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Med/Psych Update AND PSYCHOPATHOLOGY

Steroid-induced psychiatric symptoms: What you need to know

Early recognition of these symptoms is key to initiating effective interventions

s. N, age 30, presents to the emergency department for altered mental status, insomnia, and behavioral Mchanges, which she has experienced for 1 week. On evaluation, she grabs a clinician’s hand and details her busi- ness ideas and life story with no prompting. Ms. N’s mental status examination is significant for hyperverbal speech with increased rate and volume; tangential thought process; and bright, expanded affect. One week earlier, Ms. N was hospitalized for sudden-onset chest pain, weakness, and dizziness. She received 45 minutes of cardiopulmonary resuscitation prior to presentation and was found to have a ST-segment elevation myocardial infarction that required emergent left anterior descending coronary artery AGSANDREW/SHUTTERSTOCK and right coronary artery percutaneous coronary intervention to place -eluting stents. Her recovery was complicated by Yvonne Lu, BS acute cardiogenic shock, pulmonary , and hypoxic respi- Medical Student ratory failure. Subsequently, she was intubated, admitted to the University of California Irvine School of Medicine Irvine, California ICU, and received high-dose , including IV meth- ylprednisolone, 40 mg every 12 hours, which was tapered prior Lydia Ann, MD PGY-3 Psychiatry Resident to discharge. Her husband reports that since Ms. N came home, Department of Psychiatry she has been more talkative and irritable, ruminating about past University of California Irvine events, unable to sleep (<1 hour/night), and crying frequently. University of California Medical Center Orange, California She has also been endorsing visual and auditory hallucinations, with increased praying and listening to religious music. Robert McCarron, DO Professor and Vice Chair Department of Psychiatry The frequent clinical use of steroids necessitates an under- University of California Irvine standing of these ’ various adverse effects. University of California Medical Center continued Orange, California Disclosures The authors report no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products. Current Psychiatry doi: 10.12788/cp.0104 Vol. 20, No. 4 33 The manifestations of -induced have a rapid onset, possibly within hours psychiatric symptoms are broad and can of starting steroids.1 However, studies have involve affective, behavioral, and cognitive reported a median time to onset of 11.5 days; domains. While the current mechanism is 39% of cases had onset during the first week unknown, this phenomenon may be related and 62% within 2 weeks.3,6 After reducing to decreased levels of corticotropin, norepi- or stopping the steroid, it may take days to nephrine, and beta-endorphin immunoreac- weeks before symptoms start to subside.2 Steroids and tivity, as well as effects on brain regions such psychopathology as the hippocampus and amygdala. The best interventions for steroid-induced psychiatric What to consider in the symptoms are awareness and early diagno- differential Dx sis. There are no FDA-approved treatments Psychiatric symptoms that are induced by for steroid-induced psychiatric symptoms; steroids can mimic metabolic, neurologic, initial measures should include tapering or or toxic disorders. Other factors to consider discontinuing corticosteroids. include drug withdrawal/intoxication, In this article, we review the literature , and paraneoplastic syndromes.4,5 Clinical Point on the incidence, characteristics, differen- Although there is no reported correlation Mania/hypomania is tial diagnoses, proposed mechanism, risk between the location of neurologic lesions factors, and proposed treatments of steroid- and the development of specific psychiatric the most common induced psychiatric symptoms. symptoms, manic symptoms appear most steroid-induced commonly with lesions in the right frontal psychiatric symptom lobe. 4 Other factors to note include the pres- A wide range of presentations ence of new-onset psychiatric illnesses such Steroid use has increased over the past 2 as bipolar, mood, or thought disorders,4 as decades, with 10% of medical and surgi- well as psychosocial stressors that might be cal inpatients and 1% to 3% of the general contributing to the patient’s presentation.5 population taking long-term glucocorti- coids.1 Even with topical application, steroid therapy is often systemically absorbed, and Proposed mechanisms thus may lead to steroid-induced psychiatric Although the exact mechanism by which symptoms. The incidence of steroid-induced steroids induce psychiatric symptoms is psychiatric symptoms is difficult to assess unknown, several mechanisms have been because there can be a wide range of reac- proposed. One hypothesis is that steroid- tions that are dose- and time-related. Three induced psychopathology is related to reviews of a total of 122 cases reports found decreased levels of corticotropin, norepi- that an estimated 5% of patients treated nephrine, and beta-endorphin immuno- with steroids experience severe psychiatric reactivity.4,5,7 This may explain why many reactions.1-3 patients with major depressive disorder Steroid-induced psychopathology can have elevated production and/ include mood, behavioral, and/or cogni- or lack of suppression of cortisol secre- tive impairments. Mania/hypomania is the tion during a stimulation most common overall psychiatric symptom; test, and why approximately one-half of the most common mood manifestations are patients with Cushing’s disease experience anxiety and depression.4,5 Other possible ste- depressive symptoms.8 This is also likely roid-induced symptoms include psychosis, why , which typically reduce Discuss this article at , panic disorder, delirium, suicidal cortisol, are efficacious treatments for some www.facebook.com/ thinking and behavior, aggressive behav- steroid-induced psychiatric symptoms.9 MDedgePsychiatry ior, insomnia, agitation, depersonalization, Cognitive impairments from steroid and .5 The most common cogni- use may be related to these agents’ effects tive impairment is verbal or declarative on certain brain regions. One such area is memory deficit; others include distractibil- the hippocampus, an important media- ity and deficits in attention and psychomo- tor in the creation and maintenance of Current Psychiatry 34 April 2021 tor speed.5 These psychiatric symptoms can episodic and declarative memories.5,8,9 Acute use is associated with may allow hydrophobic steroid molecules decreased activity in the left hippocampus, to more easily penetrate the CNS, lead- reduced hippocampal glucose , ing to increased neuropsychiatric effects. and reduced cerebral flow in the pos- Hypoalbuminemia is another reported MDedge.com/psychiatry terior medial temporal lobe.10 Long-term risk factor, perhaps because lower levels of glucocorticoid exposure is associated with serum albumin are related to higher levels smaller hippocampal volume and lower of free and active , which levels of temporal lobe N-acetylaspartate, are normally inactive when bound to albu- a marker of neuronal viability.10 Because min.13 There also appears to be an increased working memory depends on the prefron- prevalence of steroid-induced psychopa- tal cortex and declarative memory relies on thology in women, perhaps due to greater the hippocampus, deficits in these functions propensity in women to seek medical care can be attributed to the effect of prolonged or a higher prevalence of women with med- glucocorticoid exposure on glucocorticoid ical disorders that are treated with steroids.5 or mineralocorticoid receptors in the hippo- A previous history of psychiatric disorders campus, reduction of hippocampal volume, may not increase risk.5 or elevated glutamate accumulation in Several methods for reducing risk have Clinical Point 11 that area. In addition, high cortisol levels been proposed, including using a divided- Starting valproate inhibit brain-derived neurotrophic factor, dosing regimens that may lower peak ste- which plays a crucial role in maintaining roid plasma concentrations.13,14 However, while continuing neural architecture in key brain regions the best prevention of steroid-induced corticosteroids may such as the hippocampus and prefrontal psychiatric symptoms are awareness, help lessen mania cortex.11 There is also a correlation between early diagnosis, and intervention. Studies the duration of treatment and have suggested that N-methyl-d-aspartate atrophy of the right amygdala, which is an (NMDA) antagonists15 and other agents important regulator of mood and anxiety.11 that decrease glutamate release (such as Both the hippocampus and amygdala have phenytoin and lamotrigine16) may help dense collections of glucocorticoid recep- prevent -induced hippocam- tors. This may explain why patients who pal volume loss. Lamotrigine has been receive high-dose corticosteroids can have shown to reduce the amount of atrophy in reversible atrophy in the hypothalamus and the amygdala in patients taking corticoste- amygdala, leading to deficits in emotional roids.17 Phenytoin has also been reported to learning and the response. reduce the incidence of hypomania associ- ated with corticosteroids, perhaps due to its induction of CYP450 activity and accelera- Factors that increase risk tion of steroid clearance.16 Several factors can increase the risk of steroid-induced psychopathology. The most significant is the dose; higher doses Treatment options are more likely to produce psychiatric There are no FDA-approved medications symptoms.1,5 Concurrent use of that for managing steroid-induced psychiatric increase circulating levels of corticosteroids, symptoms.1,16 Treatment is based on evi- such as inhibitors of the cytochrome P450 dence from case reports and a few small (CYP) enzyme (eg, clarithromycin), also case series (Table,2-5,17,18 page 36). increases the likelihood of developing psy- When possible, initial treatment should chiatric symptoms.1,5 Risk is also increased include discontinuing or tapering cortico- in patients with liver or renal dysfunc- steroids to <40 mg/d of prednisone-equiv- tion.1 Cerebral spinal fluid/serum albu- alent.1,4,10,18 Most studies have reported min ratio, a marker of blood-brain barrier rapid reversal of deficits in declarative damage, and low serum complement levels memory and of hippocampal volume loss were also reported to be independent risk once corticosteroids were tapered and dis- factors,12 with the thought that increased continued.1,18 One study reported that >90% Current Psychiatry permeability of the blood-brain barrier of patients recovered within 6 weeks, with Vol. 20, No. 4 35 Table Proposed treatments for steroid-induced psychiatric symptomsa Symptom Proposed treatments Mania/hypomania Mood stabilizers (valproate, lithium, lamotrigine) Antipsychotics (quetiapine, olanzapine, haloperidol), with or without a benzodiazepine Steroids and Depression SSRIs (sertraline, paroxetine) psychopathology Antipsychotics (especially risperidone) Lithium ECT Agitation Benzodiazepines Haloperidol Second-generation antipsychotics aThese proposed treatments are off-label and largely anecdotal ECT: electroconvulsive therapy; SSRIs: selective serotonin reuptake inhibitors Source: References 2-5,17,18 Clinical Point ECT is effective for patients with patients with delirium recovering more help lessen mania.2 Benzodiazepines also persistent and/or quickly (mean: 5.4 days) than those with may be useful on a short-term basis. unresponsive depression, mania, or psychosis (mean: 19.3 Depression. Steroid-induced depression steroid-induced days).3 Another found that the vast major- may be treated with sertraline or other first- ity (92%) of patients treated only with a line .5,14 Consider ECT for depression steroid taper achieved clinical recovery, patients with severe depression. Support for and 84% recovered with administration of the use of medications stems antipsychotics without a steroid taper.3 In from studies that reported steroids’ role in this study, all patients who received electro- disrupting dopamine and 5HT2 activity. convulsive therapy (ECT) recovered, as did Lithium also has been used successfully to those who received a steroid taper plus lith- manage and prevent glucocorticoid-asso- ium or antipsychotics. Steroid tapering reg- ciated affective disorder.10,18 It can be used imens are especially important for patients alone or in combination with selective sero- who have received long-term glucocorti- tonin reuptake inhibitors to alleviate depres- coid treatment. Patients need to be closely sive symptoms.10 Tricyclic antidepressants monitored for signs of new or increased are generally avoided because their anti- depression, delirium, or confusion dur- cholinergic effects can exacerbate or worsen ing the taper. If these symptoms occur, the delirium.18 In general, ECT is an effective patient should be checked for adrenocorti- treatment for persistent and/or unrespon- cal insufficiency, which can be resolved by sive steroid-induced depression,2,10 but may re-administering or increasing the dosage be difficult to use in patients with serious of the glucocorticoid.10 medical illnesses. Mania. The treatment of mania/hypomania Agitation. Medications that have been includes mood stabilizers (valproate, lithium, proposed for treating steroid-induced agita- lamotrigine) and antipsychotics (quetiapine, tion include benzodiazepines, haloperidol, olanzapine, haloperidol).2,4,5,10,14,18 Valproate and second-generation antipsychotics.5,17 has been reported to be an effective pro- Other considerations. Clinicians, patients, phylactic of corticosteroid-induced mania,2 and families should discuss in detail the perhaps because it dampens neuronal hyper- risks of steroid-induced psychiatric symp- excitability by attenuating NMDA receptors, toms so an early diagnosis and appropriate blocking voltage-dependent chan- intervention can be implemented. Before nels, and inhibiting the synthesis of cortical starting steroids, it is important to review GABAergic steroids. Starting valproate while the patient’s current list to Current Psychiatry 36 April 2021 continuing corticosteroids (if necessary) may ensure that steroid treatment is indicated, and to check for potential drug–drug inter- actions. In addition, the medical condition Related Resources that is being treated with steroids also needs • Janes M, Kuster S, Goldson TM, et al. Steroid-induced psychosis. Proc (Bayl Univ Med Cent). 2019;32(4):614-615. to be carefully reviewed, because certain ill- MDedge.com/psychiatry • Mayo Clinic. Prednisone and other corticosteroids. https:// nesses are associated with the development www.mayoclinic.org/steroids/art-20045692 5,10 of psychiatric symptoms. Drug Brand Names Young children (age <6) and older adults Haloperidol • Haldol Paroxetine • Paxil appear to be at greater risk for cognitive and Lamotrigine • Lamictal Phenytoin • Dilantin 10 Lithium • Eskalith, Lithobid Quetiapine • Seroquel memory disturbances from steroid use. In Risperidone • Risperdal addition, patients have individual levels of injection • Solu-Medrol Sertraline • Zoloft Olanzapine • Zyprexa Valproate • Depakote susceptibility to steroid-induced psychiatric symptoms that can vary over time. The risk for adverse effects may be elevated based on response to previous courses of glucocorti- coid treatment.10 While gender, age, dosage, and future studies can help uncover a and duration of treatment influence risk, it deeper understanding of the intricacies of is not possible to predict which patients will this phenomenon. Clinical Point experience psychiatric effects during a given Benzodiazepines, course of glucocorticoid therapy. Therefore, CASE CONTINUED all patients should be considered to have Mrs. N is admitted for altered mental status. haloperidol, and the potential of developing such effects, and Medical workup includes MRI of the brain, MRI second-generation should be monitored during glucocorticoid of the neck, cardiac echocardiogram, and EEG. antipsychotics have treatment and withdrawal. There is no evidence of acute structural pathol- been used to treat ogy. She is started on olanzapine, 10 mg/d at steroid-induced bedtime for manic and psychotic symptoms, Goals for future research and is discharged after 5 days. After 1 month, agitation To help reduce the severity of and cost the outpatient psychiatrist gradually decreases associated with steroid-induced psychi- and discontinues olanzapine as Mrs. N steadily atric symptoms,5,14 future studies should returns to baseline. One year after discharge, focus on controlled trials of preventative Mrs. N continues to report resolution of her strategies. In particular, recent advances in manic and psychotic symptoms. genetic mapping may help identify involve- References ment of certain or polymorphisms.5 1. Dubovsky AN, Arvikar S, Stern TA, et al. The Because current guidelines for the pre- neuropsychiatric complications of glucocorticoid use: steroid psychosis revisited. Psychosomatics. 2012;53(2): vention and treatment of steroid-induced 103-115. psychiatric symptoms are not evidence- 2. Roxanas MG, Hunt GE. Rapid reversal of corticosteroid- induced mania with sodium valproate: a case series of 20 based, controlled clinical trials are needed patients. Psychosomatics. 2012;53(6):575-581. to elucidate the optimal management of 3. Lewis DA, Smith RE. Steroid‐induced psychiatric syndromes. A report of 14 cases and a review of the literature. such symptoms. There is much interplay J Affect Disord. 1983;5(4):319-332. between many of the proposed mechanisms 4. Warren KN, Katakam J, Espiridion ED. Acute-onset mania in a patient with non-small cell lung cancer. Cureus. of steroid-induced psychiatric symptoms, 2019;11(8):e5436. continued Bottom Line Steroids can induce a wide range of psychiatric symptoms, including mania/ hypomania, anxiety, and depression. Initial treatment typically includes tapering or discontinuing the steroid when possible. Other proposed treatments include certain antipsychotics, antidepressants, and other psychotropics, but the supporting evidence is largely anecdotal or based on case studies. Additional Current Psychiatry research is needed to elucidate the mechanism and treatment recommendations. Vol. 20, No. 4 37 5. Kenna HA, Poon AW, de los Angeles CP, et al. Psychiatric behavioral effects. Am J Psychiatry. 2014;171(10):1045-1051. complications of treatment with corticosteroids: review with 12. Appenzeller S, Cendes F, Costallat LT. Acute psychosis case report. Psychiatry Clin Neurosci. 2011;65(6):549-560. in systemic lupus erythematosus. Rheumatol Int. 2008; 6. Ling MH, Perry PJ, Tsuang MT. Side effects of corticosteroid 28(3):237-243. therapy. Psychiatric aspects. Arch Gen. Psychiatry. 1981;38(4): 13. Glynne-Jones R, Vernon CC, Bell G. Is steroid psychosis 471-477. preventable by divided doses? Lancet. 1986;2(8520):1404. 7. Ularntinon S, Tzuang D, Dahl G, et al. Concurrent treatment 14. Ismail MF, Lavelle C, Cassidy EM. Steroid-induced mental of steroid-related mood and psychotic symptoms with disorders in cancer patients: a systematic review. Future risperidone. Pediatrics. 2010;125(5):e1241-e1245. Oncol. 2017;13(29):2719-2731. 8. Pokladinkova J, Meyboom RH, Vlcek J, et al. Intranasally 15. Magariños AM, McEwen BS. Stress-induced atrophy administered corticosteroids and neuropsychiatric of apical dendrites of hippocampal CA3c neurons: Steroids and disturbances: a review of the international pharma­ involvement of glucocorticoid secretion and excitatory covigilance programme of the World Health Organization. amino acid receptors. Neuroscience. 1995;69(1):89-98. psychopathology Ann Allergy Asthma Immunol. 2008;101(1):67-73. 16. Brown BS, Stuard G, Liggin JDM, et al. Effect of phenytoin 9. Walker EF, Trotman HD, Pearce BD, et al. Cortisol levels and on mood and declarative memory during prescription risk for psychosis: initial findings from the North American corticosteroid therapy. Biol Psychiatry. 2005;57(5): prodrome longitudinal study. Biol Psychiatry. 2013;74(6): 543-548. 410-417. Clinical Point 17. Desai S, Khanani S, Shad MU, et al. Attenutation of amygdala 10. Wolkowitz OM, Reus UI. Treatment of depression with atrophy with lamotrigine in patients receiving corticosteroid While certain patients antiglucocorticoid drugs. Psychosom Med. 1999;61(5): therapy. J Clin Psychopharmacol. 2009;29(3):284-287. 698-711. 18. Gable M, Depry D. Sustained corticosteroid-induced mania are at higher risk, all 11. Judd LL, Schettler PJ, Brown ES, et al. Adverse consequences and psychosis despite cessation: a case study and brief patients should be of glucocorticoid medication: psychological, cognitive, and literature review. Int J Psychiatry Med. 2015;50(4):398-404. considered to have the potential to develop steroid-induced psychiatric symptoms

Current Psychiatry 38 April 2021