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Harvard Commentaries
Harvard Commentaries
Reviewed by the Faculty of Harvard Medical School

Minding Your Mind Minding Your Mind

Boosters for Antidepressant Treatment

November 23, 2011

By Michael Craig Miller M.D.

Harvard Medical School

Antidepressants often don't work well enough. In fact, only about a third of people taking any given medication for depression will get complete relief.

When the first drug a doctor tries fails to completely relieve symptoms, there are three options:

  1. Switch to a new medication
  2. Add a second drug that acts in a different way
  3. Add psychotherapy to drug treatment

The second and third options are called "augmentation" strategies. They are especially good to try if you've only gotten partial relief from an antidepressant drug.

No two depressions are alike, so it is impossible to make one recommendation that is best for everyone. Therefore, it makes sense for you and your doctor to keep trying treatments.

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Try Talk Therapy

If you are taking an antidepressant, but haven't yet tried talk therapy, consider adding this option. A large study called the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) found that both psychotherapy and drugs are about equally effective as augmentation strategies.

About one-third of patients who had not previously responded to treatment with an antidepressant medication were as likely to improve with cognitive behavioral therapy (CBT) as they were with the addition of a second medication.

CBT is the most studied psychotherapy, but it is not the only type to consider. Your primary care doctor may be able to help you with a referral to a good therapist in your area. Psychotherapy takes more time and effort, but there is some evidence that the positive effects are longer lasting.

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Add a Second Drug

Augmenting an antidepressant with a second drug involves finding one with a different mechanism of action than the first. The reason is to target different brain pathways at the same time in the hope of providing symptom relief.

  • Bupropion – This drug affects uptake of the neurotransmitters norepinephrine and dopamine. It's often used to augment drugs such as selective serotonin reuptake inhibitors (SSRI) that act primarily on serotonin. Bupropion is also sometimes prescribed to counter sexual side effects of SSRIs. One possible drawback: Bupropion may cause tremor when combined with an SSRI or serotonin norepinephrine reuptake inhibitors (SNRI).


  • Buspirone – Among other actions, this anti-anxiety drug is a partial trigger of serotonin receptors, so it affects serotonin pathways differently from SSRIs. Randomized controlled trials have produced mixed results about this drug's efficacy at augmenting antidepressants.


  • Mirtazapine – Mirtazapine (Remeron), which increases the release of the neurotransmitter norepinephrine, tends to counter SSRI-related side effects such as anxiety and sexual dysfunction. A disadvantage of mirtazapine augmentation is that this drug may cause weight gain and sedation.


  • Antipsychotics – A number of medications in this class have been used for augmentation: aripiprazole (Abilify), extended-release quetiapine (Seroquel), olanzapine (Zyprexa), risperidone (Risperdal) and ziprasidone (Geodon). It is not clear how these drugs work to complement antidepressant medications. But because they affect neurotransmitter systems in a variety of ways, they may help the anxiety and agitation that are often part of depression. The side effects can be significant. They include weight gain, metabolic syndrome (a combination of risk factors that affect heart health), and extrapyramidal symptoms (such as muscle spasms and restlessness).


  • T3 thyroid hormone – This hormone is essential to proper regulation of mood. Over all, T3 thyroid hormone has a good side effect profile compared with other augmenting agents. However, with long-term use, this hormone may worsen cardiac arrhythmias or cause bone loss.


  • Lithium – The mechanism of action of this mood stabilizer is still not well known. It appears to interact with several neurotransmitter systems and modulates the functioning of nerve cells in helpful ways. A disadvantage to lithium augmentation is that it requires frequent blood tests to monitor lithium levels. That's because there is a small difference between a therapeutic dose and a dangerous dose that could damage vital organs.

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Consider Dietary Supplements

There's some evidence that the following supplements may help with depression.

  • Omega-3 fatty acids – These polyunsaturated fats are found naturally in fatty fish, such as salmon or mackerel. They are well known for their heart benefits. That’s why the American Heart Association recommends that people with heart disease eat enough fish to get about 1 gram of omega-3 fatty acids per day. Interest in the potential of omega-3 supplements for treating mood disorders developed after studies found lower rates of major depression, postpartum depression and bipolar disorder among people who ate more fish. The most common side effects of omega-3 supplements are mild gastrointestinal distress and fishy taste.


  • S-Adenosyl-L-methionine (SAMe) – Although the role of this molecule in brain function is not entirely clear, one theory is that SAMe promotes synthesis of neurotransmitters involved in mood regulation — serotonin, norepinephrine and dopamine. The main side effect may be cost — SAMe supplements are expensive. A month’s supply of SAMe would cost about $145, and is unlikely to be covered by insurance.


  • Folic acid – Low levels of this B vitamin have been associated not only with birth defects (such as spina bifida) but also with treatment-resistant major depression. Laboratory studies suggest that folic acid plays a crucial role in chemical reactions that affect the synthesis of neurotransmitters norepinephrine, dopamine, and serotonin. Studies of folic acid augmentation of antidepressants have generally found this vitamin to be of value, although response rates have varied — perhaps because different types of folic acid preparations were tested.

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Take Your Time

Having so many options is a source of hope. But it is also a source of confusion. The key is to work with your doctor to come up with the best approach. In fact, you may want to keep your own notes about what treatments you've tried, at what dose and for how long. Record whether or not you felt better and whether you had side effects. This kind of diligence is your best weapon against a persistent depression.

Michael Craig Miller, M.D. is editor-in-chief of the Harvard Mental Health Letter and an assistant professor of psychiatry at Harvard Medical School. Dr. Miller has an active clinical practice and has been on staff at Beth Israel Deaconess Medical Center for more than 25 years.

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