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

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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.

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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