A mechanistic breakthrough occurred when the first selective serotonin reuptake inhibitor (SSRI), fluoxetine, was developed in the late 1980s, followed soon by several other SSRIs (evolution). This triggered another massive paradigm shift away from TCAs to SSRIs because of the low cardiotoxicity of SSRIs.
Evolution then led to the development of other heterocyclic antidepressants, such as nefazodone, mirtazapine, venlafaxine, and duloxetine.
The recent exciting (pun intended again!) discovery of the efficacy of the glutamate NMDA receptor-antagonist ketamine for severe, treatment-resistant depression represents a radical breakthrough in the rapidity of remission (within 1 or 2 hours of IV administration) of depression and suicidal impulses. Until now, such rapid response was believed unattainable.
The ketamine treatment model also rep- resents several paradigm shifts: from mono- amines to glutamate; from the oral route to the IV route; from gradual (6 to 8 weeks) to abrupt (1 or 2 hours) resolution of symptoms; and from neurochemistry (monoamine neurotransmitters) to neuroplasticity (mammalian target of rapapmycin [mTOR] and brain- derived neurotrophic factor [BDNF]).
The saga will go on
Explosive growth in molecular neuroscience and deeper understanding of the pathophysiology of major psychiatric disorders bode well for an accelerating pace of radical breakthroughs in psychiatric therapies. The new revelation that symptoms of chronic neuropsychiatric disorders such as depression, mania, and schizophrenia can be re- versed within a few hours, instead of weeks, months, or years, is jubilant news for our long-suffering patients.
But even as science-driven breakthroughs accelerate and prompt paradigm shifts in treatment, we should never under-estimate the importance and value of serendipity in generating new insights that lead to the same transformative paradigm shifts in therapeutics. Scientists are equipped to make discoveries that are breakthroughs, but observant clinicians can make serendipitous discoveries that may reinvent the care of psychotic disorders. The discovery of psychiatric therapies can begin in a clinical setting—not just in the ivory tower of academia.