Augmentation for Treatment Resistant Depression

Depression is one the most complex mental health conditions. Depression can present in many different ways and can rob individuals of the ability to enjoy life and to function in their daily activities. Prolonged symptoms of intense sadness, loss of motivation, fatigue, lack of interest in activities, and hopelessness can undermine one’s personal and professional life and increase the risk for suicidal thoughts and actions. Thankfully, a range of effective treatments are available for treating depression.  

Since the causes of depression are a complex mix of genetics, biological factors, personal characteristics, environmental factors, and situational stressors - treatment is equally complex.  Psychotherapy and medications are the clinical treatments for depression.  Yet in approximately 10-30 percent of cases, traditional psychotherapy and/or antidepressants do not yield satisfactory improvement. The result? The conundrum of Treatment Resistant Depression (TRD). In these cases, psychiatrists may turn to an approach known as augmentation.


Essentially, augmentation refers to the practice of prescribing two or more medications to treat one single condition (also known as Combination Therapy). When single antidepressant medication proves ineffective in reducing symptoms, research supports the use of augmentation as a viable option. The Sequenced Treatment Alternatives to Relieve Depression study (STAR*D), followed more than 2800 participants ages 18-75 over a seven-year period. The results showed that approximately one-third of patients who had not previously responded to treatment with the SSRI citalopram (Celexa) achieved remission of depressive symptoms after augmentation with bupropion (Wellbutrin) or buspirone (BuSpar)

The STAR*D study uncovered several more viable augmentation options. Lithium is a medication typically used to treat Bipolar disorder. It's also frequently utilized in combination with antidepressants to combat TRD.  According to the study, Lithium appears to be effective when combined with a Tricyclic antidepressant (TCA).  A class of medications known as  Atypical Antipsychotics is another evidence-based augmentation option. Two in particular, Aripiprazole and Quetiapine, have been FDA approved as an adjunctive treatment for depression.



Naturally, an important precaution when introducing more medications is the consideration of potential side-effects. Zhou and colleagues conducted a meta-analysis to assess which medications are most helpful and which produce unwanted side-effects.

The meta-analysis included data on nearly a dozen different augmentation options. Results showed that: Quetiapine, Aripiprazole, Thyroid Hormone, and Lithium were significantly better than placebo as augmenting treatments for depression.  This study noted that quetiapine and aripiprazole were somewhat more effective than thyroid hormone and lithium.  


Another viable route for augmentation is in the form of natural supplements. Several supplement options have positive results in research studies for reducing depressive symptoms. Omega-3 Fatty Acids are known to improve mood. A recent study showed that combining Omega-3s with Citalopram, produced favorable results. Other supplements including creatine, SAMe, and l-methylfolate can also improve results when added to an antidepressant.

Psychotherapy is also an important part of the treatment of treatment resistant depression. In addition there are a variety of non-medication and non-supplement treatments that can help with addressing depression symptoms, for example healthy nutrition, exercise, light therapy, mindfulness and a variety of mind-body approaches.


If your depression is severe and has not responded to traditional approaches, augmentation may be a good option. You will need to work with a skilled psychiatrist to manage this more complex medication regimen. Consider working with a practitioner who is experienced with integrative psychiatry as this can allow you to develop a comprehensive approach to addressing your health.