Anhedonia: The Overlooked Core of Depression

Anhedonia: The Overlooked Core of Depression

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“Maybe they’re no longer depressed…they just don’t care anymore.”

It’s a chilling reflection shared by many of us in psychiatry — and it strikes at the heart of one of the most misunderstood symptoms in depression: anhedonia. Patients complete treatment. Their scores improve. But they aren’t living. They aren’t engaging. They simply don’t care anymore.

At the 2025 NEI Spring Congress, Dr. Roger McIntyre, a global leader in mood disorders research, delivered a groundbreaking session titled “A More Tailored and Swift Approach? Using Clinical Endophenotypes to Address Major Depressive Disorder in All of Its Variations.” In it, he tackled the limitations of conventional treatment models and emphasized the urgent need to address core, under-recognized drivers of poor outcomes—chief among them: anhedonia.

But he didn’t stop there.

Dr. McIntyre introduced the field to SAINT — the Stanford Accelerated Intelligent Neuromodulation Therapy protocol, a theta-burst TMS regimen that delivers 10 sessions per day over five days. The results?

• 79% Remission
• 86% Response Rate
• Significant improvement in motivation and engagement within days

This protocol isn’t a hopeful future. It’s a reality. And for the first time, we’re seeing targeted interventions that address not just depression, but the loss of reward and meaning that defines anhedonia.

Dr. McIntyre’s Case for Diagnostic Precision

Dr. McIntyre didn’t frame anhedonia as a secondary issue. He position edit as a core endophenotype—a biological and clinical signature that may one day earn its own diagnostic classification. And for good reason.

Anhedonia comes in at least two distinct forms:

1. Anticipatory Anhedonia

This is the inability to anticipate or look forward to pleasure. Patients withdraw not because they feel bad—but because they expect nothing at all.

“Even if I go, I won’t enjoy it.” This subtype is strongly associated with dopaminergic dysfunction and is one of the strongest predictors of suicidality, according to Dr. McIntyre’s analysis.

2. Consummatory Anhedonia

This is the inability to enjoy pleasure in the moment. Patients may go through the motions of life but experience no reward.

“I used to love music. Now it just sounds like noise.” Consummatory deficits are linked to hedonic hotspots in the brain, including the nucleus accumbens and prefrontal cortex.

These two profiles aren’t just theoretical—they map directly onto why conventional antidepressants often fail to deliver functional recovery.

Vortioxetine: A Leading Option

In discussing pharmacologic strategies, vortioxetine (Trintellix) was discussed as a unique agent that targets the complex neurobiology of anhedonia more effectively than traditional SSRIs.

Vortioxetine:

• Modulates multiple serotonin receptor subtypes
• Enhances dopamine and glutamate activity in prefrontal circuits
• Improves cognitive flexibility and reward-based decision-making

The presented data showed that vortioxetine significantly improves MADRS anhedonia subscale scores, and that this change correlates directly with gains in functionality, engagement, and motivation.

For patients who say, “I’m not sad. I just feel nothing,” vortioxetine is not just an antidepressant—it’s a pathway back to meaning.

Additional Pharmacologic Tools

In addition to vortioxetine, several other pharmacologic treatments with emerging or established efficacy for treating anhedonia and difficult-to-treat depression (DTD) were discussed:

• Bupropion – A norepinephrine-dopamine reuptake inhibitor (NDRI) targeting drive and energy
• Agomelatine – A melatonergic agonist and 5-HT2C antagonist that enhances dopaminergic transmission
• AXS-05 (dextromethorphan + bupropion) – A rapid-acting NMDA antagonist with fast onset and marked improvements in anhedonia
• Ketamine / Esketamine – NMDA antagonists shown to restore hedonic tone within hours
• Lumateperone - An SNDRI with a pro-cognitive and motivational benefits
• Venlafaxine XR – With evidence of dopaminergic action at higher doses

These agents represent a shift toward mechanism-based prescribing, rooted in neurocircuitry rather than checklists.

Non-Pharmacologic Treatments for Reward System Dysfunction

Dr. McIntyre made clear that medication alone isn’t enough—and that the future of treatment lies in interdisciplinary, circuit-level approaches, including:

• SAINT Protocol TMS – High-dose, rapid TMS achieving remission in 5 days
• Standard rTMS – Effective for anhedonia, especially targeted to the left DLPFC
• ‍tDCS – Prefrontal stimulation to increase reward sensitivity
• Behavioral Activation – Focused on anticipatory pleasure, this remains one of the best non-pharmacologic tools
• Exercise and Structured Activity – Dopamine-enhancing and engagement-driven
• CBT with hedonic tracking – Helping patients rewire their response to pleasure and reward

Call to Action: Precision Psychiatry, Now

Dr. McIntyre concluded by reminding clinicians that anhedonia is not secondary. It is primary, it is predictive, and it is often the most disabling feature our clients face—even after other symptoms improve.

The takeaway? If we’re not treating anhedonia, we’re not treating depression.

Whether it’s vortioxetine, AXS-05, SAINT TMS, or behavioral activation, we now have a growing arsenal of tools to intentionally restore joy, purpose, and motivation.

Final Word: It’s Time to Stop Treating Just the Sadness

Our job isn’t just to reduce symptom scales. Our job is to help people reconnect with their lives. As Dr. McIntyre so powerfully demonstrated at NEI, we’re entering a new chapter in psychiatry—one where we stop asking “Are they less depressed?” and start asking:

“Do they care again?”

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