A very common clinical mistake occurs when patients with bipolar depression are misdiagnosed as having MDD because most of them experience depression as their initial mood episode. These patients often end up being classified as having TRD because bipolar depression very frequently fails to respond to several of the antidepressants that are FDA-approved for MDD. When these patients are correctly diagnosed, many will respond to one of the medications specifically approved for bipolar depression that were launched over the past 15 years (quetiapine, lurasidone, and cariprazine). However, bipolar disorder is also a heterogeneous spectrum, and some patients with bipolar depression may fail to respond to any of these 3 medications and are promptly regarded as TRD. Such patients often respond to neuromodulation (TMS, ECT, or vagus nerve stimulation [VNS]), indicating that they may have a different type of bipolar depression, such as bipolar type II.
A more recent example of the falsehood of TRD as a spurious diagnosis is the dramatic and rapid response of patients who are chronically depressed (both those with MDD and those with bipolar depression) to ketamine infusions.3,4 Responders to ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, prove that nonresponders to monoamine reuptake inhibitors must not be falsely labeled as having TRD. They have a different subtype within the depression syndrome that is mediated by glutamatergic pathways, instead of monoamines such as serotonin, norepinephrine, or dopamine. In addition, unlike monoaminergic antidepressants, NMDA antagonists rapidly reverse suicidal urges, above and beyond rapidly reversing chronic, so-called TRD.
In the same vein, numerous reports have shown that buprenorphine has significant efficacy in TRD (and suicide urges, as does ketamine), which implicates opioid pathways as mediating some subtypes of TRD.5 The monoamine model of depression, which dominated the field and dragged on for half a century, has distracted psychiatric researchers from exploring and recognizing the multiple neurochemical and neuroplastic pathways of the depression syndrome, thus falsely assuming that depression is a monolithic disorder that responds to elevating the activity of brain monoamines. This major blind spot led to the ersatz concept of TRD.
Treatment-resistant schizophrenia (TRS)
Since the discovery of chlorpromazine and other antipsychotics in the 1950s, it became apparent that a subset of patients with schizophrenia do not respond to medications that block dopamine D2 receptors. Partial responders were labeled as having TRS, and complete nonresponse was called refractory schizophrenia. Many patients with severe and persistent delusions and hallucinations were permanently hospitalized, and unable to live in the community like those who responded to dopamine antagonism.
In the late 1980s, the discovery that clozapine has significant efficacy in TRS and refractory schizophrenia provided the first insight that TRS and refractory schizophrenia represent different neurobiologic subtypes of schizophrenia.6,7 The extensive heterogeneity of schizophrenia (with hundreds of genetic and nongenetic etiologies) is now widely accepted.8 Patients with schizophrenia who do not respond to dopamine receptor antagonism should not be labeled TRS, because they can respond to a different antipsychotic agent, such as clozapine, which is believed to exert its efficacy via glutamate pathways.
Continue to: But what about the 50%...