What To Do When Antidepressants Don’t Work: Options to Explore

If antidepressants didn’t work for you, you’re not alone. And you’re not out of options. There are many effective alternative treatments for depression, including the ones below which are all evidence-based and offer unique benefits. Many also have fewer side effects, making them a more attractive option than “treatment as usual.”

Antidepressants are one of the most commonly prescribed medications for depression. If your psychiatrist prescribed one (or a few), you probably started off with hope, perhaps fuelled by a friend’s success story or positive reviews online. 

Yet that optimism can turn into discouragement if the antidepressants don’t work, as is the case for 30-50% of people with major depressive disorder (MDD). The good news is there are alternative treatments for depression worth exploring.

And before we get too far into this, let’s clarify what alternatives to antidepressants we’re talking about. Owen Muir, MD, DFAACAP, an interventional psychiatrist and the co-founder and Chief medical officer of Radial, states that the term “alternative treatments” is used by many people to describe any options other than standard medications. Some of these are backed by many peer-reviewed studies while others are supported by limited evidence, if any. In this article, we’re focusing on depression treatment options that fall into the research-backed camp.

“Traditional daily oral medications like SSRIs are not the best option for all people, based on the data,” says Dr. Muir, “In some people, they work fabulously well but come with trade-offs like adverse side effects, and they offer limited effectiveness in many other cases. Our goal is to help people find the most effective treatments for them.”

Why antidepressants don’t always work

Antidepressants consist of a few drug classes, with selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) being the most commonly prescribed. 

These medications work by blocking reuptake pumps that clear mood-regulating neurotransmitters. When these neurotransmitters are cleared more slowly, as is the case when on these medications, it improves the way your brain regulates mood, although the full effects take weeks to show up.

These medications are often a psychiatrist’s go-to treatment for depression, mainly since they were the first (moderately) effective treatment option scientists discovered. The STAR*D study, one of the largest studies on major depressive disorder, further backed up these drugs when it suggested 67% of patients who tried four or fewer antidepressants experience remission, after 2 years of stepped treatment. 

That study, however, has been criticized for using methods that produced inflated estimates of remission. When researchers took a fresh look at STAR*D data, they placed the cumulative remission rate closer to 35% after treatment with multiple antidepressants. Even more eye-opening, about 30-50% of people with major depressive disorder experience no reduction in symptoms on antidepressants at all.

When this occurs, someone is said to have “treatment-resistant depression,” but this term is somewhat deceptive. As Dr. Muir points out, saying depression is “treatment resistant” because it doesn’t respond to antidepressants is like saying physical pain is treatment resistant if it doesn’t respond to Tylenol. 

Your brain operates through multiple neural circuits and neurotransmitter systems. When antidepressants don’t work, it’s just a sign that you need to explore treatments that approach depression differently or target different parts of the brain.

Neuromodulation therapies

The brain contains billions of neurons, a number which is far too big for my math-challenged mind to comprehend. These neurons help us with many things, but like an easily distracted college intern, they sometimes need a nudge in the right direction. When the neurons that support mood regulation need some help, your psychiatrist may turn to neuromodulation therapies. 

Transcranial magnetic stimulation (TMS)

Transcranial magnetic stimulation (TMS) is one of the most studied neuromodulation therapies. As if that wasn’t reason enough to consider TMS, it’s also non-invasive, doesn’t require you to undergo anesthesia, and the most effective type, Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), has a much higher remission rate than any traditional antidepressant in treatment resistant depression. 

But I’m getting ahead of myself by listing all these benefits when we haven’t discussed what TMS is. For this treatment, an electromagnetic device, usually in the shape of a cap or paddle, that rests close to your scalp. This cap houses a coil that delivers targeted magnetic pulses into the skull, inducing tiny electrical currents in specific regions of the brain. These currents help fine-tune the activity of mood-related neurons, producing changes in neural pathways.

TMS is delivered in sessions which usually last, in our modern era, fewer than ten minutes. With traditional TMS, you undergo one session a day for up to six weeks. For SAINT TMS or accelerated TMS, you participate in multiple sessions a day for up six days. 

And back to how effective it is, because that’s a point worth harping on: in one study, over 81% of those with MDD improve after 30 sessions of deep TMS. In many of these cases, MDD goes completely into remission. Alongside its high efficacy rate, TMS also has relatively few side effects. Mild scalp pain and headaches are the most commonly reported, though they often go away shortly after treatment. 

Key facts

• FDA status: For treatment resistant depression, Standard TMS has been FDA-cleared since 2008; SAINT TMS has been cleared since 2022, and SWIFT accelerated deep TMS since 2025.
• Success rate: Both SWIFT and SAINTS-TMS boasts a 60-80% remission rate
• How long it takes to work: Variable, Six days to six weeks, depending on TMS type
• Cost & insurance: Treatment can cost up to $36,000 but insurance brings down the cost greatly. At Radial, when insurance covers the TMS, patients most commonly pay a $10-$50 copay each day of treatment.  Some plans also require co-insurance, so it’s worth checking your insurance plan.

Vagus nerve stimulation (VNS)

Depression isn’t all in your head; for many it also takes the shape of digestive issues, lower heart rate variability, and other symptoms our bodies physically feel. This is a result of the mind-body connection or, to put it in medical terms, the link between the brain and parasympathetic nervous system (PNS), which regulates our body when we’re in rest and digest mode (aka not in a situation that causes fight-or-flight panic). 

Evidence keeps piling up that the PNS also plays a role in mood regulation and the development of depressive symptoms. Its role in how we feel may be another reason why antidepressants don’t always work, since these medications target neurons in the brain, not any part of the PNS system directly (though they can have downstream effects).

And one of the best ways to help the PNS play a more supportive role in how you feel? Target the communication line between the brain and PNS, aka the vagus nerve. This main nerve of your 'rest and digest' system is like a highway between your brain and body, delivering messages back and forth that help the mind and nervous system regulate how you feel, both emotionally and physically. 

Vagus nerve stimulation (VNS) essentially gives this nerve the “road work” it needs to improve this communication. For this treatment, a doctor inserts an implantable pulse generator that is wired to the vagus nerve. The device then sends currents up and down the nerve, influencing mood regulation. 

VNS can cause some side effects, including voice alteration, hoarseness, tingling, and a cough, and it’s often more expensive and less accessible than other treatments, like TMS. Not to mention it’s implanted surgically, which is usually done when a patient is under a general anaesthetic and requires recovery time after the procedure. 

Key facts

• FDA status: FDA-approved in 1997 drug resistant epilepsy; approved for treatment resistant depression specifically in 2005
• Success rate: Over 53% of patients see a reduction in depressive symptoms
• How long it takes to work: Between three to twelve months 
• Cost & insurance: High cost and not universally covered by insurance

Transcranial direct current stimulation (tDCS)

Transcranial direct current stimulation (tDCS) not only starts with the same word as TMS, but the device used looks similar too. Like TMS, the treatment is delivered through a cap placed on the scalp. Unlike TMS, tDCS uses scalp electrodes, which sit on your head and are connected to a nine volt battery. That battery sends electrical currents to targeted regions of the brain, with the aim of producing changes in neural circuits. 

The whole battery thing makes this treatment sound a bit offbeat, but early evidence suggests it may help reduce depressive symptoms. It’s also less costly than TMS, making it an attractive option for many.

If all this sounds vague, it’s because tDCS is newer. There’s still many clinical trials underway to determine if it’s a viable option, including some that are testing at-home devices. So far, reported side effects include nervousness, tinnitus, and redness or itchiness where the cap meets the scalp.

Key facts

• FDA status: Not FDA-cleared and currently in clinical trials
• Success rate: Undetermined since still in clinical trials
• How long it takes to work: Many trials deliver the treatment over 6 weeks
• Cost & insurance: Less costly than TMS but not covered by insurance since it isn’t currently FDA-cleared

Electroconvulsive therapy (ECT)

Electroconvulsive therapy is one of the oldest treatments for depression—and one that’s sometimes stigmatized. Admittedly, the history of “shock therapy” is a lot to process. “ECT was invented before antidepressants and before we had anesthesia,” explains Dr. Muir, “And ECT without anesthesia sucks because you're inducing a seizure.” 

With anesthetic drugs, ECT is an entirely different experience. In its current form, this treatment delivers dosed electrical currents to induce a controlled seizure while the patient is under anesthesia. Modern  medication makes today’s ECT a safe, humane, and effective treatment for MDD. 

Key facts:

• FDA status: Various ECT devices have been FDA-cleared for severe major depression 
• Success rate: Offers a remission rate between 63% and 78% in some studies
• How long it takes to work: Typically administered three times a week for two to four weeks 
• Cost & insurance: Can cost up to $15,000, though insurance helps cover costs

eCOT-AS, aka ProLiv^TMRx 

So far, most of the treatments we’ve discussed require you to go into a clinic or hospital. If you’re looking for an at-home option, eCOT-AS, more commonly known as ProLiv^TMRx, may be worth exploring.  

This device works differently compared to TMS ( it’s worn as a headband and produces changes in neural pathways using electrical stimulation). It specifically targets occipital nerves, which are at the back of your head, and trigeminal nerves, which are the sensory nerves on the forehead. Both are involved in mood stimulation, and early results suggest ProLiv^TMRx is more effective than a sham for MDD and has an excellent safety profile. 

Before we get too excited, this treatment is still awaiting FDA approval, and we’ll probably know more about its success rate in 2026.

Key facts:

• FDA status: Has FDA-breakthrough status, meaning it’s on the fast track for review but doesn’t yet have approval
• Success rate: Boasts a remission rate of 32%
• How long it takes to work: Treatment usually lasts eight weeks in clinical trials 
• Cost & insurance: Uncertain since it’s still moving through the FDA, but may be more affordable since it’s an at-home device

Fast-acting medications (non-SSRI)

There’s also a wide world of medications beyond typical SSRIs and SNRIs, many of which are faster acting. To determine if you’re a good candidate for any of the drugs listed below, consult a psychiatrist. 

Esketamine (Spravato)

Esketamine (brand name Spravato), is a newer medication for depression, administered as a nasal spray. Psychiatrists, such as the team at Radial, may recommend this medication for those with treatment-resistant MDD. It produces a similar antidepressant effect compared to traditional antidepressants, but works faster and has a different side-effect profile 

“Esketamine helps nerves connect together and get rewired in those brain circuits similar to SSRIs,” says Dr. Muir.. 

Key facts:

• FDA status: FDA-approved for treatment resistant depression and acute suicidality since March 5th, 2019.
• Success rate: Significantly reduces depression.
• How long it takes to work: Administered twice per week for the first four weeks, once weekly in weeks five through eight, and once every other week after as a maintenance dose
• Cost & Insurance: Up to $1,365 per week if using self-pay, though insurance often helps cover costs

Psilocybin

Psilocybin, a compound found in psychedelic mushrooms, may help reduce depressive symptoms because of its fast-acting impact on how the brain regulates mood. 

Earlier trials suggested psilocybin sends over 50% of patients into remission, but larger trials have since challenged that claim, placing the MDD remission rate closer to 25%. That said, an additional 29% of people in those bigger trials experienced a reduction in symptoms without full remission. Even though the bigger trials may offer more data than the smaller ones, psilocybin still has a long way to go (and requires many more high quality clinical studies) before it’s a go-to option for treating MDD.

Key facts:

• FDA status: Some forms have been granted FDA-breakthrough status, but none are currently approved 
• Success rate: In the largest trials, 25-29% of MDD cases went into full remission; other trial participants experienced reduced symptoms
• How long it takes to work: Trials show some reduction in symptoms in as little as four weeks
• Cost & insurance: Not yet FDA-approved or commercially available, with limited exemptions in Oregon and Colorado. 

MDMA

While ecstasy has a reputation as a party drug, its main ingredient, MDMA, has earned a place in medical research—though it’s worth noting that many reported results from clinical trials suggesting MDMA helps with conditions like PTSD have since been retracted. 

When it comes to depression, MDMA is also a mixed bag: some studies suggest it exacerbates symptoms while others propose it has antidepressant qualities. Our take? It’s probably best to wait and see if  future research points to  MDMA-assisted therapy as a viable depression treatment. 

Key facts:

• FDA status: Not FDA-approved
• Success rate: Trials suggest mixed results on if it helps depression or not
• How long it takes to work: Not yet determined by clinical trials
• Cost & insurance: Not commercially available, so no set cost 

LSD

LSD is another psychedelic treatment option. Unlike others (i.e. psilocybin), it has a special chemical structure that makes it incredibly potent, which means you only need a teeny-tiny amount for it to work. 

While LSD primarily targets receptors that release serotonin, the brain’s “happiness chemical,” it isn’t in a monogamous relationship. Instead, LSD dates around, affecting other receptors, including the ones that impact dopamine. When LSD influences serotonin and dopamine signaling, it may alter perception and cognition, potentially reducing depression and causing a neural resetting, though these effects remain under investigation.

Key facts:

• FDA status: Some versions of LSD have been granted FDA-breakthrough status, but none are FDA-approved
• Success rate: 77% of patients experiencing anxiety associated with terminal or life-threatening illness reported fewer depressive symptoms one year after treatment
• How long it takes to work: Works quickly, with results lasting up to sixteen weeks after one treatment 
• Cost & insurance: Not commercially available since it’s not FDA-approved

Brexanolone (Zulresso)

Brexanolone is an IV infusion that can be helpful for people with postpartum depression. It works on GABA receptors that regulate hormones. It’s not FDA-approved for other uses, since it doesn’t impact neurotransmitters like serotonin, which play a bigger role in other types of depression. 

Key facts:

• FDA status: FDA-approved since 2019 for postpartum depression
• Success rate: Less than 50% experience remission right after the infusion but over 82% report fewer symptoms within 30 days
• How long it takes to work: Over 60 hours in an inpatient setting
• Cost & Insurance: Up to $34,000, though insurance may help cover costs

Zuranolone 

While Brexanolone is effective, it's also expensive and complex to deliver—not everyone can go to the hospital for an IV infusion, especially when postpartum. There is an oral version of the medication, Zuranolone, though it hasn’t proven as effective in clinical trials.

Key facts:

• FDA status: FDA-approved since 2023 for postpartum depression
• Success rate: About 40% experience remission, which is lower than with Brexanolone
• How long it takes to work: At least 15 days of taking the medication
• Cost & Insurance: Up to $15,902, though insurance may help cover costs

Bupropion (Wellbutrin)

While SSRIs target serotonin receptors, bupropion (brand name Wellbutrin) targets dopamine and norepinephrine receptors, making it a unique option in the depression treatment toolkit. Its effect on these receptors can help change neural pathways, reducing the likelihood of depressive thoughts.

Key facts: 

• FDA status: FDA-approved for depression since 1985
• Success rate: Similar to more traditional antidepressants 
• How long it takes to work:  Wellbutrin usually starts improving energy and motivation within 1–2 weeks, but full antidepressant effects may take 4–6 weeks.
• Cost & insurance: From $86-351 without insurance on average, though insurance often covers some costs

Auvelity (bupropion/dextromethorphan) 

Auvelity is made up of two main active ingredients: bupropion (which we covered in the Wellbutrin section) and dextromethorphan. 

Dextromethorphan is actually the active ingredient in cough syrup, but it’s currently having a second life thanks to its effect on mood regulation. It’s an NMDA antagonist, meaning it impacts NMDA receptors.  Auvelity turns down the volume, reducing depressive symptoms. 

Key facts: 

• FDA status: FDA-approved for MDD since 2022
• Success rate: Remission rates are as high as 70%, and response rates as high as 80% in some clinical trials
• How long it takes to work:  Auvelity can start improving depressive symptoms within the first week, with full effects typically developing over 4–6 weeks.
• Cost & insurance: As high as $583 for 30 tablets, though insurance can help cover costs

Psychotherapy 

Alongside antidepressants, psychotherapy—which is psychology speak for talk therapy— is probably one of the most common mental health treatments. Therapy does work, though often alongside other treatments. In fact, what therapy is really good at is helping someone build a life after the depressive symptoms go away.

“When you've been living with depression or a mood disorder for years, you're going to make different choices,” says Dr. Muir, “So a lot of the work in therapy after these treatments is about how to reset your expectations for what your life could consist of now that depression is gone.”

Many types of therapy for depression can be helpful for this, but some of the most common therapies for depression include:

• Mentalization-Based Treatment (MBT): Explores how mental states and interpersonal relationships impact your thoughts and emotions.
• Cognitive Behavioral Therapy (CBT): Helps you identify and reframe negative thought patterns.
• Behavioral Activation: A type of therapy where you and your therapist work on boosting your engagement with healthy activities, especially those you find fulfilling or fun.
• Interpersonal Therapy (IPT): Focuses on relationship improvement and can be especially useful if depression stems from social interactions or close relationships.

Key facts:

• FDA status: Not necessary
• Success rate: One third of MDD cases go into remission with talk therapy alone, though success is higher when it’s combined with other treatments 
• How long it takes to work: Depends on the individual 
• Cost & Insurance: The average session cost is $143.26. If using insurance, your out-of-pocket cost will probably be lower.

Lifestyle-based approaches

Like therapy, lifestyle changes are a great way to treat depression and to rebuild once depression is in remission or symptoms are starting to go away.

Exercise

I’ve been a runner my whole life, and whenever I feel stressed or sad, my go-to response is to strap on my sneakers and (literally) run away from my problems. Turns out, physically running away actually helps. 

Exercise helps better modulate levels of serotonin and norepinephrine, two neurotransmitters that help regulate mood. When we sweat it out, we’re boosting these neurotransmitters and reducing depressive symptoms, which definitely explains why we experience a post-workout glow or runner’s high. Exercise also reduces inflammation, and a less inflamed brain often functions better (and that includes being more on top of mood regulation). 

Before you panic about having to run, that isn’t the only workout type that provides these benefits. Strength training, yoga, and even walking provided moderate relief to depressed patients. If unsure where to start, try a walk around the block. It’s got excellent data, also.

Key facts:

• FDA status: Not necessary.
• Success rate: Exercise reduces depression compared to no action at all or alongside other treatments 
• How long it takes to work: Depends on the individual 
• Cost & insurance: Varies based on exercise type with gym and/or yoga studio memberships, exercise equipment, and workout clothing being notable costs 

Mindfulness and meditation

Meditation and other mindfulness practices, like breathwork or mindful eating, calm the amygdala (the part of your brain that controls fear-based responses) and strengthen the prefrontal cortex (the part that helps you make logical decisions). These neurochemical changes may help reduce depressive symptoms.

On a more practical level, mindfulness helps us slow down. When we’re in the moment, we can detach from our thoughts. Mindfulness practices can even make space to change thoughts of “I am depressed” to “I am experiencing sadness right now.” 

Key facts: 

• FDA status: Not necessary
• Success rate: Reduces depressive symptoms, though may not work as well as a standalone treatment
• How long it takes to work: Varies, though it’s often recommended as a lifelong mental health booster
• Cost & Insurance: Can be free if used at-home

Nutrition and anti-inflammatory diets

Remember how exercise reduces inflammation? A well-balanced diet can lower it too. One study found that an inflammatory diet increases the risk of depression by 49% in women and 27%  in men, while an anti-inflammatory diet decreases the risk of depression and anxiety.

Anti-inflammatory food groups include:

• Fish
• Fish or olive oil
• Walnuts, almonds, and other nuts
• Tomatoes
• Green leafy vegetables, such as kale or spinach
• Whole grains like quinoa or brown rice
• Fruits like strawberries, cherries, and oranges

Key facts: 

• FDA status: Not required
• Success rate: Best used as alongside other treatments or as a prevention against depression
• How long it takes to work: Best used as a life-long tactic 
• Cost & Insurance: Varies depending on grocery costs where you live

Supplements

There is worthwhile evidence that some supplements moderately reduce depressive symptoms, though some and moderate are key words here. Three with the most evidence to support their use for mild to moderate depression are lavender oil, deplin (l-methylfolate), and magnesium. Deplin may even work to improve antidepressant responses, making it a great choice alongside medication. 

I’ve been recommended lavender for when I feel anxious or stressed by my therapist, but it turns out it works for depression too. A 2025 study shows silexan, an essential oil version of lavender, may reduce symptoms and improve cognitive functioning for those with mild to moderate depression. However, it’s important to remember that lavender’s effects are modest, with other studies suggesting lavender has a small but inconsistent effect on depression.

Magnesium is an essential mineral already found in small traces in the human body. For the past few decades, researchers have suspected that higher amounts of magnesium correlate to a reduced likelihood of experiencing depression. A groundbreaking 2017 study comparing magnesium to a placebo found that a magnesium supplement helped with mild to moderate depression within two weeks with minimal side effects. In fact 60.1% of those in the study said they would take magnesium in the future.

What popular supplement may help with mild or moderate depression but not for major depressive disorder? St. John’s Wort. While this supplement is a common depression remedy, popular doesn’t always mean beneficial. St. John’s Wort produces inconsistent effects in those with MDD and may interfere with prescribed medications, meaning it’s often best swapped for another supplement if you have MDD or take medication for depression.

Key facts:

• FDA status: Most are listed as dietary supplements by the FDA, not FDA-approved medications
• Success rate: Differs depending on severity of depression and supplement
• How long it takes to work: Varies depending on the supplement
• Cost & Insurance: Depends on the exact supplement, though they are usually more affordable than prescription drugs. Insurance will not cover them.

The bottom line

If there’s anything you should get out of this comprehensive list, it’s that you have options, even when the most commonly prescribed antidepressants don’t work. Neuromodulation therapies, medications that act faster than SSRI’s, psychotherapies, and lifestyle changes all play a role in depression success stories and allow people to rebuild a life full of joy and purpose. 

Key takeaways

• Antidepressants don’t work for 30-50% of those with major depressive disorder, but there are treatments with a higher success rate. 
• Other options include neuromodulation therapies, medications that act faster than traditional antidepressants, psychotherapies, and lifestyle interventions.
• Finding the right treatment is a highly individualized journey, but you don’t have to go it alone. A psychiatrist, like the ones at Radial, can help you navigate your options and decide what’s the best depression treatment plan.

Frequently asked questions (FAQs) 

What is the best treatment for depression?

The best treatment option often depends on the individual and what’s causing their depression, which can only be determined through psychiatric or psychological evaluation. That said, some treatment options that are more effective than standard antidepressants like SSRIs include TMS, vagus nerve stimulation, Spravato, and Auvelity. 

Is depression curable?

Depression can be curable in many cases. The key to sending depression into remission is often finding the right treatment for you. Some options, like SAINT TMS, have remission rates as high as 60-80% in clinical trials. 

Deep dive recommendations

• Radial. What is TMS? 
• American Journal of Therapeutics. Psychedelic Therapy: A Primer for Primary Care Clinicians—Ketamine.
• The Frontier Psychiatrists. Does "Psychedelic-Assisted Therapy" Have Supporting Evidence?
• The Frontier Psychiatrists. Bupropion.
• The Frontier Psychiatrists.  Hold Me Closer, Robitussin: is Auvelity (dextromethorphan/bupropion) something new in depression treatment?
• The Frontier Psychiatrists. Walking, Revisited. 
• The Frontier Psychiatrists. Essential Oils for Depression: Yes, Really.
• The Frontier Psychiatrists. Magnesium. 

The Frontier Psychiatrists. Essential Oils for Depression.