What Can You Do When Antidepressants Don’t Work?

Laukik Patil
Nov 18
5 min read

When someone has tried antidepressant medications and yet still experiences significant symptoms of depression, this may be a sign of what we call treatment-resistant depression.

In such cases, the next steps often include re-evaluating the diagnosis, optimizing or changing medications, adding psychotherapy or neuromodulation, and referring for specialized care.

This blog will walk you through evidence-based options, practical considerations, and how the journey may look when the usual antidepressants haven't delivered full relief. At Neuromed Clinic in Canada, we emphasize a systematic, patient-centred approach, grounded in the latest guidelines and research.

What is Treatment-Resistant Depression?

When standard antidepressants fail to produce a meaningful improvement, clinicians may use the term treatment-resistant depression (TRD). The definition varies, but many sources define it as an inadequate response after two or more antidepressant trials at an adequate dose and duration.

At Neuromed Clinic, we consider TRD as a signal to shift the treatment paradigm rather than simply repeating the same interventions.

Key pointers

Confirm that the diagnosis is correct (e.g., major depressive disorder rather than bipolar disorder, substance-related mood disorder or other comorbidity).
Verify that each antidepressant trial was given at an adequate dose, for at least 6 weeks, and that adherence was verified.
Rule out contributing factors: other medical conditions (thyroid, vitamin deficiency), substance use, psychosocial stressors, medication side-effects or interactions.
Consider staging models (e.g., the Maudsley Staging Model) to assess severity and plan next steps.

Why Standard Antidepressants May Not Be Enough

Even when everything seems done "by the book", antidepressants may still fail to bring full remission. Several mechanisms and clinical realities help explain this.

For example, TRD is associated with higher burden, longer duration of illness, comorbidities and neurobiological complexity.

Key pointers

Neurobiology: Alterations in neurotransmitter systems (monoamines, glutamate, GABA), neural circuits, inflammation and HPA axis dysregulation are implicated in TRD.
Clinical factors: More severe depression, earlier onset, comorbid anxiety, longer untreated duration and prior non-response increase the likelihood of TRD.
Psychological and social factors: Persistence of stress, poor sleep, unresolved trauma, and limited psychosocial support may reduce the effectiveness of standard antidepressants. Similar challenges often appear during anxiety treatment, where unaddressed lifestyle or emotional stressors can influence therapeutic progress.
Medication limitations: While antidepressants are foundational, they may not address all underlying contributors to the illness in TRD, hence the need for adjunctive or alternative treatments.

Step-by-Step When Antidepressants Don't Work

At Neuromed Clinic, when a patient presents with insufficient response to antidepressants, we follow a structured pathway. Here's how it typically unfolds.

1. Review diagnosis and adherence

Before moving on, validate that the diagnosis is correct and that the patient has been taking the medication as prescribed.

Confirm mood episode(s): rule out bipolarity, mixed features, and medical causes.
Check medication adherence: pill counts, pharmacy refill data, patient self-report.
Confirm adequate dose/duration: many guidelines suggest at least 6 weeks at a therapeutic dose.
Review side-effects or interactions that may mask response or cause non-adherence.
Check for complicating factors: sleep disorders (e.g., obstructive sleep apnea), substance use, comorbid anxiety, thyroid dysfunction, and nutritional deficiencies.

2. Optimize or switch antidepressant

If the diagnosis is confirmed and there are no major complicating factors, the next step often involves optimizing or switching the medication.

Increase dose (if tolerated) before concluding non-response.
Switch to another antidepressant with a different mechanism (e.g., from SSRI to SNRI or a different class).
Consider augmenting with another agent (e.g., adding a non-antidepressant or antidepressant of a different class) under specialist supervision.
Monitor closely for side effects and emerging response over subsequent weeks.

3. Introduce psychotherapy and comprehensive care

Medication alone may not be sufficient in TRD. Integrating psychotherapy and other supports is critical.

Evidence supports therapies like cognitive behavioural therapy (CBT), interpersonal therapy (IPT), and trauma-informed care, approaches that also play a crucial role in PTSD treatment, as effective adjuncts in TRD.
Address lifestyle factors: physical activity, sleep hygiene, nutrition, substance use reduction, and social support.
Use a collaborative care model: involving psychiatrists, psychologists, primary care and other supports. The Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines emphasise a personalized, systematic care approach.

4. Consider advanced or neuromodulation treatments

For many patients with TRD, neuromodulation or personalized therapies become key options.

Transcranial magnetic stimulation therapy for depression is a noninvasive, evidence-based treatment that uses focused magnetic pulses to stimulate brain circuits involved in mood regulation. TMS is well-supported in clinical research for patients who haven't achieved sufficient response to antidepressants and is available at the Neuromed Clinic.
Personalized care plans: Each treatment course is tailored based on symptom patterns, clinical history, and ongoing progress to ensure safe and effective outcomes.
Emerging research: Scientists continue to study other neuromodulation and pharmacologic innovations for depression. While these are not part of our current clinical offerings, we stay informed on evolving evidence to guide patients with accurate, up-to-date information.
Our focus: At Neuromed Clinic, our team evaluates the suitability of TMS for each patient, explains the process in detail, and provides continuous monitoring throughout the course of therapy.

5. Monitor, adjust and maintain

TRD is a dynamic condition. Ongoing monitoring and adjusting are crucial for long-term outcomes.

Regularly assess symptom severity (validated scales), functional status (work, relationships, daily living).
Evaluate for relapse or recurrence and implement maintenance strategies (medication, psychotherapy, lifestyle).
Collaborate with the patient to set realistic goals: full remission is ideal, but substantial improvement and restored functioning are key.
Educate and support patients and families about the chronic nature of TRD, the value of persistence and multiple pathways.

FAQs

What does "adequate trial” of an antidepressant mean?

An adequate trial typically means taking the medication at a therapeutic dose, for a sufficient period (often 6 weeks or more), with confirmed adherence and tolerability. Without those conditions, it is difficult to conclude that the medication “didn’t work”.

When should I consider neuromodulation like TMS?

If you've had at least two adequate antidepressant trials (with or without adjunctive therapy) and still have significant symptoms, neuromodulation becomes a reasonable next step. You should discuss with your psychiatrist or a specialized clinic whether options like TMS are appropriate.

Are there risks to switching or augmenting antidepressants?

Yes. Anything that changes your medication carries potential side effects, interactions, or withdrawal phenomena. That's why these steps should be supervised, especially in complex cases of TRD.

Will I always need lifetime treatment?

Not necessarily, but many people with TRD will need ongoing monitoring and possibly maintenance treatment because the risk of relapse is higher. What's most important is getting closer to remission and regaining functioning rather than just symptom reduction.

How does comorbid anxiety affect treatment resistance?

Comorbid anxiety is a known predictor of poorer response to standard antidepressants and may require targeted interventions (both pharmacologic and psychotherapeutic) to address the anxiety component. This may enhance the overall response to the depression.

Conclusion

When antidepressants don't bring relief, it doesn't mean hope is lost; it means it's time for a new approach. Treatment-resistant depression requires comprehensive, individualized care that looks beyond medication alone. With careful reassessment, the integration of psychotherapy, and advanced options like transcranial magnetic stimulation therapy for depression, patients can find meaningful recovery and improved quality of life.

Explore Advanced Depression Treatment Options at Neuromed Clinic

If you've tried multiple medications without success, you may be dealing with treatment-resistant depression. At Neuromed Clinic, we offer non-invasive therapies like TMS for depression, designed to target the root cause of persistent symptoms safely and effectively. Schedule your consultation today!