Treatment Resistant

Depression (TRD)
Anas Hassan
Content

1. Definition
2. Staging Models of TRD
3. Pharmacotherapy
4. Physical therapy
5. Psychotherapy
How is it defined?

Lack of response? Non-remittance?

Dichotomous or continuous?

How many treatment failures?

Duration of treatment? Dosage of treatment?

Definition

CANMAT Depression Guidelines 2016

- Inadequate response to two or more antidepressants

NICE Guidelines on Esketamine Treatment for TRD 2022

- Depression that has not responded to at least 2 different antidepressants in the current moderate to
severe depressive episode in adults

RANZCP Guidelines on Depression 2019

- Failure to achieve a suitable response to two or more adequate courses of pharmacotherapy

Definition

Malaysian CPG on MDD 2019

Failure to respond to two or more antidepressants at an adequate dose for an adequate duration, given
sequentially

*Adequate duration refers to at least four weeks and adequate dose refers to at least 150
mg/day of imipramine equivalent.
Staging of Treatment Resistant Depression

1. Antidepressant Treatment History Form (ATHF)

2. Thase and Rush Staging Model
3. European Staging Model
4. Massachussetts General Hospital Staging Model (MGH-s)
5. Maudsley Staging Model (MSM)
Antidepressant Treatment History Form (ATHF)

Severity - scored 0 to 5 per treatment with a possible sum score for all treatments

Failure - not defined

Adequate dose - defined in the staging schema

Adequate duration - defined in the staging schema

Reliability - good interrater reliability

Predictive validity - predictive value only limited to treatment with ECT

Antidepressant Treatment History Form (ATHF)

Staging schema

● Stage 0: no treatment
● Stage 1: Any drug <4 weeks or less than minimum adequate daily dose; for ECT 1–3 sessions
● Stage 2: Any drug ≥4 weeks at less than minimum adequate daily dose; for ECT 4–6 sessions
● Stage 3: Any drug ≥4 weeks at minimum adequate daily dose; for ECT 7–9 unilateral sessions
● Stage 4: Any drug ≥4 weeks at higher than minimum adequate daily dose; for ECT 10–12 unilateral/7–9 bilateral
ECT sessions
● Stage 5: Any drug at level 4 augmented with lithium ≥2 weeks; for ECT ≥13 unilateral/≥10 bilateral ECT sessions
Thase and Rush Staging Model

Severity - higher stages indicate greater resistance

Failure - failure to respond

Adequate dose - not defined

Adequate duration - at least 4 weeks

Reliability - not tested

Predictive validity - not assessed

Thase and Rush Staging Model

Staging schema

1. Stage I: Failure of at least one adequate trial of one major class of AD

2. Stage II: Stage 1 + failure of an adequate trial of an AD in a distinctly different class from Stage 1
3. Stage III: Stage II plus failure of adequate trial of a TCA
4. Stage IV: Stage III plus failure of an adequate trial of an MAOI
5. Stage V: Stage IV plus failure of a course of bilateral ECT
European staging model
Severity - number of weeks with treatment resistance to adequate dose of at least 2 different classes of ADs, if more than 12 months = Chronic Resistant Depression
(CRD)

Failure:

- poor response of 2nd adequate trial with different class of AD (6-8 weeks)
- Clinically relevant TRD - current episode which has not benefited from 2 trials of AD with different MOA

Adequate dose - not defined

Adequate duration - 3 categories, non-responder: 6-8 weeks, TRD (level 1) 12-16 weeks, CRD 12 months

Reliability - not tested

Predictive validity - not assessed

European staging model
3 distinct categories

Nonresponder: Nonresponse to 1 adequate trial of TCA, SSRI, MAOI, SNRI, or other AD, or ECT

TRD: Resistance to 2 or more adequate AD trials of different classes

● TRD1: 12–16 weeks

● TRD2: 18–24 weeks
● TRD3: 24–32 weeks
● TRD4: 30–40 weeks
● TRD5: 36 weeks–1 year

CRD: Resistant to several AD trials, including augmentation strategy, for at least 12 months
Massachusetts General Hospital Staging Model
(MGH-s)
Severity - Higher scores indicate a greater degree of resistance to treatment

Failure - Failure to achieve remission (refers to “inadequate response” but defines it as HAM-D ≤7, which indicates
remission)

Adequate dose - Optimization per MGH or ATR Questionnaire

Adequate duration - at least 6 weeks

Reliability - not tested

Predictive validity - Higher scores predict worse outcomes, certain studies showed MGH-s predicted non remission better
than TRSM
Massachussetts General Hospital Staging Model
(MGH-s)
Stages:

Stage 1: Nonresponse to each adequate trial

Stage 2: Optimization of dose, duration, and augmentation/ combination

Stage 3: ECT increases overall score by 3 points

Staging is primarily based on the number of AD medications used and gives a special weight for failure
of treatment with ECT (i.e., score of 3)
Maudsley Staging Model (MSM)
Severity - Not dichotomous; gives points per number of prior attempts, duration, symptoms severity, augmentation use, ECT; single score can vary
from 3 to 1

Failure - Failure to achieve remission (HAM-D21 ≤10)

Adequate dose - minimum effective doses of ADs based on Maudsley Prescribing Guidelines

Adequate duration -

Augmenting agents: at least 6 weeks, ECT: 8-session course

Reliability - not tested

Predictive validity - significantly better than TRSM

Maudsley Staging Model (MSM)

Parameters include: Scores:

● Duration (1–3 points) ● Mild (scores = 3–6),

● Symptom severity (1–5) ● Moderate (scores = 7–10)
● Number of treatment failures (1–7) ● Severe (scores = 11–15)
● Augmentation strategy use (0/1)
● ECT use (0/1)
Comparison
Take a step back, revisit
diagnosis…
Consider underlying causes of
depression that may have gone
undetected and untreated!
Treatment of TRD

● Pharmacotherapy:
○ Switching
○ Combination
○ Augmentation
● Physical treatment
● Psychotherapy as an adjunct
Pharmacotherapy

Switching

- switching from an SSRI to a non-SSRI showed higher remission rates compared to SSRI to SSRI

Combination

- May be considered
- Lack of research on TRD combination therapy
- No recommendation
- Monitor for adverse outcomes
- “California rocket fuel” - mirtazapine + venlafaxine
- RCT showed no difference in response/side effects between mirtazapine + SSRI/SNRI and placebo + SSRI/SNRI
Augmentation

- Antipsychotics
- Better response but more adverse effects
- Lithium
- Better response, no difference with placebo on adverse effects
- Anti-epileptics
- No difference in response compared to other augmenting agents
- Esketamine
- Intranasal esketamine shown to significantly reduce symptoms and suicidal thoughts
- FDA approved in the US for TRD
- Stimulants (modafinil and methylphenidate)
- Recently emerging evidence for its use in TRD

*Antipsychotics and lithium are preferred options

Esketamine (SPRAVATO)

Esketamine use in MDD with acutely suicidal behavior:

84mg twice per week for 4 weeks (may be reduced to

56mg per week if not able to tolerate)

Use of esketamine beyond 4 weeks for this indication has

not been systematically studied

*1 device = 28mg, 2 sprays, 1 each nostril, 5 minute rest after 1 device

Physical therapy

ECT:

- shown to be more effective than AD monotherapy

- Indirect comparison shows no difference between ECT + AD and ECT alone
- ECT + AD had more memory deterioration

rTMS:

- Less effective than ECT

- Less cognitive impairment
- CANMAT 2016 recommends rTMS before proceeding for ECT

Implanted vagus nerve stimulation:

- Limited evidence
Psychotherapy

Only as adjunct (Malaysian CPG)

Evidence is limited and conflicting

No specific recommendation
 Response
perspective
Each patient requires
individualised treatments
according to their
‘responsivities’ (RANZCP 2020)
Principles of the channeling response diagram

Evaluate response

Review formulation

Review treatment

Adopt and maintain the ‘response perspective’

Finding the channel

Key Points on TRD

1. No consensus on definition
2. Different staging models offer different benefits and weaknesses
3. Different patients respond to different treatments based on their ‘responsivities’
4. Discuss with patients regarding treatment options for shared decision making
References

1. Gaynes, B. N. (2018, February 9). Results: narrative review key questions. Definition of
Treatment-Resistant Depression in the Medicare Population - NCBI Bookshelf.
https://www.ncbi.nlm.nih.gov/books/NBK526364/
2. CANMAT Guidelines for Adults with Major Depressive Disorder (2016)
3. NICE Guidelines on Esketamine Treatment for TRD (2022)
4. NICE Guidelines depression in adults (2022)
5. NICE Interventional Procedures Guidance on Implanted Vagus Nerve Stimulation for TRD
(2020)
6. RANZCP CPG for Mood Disorders (2020)