Treatment-Resistant Depression

The need for viable augmentation strategies to assist in the pharmacological management of treatment-resistant depression (TRD) has become so dire that clinicians seem to perk up to any option nowadays. This is understandable given the rather paltry track record linked to traditional antidepressants when used as monotherapy in the treatment of depression.

The genesis of treatment-resistant depression is linked to how neurotransmitters are born. Cell bodies manufacture their own messenger molecules – more typically referred to as neurotransmitters. The neurotransmitters thought to play the biggest role in mood stability – norepinephrine, serotonin and dopamine – are generated via pathways that start with amino acids and end with the neurotransmitters just mentioned. The problem is that we humans are not all able to manufacture the same amount of neurotransmitters. Our individual rate of development also varies and is controlled by our genotype. And since antidepressants don’t aid in the actual making of these aforementioned messenger molecules and most certainly are not genotype-specific, remission rates among those using these medications are quite variable. Widespread clinical evidence from multiple, well-respected sources spells out the following: Only 30 percent of depressed subjects achieve remission on their first antidepressant trial; subsequent trials yield only a 40-50 percent symptom remission rate.

With remission rates as low as they are, treating clinicians are increasingly drawn to additive medication strategies that will hopefully lead to clinical improvement for their patients.

Augmentation Strategies for TRD

The goal of any augmentation strategy is to enhance neurotransmission. Medications that can be added to antidepressants include:

Lithium. The addition of lithium to the treatment regimens of non- responsive subjects has been investigated in repeated controlled studies. It is frequently the first choice for patients who have failed to respond to antidepressant monotherapy.

Thyroid Supplements. Adequate thyroid function is important not only to metabolism, but also to mood.

Psychostimulants. Before the first antidepressants were introduced to the United States market in the 1950s, stimulants were employed in the management of depression. Stimulants activate both the norepinephrine and dopamine systems.

Second-generation antipsychotics. Since many of these drugs have serotonin agonist properties, their use as augmenting agents is increasingly gaining clinical acceptance. Seroquel XR and Abilify are now FDA-approved as augmenting agents in treatment-resistant unipolar depression.

L-methylfolate and SAMe. L-methylfolate is a folic acid derivative and SAMe is an amino acid derivative. Both assist in the synthesis and subsequent generation of neurotransmitters.

Another augmentation strategy is to combine antidepressants. Antidepressants that are routinely used in combination with one another include:

  • SSRIs + Wellbutrin
  • Remeron + Effexor
  • SSRIs + Remeron
  • Effexor + Wellbutrin
  • Cymbalta + Wellbutrin

When pharmacological strategies such as those outlined above don’t work, “mechanical” strategies such as Electroconvulsive Treatment (ECT) and repetitive Transcranial Magnetic Stimulation (rTMS) should be considered.

And of course, before embarking on any antidepressant medication or augmentation strategy, the natural order of the treatment process is to first rule out any medical causes or other prescription medications that may be influencing the continuation of depressive symptoms. And then there’s substance abuse to consider – a phenomenon which complicates every single aspect of the treatment of depression.

You know what. Treating depression successfully can be downright hard!


Joe Wegmann is a licensed clinical social worker and a clinical pharmacist with over 30 years of experience in counseling and medication treatment of depression and anxiety. Joe’s new book, To learn more about Joe’s programs or to contribute a question for Joe to answer in a future article, visit his website at, or e-mail him at