Medications for depression
What medications are used for depression, how prescribers pick among them, and what to do when the first one doesn't work.
First-line options
SSRIs
SSRIs are the default for a reason. They work for depression, they work for the anxiety that so often comes along with depression, and the side effect profile is manageable for most people. Within the class, sertraline and escitalopram have the best combined evidence and tend to be the two most prescribers reach for first.
Escitalopram is often the more tolerable of the two. Sertraline has more data across anxiety indications, so it earns a slight edge when depression sits alongside panic, PTSD, or social anxiety.
Fluoxetine has the longest half-life in the class, which is helpful for people who miss doses and less helpful when it's time to switch to something else. Paroxetine works, but it's the most sedating, has the most weight gain, and the discontinuation syndrome when it's stopped abruptly can be rough. It's not usually first pick anymore. Citalopram is fine, though the FDA QT warning caps its dose at 40 mg for most adults and 20 mg for older adults, which limits headroom.
For a full walkthrough of the class, see the SSRI class page.
SNRIs
The SNRIs cover depression plus anxiety, and they add a norepinephrine effect that can help with fatigue and pain. Venlafaxine at doses over 150 mg starts to hit norepinephrine, which is where the class name earns its keep. Duloxetine is the mainstay when depression comes with chronic pain, diabetic neuropathy, or fibromyalgia, all of which it carries FDA approval for.
Desvenlafaxine is essentially the active metabolite of venlafaxine and skips one CYP step, which can help in people on other medications that would interfere. Levomilnacipran is more noradrenergic than the others in the class and has a niche when fatigue and energy are the leading symptoms.
Blood pressure can go up on SNRIs, especially venlafaxine at higher doses. It's worth checking. See the SNRI class page.
Atypical antidepressants
Bupropion is the outlier that solves a lot of problems. It doesn't hit serotonin, so sexual side effects and weight gain aren't part of the deal. It's activating rather than sedating, which suits fatigue and low energy. And it does double duty for smoking cessation. The catch is that it lowers the seizure threshold, so it's off the table in active eating disorders and untreated seizure disorders.
Mirtazapine sits at the other end. It's sedating, it stimulates appetite, and it works for depression with insomnia, poor appetite, and anxiety in one shot. It's especially useful in older adults who need weight and sleep, and less useful in anyone worried about either.
Both are considered first-line in most guidelines, though bupropion isn't the pick when anxiety is prominent because it can worsen it early on.
Second-line and augmentation
Newer atypicals
Vortioxetine has SSRI-like activity plus effects on several other serotonin receptors. The pitch is fewer sexual side effects and some cognitive benefit, though the cost is higher and nausea is the common early side effect. Vilazodone is similar in spirit and needs to be taken with food to be absorbed properly.
Both are reasonable options when an SSRI has partially worked but the side effects were the problem.
TCAs
The tricyclics still work for depression. Nortriptyline is the most tolerable of the class and has established evidence for depression and neuropathic pain. Amitriptyline works but is more anticholinergic and sedating. Desipramine is more noradrenergic and less sedating.
TCAs earn their spot in treatment-resistant depression and in patients with comorbid neuropathic pain or migraine. The reasons they're not first-line: anticholinergic burden, cardiac risk in overdose, and weight gain. In older adults, most of the class shows up on the Beers Criteria list.
Augmentation with atypical antipsychotics
When an antidepressant is partially working and the patient can tolerate it, adding a low-dose atypical antipsychotic is one of the better-supported next steps. Aripiprazole at 2 to 15 mg is FDA-approved as an adjunct. Brexpiprazole at 1 to 3 mg has the same approval and tends to be slightly less activating. Cariprazine at 1.5 to 3 mg is approved as well and has some data on the anhedonia end of the spectrum. Quetiapine XR at 150 to 300 mg is FDA-approved for depression augmentation and is heavily sedating, which cuts both ways.
Metabolic monitoring matters for all of them. Weight, waist circumference, fasting glucose, lipids. See the antipsychotic class page for the monitoring cadence.
Lithium and thyroid
Lithium at 600 to 900 mg (target level 0.4 to 0.8 mEq/L) has decades of evidence as an antidepressant augmentation strategy, and it has the added benefit of reducing suicide risk. It's underused. The tradeoffs are the blood monitoring, the renal and thyroid effects over years, and the narrow therapeutic index.
Liothyronine (T3) at 25 to 50 mcg is the other classic augmentation strategy. The STAR*D trial found T3 and lithium roughly comparable as third-step augmentations, with T3 being better tolerated.
Ketamine and esketamine
Esketamine nasal spray is FDA-approved for treatment-resistant depression and for depression with suicidal ideation, given in a monitored REMS setting. Racemic IV ketamine is used off-label at many centers with similar effect. Onset is hours to days rather than weeks.
The catch: it wears off. Maintenance dosing is required to hold the response, and long-term effects on bladder and cognition with repeated use are still being sorted out. Not the first thing tried, but earlier in the algorithm than it used to be.
Dextromethorphan-bupropion
Dextromethorphan-bupropion (Auvelity) is a fixed-dose oral combination approved in 2022 for major depression. The dextromethorphan is an NMDA antagonist (borrowing from the ketamine mechanism), and bupropion serves partly as a CYP2D6 inhibitor to keep dextromethorphan levels adequate. Onset in trials was faster than standard antidepressants, though the comparator was bupropion alone rather than an SSRI. It's an option worth considering when speed of response matters.
MAOIs
The MAOIs are the deep bench. Phenelzine, tranylcypromine, and isocarboxazid work for depression that hasn't responded to other classes, particularly atypical depression. The dietary restrictions (tyramine, hypertensive crisis) and the drug interaction burden (serotonin syndrome, hypertensive crisis) keep them off the standard algorithm.
Selegiline transdermal at 6 mg/24 hr skips the dietary restrictions because it bypasses gut MAO, though above 6 mg the dietary restrictions come back.
MAOIs are worth remembering when the standard algorithm hasn't worked. They still hold up when other things haven't.
When to consider a different approach
If two adequate antidepressant trials at adequate doses for adequate durations haven't worked, that meets the standard definition of treatment-resistant depression. The options at that point:
- Switch to a different class. If two SSRIs haven't worked, try an SNRI, bupropion, or mirtazapine.
- Augment with an atypical antipsychotic, lithium, or T3.
- Add esketamine or racemic ketamine.
- Try an MAOI.
- Refer for TMS (transcranial magnetic stimulation), which is FDA-cleared for treatment-resistant depression.
- Refer for ECT (electroconvulsive therapy), which remains the most effective treatment for severe or psychotic depression and depression with suicidal ideation.
The order isn't set. What matters is that the algorithm keeps moving. Sitting on a partial response for months is one of the more common ways treatment stalls.
For the full framework on when a medication isn't working, see why isn't my medication working.
Special considerations
Pregnancy and postpartum
Untreated depression in pregnancy carries its own risks. The general framework: sertraline is the most-studied SSRI in pregnancy and is often the pick when starting fresh. Paroxetine carries a small increased risk of cardiac malformations and is usually avoided in the first trimester. See the pregnancy safety reference.
For postpartum depression specifically, two newer options have joined the algorithm. Brexanolone is an IV infusion given over 60 hours in a monitored setting, approved in 2019. Zuranolone is an oral 14-day course approved in 2023. Both act at the GABA-A receptor and have onset measured in days.
Older adults
The Beers Criteria list flags most TCAs and paroxetine because of anticholinergic burden and fall risk. Sertraline, escitalopram, and mirtazapine (at low doses, for the appetite and sleep effects) tend to be the workhorses in geriatric depression. Duloxetine is reasonable when pain is part of the picture. See Beers Criteria for psychiatric medications.
Falls, orthostasis, and hyponatremia (SIADH from SSRIs) all matter more in older adults. Start low and titrate slower. The old rule of "start low, go slow, but go" holds.
Bipolar depression
Antidepressant monotherapy is generally avoided in bipolar depression because of the risk of switching into mania or accelerating cycling. If bipolar depression is suspected or confirmed, that's a different algorithm entirely. See medications for bipolar disorder.
Screening for a bipolar history (past manic episodes, family history, response to prior antidepressants) before starting an antidepressant is worth doing routinely.
Depression with comorbidities
Comorbidity is often what tips the choice within a class. Depression with insomnia points toward mirtazapine or an SSRI with trazodone at bedtime. Depression with sexual side effects concern points toward bupropion, vortioxetine, or vilazodone. Depression with chronic pain points toward duloxetine. Depression with smoking points toward bupropion. See the comorbidity selection guide for a fuller map.
What tips the choice
If the patient is starting fresh with no strong comorbidity signal, sertraline or escitalopram is the default. The rest of the tree branches from there:
- Anxiety prominent: SSRI, favor sertraline or escitalopram. Bupropion is a poor early pick.
- Insomnia and low appetite: mirtazapine.
- Sexual side effect concern: bupropion first, or vortioxetine, or vilazodone.
- Weight concern: bupropion, or vortioxetine. Avoid mirtazapine and paroxetine.
- Fatigue prominent: bupropion, or an SNRI at NE-active doses.
- Chronic pain: duloxetine, or venlafaxine at higher doses, or a TCA.
- Smoker who wants to quit: bupropion does both jobs.
- Prior family history of good response to a specific drug: reasonable to lean that way. Response often runs in families.
- Poor adherence pattern: fluoxetine has the longest half-life, so a missed dose isn't catastrophic.
- Cost or insurance: sertraline, fluoxetine, citalopram, escitalopram, and bupropion are all generic and cheap.
The other side of the equation is what the patient will actually take. A medication that works on paper and gets abandoned at week two hasn't worked. Discussing the likely side effects up front, and giving the medication a fair 4 to 6 week trial, is how most trials succeed or don't.
Common questions
How do I know which antidepressant is right for me? There isn't a test that predicts which one will work best. Pharmacogenomic testing (Genesight and similar) tells you which enzymes metabolize which drugs, and that has some use for dosing, but it doesn't reliably predict clinical response. The choice is usually made on comorbidities, side effect tolerability, cost, and prior response (yours or a first-degree relative's). If the first one doesn't work, that's normal, and the algorithm has clear next steps.
How long until it works? Full effect on mood is usually 4 to 6 weeks, sometimes up to 8, at an adequate dose. Some symptoms (sleep, appetite) can shift sooner. Feeling little at 2 weeks is normal and isn't a sign that the medication has failed. See starting a medication for the week-by-week picture.
Do I have to take an antidepressant forever? No, but the standard recommendation for a first episode is to continue for 6 to 12 months after full remission before considering a taper, and longer (2 years or more, or indefinitely) after recurrent episodes. Stopping should be gradual and coordinated with a prescriber. See coming off an antidepressant.
What if the first antidepressant doesn't work? The STAR*D trial showed that switching to another antidepressant or augmenting with a second agent both have reasonable success rates in the second step. The response rate drops with each subsequent step, which is why moving through the algorithm at a reasonable pace matters. Two adequate trials without response meets the definition of treatment-resistant depression, and that opens up esketamine, TMS, ECT, and MAOI options.
What about therapy? Therapy (CBT, IPT, behavioral activation) has evidence comparable to antidepressants for mild to moderate depression. For severe depression, combination treatment (medication plus therapy) outperforms either alone. Medication and therapy work through different routes and often help different symptoms. See medication or therapy.
Sources
This guide draws on current prescribing information, treatment guidelines, and public health references. It is reviewed for clinical accuracy and updated as guidance changes.
THE KNOWLEDGE PATH
Walk this topic outward.
- GUIDE Medications for depression (current)
- CLASS SSRIs
- MEDICATION Sertraline (Zoloft)
- CONDITION Major Depressive Disorder (on Shrinkopedia)
- CARE Consider depression evaluation at shrinkMD
The Knowledge Path is a curated walk. Every step is one decision away from the next.
Managing a medication needs a prescriber
Any psychiatric medication has to be started and adjusted by a clinician who can follow you over time. If you don't have a prescriber, our guides section explains the options, including in-person care and telepsychiatry, and how to choose between them.