentation
#FSHP2019Pharmacist ObjectivesPharmacist Objectives• Examine the differences between depression and
treatment resistant depression• Critique medication strategies in the
management of treatment resistant depression• Discuss the use of non-pharmacologic treatment
options• Explore the role of the pharmacist in the
management of treatment resistant depression
#FSHP2019Technician ObjectivesTechnician Objectives• Identify symptoms of treatment resistant
depression• List medications used to manage treatment
resistant depression• Recognize the role of pharmacy staff in the
management of treatment resistant depression
#FSHP2019 #FSHP2019Suicide Rates: US 1999-2017Suicide Rates: US 1999-2017
CDC 2018
1 2
3 4
5 6
7/14/2019
2
#FSHP2019Major Depressive Disorder (MDD)• Common disorder• Leading cause of disability
worldwide• Major contributor to overall
global burden of disease• Worst case suicide
World Health Organization 2019
Environment
Genes
Psychology
Biology
#FSHP2019
0
1
2
3
4
5
6
Category 1 Category 2 Category 3 Category 4
Chart Title
Series 1 Series 2 Series 3National Institute of Mental Health 2019
#FSHP2019SymptomsSymptoms• S – Sleep changes• I – Interest decrease• G – Guilt • E – Energy decrease• C – Concentration decrease• A – Appetite changes• P – Psychomotor disturbances• S – Suicidal Ideation
DSM-5Image courtesy of: depressioncomix.tumblr.com
#FSHP2019MDD DiagnosisMDD Diagnosis• At least five symptoms over a two week period
and represent a change from previous function• One of the following must be presenting
• Depressed mood• Loss of interest or pleasure
• Symptoms cause significant distress or impairment in important area of functioning
• Not attributable to the physiological effects of a substance or medical condition
• No history of mania or hypomania DSM-5
#FSHP2019Cause?
• Multiple theories exist• Monoamine deficiency most popular
Mulinari S. J Hist Neurosci. 2012. Image courtesy of: https://www.jax.org/news-and-insights/jax-blog/2015/december/happy-or-sad-the-chemistry-behind-depression
#FSHP2019Assessment of Symptoms
• Utilization of validated scales allows for simpler assessment of symptom improvement, or lack thereof
• Examples• Hamilton Depression Rating Scale (HAM-D)• Montgomery-Asberg Depression Rating Scale (MADRS)• Quick Inventory of Depression Symptomology (QIDS)• Patient Health Questionnaire 9 (PHQ-9)
APA Guidelines 2010
7 8
9 10
11 12
7/14/2019
3
#FSHP2019Depression Treatment Options – Non Pharmacologic• Cognitive Behavioral Therapy (CBT)• Electroconvulsive Therapy (ECT)• Repetitive Transcranial Magnetic Stimulation (rTMS)
DiPiro et al. Pharmacotherapy: A Pathophysiologic Approach. 2014.
#FSHP2019Depression Treatment Options -Pharmacologic• Selective Serotonin Reuptake Inhibitors (SSRIs)• Serotonin Partial Agonist/Reuptake Inhibitors (SPARIs)• Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)• Norepinephrine-Dopamine Reuptake Inhibitors (NDRIs)• Serotonin Antagonist/Reuptake Inhibitors (SARIs)• Mirtazapine• Monoamine Oxidase Inhibitors (MAOIs)• Tricyclic Antidepressants (TCAs)
Stahl SM. Antidepressants. Essential Psychopharmacology Online. 2008.
#FSHP2019
SSRIs SPARIs SNRIs NDRIs
Examples
Citalopram, escitalopram, fluoxetine, paroxetine, sertraline
Vilazodone Venlafaxine, desvenlafaxine, duloxetine, levomilnacipran
Bupropion
MOA
Selective, potent inhibition of serotonin reuptake
Inhibits serotonin reuptake and is 5HT1A partial agonist
Inhibits reuptake of serotonin and norepinephrine (varying degrees)
Inhibits reuptake of both dopamine and norepinephrine
Adverse Effects
Nausea/vomiting, activation/insomnia, sexual side effects, headaches, falls, bleeding, diaphoresis, akathisia
Headache, diarrhea, nausea
Headaches, hypertension, sexual side effects, nausea, insomnia, diaphoresis, akathisia
Hypertension, headaches, activation, insomnia, lower seizure threshold
Stahl SM. Antidepressants. Essential Psychopharmacology Online. 2008. APA Guidelines 2010.
#FSHP2019SARIs Mirtazapine MAOIs TCAs
Examples
Vortioxetine, trazodone, nefazodone
Mirtazapine Phenelzine, tranylcypromine, isocarboxazid, selegiline
Amitriptyline, amoxapine, clomipramine desipramine, doxepin, imipramine, nortriptyline
MOA
Serotonin reuptake inhibition and antagonism at one or two serotonin receptors
Alpha 2 adrenergic antagonist increased release of NE and 5HT
Irreversibly block MAO-A and MAO-B inhibits breakdown of NE, DA and 5HT
Inhibit reuptake of 5HT and NE, also have non-selective alpha1 adrenergic, muscarinic and histaminergic blocking properties
Adverse Effects
V - sexual side effects, nausea, diarrhea, dry mouthN – hepatoxicityT&N– orthostatic hypotension, sedation
Sedation, weight gain, constipation, dry mouth, increased cholesterol
Hypertensive crisis, serotonin syndrome, orthostatic hypotension, sexual side effects
Arrhythmias, anticholinergic adverse effects, sedation, weight gain, seizures, sexual side effects
Stahl SM. Antidepressants. Essential Psychopharmacology Online. 2008. APA Guidelines 2010.
#FSHP2019Depression Treatment Options –Augmenting Agents• Lithium• Triiodothyronine• Second generation antipsychotics (SGAs)• Buspirone
APA Guidelines. 2010.
#FSHP2019Phases of Treatment of MDDPhases of Treatment of MDD
Ann Intern Med. 2016;164(5):350-359.
13 14
15 16
17 18
7/14/2019
4
#FSHP2019STAR*D Trial
Rush AJ et al. Am J Psychiatry. 2006.
#FSHP2019STAR*D Trial
Rush AJ et al. Am J Psychiatry. 2006.
#FSHP2019STAR*D Trial – Recovery Rates
Stahl SM. Essential Psychopharmacology Online. 2008.
#FSHP2019
APA Guidelines 2010
#FSHP2019 #FSHP2019TRD and the Guidelines
TMAP APA WFSBPMost Recent Update 2008 2010 2013
Mention TRD? No No Yes
Definition of TRD N/A N/A
“No universally accepted definition… failed to show clinically meaningful improvement after treatment with
at least two difference antidepressant agents prescribed in adequate dosages for adequate
duration… with treatment adherence”
Recommended Treatment
MAOIs, ECT for patients that “do
not respond to other treatment”
ECT, MAOIs may be used
19 20
21 22
23 24
7/14/2019
5
#FSHP2019TRD and the Guidelines
VA / DoD – MDD ACP NICEMost Recent Update 2016 2016 2018
Mention TRD? Yes No No
Definition of TRDLack of full response despite at least two adequate treatment
trialsN/A N/A
Recommended Treatment MAOIs or TCAs, ECT, rTMS N/A ECT when “other
treatments have failed”
#FSHP2019
How long does a person have to experience symptoms of depression in order for a diagnosis of MDD to be made?A) 1 weekB) 2 weeksC) 3 weeksD) 4 weeks
Quiz Time!
#FSHP2019
How long does a person have to experience symptoms of depression in order for a diagnosis of MDD to be made?A) 1 weekB) 2 weeksC) 3 weeksD) 4 weeks
Quiz Time!#FSHP2019
Quiz Time!
According to the STAR*D trial, how many patients fail to achieve remission after 4 treatments?A) 7%B) 18%C) 33%D) 40%
#FSHP2019Quiz Time!
According to the STAR*D trial, how many patients fail to achieve remission after 4 treatments?A) 7%B) 18%C) 33%D) 40%
#FSHP2019MAOIs• Typically reserved for
patients that have not responded to alternate antidepressants due to side effect profile and drug/food interaction
• Must avoid food high in tyramine, serotonergic medications or medications that increase norepinephrine
MAO-A MAO-BSubstrates Serotonin,
norepinephrine, dopamine, tyramine
Dopamine, tyramine, phenyl-ethylamine
Stahl SM. Essential Psychopharmacology Online. 2008.
25 26
27 28
29 30
7/14/2019
6
#FSHP2019MAOIs – Foods to Avoid• Dried, aged, smoked,
fermented, spoiled meat, poultry or fish
• Broad bean pods• Aged cheeses• Tap/unpasteurized beer• Marmite• Sauerkraut• Soy products/tofu• Banana peel
Stahl SM. Essential Psychopharmacology Online. 2008.
#FSHP2019MAOIs for TRD
• Recent study found Clinical Global Impressions / Severity (CGI/S) scores to be higher (worse) in patients treated with TCAs vs. MAOIs at the end of treatment
• Previous studies also demonstrated superiority with MAOIs vs. TCAs
• Retrospective chart review, n=147• Effect decreases as number of previous treatments
increases
Kim T, et al. J of Affective Disorders. 2019.
#FSHP2019Electroconvulsive Therapy (ECT)
• Nothing like the “Cuckoo’s Nest”• General anesthesia and muscle relaxant administered• Electrodes attached to precise locations on scalp• Goal is to produce controlled and monitored seizure
lasting 30-90 seconds; patient wakes up 5-10 minutes after procedure ends
• Typically administered 3x per week until improvement observed (often at least 6-12 treatments)
Zolezzi M. Neuropsychiatr Dis Treat. 2016.
#FSHP2019ECT• Benefits from ECT noticed
earlier than oral medication
• Adverse effects include headache, upset stomach, muscle aches and memory loss
National Institute of Mental Health 2019
#FSHP2019Repetitive Transcranial Magnetic Stimulation (rTMS)Repetitive Transcranial Magnetic Stimulation (rTMS)• Uses a magnet to activate
the brain – can be targeted to specific site
• Sessions last 30-60 minutes, do not require anesthesia
• Side effects include head discomfort, mild headaches or brief lightheadedness
National Institute of Mental Health 2019
#FSHP20191st or 2nd therapy failed. Now what?
31 32
33 34
35 36
7/14/2019
7
#FSHP2019Irritability – Overlooked Clue to Response• Irritability = core diagnostic criteria in adolescents but not
adults• 40-50% of adults reporting presence of irritability for more
than ½ of current depression episode• These patients are more likely to experience a greater
number of weeks in a depressive episode• Guidelines do not systematically assess or incorporate
irritability in clinical decision making
Jha MK, et al. Am J Psychiatry. 2019.
#FSHP2019Clinical Utility of Irritability
• Goal of study by Manish K Jha et al. to determine if percent of improvement in irritability after four weeks of antidepressant therapy could predict remission or no meaningful benefit at eight weeks of therapy
• Study assessed changes in irritability in Combining Medications to Enhance Depression Outcomes (CO-MED) trial, then assessed for replication of results in a separate, unrelated sample of patients from the Suicide Assessment Methodology Study (SAMS)
Jha MK, et al. Am J Psychiatry. 2019.
#FSHP2019Clinical Utility of Irritability - Methods
Baseline
•Concise Associated Symptom Tracking (CAST-IRR)•QIDS-C
Week 4
•CAST-IRR•QIDS-C
Week 8•QIDS-C
Jha MK, et al. Am J Psychiatry. 2019.
#FSHP2019Population Data
CO-MED SAMSTimeline March 2008 - February 2009 July 2007 – February 2008N 431 163% female 67.1 69.9% Caucasian 69.2 71.2% non-Hispanic 84.2 90.2Medication used to treat
- Single blind- Escitalopram & placebo- Escitalopram & bupropion SR- Venlafaxine ER & mirtazapine
- Open label- SSRI (escitalopram,
citalopram, sertraline, paroxetine, controlled-release paroxetine or fluoxetine)
Jha MK, et al. Am J Psychiatry. 2019.
#FSHP2019Results• In CO-MED trial, higher baseline to week 4 reduction in CAST-
IRR score was independently associate with higher likelihood of reaching remission (p=0.0001) and decreased chance of no meaningful benefit (p=0.036) at week 8.
• A 25.7% greater reduction in CAST-IRR score predicted a 1.73 times higher chance of remission and 0.72 times lower chance of no meaningful benefit
• Sex or treatment arm did not significantly predict remission or no meaningful benefit
• Estimates in individual outcomes were replicated in SAMS trial
Jha MK, et al. Am J Psychiatry. 2019.
#FSHP2019General Predictors and Moderators of Depression Remission
• U.S. Department of Veterans Affairs (VA) Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D)
• Large, multisite, randomized, single-blind, parallel-assignment, three-arm VA study
• Evaluated factors that predict which of three common “next-step” medications are best used for individual patients
Zisook S, et al. Am J Psychiatry. 2019.
37 38
39 40
41 42
7/14/2019
8
#FSHP2019Treatment Arms
Inadequate Response to
Antidepressant
Switch to bupropion SR
Combine with bupropion SR
Augment with aripiprazole
Zisook S, et al. Am J Psychiatry. 2019.
#FSHP2019Variables Evaluated • Gender• Age• Ethnicity • Employment• Depressive symptom severity• Depressive symptom
chronicity• Depressive symptom subtype• Anxiety
• Mixed hypomanic symptoms• Childhood adversity• Grief• Co-occurring general
medical conditions• Co-occurring general
psychiatric conditions• Positive mental health• Quality of life
Zisook S, et al. Am J Psychiatry. 2019.
#FSHP2019Study Population
N = 1,522
Male White Black Hispanic Mean Age85% 69% 26% 10% 54.4 years
Married UnemployedTreated with
three or more antidepressants
Mean Duration of Current Episode
Mean Baseline
QIDS-C score
43% 45% 35% 87 months 16.7
Zisook S, et al. Am J Psychiatry. 2019.
#FSHP2019Results
Two potential moderators of treatment identified
Age Mixed Hypomanic SymptomsHigher remission rates with augmentation with aripiprazole for patients 65 or older
Higher remission rates with either augmentation with aripiprazole or addition of bupropion rather than switch to bupropion
Zisook S, et al. Am J Psychiatry. 2019.
#FSHP2019Looking Beyond Monoamines
• Low dose ketamine infusions have been used off label for treatment of depression
• Typical dose 0.5mg/kg IV twice a week for 6 weeks• MOA: Non-competitive NMDA receptor antagonist that
blocks glutamate• Abnormalities in glutamatergic transition with synaptic and
dendritic atrophy found in neural circuits that modulate behavior in patients with mood disorders
Daly EJ, et al. JAMA Psychiatry. 2018.
#FSHP2019Ketamine
Muller J, et al. Ther Adv Psychopharmacol. 2016.
43 44
45 46
47 48
7/14/2019
9
#FSHP2019S(+) ketamine Compared with R(-) Ketamine• Higher affinity for NMDA receptor• Higher anesthetic potency• Faster clearance• Better analgesia• Less drowsiness• Less lethargy• Less cognitive impairment• Less memory decline• Less agitated behavior
Muller J, et al. Ther Adv Psychopharmacol. 2016.
#FSHP2019
• Phase 3 randomized, double-blind, active-controlled, multicenter study
• August 2015-June 2017• Eligible participants
• 18-64 years old• Single episode (≥ 2 years) or recurrent MDD without psychotic
features• Total QIDS-C score of ≥ 34• TRD
Esketamine Trial
Popova, Vanina. Paper presented at the 2018 Annual Meeting of the American Psychiatric Association (APA), May 8, 2018, New York, NY.
#FSHP2019
• N = 223• Randomized 1:1 to receive either esketamine (56 or 84mg)
or placebo nasal spray administered twice weekly with newly initiated oral antidepressant administered daily
• MADRS score assessed 24 hours after first nasal spray dose and weekly thereafter
• Decrease in MADRS score significantly greater in esketamine group (p=0.010)
Esketamine Trial
Popova, Vanina. Paper presented at the 2018 Annual Meeting of the American Psychiatric Association (APA), May 8, 2018, New York, NY.
#FSHP2019New Kid on the Block – Spravato™
• Intranasal formulation• Received FDA approval March 5, 2019• First medication approved for indication of TRD• Must be administered in conjunction with oral
antidepressant therapy• Must be administered under direct supervision of health
care professional and monitored for at least two hours after
Spravato® [package insert]. Janssen Pharmaceuticals Inc; 2019.
TS1
#FSHP2019Spravato™
Spravato® [package insert]. Janssen Pharmaceuticals Inc; 2019.
#FSHP2019Spravato™ - Alerts• Boxed Warnings
• Risk for sedation and dissociation after administration
• Potential for abuse and misuse
• Only available through Spravato REMS program
• Increased risk of suicidal behaviors in pediatric and young adult patients taking antidepressants
• Contraindications• Aneurysmal vascular disease
or arteriovenous malformation
• Intracerebral hemorrhage• Hypersensitivity to
esketamine, ketamine or any of the excipients
Spravato® [package insert]. Janssen Pharmaceuticals Inc; 2019.
49 50
51 52
53 54
Slide 52
TS1 Themas, Samantha, 5/23/2019
7/14/2019
10
#FSHP2019Spravato™ - Precautions• Increase in blood pressure• Cognitive impairment• Impaired ability to drive or
operate machinery• Embryo-fetal toxicity
Spravato® [package insert]. Janssen Pharmaceuticals Inc; 2019.
#FSHP2019Spravato™ - Dosing
Induction Phase
• Weeks 1 to 4• Start 56mg day 1• Subsequent doses 56mg or
84mg• Administer twice per week
Maintenance Phase
• Weeks 5 to 8• Administer once weekly• 56mg or 84mg
• Weeks 9+• Administer every other week
(or weekly)• 56 or 84mg
Spravato® [package insert]. Janssen Pharmaceuticals Inc; 2019.
#FSHP2019Spravato™ - Administration
• Have patient blow nose• Insure indicator has two
green dots• Ensure patient is reclined
~45 degrees• Instruct patient to
administer – each device contains two sprays
• Patient to administer one spray in each nostril
• Patient to rest in semi reclined position for 5 minutes after each device
Spravato® [package insert]. Janssen Pharmaceuticals Inc; 2019.
#FSHP2019Spravato™ - Common Side Effects• Dissociation• Dizziness• Nausea• Sedation• Vertigo• Hypoesthesia
• Anxiety• Lethargy• Blood pressure increase• Vomiting• Feeling drunk
Spravato® [package insert]. Janssen Pharmaceuticals Inc; 2019.
#FSHP2019Spravato™ - REMS• All pharmacies must be
certified before they can purchase or dispense
• All heath care settings must be enrolled before supervising administration
• All patients must be enrolled before receiving
Spravato® [package insert]. Janssen Pharmaceuticals Inc; 2019.
#FSHP2019Pharmacist Role• Educate patients on appropriate expectations from
antidepressant therapy including efficacy, adverse effects, and drug/food interactions
• Notify prescriber of lapse in compliance or if interacting medication added to patient’s regimen
• Communicate noticeable changes in patient presentation to interdisciplinary team
• Provide education and/or offer screenings to community to increase mental health awareness and reduce stigma
55 56
57 58
59 60
7/14/2019
11
#FSHP2019Wrapping Up• TRD most commonly defined as inadequate response to
two or more antidepressant trials• Untreated (or inadequately treated) depression can have
dire consequences• Multiple factors may contribute to non-response and need
to be considered before altering patient’s treatment plan• Most current treatment guidelines recommend MAOIs or
ECT to manage TRD, and esketamine is the first medication to receive FDA approval for the indication
• More research needed on pathophysiology of TRD and effective treatment options
#FSHP2019
#FSHP2019References• Depression. World Health Organization. 2019. Retrieved from https://www.who.int/mental_health/management/depression/en/• Depression. National Institute of Mental Health. 2019. Retrieved from https://www.nimh.nih.gov/health/topics/depression/index.shtml.• American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. American Psychiatric Association,
Arlington, VA. 2013.• Mulinari S. Monoamine theories of depression: historical impact on biomedical research. J Hist Neurosci. 2012;21(4):366-92• Teter CJ, Kando JC, Wells BG. Teter C.J., Kando J.C., Wells B.G. Teter, Christian J., et al.Chapter 51. Major Depressive Disorder. In: DiPiro JT,
Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. DiPiro J.T., Talbert R.L., Yee G.C., Matzke G.R., Wells B.G., Posey L Eds. Joseph T. DiPiro, et al.eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. http://accesspharmacy.mhmedical.com.ezproxylocal.library.nova.edu/content.aspx?bookid=689§ionid=45310502. Accessed May 17, 2019.n
• Stahl SM. Antidepressants. Essential Psychopharmacology Online. 4th edition 2008. Retrieved May 15, 2019 from https://stahlonline.cambridge.org/essential_4th_chapter.jsf?page=chapter7_introduction.htm&name=Chapter%207&title=General%20principles%20of%20antidepressant%20%20action#c02598-7-1
• American Psychiatric Association. Practice guidelines for the treatment of patients with major depressive disorder, third edition. APA, 2010.
• Ann Intern Med. 2016;164(5):350-359. doi:10.7326/M15-2570• Rush AJ, Trivedi MH, Wisniewski SR et al. Acute and longer term outcomes in depressed outpatients requiring one or several treatment
steps: A STAR*D Report. Am J Psychiatry. 2006; 163:1905-1917• The World Journal of Biological Psychiatry, 2013; 14: 334–385
#FSHP2019References Continued• Kim T, Xu C, Amsterdam JD. Relative effectiveness of tricyclic antidepressants versus monoamine oxidase
inhibitor monotherapy for treatment-resistant depression. J of Affective Disorders. 2019. 250(1): 199-203.• Zolezzi M. Medication management during electroconvulsant therapy. Neuropsychiatr Dis Treat. 2016;12:931–
939. Published 2016 Apr 19. doi:10.2147/NDT.S100908• Brain Stimulation Therapist. National Institute of Mental Health. 2019. Retrieved from:
https://www.nimh.nih.gov/health/topics/brain-stimulation-therapies/brain-stimulation-therapies.shtml• Jha MK, Minhajuddin A, South C, Rush AJ, Trivedi MH. Irritability and its clinical utilization in major depressive disorder: prediction
of individual-level acute-phase outcomes using early changes in irritability and depression severity. Am J Psychiatry. 2019. 176(5):358-366.
• Kim T, Xu C, Amsterdam JD. Relative effectiveness of tricyclic antidepressants versus monoamine oxidase inhibitor monotherapy for treatment-resistant depression. J of Affective Disorders. 2019. 250(1): 199-203.
• Zolezzi M. Medication management during electroconvulsant therapy. Neuropsychiatr Dis Treat. 2016;12:931–939. Published 2016 Apr 19. doi:10.2147/NDT.S100908
• Brain Stimulation Therapist. National Institute of Mental Health. 2019. Retrieved from: https://www.nimh.nih.gov/health/topics/brain-stimulation-therapies/brain-stimulation-therapies.shtml
• Jha MK, Minhajuddin A, South C, Rush AJ, Trivedi MH. Irritability and its clinical utilization in major depressive disorder: prediction of individual-level acute-phase outcomes using early changes in irritability and depression severity. Am J Psychiatry. 2019. 176(5):358-366.
#FSHP2019
Treatment Resistant DepressionTreatment Resistant DepressionSamantha Themas, PharmD, BCPPClinical Pharmacy Specialist – Psychiatry Memorial Regional [email protected]
61 62
63 64
65