US Pharm. 2016;41(7):16-18.

Systemic corticosteroid use—such as treatment with prednisone, commonly used in respiratory disorders, rheumatoid arthritis, and other conditions common in older adults—has been associated with psychiatric adverse effects. Symptoms such as euphoria, insomnia, mood swings, personality changes, severe depression, and psychosis—referred to as corticosteroid-induced psychosis—have been estimated to develop in 5% to 18% of patients treated with corticosteroids.1 The primary risk factor for the development of corticosteroid-induced psychosis is a high dose of corticosteroids, with risk increasing  among patients taking 40 mg or more of prednisone or its equivalent daily; psychiatric adverse effects occur in 1.3% of cases when the dose is less than 40 mg daily and 18.4% of cases for doses of 80 mg daily.2-4 Additionally, some studies suggest that women are more prone to this condition.5 The therapeutic properties of corticosteroids are broad in scope (TABLE 1); it is not well understood whether corticosteroid-associated psychiatric symptoms are related to hippocampal effects, suppression of the hypothalamo–pituitary–adrenal (HPA) axis by dopamine neurotransmission, or other direct or indirect effects of corticosteroids.6-8

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Pharmacists serving senior patients should take note that glucocorticoids are the most commonly prescribed anti-inflammatory/immunosuppressant medications worldwide.9 Patients should be educated on the broad spectrum of psychiatric- and multi-organ adverse effects associated with these agents (TABLE 2) and play a participatory role in outcome development. Treatment decisions may require extensive discussion between the primary care provider and any consultants involved in the patient’s case, including the pulmonologist, rheumatologist, psychiatrist, and nephrologist.10


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PSYCHIATRIC SYMPTOMS AND CORTICOSTEROIDS

Since corticosteroids were first introduced in the 1950s, they have been associated with a spectrum of psychiatric symptoms.11 Symptoms range from subtle mood changes to memory deficits to frank psychosis that can occur at any time during treatment; reports include mania and hypomania (35%), depressive symptoms (28%), and psychotic reactions (24%).11,12 While symptoms typically develop within 3 to 4 days (median of 11 days) following the initiation of corticosteroid therapy, they can occur at any time, including after completion or discontinuation of therapy.10,13-15

Following cessation of corticosteroid therapy, it is reported that depressive symptoms persist for approximately 4 weeks; mania for 3 weeks; and delirium, for a few days. Approximately 50% of patients with corticosteroid-associated psychosis improve in 4 days and the other 50% within 2 weeks.16,17 Discontinuation of long-term glucocorticoid therapy is associated with an increased risk of both depression and delirium or confusion; older adults were found to be at higher risk of delirium or confusion.18 Individuals treated with long-acting glucocorticoids are particularly at risk.18

One study showed that patients with chronic obstructive pulmonary disease treated with oral prednisolone developed a sense of well-being referred to as “steroid euphoria,” characterized by a reduced sense of anxiety and depression when compared with patients receiving placebo, even in the absence of improvement in lung function.19 With regard to outpatients with pulmonary disease, Brown et al report that those who received 40 mg or more of corticosteroids for at least a week showed a significant increase in measurable manic symptoms. This prospective study identified a subset of patients—individuals meeting criteria for posttraumatic stress disorder—who developed dysphoric symptoms and were more likely to discontinue corticosteroids due to difficulties tolerating the mood symptoms.2

 

TREATMENT AND PREVENTION OF STEROID-INDUCED PSYCHOSIS

Corticosteroid Taper

Whenever possible, tapering corticosteroids—ideally to less than 40 mg daily—is recommended as a first step to manage corticosteroid-induced psychosis; tapering and discontinuation of steroids may be sufficient to improve psychiatric symptoms without requiring additional medications.10

According to experts, while the lack of high-quality prospective trials makes it difficult to establish an algorithm for the treatment of corticosteroid-induced psychosis, most case reports describe benefit from atypical antipsychotics and lithium.10 Studies of anticonvulsants have not supported their use.20-32 When symptoms are severe or when tapering steroids is not feasible, the following (off-label) psychopharmacologic treatment is recommended10:

 

Atypical antipsychotic agents: A low-dose atypical antipsychotic (e.g., olanzapine, risperidone, quetiapine) in conjunction with appropriate monitoring can be useful in alleviating symptoms of steroid-induced psychosis; for older adults, the lowest effective dose for the shortest effective duration is recommended.

 

Lithium: In selected individuals in whom renal insufficiency is not an issue, or in whom there is no need for a diuretic, ACE inhibitor, or non-steroidal anti-inflammatory drug (NSAID) therapy, lithium therapy may be an option; careful monitoring and vigilance for signs of toxicity is of the utmost importance in these patients. Of note, since many older adults taking corticosteroids have autoimmune illnesses that affect renal function, lithium may be difficult to use safely in this patient population.

 

Anticonvulsants: For patients in whom atypical antipsychotics or lithium are not tolerated, the use of valproic acid or carbamazepine with appropriate monitoring may be considered as alternatives.

 

Antidepressants: The use of selective serotonin reuptake inhibitors (SSRIs) may be helpful in individuals with depressive symptomatology in whom there is no history of mania; some evidence exists that tricyclic antidepressants may exacerbate the symptoms.

 

Preventing Steroid-Induced Symptoms

While clear guidelines regarding when to start preventive treatments do not exist, there are potential candidates for pretreatment with lithium or other agents, including patients who have developed psychiatric symptoms multiple times after repeated corticosteroid use or who are at high risk if psychiatric side effects occur.1

 

Use of Antipsychotics in Older Adults

Of note, antipsychotics should be used only for psychosis, as their use in nonpsychotic, agitated patients has been only marginally better than placebo in controlling symptoms (e.g., wandering, yelling, uncooperativeness) while placing these individuals at risk for severe adverse effects.33 Only when nonpharmacologic options have failed and patients are a threat to themselves or others should antipsychotics be considered for behavioral problems. Studies have shown that in patients with dementia, antipsychotic agents increased mortality and risk of stroke—thus the FDA black box warning regarding their use in this patient population.33

A baseline personal and family history, along with measurements of body-mass index, waist circumference, blood pressure, fasting plasma glucose, and fasting lipid profile, should be obtained prior to initiating an atypical antipsychotic; appropriate ongoing monitoring (e.g., weight, extrapyramidal adverse effects) is recommended. Note that while there are no clear monitoring recommendations, all antipsychotics can prolong the QTc interval.10,34,35

 

CONCLUSION

Pharmacists’ awareness of the risk of clinically significant and sometimes severe psychological, cognitive, and behavioral disturbances that may be associated with corticosteroid use is important, particularly in the vulnerable elderly in whom these symptoms may be misinterpreted. Medication therapy for corticosteroid-induced psychosis poses additional risk in the geriatric population. Discontinuation of long-term glucocorticoid therapy is associated with an increased risk of both depression and delirium or confusion, with older adults found to be at higher risk. In addition to having an awareness of this condition with its spectrum of symptoms, collaboration among clinicians regarding prevention and treatment is of the utmost importance.

 

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