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Gene Editing with CRISPR/Cas9 to Treat Corticosteroid-Induced Neuropsychiatric Disorders (2023 Review)

The widespread use of corticosteroids (CCSs) across the globe for treating inflammatory conditions has led to an increased incidence of corticosteroid-induced neuropsychiatric disorders (NPDs), raising significant public health concerns.

These disorders range from depression and anxiety to severe cognitive changes, challenging the medical community to find effective treatments.

The exploration of genetic and epigenetic factors underlying these conditions, coupled with the advent of CRISPR/Cas9 gene-editing technology, offers a promising avenue for developing targeted therapies to either prevent or cure these complex disorders.


  1. Widespread CCS Use & NPDs: Corticosteroids, while critical in treating inflammatory diseases, have been linked to an array of neuropsychiatric disorders, making their side effects a significant concern for global public health.
  2. Genetic & Epigenetic Regulation: Genetic variants and epigenetic modifications play a crucial role in the brain’s response to CCSs, influencing the development of NPDs.
  3. CRISPR/Cas9 Gene Editing: The CRISPR/Cas9 system offers groundbreaking potential for correcting genetic abnormalities associated with NPDs, providing hope for targeted and effective therapies.
  4. Challenges & Future Directions: Despite its promise, the application of CRISPR technology in treating NPDs faces several challenges, including delivery mechanisms, ethical considerations, and the need for further research to ensure safety and efficacy.

Source: Diagnostics (Basel) (2023)

Corticosteroids & Neuropsychiatric Disorders (Overview)

How Corticosteroids Cause Neuropsychiatric Disorders

Corticosteroids, widely used for their anti-inflammatory and immunosuppressive properties, can induce neuropsychiatric disorders due to their profound effects on the central nervous system (CNS).

These effects include alterations in neurotransmitter levels, disruption of the hypothalamic-pituitary-adrenal (HPA) axis, and changes in brain structure and function.

Genetic vulnerabilities and epigenetic modifications further influence an individual’s risk of developing NPDs, making the response to corticosteroids highly variable among individuals.

Specific Neuropsychiatric Disorders Caused by Corticosteroids

  • Mood Disorders: Corticosteroid use is associated with mood swings, which can range from manic episodes to severe depression. Patients might experience euphoria, irritability, or depressive symptoms even with short-term use.
  • Anxiety Disorders: Increased anxiety levels, including panic attacks and generalized anxiety disorder, have been reported in patients undergoing corticosteroid therapy.
  • Cognitive Impairments: Long-term corticosteroid use can lead to deficits in memory, attention, and executive functioning. These cognitive changes can significantly impact daily living and may not fully reverse after cessation of therapy.
  • Psychotic Disorders: Although less common, corticosteroids can induce psychotic symptoms such as hallucinations and delusions, particularly at high doses or during prolonged treatment.
  • Sleep Disturbances: Insomnia and sleep disruption are frequently observed in patients taking corticosteroids, contributing to the overall burden of NPDs.

Strategies for Prevention & Treatment

Preventative strategies involve careful screening for susceptibility to NPDs before initiating corticosteroid therapy, dose optimization to minimize exposure while maintaining therapeutic efficacy, and close monitoring of psychiatric symptoms during treatment.

Treatment approaches for established NPDs include the use of psychiatric medications, counseling, and, in some cases, adjustment or discontinuation of corticosteroid therapy.

Emerging strategies focus on identifying and modifying genetic and epigenetic factors that increase the risk of NPDs, aiming for a more personalized approach to prevention and treatment.

Gene Editing with CRISPR as a Treatment

Gene editing, particularly through CRISPR/Cas9 technology, offers a novel and potentially transformative approach to preventing and treating corticosteroid-induced NPDs.

By directly targeting the genetic and epigenetic contributors to these disorders, gene editing can provide a more precise and personalized therapeutic strategy.

This approach could enable the correction of genetic variants or epigenetic alterations that predispose individuals to adverse psychiatric responses, potentially preventing the onset of NPDs or offering new avenues for treatment.

The ability to precisely modify the genome holds the promise of addressing the root causes of these disorders, offering hope for more effective and lasting solutions.

Some Genes Implicated in Corticosteroid-Induced Neuropsychiatric Disorders

The development of NPDs in response to corticosteroid therapy involves complex interactions between genetic predisposition and environmental factors, including the pharmacological action of corticosteroids.

  1. NR3C1 (Nuclear Receptor Subfamily 3, Group C, Member 1): This gene encodes the glucocorticoid receptor, which mediates the effects of corticosteroids. Variants in NR3C1 can affect the sensitivity and response of the HPA axis to stress and corticosteroids, potentially influencing the risk of developing mood disorders and other NPDs.
  2. FKBP5 (FK506 Binding Protein 5): FKBP5 regulates glucocorticoid receptor sensitivity. Polymorphisms in this gene have been associated with an increased risk of mood and anxiety disorders, particularly in the context of stress or corticosteroid exposure.
  3. CRHR1 (Corticotropin-Releasing Hormone Receptor 1): This gene plays a critical role in the stress response. Variations in CRHR1 have been linked to differences in stress reactivity, which may modulate the risk of anxiety and depression under corticosteroid treatment.
  4. BDNF (Brain-Derived Neurotrophic Factor): BDNF is involved in neuroplasticity, stress response, and resilience. Genetic variations in BDNF may influence the susceptibility to cognitive impairments and mood disorders associated with corticosteroid use.
  5. COMT (Catechol-O-Methyltransferase): COMT is essential for the breakdown of dopamine and other catecholamines in the brain. Variants of the COMT gene can affect dopaminergic neurotransmission, potentially impacting mood regulation and vulnerability to psychotic symptoms in patients treated with corticosteroids.

Corticosteroid-Related Psychiatric Disorders & Gene Editing (2023)

Manisha Singh et al. highlighted adverse effects associated with corticosteroid use, offering detailed insights into the genetic and epigenetic underpinnings that contribute to these conditions – as well as potential genetic treatments.

1. Genetic Variants & Epigenetic Factors

Genetic Predisposition

The review emphasizes the role of genetic variants in influencing individual susceptibility to NPDs following corticosteroid therapy.

Specific genetic markers, including polymorphisms in genes related to the stress response and neurotransmitter systems, have been linked to an increased risk of developing psychiatric symptoms after corticosteroid exposure.

These findings suggest that genetic predisposition plays a crucial role in determining the neurological impact of corticosteroids.

Epigenetic Modifications

Epigenetic mechanisms, such as DNA methylation, histone modification, and non-coding RNA interference, are highlighted as key factors in regulating gene expression in response to corticosteroid exposure.

These modifications can alter neuronal function and development, potentially leading to the onset of NPDs.

The review points to the dynamic nature of epigenetic changes, which can be influenced by environmental factors including drug use, stress, and diet, thereby modifying the risk of developing NPDs in susceptible individuals.

2. CRISPR/Cas9 Gene Editing for Treatment

Mechanism of Action

CRISPR/Cas9’s ability to precisely edit the genome is underscored as a transformative approach for directly addressing the genetic causes of corticosteroid-induced NPDs.

The system allows for targeted modifications, including knocking out harmful genes, correcting mutations, or inserting therapeutic genes, offering a high degree of specificity in gene editing.

Therapeutic Potential

The review provides detailed examples of how CRISPR/Cas9 has been utilized in research settings to model NPDs and explore potential interventions.

By editing genes implicated in stress response pathways, neurotransmitter regulation, and neuronal development, CRISPR/Cas9 offers a pathway to correct the underlying genetic aberrations associated with NPDs.

This approach holds promise for developing targeted therapies that could prevent or mitigate the neuropsychiatric effects of corticosteroids.

3. Challenges & Ethical Considerations

Delivery to the Brain

One of the critical challenges highlighted is the efficient delivery of CRISPR/Cas9 components to the brain.

The need to cross the blood-brain barrier and achieve targeted gene editing without affecting non-target cells or causing off-target effects remains a significant hurdle.

Safety & Off-target Effects

Concerns regarding the safety of CRISPR/Cas9, including potential unintended edits elsewhere in the genome, are discussed in depth.

The review calls for comprehensive studies to assess the long-term implications of gene editing and the development of strategies to minimize off-target effects.

Ethical & Regulatory Issues

The ethical implications of gene editing in humans, particularly for conditions that affect mental health and behavior, are a major focus.

The review emphasizes the need for a careful ethical framework to guide research and clinical applications, ensuring that interventions are safe, effective, and accessible to those in need.

Corticosteroid-Induced Psychiatric Disorders, Molecular Biology, Gene Editing (2023 Paper)

The aim of the paper was to provide a comprehensive overview of the emerging concerns associated with corticosteroid-induced neuropsychiatric disorders (NPDs), explore the molecular biology approaches that could revitalize NPD therapy, and evaluate the potential of gene-editing-based therapeutic strategies, particularly focusing on CRISPR/Cas9, to prevent or cure these disorders.


  • The review utilized a comprehensive literature search to gather data on the incidence and mechanisms of corticosteroid-induced NPDs, the role of genetic variants and epigenetic modifications in these conditions, and the latest advancements in gene-editing technologies.
  • It focused on articles, studies, and reports that detailed the molecular pathways affected by corticosteroids, the association between specific genetic markers and the risk of developing NPDs, and the application of CRISPR/Cas9 in modeling and potentially treating these disorders.
  • This methodological approach allowed for an in-depth analysis of the existing knowledge base and identification of areas where gene-editing techniques could offer new therapeutic opportunities.


  • Increased Incidence of NPDs: There is a significant rise in neuropsychiatric disorders attributed to corticosteroid use, including depression, anxiety, bipolar disorders, and psychosis, underscoring the clinical and public health challenge they represent.
  • Genetic & Epigenetic Factors: Many neuronal functional activities and susceptibility to NPDs are influenced by genomic variants and epigenetic factors such as DNA methylation and histone modification. These modifications can alter normal cerebral development and functioning, contributing to the pathogenesis of NPDs.
  • CRISPR/Cas9 Potential: The review emphasized the potential of CRISPR/Cas9 gene editing as a revolutionary approach for addressing the genetic basis of corticosteroid-induced NPDs. By targeting specific genetic and epigenetic alterations, CRISPR/Cas9 offers a promising avenue for developing precise and personalized therapies.
  • Therapeutic Strategies: It discussed various gene therapy interventions, including the CRISPR/Cas9 approach, for correcting genetic alterations that predispose individuals to NPDs, offering hope for more effective treatments and potentially curing these conditions in the future.


  • Complexity of Neuropsychiatric Disorders: NPDs are multifactorial and polygenic, involving complex interactions between genetic predispositions and environmental factors, making it challenging to identify specific targets for gene editing.
  • Delivery Mechanisms: Effective delivery of CRISPR/Cas9 components to target cells in the brain remains a significant hurdle, given the need to cross the blood-brain barrier and achieve precise editing without affecting non-target cells.
  • Ethical & Safety Concerns: The ethical implications of gene editing in humans, including potential off-target effects and long-term consequences of genomic alterations, are still matters of intense debate and require careful consideration.
  • Limited Clinical Applications: While CRISPR/Cas9 has shown promise in preclinical models, its application in clinical settings for treating NPDs is still in the early stages, and more research is needed to establish safety, efficacy, and regulatory approval pathways.

Why it may be better to target the disease itself instead of genes in corticosteroid therapy…

Targeting the underlying disease with gene editing, rather than focusing on the body’s response to corticosteroids, presents a more direct and potentially transformative approach to treatment.

This strategy aligns with the principles of precision medicine, aiming to address the root cause of diseases at the genetic level.

Direct Disease Modification

Gene editing has the potential to correct the genetic abnormalities at the heart of a disease, offering not just symptomatic relief but a curative outcome.

This starkly contrasts with managing corticosteroid responses, which only addresses the side effects of a treatment rather than the disease itself.

Long-term Efficacy & Cost-effectiveness

Sustainable Solutions: By correcting the disease at its genetic source, gene editing offers a long-term solution, potentially freeing patients from the need for ongoing treatments and the burden of their side effects. This could lead to significant cost savings over a patient’s lifetime, reducing the financial burden on healthcare systems.

Reduced Dependency on Pharmaceuticals: Targeting the disease directly decreases reliance on corticosteroids and other medications, which often come with a host of side effects and can significantly impact a patient’s quality of life.

Improved Patient Outcomes

Enhanced Quality of Life: Patients who receive a one-time, curative treatment can experience a dramatic improvement in their quality of life compared to those managing chronic conditions with medications like corticosteroids. This includes avoiding the psychological and physical side effects associated with long-term steroid use.

Precision & Personalization: Gene editing allows for tailored treatments based on an individual’s genetic makeup, offering a level of personalization that traditional pharmacological approaches cannot match. This precision can lead to higher efficacy rates and reduced risk of adverse effects.

Ethical & Practical Considerations

Proactive vs. Reactive Approach: From an ethical standpoint, targeting the disease itself is a more proactive approach to healthcare, focusing on eliminating the condition before it manifests severe symptoms or requires intensive treatment. This contrasts with the reactive approach of managing corticosteroid side effects, which only becomes necessary after the fact.

Technological & Scientific Advancement: Pursuing gene editing for disease treatment encourages further technological and scientific development. It pushes the boundaries of what’s possible in medicine, paving the way for innovative treatments that could benefit a wide range of conditions beyond those currently treated with corticosteroids.

Conclusion: Corticosteroid-Neuropsychiatric Reactions & Gene Editing

The comprehensive review on corticosteroid-induced neuropsychiatric disorders (NPDs) illuminates the intricate interplay between genetic predispositions, epigenetic modifications, and the adverse psychiatric effects of corticosteroid therapy.

It underscores the significance of CRISPR/Cas9 gene-editing technology as a groundbreaking approach for addressing the genetic underpinnings of these disorders, offering hope for targeted and effective treatments.

Despite the promise of CRISPR/Cas9, the review also highlights the challenges and ethical considerations that accompany its application, emphasizing the need for rigorous research, careful ethical deliberation, and interdisciplinary collaboration.

The potential of gene editing to revolutionize the treatment of corticosteroid-induced NPDs is substantial, promising more personalized and precise interventions.

However, realizing this potential will require overcoming technical obstacles, ensuring safety and ethical integrity, and conducting comprehensive clinical trials.

As the field advances, the integration of genetic insights with innovative therapeutic strategies holds the key to mitigating the neuropsychiatric side effects of corticosteroids and improving patient outcomes.


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