The Jesalva Algorithm: Principle #2-Comorbidity is the RULE not the exception

Patients with Treatment Resistant Depression (TRD) have more than one disease state at a time.  TRD is defined as a depression that has not improved with 3 or more psychotropic medications including antidepressants, mood stabilizers, stimulants or second generation antipsychotics. ​

TRD could also mean an initial improvement in the depression followed by a gradual loss of efficacy over time.  This happens when, for example, an antidepressant medication works for a few months followed by a gradual decline in its effectiveness until it feels that the medication is no longer working.  Often times, a subsequent trial of another antidepressant could have the same effects.
Comorbidity is important to recognize early in treatment because it could account for the difficulty in maintaining medication effectiveness.  It is not unusual to have a major depressive disorder with an anxiety disorder.  It is also not unusual to have a bipolar disorder, generalized anxiety disorder and attention deficit disorder all occurring at the same time.  Some patients may have all of the above plus a substance use disorder and perhaps chronic pain.  These patients tend to be very challenging indeed.
It is up to the clinician to tease out each disease state and treat each one independently to remission.