Long-term Effects of Corticosteroids on Brain

Introduction

Corticosteroids, or glucocorticoid hormones (GCs), are produced in response to stress. This state is a threat to homeostasis (state of equilibrium). Adverse effects of GCs can be found in patients with endogenous or exogenous Cushing’s syndrome (a condition caused by long-term exposure to high levels of cortisol). When high levels of GCs are given, Cushing syndromepatients may develop physical and mental alterations like obesity, hypertension, menstrual irregularities, and neuropsychiatric pathologies. Cortisol affects brain functions like food intake, cognition, emotions, and autonomic responses. Structural and chemical changes can be observed in the brain.

What Are Glucocorticoids (GCs)?

GCs are steroid hormones released from the adrenal cortex, and the hypothalamic-pituitary-adrenal axis controls plasma concentration. They are used in diseases like asthma, immune-related and rheumatological diseases (conditions affecting muscles, joints, ligaments, and bones). When taken in high doses, adverse effects on psychology can be seen in 20 percent of patients, like depression, mania (mood disorder), and psychosis (a disconnection from reality). These symptoms can be reversible if GCs are discontinued among 75 percent of patients.

How Do Glucocorticoids or GCs Act?

GCs affect biological processes like growth, metabolism, immunity, and stress response. These hormones bind with specific receptors called mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). When a drug binds to a receptor forming a complex, it changes anti-inflammatory genes (NF-kB, AP-1, STAT, NFTA, c-Jun, Fos). It stops the production of cytokines and pro-inflammatory proteins (chemotactic proteins and adhesion molecules).

GCs affect metabolisms of glucose, lipid, protein, bone and cartilage, muscle function, cardiovascular system, hemolymphopoietic tissue, and reproductive physiology. They also control hunger, the sleep-wake cycle (circadian rhythms), learning, and memory.

How Do Glucocorticoids Affect the Brain?

Steroid receptors are present in different areas of the brain. Their function is to maintain many neurotransmitters (serotonin, dopamine). Glucocorticoids bring effects by acting on the hippocampal level, a structure that is involved in processing emotional information and memory.

Many studies have shown that a high level of cortisol results in hippocampal atrophy resulting in damage and cognitive impairment (reasoning, thinking, and remembering). Negative feedback causes activation of the hypothalamic-pituitary-adrenal axis, leading to increased cortisol production and damage to the brain structures.

Apart from therapeutic use, GCs have adverse effects, like

• Weight gain.

• Osteoporosis (bones become brittle and weak).

• Hyperglycemia (high blood glucose).

• Psychiatric and cognitive disturbances. These are the adverse effects on the central nervous system.

Behavioral Effects:

• Increased uptake of cortisone leads to Increased appetite resulting in weight gain.

• Restlessness and insomnia were observed.

• Steroid euphoria: Sense of well-being when treated with Prednisolone.

• Altered behavior like agitation and insomnia when injections of methylprednisolone are given.

• Muscle stiffness, insomnia, and abnormal behaviors like silence and stillness when prolonged treatment or high-dose corticosteroids were given.

Psychic Effects:

Some of the psychic effects are

• Depression (40.5 percent).

• Mania (27 percent).

• Psychosis (13.9 percent).

• Delirium (10.1 percent).

• Emotional disturbance.

• Irritability.

• Auditory hallucinations.

• Paranoia (unjustified suspicion).

• Altered consciousness.

• Disorientation.

Cognitive Effects:

Some cognitive effects are

• Difficulty in concentrating.

• Poor memory.

• Decreased hippocampal volume.

• Brain atrophy.

• Dementia (a group of symptoms affecting thinking, memory, and social abilities).

• Delirium.

What Is the Mechanism of Adverse Effects on CNS Due to Corticosteroids?

Administration of prednisone causes decreased levels of corticotrophin, norepinephrine, and beta-endorphin in cerebrospinal fluid. Increased release of glutamate occurs due to corticosteroid intake, and in turn, glutamate causes neuronal toxicity due to accumulation.

What Is the Onset and Incidence of Adverse Effects of Corticosteroids?

The appearance of symptoms varies by corticosteroids. It may arise at the start of the therapy, during, or at the end; 86 percent appear in the first five days of treatment. According to studies, the onset of psychiatric symptoms occurs an average of 11.5 days after the start of the therapy. Eighty-nine percent of patients develop symptoms in the first six weeks, 62 percent develop within two weeks, and 39 percent of patients develop in the first week. Duration of neuropsychiatric effects is highly variable depending on severity, treatment discontinuation, and other drugs given as a treatment.

What Are the Risk Factors for the Adverse Effects of Corticosteroids?

Adverse effects of psychiatric type depend on routes of administration, dose, gender, and age of the patient.

• When the dose is considered, 1.3 percent of the cases affected with psychiatric effects can be seen when a 40 milligrams daily dosage is given.18.4 percent can be found when the dosage of 80 milligrams is given daily.

• Some studies show that women are more affected than men by psychiatric manifestations.

• Studies have shown that ten years of the age group who received steroid therapy generally show hyperactivity, irritability, insomnia, decreased attention, and memory.

How Is It Diagnosed?

Diagnosis is made by using the following techniques

Magnetic Resonance Imaging (MRI): Changes in volume may be observed in the grey and white matter of the brain in Cushing’s syndrome patients.

MRI-Based Brain Volumetric Analysis: Volumes from many brain areas, like the corpus callosum and the cortical regions, get reduced. Increased volumes can be observed in the medial amygdala, bed nucleus of the stria terminalis, and hypothalamus.

Immunohistochemistry: Showed lower immunoreactivity of myelin basic protein (MBP) in many regions of the brain, but paradoxically increased MBP signal in the male cingulate cortex is seen.

Also observed were decreased glial fibrillary acidic protein (GFAP, a marker for reactive astrocytes) and ionized calcium-binding adapter molecule 1 (IBA1, a marker for activated microglia) in the cingulate regions of the anterior corpus callosum and hippocampus.

What Is The Treatment?

Treatment options are

• Discontinuation of the corticosteroids may help in symptom disappearance.

• Some may need therapeutic action, like reducing the dose or discontinuing the treatment with corticosteroids.

• Medications to treat psychiatric or neurological symptoms can be given.

• Mood-stabilizing drugs like lithium and valproic acid control symptoms caused by corticosteroids.

• Antidepressive drugs are different; tricyclic antidepressants could lead to a significant worsening of symptoms.

• Carbamazepine reduces neurotoxic effects. Selective serotonin reuptake inhibitors may improve symptoms of depression.

Conclusion:

Psychiatric effects are always tricky to assess and treat, as many side effects are unnoticed and neglected. Hence knowing about the corticosteroid's adverse effects on the brain is essential to notice these changes immediately. Early diagnosis is always better than late to accomplish effective treatment results. This helps in the determination of the dosage of corticosteroids to be given.