Antidepressants work well at managing symptoms in most people with major depressive disorder (MDD). Yet only one-third of people will find adequate relief from their symptoms with the first drug they try. About 10 to 30 percent of people with MDD won’t get complete relief from an antidepressant, no matter which one they take at first. Others will get better temporarily, but eventually, their symptoms may return.

If you experience things like sadness, poor sleep, and low self-esteem and medication isn’t helping, it’s time talk to your doctor about other options. Here are six questions to lead you through the discussion and get you on the right treatment path.

1. Am I taking my medication the right way?

Up to half of people living with depression don’t take their antidepressant the way their doctor prescribed — or at all. Skipping doses can affect how well the medication works.

If you haven’t done so already, go over the dosing instructions with your doctor to make sure you’re taking the drug correctly. Don’t ever stop taking your medication abruptly or without consulting your doctor. If side effects are bothering you, ask your doctor whether you can switch to a lower dose, or to another drug with fewer side effects.

2. Am I on the right drug?

Several different types of antidepressants are approved to treat MDD. Your doctor might have started you on a selective serotonin reuptake inhibitor (SSRI) like fluoxetine (Prozac) or paroxetine (Paxil).

Other options include:

  • serotonin-norepinephrine reuptake inhibitors (SNRIs) like duloxetine (Cymbalta) and venlafaxine (Effexor XR)
  • atypical antidepressants like bupropion (Wellbutrin) and mirtazapine (Remeron)
  • tricyclic antidepressants such as nortriptyline (Pamelor) and desipramine (Norpramin)

Finding the drug that works for you can take some trial and error. If the first drug you try doesn’t help after a few weeks, your doctor can switch you to another antidepressant. Be patient, because it can take three or four weeks for your medication to start working. In some cases, it can take up to 8 weeks before noticing changes in your mood.

One way your doctor can match you to the right drug is with the cytochrome P450 (CYP450) test. This test looks for certain gene variations that affect how your body processes antidepressants. This can help your doctor determine which drugs may be better processed by your body, leading to fewer side effects and improved effectiveness.

3. Am I taking the right dose?

Your doctor might start you on a low dose of an antidepressant to see if it works. If it doesn’t, they will slowly increase the dose. The goal is to give you enough medication to relieve your symptoms, without causing unpleasant side effects.

4. What are my other treatment options?

Antidepressant drugs aren’t the only treatment option for MDD. You can also try psychotherapy such as cognitive behavioral therapy (CBT). With CBT, you work with a therapist who helps you identify harmful patterns of thinking and find more effective ways to cope with the challenges in your life. Research finds that the combination of medication and CBT works better on depression symptoms than either treatment alone.

Vagus nerve stimulation (VNS) is another treatment doctors use for depression when antidepressants aren’t effective. In VNS, a wire is threaded along the vagus nerve that runs from the back of your neck to your brain. It’s attached to a pacemaker-like device that transmits electrical impulses to your brain to relieve depression symptoms.

For very severe depression, electroconvulsive therapy (ECT) is also an option. This isn’t the same “shock therapy” that was once given to patients in mental asylums. ECT is a safe and effective therapy for depression that uses mild electric currents in an attempt to alter brain chemistry.

5. Could other issues be causing my symptoms?

There are many factors that can worsen depressive symptoms. It’s possible that something else going on in your life is making you sad, and medication alone isn’t enough to resolve the problem.

Consider these other factors that can cause a sad mood:

  • a recent life upheaval, such as the loss of a loved one, retirement, a major move, or divorce
  • loneliness from living alone or not having enough social interaction
  • a high-sugar, processed diet
  • too little exercise
  • high stress from a difficult job or an unhealthy relationship
  • drug or alcohol use

6. Are you sure I’m depressed?

If you’ve tried several antidepressants and they haven’t worked, it’s possible that another medical condition or drug you take is the reason you’re experiencing symptoms of MDD.

Conditions that can cause depression-like symptoms include:

  • an overactive or underactive thyroid (hypothyroidism or hyperthyroidism)
  • heart failure
  • lupus
  • Lyme disease
  • diabetes
  • dementia
  • multiple sclerosis (MS)
  • stroke
  • Parkinson’s disease
  • chronic pain
  • anemia
  • obstructive sleep apnea (OSA)
  • substance abuse
  • anxiety

Drugs that may cause depressive symptoms include:

  • opioid pain relievers
  • high blood pressure medications
  • corticosteroids
  • birth control pills
  • sedatives

If a medication is causing your symptoms, switching to a different drug might help.

It’s also possible that you have another mental health condition, like bipolar disorder. If that is the case, you will need to discuss other treatment options with your doctor. Bipolar disorder and other mental health conditions require different treatment from MDD.