Violeta O. Tan, MD; and Natalie L. Rasgon, MD, PhD, are with Stanford University, Department of Psychiatry and Behavioral Sciences.
Dr. Tan and Dr. Rasgon have disclosed no relevant financial relationships.
The authors would like to thank Craig Barr Taylor, MD, Professor and Director of the Psychiatry Residency Training Program at Stanford University, for his support and direction in their efforts. They would also like to acknowledge Christophe Gimmler, MD, Hospitalist at the Palo Alto VA, and Paul Helgerson, MD, Chief of Inpatient Medicine at the Palo Alto VA and Clinical Assistant Professor of Internal Medicine at Stanford, for their assistance.
Address correspondence to: Violeta O. Tan, MD, Stanford University, Department of Psychiatry and Behavioral Sciences, 401 Quarry Road, Palo Alto, CA 94305; or e-mail firstname.lastname@example.org.
A 54-year-old man with history of depression and posttraumatic stress disorder (PTSD) was re-admitted to the hospital with the chief complaint of malaise. Previous admission 9 days prior was for a urinary tract infection (UTI), which was treated with ciprofloxacin 500 mg bid. During this first admission, his outpatient psychotropic medications (quetiapine 300 mg/day and bupropion 225 mg/day) were restarted without titration. He had self-discontinued these agents 6 to 8 months prior after reportedly feeling well. Patient was discharged on hospital day 4 in stable condition with ciprofloxacin 500 mg bid, quetiapine 300 mg/day, and bupropion 225 mg/day. He was feeling well until 5 days after discharge when he began experiencing fatigue, warmth, chills, and loose stools, for which he was re-admitted to the hospital.
During this second hospitalization, review of symptoms was significant for mild headache and 3 to 4 days of reproducible chest wall pain. Physical exam was benign, except for noted lethargy and tenderness to palpation in the mid-clavicular line at his 5th rib. Baseline labs were normal except for elevated eosinophils ranging from 6.5% to 8.3%, which were previously within normal limits during initial hospitalization. Past medical history was significant for a history of pulmonary nodules, depression, and PTSD. Social history was significant for a 20+ pack/year smoking history.
An extensive work-up for organic causes of fatigue and weight loss was undertaken. Infectious etiologies were pursued because the patient had recently been hospitalized for a urinary tract infection (UTI), and resistance was in question. Urinalysis, urine cultures, and white blood cell (WBC) count were all normal, however. Three sets of blood cultures were held for 21 days for fastidious organisms, and returned negative with the exception of Propionibacterium in one of the bottles. A lumbar puncture (LP) was performed and was normal except for mildly elevated protein. HIV antibody (Ab), syphilis enzyme-linked immunosorbent assay (ELISA), and lyme Ab all returned negative. The patient completed a full course of antibiotics for his previous UTI without consequence. Malignancy was also considered in light of his history of pulmonary nodules and smoking. However, a computerized tomography (CT) of the chest revealed no change in the pulmonary nodules as well as a normal chest wall without bony abnormalities. Rheumatologic causes were considered, but C-reactive protein (CRP) was within normal limits, and erythrocyte sedimentation rate (ESR) was only borderline high.
In examining endocrine causes, early morning cortisol level was low at 2.5 μg/mL. Cosyntropin stimulation test was performed with cortisol appropriately increasing from 4.2 μg/mL to 20.4 μg/mL, suggesting that primary adrenal insufficiency was unlikely. Brain magnetic resonance imaging (MRI) showed no evidence of pituitary microadenoma, and hormone levels including testosterone, prolactin, and insulin-like growth factor (IGF) were within normal limits. However, adrenocorticotropic hormone (ACTH) level was noted to be < 5 pg/mL, which was indicative of secondary or tertiary adrenal in-sufficiency. A review of the patient’s medications was undertaken, specifically his psychotropic medications, which had recently been restarted during his previous hospitalization after he self-discontinued them for several months. The potential for quetiapine to reduce ACTH and cortisol secretion in healthy subjects was considered. Given the potential mood benefits with quetiapine, he was continued on this agent while Prednisone 20 mg qam/10 mg qhs was initiated, after which the patient’s condition improved markedly.
Adrenal Insufficiency Caused by Quetiapine
He was discharged on this dose of Prednisone and given follow-up appointments with an endocrinologist and his psychiatrist for further management. Eventually, his outpatient psychiatrist and endocrinologist both agreed to taper and discontinue quetiapine while adding a replacement psychotropic agent, aripiprazole. His prednisone was simultaneously tapered from 20 mg qam/10 mg qhs to 5 mg qam/2.5 mg qhs. In subsequent follow-up visits, the patient reported not sleeping as well and having lethargy during the day, feeling that aripiprazole was not helping him as quetiapine had. Cosyntropin stimulation test was repeated during the prednisone taper with normal response, poststimulation yielding cortisol level of 20.8 μg/dL. He was re-stimulated 4 months later, again with normal response and post-stimulation cortisol level at 22.5 μg/dL. Given the two normal stimulation tests on non-suppressive doses of prednisone, his endocrinologists subsequently discontinued the corticosteroid. Six months later, the patient’s morning serum cortisol level was rechecked and found to be normal at 13.5 μg/mL, which was evidence toward resolved adrenal insufficiency in the absence of quetiapine.
Adrenal insufficiency is a rare but life-threatening disease when overlooked. The condition often presents ambiguously with nonspecific presenting symptoms such as fatigue, anorexia, and weight loss.1 Psychotropic medications are less recognized as causative factors, contributing to this diagnostic challenge. Although atypical antipsychotics have been shown to reduce cortisol levels with consequent improvement in psychopathology, the extent of cortisol reduction may be detrimental. Understanding the relationship of antipsychotics on the hypothalamic pituitary adrenal axis and recognizing the variable presentations of adrenal insufficiency can be key in accurate diagnoses and management.
Adrenal Insufficiency and Clinical Manifestations
Adrenal insufficiency syndrome is characterized by an impaired ability of the adrenal cortex to produce cortisol in response to normal physiologic demands.2 The syndrome is caused by either primary adrenal failure or by impairment of the hypothalamic-pituitary corticotropic axis.1 Primary adrenal insufficiency, or Addison’s disease, occurs when there is destruction of adrenal tissue resulting in diminished excretion of cortisol. Secondary adrenal insufficiency may be caused by any disease process that affects the anterior pituitary and interferes with ACTH secretion. This may be due to compromised hypothalamic-pituitary system or suppressed adrenal-pituitary axis by exogenous steroids.2 In addition, tertiary adrenal insufficiency can be caused by any process that involves the hypothalamus and interferes with the corticotropin-releasing hormone (CRH) secretion, the most common causes being abrupt cessation of high-dose glucocorticoid therapy and treatment of Cushing’s syndrome, an endocrine disorder caused by high levels of cortisol in the blood from a variety of causes.3
The main symptom of chronic adrenal insufficiency is severe fatigue, which was our patient’s primary presenting complaint. This can be accompanied by lack of stamina, loss of energy, reduced muscle strength, increased irritability, and depression. Affected women frequently complain of impaired libido.1 Occasionally, gastrointestinal (GI) symptoms may predominate as primary complaints with nausea, vomiting, and diarrhea,2 as was noted in our patient. Both glucocorticoid and mineralocorticoid secretion are compromised in primary adrenal insufficiency. Mineralocorticoids, being controlled by the renin-angiotensin system, are preserved in secondary adrenal insufficiency. These deficiencies account for the clinical manifestations of the disorder. Deficiency of glucocorticoids leads to weight loss, nausea, anorexia, and muscle and joint pain,1 which were some of the same symptoms noted in our case. Laboratory findings suggestive of glucocorticoid deficiency can include lymphocytosis, mild anemia, and eosinophilia,1 which was detected in our patient on readmission and corrected after treatment with prednisone. Deficiencies of both glucocorticoid and mineralocorticoid lead to certain unique signs and symptoms associated with Addison’s disease that are absent in secondary adrenal in-sufficiency. These may include hyperpigmented skin in sun-exposed areas, salt cravings, hyperkalemia, and hyponatremia.3
Because most of these symptoms are nonspecific, misdiagnosis is a common occurrence. Estimates suggest that 50% of patients have signs and symptoms of Addison’s disease for more than 1 year before a diagnosis is established.4 Patients with hypocortisolemia can, furthermore, present with symptoms that easily meet criteria for psychiatric disorders such as PTSD, bipolar disorder, attention deficit disorder, depression, or anxiety disorders,5 making them vulnerable to false diagnoses and potentially fatal consequences. Alternatively, the symptoms of adrenal insufficiency may be mistaken for side effects commonly associated with antipsychotic agents. Mortality in secondary adrenal insufficiency is mainly because of vascular and respiratory disease due to hypopituitarism or deficiencies of other hormonal axes. Although mortality in primary adrenal insufficiency has not been studied, life expectancy may be reduced from unrecognized adrenal crisis. Chronic adrenal in-sufficiency also has an adverse effect on health-related quality of life that is comparable to that of congestive heart failure.1
Psychiatric Disorders and Antipsychotic Effects on HPA Axis
Understanding the potential effects of psychiatric disorders and antipsychotics on the hypothalamic-pituitary-adrenal (HPA) axis can prevent missed diagnoses of adrenal insufficiency. HPA axis dysfunction is a frequent finding in psychiatric disorders, including psychotic depression and schizophrenia, and manifests as hypersecretion rather than an insufficiency of cortisol.6,7 Overactivity of the HPA axis is consistently found in patients suffering from major depression, and elevated cortisol levels are linked to both the general symptomatology of depression and negative symptoms in schizophrenia.6 Studies have demonstrated that atypical antipsychotics may cause a reduction in cortisol levels usually in association with an improvement in psychopathology.6 To our knowledge, the only atypical antipsychotics studied so far for their influence on cortisol levels are amisulpride, clozapine, olanzapine, and quetiapine.6
Quetiapine is an atypical antipsychotic developed in 1984 approved by the U.S. Food and Drug Administration (FDA) for treatment of schizophrenia, acute bipolar mania, and bipolar depression.8,9 In May 2008, the FDA approved quetiapine for the maintenance treatment of patients with bipolar I disorder, as adjunct to lithium or divalproex.10 Beyond what the FDA has approved, the medication may also have potent antidepressant and anxiolytic effects in patients with psychotic disorders and obsessive-compulsive disorder (OCD). A recent study among patients in a psychiatric hospital found quetiapine extensively used off-label for conditions including depression, agitation or insomnia.11 Its mechanism of action includes antagonism at serotonin 2A (5-HT2A) receptors relative to dopamine2 (D2) receptors.8
In a double-blind, placebo-controlled, randomized cross-cover study by Cohrs et al, two different doses of quetiapine (100 mg and 25 mg) significantly decreased the total amount of nocturnal urinary cortisol excretion when compared with placebo.12 This was followed by another double-blind, placebo-controlled, randomized cross-cover study in healthy subjects comparing atypical antipsychotics quetiapine (50 mg) and olanzapine (5 mg) with haloperidol (3 mg) and placebo on plasma ACTH and cortisol levels. Results revealed that oral administration of quetiapine and olanzapine markedly reduced ACTH and cortisol from baseline in comparison with placebo and that haldol had no effect.6 In our patient, quetiapine was restarted without titering at a dose higher than recommended at 300 mg daily (50 mg qam, 50 mg qnoon, 200 mg qhs) with a consequent low cortisol value. Therefore, the finding of hypocortisolemia is not surprising, considering the significant cortisol reduction seen in studies with quetiapine doses as low as 25 mg.12
The mechanism of low plasma cortisol levels after administration of quetiapine has been attributed to a reduction in ACTH levels. Quetiapine’s 5-HT2 receptor blocking properties are particularly thought to cause this strong inhibitory effect on ACTH and cortisol secretion. Other receptors blocked by quetiapine including dopaminergic, adrenergic, or histaminergic receptors might also be involved in mediating the suppression of HPA-axis hormone secretion.6 It is uncertain whether the observed reduction of ACTH and cortisol levels, after administration of atypical antipsychotics such as quetiapine, is still detectable after intermediate or long-term use of such drugs. There is, however, evidence from a 6-week olanzapine treatment study in schizophrenic patients demonstrating an ongoing reduction of ACTH and cortisol.6
Other Causes of Hypocortisolemia
Other factors were evaluated as potential causes for our patient’s decrease in cortisol levels. First, it is known that aging is associated with hormone deficiencies as most of the body’s hormones diminish.5 Second, numerous studies have shown that people with PTSD, of which our patient was previously diagnosed, have low cortisol.5 Third, although a healthy stress response triggers cortisol to increase, as would be expected in our patient suffering from a UTI, ongoing infection and trauma can lead to a point when the adrenal gland can no longer produce enough cortisol, resulting in an inadequate response to stress. A limitation to our case is that there was no prior cortisol level available for comparison.
An obvious question that arises is why other cases of quetiapine initiation occur without consequent adrenal insufficiency. Given that the symptoms of adrenal insufficiency are ambiguous to begin with, it is plausible that such cases simply go undiagnosed. Another reason is that, in attempting to restart the psychotropic medication, our patient was given a higher than usual starting dose of quetiapine without titration, perhaps magnifying symptoms that would have otherwise gone unnoticed. Finally, because infection and stress may be contributing factors to hypocortisolemia, this combined with the initiation of quetiapine may have exacerbated the clinical picture.
Ciprofloxacin or bupropion, other medications initiated in the course of our patient’s hospitalization, were unlikely causes of our patient’s condition. Although ciprofloxacin potently inhibits the metabolism of several drugs, it has been studied to have no effect on cortisol concentration.13 Bupropion, similarly, has been shown to have no effect on ACTH, likely because the consequent rise of dopamine inhibits the release of the pituitary hormones.14
Confirming the clinical diagnosis of adrenal insufficiency involves demonstrating inappropriately low cortisol secretion, determining whether the cortisol deficiency is dependent or independent of ACTH deficiency, and detecting the cause of the disorder. Because serum cortisol concentrations are higher at about 6 AM than at other times of day, an early-morning, low serum cortisol concentration less than 3 μg/dL is presumptive of adrenal insufficiency, while values below 10 μg/dL strongly suggests the diagnosis. To differentiate primary adrenal insufficiency from secondary and tertiary insufficiency, stimulating the adrenal gland with exogenous ACTH (cosyntropin) and measuring serum cortisol levels before and at various intervals after provocation is necessary. A normal response after high-dose ACTH stimulation, which is a rise in serum cortisol concentration after 30 or 60 minutes to a peak of 18 mcg/dL to 20 mcg/dL, excludes primary adrenal insufficiency. Low-dose ACTH stimulation test is helpful in providing a more sensitive index of adrenocortical responsiveness in those with suspected secondary or tertiary adrenal insufficiency. Corticotropin releasing hormone (CRH) stimulation test is used to differentiate between secondary and tertiary adrenal insufficiency. In both conditions, cortisol levels are low at baseline and remain low after stimulation with CRH. However, in patients with secondary adrenal insufficiency, there is little or no ACTH response, whereas in tertiary disease, there is an exaggerated and prolonged response of ACTH to CRH stimulation, not followed by an appropriate cortisol response.3,15,16
Treatment and Summary
Treatment of adrenal insufficiency usually involves glucocorticoid replacement given in two or three daily doses, with one-half to two-thirds of the daily dose given in the morning to mimic the physiological cortisol secretion pattern. Hydrocortisone or a longer-acting synthetic glucocorticoid such as prednisone may be employed. Treatment surveillance is based mainly on clinical grounds, taking into account signs and symptoms suggestive of glucocorticoid over-replacement or underreplacement.1 Mineralocorticoid replacement is required in primary adrenal insufficiency if aldosterone is deficient and consists of oral fludrocortisone administration.17
Although it would seem appropriate to discontinue the offending agent as an immediate intervention, the risks of worsening the patient’s psychiatric symptoms versus benefits of preventing adrenal insufficiency sequela should be weighed. In our case, this patient was continued on his quetiapine while prednisone was initiated, and the patient reported improvement in his symptoms by the time of discharge. He was noted to symptomatically improve both in energy and mood. He was, however, on high-dose steroids, which are associated with dose-dependent, initial changes in mood including depression or, more commonly, euphoria.18 In the course of his outpatient care, he was tapered off quetiapine as a precaution. In the case that the medication could be related to his recent adrenal insufficiency, he was started on aripiprazole instead. Our patient subsequently reported difficulty sleeping and daytime lethargy. Although his prednisone was also being tapered, repeat cosyntropin stimulation tests were normal, suggesting the cause for his most recent symptoms were less likely endocrine related and more likely mood related in the context of changing medications.
This case highlights the potential effects of antipsychotics on the HPA axis with potentially dangerous decreases in cortisol secretion. Psychiatric disorders are more often associated with hypersecretion of cortisol, and reduction in cortisol levels is commonly associated with improvement in psychopathology. Although the cortisol lowering properties of atypical antipsychotics may be clinically helpful for depression, an amelioration of negative symptomatology, and cognitive deficits,6 our case demonstrates that such reduction of cortisol may be to a detrimental extent. Administration of quetiapine, particularly at higher than recommended starting doses without appropriate titration, may contribute to marked reduction of ACTH and cortisol secretion. Recognizing this phenomenon can be critical in diagnosing and managing a potentially grave condition. Further studies are warranted examining the duration and extent of cortisol reduction with quetiapine and other antipsychotic agents, reasons selective cases would present with adverse events, and appropriate management with alternate agents that address the psychiatric condition while limiting cortisol reduction. In the meantime, clinicians prescribing atypical antipsychotic agents should be aware of this potential consequence on the HPA axis.
- Arlt W, Allolio B. Adrenal insufficiency. Lancet. 2003;361(9372):1881–1883. doi:10.1016/S0140-6736(03)13492-7 [CrossRef]
- Torrey SP. Recognition and management of adrenal emergencies. Emerg Med Clin North Am. 2005;2(3):687–702. doi:10.1016/j.emc.2005.03.003 [CrossRef]
- Charmandari E, Chrousos G. Adrenal insufficiency. Adrenal Physiology and Diseases. 2003. Accessed January 1, 2007, from http://www.endotext.org/adrenal/adrenal13/adrenal13.htm.
- Kannisto S, Korppi M, Remes K, Voutilainen R. Adrenal suppression, evaluated by a low dose adrenocorticotropin test, and growth in asthmatic children treated with inhaled steroids. J Clin Endocrinol Metab. 2000;85(2):652–657. doi:10.1210/jc.85.2.652 [CrossRef]
- Schuder SE. Stress-induced hypocortisolemia diagnosed as psychiatric disorders responsive to hydrocortisone replacement. Ann N Y Acad Sci. 2005;1057:466–478. doi:10.1196/annals.1356.036 [CrossRef]
- Cohrs S, Röher C, Jordan W, et al. The atypical antipsychotics olanzapine and quetiapine, but not haloperidol, reduce ACTH and cortisol secretion in healthy subjects. Psychopharmacology (Berl). 2006;185(1):11–18. doi:10.1007/s00213-005-0279-x [CrossRef]
- Reincke M, Allolio B, Würth G, Winkelmann W. The hypothalamic-pituitary-adrenal axis in critical illness: response to dexamethasone and corticotropin-releasing hormone. J Clin Endocrinol Metab. 1993;77(1):151–156. doi:10.1210/jc.77.1.151 [CrossRef]
- Schatzberg A, Nemeroff C. Essentials of Clinical Psychopharmacology. 2nd ed. Washington DC: American Psychiatric Publishing; 2006:263–275.
- FDA approves Seroquel (quetiapine fumarate) for bipolar depression treatment October 20, 2006. Doctor’s Guide Channels. Accessed August 25, 2008 from http://www.docguide.com/news/content.nsf/news/852571020057CCF68525720D006C77FF.
- FDA approves quetiapine for maintenance treatment in bipolar disorder. May 2008. Doctor’s Guide Channels. Accessed August 25, 2008 from http://www.docguide.com/news/content.nsf/news/852571020057CCF685257449006D3D87
- Phillip NS, Mello K, Carpenter LL, Tyrka AR, Price LH. Patterns of quetiapine use in psychiatric inpatients: an examination of off-label use. Ann Clin Psychiatry. 2008;20(1):15–20. doi:10.1080/10401230701866870 [CrossRef]
- Cohrs S, Pohlmann K, Guan Z, et al. Quetiapine reduces nocturnal urinary cortisol excretion in healthy subjects. Psychopharmacology (Berl). 2004;174(3):414–420. doi:10.1007/s00213-003-1766-6 [CrossRef]
- Waite NM, Edwards DJ, Arnott WS, Warbasse LH. Effects of ciprofloxacin on testosterone and cortisol concentrations in healthy males. Antimicrob Agents Chemother. 1989;33(11):1875–1877.
- Piacentini MF, Clinckers R, Meeusen R, Sarre S, Ebinger G, Michotte Y. Effect of bupropion on hippocampal neurotransmitters and on peripheral hormonal concentrations in the rat. J Appl Physiol. 2003;95(2):652–656.
- Nieman L. Diagnosis of adrenal insufficiency. Up to Date. Accessed May 26, 2006, from http://www.uptodate.com/online/content/topic.do?topicKey=adrenal/4314&selectedTitle=2~150&source=search_result.
- Nieman L. Clinical manifestations of adrenal insufficiency. Up to Date. Accessed June 28, 2006 from http://www.uptodate.com/online/content/topic.do?topicKey=adrenal/5492&selectedTitle=3~150&source=search_result.
- Chrousos G, Fradkin J. Addison’s disease. Endocrine and Metabolic Diseases Information Services. Accessed June 28, 2006 from http://endocrine.niddk.nih.gov/pubs/addison/addison.htm.
- Brown ES, Chandler PA. Mood and cognitive changes during systemic corticosteroid therapy. Prim Care Companion J Clin Psychiatry. 2001;3(1):17–21. doi:10.4088/PCC.v03n0104 [CrossRef]