Schizophrenia is a chronic mental disorder that affects how an individual thinks, behaves, and perceives reality. While it presents with a range of symptoms, it is most commonly characterized by hallucinations, delusions, and difficulty expressing emotions. In addition to these symptoms, schizophrenia also impacts cognitive function, social interactions, and daily living, making it one of the leading causes of disability worldwide.1
Although current treatments can significantly reduce psychotic symptoms, they do not fully address the underlying biological mechanisms of the disorder. Research suggests that schizophrenia is rooted in brain development and neural connectivity, with disruptions in specific signaling pathways, such as the Wnt pathway, potentially playing a role in its development.1 Understanding these mechanisms could pave the way for more effective treatments in the future.
The Basics of Wnt Signaling
Wnt signaling is a crucial pathway involved in cell development, differentiation, and neural function. It is divided into three main pathways:
- Canonical Wnt Pathway: This pathway is β-catenin-dependent and involves glycogen synthase kinase 3 beta (GSK3β) and β-catenin. It regulates gene transcription by controlling the stability of β-catenin.
- Wnt-Calcium Pathway: This pathway is β-catenin-independent and leads to an increase in intracellular calcium levels. It activates protein kinase C (PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII), which will influence cell movement and signaling.
- Non-Canonical/Planar Cell Polarity (PCP) Pathway: This pathway is β-catenin-independent, and involves Disheveled (Dvl) activation, which then stimulates Rho and Rac which are two proteins responsible for cytoskeletal organization and cell polarity.
A pictural representation of the different pathways can be found in Figure 1 below.
Figure 1. The three main Wnt signaling pathways. (a) canonical Wnt signaling, (b) Wnt-calcium signaling, and (c) non-canonical Wnt/planar cell polarity signaling. 1
Each of these pathways plays a distinct role in cellular function, but it is the canonical Wnt pathway that is most often associated with schizophrenia. The two key components in this pathway are GSK3β and β-catenin.
Under normal conditions, active GSK3β promotes the degradation of β-catenin, decreasing its concentration in the cell which will result in inhibiting gene transcription. However, when GSK3β is inhibited, β-catenin remains stable and accumulates in the nucleus, where it activates Wnt target genes. Dysregulation of this process has been implicated in schizophrenia, suggesting that altered Wnt signaling may contribute to the disorder’s underlying neurobiological mechanisms.
Figure 2 give a good overall drawing of the many pathways of Wnt signaling.
Figure 2. A diagram that illustrates the pathways of Wnt signaling and how some medications alter this pathway.1
Here is an article that takes a deep dive into understanding the canonical Wnt pathway and how it might play a role in schizophrenia.
Medications and Their Effects on the Wnt Pathway
Since Wnt signaling plays a key role in brain development and synaptic plasticity, it is not surprising that some schizophrenia medications interact with this pathway. Two major classes of medications include lithium and dopamine D2 receptor antagonists (antipsychotics). These medications have been shown to influence Wnt signaling, particularly by affecting GSK3β and β-catenin levels.
Lithium is a mood stabilizer commonly used as a first-line treatment for bipolar disorder, but research suggests it may also provide therapeutic benefits for schizophrenia.1,2 Once inside the cell, lithium inhibits GSK3β, preventing it from degrading β-catenin. As a result, β-catenin accumulates, enters the nucleus, and promotes gene transcription. This mechanism is believed to contribute to lithium’s neuroprotective and mood-stabilizing effects, which may help improve symptoms in some individuals with schizophrenia.2
Traditional antipsychotic medications primarily work by blocking dopamine D2 receptors. This blockade prevents β-arrestin from inhibiting AKT, leading to AKT being active. Since AKT inhibits GSK3β, this cascade results in reduced GSK3β activity and an increase in β-catenin levels.1
Lithium’s Role in Treating Mood Disorders
Lithium has long been a key treatment for mood disorders, especially bipolar disorder. Additionally, research has highlighted its potential benefits for major depressive disorder (MDD).2 One of lithium’s most significant effects is its ability to reduce suicidal thoughts and behaviors, making it one of the few psychiatric medications known to have anti-suicidal properties.
Lithium helps modulate key neurotransmitters, including dopamine and serotonin. It is believed to reduce excessive dopamine activity, often linked to psychosis, while simultaneously increasing serotonin levels, contributing to its antidepressant effects.3 This dual action stabilizes mood and helps reinstate homeostasis.
Beyond neurotransmitter regulation, lithium is thought to enhance synaptic plasticity and strengthen neural connectivity.2Research indicates that lithium can strengthen connections in brain regions involved in emotion regulation, such as the prefrontal cortex and hippocampus. This neuroprotective effect has led researchers to explore lithium’s potential in treating neurodegenerative diseases like Alzheimer’s disease, due to its ability to support neuronal survival and cognitive function.
While lithium is primarily used for bipolar disorder, emerging research suggests it may also benefit individuals with schizophrenia, particularly those experiencing mood symptoms. Given that both schizophrenia and mood disorders involve dysregulated Wnt signaling and abnormal neural connectivity, lithium’s ability to modulate these pathways may help explain its therapeutic effects in both conditions.
Here is an article on how lithium can play a role in neuroplasticity and its potential for mood disorders.
Final Thoughts
While there are numerous medications available for schizophrenia, much remains to be learned about their mechanisms and optimal use. Lithium can significantly address many mood-related symptoms of the disorder, but it does not effectively target the psychiatric symptoms associated with schizophrenia. Therefore, combining lithium with antipsychotic medications is often a common strategy to support individuals with this condition.
However, antipsychotic medications come with their own set of concerns, including significant side effects. Combining two medications that influence major biological pathways may introduce additional complications. Continued research is essential, and it may eventually lead to the discovery of an ideal combination of treatments that can improve the quality of life for those affected by schizophrenia.
References
(1) Singh, K. K. An Emerging Role for Wnt and GSK3 Signaling Pathways in Schizophrenia. Clin Genet 2013, 83 (6), 511–517. https://doi.org/10.1111/cge.12111.
(2) Gray, J. D.; Mcewen, B. S. Lithium’s Role in Neural Plasticity and Its Implications for Mood Disorders. Acta Psychiatr Scand 2013, 128 (5), 347–361. https://doi.org/10.1111/acps.12139.
(3) Pérez de Mendiola, X.; Hidalgo-Mazzei, D.; Vieta, E.; González-Pinto, A. Overview of Lithium’s Use: A Nationwide Survey. Int J Bipolar Disord 2021, 9 (1). https://doi.org/10.1186/s40345-020-00215-z.
