What defines Treatment Resistant Depression (TRD)
Stage 1: more than one adequate trial of 1 major class of antidepressants
Stage 2: Failure of more than 2 adequate trials of two different classes of antidepressants
Stage 3: stage 2 + TCA
Stage 4: Stage 3 + MAOI
Stage 5: Stage 4 + bilateral ECT
With every medication or neuromodulation procedure used that doesn’t work, the more treatment resistant the depression becomes.
Antidepressant Response Rates
Frist Medication Trial: 50% respond and 37% have remission
Second Medication Trial: Another 29% respond and 31% have remission
Third Medication Trial: 17% respond and 14% have remission
Fourth Medication Trial: 16% respond and 13% have remission
The overall cumulative remission rates are 67%, keeping in mind that people who progressed through more treatment stages had higher relapse rates and more residual symptoms including anhedonia, emotional blunting, and lack of motivation.
If someone is having a poor response to medication, what do you do?
We know that bipolar disorder is missed in a significant number of patients who present with depression about one in five will be misdiagnosed. We also know that antidepressants can be mood destabilizing in bipolar illness resulting in mixed features and rapid cycling. Other things that can interfere with response include substance use disorder, personality traits, and PTSD.
Medical Comorbidities that can interfere with antidepressant response include hypothyroidism, Cushing disease, Parkinson’s disease, cancer, vitamin/nutritional deficiencies, and viral infections
Psychosocial factors that contribute to treatment resistance
-Female sex
-Older Age
-Single Unmarried (happiness studies indicate that good relationships are very important)
-Unemployment
Symptoms that make TRD more Likely
-Recurrent episodes usually 3 or more
-Severe depression and inpatient admission
-Anxiety, Insomnia, or Migraine
When Your First Choice Fails
There are several approaches
-Switch antidepressant classes
-Combine antidepressants
-Add a dopamine blocking medication
-Add L-methylfolate
-Add Psychotherapy
-Start Neuromodulation
What’s the most effective strategy
Hands down the most effective thing to do if a patient has a poor response to the initial antidepressant treatment is to add a dopamine blocking medication. Response and remission rates are much higher, but it comes at the price of increased side effect potential.
What are the most used Dopamine Blockers in Antidepressant Augmentation
-Quetiapine
-Olanzapine
-Risperidone
-Aripiprazole
-Ziprasidone
Older patients 65 years and older respond better to aripiprazole augmentation than switch to bupropion, or combination with bupropion.
Brexpiprazole: 1-3 mg/day Adjunctive for Depression
Most Common Concerns patients have about being on dopamine Blocking Medication
-Weight gain 60% of people report this concern
-Metabolic side effects
-EPS
-Sedation
-Akathisia
-Prolactin-related Effects
Anti-Inflammatory Medications
For those with elevated inflammatory biomarkers specifically c-reactive protein there is some emerging evidence that these treatments work.
-Medications like Celecoxib, Omega-3 fatty acids, statin drugs and minocycline
-Weight loss
-Effect Size: 0.55
-Higher response and remission rates
-May only work in those with high inflammatory biomarkers
Glutamate Modulators
-Ketamine Infusions and Esketamine: both work and a reasonable option if TRD
-There are several medications in development
Psychotherapy in TRD
Unfortunately, what we find with TRD is psychotherapy does not prevent TRD, it doesn’t mean there is no benefit it just means future episodes will not be prevented by psychotherapy. On its own, psychotherapy may not be as helpful as we would like in TRD but when combined with medication it does help. That tells us about the importance of evaluating severity of depressive episode.
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