Most Missouri adults with depression are managed in primary care, and most of the time that is exactly right. The harder question is what happens at the point where two reasonable antidepressant trials have not produced an adequate response. This explainer is for the physicians, nurse practitioners, and physician assistants who make that call, and it pairs the clinical framing with what our own survey says about how patients see the same moment.
What patients report
Our commissioned Pollfish survey reached 443 people between 18 and 64 spread over ten states, Missouri one of them, and it closed June 23, 2026. One question gauged personal and secondhand experience with standard medication failing against depression, anxiety, or PTSD.
Seventy-two percent answered in the affirmative. Thirty-seven percent reported it as their own experience only, 13 percent said it applied to both themselves and someone close, and 22 percent said it applied only to someone close. The remaining 28 percent said no.
Treat those as final, validated figures, but as self-report rather than clinical classification. They do not estimate TRD prevalence. They do show that the patient experience of "the medicine did not work" is widespread among ordinary adults in the region.
The working definition
Treatment-resistant depression is most often operationalized as major depressive disorder with inadequate response to at least two antidepressant trials of adequate dose and duration in the current episode. Guidelines and payers differ in the details, including what counts as adequate duration and whether augmentation trials count, so it is worth knowing which definition the patient's insurer applies.
Before applying the label, most clinicians check for pseudo-resistance:
- Adequacy of trials. Were doses therapeutic, and was each trial long enough to judge?
- Adherence and tolerability. Did the patient take the medication consistently, and did side effects cut trials short?
- Diagnostic accuracy. Could this be bipolar spectrum illness, a primary anxiety or trauma disorder, or depression secondary to another condition?
- Medical and substance contributors. Thyroid disease, sleep disorders, chronic pain, alcohol or other substance use, and interacting medications.
- Psychosocial load. Ongoing stressors that may be sustaining symptoms.
Why the label matters in practice
It changes the conversation with the patient, who often assumes a failed trial is a personal failure. It opens the door to a broader treatment set. And it is frequently the criterion insurers use to authorize escalation. Clear documentation of each trial, with drug, dose, duration, and outcome, is the single most useful thing a PCP can build for a patient heading toward specialty care.
Options after two trials
These are the broad categories, not a protocol. Sequencing depends on the patient and, often, on specialist input.
- Optimization and switching. Dose optimization, switching within or across classes.
- Augmentation and combination. Adding a second agent with evidence for augmentation, or combining antidepressants.
- Psychotherapy. Evidence-based therapy added or intensified, which is useful at any stage.
- TMS. FDA-cleared, drug-free, delivered in frequent sessions over several weeks.
- Esketamine nasal spray (Spravato). FDA-approved for adults with TRD. Administered under direct observation in a healthcare setting certified under the Spravato REMS, with post-dose monitoring for sedation, dissociation, and blood pressure changes. Driving is off limits for the rest of that day and resumes only after restful sleep.
- Other specialty treatments. ECT and other interventions typically managed through psychiatry.
Off-label racemic ketamine, by infusion or through at-home telehealth programs, sits outside this FDA-approved framework. Patients frequently confuse it with esketamine. It is worth addressing that directly, especially because at-home programs involve far less monitoring. For patients who want a plain-language summary, this Spravato overview for patients can serve as a handout.
What patients know when they walk in
Very little about the later options. In our sample, Spravato was an unknown name to 73 percent, and only 6 percent could describe it; TMS awareness ran around one in four. The practical consequence is that patients rarely request these by name. If you do not raise them, they may never come up.
Patients also expect you to be the one who raises them. More than half of respondents, 56 percent, would go to their primary care physician first, and three quarters would take their own doctor's recommendation over any other source when deciding whether to try a new treatment. That is a strong mandate for primary care to lead the escalation conversation, even when the treatment itself is delivered elsewhere.
Missouri-specific considerations
Payer mix. Among payers, respondents most often named commercial coverage (39 percent), then Medicaid (37 percent) in a near tie, and Medicare (23 percent). For Missouri patients, that means MO HealthNet's prior authorization criteria and preferred drug list are as relevant as any commercial policy. Check current criteria before assuming a pathway is or is not available.
Geography. Specialized services cluster in the St. Louis and Kansas City metros, with more limited options in rural counties. Proximity was a top-two provider priority for 43 percent of respondents, and esketamine's early phase involves frequent visits with a required ride home. For rural patients, travel burden can decide feasibility.
Coverage expectations. Eighty-five percent of respondents named insurance coverage among their top-two priorities. A slim majority would accept extra administrative steps to keep treatment covered. Patients will tolerate prior authorization if someone explains it and helps them through it.
A simple workflow
- Measure response at each follow-up with a standard tool.
- After a second inadequate trial, screen for pseudo-resistance.
- Name the situation to the patient in plain language.
- Discuss the next options, including referral where appropriate.
- Send a referral packet with the full trial history to speed authorization.
None of this requires a primary care office to deliver specialty treatment itself. It requires recognizing the moment, explaining it honestly, and handing the patient to the next clinician with a record that makes their job, and the insurer's decision, faster.
Include crisis resources in every depression follow-up. Between visits, patients can use 988, by call or text, whenever they need the Suicide and Crisis Lifeline, with no callback wait, and veterans can press 1.
Methodology
The Pollfish consumer panel returned 443 responses to our survey before it closed June 23, 2026. Respondents were adults 18 to 64 from Iowa, Missouri, Oklahoma, Illinois, Nebraska, Ohio, Kansas, Minnesota, Indiana, and Wisconsin. Only top-line figures appear here, each drawn from Pollfish's final validated responses. The publisher commissioned and fully paid for the survey. This explainer is educational and does not replace clinical guidelines or judgment.