Depression is treated with medication, psychotherapy, or a combination of both, and the best approach depends on how severe your symptoms are and how you respond to initial treatment. Combining medication with therapy improves remission rates by about 10% over either one alone, making it the most effective strategy for most people. Beyond these core treatments, exercise, brain stimulation, and newer rapid-acting options like nasal spray esketamine are expanding what’s available, especially for people who haven’t responded to standard approaches.
Antidepressant Medications
The most commonly prescribed antidepressants are SSRIs, which work by keeping more serotonin available between nerve cells in the brain. Serotonin is a chemical messenger involved in mood regulation, and SSRIs block its reabsorption so it stays active longer. These are typically the first medication a doctor will try because they tend to have fewer side effects than older classes of antidepressants.
If SSRIs don’t work well enough, the next step is often an SNRI, which works similarly but also increases norepinephrine, another brain chemical tied to energy and alertness. Other options include older drug classes like tricyclics and MAOIs, which affect a broader set of brain chemicals and are usually reserved for cases where newer medications haven’t helped.
One important thing to know: antidepressants don’t work immediately. Physical symptoms like sleep disruption and appetite changes often improve within the first week or two, but the emotional lift, the actual improvement in mood, typically takes four to six weeks at a full dose. This lag is one of the most common reasons people stop taking medication too early, assuming it isn’t working. For people who haven’t responded to at least one adequate medication trial, response rates drop to roughly 50% to 60%, which is why switching medications or adding a second treatment is common.
Psychotherapy
Two forms of therapy have the strongest evidence for depression. Cognitive behavioral therapy (CBT) helps you identify and change thought patterns that reinforce depressive feelings. It’s structured, usually runs 12 to 20 sessions, and focuses on building practical skills you can use between appointments and after therapy ends. In one major trial of people who hadn’t improved on medication alone, adding CBT more than doubled the response rate after six months (46% vs. 22%).
Interpersonal therapy (IPT) takes a different angle. Instead of targeting thought patterns, it focuses on your relationships and social functioning, working through problems like grief, conflict, role transitions, or isolation that may be feeding your depression. A large meta-analysis found IPT produced meaningful improvements in social functioning and significant reductions in both depression and anxiety symptoms. IPT was originally developed for adults but has been adapted for adolescents as well, since relationship difficulties and developmental transitions often overlap in that age group.
Both CBT and IPT are time-limited, meaning they’re designed to produce results within a set number of sessions rather than continuing indefinitely. Other approaches, including psychodynamic therapy and behavioral activation, also have evidence supporting their use, though the research base is smaller.
Combining Medication and Therapy
Using both medication and therapy together consistently outperforms either one on its own, though the advantage is modest in mild to moderate cases. Across multiple meta-analyses, combination treatment raises remission rates by about 10 percentage points. Where the combination really shines is in chronic or more severe depression. In one landmark study of patients with chronic depression, combination treatment achieved a 48% remission rate compared to 29% for medication alone and 33% for therapy alone.
For milder depression, starting with therapy or medication alone is reasonable. But if you haven’t improved after two to three months on a single treatment, adding the other modality is one of the most evidence-backed next steps available.
Exercise as Treatment
Exercise is not just a lifestyle recommendation. A large systematic review published in The BMJ found that physical activity produces clinically meaningful reductions in depressive symptoms, with effects proportional to intensity. Vigorous exercise like running or interval training had the strongest effects, but even light activity like walking or yoga still produced significant benefits.
Shorter programs around 10 weeks appeared to work somewhat better than longer ones stretching to 30 weeks, though the researchers noted high uncertainty in that finding. The optimal weekly “dose” of exercise wasn’t clearly defined, but the pattern was consistent: more intense activity correlated with greater improvement. For people with mild to moderate depression, exercise can be a standalone treatment. For more severe cases, it works best alongside medication or therapy.
Treatment-Resistant Depression
If you’ve tried two different antidepressants at adequate doses for six to eight weeks each without meaningful improvement, you meet the clinical definition of treatment-resistant depression, or TRD. This isn’t rare. Roughly one-third of people with major depression don’t respond adequately to first-line treatments.
The standard approach at this stage involves augmentation, adding a second medication to boost the effect of the first. This might mean pairing an antidepressant with a low dose of a different class of medication. The challenge is that stacking multiple medications increases side effects and treatment burden without always producing the expected benefit.
Esketamine Nasal Spray
For treatment-resistant depression, the FDA has approved an esketamine nasal spray that works through an entirely different brain system than traditional antidepressants. Rather than targeting serotonin or norepinephrine, it acts on glutamate signaling, which can produce noticeable mood improvements within hours to days rather than weeks.
The tradeoff is that it requires significant supervision. You can’t pick up this medication at a pharmacy and use it at home. Every dose must be administered in a certified healthcare setting, and you’ll be monitored for at least two hours afterward because of risks including sedation, dissociation (a feeling of being detached from yourself), and blood pressure spikes. During the first month, sessions happen twice per week, then taper to once weekly and eventually every two weeks. You can’t drive until the next day after a restful sleep, and you need to avoid eating for two hours before each session.
The same medication is also approved for adults with major depression who are experiencing acute suicidal thoughts, making it one of the few treatments specifically indicated for that situation.
Brain Stimulation Therapies
Several non-medication, non-therapy options exist for depression that hasn’t responded to standard treatments. Transcranial magnetic stimulation (TMS) uses magnetic pulses delivered through a device placed against the scalp to stimulate nerve cells in brain regions involved in mood regulation. It’s done in an office setting, requires no anesthesia, and typically involves daily sessions over four to six weeks.
Electroconvulsive therapy (ECT) remains one of the most effective treatments for severe, treatment-resistant depression. It involves brief electrical stimulation of the brain under general anesthesia, usually two to three times per week for several weeks. Despite its reputation, modern ECT uses much lower electrical currents than historical versions and is considered safe, though short-term memory issues during the treatment course are common. Response rates for ECT are higher than for most other interventions, making it a strong option when other treatments have failed.
What a Typical Treatment Path Looks Like
Most people start with either an SSRI, therapy, or both, depending on symptom severity and personal preference. Mild depression may respond to therapy or exercise alone. Moderate to severe depression usually warrants medication, therapy, or the combination. You should expect to give any antidepressant a full trial of four to six weeks before judging whether it’s working, and your doctor may adjust the dose during that window.
If the first approach doesn’t work, the next steps typically include switching to a different medication, adding therapy if you started with medication alone, or augmenting your current medication with a second one. If two full medication trials fail, you enter treatment-resistant territory, where options like esketamine, TMS, or ECT become appropriate. The key takeaway is that not responding to the first treatment is common and expected, not a sign that depression is untreatable. Most people eventually find an approach that works, though it can take patience and several adjustments to get there.