Case Study 3: When an SSRI Improved Mood but Increased Anxiety

Reason to come to PPI: The antidepressant was helping—but the patient felt increasingly anxious.

A patient came to Personalized Prescribing after taking an SSRI antidepressant.

The medication was helping their depression. Their mood had improved and they felt that the antidepressant was doing something positive.

However, there was a problem.

The patient also experienced:

• Increased anxiety
• Feeling tense or “on edge”
• Restlessness
• Greater sensitivity to stress
• Difficulty feeling calm This created a frustrating situation: The medication was helping the depression, but the patient did not feel well overall.

The question became: Why would increasing serotonin improve mood but also contribute to anxiety?

PPI First Looked at Drug Metabolism

PPI examined the patient’s pharmacokinetic genes, including liver enzymes involved in processing antidepressants.

The results showed that the patient’s relevant liver enzymes were functioning as expected.

In simple terms:

1. The medication was being processed normally
2. There was no obvious genetic metabolism problem explaining the anxiety.

PPI then looked more closely at the serotonin system itself.

The Serotonin Transporter and Autoreceptor Looked Normal

Two important parts of the serotonin pathway were considered:

• SLC6A4- The gene involved in the serotonin transporter—the main target of SSRIs.
• HTR1A- A serotonin receptor involved in regulating serotonin release. Neither appeared to provide a strong explanation for the patient’s unusual response.

But another finding stood out.

The patient’s genetic profile suggested higher HTR2A receptor activity or expression.

HTR2A is the gene that helps make the Serotonin 2A receptor — 5-HT2A

This is a postsynaptic serotonin receptor, meaning it receives serotonin signals after serotonin has been released.

The 5-HT2A receptor is found in important brain areas involved in:

• Mood
• Thinking
• Emotional responses
• Stress
• Perception It is particularly important because many 5-HT2A receptors are located on brain cells that communicate using glutamate.

What May Have Been Happening?

SSRIs increase serotonin signaling by blocking the serotonin transporter. For most patients, this can help improve depression and anxiety over time.

However, serotonin does not act on just one receptor. Increasing serotonin means that more serotonin can stimulate many different serotonin receptors, including 5-HT2A.

In this patient, PPI’s findings suggested that the 5-HT2A pathway might be particularly responsive.

A simplified explanation is:

1. SSRI increases serotonin
2. More serotonin reaches postsynaptic receptors
3. Greater stimulation of a highly active 5-HT2A pathway
4. Increased excitatory signaling in certain brain circuits
5. Anxiety and overstimulation may occur

5-HT2A receptors can influence glutamate signaling in the cerebral cortex, although the relationship is complex and depends on the brain region and surrounding circuitry.

Glutamate — The Brain’s Activating Signal

Glutamate is the brain’s main excitatory or activating neurotransmitter.

It is important for normal:

• Thinking

• Learning

• Memory

• Brain communication But when excitatory signaling becomes poorly regulated in stress- and anxiety-related circuits, it may contribute to feelings of:

• Overactivation

• Tension

• Restlessness

• Anxiety Glutamate signaling has been extensively studied as one of several systems involved in anxiety.

A simple analogy is: Glutamate is part of the brain’s accelerator.

In a susceptible person, excessive stimulation of certain excitatory pathways could make it more difficult for the brain to settle down.

HTR2A and the Stress Response

There was another reason the HTR2A finding was interesting.

Serotonin also communicates with the body’s major stress-response system: The HPA Axis

The HPA axis helps control the release of Cortisol our major stress hormone.

Serotonin can stimulate this stress system, and 5-HT2A receptors are among the serotonin receptors involved in HPA-axis activation.

A simplified pathway is:

1. Serotonin signaling increases
2. Serotonin receptors involved in the stress system are activated
3. HPA-axis activity may increase
4. Cortisol response increases
5. The person may feel more activated or sensitive to stress

Cortisol and anxiety are not related in a simple “more cortisol = more anxiety” manner—the HPA axis can be overactive, underactive or poorly regulated depending on the person and condition.

The Pieces Began to Fit Together

The patient’s results showed:

• Normal medication metabolism
• No major concern with the serotonin transporter
• No major concern with serotonin autoreceptor regulation
• A genetic pattern suggesting stronger HTR2A-related signaling
• Mood improved on an SSRI, but anxiety increased A possible pharmacodynamic explanation emerged The SSRI appeared capable of helping the patient’s depression.

But increasing serotonin may also have produced unwanted stimulation of a serotonin pathway involved in excitatory and stress-related signaling.

Importantly, this was considered a possible contributor, not proof that HTR2A alone caused the patient’s anxiety.

A Broader Medication Strategy

As the patient was benefiting from serotonin treatment, the PPI pharmacist recommended discussing a combination of their current SSRI (Escitalopram) and Mirtazapine.

The reasoning was straightforward.

Escitalopram - Primarily supports the Serotonin system and may continue to help with mood.

Mirtazapine- blocks the HTR2A receptors and reduce Glutamate release and reduce anxiety.

The strategy therefore became:

• Continue supporting serotonin
• Add Mirtazapine as an adjunct Address a broader range of the patient’s symptoms

What Happened Next

After the medication plan was implemented by the treating clinician, the patient’s response was dramatic. At follow-up, the patient described they no longer experience anxiety and feeling significantly well with the medication combinations.

Improved mood does not always mean that all of the brain systems involved in depression have been adequately treated.

Why This Case Matters

If the patient had received a pharmacogenomic test that looked only at:

• CYP2D6
• CYP2C19 and other liver enzymes, the report might simply have shown: “Normal metabolism.”

That result would be useful—but it would not explain why the patient:

felt emotionally better while simultaneously: becoming more anxious.

PPI’s broader approach allowed the pharmacist to look beyond how the medication was processed and consider: What happened after serotonin reached the brain.

Pharmacokinetics vs. Pharmacodynamics

This case illustrates the difference particularly well.

Pharmacokinetics

Is the body processing the SSRI properly?

For this patient:

Yes.

But then comes another question.

Pharmacodynamics

How is the patient’s serotonin system responding once the medication reaches the brain?

That was where the additional information became important.

The Takeaway

A mental health medication can: help one group of symptoms while: worsening another.

Thus, PPI also considers:

• Drug metabolism
• Transporters
• Autoreceptors
• Postsynaptic receptors
• Current symptoms
• Previous medication response A more complete picture of why a medication may help, fail or cause unwanted effects

Important Note

This case should not be interpreted to mean that an HTR2A genetic result can prove that an SSRI caused anxiety or that people with a particular HTR2A variant should avoid SSRIs. SSRIs are also established treatments for anxiety disorders, although some patients can experience increased anxiety or nervousness, particularly during treatment initiation.

The evidence for using HTR2A and other pharmacodynamic genes to guide individual prescribing remains developing. PPI therefore considers these findings as part of a broader, multigene and clinical assessment rather than using HTR2A alone as a medication-selection rule.