Dr Anantha Shekhar, MD PhD, Dean of the University of Pittsburgh School of Medicine, explores synapse structure and function in neuroscience and how neuroplasticity can present new opportunities for drug development. With contributions from Rob Houghtaling, MS and John Donello, PhD, Gate Neurosciences.

In March 2019, the US FDA approved Spravato, a nasal spray version of ketamine, as a new fast-acting therapy for patients with depression. This marked the first approval of a new drug mechanism to treat depression in over half a century¹.

Since 2000, when ketamine’s rapid antidepressant effects were first observed in humans, psychiatry researchers have explored how ketamine fits into depression disease biology. Ketamine works rapidly to relieve depression within hours after administration and has long-lasting effects, with patients seeing benefits for days to weeks from a single dose. This is quite a paradigm-shift from traditional antidepressants, like Prozac, which are dosed every day and can take weeks to start working.

We now understand that ketamine’s rapid and durable effects on depression are because of its ability to enhance synapse structure, function, and plasticity. Synaptic plasticity, or the ability of neurons to form and maintain new connections (synapses), is a brain process crucial to learning, memory, mood and sleep. Today, there is a growing focus from biotech companies and researchers on developing therapies that modulate molecular targets central to synaptic plasticity pathways to treat depression, schizophrenia, PTSD, autism, and neurodegenerative diseases².

Therapies that target synaptic structure, function, and plasticity have the power to reshape treatment of neuropsychiatric diseases. Recently, plasticity-enhancing psychedelics like LSD or psilocybin (magic mushrooms), have had a resurgence and attracted significant attention from the psychiatry field due to their lasting remission potential. Newer companies, like Delix Therapeutics, Gilgamesh Pharmaceuticals, and Gate Neurosciences are developing molecules that can enhance synaptic function and plasticity, but without the ‘trip’ or side effects of psychedelics and ketamine. 

Because this new, class of therapies has long-lasting effects on synapses from a single dose, the psychiatry field may need to rethink traditional approaches to translational drug development. Synaptic plasticity is a natural, balanced, and notably dynamic brain process – successful development of plasticity drugs likely requires adaptation from drug developers, including consideration of new pharmacology models and use of precision medicine tools in clinical development.  

Synaptic plasticity & depression

The weakening and loss of synaptic connections in the brain, as the basis for depression, is a compelling alternative to old disease models focused only on neurotransmitter signaling. The monoamine hypothesis, popularised in the 1960s, focused on imbalances in certain neurotransmitters. This led to the development of traditional antidepressants like Prozac. Monoamine drugs are effective in some patients but leave a lot to be desired: around 30-40% of patients are simply unresponsive to multiple lines of therapy and for patients who do respond, it can take four to six weeks for symptoms to improve³. 

Yale neuroscientist Ronald Duman was an early pioneer in developing alternative models of depression disease biology. He theorised that depression is caused by the loss of synaptic strength and disruption of synaptic plasticity, rather than simply an imbalance of neurotransmitters⁴. Duman conducted animal studies showing how ketamine causes robust and rapid antidepressant effects because of its restoration of synaptic density and function. Further, Duman found that traditional antidepressants also restored synaptic density and function – but the effect took a long time, similar to observations in patients¹. 

Finally, Duman’s neuroscience group at Yale, including Dr Robert Berman first demonstrated in humans that ketamine had rapid-acting antidepressant effects within a day and the effects lasted several days after a single dose⁵. Since Dr Berman’s study, there has been a surge in research on new drug mechanisms that can rapidly and durably enhance synaptic plasticity to treat depression. 

Ketamine as a weekly-dosed treatment limited by side effects 

Today, low doses of ketamine are used increasingly as potent antidepressants for patients who do not respond to traditional treatment options. However, its widespread use is limited by significant side effects such as dissociation and safety liabilities. Ketamine had previously been FDA-approved for anesthesia and is commonly abused as a party drug. These side effects are usually transient and last for up to two hours. But after the side effects wear off, patients still benefit from symptom improvement for days up to one week.

Ketamine treatment typically involves a once-weekly intravenous infusion or nasal spray, in the case of Spravato. The FDA label for Spravato recommends a twice-per-week induction phase, followed by a maintenance phase of administration either once every week or once every two weeks. This infrequent model of administration makes sense – patients are less burdened by severe side effects while still getting a lasting therapeutic benefit after leaving the physician’s office. Dosing a patient with ketamine every single day is simply not practical. 

Development models

Ketamine’s weekly dosing paradigm offers a compelling learning opportunity for the psychiatry field and challenges us to rethink standard drug development practices. As new and innovative plasticity-enhancing drugs are developed by biotech and pharma companies, with better side effect profiles versus ketamine, should these compounds be dosed weekly too? Or if they are well-tolerated, can they be dosed every day like traditional antidepressants? 

In the traditional pharmacology model used for psychiatric drugs, a drug’s therapeutic effect depends on whether it is presently bound to its target. For example, anti-anxiety drugs like Xanax work by increasing the amount of the neurotransmitter GABA in the brain to promote calmness and relaxation. Xanax’s anti-anxiety effects are strong while the drug is occupying GABA receptors, however, once the drug starts washing out of the brain after ~12 hours, its therapeutic effects start to diminish. The drug must be dosed frequently enough to be continuously present in the brain at sufficiently high concentrations for its therapeutic effect.

Drug targets that are key to synaptic plasticity processes, like NMDA, AMPA and BDNF, may demand a more thoughtful approach to translational drug development. For instance, ketamine is an NMDA receptor antagonist that blocks the receptor for several hours, however, long-enduring effects on synapses are observed well-beyond when the drug has been washed out of the brain. Ketamine triggers a cascade of downstream molecular pathways resulting in changes to synapses lasting for days to weeks. Optimal dosing and redosing approaches for plasticity drugs may depend on pharmacodynamic effects, rather than pharmacokinetic effects. 

Gate Neurosciences is one example of a biotech company that is applying new biomarker approaches and functional measures to research the interplay between dosing and pharmacodynamic effects of its NMDA-targeted drugs that enhance synaptic structure and function. Gate’s lead molecule, zelquistinel, is being administered as a once-weekly oral tablet in its upcoming Phase II depression study, despite being well-tolerated with no ketamine-like side effects. 

Looking to the future 

Historically, neuroscience has been a challenging area of drug development. Persistent clinical trial failures over the past few decades led to neuropsychiatry divestment from many pharmaceutical companies. Today, we are seeing a resurgence in neuropsychiatry and renewed strategic interest from pharmaceutical companies. New potent drug mechanisms, like those that can safely enhance synaptic structure, function, and plasticity, alongside advances in precision biomarker approaches have reinvigorated the field. We are just now on the forefront of ushering in a transformative class of new depression therapies with rapid activity and potential for lasting remission, offering hope for countless patients in desperate need of new treatment options. As the psychiatry field continues to realise the promise of synaptic plasticity modulators, drug developers should be flexible in thinking about new pharmacology models and translational tactics to ensure success. 

From DDW Volume 25 – Issue 3, Summer 2024 Read the digital issue

References

1. Musazzi L. Esketamine: the first glutamatergic drug for the management of treatment- resistant depression. Pharm Adv. 2020;02(03).
2. Marzola P, Melzer T, Pavesi E, et al. Exploring the Role of Neuroplasticity in Development, Aging, and Neurodegeneration. Brain Sciences. 2023;13(12):1610.
3. McIntyre RS, Alsuwaidan M, Baune BT, et al. Treatment‐resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry. 2023;22(3):394-412.
4. Duman RS. Synaptic plasticity and mood disorders. Mol Psychiatry 2002; 7 Suppl 1:S29-34.
5. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000; 47(4):351-4.

About the author:

Anantha Shekhar is the Chief Scientific Officer of Gate Neurosciences, a nationally recognised leader in neuropsychiatry, and currently serves as the Dean of the Medical School and Senior Vice Chancellor for Health Sciences at the University of Pittsburgh.