Case 2, Episode 4: Medication Strategy Reimagined – When “Nothing Works”
“They keep switching the meds. I take them, I wait, I hope. Then it fades—or nothing happens at all. It’s like everyone’s just guessing.”
— Marcus, 48
This is the moment many clinicians dread:
The patient has tried five, six, even ten medications.
Nothing seems to help—or the effect disappears just as things start to improve.
Words like “treatment-resistant depression[1]” get thrown around. But what if Marcus isn’t resistant to treatment[2]—he’s just never had a treatment plan that made sense to him, or for him?
Welcome to the art and science of reimagining medication strategy.
Step One: Redefine the Goal
We don’t need to “cure” depression.
We need to help Marcus:
Sleep through the night
Wake up without dread
Feel small sparks of interest again
Rebuild his sense of agency
That’s the target: meaningful function, not chemical perfection.[3]
Step Two: Assess the History with Precision
Before prescribing anything new, map what’s been tried and what’s been missed.
Marcus’s Medication History:
SSRIs: Sertraline, escitalopram – partial relief, “emotional flattening”
SNRIs: Duloxetine, venlafaxine – GI side effects, discontinued
Bupropion: Brief boost in motivation, but worsened anxiety
Mirtazapine: Sedating, but increased appetite and weight
Lithium: Discontinued after side effects (tremor, fogginess)
Aripiprazole: Used as adjunct, led to apathy and weight gain
That’s a lot of data—but not necessarily direction.
Step Three: Build a Decision Tree
Rather than guessing what’s next, create an algorithmic treatment map.[4]
1. Have we optimized any class?
Was sertraline titrated above 100mg?
Did we ever try fluoxetine, known for energy and long half-life?
Has any med been combined strategically—not just sequentially?
2. Have we used augmenting agents wisely?
Buspirone for anxiety + depression?
Thyroid hormone (T3) as augmentation, even if TSH is normal?
Low-dose lithium, slower titration to tolerate side effects?
3. Have we gone outside the box?
Ketamine (IV or intranasal) for rapid-acting antidepressant effect
TMS (Transcranial Magnetic Stimulation), especially if meds are poorly tolerated
MAOIs – often forgotten, but still effective for atypical or chronic depression
Psychostimulants – cautiously, when fatigue and anhedonia dominate
Example: A Personalized Algorithm for Marcus
If: Marcus continues to report low motivation + emotional numbness
Then: Consider fluoxetine + low-dose bupropion combo
If: Energy improves but anxiety rises
Then: Add buspirone or consider switching to vortioxetine (Brintellix) for cognitive boost
If: Pharmacological strategies fail after optimization
Then: Introduce neuromodulation options (TMS > ECT > ketamine)
If: Treatment burden is too high
Then: Reassess goals, focus on therapy, meaning-making, somatic interventions
This isn’t a protocol. It’s a living roadmap—adaptive, honest, collaborative.
Step Four: Rebuild the Patient’s Relationship to Treatment
Medication isn’t just about molecules. It’s about meaning.[5] Patients like Marcus often internalize failure after failed med trials:
“If nothing works, it must be me.”
As clinicians, we must:
Debrief each trial—what helped, what didn’t, how it felt
Center agency—“Here’s what I’m thinking. What do you think?”
Name the process—“This may take time, but we’re building a new approach together.”
Avoid hype, avoid despair—balance realism with respect
Coming Up Next: Episode 5 – Therapy That Goes Deeper
Marcus doesn’t just need a different medication.
He needs a new way of being with himself.[6]
Next time, we’ll explore:
Why standard CBT may fall short in chronic depression
The role of psychodynamic and schema work
How therapy can help patients remember what they’ve disowned
And how to shift from “symptom control” to self-reclamation
Because the goal isn’t just fewer bad days.
It’s a life Marcus can call his own again.
Reflective Prompt for You
What’s your framework when meds don’t “work”?
Do you find yourself switching too quickly—or staying too long with something out of fear?
How do you help your patients stay engaged in the process, even after disappointment?
Your approach could shift someone else’s practice.
References
[1] Souery, Daniel, George I. Papakostas, and Madhukar H. Trivedi. "Treatment-resistant depression." Journal of Clinical Psychiatry 67 (2006): 16.
[2] Sackeim, Harold A. "The definition and meaning of treatment-resistant depression." Journal of Clinical Psychiatry 62 (2001): 10-17.
[3] Pinho, Lara Guedes de, et al. "Patient-centered care for patients with depression or anxiety disorder: an integrative review." Journal of personalized medicine 11.8 (2021): 776.
[4] Zhu, Tingshao, et al. "Using decision tree to predict mental health status based on web behavior." 2011 3rd Symposium on Web Society. IEEE, 2011.
[5] Sun, Fan‐Ko, et al. "Meaning in life as a mediator of the associations among depression, hopelessness and suicidal ideation: A path analysis." Journal of psychiatric and mental health nursing 29.1 (2022): 57-66.
[6] Montesano, Adrián, et al. "Depression and identity: Are self-constructions negative or conflictual?." Frontiers in psychology 8 (2017): 877.