Mechanism of Action of SSRIs

Author: Flavio Guzman, MD

The video below discusses the role of 5HT1A receptors in the mechanism of action of selective serotonin reuptake inhibitors (SSRIs).

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Introduction

Slide 1 

In the next slides we’ll be discussing the mechanism of action of selective serotonin reuptake inhibitors, or SSRIs.

Slide 2

This presentation can be divided into three sections.

  1. The first secion is a brief overview of the monoamine theory of depression and its limitations.
  2. The second section discusses the effects of 5HT1A receptor downregulation on the mechanism of action of SSRIs.
  3. The third section presents recent findings on the role of BDNF in depression.

The monoamine theory of depression

Slide 3 

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What does the monoamine theory of depression hold? This theory postulates that depression might be caused by a decrease in serotonergic and noradrenergic neurotransmission.

SSRIs are pharmacologically active at their molecular and cellullar sites of action almost immediately. If the reuptake of serotonin or norepinephrine is blocked, this causes an increase in neurotransmitter availability at the synaptic cleft.

However, here comes the fact that poses a big limitation for the monoamine theory of depression: antidepressant effects are generally not seen until 2 to 4 weeks of continuous treatment.

So, the question is how can we explain this discrepancy between immediate inhibition of serotonin reuptake and clinical effects.

In the next slides we’ll explore the hypothesis that might explain the delayed therapeutic effect of antidepressants.

The role of  5HT1A receptors

Slide 4

Now we will discuss the role of 5HT1A receptor downregulation in the mechanism of action of SSRIs.

Slide 5 

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We’ll begin by introducing some relevant features before starting with the effects of SSRIs.

This image shows a serotonergic neuron.

We can see the somatodendritic region, the axon and the presynaptic terminal. Here is also depicted a postsynaptic neuron that is stimulated by the serotonergic neuron.

Slide 6 

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The next element we need to integrate for a better understanding is the 5HT1A receptor. There are 14 subtypes of serotonin receptors, the 5HT1A is one of them.

When this receptor is stimulated it inhibits firing of serotonergic neurons, this means that it works as an autoreceptor that inhibits serotonergic activity.

Slide 7 

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Here 5HT1A receptors are expressed in the somatodendritic region of a serotonergic neuron. This picture is a schematic representation that emphazises the role of 5HT1A receptors as inhibitory autoreceptors.

Slide 8 

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The serotonin transporter (SERT) is a monoamine transporter protein.

This is a membrane protein that transports  serotonin from synaptic spaces into presynaptic neurons.

Slide 9

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Selective serotonin reuptake inhibitors and other antidepressants block the SERT transporter. The result is an increased availability of serotonin in the synaptic space.

Slide 10

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If we compare this image with the previous illustration showing the somatodendritic region, the difference is that you can see an increase of serotonin concencentration. This has implications in terms of regulation of 5HT1A receptors.

Slide 11

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This step is key in our explanation. Why? Here we can see the effects of increased serotonin concentrations.

If you pay attention there is an important difference with the previous slides: there are less 5HT1A receptors, this is, 5HT1A receptors are downregulated.

As a response to serotonin stimulation, the serotonergic neuron reduces the number of 5HT1A receptors, this phenomenon is known as downregulation. Since downregulation is mediated by genomic mechanisms, the reduction of 5HT1A receptors is not immediate, this occurs in weeks.

This has been proposed as a possible explanation of antidepressants’ delay in therapeutic effects.

Slide 12

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Now we can see the effects of 5HT1A downregulation on the serotonergic neuron. Here the focus is not on the somatodendritic region, but on the entire neuron. Since there are less 5HT1A receptors expressed in the somatodendritic region, the neuron is now disinhibited.

As a consequence, firing rate is increased. This in turn increases serotonin release to the synaptic space, which stimulates postsynaptic serotonin receptors.

In summary, inhibition of serotonin reuptake increases serotonin concentration, which causes a downregulation of 5HT1A receptors. After the number of 5HT1A receptors is reduced, the neuron is disinhibited to release more serotonin in the synaptic space.

BDNF and the neurotrophic hypothesis of depression

Slide 13

In the last section we’ll review recent findings on the role of BDNF in depression.

Slide 14 

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The neurotrophic hypothesis of depression proposes that depression is associated with reduced brain BDNF levels in the hippocampus. So, antidepressant treatments alleviate depressive symptoms and increase BDNF levels.

Slide 15 

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This diagram shows a model that overlaps degree of impairment of neuronal plasticity with clinical severity of depression. According to this paper by Lee and colleagues, suicide behaviour can be a consequence of very severe impaired neuronal plasticity. Antidepressant treatments promote several forms of neuronal plasticity, including BDNF activity, which can develop antidepressant response. It has been proposed that the neuronal plastic change can recover depressed mood.

References and further reading

  1. Brunton LB, Lazo JS, Parker KL, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill; 2010.
  2. Stahl, S M. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 4th ed. New York: Cambrigde University Press; 2013
  3. Lee BH, Kim YK. The roles of BDNF in the pathophysiology of major depression and in antidepressant treatment. Psychiatry investigation. 2010;7(4):231-5.

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