Case Study 4: When an SSRI Helped Mood but Left the Patient Drained and Unmotivated

**The depression improved—**but the patient still had no energy, drive or motivation.

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

The medication had helped some of the patient’s depressive symptoms, but they continued to feel:

• Drained
• Unmotivated
• Mentally tired
• Unable to get interested in work
• Low in drive and productivity
• Unable to feel like their normal self The patient’s mood was somewhat better, but they still felt:

“I just don’t have the energy or motivation to do anything.”

This raised an important question:

Why was serotonin treatment helping mood but not restoring energy and motivation?

PPI Looked Beyond Serotonin

Serotonin is important for mood and emotional regulation.

But symptoms such as:

• Motivation
• Mental energy
• Reward
• Concentration
• Getting started on tasks also involve dopamine and norepinephrine.

PPI therefore looked at genes involved in these systems.

One important finding stood out: The patient had a genetic pattern associated with higher COMT enzyme activity.

COMT stands for: Catechol-O-Methyltransferase

COMT is an enzyme that helps break down brain chemicals called catecholamines, including dopamine and norepinephrine.

It is particularly important for regulating dopamine in the Prefrontal cortex the part of the brain involved in:

• Motivation
• Attention
• Planning
• Working memory
• Mental effort
• Getting things done Some COMT genetic variants are associated with higher enzyme activity and lower dopamine availability in the prefrontal cortex.

A simple way to think about it is:

1. Dopamine is released
2. COMT helps clear it away
3. Highly active COMT clears dopamine more quickly
4. Less dopamine may remain available in certain brain circuits

Another Dopamine-Breakdown Gene MAOB was Also Important

PPI also identified a pattern involving: MAOB

MAO-B is another enzyme involved in the breakdown of dopamine. COMT and MAO-B both participate in dopamine metabolism, although their roles differ across brain regions.

Taken together, the patient’s results suggested a possible inherited tendency toward:

lower dopamine-related signaling

particularly in systems important for motivation and mental energy.

It is more accurate to describe this as a genetic tendency in dopamine regulation, rather than saying the patient was born with a measured “low dopamine level.”

What May Have Happened on the SSRI?

The SSRI increased serotonin signaling and helped improve the patient’s mood.

However, serotonin, dopamine and norepinephrine systems interact with one another.

In some brain circuits, increased serotonin signaling can reduce dopamine or norepinephrine activity through certain serotonin receptors. This has been proposed as one reason some patients experience residual symptoms such as fatigue, low energy and reduced motivation despite an improvement in mood.

For this patient, the picture was:

1. SSRI improves serotonin-related symptoms
2. Mood improves

but:

1. The patient may already have relatively less efficient dopamine/norepinephrine signaling
2. Motivation, energy and drive remain low
3. The antidepressant response feels incomplete

Importantly, an SSRI does not simply lower dopamine throughout the brain. The interaction depends on the receptor and brain circuit involved.

The Genetic Findings Helped Explain the Symptoms

The patient’s results suggested:

• Higher COMT activity
• Additional dopamine-metabolism influence from MAOB
• Persistent symptoms of low motivation and energy
• Partial improvement on an SSRI A possible dopamine and norepinephrine treatment gap The PPI pharmacist therefore considered whether simply increasing serotonin was enough for this patient.

A Broader Medication Strategy

Rather than stopping an SSRI that was already helping the patient’s mood, the PPI pharmacist recommended discussing the addition of Bupropion with the patient’s treating clinician.

Bupropion works differently from an SSRI.

Its antidepressant activity is believed to involve mainly:

• Norepinephrine
• Dopamine rather than serotonin only. Canadian product information describes bupropion as acting through noradrenergic and possibly dopaminergic mechanisms and inhibiting norepinephrine and dopamine reuptake.

The strategy became:

• Keep the serotonin benefit from the SSRI
• Add norepinephrine and dopamine support with bupropion Address both mood and motivation

What Happened?

The treating clinician added bupropion to the patient’s existing SSRI treatment.

The patient’s response was very positive.

At follow-up, the patient reported:

• More energy
• Greater motivation
• Improved interest in work
• Better drive and concentration
• A much greater sense of overall wellbeing The patient described feeling: “Amazing.”

Why This Case Matters

If treatment had focused only on: “Is the SSRI improving depression?” the patient’s residual symptoms might have been overlooked.

PPI instead considered:

• Which symptoms improved?
• Which symptoms remained?
• What did the dopamine and norepinephrine pathway genetics suggest?
• Could a broader medication mechanism better address the remaining symptoms? A more personalized treatment strategy

The Bigger Picture

This case demonstrates why depression is not simply: “low serotonin.”

Different symptoms can involve different brain systems.

• Serotonin- may be particularly important for mood, anxiety and emotional regulation.
• Dopamine- is strongly involved in motivation, reward, pleasure and drive.
• Norepinephrine- is involved in energy, attention and alertness. A person may improve in one area while continuing to struggle in another.

The Takeaway

The goal of treatment is not simply: “Did the antidepressant improve mood?”

A more complete question is:

“Did the patient regain mood, motivation, energy, interest and everyday functioning?”

For this patient: Serotonin support helped mood, but Dopamine and norepinephrine-related symptoms remained.

PPI’s genetic and symptom assessment helped identify a possible reason and supported consideration of a medication strategy targeting more than one neurotransmitter system.

Important Note

This individual case does not mean that a COMT or MAOB result can independently prove that someone has low dopamine or predict that bupropion will work. COMT genetic variation can meaningfully affect enzyme activity and prefrontal dopamine regulation, but its value for selecting antidepressant treatment is still developing. Evidence for many MAOB pharmacodynamic markers is even less established.

PPI therefore uses these findings as supporting information within a broader assessment of symptoms, medication history, pharmacokinetics and multiple pharmacodynamic pathways, rather than as stand-alone prescribing rules.