THE IMPACT OF TREATMENT

RESISTANCE ON MAJOR
DEPRESSIVE DISORDER
PATIENTS
DR. IRINA NIȚULESCU
5TH YEAR PSYCHIATRY RESIDENT
COUNTY CLINICAL EMERGENCY
HOSPITAL OF CONSTANTA, ROMANIA
A. DISCLAIMER:
• THE SYMPOSIUM IS ORGANIZED AND SUPPORTED BY JANSSEN ROMANIA (JOHNSON&JOHNSON ROMANIA SRL)
• THE VIEWS EXPRESSED IN THESE SLIDES ARE THOSE OF THE INDIVIDUAL FACULTY MEMBERS AND DO NOT
NECESSARILY REFLECT THE VIEWS OF JANSSEN, PHARMACEUTICAL COMPANIES OF JOHNSON & JOHNSON IN
EMEA

B. FINANCIAL DISCLOSURES:

FINANCIAL
• RESEARCH SUPPORT/P.I.: NA

DISCLOSURE
• EMPLOYEE: COUNTY CLINICAL EMERGENCY HOSPITAL OF CONSTANTA, ROMANIA
• CONSULTANT: NA
• MAJOR STOCKHOLDER: NA
• SPEAKERS BUREAU: NA
• HONORARIA: NA
• SCIENTIFIC ADVISORY BOARD: NA
 INTRODUCTION

• “depression is a common mental disorder, with more than 264 million

people of all ages suffering from depression globally, being a leading
cause of disability worldwide and a major contributor to the overall global
burden of disease” (World Health Organization)

• Research shows one third of patients treated for depression will become
treatment resistant.
Research conducted on treatment resistant depression highlighted:

– “There is not yet a standardized definition for TRD and existing definitions have key differences.”
– “Health-related quality of life decreases with increasing levels of TRD.”
– “We found that self-harming behavior not resulting in death was significantly more frequent in the
TRD group than in the non-TRD group.”
– “The general principles and issues that are involved in treating resistant depression in adults include the
following:
• Reassess the diagnosis;
• Assess adherence;
• Treatment strategies;
• Duration of an adequate drug trial.”
– “For patients with severe unipolar major depression that is treatment resistant, electroconvulsive therapy
(ECT) is often the treatment of choice.”
– “Pharmacotherapy options for severe, treatment resistant depression include antidepressants, intravenous
ketamine, and intranasal esketamine. No head-to-head randomized trials have compared these three
options; thus, the choice depends upon availability and patient preference.”
– “Symptom severity, psychotic symptoms, suicidal risk, generalized anxiety disorder, inpatient status,
higher number of antidepressants administered previously, and lifetime depressive episodes as well as
longer duration of the current episode increased the risk of treatment resistance.”
– “Up to 60% of patients do not show sufficient symptom relief after the first AD trial was applied and a
third of these report hardly any alleviation even when multiple ADs are administered.”
Guidelines for diagnosing a treatment resistant major depressive disorder(TDR):
1. Assuring that the diagnosis is accurate;
2. Defining clinical response by using a standardized method;
3. Determining the number of failed adequate treatment trials the patient has gone
through.
 OBJECTIVE

• The objective of this study is to highlight the impact of treatment

resistance on Major Depressive Disorder patients.
 METHOD

This case study follows a group of 10 women diagnosed with depression with ages between 60 and 80 over the
course of a year.

P.M. 62 years old, admitted in January, April, and August 2020 for
major depressive episodes with melancholic and dissociative
symptoms.
V.E. 70 years old, admitted in February and July 2020 for major
depressive episodes associated with anxiety.
U.G. 66 years old, admitted in February, May, and September 2020
for major depressive episodes, the first with psychotic features.
A.P. 64 years old, admitted in April and September 2020 for a major
depressive episode and in January 2021, associating a suicide
attempt.
S.A. 67 years old, admitted in August and November 2020 for
major depressive episodes with somatic features.
C.N. 65 years old, admitted in August and November 2020 for
major depressive episodes associated with anxiety.
S.I. 77 years old, admitted in October 2020 and January 2021 for
major depressive episodes with somatic features.
A.E. 80 years old, admitted in November 2020 and January 2021
for major depressive episodes with somatic features.

M.V. 73 years old, admitted in May and November 2020 for major
depressive episodes with psychotic features.

C.M. 67 years old, admitted in June and December 2020 for major
 RESULTS

• 20 to 40 years of medical care;

• Residual symptoms and frequent relapses that require hospitalization;
• Loss of hope of ever achieving remission;
• Risen risk of decreased patient treatment compliance;
• Higher frequency of suicide attempts and ideation;
• Loss of trust in mental healthcare, leading to deficient physician-patient interactions.
 Residual Symptoms
12

10

0
insomnia diminished interest or pleasure in all, decrease appetite fatigue
or almost all, activities most of the day

YES NO
Hospitalizations during the last year

2 hospitalizations 3 hospitalizations
don’t think they will ever get better think they will get better
 Treatment adherence
8

thought about stopping their medication admit stopping their medication

never thought about stopping their medication
 Suicidal behavior

0 2 4 6 8 10 12

suicide ideation suicide attempt

 Physician-patient interactions
100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0%
changed their psychiatrist during the last 3 years lied to their psychiatrist

YES NO
 Treatment trials

Patient Treatment before admission Treatment during hospitalization

P.M. Duloxetine 120mg/day Sertraline 150mg/day
Quetiapine 100mg/day Diazepam 20mg/day
Quetiapine 300mg/day
V.E. Escitalopram 10mg/day Escitalopram 20mg/day
Quetiapine 150mg/day Lorazepam 3mg/day
Quetiapine 300mg/day
U.G. Mirtazapine 30mg/day Mirtazapine 30mg/day
Aripiprazole 5mg/day Lorazepam 2mg/day
Aripiprazole 10mg/day
A.P. Venlafaxine 75mg/day Venlafaxine 150mg/day
Bromazepam 3mg/day
Quetiapine 200mg/day
M.V. Duloxetine 120mg/day Paroxetine 40mg/day
Quetiapine 50mg/day Diazepam 20mg/day
Quetiapine 300mg/day
Patient Treatment before admission Treatment during hospitalization
C.M. Trazodone 150mg/day Sertraline 150mg/day
Bromazepam 3mg/day
Olanzapine 10mg/day
S.A. Mirtazapine 30mg/day Escitalopram 10mg/day
Mirtazapine 30mg/day
Lorazepam 3mg/day
C.N. Escitalopram 10mg/day Escitalopram 20mg/day
Lorazepam 3mg/day
Gabapentin 900mg/day
S.I. Duloxetine 60mg/day Paroxetine 40mg/day
Bromazepam 3mg/day
Quetiapine 200mg/day
A.E. Sertraline 150mg/day Duloxetine 120mg/day
Lorazepam 2mg/day
Quetiapine 200mg/day
Clinical responses measured by using the Montgomery-Åsberg Depression Rating Scale
(MADRS), reaching a maximum of 40% score improvement, and an average of 30%.

Patient Admission day score Discharge day score

P.M. 48 33
V.E. 38 29
U.G. 40 28
A.P. 46 32
M.V. 48 34
C.M. 46 30
S.A. 38 26
C.N. 40 24
S.I. 36 22
A.E. 40 28
As longer cumulative duration of lifetime depression and total number of recurrent episodes are
also associated with hippocampal volume loss, these 10 patients now face a poorer clinical
response to medication and early signs of cognitive decline.

short-term memory loss no signs of cognitive decline

Another treatment option is electroconvulsive therapy. But, nonetheless, none of the 10 patients
accepted.

ECT

because of its stigma didn't/couldn't travel

 Newer research shows ketamine as a
promising option for treatment resistant
major depression:
• Racemic ketamine
– approved as an anesthetic by the FDA, used
off-label to treat depression;
– infusion into the bloodstream;
– a mixture of two mirror-image molecules:
“R” and “S” ketamine.
• Esketamine
– became the first FDA approved drug with a
new mechanism (NMDA glutamate
receptor antagonist) to treat depression in
more than half a century in March 2019;
– given as a nasal spray;
– uses only the “S” molecule.
Krystal et al. (2020) Cell
THE HISTORY OF (S-)KETAMINE

Krystal et al. (2020) Cell

 Add-on Esketamine Vs. Add-on SGAP

Esketamine nasal spray

Second generation AP

Esketamine nasal spray augmentation trials (OR= 4.1)

SGAP augmentation trials (OR = 2.05)
The effect size for intranasal esketamine was nearly twice as high as those for the second-generation
antipsychotics.

ESK (4.1) > OLA (3.1) > ARIP (2.3) > QUET (1.3)
Dold et al. (2020) Int J Neuropsychopharmacol
CONCLUSIONS
• TRD rises the risk of decreased patient compliance treatment and suicide
attempts and ideation and lowers the trust in mental healthcare, leading to
deficient physician-patient interactions;
• TRD is a matter which seeks more attention;
• Physicians must correctly diagnose treatment resistant depression;
• Suggesting electroconvulsive therapy or newer treatment options like
Esketamine shouldn’t be delayed too long;
• Further research is also needed regarding the new available treatment option,