Why SSRIs and SNRIs May Cause More Anxiety

SSRIs (Selective Serotonin Reuptake Inhibitors) and SNRIs (Serotonin Norepinephrine Reuptake Inhibitors) are prescribed for depression and anxiety, but they commonly cause more fear and anxiety when first taking the medication for the first few weeks of treatment. After this period of increased anxiety symptoms on the SSRI or SNRI, then the anxiety subsides and eventually the medication treats the baseline anxiety symptoms that were present before treatment with the medication.

So how does this exactly occur in the brain, where SSRIs and SNRIs trigger anxiety? A recent study found a pathway in the brain which may be responsible for this treatment side effect. When mice are subjected to a mild shock on their paws, this induces stress and anxiety. So the shock activates the dorsal raphe nucleus (DRN) in the brainstem to release serotonin to the bed nucleus of the stria terminalis (BNST). Subsequently, the serotonin released from the DRN serotonin neurons bind to the serotonin 2C receptors on the BNST, which in turn inhibits the ventral tegmental area (VTA) and lateral hypothalamus (LH). This inhibition of the VTA and LH worsens fear and anxiety. When the VTA and LH were not inhibited, then this led to reduced anxiety symptoms.

When the scientists applied fluoxetine to the 2C receptors on the BNST, then this also worsened the fear and anxiety. What was interesting was that the activated BNST neuron released corticotropin releasing factor (CRF), which is a stress-signaling hormone which tells the adrenal glands to release the stress hormone cortisol. So when a CRF antagonist (CRF blocking drug) was applied, this greatly reduced the anxiety induced by the fluoxetine.

The next step is to determine if there are DRN to BNST serotonin pathways in humans. If this does exist in humans, then medications such as CRF antagonists might be prescribed concurrently with SSRIs/SNRIs to prevent the anxiety triggered by the SSRI/SNRI during the first few weeks.

photo credit: Ars Electronica Pathfinding in the Human-Computer Medicine / Fraunhofer Institute for Medical Image Computing MEVIS (DE) via photopin (license)