What Can I Do If Therapy and Meds Aren’t Working for My Depression?

In the U.S., about 7% of adults have at least one major depressive episode annually. About half of these people receive medication. The problem is that depression is a complicated condition, and what works for some people may not work for others. Some people may respond to antidepressants, while about a third of folks may have to cycle through different medications and dosages until they find something that works for them — if at all. 

If you’ve been diagnosed with depression and tried therapy and medication but feel they just aren’t helping, you may be dealing with treatment-resistant depression (TRD). If that’s the case, there are alternative forms of treatment you can try.  While it’s important to stay in communication with your healthcare provider every step of the way.

Let’s review a few alternative treatment options to consider and what the research tells us about how they work.

Failing to respond to depression treatment is more common than you might think. About 30% of people diagnosed with major depressive disorder (MDD) have treatment-resistant depression (TRD), characterized by persistent depressive symptoms despite multiple treatment attempts.  

TRD can be frustrating, especially if you’ve been dealing with depression for a while. Depression treatment varies from person to person, and there can be several reasons why medication isn’t helping, such as the severity of the condition, your genetic makeup and family history, your social situation as well as any comorbid illnesses. 

That’s why it’s important to keep your providers up to date on your efforts—they may decide to change your dose, switch medications, or add another treatment (such as therapy or a second medication) to your care plan. 

Generally, you should stick with your prescribed treatment for six to eight weeks before it’s considered ineffective, although your doctor may change your treatment plan sooner if deemed necessary. Medication and talk therapy are the most common ways to treat depression, but they’re not your only options. 

Other, more extensively studied types of therapy for TRD include transcranial magnetic stimulation, ketamine therapy, and Spravato (esketamine). Here’s what you should know about these treatments.

TMS therapy is a noninvasive (surgery and medication-free) treatment that applies a series of short magnetic pulses to stimulate specific brain regions and ease depressive symptoms. It’s safe, FDA-approved, and has minimal side effects.

TMS therapy begins with an initial evaluation with a healthcare provider. Your doctor will talk about the process and how to prepare for treatment. TMS is an outpatient procedure, which means you’ll go home same-day.

TMS involves the use of a specially designed electromagnetic device. The machine’s magnetic pulses induce small electric currents that change the firing patterns of neurons, which “resets” specific areas of the brain that regulate your mood. The sensation feels like a tapping on your scalp. 

A typical course of treatment involves daily TMS sessions over four to six weeks. People typically feel better after 10 to 15 sessions. 

TMS has been shown to be at least twice as effective as standard treatments for TRD. Patients typically feel relief from their symptoms anywhere from six months to several years. In a review examining the efficacy of TMS for MDD, patients receiving TMS were more than five times as likely to achieve remission from depression than those receiving a placebo. 

TMS therapy is FDA-approved for the treatment of depression and obsessive-compulsive disorders, and it is covered by insurance if it’s deemed a medically necessary form of treatment.

Ketamine is a dissociative anesthetic, which means that it makes people feel detached from their body and environment in doses used for pain and sedation.  It has a long history as a surgical anesthetic and analgesic (pain relief) medication that’s used for adults, children, and animals. 

As an off-label use, ketamine has been consistently proven over more than 20 years of peer reviewed research to help treatment-resistant conditions like depression and alleviate suicidal ideations. Ketamine works quickly, which is one of the reasons it’s so sought after as a mental health treatment: while other treatment options can take weeks to take effect, many patients can feel ketamine’s effects within an hour.

Ketamine works in two important ways in patients with TRD.   It has unique effects on the neurotransmitter glutamate, which is a major messenger throughout your central nervous system. It primarily works by allowing glutamate levels to temporarily increase in your brain, which may have downstream effects that contribute to ketamine’s antidepressant effects. 

Ketamine also works on chemicals in your brain called BDNF and VEGF.  These chemicals increase connections between neurons.  It is theorized that these “growth factors”  allow your brain to create new pathways for managing things like your emotions and mood.  

Ketamine therapy generally takes place at an outpatient facility and is available in several forms, including intravenous (IV) infusion, intramuscular injection, sublingual (under the tongue) liquid, and lozenges. Nobody loves needles, but IV injections have been shown to have the most rapid effects on mood disorders.

Treatment begins with an initial evaluation to set expectations and help you prepare for your session. Ketamine infusion therapy generally involves a series of six infusions over several weeks, depending on your response, your provider may adjust your treatment plan in consultation with your psychiatrist or primary care provider. During your session, you’ll feel relaxed, detached, and calm. 

Ketamine is generally considered safe: in 2019, National Institutes of Health researchers found that a low-dose ketamine infusion had minimal side effects among patients with TRD.

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Evidence suggests that ketamine is a promising treatment option for TRD. In 2014, researchers found that ketamine’s dissociative side effects predicted a more robust and sustained antidepressant response among 108 participants. Separate studies have also found that ketamine effectively reduces suicidality among people with TRD and significantly improves depressive symptoms within hours after administration.

Health insurance generally doesn’t cover ketamine therapy because it’s not FDA-approved for the treatment of mood disorders, so patients generally have to pay out-of-pocket.

Nasal spray targeting NMDA receptors to rapidly relieve severe depression.

Spravato is the brand name for esketamine, a derivative of ketamine. In 2019, the FDA approved Spravato for the treatment of TRD and suicidal ideation when combined with an oral antidepressant. 

Spravato is a nasal spray that targets specific landing pads in your brain called NMDA receptors. Like ketamine, esketamine allows glutamate to temporarily increase in the brain. Ketamine’s antidepressant effects may stem from the way it impacts other chemical messengers and pathways in the brain. In contrast, esketamine’s effects are primarily focused on those NMDA receptors and glutamate. 

During a dosing session, patients administer the nasal spray themselves under a licensed provider’s supervision. Spravato contains 28 milligrams of esketamine, and the patient uses two to three devices per treatment. Esketamine’s effects peak after about 40 minutes, and sessions take about two hours from start to finish. Treatment usually lasts for eight weeks, one to two times per week.

Esketamine is generally considered safe. Potential side effects include headache, dizziness, and dissociation. 

Studies have shown that esketamine can improve depressive symptoms and help maintain these improvements long term. One 2023 study focusing on esketamine’s effects in patients with TRD found that almost half of patients were in remission after one year of treatment. 

Unlike ketamine, Spravato is more commonly covered by insurance because it’s FDA-approved for TRD when combined with an oral antidepressant. Talk to your doctor if you’re interested in learning more about Spravato.

Medication and therapy are life-saving interventions that can help people manage and recover from depression. However, it’s also worth considering your lifestyle as part of your overall care plan and complementing your treatment with habits and practices that support your health.