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HCN Channel Targets for Novel Antidepressant Treatment
Open accessAbstract
Major depressive disorder (MDD) is a chronic and potentially life threatening illness that carries a staggering global burden. Characterized by depressed mood, MDD is often difficult to diagnose and treat owing to heterogeneity of syndrome and complex etiology. Contemporary antidepressant treatments are based on improved monoamine-based formulations from serendipitous discoveries made > 60 years ago. Novel antidepressant treatments are necessary, as roughly half of patients using available antidepressants do not see long-term remission of depressive symptoms. Current development of treatment options focuses on generating efficacious antidepressants, identifying depression-related neural substrates, and better understanding the pathophysiological mechanisms of depression. Recent insight into the brain's mesocorticolimbic circuitry from animal models of depression underscores the importance of ionic mechanisms in neuronal homeostasis and dysregulation, and substantial evidence highlights a potential role for ion channels in mediating depression-related excitability changes. In particular, hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are essential regulators of neuronal excitability. In this review, we describe seminal research on HCN channels in the prefrontal cortex and hippocampus in stress and depression-related behaviors, and highlight substantial evidence within the ventral tegmental area supporting the development of novel therapeutics targeting HCN channels in MDD. We argue that methods targeting the activity of reward-related brain areas have significant potential as superior treatments for depression.
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“Available evidence suggests a plausible HCN-linked phenotype involving cognitive inertia and slowed affective transitions, but this remains a translational hypothesis rather than a validated treatment mechanism [290,291].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [290]
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“meta-analytic datasets suggest comparable efficacy to several standard treatments when dose and resistance are considered, with emerging hints of cognitive improvement alongside mood change [290]”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [290]
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“Clinically, dorsolateral prefrontal transcranial direct current stimulation (tDCS) yields the largest benefits in patients with psychomotor retardation and executive disturbance”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [290]
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Metadata
- Authors
- Ku, S. M., & Han, M.-H.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Han, Ming-Hu
- ORCID
- Han, Ming-Hu
- Venue
- Neurotherapeutics
- Publisher
- Elsevier BV
- Published
- 2017-07
- Volume
- 14
- Issue
- 3
- Pages
- 698-715
- ISSN
- 1878-7479 (ISSN-L)
- PMC
- PMC5509632
- OpenAlex
- W2619412584
- Cited by
- 54
- References
- 291
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 9 · 2023: 9 · 2022: 4 · 2021: 5 · 2020: 9 · 2019: 4 · 2018: 4 · 2017: 2
- FWCI
- 0.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neurotherapeutics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (R21MH112081, F31MH108326)
- Brain and Behavior Research Foundation (NARSAD)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- HCN channels, major depressive disorder, antidepressant drug development, neuronal excitability, mesocorticolimbic circuitry, prefrontal cortex, hippocampus, ventral tegmental area, stress
- MeSH terms
- Animals, Antidepressive Agents, Brain, Major Depressive Disorder, Humans, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
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