An Unexplained Exacerbation of Depression, Anxiety, and Panic Rebecca Swenson, PMHNP-BC, FNP-BC

Cases That Test Your Skills

An unexplained exacerbation of depression, anxiety, and panic Rebecca Swenson, PMHNP-BC, FNP-BC

Mr. P, age 33, has multiple panic attacks every day. His depression How would you and anxiety, which had been fairly well-controlled, are getting handle this case? Answer the challenge worse. How would you help him? questions at MDedge.com/ psychiatry and see how your colleagues responded

CASE Depression, anxiety, and 20 mg/d, and these medications provided panic attacks moderate relief of his depressive/anxious At the urging of his parents Mr. P, age 33, symptoms. However, he stopped taking both presents to the partial hospitalization pro- medications approximately 3 or 4 weeks gram (PHP) for worsening depression and ago when he ran out. He also takes pro- anxiety, daily panic attacks with accompany- pranolol, 20 mg/d, sporadically, for hyper- ing diaphoresis and headache, and the possi- tension. In the past, he had been prescribed bility that he may have taken an overdose of carvedilol, clonidine, and lisinopril—all with zolpidem. Mr. P denies taking an intentional varying degrees of relief of his hypertension. overdose of zolpidem, claiming instead that He denies a family history of hypertension or he was having a sleep-walking episode and any other chronic or acute health problems. did not realize how many pills he took. He reports that he has been sober from alco- In addition to daily panic attacks, Mr. P hol for 19 months but smokes 1 to 2 mari- reports having trouble falling asleep, over- juana cigarettes a day. whelming sadness, and daily passive suicidal ideation without a plan or active intent. Mr. P cannot identify a specific trigger to this EVALUATION Elevated blood most recent exacerbation of depressed/anx- pressure and pulse ious mood, but instead describes it as slowly Mr. P’s physical examination and medical building over the past 6 to 8 months. Mr. P review of systems are unremarkable, except for says the panic attacks occur without warning an elevated blood pressure (190/110 mm Hg) and states, “I feel like my heart is going to jump and pulse (92 beats per minute); he also out of my chest; I get a terrible headache, and has a headache. A repeat blood pressure I sweat like crazy. Sometimes I just feel like test later in the day is 172/94 mm Hg, with I’m about to pass out or die.” Although these a pulse of 100 beats per minute. His urine episodes had been present for approximately drug screen is positive only for delta-9- 2 years, they now occur almost daily. tetrahydrocannabinol (THC). continued Ms. Swenson is an Advanced Practice Nurse Practitioner, Broadstep Behavioral Health, Milwaukee, Wisconsin. HISTORY Inconsistent adherence Disclosure For the last year, Mr. P had been taking alpra- The author reports no financial relationships with any companies whose products are mentioned in this article, or with manufacturers Current Psychiatry zolam, 0.5 mg twice daily, and paroxetine, of competing products. Vol. 19, No. 6 39 Cases That Test Your Skills

Table 1 Which tests should be ordered to rule out a serious medical condition mimicking Symptoms of pheochromocytoma depression, anxiety, and/or panic attacks? More common Less common a) complete blood count (CBC) with Hypertension Abdominal pain, differential nausea, vomiting, b) thyroid-stimulating hormone (TSH) level and diarrhea with reflex Sweating Pallor c) porphyrin tests Headache Hallucinations d) serum metanephrines test

Anxiety and panic Agitation/apprehension (approximately 30% of patients) The author’s observations Clinical Point Tremor A CBC with differential is helpful for rul-

Sources: References 5-7 ing out infection and anemia as causes of Epinephrine and anxiety and depression.1 In Mr. P’s case, norepinephrine are there were no concerning symptoms that produced in excess by Table 2 pointed to anemia or infection as likely causes of his anxiety, depression, or panic an adrenal or extra- Pheochromocytoma: adrenal tumor seen in attacks. A TSH level also would be reason- A rare, often-missed diagnosis able, because hyperthyroidism can present pheochromocytoma Annual incidence in the general population is as anxiety, while hyperthyroidism or hypo- 2 to 8 cases per 1 million people (.000002% thyroidism each can present as depression.1 to .000008%) However, both Mr. P’s medical history and In patients with hypertension, the annual physical examination were not concerning incidence is 0.1% to 1.0% for thyroid disease, making it unlikely that In patients with adrenal mass, the annual he had either of those conditions. A review incidence is 5% of Mr. P’s medical records indicated that Age: 30s to 50s within the past 6 months, his primary care Men and women are equally affected physician (PCP) had ordered a CBC and Autopsy studies suggest that 50% of TSH test; the results of both were within pheochromocytomas go undiagnosed normal limits.

Sources: References 6,8 Serum porphyrin tests can exclude porphyria as a contributor to Mr. P’s anxiety and depression. Porphyrias are a group Table 3 of 8 inherited disorders that involve accu- mulation of heme precursors (porphyrins) Causes of false-positive results 2 on serum metanephrines testing in the CNS and subcutaneous tissue. Collectively, porphyrias affect approxi- Prescription medications Other mately 1 in 200,000 people.2 Anxiety and Tricyclic antidepressants Acetaminophen depression are strongly associated with Discuss this article at Monoamine oxidase Caffeine porphyria, but do not occur secondary to www.facebook.com/ inhibitors the illness; depression and anxiety appear MDedgePsychiatry Phenothiazines Nicotine to be intrinsic personality features in people with porphyria.3 Skin lesions and Buspirone Alcohol withdrawal abdominal pain are the most common Beta-blockers Clonidine symptoms,3 and there is a higher incidence withdrawal of hypertension in people with porphyria Current Psychiatry Source: References 6,7 40 June 2020 than in the general population.4 Mr. P does Cases That Test Your Skills

Table 4 Mr. P’s serum metanephrines test results Metabolite Mr. P’s results Interpretation Normetanephrine 0.93 nmol/L (reference range: A value of >2.2 nmol/L is confirmatory for 0.00 to 0.89) pheochromocytoma9 A value of <0.9 excludes pheochromocytoma9 Metanephrines 0.54 nmol/L (reference range: A value of >1.1 nmol/L is confirmatory9 0.00 to 0.49) A value of <0.5 excludes pheochromocytoma9

not report any heritable disorders, nor does 6 hours each day, visiting his PCP would be he appear to have any CNS disturbance or inconvenient, so the treatment team orders Clinical Point unusual cutaneous lesions, which makes it the serum metanephrines test. If a positive unlikely that this disorder is related to his result is found, Mr. P will be referred to his Mr. P had the classic psychiatric symptoms. PCP for further assessment and follow-up triad of symptoms of A serum metanephrines test measures care with endocrinology. pheochromocytoma: the metabolites of epinephrine and nor- hypertension, epinephrine. These catecholamines are sweating, and produced in excess by an adrenal or extra- TREATMENT Pharmacotherapy to headache adrenal tumor seen in pheochromocytoma. target anxiety and panic The classic triad of symptoms of pheochro- Next, the treatment team establishes a safety mocytoma are hypertension, sweating, plan for Mr. P, and restarts paroxetine, 20 mg/d, and headache; approximately 30% of to target his depressed and anxious mood. patients report significant anxiety and Alprazolam, 0.5 mg twice daily, is started to panic (Table 1,5-7 page 40). This type of target anxious mood and panic symptoms, tumor is rare, with an annual incidence of and to allow time for the anxiolytic properties only 2 to 8 cases per 1 million individu- of the paroxetine to become fully effective. The als. Among people with hypertension, the alprazolam will be tapered and stopped after annual incidence is 0.1% to 1.0%, and for 2 weeks. Mr. P is started on hydroxyzine, 1 to 2 those with an adrenal mass, the annual inci- 25-mg tablets 2 to 3 times daily as needed for dence is 5% (Table 2,6,8 page 40). Autopsy anxious mood and panic symptoms. studies suggest that up to 50% of pheo- The serum metanephrines test results chromocytomas are undiagnosed.8 Left are equivocal, with a slight elevation of untreated, pheochromocytoma can result in both epinephrine and norepinephrine that hypertensive crisis, arrhythmia, myocardial is too low to confirm a diagnosis of pheo- infarction, multisystem organ failure, and chromocytoma but too elevated to exclude it premature death.7 Table 36,7 (page 40) high- (Table 49). With Mr. P’s consent, the treatment lights some causes of false-positive serum team contacts his PCP and convey the results on metanephrines testing. of this test. Mr. P schedules an appointment with his PCP for the following week for further assessment and confirmatory pheochromo- EVALUATION Metanephrines testing cytoma testing. Mr. P has what appears to be treatment- After 1 week, Mr. P remains anxious, with resistant hypertension, accompanied by the a slight reduction in panic attacks from mul- classic symptoms observed in most patients tiple attacks each day to 3 or 4 attacks per with pheochromocytoma. Because Mr. P is week. The team considers adding an addi- Current Psychiatry participating in the PHP 6 days per week for tional anxiolytic agent. Vol. 19, No. 6 41 continued Cases That Test Your Skills

pressure.5-7 Patients with pheochromocy- Related Resources toma-related anxiety typically have sub- • National Organization for Rare Disorders. Rare Disease stantial or complete resolution of anxiety and Database: pheochromocytoma. www.rarediseases.org/ rare-diseases/pheochromocytoma/. panic attacks after tumor resection.6,8,10 • Young WF Jr. Clinical presentation and diagnosis of Because of their ability to raise catechol- pheochromocytoma. UpToDate. www.uptodate.com/ contents/clinical-presentation-and-diagnosis-of- amine levels, several medications, including pheochromocytoma. Published January 2020. some psychotropics, can lead to false-pos- Drug Brand Names itive results on serum and urine metaneph- Alprazolam • Xanax Lisinopril • Prinivil, Zestril rines testing. Tricyclic antidepressants and Amitriptyline • Elavil Paroxetine • Paxil beta-blockers can cause false-positive results Buspirone • Buspar Prazosin • Minipress Carvedilol • Coreg Propranolol • Inderal on plasma assays, while buspirone can Clonidine • Catapres Terazosin • Hytrin cause false-positives on urinalysis assays.5 Doxazosin • Cardura Trazodone • Desyrel Clinical Point Hydroxyzine • Vistaril Zolpidem • Ambien Trazodone, on the other hand, exhibits no catecholaminergic activity and its alpha-1 Several medications, adrenergic antagonism may actually have including some some benefit in pheochromocytoma.11 psychotropics, Which of the following anxiolytic agents Alpha-1 adrenergic antagonism with doxa- can lead to false- would be the safest option to prescribe until zosin, prazosin, or terazosin is the first-line of positive results on confirmatory testing can confirm or rule out treatment in reducing pheochromocytoma- pheochromocytoma? related hypertension.7 Treatment with a beta- metanephrines testing a) buspirone blocker is safe only after alpha-adrenergic b) propranolol blockade occurs. While beta-blockers are c) trazodone useful for reducing the palpitations and anx- d) amitriptyline iety observed in patients with pheochromocytoma, they must not be used alone due to the risk of hypertensive crisis resulting from The author’s observations unopposed alpha-adrenergic agonist acti- The triad of symptoms in pheochromo- vated vasoconstriction.5,7 cytoma results directly from the intermit- tent release of catecholamines into systemic circulation. Surges of epinephrine and TREATMENT CBT provides benefit norepinephrine lead to headaches, palpi- Mr. P decides against receiving an additional tations, diaphoresis, and (less commonly) agent for anxiety and instead decides to wait gastrointestinal symptoms such as nausea, for the outcome of the confirmatory pheo- vomiting, and constipation. Persistent or chromocytoma testing. He continues to take episodic hypertension may be present, with alprazolam, and both his depressed mood and 13% of patients maintaining a normal blood anxiety improve. His panic attacks continue

Bottom Line Pheochromocytoma is a tumor of the adrenal gland. The classic triad of symptoms of this rare condition is hypertension, sweating, and headache; approximately 30% of patients report significant anxiety and panic. Several medications, including tricyclic antidepressants, beta-blockers, and buspirone, can lead to false-positive results on the serum and urine metanephrines testing used to Current Psychiatry 42 June 2020 diagnose pheochromocytoma. Cases That Test Your Skills

to lessen, and he appears to benefit from condition in patients who present with cognitive-behavioral therapy provided dur- treatment-resistant hypertension and/or ing group therapy. Mr. P is advised by his PCP treatment-resistant anxiety. to taper and stop the alprazolam 3 to 5 days before his 24-hour urine metanephrines test References 1. Morrison J. When psychological problems mask medical because benzodiazepines can lead to false- disorders: a guide for psychotherapists. 2nd ed. New York, positive results on a urinalysis assay.7 NY: The Guilford Press; 2015. 2. American Porphyria Foundation. About porphyria. https:// porphyriafoundation.org/patients/about-porphyria. Accessed May 13, 2020. OUTCOME Remission of anxiety 3. Millward L, Kelly P, King A, et al. Anxiety and depression in the acute porphyrias. J Inherit Metab Dis. 2005;28(6): and depression 1099-1107. Mr. P has a repeat serum metanephrines test 4. Bonkovsky H, Maddukuri VC, Yazici C, et al. Acute porphyrias in the USA: features of 108 subjects from and a 24-hour urinalysis assay. Both are nega- porphyria consortium. Am J Med. 2014;127(12): Clinical Point tive for pheochromocytoma. His PCP refers 1233-1241. him to cardiology for management of treat- 5. Tsirlin A, Oo Y, Sharma R, et al. Pheochromocytoma: a Rule out review. Maturitas. 2014;77(3):229-238. pheochromocytoma ment-resistant hypertension. He is discharged 6. Leung A, Zun L, Nordstrom K, et al. Psychiatric emergencies from the PHP and continues psychotherapy for physicians: clinical management and approach to in patients with distinguishing pheochromocytoma from psychiatric and for depression and anxiety in an intensive thyrotoxic diseases in the emergency room. J Emerg Med. treatment-resistant 2017;53(5):712-716. outpatient program (IOP). Throughout his hypertension and/or PHP and IOP treatments, he continues to take 7. Garg M, Kharb S, Brar KS, et al. Medical management of pheochromocytoma: role of the endocrinologist. treatment-resistant paroxetine and hydroxyzine. He achieves a Indian J Endocrinol and Metab. 2011;15(suppl successful remission of his anxiety and depres- 4):S329-S336. doi: 10.4103/2230-8210.86976. anxiety 8. Zardawi I. Phaeochromocytoma masquerading as anxiety sion, with partial but significant remission of and depression. Am J Case Rep. 2013;14:161-163. his panic attacks. 9. ARUP Laboratories. Test directory. https://www. aruplab.com. Accessed February 11, 2020. 10. Sriram P, Raghavan V. Pheochromocytoma presenting as anxiety disorder: a case report. Asian J Psychiatr. 2017;29: The author’s observations 83-84. Although Mr. P did not have pheochromo- 11. Stahl SM. Stahl’s essential psychopharmacology: neuroscientific basis and practical applications. Cambridge, cytoma, it is important to rule out this rare UK: Cambridge University Press; 2013.

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