Supported by an educational grant from Otsuka America Pharmaceutical, Inc. and Lundbeck.
Faculty
Professor of Family MedicineBoston University School of Medicine
Boston, Massachusetts
Professor of PsychiatryPerelman School of Medicine,
University of Pennsylvaniaand the Corporal Michael J. Crescenz
VAMCPhiladelphia, Pennsylvania
Larry Culpepper, MD, MPH Michael E. Thase, MD
Faculty Disclosure• Dr. Culpepper: Advisory Board—AbbVie Pharmaceuticals, Acadia Pharmaceuticals, Allergan
Pharmaceuticals, Eisai Pharmaceuticals, Merck & Co., Takeda Pharmaceuticals; Consultant—AbbVie Pharmaceuticals, Acadia Pharmaceuticals, Allergan Pharmaceuticals, Eisai Pharmaceuticals, Merck & Co., Takeda Pharmaceuticals; Editor—Physicians Postgraduate Press; Royalties—UpToDate; Stock—M-3 Information, LLC.
• Dr. Thase: Consultant—Acadia, Inc., Akili, Inc., Alkermes, Inc., Allergan, Clexio, Gerson Lehrman Group, Inc., Guidepoint Global, LLC, Janssen Pharmaceuticals, Inc., H. Lundbeck A/S, Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., Sage Pharmaceuticals, Sunovion Pharmaceuticals Inc., Takeda Pharmaceutical Company Ltd.; Employment (spouse)—Dr. Diane Sloan is Senior Medical Director of Peloton Advantage, which does business with several pharmaceutical companies; Grant/Research Support—Acadia, Inc., Alkermes, Allergan, Axsome, Inc., Intracellular Inc., Janssen Pharmaceuticals, Inc., Myriad (AssureRx), National Institute of Mental Health, Patient Centered Outcomes Research Institute; Royalties—American Psychiatric Foundation, Guilford Publications, Herald House, W.W. Norton & Company, Inc., Wolters Kluwer Health.
Disclosure• The faculty have been informed of their responsibility to disclose to the
audience if they will be discussing off-label or investigational use(s) of drugs, products, and/or devices (any use not approved by the US Food and Drug Administration).– Dr. Thase will be discussing off-label use of drugs in the presentation and will
identify those issues.
• Applicable CME staff have no relationships to disclose relating to the subject matter of this activity.
• This activity has been independently reviewed for balance.
Learning Objectives
• Examine continuing barriers to the optimal management of major depressive disorder (MDD) and factors to consider when determining treatment selection and sequencing for patients with inadequate response
• Outline the neurobiological targets of agents for MDD treatment augmentation and their implications for treatment individualization
• Improve MDD treatment strategies to achieve full remission, including the effective recognition and treatment of residual symptoms
The Unrelenting Burden of Inadequate Treatment Response in Major Depressive Disorder
Larry Culpepper, MD, MPHProfessor of Family Medicine
Boston University School of MedicineBoston, Massachusetts
Overview • Suboptimal response and remission rates• Real-world impact of inadequate response• Defining remission• Prevalence of residual symptoms and impact on response/remission• Efficacy barriers with current antidepressant regimens• Managing inadequate response: An ongoing challenge• Addressing residual symptoms
The Global Burden of Depression
• Among most common and disabling condition worldwide
• 70 million years lost to disability• 1 million suicides annually and rising• 1 in 3 patients do not respond to
available treatments
CNS = central nervous system.Whiteford HA, et al. Lancet. 2013;382(9904):1575-1586.
Depression Accounts for Greatest Disability among All CNS Disorders
Prevalence of Depression and Anxiety by Income
• Major depression increases within 1 year of:– increased financial strain (OR=1.47)– increased deprivation
(OR=1.19)
• Low SES even more strongly associated with maintenance of depression than onset
SES = socioeconomic status.Sturm R, et al. BMJ. 2002;324(7328):20-23. Lorant V, et al. Br J Psychiatry. 2007;190:293-298. Lorant V, et al. Am J Epidemiol. 2003;157(2):98-112.
-113579
111315
Prev
alen
ce (%
)
Adjusted for age, sex, race/ethnicity, family composition
Treatment Challenges of MDDUndiagnosed and Under-Treated
Samples H, et al. J Gen Intern Med. 2020;35(1):12-20. Kessler RC, et al. JAMA. 2003;289(23):3095-3105. Bureau of Health, Workforce Health Resources and Services Administration (HRSA). June 30, 2020. Accessed September 2, 2020. https://data.hrsa.gov/Default/GenerateHPSAQuarterlyReport
Patients with MDD in the last 12 months
48.4% of patientswith MDD did not
receive any treatment
51.6% of patients with MDD
received some treatment
58.1% of treated patients received
inadequate treatment
41.9% of treated patients received at
least minimally adequate treatment
Depression screening conducted on fewer than 3% patients in ambulatory care settings
Over 100 million people in the United States reside in a mental health professional shortage area
≥ 80% Adherence and Persistence across Therapeutic Classes in MDD
AD = antidepressant; SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin–norepinephrine reuptake inhibitor; TCA = tricyclic antidepressant; MAOI = monoamine oxidase inhibitor.Keyloun KR, et al. CNS Drugs. 2017;31(5):421-432.
Even in Patients Responding to Treatment, Residual Symptoms are the Norm
• Most common residual symptom domains (STAR*D)– Sleep disturbance (71.7%)– Appetite/weight disturbance (35.9%)
• Patients in remission with fluoxetine:– > 90% had at least 1 residual symptom (median=4)– Most common were sleep disturbances (insomnia 48.2%, hypersomnia
35.9%, and anxiety 52.7%)• 3-year study of patients in remission:
– Average of 2 symptoms present during remissions– Cognitive problems, lack of energy, and sleeping problems dominated the
course of depression and were present 85% to 94% of the time during episodes and 39% to 44% of time during remissions
STAR*D = Sequenced Treatment Alternatives to Relieve Depression.Nierenberg AA, et al. Psychol Med. 2010;40(1):41-50. Iovieno N, et al. Depress Anxiety. 2011;28(2):137-144. Conradi HJ, et al. Psychol Med. 2011;41(6):1165-1174.
Consequences of Not Reaching Remission
• Higher risk of relapse• More rapid relapse• Increased rate of recurrence• Shorter well intervals and fewer
symptom-free weeks• More chronic depressive episodes• Increased overall mortality
– Increases suicide– Increased morbidity and mortality
from comorbid medical disorders
• Medical, psychiatric, emergency care
• More psychiatric hospitalizations• More benefits received through
welfare or disability insurance• Continued professional and social
impairment
Affects Disease Course Increases Direct and Indirect Costs
Judd LL, et al. Am J Psychiatry. 2000;157(9):1501-1504. Paykel ES, et al. Psychol Med. 1995;25(6):1171-1180. Paykel ES. Psychopathology. 1998;31(1):5-14. Fawcett J. Br J Psychiatry Suppl. 1994;(26):37-41. Papakostas GI. J Clin Psychiatry. 2009;70 Suppl 6:16-25.
Proportion of Patients With and Without Residual Symptoms: Relapse after Remission
P
Only Remitters Return toNormal Functioning
Miller IW, et al. J Clin Psychiatry. 1998;59(11):608-619. Fried EI, et al. PLoS One. 2014;9(2):e90311.
Wor
k C
ompo
site
Sca
le o
f the
Soc
ial
Adj
ustm
ent S
cale
—Se
lf-R
epor
t (M
ean ±
SD)
P.05 vs nonresponse and response
Relative importance of depressive symptoms on overall impairment (STAR*D Study)
Strongest Effects• Work: early insomnia • Close relationships: self-blame• Social activities: interest loss• Home management: fatigue
QIDS-SR = Quick Inventory of Depressive Symptoms Self-Report.Jha MK, et al. Am J Psychiatry. 2016;173(12):1196-1204.
Inadequate Response Leads to Work Impairment
Early improvement in
work productivity is
associated with much higher
remission rates after 3 and 7
months
Many Patients with MDD Self-Report as Non-remitters Despite Reaching Clinically Defined Remission
HAM-D-17 = 17-item Hamilton Rating Scale for Depression.Zimmerman M, et al. J Clin Psychiatry. 2012;73(6):790-795. Nierenberg AA, et al. Psychol Med. 2010;40(1):41-50.
63 patients with MDD (45%)did not consider themselves to be in remission
142 patients with MDD
in remission (HAM‐D‐17 score ≤ 7)
When compared with self-reported remitters, self-reported non-remitters reported significantly*
• Greater functional impairment• Poorer quality of life• Decreased likelihood to be satisfied with life
Most Frequent Symptoms Not Present at Baseline but at Remission:• Mid-nocturnal insomnia (24%)• Increased weight (16%)• Hypersomnia (14%)• Decreased weight (11%)• Early morning insomnia (10%)
Patient-Identified Factors in Determining Remission from Depression
Zimmerman M, et al. Am J Psychiatry. 2006;163(1):148-150.
Factor Identifying as Very Important (N=535) (%)Identifying as Most Important
(N=487) (%)Positive mental health (eg, optimism, self-confidence) 77 17Feeling like my usual, normal self 76 14Absence of symptoms of depression 71 11General sense of well-being 70 11Feeling in emotional control 72 9Return to usual level of functioning at work, home, or school 74 8Positive outlook on life 66 8Satisfaction with life 58 7Able to cope with the normal stress of life 68 5Participating in and enjoying relationships with family and friends 71 4Feeling happy most of the time 48 4Participating in and enjoying usual activities 68 2Not overwhelmed by stress 51 2Coping well with stressful events 59 2Functioning well 70 2Able to fulfill usual responsibilities 67 1
Patient Medication Nonadherence May Be Underappreciated by Physicians
Observational study (N=147) of patients taking antidepressant therapy for any condition
Hunot VM, et al. Prim Care Companion J Clin Psychiatry. 2007;9(2):91-99.
19%
50%
Took their medications according to clinical guidelines during the 6-month
dosing periodDiscontinued
Treatment
89% did not inform their
doctor
Of those who stopped prematurely
Factors Contributing to NonadherenceTreatment Factors
– Tolerability of adequate doses– Combination therapies increase
side effects– Prolonged treatment without
response– Lack of maintenance efficacy
Disorder Factors• Chronicity• Severity of illness• Comorbid Axis I or III disorders
Patient Factors• Attitude• Information• Social support
Shelton RC, et al. CNS Drugs. 2010;24(2):131-161. Souery D, et al. Int Clin Psychopharmacol. 1998;13 Suppl 2:S13-S18.
Up to one-half of “treatment-resistant” depressions are improperly dosed or nonadherent
Determinants of Adherence during 7 Days before Psychiatric Hospital Admission
*Emotional maltreatment as child P=.031. N=370.BDI = Beck Depression Inventory.Baeza-Velasco C, et al. Depress Anxiety. 2019;36(3):244-251.
Variables OR 95% CIMarital status 0.614 (0.352–1.071)# Psychiatric hospitalizations 0.917 (0.815–1.032)Depression severity (BDI) 0.934 (0.895–0.974)Suicidal ideation 0.506 (0.259–0.988)Medication side effects 1.26 (0.911–1.742)Favorable medication attitude 1.175 (0.906–1.525)Emotional maltreatment* 0.991 (0.944–1.041)Physical pain 0.886 (0.801–0.980)
A Prospective Study of Antidepressant Adherence and Suicide Risk: Results
• Results: mean baseline PHQ-9 = 7; adherence = 85% of days• Greater adherence to medication was associated with lower suicidal ideation
at 1-year follow-up (OR=.61; P=.047)• Association was significant for SSRIs, but not SNRIs
N=344 adults with no suicidal ideation at baseline.PHQ-9 = 9-item Patient Health QuestionnaireHenein F, et al. Prim Care Companion CNS Disord. 2016;18(6):10.4088/PCC.16l01935.
Unadjusted Adjusted*OR (95% CI) P-value OR (95% CI) P-value
SSRIs (n=243) 0.57 (0.34–0.96) .0330.52
(0.29–0.92) .025
SNRIs (n=144) 0.63 (0.34–1.18) .1500.61
(0.32–1.18) .140
Combined (n=344) 0.63 (0.40–0.99) .0440.61
(0.38–0.99) .047
Impact of Treatment-Emergent Symptoms
Jha MK, et al. Int J Neuropsychopharmacol. 2018;21(4):325-332.
Remission at Week 12
Chronic disease management: Which domains to target? Depression, side effects, and other symptom domains
Persistent or Worsening Sleep Disturbance Decreases Remission and Increases Suicidal Ideation
Clinical Outcomes at 12 Months
Worsening Sleep
Persistent Sleep
MDD vs nondepressed 28.6 (12.15–67.34) 12.2 (5.43–27.29)
Significant minor depression vs nondepressed 11.9 (5.67–24.89) 3.1 (1.56–6.30)
Remitted (HAM-D < 10) vs non-remitted 0.52 (0.46–0.57) 0.59 (0.54–0.65)
Remitted (HAM-D < 7) vs non-remitted 0.59 (0.53–0.66) 0.64 (0.59–0.71)
Suicidal ideation vs no suicidal ideation 1.10 (1.005–1.199) 1.02 (0.94–1.10)
N=599.Gallo JJ, et al. Sleep. 2020:zsaa063.
Improving sleep (Odd ratios adjusted for baseline age, gender, ethnicity, marital status, education, medical comorbidity, baseline depression diagnosis, depression severity (without insomnia), suicidal ideation, and intervention condition.)
Patients with Stronger Preferences Tend to Dropout of
Treatment if Mismatched
CBT = cognitive-behavioral therapy.Dunlop BW, et al. Am J Psychiatry. 2017;174(6):546-556.
18- to 65-year-olds with treatment-naïve MDD randomly assigned to 12 weeks of escitalopram (10–20 mg/day), duloxetine (30–60 mg/day), or CBT (16 50-minute sessions).
Completion
Remission
Establishing a Therapeutic Alliance Early in Treatment is a Powerful Remission Tool
Geerts E, et al. J Affect Disord. 1996;40(1-2):15-21. Krupnick JL, et al. J Consult Clin Psychol. 1996;64(3):532-539.
35
‐1.5
30
25
20
15
10
5
0
‐5‐1.0 ‐0.5 0.0 0.5 1.0
Change of Attunement during First Clinical Interview
Impr
ovem
ent (
HA
M-D
T1
–T2)
Β=.46, P=.009
Steps to Improve Patient Adherence• Identify patients at risk, including those who
– Underestimate symptom severity – Believe that symptoms will be temporary despite past experiences to the
contrary– Have never used an antidepressant– Believe that symptoms are randomly caused– Feel bewildered by their symptoms
• Offer frequent contact and communication– Patients with ≥ 3 follow-up visits are more likely to adhere– Patients who discuss adverse events are less likely to discontinue therapy
Aikens JE, et al. Ann Fam Med. 2008;6(1):23-29. Bull SA, et al. JAMA. 2002;288(11):1403-1409.
Early Contacts by Office Staff Improves Treatment Initiation
RateNon-initiation 13.5%Suboptimal (≤ 80% days) 15.2%Discontinued prematurely 37.1%
DiMatteo MR, et al. Arch Intern Med. 2000;160(14):2101-2107. Simon GE, et al. BMJ. 2000;320(7234):550-554. Holvast F, et al. Fam Pract. 2019;36(1):12-20.
Phone call at 1 to 3 days can improve initiation of medication
• 3 questions• Did you get the prescription filled?• Did you take the first dose?• Any questions for us?
• Takes 3 to 4 minutes• Initial nonadherence particularly a
concern with anxious patients
Patients frequently do not initiate or continue care
Enhanced Care Programs Can Improve Outcomes and Satisfaction
*P
Data Snapshot: Components of Effective Practice Systems
*Only for patients prescribed an adequate antidepressant dose. Von Korff M, et al. BMJ. 2001;323(7319):948-949.
Randomized TrialEvidence-
Based Guideline
Patients ID-ed by
Screening
Enhanced Patient
Education
Case Management
Mental Health
Specialist Involvement
More Effective
Than Usual Care
Katon Yes No Yes Yes High Yes
Katzelnick Yes Yes Yes Yes Medium Yes
Rost Yes Yes Yes Yes Medium Yes
Hunkeler Yes No Yes Yes Low Yes
Wells Yes Yes Yes Yes Variable Yes
Simon: case management Yes No Yes Yes Low Yes
Peveler: nurse counseling No No Yes Yes None Partial*
Simon: feedback only Yes No Yes No None No
Peveler: patient education only No No Yes No None No
Callahan Yes Yes Yes No None No
Dowrick Yes Yes No No None No
Thompson Yes No No No None No
Comorbidities Affect Depression OutcomesThe Majority of Patients with Depression Have at Least 1 Medical Comorbidity
DM = diabetes mellitus; CAD = coronary artery disease; CHF = congestive heart failure; CVA = cerebrovascular accident; COPD = chronic obstructive pulmonary disease; HTN = hypertension.Culpepper L, et al. Am J Med. 2015;128(9 Suppl):S1-S15. Druss BJ, et al. Mental disorders and medical comorbidity. Research Synthesis Report No. 21. February 2011. Accessed September 3, 2020. https://www.rwjf.org/en/library/research/2011/02/mental-disorders-and-medical-comorbidity.html. Egede LE. Gen Hosp Psychiatry. 2007;29(5):409-416.
Depression Comorbidity Remission Decreases as Comorbidities Increase
3.213.15
1.962.3
21.96
3.92.22
1
0 1 2 3 4
COPDCVACHFCADHTNDM
21
NONE 1
0.740.67
0.38
0.0
0.5
1.0
0 1 2 3 >4# of ComorbiditiesaORs of Depression
Odd
s of
Rem
issi
on
Com
orbi
ditie
s
1
Manage All Comorbidities Concurrently,Not Single Conditions Sequentially
A1C = glycated hemoglobin; BP = blood pressure; LDL = low-density lipoprotein.Katon WJ, et al. N Engl J Med. 2010;363(27):2611-2620.
Multi-Condition Collaborative Care Study*
Comparison StudiesFocusing on 1 Outcome
Depression Effect size: 0.65 Effect size: 0.25 37 Collaborative Depression Trials
A1C Change: 0.58% Change: 0.42% 66 Diabetes Trials
Systolic BP Change: 5.1 mm Hg Change: 4.5 mm Hg 44 Hypertension Trials
• Significant change in LDL of 6.9 mg/dL in the Collaborative Care Study• $594 lower outpatient costs ($1116 for Medicare) at 24 months
Measurement-Based Care
Katon WJ, et al. N Engl J Med. 2010;363(27):2611-2620. Kennedy SH, et al. Can J Psychiatry. 2016;61(9):540-560. Trangle M, et al. Institute for Clinical Systems Improvement. Updated March 2016. Accessed September 2, 2020. https://roar.nevadaprc.org/system/documents/4068/original/NPRC.3054.Depr-Interactive0512b.pdf?1471560355
Evidence Based GuidelineMeasurement Tools
Care Manager
Tracking System
BP = blood pressure; OOT = out of trend.
34
48
71
50
79
23
30
45
39
27
0 10 20 30 40 50 60 70 80
Oral hypoglycemics
Insulin
Antihypertensives
Lipid lowering
Antidepressants
Usual CareIntervention
% of Patients with 1 Adjustments in 12 Months
Katon WJ, et al. N Engl J Med. 2010;363(27):2611-2620.
P=.006
P=.08
P
Overcoming Inadequate Response A Focus on Augmentation
Michael E. Thase, MDProfessor of Psychiatry
Perelman School of Medicine, University of Pennsylvaniaand the Corporal Michael J. Crescenz VAMC
Philadelphia, Pennsylvania
Outpatient Treatment of Major Depressive Disorder Overview Circa 2020
• Outpatients’ depressive episodes appear to be comparably responsive to antidepressant medications or focused, time-limited psychotherapies
• Differential outcomes may be influenced by preference, motivation for change, and adherence
• When effective, time-to-benefit is shorter/faster for antidepressants• Pharmacotherapy often preferred when severity is high or there is urgency
for improvement because of disability or impairment• Combined pharmacotherapy + psychotherapy has additive benefits for
patients with more chronic, severe, or complicated illnesses• Access to care is important and psychotherapy is not always readily available• A large body of intervention research suggests that the nonspecific elements
of treatment account for much of benefit done by first- and second-line therapies
Antidepressants: Unmet Needs Circa 2020• Limited specific efficacy (~ 10% to 20% advantage vs placebo in RCTs)
• Intolerable side effects for ~ 10%
• Inconsistent effects on key symptoms (insomnia, anxiety, cognition)
• Relatively slow onset of action
• Approximately 20% to 30% rate of TRD
• We need better alternatives: After 50 years of drug development focused on monoamines, more medications with novel mechanisms of action needed
RCT = randomized controlled trial; TRD = treatment-resistant depression.Thase ME. CNS Spectr. 2017;22(S1):39-48.
Most Antidepressants Target Serotonin and/or Norepinephrine Neurotransmission: Key Insights Dating Back to the 1960s
Cooper JR, et al. The Biochemical Basis of Neuropharmacology. Eighth Edition. Oxford University Press; 2003.
DrugsReceptors
D2 D3 5-HT1A 5-HT2A 5-HT2C 5-HT7 α1A α2C H1 M1
Aripiprazole 0.34 0.8 1.7 3.4 15 39 57 1000 61 1000
Clozapine 160 555 120 5.4 9.4 6.3 1.6 90 1.1 6.2
Iloperidone 6.3 7.1 168 5.6 1000 22 0.36 4.7 437 1000
Ziprasidone 4.8 7.2 3.4 0.4 1.3 1000 10 1000 47 1000
Lurasidone 1 1000 6.4 0.5 1000 0.5 1000 11 1000 1000
Risperidone 3.57 3.6 423 0.17 12 6.6 5 1.3 20.1 1000
Asenapine 1.3 0.42 2.5 0.06 0.03 0.13 1.2 1.2 1 1000
Olanzapine 11 47 7 4 11 1000 19 1000 7 73
Brexpiprazole 0.3 1.1 0.12 0.47 1000 3.7 3.8 0.59 19 1000
Cariprazine 0.49 0.085 3 19 134 111 155 1000 23 1000
Receptor Profiles of Various Atypical Antipsychotics
US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/.
Depressive Neurobiology is Now Known to be Multidetermined and Multifactorial
• Recurrent depressive episodes may result in enduring functional and structural alterations in the sensitive brain areas
• Disruption in corticolimbic circuitry may create neuroendocrine, neuroimmune, and sympathetic dysregulation
• Inadequate monoamine and neurotrophic signaling combined with excessive glutaminergic and inflammatory cytokine transmission damage vulnerable glia-neuron units
• An altered glia-neuron relationship may further impede corticolimbic function
5-HT = serotonin; ACTH = adrenocorticotropic hormone; AVP = arginine vasopressin; BDNF = brain-derived neurotrophic factor; CORT = cortisol; CRH = corticotropin-releasing hormones; DA = dopamine; GABA = gamma-aminobutyric acid; GRP = gastrin-releasing peptide; IL = interleukin; JAK-STAT = janus kinase / signal transducer and transcription; MAP = mitogen-activated protein; NE = norepinephrine; NMB = neuromedin B; NFκB = nuclear factor-κB TNF = tumor necrosis factor.Anisman H. J Psychiatry Neurosci. 2009;34(1):4-20. Anisman H, et al. Prog Neurobiol. 2008;85(1):1-74.
GABAModulation
Apoptotic Oxidative
NE
DA
+
+
+
++
+
− −
−
−
++++ +
+++
++
GRP/NMB
Neuroplasticity
Growth Factors(eg, BDNF)
JAK-STAT
MAP kinase
NFκB
ACTH
Depression
Stressors
Cytokine(eg, IL-1, TNF-)
CORT
CRH/AVP 5-HT
The Glutamate Synapse Offers Multiple Novel Targets That May Rapidly Dampen Pathological Activation or Enhance Resilience
Murrough JW, et al. Nat Rev Drug Discov. 2017;16(7):472-486.42
Contemporary Antidepressant Therapy Follows an Implicit Algorithm: From Simpler to More Complex
• Level I: Begin with an adequate trial of a first-line antidepressant (usually a generic formulation of an SSRI or SNRI)
• Level II: Switch to another first-line antidepressant (some favor switching to a different type of medication, eg, mirtazapine)
• Level III: Patented antidepressants, combination and adjunctive strategies, or older antidepressants (ie, TCAs or MAOIs)
• Level IV: Neuromodulation strategies (TMS or ECT), ketamine infusions, or intranasal esketamine
• Level V: VNS or unproven or experimental strategiesECT = electroconvulsive therapy; MAOI = monoamine oxidase inhibitor; SNRI = serotonin–norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; TMS = transcranial magnetic stimulation; VNS = vagus nerve stimulation. American Psychiatric Association Work Group on Major Depressive Disorder. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. Third Edition. 2010. Accessed September 2, 2020. https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf. Thase ME. CNS Spectr. 2017;22(S1):39-48.
Therapeutic Decrement in STAR*D Progressive Decline in Remission Rates
McGrath PJ, et al. Am J Psychiatry. 2006;163(9):1531-1541. Rush AJ, et al. Am J Psychiatry. 2006;163(11):1905-1917. Nierenberg AA, et al. Am J Psychiatry. 2006;163(9):1519-1530. Trivedi MH, et al. J Clin Psychiatry. 2006;67(9):1458-1465. Trivedi MH, et al. N Engl J Med. 2006;354(12):1243-1252.Fried EI, et al. PLoS One. 2014;9(2):e90311.
Rem
issi
on (%
)
10
20
30
40 Level 2(1 failure)
Level 3(2 failures)
Level 4(3 failures)
11.9 weeks 8–10 weeks
< 14 weeks
< 14 weeks
Mono = monotherapyAugm = combination treatment
AugmMono
Mono
Mono Augm
MonoAugm
Treatment ResistanceLow High
Level 1
When a Level I strategy is ineffective … Try to ensure that the patient was adherent to prescribed therapy Reconsider the possibility of undisclosed substance abuse Reconsider the possibility of an occult medical illness Re-examine the accuracy of your diagnosis
– Bipolarity– Psychosis– PTSD– OCD
Redefine target symptoms and consider potentially better matches Could adding exercise or psychotherapy make a difference?
OCD = obsessive-compulsive disorder; PTSD = posttraumatic stress disorder.
Nemeroff CB, et al. Proc Natl Acad Sci U S A. 2003;100(24):14293-14296.
“Among those with a history of early childhood trauma (loss of parents at an early age, physical or sexual abuse, or neglect)
psychotherapy alone was superior to antidepressant
monotherapy.”
When a Level I strategy is ineffective … Try to ensure that the patient was adherent to prescribed therapy Reconsider the possibility of undisclosed substance abuse Reconsider the possibility of an occult medical illness Re-examine the accuracy of your diagnosis
– Bipolarity– Psychosis– PTSD– OCD
Redefine target symptoms and consider potentially better matches Could adding exercise or psychotherapy make a difference?
Exercise Improves Depressive Symptoms in MDD
• No difference between exercise and psychological therapy; BDI −0.29 (−3.04 to 2.47)
• 4 trials (n=298) found no difference between exercise and antidepressant therapy; BDI −1.05 (−3.23 to 1.14)
• Clinically may be combined with patient activation strategies
Meta-analysis of Exercise for MDDExercise for Depression Reduces BDI by 5 points
Cooney G, et al. JAMA. 2014;311(23):2432-2433.
Aerobic exercise, BDI, −5.23 (−7.32 to −3.23)Resistance exercise, BDI, −9.79 (−14.44 to −3.71)
Behavioral Activation is a Potent Adjunctive Therapy in MDD
Meta-analysis of 16 studies• 780 participants• Large effect size = 0.87 (0.60–1.15) • Heterogeneity was low in all
analyses• Comparisons with other
psychological treatments non-significant (effect size of 0.13 in favor of activity scheduling)
• No difference compared to cognitive therapy (difference was 0.02 effect size)
• Benefits retained at follow-up
Cuijpers P, et al. Clin Psychol Rev. 2007;27(3):318-326.
• Patients learn techniques to monitor their mood and daily activities to see their connection
• Patients learn to increase number of pleasant activities and positive interactions with their environment
Your favorite first-line therapy has failed: Should you switch or combine or use an adjunct?
• Parsimony favors switching
• Adjuncts usually easier to implement (ie, avoids washout and cross-titration)
• STAR*D did not answer this question definitively
• However, “optics” favored adjunctive strategies and
• STAR*D clinicians only favored switching when the index antidepressant was poorly tolerated
STAR*D: “Optical” Advantage for Adjunctive/Combined Strategies over Switching to Alternate Antidepressants
Rush AJ, et al. Am J Psychiatry. 2006;163(11):1905-1917.
The Case for Combined and Adjunctive Strategies• Builds on partial success of first therapy
• Avoiding washout is a pragmatic benefit for patients– No risk of discontinuation symptoms– Preserves symptom-reducing effects of first drug– Can capitalize on known drug–drug interactions
• Benefits are often more rapid than those of switching
• Can choose medications to target specific symptoms
Fava M, et al. Biol Psychiatry. 2006;59(11):1052-1060. McCall WV, et al. J Clin Sleep Med. 2010;6(4):322-329.
Conclusions: Eszopiclone treatment of insomnia in patients with depression leads to superior improvement in HRQOL, depression severity, and sleep.
Combined and Adjunctive Strategies Definitions and Methods
• By current convention, an “adjunct” is added to an antidepressant when there has been a suboptimal response
• The FDA defines “augmentation” when the second medication enhances the mechanistic action of the first
• A combination is either:– A formulation that combines an antidepressant + an adjunct OR– Prescription of 2 antidepressants at the same
Combining Antidepressants• Once considered indicative of bad practice, the pioneering study of
Nelson et al. with fluoxetine and desipramine changed practice
• Combining newer generation antidepressants now widely used
• Most newer combinations are safe; caveats regarding drug–drug and drug–drug–gene interactions
• Bupropion, mirtazapine, and trazodone preferred for use in antidepressant combinations; only mirtazapine’s efficacy confirmed by meta-analysis
• Conflicting results in RCTs
Thase ME. Curr Psychiatry Rep. 2013;15(10):403. Nelson JC, et al. Arch Gen Psychiatry. 1991;48(4):303-307. Henssler J, et al. Can J Psychiatry. 2016;61(1):29-43. Blier P, et al. Am J Psychiatry. 2010;167(3):281-288. Rush AJ, et al. Am J Psychiatry. 2011;168(7):689-701.
Meta-Analysis of RCTs of Antidepressant CombinationsAre some antidepressant combinations superior to others?
Henssler J, et al. Can J Psychiatry. 2016;61(1):29-43.
54
25
68
52
73
58
65
46
0
10
20
30
40
50
60
70
80
Responders Remitters
Perc
enta
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f pat
ient
s
FLU (n=28) FLU + MIRT (n=26)VEN + MIRT (n=25) BUP + MIRT (n=25)
Concurrent Combined Antidepressants Contrasting Results of 2 RCTs
*P
Commonly Used Adjunctive Strategies Circa 2020 Lithium and other mood stabilizers
Thyroid hormones
L-methylfolate
Modafinil and psychostimulants
Buspirone and benzodiazepines
Second-generation antipsychotics
Adjunctive Therapy with Lithium Salts• Efficacy data dating to early 1980s, but no longer widely used in
the United States• Definitely effective with TCAs (meta-analytic P
Review: Lithium augmentation Comparison: 01 Lithium augmentation studies Outcome: 01 Response rates Study Treatment Control OR (fixed) Weight OR (fixed) or sub-category n/N n/N 95% CI % 95% CI Bauman 1996 6/10 2/14 4.48 9.00 [1.27, 63.89] Browne 1990 3/7 2/10 6.33 3.00 [0.35, 25.87] Heninger 1983 5/8 0/7 1.38 23.57 [1.00, 556.08] Joffe 1993 9/17 3/16 9.78 4.88 [1.01, 23.57] Kantor 1986 1/4 0/3 2.61 3.00 [0.09, 102.05] Katona 1995 15/29 8/32 24.69 3.21 [1.09, 9.48] Nierenberg 2003 2/18 3/17 18.44 0.58 [0.08, 4.01] Schoepf 1989 7/14 0/13 1.74 27.00 [1.35, 541.57] Stein 1993 2/16 4/18 22.15 0.50 [0.08, 3.19] Zusky 1988 3/8 2/8 8.40 1.80 [0.21, 15.41] Total (95% CI) 131 138 100.00 3.11 [1.80, 5.37] Total events: 53 (Treatment), 24 (Control) Test for heterogeneity: Chi² = 11.90, df = 9 (P = 0.22), I² = 24.4% Test for overall effect: Z = 4.06 (P < 0.0001)
0.01 0.1 1 10 100 Favors control Favors treatment
Meta-Analysis of Placebo-Controlled Studies of Lithium Augmentation
Overall pooled response rates: lithium 40.5% (53/131), placebo 17.4% (24/138)
Crossley NA, et al. J Clin Psychiatry. 2007;68(6):935-940.
Day
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AD
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re Quetiapine XR 300 mg + AD (n=229)Quetiapine XR 300 mg (n=225)
Open-label Study: MADRS Total Score
0-2
-5
-8
-11
-14
-17
-20
P=.003
40 8 22 43
P=.004P=.024
P=.061P
Adjunctive Thyroid Hormone• 12 published studies (no RCTs since 2007)• Efficacy established vs placebo (added to TCAs or SSRIs)• Significantly better implementation than lithium in STAR*D• T3 (25–50 µg/day) preferred by psychiatrists over T4• Safe in short-run (but try not to suppress TSH below 0.5 iu during
longer-term Rx to minimize risk of osteoporosis)• Arguably the adjunctive treatment of choice for patients with elevated
TSH levels or treated hypothyroidism• Higher doses sometimes used in depression within the bipolar
spectrum, especially rapid cyclingT3 = triiodothyronine; T4 = thyroxin; TSH = thyroid-stimulating hormone.Aronson R, et al. Arch Gen Psychiatry. 1996;53(9):842-848. Cooper-Kazaz R, et al. Arch Gen Psychiatry. 2007;64(6):679-688. Nierenberg AA, et al. Am J Psychiatry. 2006;163(9):1519-1530. Khandelwal D, et al. Drugs. 2012;72(1):17-33. Pilhatsch M, et al. J Affect Disord. 2018;238:213-217.
Adjunctive Therapy with Thyroid Hormone in STAR*DResults of Level 3 Comparison with Lithium
Nierenberg AA, et al. Am J Psychiatry. 2006;163(9):1519-1530.
Adjunctive Therapy with Second-Generation Antipsychotics
• Most intensively studied adjunctive strategy for MDD• Treatment of first choice for psychotic depressions• For TRD, quetiapine, aripiprazole, and brexpiprazole are FDA-
approved, as is olanzapine + fluoxetine; positive studies for risperidone, cariprazine, and pimavanserin
• Important differences in side-effect profiles• Relative efficacy and optimal duration of therapy not established• Cost-effectiveness unlikely, but not adequately studied• Long-term safety concerns, especially metabolic complications, but risk
of tardive dyskinesia is also an issue
Thase ME. Psychiatr Clin North Am. 2016;39(3):477-486. Zhou X, et al. J Clin Psychiatry. 2015;76(4):e487-e498. Flint AJ, et al. JAMA. 2019;322(7):622-631. Mohamed S, et al. JAMA. 2017;318(2):132-145. Bauer M, et al. J Affect Disord. 2013;151(1):209-219.
*300 mg/day.Berman RM, et al. J Clin Psychiatry. 2007;68(6):843-853. Tohen M, et al. J Clin Psychiatry. 2010;71(4):451-62. El-Khalili N, et al. Int J Neuropsychopharmacol. 2010;13(7):917-932. Thase ME, et al. J Clin Psychiatry. 2015;76(9):1224-1231.
MDD Treatment Augmentation: Key Studies of Second-Generation Antipsychotics
N Mean Change in MADRS After 6 Wks
Agent Comparator MDD Population Treatment Comparator Treatment Comparator P-value
Aripiprazole + antidepressant Placebo
Incomplete response 184 178 -8.80 -5.80
Efficacy of Second-Generation Antipsychotics in the Adjunctive Treatment of MDD
*Risperidone is not indicated for the adjunctive treatment of MDD.“Standard dose” defined as equal to or more than the defined daily dose by the FDA-approved indications; “low dose” defined as less than half of the defined dose by the FDA-approved indicationsZhou X, et al. Int J Neuropsychopharmacol. 2015;18(11):pyv060.
Drug SMD vs Placebo (95% CrI)Quetiapine mean 250–400 mg/day (n=345)Risperidone* standard dose (n=217)Quetiapine mean 150–250 mg/day (n=344)Aripiprazole standard dose (n=746)Aripiprazole low dose (n=253)OFC standard dose (n=599)OFC low dose (n=59)
-1.0 -0.5 0.0 0.5 1.0
Favors treatment Favors placebo
Network meta-analysis of primary efficacy data (MADRS or HAM-D-17 scores)
VAST-D: Acute Phase Response Time to Event Analysis
Life Table Regression 95% Confidence IntervalTreatment Comparison HR Lower Upper P-valueAugmentation vs Switching
AD+BUP vs Switching 1.05 0.89 1.23 .56AD+ARI vs Switching 1.32 1.13 1.54 .0003
Augmentation vs AugmentationAD+ARI vs AD+BUP 1.23 1.05 1.43 .007
ARI = aripiprazole; BUP = bupropion; HR = hazard ratio.Mohamed S, et al. JAMA. 2017;318(2):132-145.
Adjunctive Brexpiprazole: Efficacy on Depressive Symptoms (MADRS)
*P
Unresolved Questions about Adjunctive Second-Generation Antipsychotics
• Is effectiveness enhanced by matching drugs to patients’ symptom profiles?
• When effective, how long should it be continued?• If therapy must be continued, what is the risk of tardive
dyskinesia across years of therapy?• Are these strategies truly cost-effective compared to other
adjuncts (ie, lithium) or antidepressant combinations?
Thase ME. Psychiatr Clin North Am. 2016;39(3):477-486.
Intranasal Esketamine: First FDA-Approved Treatment for TRD and MDD with Suicidal Ideation
• Antidepressant effects of sub-anesthetic doses of ketamine first serendipitously discovered in 1999; its large and rapid effects now extensively replicated
• S-ketamine is the more potent stereoisomer of racemic ketamine for the NMDA receptor
• Intranasal delivery for physician/patient convenience• 84 mg intranasal dose ~ 0.5 mg/kg IV racemic ketamine• FDA approved in 2019 for adjunctive therapy of TRD• 2 positive Phase 3 inpatient studies in MDD with Suicidal Ideation
reported 2019; FDA approved indication August 2020NMDA = N-methyl-D-aspartate. Newport DJ, et al. Am J Psychiatry. 2015;172(10):950-966. Kryst J, et al. Expert Opin Pharmacother. 2020;21(1):9-20.
Summary of Findings: Adjunctive Esketamine for TRD
Left and right of 0: better than AD + placebo, worse than AD + placebo, respectively. *As 84 mg was not significant at the 2-sided 0.05 level, 56 mg could not be formally evaluated, and the 2-sided P-value for this dose is considered to be nominal.Fedgchin M, et al. Int J Neuropsychopharmacol. 2019;22(10):616-630. Popova V, et al. Am J Psychiatry. 2019;176(6):428-438. Ochs-Ross R, et al. Am J Geriatr Psychiatry. 2020;28(2):121-141.
Primary Endpoint Secondary Endpoints
MADRS Sheehan DisabilityScale (SDS)Patient Health
Questionnaire (PHQ-9)
TRANSFORM-1 (3001)
Esketamine 56 mg + Oral AD
Esketamine 84 mg + Oral AD
TRANSFORM-2 (3002)
Flex Esketamine + Oral AD
TRANSFORM-3 (3005)
Flex Esketamine + Oral AD
Favors Esk + AD Favors AD + Placebo0
-10 -8 -6 -4 -2 0 2 -10 -8 -6 -4 -2 0 2 -10 -8 -6 -4 -2 0 2
P=.027*
P=.088
P=.020
P=.059
Treatment Considerations with Esketamine• Transient elevation of blood pressure and infrequent cases of
sustained over-sedation• Abuse liability (class III: same as ketamine)• Issues pertaining to cost and access• REMS certification of sites: includes a registry and safety protocol –
2-hour observation and driving restriction • Patients do not possess the drug: it is not sold at retail pharmacies and
access tied to systems/prescribers• Strong concerns about relationships to drugs of abuse and opioids
expressed following FDA approval
Kryst J, et al. Expert Opin Pharmacother. 2020;21(1):9-20. Schatzberg AF. Am J Psychiatry. 2019;176(6):422-424. Kim J, et al. N Engl J Med. 2019;381(1):1-4.
Summary• The profound societal and personal burdens caused by MDD can be
reduced by:– Prompt recognition and a careful collaborative approach to
treatment with prospective monitoring to ensure adherence– Identifying and addressing medical and psychiatric comorbidities– Systematically working through treatment algorithms, including
psychotherapy and a range of adjunctive strategies for patients who do not respond to antidepressant monotherapy
– Continued efforts to develop truly novel treatments that may help some individuals who do not benefit from current medications