New Explanation Proposed for SSRI Treatment Resistance

Findings from a recent study may provide an explanation as to why some patients taking selective serotonin reuptake inhibitors (SSRIs) for mood and anxiety disorders do not benefit from these drugs. The preclinical research is published in Frontiers of Behavioral Neuroscience.

Jeremy D. Coplan, MD, and colleagues presented an explanation as to why low serotonin levels could not be detected in depression without suicidal intent even though many antidepressants work by increasing serotonin in mood regulation areas (eg, hippocampus). The team explained that the hippocampus and other key brain structures involved in mood maintenance do not get enough serotonin due to reduced serotonin release through a negative feedback mechanism in the raphe nucleus. The high serotonin levels in the raphe nucleus get higher from the use of SSRIs and the serotonin neuron may be unable to adapt, leading to a serotonin deficit (as seen with hippocampus shrinkage).

RELATED: Review: SSRI Use Ups Risk of Upper GI Bleeding

Coplan and his team cited other studies where high serotonin in the raphe nucleus and low serotonin in the prefrontal cortex were seen in people who committed suicide. For treatment-resistant patients, Coplan proposed augmentation therapies as seen in hypertension and diabetes management. Other methods may be to shut glutamate input into the raphe nucleus and to use drugs that block noradrenergic input into the dorsal raphe.

They concluded that more studies should be done to better understand and improve future treatment options.

For more information visit