Augmentation Agents for Treatment Resistant Depression

Treatment resistant depression (TRD) can be defined as a lack of significant improvement after two adequate trials of two different antidepressants from two different pharmacologic classes (SSRIs, SNRIs and/or bupropion). 

Studies indicate that about 30% of patients fail to respond to the standard antidepressants. 

Research has shown that switching antidepressants within a class, say from Zoloft to Prozac, is no more effective than doing nothing. 

Atypical antipsychotics are the best-studied TRD augmentation agents. A recent meta-analysis (combining data from multiple studies) has shown that only two atypicals—Abilify (aripiprazole) and risperidone—show improved functioning when paired with an SSRI. 

I favor Abilify for TRD because it has more positive trials, side effects are minimal and the neurochemical effects make sense. 

Abilify is a partial agonist at D₂ receptors. This property reduces dopamine output when dopamine concentrations are high thus reducing racing thoughts and other symptoms of hypomania (symptoms less severe than mania) and increases dopamine output when dopamine concentrations are low thus improving depression.

In addition, the serotonin 5-HT_1A partial agonist properties of Abilify also makes Abilify a suitable choice for adjunctive treatment in TRD patients. 

Akathisia (inner restlessness and inability to stay still) is the most common dose dependent side effect. 

Because higher doses are most likely to cause akathisia, I start patients on ½ of a 5 mg tablet daily for one week and then increase to a full 5 mg tablet daily. I keep the patient on 5 mg for one month. For those who fail to respond at this dose I gradually increase the dose. 

The average dose in efficacy trials was 11 mg but I have found that most of my patients respond to the 5 mg dose. Almost none have responded to a dose lower than 5 mg.

Because Abilify is energizing most patients take Abilify in the morning; 10% of patients develop grogginess from Abilify so they take the medicine at bedtime. 

If patients fail to respond to Abilify or if they develop side effects, risperidone 0.5 mg to 3 mg provides an option. Side effects include sleepiness, fatigue, EPS (muscle stiffness) and prolactinemia. 

Lithium should be considered as a first-line treatment in patients who are at risk for suicide. In a meta-analysis lithium reduced the risk of suicide fivefold in major depression and sixfold in bipolar disorder. I discussed lithium in a previous blog. 

PS: Control trials are largely negative in an SSRI augmented with bupropion or Lamictal (lamotrigine) in the treatment of TRD.

PSS: Rexulti (brexpiprazole) offers a neurochemical profile that indicates it may be a better treatment for TRD than Abilify but not enough head-to-head studies have been done to confirm that possibility. Besides, Rexulti is much more expensive than Abilify.