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Addressing the unmet need for synaptic regeneration in Schizophrenia
October marks the annual occurrence of several international events aimed at expanding awareness of mental health disorders, including schizophrenia. In this blog post, Spinogenix Chief Science Officer Dr. Peter Vanderklish and Chief Medical Advisor Dr. Craig Erickson provide insights into how synaptic regeneration with SPG302 may provide a new and potentially transformative therapeutic approach in schizophrenia.
What is schizophrenia?
Schizophrenia is a highly debilitating neuropsychiatric condition affecting up to 26 million people worldwide and 2.8 million in the US 1. Typically emerging in late adolescence to early adulthood, a formal diagnosis of schizophrenia requires the presence of psychosis represented by signs and symptoms of reality distortion (e.g. delusions, paranoia and/or hallucinations) and disorganized thoughts or behaviors. These defining psychotic features of schizophrenia, referred to as “positive symptoms”, can present as a single episode or be recurrent and often refractory to treatment. In addition to positive symptoms, individuals with schizophrenia frequently demonstrate some combination of “negative” symptoms (e.g. anhedonia, social withdrawal, reduced communication and motivation, and flat affect) and cognitive deficits (e.g. problems with memory, attention and planning). High levels of anxiety are also common.
The nature and extent of schizophrenia symptoms can have a profound negative impact on quality of life, affecting family and social relationships, school and work, wellbeing and physical health. A majority (~80-90%) of those with schizophrenia are unemployed 2.
Accordingly, schizophrenia is a major contributor to homelessness in the US where 10-20% of the over 600,000 homeless suffer from schizophrenia 2,3. Schizophrenia is also associated with a high mortality rate. A staggering half of all patients with schizophrenia will attempt suicide at least one time, with 2 to 5% dying by suicide 4. Overall, individuals with schizophrenia have a 15-year reduction in their average lifespan 5 due to a combination of accidents, suicide, and medical comorbidities such as cardiovascular disease that are more common in individuals with schizophrenia and can be exacerbated by commonly prescribed antipsychotic medications. The prevalence of schizophrenia and the heavy toll it takes on individuals translate to a large societal burden. From an economic perspective, direct medical costs exceed $62 billion per year and, if including indirect costs like productivity loss, annual costs exceed $300 billion 6.
Current treatments
Since the discovery of the first antipsychotic in the 1950s, chlorpromazine, drugs aimed at reducing dopamine signaling have been the main treatment option for controlling positive symptoms in schizophrenia. Newer antipsychotics in this class, termed “atypical antipsychotics”, also target a subset of receptors for serotonin and other neurotransmitters. However, these drugs leave psychosis inadequately controlled in many patients and have little effect on negative and cognitive symptoms 7. Moreover, up to a third of schizophrenia patients are considered treatment resistant to these medications, and roughly half of all patients exhibit poor compliance or refuse treatment altogether 7,8. New antipsychotics targeting muscarinic acetylcholine receptors, such as the recently approved drug Cobenfy, hold promise of improving the control of psychosis, with additional benefits on cognitive and negative symptoms 9. While old and new therapeutic strategies provide valuable options for patients, none address a feature of schizophrenia pathogenesis that may be a major driver of all symptom domains of schizophrenia – the loss of glutamatergic synapses.
Synapse loss in schizophrenia and how SPG302 may help
Synapse loss may be a critical convergence point among a wide range of factors that contribute to schizophrenia risk. A picture of schizophrenia etiology has emerged in which diverse genetic and environmental risk factors summate over a time frame that spans from prenatal brain development to early adulthood 10-13. In this model, schizophrenia is to some extent a neurodevelopmental disorder set in motion in utero by genetic lesions, maternal infection and other perinatal stressors that is subsequently exacerbated during the course of development by additional environmental factors, such as psychological stress. While many factors are at play, a wealth of histological, genetic and other data point to synapse loss as a key convergence point among genetic and environmental risk factors 13,14. Large reductions in glutamatergic synapses are observed in frontal cortical regions, hippocampus and other brain areas in schizophrenia, and are a contributor to the observed reductions in grey matter volume in schizophrenia 13,15. Exaggerated pruning of synapses by microglia is thought to be a major contributor to synapse loss and to be a pathomechanism that integrates both genetic risk factors 12-14 – e.g. mutation of the complement pathway gene, C4 16, maternal infection 17 and psychological stress 13,18. Interestingly, synapse loss and reductions in dendritic arborization do not appear to be accompanied by loss of neurons, supporting the view that schizophrenia involves an altered developmental trajectory of synaptic connectivity in affected circuits, rather than a neurodegenerative condition.
The ramifications of glutamatergic synapse loss in schizophrenia may be far reaching and impact all symptom domains 13. A reduction in glutamatergic activity in the prefrontal cortex has been proposed to result in hyperactivity of midbrain dopaminergic neurons that are involved in the genesis of positive symptoms of schizophrenia 19. It is of interest in this regard that treatment resistant schizophrenia is associated with a greater degree of frontal grey matter loss 20 and that clozapine, which is efficacious in roughly 30-50% of resistant cases, may promote synaptogenesis and have other beneficial effects on glutamatergic neurons in schizophrenia 21. Loss of synapses in the prefrontal cortex and hippocampus have also been implicated in negative symptoms, which partly overlap with symptoms of other conditions such as major depressive disorder that also involve synapse loss 13. With regard to cognitive symptoms, it is notable that synapse loss is a key driver of cognitive deficits across a wide range of other conditions, and it has long been postulated that synaptic regeneration could be of great therapeutic benefit in this domain. In schizophrenia, cognitive deficits are of added concern as those with moderate or severe cognitive impairment have a 100% increase in relapse-related hospitalizations and an overall 50% increase in the need for outpatient visits and inpatient admissions 22.
Spinogenix is positioning SPG302 as the first synaptogenic therapy in schizophrenia, with the potential to improve the control of positive symptoms as well as negative and cognitive domain symptoms that are poorly addressed by current medications. SPG302, already in clinical development for amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease, has rapid synaptic regenerative activity and has been shown in preclinical studies to increase synaptic density in hippocampus and prefrontal cortex 23. Our recently initiated Phase 2 clinical trial in Australia (NCT06442462) is a placebo-controlled, double-blind study evaluating the safety, tolerability and efficacy of SPG302 in subjects with a primary diagnosis of schizophrenia. Patients will be randomized at a 1:1 ratio to receive SPG302 or placebo as a daily pill taken orally for 6 weeks. During this time, a set of behavioral outcome measures will be used to assess positive, negative and cognitive symptoms. In addition, we have included quantitative measures of brain activity and sensorimotor gating. Electroencephalography (EEG) will be used to record resting brain activity and neural activity changes induced by sensory stimuli, such as a measure called “mismatch negativity” that is altered in schizophrenia. Smooth pursuit eye tracking, a measure of sensorimotor integration that is altered in schizophrenia, will also be performed. The suite of outcome measures deployed in our study covers the range of potential benefits of SPG302 and has the added potential to find evidence of improvements in brain activity. Results of the trial will be used to help design larger, multinational trials that will include sites in the United States. We are excited by prospects of SPG302 as a first-in-class synaptic regenerative approach to schizophrenia, with the potential to provide a valuable new therapeutic option to patients who are underserved or resistant to current standard of care medications.
- Jauhar S, et al. (2022) Schizophrenia. Lancet 399: 473-486.
- Lin D, et al. (2022) Unemployment, homelessness, and other societal outcomes in patients with schizophrenia: a real-world retrospective cohort study of the United States Veterans Health Administration database : Societal burden of schizophrenia among US veterans. BMC Psychiatry 22: 458.
- Gutwinski S, et al. (2021) The prevalence of mental disorders among homeless people in high-income countries: An updated systematic review and meta-regression analysis. PLoS Med 18: e1003750.
- Dutta R, et al. (2010) Reassessing the long-term risk of suicide after a first episode of psychosis. Arch Gen Psychiatry 67: 1230-1237.
- Keshavan MS, et al. (2024) Schizophrenia A Practical Primer Second Edition: Routledge.
- Alliance SaPA (2020) Schizophrenia cost in the United States. sczaction.org.
- Correll CU, et al. (2024) What Remains to Be Discovered in Schizophrenia Therapeutics: Contributions by Advancing the Molecular Mechanisms of Drugs for Psychosis and Schizophrenia. Biomolecules 14.
- Acosta FJ, et al. (2012) Medication adherence in schizophrenia. World J Psychiatry 2: 74-82.
- Horan WP, et al. (2024) Efficacy of KarXT on negative symptoms in acute schizophrenia: A post hoc analysis of pooled data from 3 trials. Schizophr Res 274: 57-65.
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- Murray RM, et al. (2017) 30 Years on: How the Neurodevelopmental Hypothesis of Schizophrenia Morphed Into the Developmental Risk Factor Model of Psychosis. Schizophr Bull 43: 1190-1196.
- Chafee MV, et al. (2022) Unmasking Schizophrenia: Synaptic Pruning in Adolescence Reveals a Latent Physiological Vulnerability in Prefrontal Recurrent Networks. Biol Psychiatry 92: 436-439.
- Howes OD, et al. (2023) The synaptic hypothesis of schizophrenia version III: a master mechanism. Mol Psychiatry 28: 1843-1856.
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- Howes OD, et al. (2023) Neuroimaging in schizophrenia: an overview of findings and their implications for synaptic changes. Neuropsychopharmacology 48: 151-167.
- Sekar A, et al. (2016) Schizophrenia risk from complex variation of complement component 4. Nature 530: 177-183.
- Hanson KL, et al. (2022) Impact of Maternal Immune Activation on Nonhuman Primate Prefrontal Cortex Development: Insights for Schizophrenia. Biol Psychiatry 92: 460-469.
- Howes OD, et al. (2017) Inflammation and the neural diathesis-stress hypothesis of schizophrenia: a reconceptualization. Transl Psychiatry 7: e1024.
- Sonnenschein SF, et al. (2020) Dysregulation of Midbrain Dopamine System and the Pathophysiology of Schizophrenia. Front Psychiatry 11: 613.
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- Hribkova H, et al. (2022) Clozapine Reverses Dysfunction of Glutamatergic Neurons Derived From Clozapine-Responsive Schizophrenia Patients. Front Cell Neurosci 16: 830757.
- Correll CU, et al. (2024) The Economic Impact of Cognitive Impairment and Negative Symptoms in Schizophrenia: A Targeted Literature Review With a Focus on Outcomes Relevant to Health Care Decision-Makers in the United States. J Clin Psychiatry 85.
- Trujillo-Estrada L, et al. (2021) SPG302 Reverses Synaptic and Cognitive Deficits Without Altering Amyloid or Tau Pathology in a Transgenic Model of Alzheimer’s Disease. Neurotherapeutics.