Confusion abounds about how antidepressants work in anxiety disorders.

SSRIs (selective serotonin reuptake inhibitors) and SNRIs (serotonin norepinephrine reuptake inhibitors) are antidepressant medications that are also used to treat anxiety disorders in addition to depression.

A recent article in Forbes (DiSalvo, 2015) highlights the confusion regarding how SSRIs and SNRIs work in anxiety disorders. This article highlighted a study which found that serotonin was increased in the amygdala in subjects with anxiety (Frick et al., 2015).

So this study has led people to question how SSRIs and SNRIs can help for anxiety as these medications seemingly increase serotonin in the brain. But if increased serotonin was found in the amygdala of subjects with anxiety, then how do these antidepressants work?

To clarify the confusion, it’s not a simple matter of a chemical imbalance and the antidepressant correcting that imbalance.

Focusing only on the neurotransmitters and the receptors in the synapse (the space and connection between neurons) is so 1990s and 2000s.

Psychopharmacology has advanced to the point where the neurobiology of anxiety is understood at what happens downstream from the synapse, neurotransmitters and receptors.

It is now about post-synaptic 2nd-messenger systems activated by the binding of neurotransmitters to post-synaptic receptors.

It is about how anxiety is mediated by fear circuits made up of neuronal bundles connecting the amygdala to different parts of the brain.

It is about how the activation of the amygdala triggers the sympathetic nervous system and the HPA axis (hypothalamic-pituitary-adrenal axis) to manifest the fight or flight response and how the subsequent release of stress hormones from the adrenal glands interacts with the brain and fear circuits to further mediate the anxiety response.

It is no longer sufficient to focus only on the synapse, neurotransmitter, and receptors to explain how these medications work for the treatment of anxiety disorders. It is now about post-synaptic 2nd-mesenger systems, brain circuits, and whole body responses. This is how we do things now in the 2010s and beyond.

The Neurobiology of Anxiety

So we have to discuss the neurobiology of anxiety to really understand how SSRIs and SNRIs work. In the brain, serotonergic neurons project from the raphe nuclei, located in the brainstem, to the amygdala, located in the temporal lobes bilaterally.

So these serotonergic neurons project to the amygdala, and have an inhibitory effect on the amygdala. The inhibitory effect comes about as the serotonin (5HT) receptors located post-synaptically bind to 5HT and are inhibitory when Gi is activated and there is a reduction of adenylate cyclase activity (Ressler and Nemeroff, 2000).

So this 2nd messenger system is inhibitory downstream after the serotonin binds to the post-synaptic receptor.

When you are exposed to a stressor, danger, or feared object/situation, your amygdala becomes activated and it causes your fear circuits to be overactive. When your fear circuits that are based on the amygdala become overactive, then this triggers the fight or flight response, which manifest as the physical symptoms of anxiety.

If you want to reduce the anxiety caused by the stressor, then you can take an SSRI or an SNRI, which acts on the serotonergic neurons that are projecting from the raphe nuclei to the amygdala.

The SSRI/SNRI will block the reuptake of serotonin in the synapse, and this effectively will increase the concentration of serotonin, which then binds more to the postsynaptic serotonin receptors and then has an inhibitory effect downstream, and ultimately reduces the overactivity of the amygdala.

Thus, serotonergic agents such as SSRIs and SNRIs reduce anxiety by increasing serotonin input to the amygdala.

In summary, its not as simple as high or low levels of serotonin causing anxiety or how SSRIs/SNRIs correct that chemical imbalance. It is about the complex interactions of different brain and body systems as discussed above. Dont be swayed by pop psychology and amateur explanations of complex brain phenomenon for explaining SSRIs, serotonin and anxiety.


The Popular Assumption About SSRI Meds That Could Be Completely Wrong. DiSalvo, David. Psych Central. Retrieved on September 21, 2015 from

Serotonin Synthesis and Reuptake in Social Anxiety Disorder: A Positron Emission Tomography Study. Frick A, hs F, Engman J, Jonasson M, Alaie I, Bjrkstrand J, Frans , Faria V, Linnman C, Appel L, Wahlstedt K, Lubberink M, Fredrikson M, Furmark T. JAMA Psychiatry. 2015 Aug 1;72(8):794-802. Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders. Ressler KJ, Nemeroff CB. Depress Anxiety. 2000;12 Suppl 1:2-19. Review.

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