Treatment Resistant Depression FSHP Final (002).pptx - Read-Only · 2019-07-23 · 7/14/2019 1...

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#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

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#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

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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

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#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.

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#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

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#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


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#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


#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?

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#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)


#FSHP2019Clinical Utility of Irritability - Methods

Baseline

•Concise Associated Symptom Tracking (CAST-IRR)•QIDS-C

Week 4

•CAST-IRR•QIDS-C

Week 8•QIDS-C


#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)


#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


#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.

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#FSHP2019Treatment Arms

Inadequate Response to

Antidepressant

Switch to bupropion SR

Combine with bupropion SR

Augment with aripiprazole


#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


#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


#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


#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.

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#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™


#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


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#FSHP2019Spravato™ - Precautions• Increase in blood pressure• Cognitive impairment• Impaired ability to drive or

operate machinery• Embryo-fetal toxicity


#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


#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


#FSHP2019Spravato™ - Common Side Effects• Dissociation• Dizziness• Nausea• Sedation• Vertigo• Hypoesthesia

• Anxiety• Lethargy• Blood pressure increase• Vomiting• Feeling drunk


#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


#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

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#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&sectionid=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]

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Treatment Resistant Depression FSHP Final (002).pptx - Read-Only · 2019-07-23 · 7/14/2019 1...

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