If you have major depressive disorder (MDD), you’re likely already taking at least one antidepressant. Combination drug therapy is a type of treatment that many doctors and psychiatrists have been increasingly utilizing during the past decade.   

The Role of Medications

Until recently, doctors prescribed an antidepressant medication from only a single class of drugs, one at one time. This is called monotherapy. If that drug failed, they might try another medicine 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. One study found that using a combination approach at the first sign of MDD may double the likelihood of remission.

Atypical Antidepressants

On its own, bupropion is very effective at treating MDD, but it may also be used in conjunction with other medications in difficult-to-treat depression. 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). It’s generally well tolerated in people who’ve experienced severe side effects from other antidepressant medication. It can also relieve some of the sexual side effects (decreased libido, anorgasmia) 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 residual symptoms in people taking SSRIs with atypical antipsychotics, such as aripiprazole. The possible side effects associated with these medications, such as weight gain, muscle tremors, and metabolic disturbances, should be carefully considered as they may prolong or worsen some symptoms of depression.


Some doctors use L-Triiodothyronine (T3) in combination therapy with tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). Research suggestions T3 is better at speeding up the body’s response to treatment than increasing the likelihood a person will enter remission.


D-amphetamine (Dexedrine) and methylphenidate (Ritalin) are stimulants used to treat depression. They can be used as monotherapy, but they may also be used in a combination therapy with antidepressant medications. They’re most helpful when the desired effect is a quick response. Patients who are debilitated, or those who have comorbid conditions (such as a stroke) or chronic medical illnesses, may be good candidates for this combination.

Combination Therapy as First-Line Treatment

Success rates of monotherapy treatment are relatively low, and therefore many researchers and doctors believe the first and best approach to treating MDD is combination treatments. Still, many doctors will begin treating with a single antidepressant medication.

Before making a decision about the medication, give it time to work. After a trial period (usually about 2 to 4 weeks), if you don’t show an adequate response, your doctor may wish to change medications or add an additional medication to see if the combination helps your treatment plan succeed.