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If you have major depressive disorder (MDD), you may be taking at least one antidepressant.

Combination drug therapy is a type of treatment that many doctors and psychiatrists have been increasingly using during the past decade.

Until recently, doctors prescribed an antidepressant medication from only a single class of drugs, one medication at one time. This is called monotherapy.

Doctors generally start at a lower dosage, increasing the dosage of the medication before ruling out it isn’t working.

If that happens, they might try another medication within that class, or switch to another class of antidepressants entirely.

Research now suggests that taking antidepressants from multiple classes may be the best way to treat MDD.

On its own, bupropion is very effective at treating MDD, but it may also be used with other medications for depression that’s difficult to treat.

In fact, bupropion is one of the most commonly used combination therapy medications. It’s often used with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).

Bupropion is generally well tolerated in people who’ve experienced severe side effects from other antidepressant medications.

It can also relieve some of the sexual side effects (like decreased libido or difficulty reaching orgasm) associated with popular SSRIs and SNRIs.

For people experiencing loss of appetite and insomnia, mirtazapine may be an option. Its most common side effects are weight gain and sedation.

However, mirtazapine hasn’t been studied in depth as a combination medication.

Research suggests there may be some benefit in treating persistent symptoms in people taking SSRIs with atypical antipsychotics, such as aripiprazole.

Some possible side effects associated with these medications include:

  • weight gain
  • muscle tremors
  • metabolic disturbances

Carefully consider the pros and cons of antipsychotics with your doctor. Their side effects may prolong or worsen some symptoms of depression.

Some doctors use L-triiodothyronine (T3) in combination with tricyclic antidepressants (TCAs).

Research suggests that T3 with a TCA may lead to a faster response to treatment compared with taking a TCA alone, but more research is needed.

The dose typically used for this purpose is 25 micrograms (mcg) a day of triiodothyronine. If that dosage doesn’t provide the desired results after about a week, it’s increased to 50 mcg a day.

D-amphetamine (Dexedrine) and methylphenidate (Ritalin) are stimulants used to treat depression. They can be used alone, but they may also be used in combination with antidepressant medications.

Many clinicians find that supplementing antidepressants with low doses of stimulants, such as methylphenidate, may help improve depression that doesn’t respond to treatment that well.

However, not all clinical trials have shown benefits from this strategy.

Stimulants are most helpful when the desired effect is a quick response. People with severe depression symptoms or other conditions, such as chronic illnesses, may be good candidates for this combination.

Success rates of monotherapy treatment are relatively low. Therefore, many researchers and doctors believe the first and best approach to treating MDD is combination treatments.

Still, many doctors will begin treatment with a single antidepressant medication.

Before making a decision about the medication, give it time to work.

When you start taking an antidepressant, it’s not uncommon to start with a lower dosage and gradually increase it to reduce the risk of side effects.

If the medication isn’t working as desired after a trial period — usually about 6 to 8 weeks — your doctor may wish to change medications or add a medication to see whether the combination helps.