What to Do When Antidepressants Don’t Work (and Why)

Signs Your Antidepressant Isn’t Working

Depression isn’t a one-size-fits-all condition, and neither is its treatment. While antidepressants help many people, they don’t work the same way for everyone, and there are many reasons you might not be getting the relief you hoped for.

If your medication isn’t bringing the relief you expected, it doesn’t mean you’re out of options. There are many possible reasons a treatment may fall short, including:

• It needs more time or a dose adjustment. Most antidepressants take weeks to reach full effect, and some people need careful dose changes before benefits appear.
• Stress, life changes, or trauma. Ongoing stress, major transitions, or unresolved trauma can intensify symptoms and make medications seem less effective.
• Alcohol or substance use. Drinking alcohol or using other substances can blunt the effects of antidepressants and sometimes worsen depression.
• Medication or supplement interactions. Other prescriptions, over-the-counter drugs, or supplements may interfere with how your antidepressant works.
• Medical or hormonal conditions. Thyroid disorders, pregnancy, or age-related changes can affect mood and how your body processes medication.
• Antidepressant tolerance. In some cases, a medication that once worked well may lose its effectiveness over time.
• A possible misdiagnosis. Conditions such as bipolar disorder can look like depression, but often don’t respond well to antidepressants alone.
• The biological complexity of depression. Research shows that depression is biologically complex and far more than just a serotonin imbalance, which helps explain why today’s medications don’t work for everyone.

Identifying which of these factors may apply to you is something a qualified mental health professional can help with. Understanding the “why” is often the first step toward finding what will work better for you.

First things first: don’t stop or change your medication on your own. Suddenly stopping an antidepressant can lead to withdrawal symptoms and, in some cases, make depression worse. Instead, partner closely with your provider. Finding what works best for you is a process, and you don’t have to navigate it alone.

Together, your clinician may explore several options, such as:

• Giving it more time if you’re still early in treatment, since many antidepressants take several weeks to show full benefit.
• Adjusting the dose if it’s too high and causing side effects or too low and not adequately addressing your symptoms.
• Switching to a different antidepressant class that works on other brain pathways.
• Combining antidepressants to target symptoms from multiple angles.
• Adding an augmentation medication, such as an antipsychotic or lithium, to boost response.
• Incorporating psychotherapy, like CBT or talk therapy, alongside medication.
• Addressing lifestyle factors like sleep, stress, or substance use, which can undermine treatment.
• Exploring medication-free treatments like TMS therapy.

Personalized care can take time, but going through a little trial and error on the path to finding the right treatment plan is well worth it in the long run.

When antidepressants alone aren’t enough (or aren’t the right fit), there are still effective, evidence-based ways to treat depression. For many people, especially those with treatment-resistant depression, non-medication options can open the door to real, lasting relief.

Transcranial magnetic stimulation, or TMS, is a noninvasive, FDA-approved therapy that uses targeted magnetic pulses to stimulate brain circuits involved in mood regulation. Most protocols focus on the left dorsolateral prefrontal cortex (an area often underactive in depression).

TMS doesn’t involve anesthesia or systemic medications, and sessions are done while you’re awake. Across studies, about 50–55% of patients respond, with 30–35% reaching remission, even after medications have failed. Side effects are typically mild and short-lived, such as scalp discomfort or a headache, and serious risks are rare.

Newer TMS approaches, including accelerated and individualized protocols, are showing especially promising results. In one Stanford study, an advanced form of TMS led to rapid remission in nearly 80% of people with severe, treatment-resistant depression.

TMS therapy for depression is an excellent option for individuals seeking effective care beyond medication.

If your antidepressant isn’t helping, start with the provider who prescribed it, whether that’s your primary care doctor or a mental health clinician. They can review your symptoms, side effects, and how long you’ve been on the medication. From there, they can guide the next steps.

If depression persists or becomes more complex, it may be time to see a psychiatrist or a specialty clinic with experience in treatment-resistant depression. A thorough evaluation looking at your diagnosis, medication history, medical conditions, substance use, and life stressors matters.

Most of all, advocate for yourself. Ask questions. Seek a second opinion if needed. At TrueNorth IMH, we specialize in advanced depression care, including TMS therapy, and partner with you to find options when standard treatments haven’t been enough.