A Paradigm Shift in Antidepressant Therapy

Jun 5, 2025 • BY Elijah S
Infographic: A Paradigm Shift in Antidepressant Therapy

A Paradigm Shift in Antidepressant Therapy

Moving Beyond Serotonin: The Established Role of Neuroplasticity and Direct TrkB Modulation

The Current Standard: SSRIs and Their Inherent Limitations

For decades, Selective Serotonin Reuptake Inhibitors (SSRIs) have been a primary treatment for depression, based on the theory of correcting a “serotonin imbalance.” However, this model is definitively challenged by significant clinical limitations and recent research highlighting a more complex neurobiological reality.[1], [2]

Delayed Onset of Therapeutic Action

4-6+

Weeks

Patients typically wait weeks for therapeutic effects, a delay suggesting that immediate serotonin modulation is not the primary driver of clinical improvement.[4], [5]

Inconsistent Patient Response Rates

A substantial proportion of patients do not achieve adequate remission with the first SSRI prescribed, often leading to a “trial and error” treatment approach.[1]

Challenging Side Effect Profile

●Sexual Dysfunction

●Weight Changes & Nausea

●Sleep Disturbance

●Discontinuation Syndrome

Common adverse effects can be distressing and frequently lead to treatment non-adherence or discontinuation.[9], [11]

The True Mechanism: Neuroplasticity & Direct TrkB Activation

Converging evidence demonstrates that antidepressants achieve their effects by promoting neuroplasticity—the brain’s capacity for adaptation and rewiring. This process is critically mediated by Brain-Derived Neurotrophic Factor (BDNF) and its receptor, TrkB.[7], [8]

Pivotal Discovery: Direct TrkB Receptor Binding

Landmark research (Casarotto et al., 2021) has shown that numerous antidepressants, including SSRIs, directly bind to the TrkB receptor.[4] This molecular interaction is fundamental to their therapeutic action. Psychedelic compounds also bind TrkB, exhibiting notably higher affinity.[15]

(Illustrative TrkB Binding Affinity: SSRIs vs. Psychedelics)

The direct engagement of TrkB, even if with lower affinity by SSRIs, underscores its role as a central therapeutic target. More potent and direct TrkB modulation offers a clear path to faster and more robust antidepressant outcomes.

The Neuroplasticity Pathway: Essential for Recovery

BDNF Production[7]

(Brain-Derived Neurotrophic Factor)

TrkB Receptor Activation[4], [8]

(The Receptor for BDNF’s Action)

Enhanced Neuroplasticity

Increased Neuronal Growth, Synaptic Strengthening, and Resilience

This pathway is fundamental for the repair and strengthening of neural circuits. Effective antidepressant action relies on robust engagement of this system.

Mechanisms of Neuroplasticity: Indirect vs. Direct TrkB Modulation

The fundamental difference between traditional SSRIs and next-generation Trk-PAMs like ACD856 lies in *how* they engage the critical TrkB pathway, which directly influences their therapeutic onset, efficacy, and side effect profiles.

SSRIs: The Indirect, Less Efficient Route

1. Inhibit Serotonin Transporter (SERT)
↓
2. Gradual Drug Accumulation in Brain
↓
3. Lower-Affinity Binding to TrkB[4]
↓
4. Delayed and Variable Neuroplastic Effects

This multi-step, less direct TrkB engagement contributes to the delayed onset and inconsistent efficacy seen with SSRIs.

ACD856: The Direct, High-Potency Path

1. Directly Binds & Allosterically Modulates Trk Receptors[3], [12]
↓
2. Potently Enhances Endogenous BDNF Signaling (TrkB EC50 ≈ 295 nM)[12]
↓
3. Promotes Robust & Potentially Rapid Neuroplastic Effects

By directly and potently targeting the core neuroplasticity machinery, Trk-PAMs like ACD856 are designed for faster, more reliable, and comprehensive therapeutic action.

ACD856: A Novel Trk-PAM Therapeutic

ACD856 is a Trk-PAM (Positive Allosteric Modulator of Trk receptors). It is engineered to precisely enhance the brain’s innate neuroplasticity systems, offering a range of therapeutic benefits demonstrated in preclinical and early clinical research.[3], [12]

🧠

Cognitive Enhancement

Preclinical studies show significant improvements in memory and concentration, addressing cognitive deficits associated with neurological conditions.[10], [13]

🛡️

Neuroprotection

Demonstrates robust neuroprotective properties in preclinical models, safeguarding neurons and promoting long-term brain health.[13]

🔥

Anti-inflammatory Action

Significantly reduces key pro-inflammatory markers in relevant models, addressing neuroinflammation implicated in depression and cognitive decline.[14]

😊

Mood Regulation

Offers a targeted approach to alleviating depressive symptoms by directly fostering healthy brain function and adaptive plasticity.[12]

Comparative Analysis: SSRIs vs. ACD856

Feature SSRIs (e.g., Fluoxetine) ACD856 (Trk-PAM)
Primary Target Serotonin Transporter (SERT) Trk Receptors (A, B, C)[3], [12]
Mechanism Indirect, lower-affinity TrkB modulation (micromolar range) via serotonin system[4] Direct, potent positive allosteric modulation of Trk signaling (TrkB EC50 ≈ 295 nM)[12]
Expected Onset of Action Delayed (4-6+ weeks)[1] Potential for Faster Onset (Based on direct mechanism and preclinical data)[4], [12]
Therapeutic Scope Primarily mood Mood Regulation, Cognitive Enhancement, Neuroprotection, Anti-inflammatory Effects[3], [10], [12], [13], [14]
Common Side Effects Sexual dysfunction, weight gain, nausea, sleep disturbance[9], [11] Favorable safety & tolerability profile in Phase 1 human trials[11]

The Trajectory for Trk-PAMs: Clinical Development and Considerations

ACD856 has shown considerable promise in foundational research and early clinical studies. Continued investigation is critical to fully establish its therapeutic role and to understand the long-term implications of this targeted neurotrophic modulation.

Development Pipeline & Key Milestones

Preclinical Validation

Potent antidepressant-like, cognitive-enhancing, neuroprotective, and anti-inflammatory effects demonstrated in various animal models.[3], [10], [12], [13], [14]

Phase 1 Human Trials COMPLETE

Established good safety, tolerability, CNS penetration, and evidence of central target engagement (via qEEG) in healthy volunteers.[11]

Phase 2 Clinical Trials PREPARING

Upcoming trials to evaluate efficacy in patient populations, initially for Alzheimer’s Disease, with significant potential for depression.[3]

Phase 3 & Regulatory Review

Large-scale trials to confirm efficacy and long-term safety, prerequisite for regulatory approval.

Key Considerations for Trk-PAM Development

  • ⚖️

    Balanced Physiological Signaling

    Ensuring Trk pathway modulation remains within physiological ranges, leveraging the “event-dependent” nature of PAMs to avoid over-activation and maintain homeostasis. Excessive activation could disrupt neuronal homeostasis and potentially lead to excitotoxicity or astroglial-mediated neurotoxicity, which is not seen in selective TrkB PAMs such as ACD856.[17]

  • 🎯

    Patient Stratification & Precision

    Identifying patient subgroups most likely to benefit, possibly through biomarkers of Trk pathway function, to enable personalized treatment strategies. Depression is heterogeneous; a targeted approach might only benefit those with specific neurotrophic deficits, but the cognitive benefits may be wider spread.[7]

  • ⏳

    Long-Term Safety & Efficacy

    Comprehensive monitoring of chronic Trk modulation to confirm sustained safety, tolerability, and efficacy over extended treatment periods. The long-term effects of chronic Trk modulation are still being studied, but the selective nature and novel mechanism of ACD856 is promising.

Real World Anecdotes

Experienced Nootropic User

  • Doses are detectable at 5-10mg and upwards, with varying intensities and a plateau.
  • Doses of 20mg are highly noticeable in alterations to perceived mood and playfulness, memory is enhanced in fidelity upon recall at this dose and lower, and when doing physical actions, the rate-of-correction for suboptimal movement is much faster. Learning in general becomes more flexible with concepts becoming easier to integrate and relate to others already known.
  • Long-term use solidifies and intensifies all the above besides alterations in color, sleep is noticeably more consistent in terms of when and duration, habits become easier to both create and to break out of, and overall cognitive flexibility and information-integration become noticeably enhanced to a moderate degree. The effects are consistent, and the improved fidelity of memories made during this time are more detailed upon introspection.

Intelligence Biohacking Innovator

  • I quit nicotine, started actually doing things to make my days more meaningful be it from doing activities after work or doing more work while at work.
  • 15-20mg ACD for the past 1-2 weeks or so, before that I would do 5-10mg and sometimes 20mg.
  • I’ve been on ACD856 consistently for well over a month and inconsistently for a couple months.

Nootropic User

  • Reaction time greatly improved. Not only do I react faster to stressful situations, but I did so calmly.
  • Increased confidence while biking without overconfidence. I tried more jumps at higher speeds while not crashing.
  • Not randomly ruminating on the events of the past that would politely be considered me being lesser-intelligent.
  • Strong and quick antidepressant effect.

Key References

  1. NHS. (n.d.). Treatment – Depression in adults. Accessed June 4, 2025, from nhs.uk
  2. Moncrieff, J., Cooper, R. E., Stockmann, T., Amendola, S., Hengartner, M. P., & Horowitz, M. A. (2022). The serotonin theory of depression: a systematic umbrella review of the evidence. *Molecular Psychiatry*, *28*(8), 3243-3256.
  3. AlzeCure Pharma. (n.d.). NeuroRestore. Accessed June 4, 2025, from alzecurepharma.se
  4. Casarotto, P. G., Girych, M., Fred, S. M., Kovaleva, V., Moliner, R., Enkavi, G., … & Castrén, E. (2021). Antidepressant drugs act by directly binding to TRKB neurotrophin receptors. *Cell*, *184*(5), 1299-1313.e19. PMC7938888
  5. Castrén, E., & Monteggia, L. M. (2021). Brain-Derived Neurotrophic Factor Signaling in Depression and Antidepressant Action. *Biological Psychiatry*, *90*(2), 128-136.
  6. bpacnz. (2021). The role of medicines in the management of depression in primary care. Accessed June 4, 2025, from bpac.org.nz
  7. Shirayama, Y., Chen, A. C. H., Nakagawa, S., Russell, D. S., & Duman, R. S. (2002). Brain-Derived Neurotrophic Factor Produces Antidepressant Effects in Behavioral Models of Depression. *Journal of Neuroscience*, *22*(8), 3251-3261. jneurosci.org
  8. Björkholm, C., & Monteggia, L. M. (2016). BDNF – a key transducer of antidepressant effects. *Neuropharmacology*, *102*, 72-79.
  9. Edinoff, A. N., Akuly, H. A., Hanna, T. A., et al. (2021). Selective Serotonin Reuptake Inhibitors and Adverse Effects: A Narrative Review. *Neurology International*, *13*(3), 387-401. mdpi.com
  10. Forsell, P., Madjid, N., Ladds, M. J., et al. (2023). Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction. *Pharmaceuticals*, *16*(8), 1134. PMC8391421
  11. Lindberg, O., K Rekar, V., Nilsen, A., et al. (2024). Safety, Tolerability, Pharmacokinetics and Quantitative Electroencephalography Assessment of ACD856, a Novel Positive Allosteric Modulator of Trk-Receptors Following Multiple Doses in Healthy Subjects. *Clinical Pharmacology in Drug Development*, *13*(4), e12023. sciencedirect.com
  12. Madjid, N., Ladds, M.J., Sandin, J., et al. (2023). Antidepressant effects of novel positive allosteric modulators of Trk-receptor mediated signaling – a potential therapeutic concept?. *Psychopharmacology (Berl)*, *240*(7), 1547-1561. PMC10349764
  13. Al-Tai, H. Q., Wågberg, M., Nygren, J., et al. (2023). Neuroprotective and Disease-Modifying Effects of the Triazinetrione ACD856, a Positive Allosteric Modulator of Trk-Receptors for the Treatment of Cognitive Dysfunction in Alzheimer’s Disease. *International Journal of Molecular Sciences*, *24*(13), 10990. PMC10342804
  14. AlzeCure Pharma. (2024). AlzeCure Reports Anti-Inflammatory Effects with NeuroRestore ACD856 with Relevance to Alzheimer’s Leading to New Patent Application. BioSpace. Accessed June 4, 2025, from biospace.com
  15. Moliner, R., Girych, M., Brunello, C. A., et al. (2023). Psychedelics promote plasticity by directly binding to BDNF receptor TrkB. *Nature Neuroscience*, *26*(6), 1034-1045.
  16. Regan, P. M., Gissen, R., Anderson, K. M., et al. (2019). Pharmacological interrogation of TrkA-mediated mechanisms in hippocampal-dependent memory consolidation. *Neuropsychopharmacology*, *44*(10), 1817-1826. PMC6590805
  17. Ignatyeva, V. V., Savelieva, K. V., & Ninkina, N. N. (2018). TrkB Receptor Signalling: Implications in Neurodegenerative, Psychiatric and Proliferative Disorders. *International Journal of Molecular Sciences*, *19*(6), 1645. PMC6032338
  18. Reiche, L. L., & Björkholm, C. (2024). Positive Allosteric Modulators of Trk Receptors for the Treatment of Alzheimer’s Disease. *Pharmaceutics*, *16*(5), 654. PMC11357672

The Future: Precision Neuroplasticity Enhancement

The evolution from broadly acting SSRIs to precisely targeted Trk-PAMs like ACD856 represents a significant advancement in psychiatric pharmacotherapy. This progress reflects a commitment to rationally designed drugs that address the underlying neurobiology of brain disorders, paving the paving for more effective and personalized medical interventions.

Leave a Reply

Your email address will not be published. Required fields are marked *