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Psychiatric and nonpsychiatric indications for mood stabilizers and select antiepileptics
Mr. B, age 64, is being treated in the psychiatric clinic for generalized anxiety disorder. He also has a history of type 2 diabetes mellitus and osteoarthritis. His present medications include metformin 500 mg twice daily, escitalopram 20 mg/d, and a multivitamin.
Three months after a shingles outbreak on his left trunk, Mr. B develops a sharp, burning pain and hypersensitivity to light in the same area as the shingles flare-up. He is diagnosed with postherpetic neuralgia. Despite a 12-week trial of cognitive-behavioral therapy, Mr. B continues to report excessive worry, irritability, poor concentration, psychomotor restlessness, and poor sleep.
Contrasting with the serendipitous discovery of iproniazid and chlorpromazine leading to the development of the current spectrum of antidepressant and antipsychotic agents, discovery of the benefits various antiepileptic agents have in bipolar disorder has not led to a similar proliferation of medication development for bipolar mania or depression.1-3 Divalproex, one of the most commonly used antiepileptic drugs (AEDs) in psychiatry, was thought to be an inactive organic solvent until it was used in 1962 to test the anticonvulsant activity of other compounds. This led to the discovery and subsequent use of divalproex in patients with epilepsy, followed by FDA approval in bipolar disorder.4,5 Off-label use of many AEDs as mood-stabilizing agents in bipolar disorder led to the emergence of carbamazepine, divalproex, and lamotrigine, which joined lithium as classic mood-stabilizing agents.4,6-8 Amid varying definitions of “mood stabilizer,” many AEDs have failed to demonstrate mood-stabilizing effects in bipolar disorder and therefore should not all be considered mood stabilizers.9 Nonetheless, the dual use of a single AED for both psychiatric and nonpsychiatric indications can decrease polypharmacy and increase acceptability of medications in patients who have low insight into their illness.10,11
Because AEDs were originally purposed to treat neurologic disease, psychiatric indications must first be established before considering other indications. AEDs as a class have broad pharmacologic actions, but are generally CNS depressants, decreasing brain signaling through mechanisms such as ion channel antagonism (carbamazepine, gabapentin) or alterations to gamma-aminobutyric acid/glutamate signaling (divalproex, topiramate).4,6,12,13 Compared to antidepressants and antipsychotics, whose primary use for psychiatric conditions is firmly rooted in evidence, rational use of AEDs for psychiatric conditions and symptoms depends on the agent-specific efficacy. Patients with comorbid psychiatric and neurologic disorders are ideal candidates for dually indicated AEDs due to these agents’ class effects rooted in epilepsy. Due to the history of positive psychiatric benefits with AEDs, newer agents may be psychiatrically beneficial but will likely follow the discovery of these benefits in patients for whom epilepsy is the primary diagnosis.
Consider the limitations
Using AEDs to reduce polypharmacy should be done judiciously from a drug-drug interaction perspective, because certain AEDs (eg, carbamazepine, divalproex) can greatly influence the metabolism of other medications, which may defeat the best intentions of the original intervention.4,6
Several other limitations should be considered. This article does not include all AEDs, only those commonly used for psychiatric indications with known nonpsychiatric benefits. Some may worsen psychiatric conditions (such as rage and irritability in the case of levetiracetam), and all AEDs have an FDA warning regarding suicidal behaviors and ideation.14,15 Another important limitation is the potential for differential dosing across indications; tolerability concerns may limit adequate dosing across multiple uses. For example, topiramate’s migraine prophylaxis effect can be achieved at much lower doses than the patient-specific efficacy dosing seen in binge eating disorder, with higher doses increasing the propensity for adverse effects.13,16Dual-use AEDs should be considered wherever possible, but judicious review of evidence is necessary to appropriately adjudicate a specific patient’s risk vs benefit. The Table4,6-9,12,13,16-68 provides information on select AEDs with both psychiatric and nonpsychiatric indications, including both FDA-approved and common off-label uses. These indications are limited to adult use only.
CASE CONTINUED
After reviewing Mr. B’s medical history, the treating medical team decides to cross-taper escitalopram to duloxetine 30 mg twice daily. Though his pain lessens after several weeks, it persists enough to interfere with Mr. B’s daily life. In addition to duloxetine, he is started on pregabalin 50 mg 3 times a day. Mr. B’s pain decreases to a tolerable level, and he reports decreased worrying and restlessness, and improvements in concentration and sleep.
1. Meyer JM. A concise guide to monoamine oxidase inhibitors. Current Psychiatry. 2017;16(12):14-16,18-23,47,A.
2. Ban TA. Fifty years chlorpromazine: a historical perspective. Neuropsychiatr Dis Treat. 2007;3(4):495-500.
3. López-Mun
4. Depakote [package insert]. North Chicago, IL: AbbVie, Inc; 2021.
5. Henry TR. The history of valproate in clinical neuroscience. Psychopharmacol Bull. 2003;37 Suppl 2:5-16.
6. Tegretol and Tegretol-XR [package insert]. East Hanover, NJ: Pharmaceuticals Co.; 2020.
7. Lamictal [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2009.
8. Lithobid [package insert]. Baudette, MN: ANI Pharmaceuticals, Inc; 2009.
9. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97-170.
10. National Alliance on Mental Illness. Anosognosia. Common with mental illness. Accessed March 3, 2022. https://www.nami.org/About-Mental-Illness/Common-with-Mental-Illness/Anosognosia
11. Hales CM, Servais J, Martin CB, et al. Prescription drug use among adults aged 40-79 in the United States and Canada. NCHS Data Brief. 2019(347):1-8.
12. Neurontin [package insert]. New York, NY: Pfizer; 2017.
13. Topamax [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2009.
14. Molokwu OA, Ezeala-Adikaibe BA, Onwuekwe IO. Levetiracetam-induced rage and suicidality: two case reports and review of literature. Epilepsy Behav Case Rep. 2015;4:79-81.
15. U.S. Food & Drug Administration. FDA Statistical Review and Evaluation. Antiepileptic Drugs and Suicidality. 2008. Accessed March 3, 2022. https://www.fda.gov/files/drugs/published/Statistical-Review-and-Evaluation--Antiepileptic-Drugs-and-Suicidality.pdf
16. McElroy SL, Hudson JI, Capece JA, et al. Topiramate for the treatment of binge eating disorder associated with obesity: a placebo-controlled study. Biol Psychiatry. 2007;61(9):1039-1048.
17. Zhang ZJ, Kang WH, Tan QR, et al. Adjunctive herbal medicine with carbamazepine for bipolar disorders: a double-blind, randomized, placebo-controlled study. J Psychiatr Res. 2007;41(3-4):360-369.
18. Kleindienst N, Greil W. Differential efficacy of lithium and carbamazepine in the prophylaxis of bipolar disorder: results of the MAP study. Neuropsychobiology. 2000;42 Suppl 1:2-10.
19. Goodwin GM, Haddad PM, Ferrier IN, et al. Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2016;30(6):495-553.
20. Davis LL, Bartolucci A, Petty F. Divalproex in the treatment of bipolar depression: a placebo-controlled study. J Affect Disord. 2005;85(3):259-266.
21. Gyulai L, Bowden CL, McElroy SL, et al. Maintenance efficacy of divalproex in the prevention of bipolar depression. Neuropsychopharmacology. 2003;28(7):1374-1382.
22. Limdi NA, Shimpi AV, Faught E, et al. Efficacy of rapid IV administration of valproic acid for status epilepticus. Neurology. 2005;64(2):353-355.
23. Temkin NR, Dikmen SS, Anderson GD, et al. Valproate therapy for prevention of posttraumatic seizures: a randomized trial. J Neurosurg. 1999; 91(4):593-600.
24. Reus VI, Fochtmann LJ, Bukstein O, et al. The American Psychiatric Association practice guideline for the pharmacological treatment of patients with alcohol use disorder. Am J Psychiatry. 2018;175(1):86-90.
25. US Dept of Veterans Affairs, US Dept of Defense, The Management of Substance Use Disorders Work Group. VA/DoD clinical practice guideline for the management of substance use disorders. US Dept of Veterans Affairs/Dept of Defense; 2015. Accessed March 3, 2022. http://www.healthquality.va.gov/guidelines/MH/sud/VADoDSUDCPGRevised22216.pdf
26. Myrick H, Malcolm R, Randall PK, et al. A double-blind trial of gabapentin versus lorazepam in the treatment of alcohol withdrawal. Alcohol Clin Exp Res. 2009;33(9):1582-1588.
27. Ahmed S, Stanciu CN, Kotapati PV, et al. Effectiveness of gabapentin in reducing cravings and withdrawal in alcohol use disorder: a meta-analytic review. Prim Care Companion CNS Disord. 2019;21(4):19r02465.
28. Pande AC, Davidson JR, Jefferson JW, et al. Treatment of social phobia with gabapentin: a placebo-controlled study. J Clin Psychopharmacol. 1999;19(4):341-348.
29. Ryan NM, Birring SS, Gibson PG. Gabapentin for refractory chronic cough: a randomized, double-blind, placebo-controlled trial. Lancet. 2012;380(9853):1583-1589.
30. Gibson P, Wang G, McGarvey L, et al. Treatment of unexplained chronic cough: CHEST guideline and expert panel report. Chest. 2016;149(1):27-44.
31. Arnold LM, Goldenberg DL, Stanford SB, et al. Gabapentin in the treatment of fibromyalgia: a randomized, double-blind, placebo-controlled, multicenter trial. Arthritis Rheum. 2007;56(4):1336-1344.
32. Alonso-Navarro H, Rubio L, Jiménez-Jiménez FJ. Refractory hiccup: successful treatment with gabapentin. Clin Neuropharmacol. 2007;30(3):186-187.
33. Jatzko A, Stegmeier-Petroianu A, Petroianu GA. Alpha-2-delta ligands for singultus (hiccup) treatment: three case reports. J Pain Symptom Manage. 2007;33(6):756-760.
34. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162-173.
35. Moore RA, Wiffen PJ, Derry S, et al. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2014;2014(4):CD007938.
36. Yuan M, Zhou HY, Xiao ZL, et al. Efficacy and safety of gabapentin vs. carbamazepine in the treatment of trigeminal neuralgia: a meta-analysis. Pain Pract. 2016;16(8):1083-1091.
37. Weisshaar E, Szepietowski JC, Darsow U, et al. European guideline on chronic pruritus. Acta Derm Venereol. 2012;92(5):563-581.
38. Garcia-Borreguero D, Silber MH, Winkelman JW, et al. Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-Foundation. Sleep Med. 2016;21:1-11.
39. Cobin RH, Goodman NF; AACE Reproductive Endocrinology Scientific Committee. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on menopause—2017 update [published correction appears in Endocr Pract. 2017;23 (12):1488]. Endocr Pract. 2017;23(7):869-880.
40. Calabrese JR, Suppes T, Bowden CL, et al. A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder: Lamictal 614 Study Group. J Clin Psychiatry. 2000;60(11):841-850.
41. May A, Leone M, Afra J, et al. EFNS guidelines on the treatment of cluster headache and other trigeminal-autonomic cephalalgias. Eur J Neurol. 2006;13(10):1066-1077.
42. Stein G, Bernadt M. Lithium augmentation therapy in tricyclic-resistant depression. A controlled trial using lithium in low and normal doses. Br J Psychiatry. 1993;162:634-640.
43. Craft M, Ismail IA, Krishnamurti D, et al. Lithium in the treatment of aggression in mentally handicapped patients: a double-blind trial. Br J Psychiatry. 1987;150:685-689.
44. Cipriani A, Pretty H, Hawton K, et al. Lithium in the prevention of suicidal behavior and all-cause mortality in patients with mood disorders: a systematic review of randomized trials. Am J Psychiatry. 2005;162(10):1805-1819.
45. Dickstein G, Shechner C, Adawi F, et al. Lithium treatment in amiodarone-induced thyrotoxicosis. Am J Med. 1997;102(5):454-458.
46. Bogazzi F, Bartalena L, Brogioni S, et al. Comparison of radioiodine with radioiodine plus lithium in the treatment of Graves’ hyperthyroidism. J Clin Endocrinol Metab. 1999;84(2):499-503.
47. Lyrica [package insert]. New York, NY: Parke-Davis, Division of Pfizer Inc; 2020.
48. Lydiard RB, Rickels K, Herman B, et al. Comparative efficacy of pregabalin and benzodiazepines in treating the psychic and somatic symptoms of generalized anxiety disorder. Int J Neuropsychopharmacol. 2010;13(2):229-241.
49. Pande AC, Feltner DE, Jefferson JW, et al. Efficacy of the novel anxiolytic pregabalin in social anxiety disorder: a placebo-controlled, multicenter study. J Clin Psychopharmacol. 2004;24(2):141-149.
50. Vertigan AE, Kapela SL, Ryan NM, et al. Pregabalin and speech pathology combination therapy for refractory chronic cough: a randomized controlled trial. Chest. 2016;149(3):639-648.
51. Matsuda KM, Sharma D, Schonfeld AR, et al. Gabapentin and pregabalin for the treatment of chronic pruritus. J Am Acad Dermatol. 2016;75(3):619-625.e6.
52. Allen R, Chen C, Soaita A, et al. A randomized, double-blind, 6-week, dose-ranging study of pregabalin in patients with restless legs syndrome. Sleep Med. 2010;11(6):512-519.
53. Loprinzi CL, Qin R, Balcueva EP, et al. Phase III, randomized, double-blind, placebo-controlled evaluation of pregabalin for alleviating hot flashes, N07C1 [published correction appears in J Clin Oncol. 2010;28(10):1808]. J Clin Oncol. 2010;28(4):641-647.
54. Dunlop BW, Papp L, Garlow SJ, et al. Tiagabine for social anxiety disorder. Hum Psychopharmacol. 2007;22(4):241-244.
55. Paparrigopoulos T, Tzavellas E, Karaiskos D, et al. An open pilot study of tiagabine in alcohol dependence: tolerability and clinical effects. J Psychopharmacol. 2010;24(9):1375-1380.
56. Gabitril [package insert]. North Wales, PA: Teva Pharmaceuticals USA, Inc; 2015.
57. Johnson BA, Ait-Daoud N, Bowden C, et al. Oral topiramate for treatment of alcohol dependence: a randomised controlled trial. Lancet. 2003;361(9370):1677-1685.
58. Linde M, Mulleners WM, Chronicle EP, et al. Topiramate for the prophylaxis of episodic migraine in adults. Cochrane Database Syst Rev. 2013;2013(6):CD010610.
59. Pascual J, Láinez MJ, Dodick D, et al. Antiepileptic drugs for the treatment of chronic and episodic cluster headache: a review. Headache. 2007;47(1):81-89.
60. Ondo WG, Jankovic J, Connor GS, et al. Topiramate in essential tremor: a double-blind, placebo-controlled trial. Neurology. 2006;66(5):672-677.
61. Ko YH, Joe SH, Jung IK, et al. Topiramate as an adjuvant treatment with atypical antipsychotics in schizophrenic patients experiencing weight gain. Clin Neuropharmacol. 2005;28(4):169-175.
62. Wilding J, Van Gaal L, Rissanen A, et al. A randomized double-blind placebo-controlled study of the long-term efficacy and safety of topiramate in the treatment of obese subjects. Int J Obes Relat Metab Disord. 2004;28(11):1399-1410.
63. Rosenstock J, Hollander P, Gadde KM, et al. A randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy and safety of topiramate controlled release in the treatment of obese type 2 diabetic patients. Diabetes Care. 2007; 30(6):1480-1486.
64. McElroy SL, Kotwal R, Guerdjikova AI, et al. Zonisamide in the treatment of binge eating disorder with obesity: a randomized controlled trial. J Clin Psychiatry. 2006;67(12):1897-1906.
65. Zonegran [package insert]. Teaneck, NJ: Eisai Inc; 2006.
66. Drake ME Jr, Greathouse NI, Renner JB, et al. Open-label zonisamide for refractory migraine. Clin Neuropharmacol. 2004;27(6):278-280.
67. Matsunaga S, Kishi T, Iwata N. Combination therapy with zonisamide and antiparkinson drugs for Parkinson’s disease: a meta-analysis. J Alzheimers Dis. 2017;56(4):1229-1239.
68. Gadde KM, Kopping MF, Wagner HR 2nd, et al. Zonisamide for weight reduction in obese adults: a 1-year randomized controlled trial. Arch Intern Med. 2012;172(20):1557-1564.
Mr. B, age 64, is being treated in the psychiatric clinic for generalized anxiety disorder. He also has a history of type 2 diabetes mellitus and osteoarthritis. His present medications include metformin 500 mg twice daily, escitalopram 20 mg/d, and a multivitamin.
Three months after a shingles outbreak on his left trunk, Mr. B develops a sharp, burning pain and hypersensitivity to light in the same area as the shingles flare-up. He is diagnosed with postherpetic neuralgia. Despite a 12-week trial of cognitive-behavioral therapy, Mr. B continues to report excessive worry, irritability, poor concentration, psychomotor restlessness, and poor sleep.
Contrasting with the serendipitous discovery of iproniazid and chlorpromazine leading to the development of the current spectrum of antidepressant and antipsychotic agents, discovery of the benefits various antiepileptic agents have in bipolar disorder has not led to a similar proliferation of medication development for bipolar mania or depression.1-3 Divalproex, one of the most commonly used antiepileptic drugs (AEDs) in psychiatry, was thought to be an inactive organic solvent until it was used in 1962 to test the anticonvulsant activity of other compounds. This led to the discovery and subsequent use of divalproex in patients with epilepsy, followed by FDA approval in bipolar disorder.4,5 Off-label use of many AEDs as mood-stabilizing agents in bipolar disorder led to the emergence of carbamazepine, divalproex, and lamotrigine, which joined lithium as classic mood-stabilizing agents.4,6-8 Amid varying definitions of “mood stabilizer,” many AEDs have failed to demonstrate mood-stabilizing effects in bipolar disorder and therefore should not all be considered mood stabilizers.9 Nonetheless, the dual use of a single AED for both psychiatric and nonpsychiatric indications can decrease polypharmacy and increase acceptability of medications in patients who have low insight into their illness.10,11
Because AEDs were originally purposed to treat neurologic disease, psychiatric indications must first be established before considering other indications. AEDs as a class have broad pharmacologic actions, but are generally CNS depressants, decreasing brain signaling through mechanisms such as ion channel antagonism (carbamazepine, gabapentin) or alterations to gamma-aminobutyric acid/glutamate signaling (divalproex, topiramate).4,6,12,13 Compared to antidepressants and antipsychotics, whose primary use for psychiatric conditions is firmly rooted in evidence, rational use of AEDs for psychiatric conditions and symptoms depends on the agent-specific efficacy. Patients with comorbid psychiatric and neurologic disorders are ideal candidates for dually indicated AEDs due to these agents’ class effects rooted in epilepsy. Due to the history of positive psychiatric benefits with AEDs, newer agents may be psychiatrically beneficial but will likely follow the discovery of these benefits in patients for whom epilepsy is the primary diagnosis.
Consider the limitations
Using AEDs to reduce polypharmacy should be done judiciously from a drug-drug interaction perspective, because certain AEDs (eg, carbamazepine, divalproex) can greatly influence the metabolism of other medications, which may defeat the best intentions of the original intervention.4,6
Several other limitations should be considered. This article does not include all AEDs, only those commonly used for psychiatric indications with known nonpsychiatric benefits. Some may worsen psychiatric conditions (such as rage and irritability in the case of levetiracetam), and all AEDs have an FDA warning regarding suicidal behaviors and ideation.14,15 Another important limitation is the potential for differential dosing across indications; tolerability concerns may limit adequate dosing across multiple uses. For example, topiramate’s migraine prophylaxis effect can be achieved at much lower doses than the patient-specific efficacy dosing seen in binge eating disorder, with higher doses increasing the propensity for adverse effects.13,16Dual-use AEDs should be considered wherever possible, but judicious review of evidence is necessary to appropriately adjudicate a specific patient’s risk vs benefit. The Table4,6-9,12,13,16-68 provides information on select AEDs with both psychiatric and nonpsychiatric indications, including both FDA-approved and common off-label uses. These indications are limited to adult use only.
CASE CONTINUED
After reviewing Mr. B’s medical history, the treating medical team decides to cross-taper escitalopram to duloxetine 30 mg twice daily. Though his pain lessens after several weeks, it persists enough to interfere with Mr. B’s daily life. In addition to duloxetine, he is started on pregabalin 50 mg 3 times a day. Mr. B’s pain decreases to a tolerable level, and he reports decreased worrying and restlessness, and improvements in concentration and sleep.
Mr. B, age 64, is being treated in the psychiatric clinic for generalized anxiety disorder. He also has a history of type 2 diabetes mellitus and osteoarthritis. His present medications include metformin 500 mg twice daily, escitalopram 20 mg/d, and a multivitamin.
Three months after a shingles outbreak on his left trunk, Mr. B develops a sharp, burning pain and hypersensitivity to light in the same area as the shingles flare-up. He is diagnosed with postherpetic neuralgia. Despite a 12-week trial of cognitive-behavioral therapy, Mr. B continues to report excessive worry, irritability, poor concentration, psychomotor restlessness, and poor sleep.
Contrasting with the serendipitous discovery of iproniazid and chlorpromazine leading to the development of the current spectrum of antidepressant and antipsychotic agents, discovery of the benefits various antiepileptic agents have in bipolar disorder has not led to a similar proliferation of medication development for bipolar mania or depression.1-3 Divalproex, one of the most commonly used antiepileptic drugs (AEDs) in psychiatry, was thought to be an inactive organic solvent until it was used in 1962 to test the anticonvulsant activity of other compounds. This led to the discovery and subsequent use of divalproex in patients with epilepsy, followed by FDA approval in bipolar disorder.4,5 Off-label use of many AEDs as mood-stabilizing agents in bipolar disorder led to the emergence of carbamazepine, divalproex, and lamotrigine, which joined lithium as classic mood-stabilizing agents.4,6-8 Amid varying definitions of “mood stabilizer,” many AEDs have failed to demonstrate mood-stabilizing effects in bipolar disorder and therefore should not all be considered mood stabilizers.9 Nonetheless, the dual use of a single AED for both psychiatric and nonpsychiatric indications can decrease polypharmacy and increase acceptability of medications in patients who have low insight into their illness.10,11
Because AEDs were originally purposed to treat neurologic disease, psychiatric indications must first be established before considering other indications. AEDs as a class have broad pharmacologic actions, but are generally CNS depressants, decreasing brain signaling through mechanisms such as ion channel antagonism (carbamazepine, gabapentin) or alterations to gamma-aminobutyric acid/glutamate signaling (divalproex, topiramate).4,6,12,13 Compared to antidepressants and antipsychotics, whose primary use for psychiatric conditions is firmly rooted in evidence, rational use of AEDs for psychiatric conditions and symptoms depends on the agent-specific efficacy. Patients with comorbid psychiatric and neurologic disorders are ideal candidates for dually indicated AEDs due to these agents’ class effects rooted in epilepsy. Due to the history of positive psychiatric benefits with AEDs, newer agents may be psychiatrically beneficial but will likely follow the discovery of these benefits in patients for whom epilepsy is the primary diagnosis.
Consider the limitations
Using AEDs to reduce polypharmacy should be done judiciously from a drug-drug interaction perspective, because certain AEDs (eg, carbamazepine, divalproex) can greatly influence the metabolism of other medications, which may defeat the best intentions of the original intervention.4,6
Several other limitations should be considered. This article does not include all AEDs, only those commonly used for psychiatric indications with known nonpsychiatric benefits. Some may worsen psychiatric conditions (such as rage and irritability in the case of levetiracetam), and all AEDs have an FDA warning regarding suicidal behaviors and ideation.14,15 Another important limitation is the potential for differential dosing across indications; tolerability concerns may limit adequate dosing across multiple uses. For example, topiramate’s migraine prophylaxis effect can be achieved at much lower doses than the patient-specific efficacy dosing seen in binge eating disorder, with higher doses increasing the propensity for adverse effects.13,16Dual-use AEDs should be considered wherever possible, but judicious review of evidence is necessary to appropriately adjudicate a specific patient’s risk vs benefit. The Table4,6-9,12,13,16-68 provides information on select AEDs with both psychiatric and nonpsychiatric indications, including both FDA-approved and common off-label uses. These indications are limited to adult use only.
CASE CONTINUED
After reviewing Mr. B’s medical history, the treating medical team decides to cross-taper escitalopram to duloxetine 30 mg twice daily. Though his pain lessens after several weeks, it persists enough to interfere with Mr. B’s daily life. In addition to duloxetine, he is started on pregabalin 50 mg 3 times a day. Mr. B’s pain decreases to a tolerable level, and he reports decreased worrying and restlessness, and improvements in concentration and sleep.
1. Meyer JM. A concise guide to monoamine oxidase inhibitors. Current Psychiatry. 2017;16(12):14-16,18-23,47,A.
2. Ban TA. Fifty years chlorpromazine: a historical perspective. Neuropsychiatr Dis Treat. 2007;3(4):495-500.
3. López-Mun
4. Depakote [package insert]. North Chicago, IL: AbbVie, Inc; 2021.
5. Henry TR. The history of valproate in clinical neuroscience. Psychopharmacol Bull. 2003;37 Suppl 2:5-16.
6. Tegretol and Tegretol-XR [package insert]. East Hanover, NJ: Pharmaceuticals Co.; 2020.
7. Lamictal [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2009.
8. Lithobid [package insert]. Baudette, MN: ANI Pharmaceuticals, Inc; 2009.
9. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97-170.
10. National Alliance on Mental Illness. Anosognosia. Common with mental illness. Accessed March 3, 2022. https://www.nami.org/About-Mental-Illness/Common-with-Mental-Illness/Anosognosia
11. Hales CM, Servais J, Martin CB, et al. Prescription drug use among adults aged 40-79 in the United States and Canada. NCHS Data Brief. 2019(347):1-8.
12. Neurontin [package insert]. New York, NY: Pfizer; 2017.
13. Topamax [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2009.
14. Molokwu OA, Ezeala-Adikaibe BA, Onwuekwe IO. Levetiracetam-induced rage and suicidality: two case reports and review of literature. Epilepsy Behav Case Rep. 2015;4:79-81.
15. U.S. Food & Drug Administration. FDA Statistical Review and Evaluation. Antiepileptic Drugs and Suicidality. 2008. Accessed March 3, 2022. https://www.fda.gov/files/drugs/published/Statistical-Review-and-Evaluation--Antiepileptic-Drugs-and-Suicidality.pdf
16. McElroy SL, Hudson JI, Capece JA, et al. Topiramate for the treatment of binge eating disorder associated with obesity: a placebo-controlled study. Biol Psychiatry. 2007;61(9):1039-1048.
17. Zhang ZJ, Kang WH, Tan QR, et al. Adjunctive herbal medicine with carbamazepine for bipolar disorders: a double-blind, randomized, placebo-controlled study. J Psychiatr Res. 2007;41(3-4):360-369.
18. Kleindienst N, Greil W. Differential efficacy of lithium and carbamazepine in the prophylaxis of bipolar disorder: results of the MAP study. Neuropsychobiology. 2000;42 Suppl 1:2-10.
19. Goodwin GM, Haddad PM, Ferrier IN, et al. Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2016;30(6):495-553.
20. Davis LL, Bartolucci A, Petty F. Divalproex in the treatment of bipolar depression: a placebo-controlled study. J Affect Disord. 2005;85(3):259-266.
21. Gyulai L, Bowden CL, McElroy SL, et al. Maintenance efficacy of divalproex in the prevention of bipolar depression. Neuropsychopharmacology. 2003;28(7):1374-1382.
22. Limdi NA, Shimpi AV, Faught E, et al. Efficacy of rapid IV administration of valproic acid for status epilepticus. Neurology. 2005;64(2):353-355.
23. Temkin NR, Dikmen SS, Anderson GD, et al. Valproate therapy for prevention of posttraumatic seizures: a randomized trial. J Neurosurg. 1999; 91(4):593-600.
24. Reus VI, Fochtmann LJ, Bukstein O, et al. The American Psychiatric Association practice guideline for the pharmacological treatment of patients with alcohol use disorder. Am J Psychiatry. 2018;175(1):86-90.
25. US Dept of Veterans Affairs, US Dept of Defense, The Management of Substance Use Disorders Work Group. VA/DoD clinical practice guideline for the management of substance use disorders. US Dept of Veterans Affairs/Dept of Defense; 2015. Accessed March 3, 2022. http://www.healthquality.va.gov/guidelines/MH/sud/VADoDSUDCPGRevised22216.pdf
26. Myrick H, Malcolm R, Randall PK, et al. A double-blind trial of gabapentin versus lorazepam in the treatment of alcohol withdrawal. Alcohol Clin Exp Res. 2009;33(9):1582-1588.
27. Ahmed S, Stanciu CN, Kotapati PV, et al. Effectiveness of gabapentin in reducing cravings and withdrawal in alcohol use disorder: a meta-analytic review. Prim Care Companion CNS Disord. 2019;21(4):19r02465.
28. Pande AC, Davidson JR, Jefferson JW, et al. Treatment of social phobia with gabapentin: a placebo-controlled study. J Clin Psychopharmacol. 1999;19(4):341-348.
29. Ryan NM, Birring SS, Gibson PG. Gabapentin for refractory chronic cough: a randomized, double-blind, placebo-controlled trial. Lancet. 2012;380(9853):1583-1589.
30. Gibson P, Wang G, McGarvey L, et al. Treatment of unexplained chronic cough: CHEST guideline and expert panel report. Chest. 2016;149(1):27-44.
31. Arnold LM, Goldenberg DL, Stanford SB, et al. Gabapentin in the treatment of fibromyalgia: a randomized, double-blind, placebo-controlled, multicenter trial. Arthritis Rheum. 2007;56(4):1336-1344.
32. Alonso-Navarro H, Rubio L, Jiménez-Jiménez FJ. Refractory hiccup: successful treatment with gabapentin. Clin Neuropharmacol. 2007;30(3):186-187.
33. Jatzko A, Stegmeier-Petroianu A, Petroianu GA. Alpha-2-delta ligands for singultus (hiccup) treatment: three case reports. J Pain Symptom Manage. 2007;33(6):756-760.
34. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162-173.
35. Moore RA, Wiffen PJ, Derry S, et al. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2014;2014(4):CD007938.
36. Yuan M, Zhou HY, Xiao ZL, et al. Efficacy and safety of gabapentin vs. carbamazepine in the treatment of trigeminal neuralgia: a meta-analysis. Pain Pract. 2016;16(8):1083-1091.
37. Weisshaar E, Szepietowski JC, Darsow U, et al. European guideline on chronic pruritus. Acta Derm Venereol. 2012;92(5):563-581.
38. Garcia-Borreguero D, Silber MH, Winkelman JW, et al. Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-Foundation. Sleep Med. 2016;21:1-11.
39. Cobin RH, Goodman NF; AACE Reproductive Endocrinology Scientific Committee. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on menopause—2017 update [published correction appears in Endocr Pract. 2017;23 (12):1488]. Endocr Pract. 2017;23(7):869-880.
40. Calabrese JR, Suppes T, Bowden CL, et al. A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder: Lamictal 614 Study Group. J Clin Psychiatry. 2000;60(11):841-850.
41. May A, Leone M, Afra J, et al. EFNS guidelines on the treatment of cluster headache and other trigeminal-autonomic cephalalgias. Eur J Neurol. 2006;13(10):1066-1077.
42. Stein G, Bernadt M. Lithium augmentation therapy in tricyclic-resistant depression. A controlled trial using lithium in low and normal doses. Br J Psychiatry. 1993;162:634-640.
43. Craft M, Ismail IA, Krishnamurti D, et al. Lithium in the treatment of aggression in mentally handicapped patients: a double-blind trial. Br J Psychiatry. 1987;150:685-689.
44. Cipriani A, Pretty H, Hawton K, et al. Lithium in the prevention of suicidal behavior and all-cause mortality in patients with mood disorders: a systematic review of randomized trials. Am J Psychiatry. 2005;162(10):1805-1819.
45. Dickstein G, Shechner C, Adawi F, et al. Lithium treatment in amiodarone-induced thyrotoxicosis. Am J Med. 1997;102(5):454-458.
46. Bogazzi F, Bartalena L, Brogioni S, et al. Comparison of radioiodine with radioiodine plus lithium in the treatment of Graves’ hyperthyroidism. J Clin Endocrinol Metab. 1999;84(2):499-503.
47. Lyrica [package insert]. New York, NY: Parke-Davis, Division of Pfizer Inc; 2020.
48. Lydiard RB, Rickels K, Herman B, et al. Comparative efficacy of pregabalin and benzodiazepines in treating the psychic and somatic symptoms of generalized anxiety disorder. Int J Neuropsychopharmacol. 2010;13(2):229-241.
49. Pande AC, Feltner DE, Jefferson JW, et al. Efficacy of the novel anxiolytic pregabalin in social anxiety disorder: a placebo-controlled, multicenter study. J Clin Psychopharmacol. 2004;24(2):141-149.
50. Vertigan AE, Kapela SL, Ryan NM, et al. Pregabalin and speech pathology combination therapy for refractory chronic cough: a randomized controlled trial. Chest. 2016;149(3):639-648.
51. Matsuda KM, Sharma D, Schonfeld AR, et al. Gabapentin and pregabalin for the treatment of chronic pruritus. J Am Acad Dermatol. 2016;75(3):619-625.e6.
52. Allen R, Chen C, Soaita A, et al. A randomized, double-blind, 6-week, dose-ranging study of pregabalin in patients with restless legs syndrome. Sleep Med. 2010;11(6):512-519.
53. Loprinzi CL, Qin R, Balcueva EP, et al. Phase III, randomized, double-blind, placebo-controlled evaluation of pregabalin for alleviating hot flashes, N07C1 [published correction appears in J Clin Oncol. 2010;28(10):1808]. J Clin Oncol. 2010;28(4):641-647.
54. Dunlop BW, Papp L, Garlow SJ, et al. Tiagabine for social anxiety disorder. Hum Psychopharmacol. 2007;22(4):241-244.
55. Paparrigopoulos T, Tzavellas E, Karaiskos D, et al. An open pilot study of tiagabine in alcohol dependence: tolerability and clinical effects. J Psychopharmacol. 2010;24(9):1375-1380.
56. Gabitril [package insert]. North Wales, PA: Teva Pharmaceuticals USA, Inc; 2015.
57. Johnson BA, Ait-Daoud N, Bowden C, et al. Oral topiramate for treatment of alcohol dependence: a randomised controlled trial. Lancet. 2003;361(9370):1677-1685.
58. Linde M, Mulleners WM, Chronicle EP, et al. Topiramate for the prophylaxis of episodic migraine in adults. Cochrane Database Syst Rev. 2013;2013(6):CD010610.
59. Pascual J, Láinez MJ, Dodick D, et al. Antiepileptic drugs for the treatment of chronic and episodic cluster headache: a review. Headache. 2007;47(1):81-89.
60. Ondo WG, Jankovic J, Connor GS, et al. Topiramate in essential tremor: a double-blind, placebo-controlled trial. Neurology. 2006;66(5):672-677.
61. Ko YH, Joe SH, Jung IK, et al. Topiramate as an adjuvant treatment with atypical antipsychotics in schizophrenic patients experiencing weight gain. Clin Neuropharmacol. 2005;28(4):169-175.
62. Wilding J, Van Gaal L, Rissanen A, et al. A randomized double-blind placebo-controlled study of the long-term efficacy and safety of topiramate in the treatment of obese subjects. Int J Obes Relat Metab Disord. 2004;28(11):1399-1410.
63. Rosenstock J, Hollander P, Gadde KM, et al. A randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy and safety of topiramate controlled release in the treatment of obese type 2 diabetic patients. Diabetes Care. 2007; 30(6):1480-1486.
64. McElroy SL, Kotwal R, Guerdjikova AI, et al. Zonisamide in the treatment of binge eating disorder with obesity: a randomized controlled trial. J Clin Psychiatry. 2006;67(12):1897-1906.
65. Zonegran [package insert]. Teaneck, NJ: Eisai Inc; 2006.
66. Drake ME Jr, Greathouse NI, Renner JB, et al. Open-label zonisamide for refractory migraine. Clin Neuropharmacol. 2004;27(6):278-280.
67. Matsunaga S, Kishi T, Iwata N. Combination therapy with zonisamide and antiparkinson drugs for Parkinson’s disease: a meta-analysis. J Alzheimers Dis. 2017;56(4):1229-1239.
68. Gadde KM, Kopping MF, Wagner HR 2nd, et al. Zonisamide for weight reduction in obese adults: a 1-year randomized controlled trial. Arch Intern Med. 2012;172(20):1557-1564.
1. Meyer JM. A concise guide to monoamine oxidase inhibitors. Current Psychiatry. 2017;16(12):14-16,18-23,47,A.
2. Ban TA. Fifty years chlorpromazine: a historical perspective. Neuropsychiatr Dis Treat. 2007;3(4):495-500.
3. López-Mun
4. Depakote [package insert]. North Chicago, IL: AbbVie, Inc; 2021.
5. Henry TR. The history of valproate in clinical neuroscience. Psychopharmacol Bull. 2003;37 Suppl 2:5-16.
6. Tegretol and Tegretol-XR [package insert]. East Hanover, NJ: Pharmaceuticals Co.; 2020.
7. Lamictal [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2009.
8. Lithobid [package insert]. Baudette, MN: ANI Pharmaceuticals, Inc; 2009.
9. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97-170.
10. National Alliance on Mental Illness. Anosognosia. Common with mental illness. Accessed March 3, 2022. https://www.nami.org/About-Mental-Illness/Common-with-Mental-Illness/Anosognosia
11. Hales CM, Servais J, Martin CB, et al. Prescription drug use among adults aged 40-79 in the United States and Canada. NCHS Data Brief. 2019(347):1-8.
12. Neurontin [package insert]. New York, NY: Pfizer; 2017.
13. Topamax [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2009.
14. Molokwu OA, Ezeala-Adikaibe BA, Onwuekwe IO. Levetiracetam-induced rage and suicidality: two case reports and review of literature. Epilepsy Behav Case Rep. 2015;4:79-81.
15. U.S. Food & Drug Administration. FDA Statistical Review and Evaluation. Antiepileptic Drugs and Suicidality. 2008. Accessed March 3, 2022. https://www.fda.gov/files/drugs/published/Statistical-Review-and-Evaluation--Antiepileptic-Drugs-and-Suicidality.pdf
16. McElroy SL, Hudson JI, Capece JA, et al. Topiramate for the treatment of binge eating disorder associated with obesity: a placebo-controlled study. Biol Psychiatry. 2007;61(9):1039-1048.
17. Zhang ZJ, Kang WH, Tan QR, et al. Adjunctive herbal medicine with carbamazepine for bipolar disorders: a double-blind, randomized, placebo-controlled study. J Psychiatr Res. 2007;41(3-4):360-369.
18. Kleindienst N, Greil W. Differential efficacy of lithium and carbamazepine in the prophylaxis of bipolar disorder: results of the MAP study. Neuropsychobiology. 2000;42 Suppl 1:2-10.
19. Goodwin GM, Haddad PM, Ferrier IN, et al. Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2016;30(6):495-553.
20. Davis LL, Bartolucci A, Petty F. Divalproex in the treatment of bipolar depression: a placebo-controlled study. J Affect Disord. 2005;85(3):259-266.
21. Gyulai L, Bowden CL, McElroy SL, et al. Maintenance efficacy of divalproex in the prevention of bipolar depression. Neuropsychopharmacology. 2003;28(7):1374-1382.
22. Limdi NA, Shimpi AV, Faught E, et al. Efficacy of rapid IV administration of valproic acid for status epilepticus. Neurology. 2005;64(2):353-355.
23. Temkin NR, Dikmen SS, Anderson GD, et al. Valproate therapy for prevention of posttraumatic seizures: a randomized trial. J Neurosurg. 1999; 91(4):593-600.
24. Reus VI, Fochtmann LJ, Bukstein O, et al. The American Psychiatric Association practice guideline for the pharmacological treatment of patients with alcohol use disorder. Am J Psychiatry. 2018;175(1):86-90.
25. US Dept of Veterans Affairs, US Dept of Defense, The Management of Substance Use Disorders Work Group. VA/DoD clinical practice guideline for the management of substance use disorders. US Dept of Veterans Affairs/Dept of Defense; 2015. Accessed March 3, 2022. http://www.healthquality.va.gov/guidelines/MH/sud/VADoDSUDCPGRevised22216.pdf
26. Myrick H, Malcolm R, Randall PK, et al. A double-blind trial of gabapentin versus lorazepam in the treatment of alcohol withdrawal. Alcohol Clin Exp Res. 2009;33(9):1582-1588.
27. Ahmed S, Stanciu CN, Kotapati PV, et al. Effectiveness of gabapentin in reducing cravings and withdrawal in alcohol use disorder: a meta-analytic review. Prim Care Companion CNS Disord. 2019;21(4):19r02465.
28. Pande AC, Davidson JR, Jefferson JW, et al. Treatment of social phobia with gabapentin: a placebo-controlled study. J Clin Psychopharmacol. 1999;19(4):341-348.
29. Ryan NM, Birring SS, Gibson PG. Gabapentin for refractory chronic cough: a randomized, double-blind, placebo-controlled trial. Lancet. 2012;380(9853):1583-1589.
30. Gibson P, Wang G, McGarvey L, et al. Treatment of unexplained chronic cough: CHEST guideline and expert panel report. Chest. 2016;149(1):27-44.
31. Arnold LM, Goldenberg DL, Stanford SB, et al. Gabapentin in the treatment of fibromyalgia: a randomized, double-blind, placebo-controlled, multicenter trial. Arthritis Rheum. 2007;56(4):1336-1344.
32. Alonso-Navarro H, Rubio L, Jiménez-Jiménez FJ. Refractory hiccup: successful treatment with gabapentin. Clin Neuropharmacol. 2007;30(3):186-187.
33. Jatzko A, Stegmeier-Petroianu A, Petroianu GA. Alpha-2-delta ligands for singultus (hiccup) treatment: three case reports. J Pain Symptom Manage. 2007;33(6):756-760.
34. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162-173.
35. Moore RA, Wiffen PJ, Derry S, et al. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2014;2014(4):CD007938.
36. Yuan M, Zhou HY, Xiao ZL, et al. Efficacy and safety of gabapentin vs. carbamazepine in the treatment of trigeminal neuralgia: a meta-analysis. Pain Pract. 2016;16(8):1083-1091.
37. Weisshaar E, Szepietowski JC, Darsow U, et al. European guideline on chronic pruritus. Acta Derm Venereol. 2012;92(5):563-581.
38. Garcia-Borreguero D, Silber MH, Winkelman JW, et al. Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-Foundation. Sleep Med. 2016;21:1-11.
39. Cobin RH, Goodman NF; AACE Reproductive Endocrinology Scientific Committee. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on menopause—2017 update [published correction appears in Endocr Pract. 2017;23 (12):1488]. Endocr Pract. 2017;23(7):869-880.
40. Calabrese JR, Suppes T, Bowden CL, et al. A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder: Lamictal 614 Study Group. J Clin Psychiatry. 2000;60(11):841-850.
41. May A, Leone M, Afra J, et al. EFNS guidelines on the treatment of cluster headache and other trigeminal-autonomic cephalalgias. Eur J Neurol. 2006;13(10):1066-1077.
42. Stein G, Bernadt M. Lithium augmentation therapy in tricyclic-resistant depression. A controlled trial using lithium in low and normal doses. Br J Psychiatry. 1993;162:634-640.
43. Craft M, Ismail IA, Krishnamurti D, et al. Lithium in the treatment of aggression in mentally handicapped patients: a double-blind trial. Br J Psychiatry. 1987;150:685-689.
44. Cipriani A, Pretty H, Hawton K, et al. Lithium in the prevention of suicidal behavior and all-cause mortality in patients with mood disorders: a systematic review of randomized trials. Am J Psychiatry. 2005;162(10):1805-1819.
45. Dickstein G, Shechner C, Adawi F, et al. Lithium treatment in amiodarone-induced thyrotoxicosis. Am J Med. 1997;102(5):454-458.
46. Bogazzi F, Bartalena L, Brogioni S, et al. Comparison of radioiodine with radioiodine plus lithium in the treatment of Graves’ hyperthyroidism. J Clin Endocrinol Metab. 1999;84(2):499-503.
47. Lyrica [package insert]. New York, NY: Parke-Davis, Division of Pfizer Inc; 2020.
48. Lydiard RB, Rickels K, Herman B, et al. Comparative efficacy of pregabalin and benzodiazepines in treating the psychic and somatic symptoms of generalized anxiety disorder. Int J Neuropsychopharmacol. 2010;13(2):229-241.
49. Pande AC, Feltner DE, Jefferson JW, et al. Efficacy of the novel anxiolytic pregabalin in social anxiety disorder: a placebo-controlled, multicenter study. J Clin Psychopharmacol. 2004;24(2):141-149.
50. Vertigan AE, Kapela SL, Ryan NM, et al. Pregabalin and speech pathology combination therapy for refractory chronic cough: a randomized controlled trial. Chest. 2016;149(3):639-648.
51. Matsuda KM, Sharma D, Schonfeld AR, et al. Gabapentin and pregabalin for the treatment of chronic pruritus. J Am Acad Dermatol. 2016;75(3):619-625.e6.
52. Allen R, Chen C, Soaita A, et al. A randomized, double-blind, 6-week, dose-ranging study of pregabalin in patients with restless legs syndrome. Sleep Med. 2010;11(6):512-519.
53. Loprinzi CL, Qin R, Balcueva EP, et al. Phase III, randomized, double-blind, placebo-controlled evaluation of pregabalin for alleviating hot flashes, N07C1 [published correction appears in J Clin Oncol. 2010;28(10):1808]. J Clin Oncol. 2010;28(4):641-647.
54. Dunlop BW, Papp L, Garlow SJ, et al. Tiagabine for social anxiety disorder. Hum Psychopharmacol. 2007;22(4):241-244.
55. Paparrigopoulos T, Tzavellas E, Karaiskos D, et al. An open pilot study of tiagabine in alcohol dependence: tolerability and clinical effects. J Psychopharmacol. 2010;24(9):1375-1380.
56. Gabitril [package insert]. North Wales, PA: Teva Pharmaceuticals USA, Inc; 2015.
57. Johnson BA, Ait-Daoud N, Bowden C, et al. Oral topiramate for treatment of alcohol dependence: a randomised controlled trial. Lancet. 2003;361(9370):1677-1685.
58. Linde M, Mulleners WM, Chronicle EP, et al. Topiramate for the prophylaxis of episodic migraine in adults. Cochrane Database Syst Rev. 2013;2013(6):CD010610.
59. Pascual J, Láinez MJ, Dodick D, et al. Antiepileptic drugs for the treatment of chronic and episodic cluster headache: a review. Headache. 2007;47(1):81-89.
60. Ondo WG, Jankovic J, Connor GS, et al. Topiramate in essential tremor: a double-blind, placebo-controlled trial. Neurology. 2006;66(5):672-677.
61. Ko YH, Joe SH, Jung IK, et al. Topiramate as an adjuvant treatment with atypical antipsychotics in schizophrenic patients experiencing weight gain. Clin Neuropharmacol. 2005;28(4):169-175.
62. Wilding J, Van Gaal L, Rissanen A, et al. A randomized double-blind placebo-controlled study of the long-term efficacy and safety of topiramate in the treatment of obese subjects. Int J Obes Relat Metab Disord. 2004;28(11):1399-1410.
63. Rosenstock J, Hollander P, Gadde KM, et al. A randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy and safety of topiramate controlled release in the treatment of obese type 2 diabetic patients. Diabetes Care. 2007; 30(6):1480-1486.
64. McElroy SL, Kotwal R, Guerdjikova AI, et al. Zonisamide in the treatment of binge eating disorder with obesity: a randomized controlled trial. J Clin Psychiatry. 2006;67(12):1897-1906.
65. Zonegran [package insert]. Teaneck, NJ: Eisai Inc; 2006.
66. Drake ME Jr, Greathouse NI, Renner JB, et al. Open-label zonisamide for refractory migraine. Clin Neuropharmacol. 2004;27(6):278-280.
67. Matsunaga S, Kishi T, Iwata N. Combination therapy with zonisamide and antiparkinson drugs for Parkinson’s disease: a meta-analysis. J Alzheimers Dis. 2017;56(4):1229-1239.
68. Gadde KM, Kopping MF, Wagner HR 2nd, et al. Zonisamide for weight reduction in obese adults: a 1-year randomized controlled trial. Arch Intern Med. 2012;172(20):1557-1564.
Nonpsychiatric indications for antidepressants and antipsychotics
Ms. A, age 45, is hospitalized for abdominal pain. She is noted to have hiccups, the onset of which she reports was >1 month ago and did not have a clear precipitant. Abdominal and head imaging return no acute findings, and data from a serum electrolyte test, hepatic function test, and thyroid function test are within normal limits. The medical team notices that Ms. A’s speech is pressured, she hardly sleeps, and she appears animated, full of ideas and energy.
Ms. A has a history of bipolar I disorder, hypertension, hyperlipidemia, gastroesophageal reflux disease, and hypothyroidism. Her present medications include hydrochlorothiazide 25 mg/d; levothyroxine 25 mcg/d; omeprazole 20 mg/d; and lovastatin 20 mg/d. She states that she was remotely treated for bipolar disorder, but she was cured by a shamanic healer, and therefore no longer needs treatment.
Approximately 35% of adults in the United States age 60 to 79 reported taking ≥5 prescription medications in 2016, compared to 15% of adults age 40 to 59.1 In a study of 372 patients with advanced, life-limiting illness, Schenker et al2 found that those who took multiple medications (mean: 11.6 medications) had a lower quality of life and worse symptoms. Optimizing medications to patients’ specific needs and diagnoses in order to reduce pill burden can be a favorable intervention. In addition, some patients—approximately 30% of those with schizophrenia and 20% of those with bipolar disorder—may not have insight into their mental illness as they do with their medical conditions, and may be more accepting of treatment for the latter.3 Dual-indication prescribing may be a useful way to decrease polypharmacy, reduce potential drug-drug interactions (DDIs), increase patient acceptance and adherence, and improve a patient’s overall health.
Continue on for: Multiple uses for antidepressants and antipsychotics...
Multiple uses for antidepressants and antipsychotics
One of the first medications discovered to have antidepressant effects was iproniazid, a monoamine oxidase inhibitor (MAOI) initially used to treat tuberculosis.4 Since then, numerous classes of antidepressant medications have been developed that capitalize on monoamine reuptake through several different mechanisms of action. These drugs can be grouped into subclasses that include selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, MAOIs, and others. True to their roots in iproniazid, these medications can have a myriad of effects not limited to mental health and can therefore be beneficial for a variety of comorbid conditions.
As was the case with antidepressants, the first medication approved in the antipsychotic class, chlorpromazine, was serendipitously discovered to treat psychosis and agitation after being approved and used to treat presurgical apprehension.5 The term “antipsychotic” is almost a misnomer given these agents’ broad pharmacology profiles and impact on various mental illnesses, including bipolar disorder, depressive disorders, anxiety disorders, and many other mental conditions. First-generation antipsychotics (FGAs) were the first to enter the market; they work primarily by blocking dopamine-2 (D2) receptors. Second-generation antipsychotics have less movement-based adverse effects than FGAs by having higher affinity for serotonin 5-HT2A receptors than for D2 receptors. However, they tend to carry a higher risk for weight gain and metabolic syndrome.
Antidepressants and antipsychotics are widely utilized in psychiatry. Many have been found to have additional uses beyond their original FDA-approved indication and can therefore be beneficial for a variety of comorbid conditions.
One limitation of using psychiatric medications for nonpsychiatric indications is that different doses of antidepressants and antipsychotics are typically targeted for different indications based on receptor binding affinity. A common example of this is trazodone, where doses below 100 mg are used as needed for insomnia, but higher doses ranging from 200 to 600 mg/d are used for depression. Another important consideration is DDIs. For example, the possibility of adding an agent such as fluoxetine to a complex pain regimen for fibromyalgia could impact the clearance of other agents that are cytochrome P450 (CYP) 2D6 substrates due to fluoxetine’s potent inhibition of the enzyme.6,7 Table 16-51, Table 252-68, Table 369-107, and Table 4108-123 provide information on select antidepressants, while Table 5124-140 and Table 6141-171 provide information on select antipsychotics. Each table lists psychiatric and nonpsychiatric indications for the respective medications, including both FDA-approved (where applicable) and common off-label uses. Most of the indications listed are for adult use only, unless otherwise noted.
Continue on to: Case Continued...
CASE CONTINUED
After reviewing Ms. A’s medical history, the treatment team initiates chlorpromazine, 25 mg 3 times a day, for intractable hiccups, and increases the dosage to 50 mg 3 times a day after 3 days. Chlorpromazine is FDA-approved for treating bipolar mania, and also for treating intractable hiccups. Shortly thereafter, Ms. A’s hiccups subside, she sleeps for longer periods, and her manic symptoms resolve.
1. Hales CM, Servais J, Martin CB, et al. Prescription drug use among adults aged 40-79 in the United States and Canada. National Center for Health Statistics (Centers for Disease Control and Prevention). 2019. NCHS Data Brief No. 347. https://www.cdc.gov/nchs/products/databriefs/db347.htm
2. Schenker Y, Park SY, Jeong K, et al. Associations between polypharmacy, symptom burden, and quality of life in patients with advanced, life-limiting illness. J Gen Intern Med. 2019;34(4):559-566.
3. National Alliance on Mental Illness. Anosognosia. 2021. https://www.nami.org/About-Mental-Illness/Common-with-Mental-Illness/Anosognosia
4. Meyer JM. A concise guide to monoamine oxidase inhibitors. Current Psychiatry. 2017;16(12):14-16,18-23,47,A.
5. Ban TA. Fifty years chlorpromazine: a historical perspective. Neuropsychiatr Dis Treat. 2007;3(4):495-500.
6. Prozac [package insert]. Indianapolis, IN: Eli Lilly and Company; 2009.
7. Arnold LM, Hess EV, Hudson JI, et al. A randomized, placebo-controlled, double-blind, flexible-dose study of fluoxetine in the treatment of women with fibromyalgia. Am J Med. 2002;112(3):191-197.
8. Celexa [package insert]. St. Louis, MO: Forest Pharmaceuticals, Inc; 2009.
9. Porsteinsson AP, Drye LT, Pollock BG, et al. Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA. 2014;311(7):682-691.
10. McElroy SL, Hudson JI, Malhotra S, et al. Citalopram in the treatment of binge-eating disorder: a placebo-controlled trial. J Clin Psychiatry. 2003;64(7):807-813.
11. Blank S, Lenze EJ, Mulsant BH, et al. Outcomes of late-life anxiety disorders during 32 weeks of citalopram treatment. J Clin Psychiatry. 2006;67(3):468-472.
12. Lenze EJ, Mulsant BH, Shear MK, et al. Efficacy and tolerability of citalopram in the treatment of late-life anxiety disorders: results from an 8-week randomized, placebo-controlled trial. Am J Psychiatry. 2005;162(1):146-150.
13. Montgomery SA, Kasper S, Stein DJ, et al. Citalopram 20 mg, 40 mg and 60 mg are all effective and well tolerated compared with placebo in obsessive-compulsive disorder. Int Clin Psychopharmacol. 2001;16(2):75-86.
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15. Perna G, Bertani A, Caldirola D, et al. A comparison of citalopram and paroxetine in the treatment of panic disorder: a randomized, single-blind study. Pharmacopsychiatry. 2001;34(3):85-90.
16. Wikander I, Sundblad C, Andersch B, et al. Citalopram in premenstrual dysphoria: is intermittent treatment during luteal phases more effective than continuous medication throughout the menstrual cycle? J Clin Psychopharmacol. 1998;18(5):390-398.
17. English BA, Jewell M, Jewell G, et al. Treatment of chronic posttraumatic stress disorder in combat veterans with citalopram: an open trial. J Clin Psychopharmacol. 2006;26(1):84-88.
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Ms. A, age 45, is hospitalized for abdominal pain. She is noted to have hiccups, the onset of which she reports was >1 month ago and did not have a clear precipitant. Abdominal and head imaging return no acute findings, and data from a serum electrolyte test, hepatic function test, and thyroid function test are within normal limits. The medical team notices that Ms. A’s speech is pressured, she hardly sleeps, and she appears animated, full of ideas and energy.
Ms. A has a history of bipolar I disorder, hypertension, hyperlipidemia, gastroesophageal reflux disease, and hypothyroidism. Her present medications include hydrochlorothiazide 25 mg/d; levothyroxine 25 mcg/d; omeprazole 20 mg/d; and lovastatin 20 mg/d. She states that she was remotely treated for bipolar disorder, but she was cured by a shamanic healer, and therefore no longer needs treatment.
Approximately 35% of adults in the United States age 60 to 79 reported taking ≥5 prescription medications in 2016, compared to 15% of adults age 40 to 59.1 In a study of 372 patients with advanced, life-limiting illness, Schenker et al2 found that those who took multiple medications (mean: 11.6 medications) had a lower quality of life and worse symptoms. Optimizing medications to patients’ specific needs and diagnoses in order to reduce pill burden can be a favorable intervention. In addition, some patients—approximately 30% of those with schizophrenia and 20% of those with bipolar disorder—may not have insight into their mental illness as they do with their medical conditions, and may be more accepting of treatment for the latter.3 Dual-indication prescribing may be a useful way to decrease polypharmacy, reduce potential drug-drug interactions (DDIs), increase patient acceptance and adherence, and improve a patient’s overall health.
Continue on for: Multiple uses for antidepressants and antipsychotics...
Multiple uses for antidepressants and antipsychotics
One of the first medications discovered to have antidepressant effects was iproniazid, a monoamine oxidase inhibitor (MAOI) initially used to treat tuberculosis.4 Since then, numerous classes of antidepressant medications have been developed that capitalize on monoamine reuptake through several different mechanisms of action. These drugs can be grouped into subclasses that include selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, MAOIs, and others. True to their roots in iproniazid, these medications can have a myriad of effects not limited to mental health and can therefore be beneficial for a variety of comorbid conditions.
As was the case with antidepressants, the first medication approved in the antipsychotic class, chlorpromazine, was serendipitously discovered to treat psychosis and agitation after being approved and used to treat presurgical apprehension.5 The term “antipsychotic” is almost a misnomer given these agents’ broad pharmacology profiles and impact on various mental illnesses, including bipolar disorder, depressive disorders, anxiety disorders, and many other mental conditions. First-generation antipsychotics (FGAs) were the first to enter the market; they work primarily by blocking dopamine-2 (D2) receptors. Second-generation antipsychotics have less movement-based adverse effects than FGAs by having higher affinity for serotonin 5-HT2A receptors than for D2 receptors. However, they tend to carry a higher risk for weight gain and metabolic syndrome.
Antidepressants and antipsychotics are widely utilized in psychiatry. Many have been found to have additional uses beyond their original FDA-approved indication and can therefore be beneficial for a variety of comorbid conditions.
One limitation of using psychiatric medications for nonpsychiatric indications is that different doses of antidepressants and antipsychotics are typically targeted for different indications based on receptor binding affinity. A common example of this is trazodone, where doses below 100 mg are used as needed for insomnia, but higher doses ranging from 200 to 600 mg/d are used for depression. Another important consideration is DDIs. For example, the possibility of adding an agent such as fluoxetine to a complex pain regimen for fibromyalgia could impact the clearance of other agents that are cytochrome P450 (CYP) 2D6 substrates due to fluoxetine’s potent inhibition of the enzyme.6,7 Table 16-51, Table 252-68, Table 369-107, and Table 4108-123 provide information on select antidepressants, while Table 5124-140 and Table 6141-171 provide information on select antipsychotics. Each table lists psychiatric and nonpsychiatric indications for the respective medications, including both FDA-approved (where applicable) and common off-label uses. Most of the indications listed are for adult use only, unless otherwise noted.
Continue on to: Case Continued...
CASE CONTINUED
After reviewing Ms. A’s medical history, the treatment team initiates chlorpromazine, 25 mg 3 times a day, for intractable hiccups, and increases the dosage to 50 mg 3 times a day after 3 days. Chlorpromazine is FDA-approved for treating bipolar mania, and also for treating intractable hiccups. Shortly thereafter, Ms. A’s hiccups subside, she sleeps for longer periods, and her manic symptoms resolve.
Ms. A, age 45, is hospitalized for abdominal pain. She is noted to have hiccups, the onset of which she reports was >1 month ago and did not have a clear precipitant. Abdominal and head imaging return no acute findings, and data from a serum electrolyte test, hepatic function test, and thyroid function test are within normal limits. The medical team notices that Ms. A’s speech is pressured, she hardly sleeps, and she appears animated, full of ideas and energy.
Ms. A has a history of bipolar I disorder, hypertension, hyperlipidemia, gastroesophageal reflux disease, and hypothyroidism. Her present medications include hydrochlorothiazide 25 mg/d; levothyroxine 25 mcg/d; omeprazole 20 mg/d; and lovastatin 20 mg/d. She states that she was remotely treated for bipolar disorder, but she was cured by a shamanic healer, and therefore no longer needs treatment.
Approximately 35% of adults in the United States age 60 to 79 reported taking ≥5 prescription medications in 2016, compared to 15% of adults age 40 to 59.1 In a study of 372 patients with advanced, life-limiting illness, Schenker et al2 found that those who took multiple medications (mean: 11.6 medications) had a lower quality of life and worse symptoms. Optimizing medications to patients’ specific needs and diagnoses in order to reduce pill burden can be a favorable intervention. In addition, some patients—approximately 30% of those with schizophrenia and 20% of those with bipolar disorder—may not have insight into their mental illness as they do with their medical conditions, and may be more accepting of treatment for the latter.3 Dual-indication prescribing may be a useful way to decrease polypharmacy, reduce potential drug-drug interactions (DDIs), increase patient acceptance and adherence, and improve a patient’s overall health.
Continue on for: Multiple uses for antidepressants and antipsychotics...
Multiple uses for antidepressants and antipsychotics
One of the first medications discovered to have antidepressant effects was iproniazid, a monoamine oxidase inhibitor (MAOI) initially used to treat tuberculosis.4 Since then, numerous classes of antidepressant medications have been developed that capitalize on monoamine reuptake through several different mechanisms of action. These drugs can be grouped into subclasses that include selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, MAOIs, and others. True to their roots in iproniazid, these medications can have a myriad of effects not limited to mental health and can therefore be beneficial for a variety of comorbid conditions.
As was the case with antidepressants, the first medication approved in the antipsychotic class, chlorpromazine, was serendipitously discovered to treat psychosis and agitation after being approved and used to treat presurgical apprehension.5 The term “antipsychotic” is almost a misnomer given these agents’ broad pharmacology profiles and impact on various mental illnesses, including bipolar disorder, depressive disorders, anxiety disorders, and many other mental conditions. First-generation antipsychotics (FGAs) were the first to enter the market; they work primarily by blocking dopamine-2 (D2) receptors. Second-generation antipsychotics have less movement-based adverse effects than FGAs by having higher affinity for serotonin 5-HT2A receptors than for D2 receptors. However, they tend to carry a higher risk for weight gain and metabolic syndrome.
Antidepressants and antipsychotics are widely utilized in psychiatry. Many have been found to have additional uses beyond their original FDA-approved indication and can therefore be beneficial for a variety of comorbid conditions.
One limitation of using psychiatric medications for nonpsychiatric indications is that different doses of antidepressants and antipsychotics are typically targeted for different indications based on receptor binding affinity. A common example of this is trazodone, where doses below 100 mg are used as needed for insomnia, but higher doses ranging from 200 to 600 mg/d are used for depression. Another important consideration is DDIs. For example, the possibility of adding an agent such as fluoxetine to a complex pain regimen for fibromyalgia could impact the clearance of other agents that are cytochrome P450 (CYP) 2D6 substrates due to fluoxetine’s potent inhibition of the enzyme.6,7 Table 16-51, Table 252-68, Table 369-107, and Table 4108-123 provide information on select antidepressants, while Table 5124-140 and Table 6141-171 provide information on select antipsychotics. Each table lists psychiatric and nonpsychiatric indications for the respective medications, including both FDA-approved (where applicable) and common off-label uses. Most of the indications listed are for adult use only, unless otherwise noted.
Continue on to: Case Continued...
CASE CONTINUED
After reviewing Ms. A’s medical history, the treatment team initiates chlorpromazine, 25 mg 3 times a day, for intractable hiccups, and increases the dosage to 50 mg 3 times a day after 3 days. Chlorpromazine is FDA-approved for treating bipolar mania, and also for treating intractable hiccups. Shortly thereafter, Ms. A’s hiccups subside, she sleeps for longer periods, and her manic symptoms resolve.
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94. Goldsobel AB, Rohr AS, Siegel SC, et al. Efficacy of doxepin in the treatment of chronic idiopathic urticaria. J Allergy Clin Immunol. 1986;78(5 Pt 1):867-873.
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98. Laederach-Hofmann K, Graf C, Horber F, et al. Imipramine and diet counseling with psychological support in the treatment of obese binge eaters: a randomized, placebo-controlled double-blind study. Int J Eat Disord. 1999;26(3):231-244.
99. Sindrup SH, Bach FW, Madsen C, et al. Venlafaxine versus imipramine in painful polyneuropathy: a randomized, controlled trial. Neurology. 2003;60(8):1284-1289.
100. Lin HH, Sheu BC, Lo MC, et al. Comparison of treatment outcomes of imipramine for female genuine stress incontinence. Br J Obstet Gynaecol. 1999;106(10):1089-1092.
101. Pamelor (nortriptyline) [package insert]. Hazelwood, MO: Mallinckrodt Inc; 2007.
102. Spencer T, Biederman J, Wilens T, et al. Nortriptyline treatment of children with attention-deficit hyperactivity disorder and tic disorder or Tourette’s syndrome. J Am Acad Child Adolesc Psychiatry. 1993;32(1):205-210.
103. Atkinson JH, Slater MA, Williams RA, et al. A placebo-controlled randomized clinical trial of nortriptyline for chronic low back pain. Pain. 1998;76(3):287-296.
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106. Jorge RE, Robinson RG, Arndt S, et al. Mortality and poststroke depression: a placebo-controlled trial of antidepressants. Am J Psychiatry. 2003;160(10):1823-1829.
107. Martin MR, Schiff AA. Fluphenazine/nortriptyline in the irritable bladder syndrome. A double-blind placebo-controlled study. Br J Urol. 1984;56(2):178-179.
108. Wellbutrin (bupropion hydrochloride) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2017.
109. Maneeton N, Maneeton B, Srisurapanont M, et al. Bupropion for adults with attention-deficit hyperactivity disorder: meta-analysis of randomized, placebo-controlled trials. Psychiatry Clin Neurosci. 2011;65(7):611-617.
110. Li DJ, Tseng PT, Chen YW, et al. Significant treatment effect of bupropion in patients with bipolar disorder but similar phase-shifting rate as other antidepressants: a meta-analysis following the PRISMA guidelines. Medicine (Baltimore). 2016;95(13):e3165.
111. Clayton AH, Warnock JK, Kornstein SG, et al. A placebo-controlled trial of bupropion SR as an antidote for selective serotonin reuptake inhibitor-induced sexual dysfunction. J Clin Psychiatry. 2004;65(1):62-67.
112. Safarinejad MR. Reversal of SSRI-induced female sexual dysfunction by adjunctive bupropion in menstruating women: a double-blind, placebo-controlled and randomized study. J Psychopharmacol. 2011;25(3):370-378.
113. Remeron (mirtazapine) [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; 2020.
114. Boshuisen ML, Slaap BR, Vester-Blokland ED, et al. The effect of mirtazapine in panic disorder: an open label pilot study with a single-blind placebo run-in period. Int Clin Psychopharmacol. 2001;16(6):363-368.
115. Sarchiapone M, Amore M, De Risio S, et al. Mirtazapine in the treatment of panic disorder: an open-label trial. Int Clin Psychopharmacol. 2003;18(1):35-38.
116. Connor KM, Davidson JR, Weisler RH, et al. A pilot study of mirtazapine in post-traumatic stress disorder. Int Clin Psychopharmacol. 1999;14(1):29-31.
117. Wichniak A, Wierzbicka A, Walecka M, et al. Effects of antidepressants on sleep. Curr Psychiatry Rep. 2017;19(9):63.
118. Bedtsen L, Jensen R. Mirtazapine is effective in the prophylactic treatment of chronic tension-type headache. Neurology. 2004;62(10):1706-1711.
119. AbdelFattah MR, Jung SW, Greenspan MA, et al. Efficacy of antidepressants in the treatment of obstructive sleep apnea compared to placebo. A systemic review with meta-analysis. Sleep Breath. 2020;24(2):443-453.
120. Desyrel [package insert]. Locust Valley, NY: Pragma Pharmaceuticals, LLC; 2017.
121. Lebert F, Stekke W, Hasenbroekx C, et al. Frontotemporal dementia: a randomized, controlled trial with trazodone. Dement Geriatr Cogn Disord. 2004;17(4):355-359.
122. Sultzer DL, Gray KF, Gunay I, et al. A double-blind comparison of trazodone and haloperidol for treatment of agitation in patients with dementia. Am J Geriatr Psychiatry. 1997;5(1):60-69.
123. Yi XY, Ni SF, Ghadami MR, et al. Trazodone for the treatment of insomnia: a meta-analysis of randomized placebo-controlled trials. Sleep Med. 2018;45:25-32.
124. Chlorpromazine hydrochloride [package insert]. Minneapolis, MN: Upsher-Smith Laboratories, Inc; 2010.
125. Bigal ME, Bordini CA, Speciali JG. Intravenous chlorpromazine in the emergency department treatment of migraines: a randomized controlled trial. J Emerg Med. 2002;23(2):141-148.
126. Bell R, Montoya D, Shuaib A, et al. A comparative trial of three agents in the treatment of acute migraine headache. Ann Emerg Med. 1990;19(10):1079-1082.
127. Committee on Practice Bulletins-Obstetrics. ACOG Practice Bulletin No. 189: Nausea and vomiting of pregnancy. Obstet Gynecol. 2018;131(1):e15-e30.
128. Fluphenazine hydrochloride [package insert]. Philadelphia, PA: Lannett Company, Inc; 2019.
129. Bonelli RM, Wenning GK. Pharmacological management of Huntington’s disease: an evidence-based review. Curr Pharm Des. 2006;12(21):2701-2720.
130. Haldol [package insert]. Columbus, OH: American Health Packaging; 2020.
131. MacDonald K, Wilson M, Minassian A, et al. A naturalistic study for intramuscular haloperidol versus intramuscular olanzapine for the management of acute agitation. J Clin Psychopharmacol. 2012;32(3):317-322.
132. Goikolea JM, Colom F, Capapey J, et al. Faster onset of antimanic action with haloperidol compared to second-generation antipsychotics. A meta-analysis of randomized clinical trials in acute mania. Eur Neuropsychopharmacol. 2013;23(4):305-316.
133. Girard TD, Exline MC, Carson SS, et al. Haloperidol and ziprasidone for treatment of delirium in critical illness. N Engl J Med. 2018;379(26):2506-2516.
134. Lohr L. Chemotherapy-induced nausea and vomiting. Cancer J. 2008;14(2):85-93.
135. Büttner M, Walder B, von Elm E, et al. Is low-dose haloperidol a useful antiemetic?: A meta-analysis of published and unpublished randomized trials. Anesthesiology. 2004;101(6):1454-1463.
136. Perphenazine [package insert]. Princeton, NJ: Sandoz Inc; 2010.
137. Compazine [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2004.
138. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med. 2008;358(23):2482-2494.
139. Chen JJ, Frame DG, White TJ. Efficacy of ondansetron and prochlorperazine for the prevention of postoperative nausea and vomiting after total hip replacement or total knee replacement procedures: a randomized, double-blind, comparative trial. Arch Intern Med. 1998;158(19):2124-2128.
140. Campbell K, Rowe H, Azzam H, et al. The management of nausea and vomiting of pregnancy. J Obstet Gynaecol Can. 2016;38(12):1127-1137.
141. Abilify [package insert]. Rockville, MD: Otsuka America Pharmaceutical, Inc; 2014.
142. Kinon BJ, Stauffer VL, Kollack-Walker S, et al. Olanzapine versus aripiprazole for the treatment of agitation in acutely ill patients with schizophrenia. J Clin Psychopharmacol. 2008;28(6):601-607.
143. Iannuzzi GL, Patel AA, Stewart JT. Aripiprazole and delusional disorder. J Psychiatr Pract. 2019;25(2):132-134.
144. Campbell EH, Elston DM, Hawthorne JD, et al. Diagnosis and management of delusional parasitosis. J Am Acad Dermatol. 2019;80(5):1428-1434.
145. Sayyah M, Sayyah M, Boostani H, et al. Effects of aripiprazole augmentation in treatment-resistant obsessive-compulsive disorder (a double-blind clinical trial). Depress Anxiety. 2012;29(10):850-854.
146. Lin WC, Chou YH. Aripiprazole effects on psychosis and chorea in a patient with Huntington’s disease. Am J Psychiatry. 2008;165(9):1207-1208.
147. Li X, Tang Y, Wang C. Adjunctive aripiprazole versus placebo for antipsychotic-induced hyperprolactinemia: meta-analysis of randomized controlled trials. PLoS One. 2013;8(8):e70179.
148. Zyprexa [package insert]. Indianapolis, IN: Eli Lilly and Company; 1997.
149. Attia E, Steinglass JE, Walsh BT, et al. Olanzapine versus placebo in adult outpatients with anorexia nervosa: a randomized clinical trial. Am J Psychiatry. 2019;176(6):449-456.
150. Dennehy EB, Doyle K, Suppes T. The efficacy of olanzapine monotherapy for acute hypomania or mania in an outpatient setting. Int Clin Psychopharmacol. 2003;18(3):143-145.
151. Grover S, Kumar V, Chakrabarti S. Comparative efficacy study of haloperidol, olanzapine and risperidone in delirium. J Psychosom Res. 2011;71(4):277-281.
152. Bosmans A, Verbanck P. Successful treatment of delusional disorder of the somatic type or “delusional parasitosis” with olanzapine. Pharmacopsychiatry. 2008;41(3):121-122.
153. Meyers BS, Flint AJ, Rothschild AJ, et al; STOP-PD Group. A double-blind randomized controlled trial of olanzapine plus sertraline vs olanzapine plus placebo for psychotic depression: the study of pharmacotherapy of psychotic depression (STOP-PD). Arch Gen Psychiatry. 2009;66(8):838-847.
154. Rothschild AJ, Williamson DJ, Tohen MF, et al. A double-blind, randomized study of olanzapine and olanzapine/fluoxetine combination for major depression with psychotic features. J Clin Psychopharmacol. 2004;24(4):365-373.
155. Navari RM, Gray SE, Kerr AC. Olanzapine versus aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a randomized phase III trial. J Support Oncol. 2011;9(5):188-195.
156. Bonelli RM, Mahnert FA, Niederwieser G. Olanzapine for Huntington’s disease: an open label study. Clin Neuropharmacol. 2002;25(5):263-265.
157. Seroquel [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2013.
158. Khan A, Atkinson S, Mezhebovsky I, et al. Extended-release quetiapine fumarate (quetiapine XR) as adjunctive therapy in patients with generalized anxiety disorder and a history of inadequate treatment response: a randomized, double-blind study. Ann Clin Psychiatry. 2014;26(1):3-18.
159. Dold M, Aigner M, Lanzenberger R, et al. Antipsychotic augmentation of serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder: a meta-analysis of double-blind, randomized, placebo-controlled trials. Int J Neuropsychopharmacol. 2013;16(3):557-574.
160. Villarreal G, Hamner MB, Cañive JM, et al. Efficacy of quetiapine monotherapy in posttraumatic stress disorder: a randomized, placebo-controlled trial. Am J Psychiatry. 2016;173(12):1205-1212.
161. Fernandez HH, Friedman JH, Jacques C, et al. Quetiapine for the treatment of drug-induced psychosis in Parkinson’s disease. Mov Disord. 1999;14(3):484-487.
162. Doroudgar S, Chou T, Yu J, et al. Evaluation of trazodone and quetiapine for insomnia: an observational study in psychiatric inpatients. Prim Care Companion CNS Disord. 2013;15(6):PCC.13m01558. doi: 10.4088/PCC.13m01558
163. Risperdal [package insert]. Titusville, NJ: Janssen Pharamceuticals, Inc; 2007.
164. Lim HK, Kim JJ, Pae CU, et al. Comparison of risperidone orodispersible tablet and intramuscular haloperidol in the treatment of acute psychotic agitation: a randomized open, prospective study. Neuropsychobiology. 2010;62(2):81-86.
165. Currier GW, Chou J, Feifel D, et al. Acute treatment of psychotic agitation: a randomized comparison of oral treatment with risperidone and lorazepam versus intramuscular treatment with haloperidol and lorazepam. J Clin Psychiatry. 2004;65(3):386-394.
166. Bahk WM, Yoon JS, Kim YH, et al. Risperidone in combination with mood stabilizers for acute mania: a multicentre, open study. Int Clin Psychopharmacol. 2004;19(5):299-303.
167. Freudenmann RW, Lepping P. Second-generation antipsychotics in primary and secondary delusional parasitosis: outcome and efficacy. J Clin Psychopharmacol. 2008;28(5):500-508.
168. Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry. 2009;166(9): 980-991.
169. McDougle CJ, Epperson CN, Pelton GH, et al. A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessive-compulsive disorder. Arch Gen Psychiatry. 2000;57(8):794-801.
170. Scahill L, Leckman JF, Schulz RT, et al. A placebo-controlled trial of risperidone in Tourette syndrome. Neurology. 2003;60(7):1130-1135.
171. Dallocchio C, Buffa C, Tinelli C, et al. Effectiveness of risperidone in Huntington Chorea patients. J Clin Psychopharmacol. 1999;19(1):101-103.
The COPD patient who couldn’t stop worrying
CASE A passive wish to die
Ms. M, age 76, has a history of major depressive disorder, unspecified anxiety disorder, and severe chronic obstructive pulmonary disease (COPD), for which she requires supplemental oxygen. She is admitted to a psychiatric hospital after several months of increased dysphoria, rumination, anhedonia, and a passive wish to die. She also has a decreased appetite and has lost 10 lb, experiences frequent daily episodes of shortness of breath and associated racing thoughts, and has a rapid heart rate.
HISTORY Past medication trials
In addition to COPD, Ms. M’s medical history includes hypertension. Past psychotropic medication trials used to treat her depression and anxiety have included aripiprazole, 5 mg/d; duloxetine, 60 mg/d; fluoxetine, 40 mg/d; mirtazapine, 30 mg nightly; buspirone, 10 mg twice daily; and clonazepam, 0.5 mg twice daily. She has no history of psychotherapy, and because of her uncontrolled anxiety and depression, she has never completed a pulmonary rehabilitation program.
Her current medications include salmeterol, 50 mcg inhaled twice daily, for COPD; amlodipine, 10 mg/d, for hypertension; buspirone, 10 mg twice daily, for anxiety; and duloxetine, 60 mg/d, for depression.
EXAMINATION No evidence of dementia
On examination, Ms. M is alert and oriented to person, place, date, and situation. Overall, she has mild difficulty with attention and short-term recall, which appears to be due to poor effort; intact long-term memory; and is able to abstract appropriately. There is no evidence of dementia.
A mental status exam reveals a frail, elderly woman with fair-to-poor hygiene, cooperative behavior, slowed motor activity, slowed speech with low volume, low mood, and depressed affect with constricted range. Her thought process is linear, her thought content includes passive death wishes, and she does not have hallucinations.
Bitemporal electroconvulsive therapy (ECT), 1.0 ms pulse width at 1.5 times Ms. M’s seizure threshold 3 times weekly, is initiated to treat her depression, with seizure duration averaging 45 seconds for each session. She receives a total of 8 treatments over the course of admission. Buspirone, 10 mg twice daily, is stopped shortly after admission, but she continues to receive duloxetine, 60 mg/d. Ms. M continues to have shortness of breath, palpitations, fearful ruminations about the future, and difficulty falling asleep.
[polldaddy:10673878]
The authors’ observations
The treatment team explores other options, such as benzodiazepines, psychotherapy modalities, and mindfulness exercises, to treat Ms. M’s anxiety and comorbid COPD. Lorazepam, 0.5 mg twice daily, was chosen to treat her acute anxiety. Due to Ms. M’s need for supplemental oxygen, the treatment team attempted to mitigate the risk of using a benzodiazepine by limiting its use to the minimum effective dose. The teams also looked for alternative therapies.
Continue to: Evalution of anxiety...
Evaluation of anxiety and depression in a patient with COPD is complicated by a high degree of symptom overlap. Patients with COPD may experience anxiety symptoms such as shortness of breath, rapid heart rate, numbness/tingling, and racing thoughts, and/or depressive symptoms such as decreased energy, impaired sleep, and impaired concentration. It can therefore be difficult to discern if a symptom is attributable to the physical diagnosis, the psychiatric diagnosis, or a combination of both. Catastrophic thinking about mild physical symptoms is common in patients with COPD. This can lead to hyperventilation and hypocapnia (manifested by lightheadedness, dizziness, paresthesia, and altered consciousness), with a reciprocally escalating cascade of anxiety and somatic symptoms.1
First-line therapy for anxiety disorders with comorbid COPD is CBT and other nonpharmacologic interventions.2,3
Although there is little evidence that traditional pharmacologic treatments (eg, antidepressants, benzodiazepines) have a statistically significant effect on anxiety and depression in COPD, studies have found that they have some clinical benefit.3 Risks, however, limit the utility of certain agents. Sedative-hypnotics potentially decrease respiratory drive and, particularly in older patients, antidepressants’ sedating effects can increase the risk of falls3 leading to increased morbidity, hospitalization, and mortality.
TREATMENT Mindfulness techniques and meditation
Ms. M’s symptoms show no improvement with the addition of lorazepam, 0.5 mg twice daily. A clinician teaches Ms. M mindfulness techniques, and she begins a trial of daily, individual, guided meditation using a meditation app. Respiratory therapists also instruct her on controlled breathing techniques such as pursed-lips breathing, diaphragmatic breathing, and deep breathing. They also encourage Ms. M to participate in the daily exercise group while on the unit.
[polldaddy:10673881]
The authors’ observations
Research indicates that low doses of opioids are safe and effective for refractory breathlessness in patients with severe COPD(those with an arterial partial pressure of oxygen ≤55 mm Hg or arterial oxygen saturation ≤88%).6,7
Continue to: The current opioid crisis...
The current opioid crisis prompts additional caution in prescribing, especially when considering using short-acting, immediate-release opioids such as morphine, which have a greater potential for abuse and dependence.
Many patients with COPD in the end-of-life phase and in severe pain or discomfort due to the advanced stages of their illness receive opioids as part of palliative care. Patients with COPD whose medical care is predominantly palliative may benefit greatly from being prescribed opioids. Most patients with COPD who find relief from low-dose opioids usually have 6 to 12 months to live, and low-dose opioids may help them obtain the best possible quality of life.
Choosing opioids as a treatment involves the risk of physiologic dependence and opioid use disorder. For Ms. M, the potential benefits were thought to outweigh such risks.
OUTCOME Breathlessness improves, anxiety decreases
Ms. M’s lorazepam is discontinued, and immediate-release morphine is prescribed at a low dose of 1 mg/d on an as-needed basis for anxiety with good effect. Ms. M’s breathlessness improves, leading to an overall decrease in anxiety. She does not experience sedation, confusion, or adverse respiratory effects.
Ms. M’s anxiety and depression improve over the course of the hospitalization with this regimen. On hospital Day 25, she is discharged with a plan to continue duloxetine, 60 mg/d, ECT twice weekly, and low-dose morphine, 1 mg/d, as needed for anxiety. She is referred for pulmonary rehabilitation and CBT to maintain remission.
[polldaddy:10673882]
Continue to: The authors' observations
The authors’ observations
Ms. M’s case highlights several challenges associated with treating psychiatric illness in a patient with a chronic medical illness. The relationship between COPD, anxiety, and depression is complex, and is associated with reduced quality of life, increasing severity of pulmonary disease, increased dyspnea, a sense of loss and inability to cope, and decreased self-efficacy and adherence to treatment.9-11
Bottom Line
When traditional antidepressant and anxiolytic therapies have not sufficiently helped, consider low-dose, once-daily opioids to address refractory breathlessness in a patient with COPD with comorbid anxiety and depression. This treatment can lead patients to participate in rehabilitation therapies and improve their quality of life.
Related Resources
- Alexopoulos G, Kiosses D, Sirey J, et al. Untangling therapeutic ingredients of a personalized intervention for patients with depression and severe COPD. Am J Geriatr Psychiatry. 2014;22(11):1316-1324.
- Jackson D, Banerjee S, Sirey J, et al. Two interventions for patients with major depression and severe chronic obstructive pulmonary disease: impact on quality of life. Am J Geriatr Psychiatry. 2018;27(5):502-511.
Drug Brand Names
Amlodipine • Norvasc
Aripiprazole • Abilify
Buspirone • Buspar
Clonazepam • Klonopin
Duloxetine • Cymbalta
Fluoxetine • Prozac
Hydromorphone • Dilaudid
Levodopa • Sinemet
Lorazepam • Ativan
Mirtazapine • Remeron
Morphine • MS Contin
Naloxone • Narcan
Oxycodone • Oxycontin
Salmeterol • Serevent Diskus
1. Harnett D. The difficult-to-treat psychiatric patient with comorbid medical illness. In: Dewan M, Pies R, eds. The difficult-to-treat psychiatric patient. Washington, DC: American Psychiatric Association Publishing; 2001:325-357.
2. Panagioti M, Scott C, Blakemore A, et al. Overview of the prevalence, impact, and management of depression and anxiety in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2014;9:1289-1306.
3. Cafarella P, Effing T, Usmani ZA, et al. Treatments for anxiety and depression in patients with chronic obstructive pulmonary disease: a literature review. Respirology. 2012;17(4):627-638.
4. Heslop-Marshall K, Baker C, Carrick-Sen D, et al. Randomised controlled trial of cognitive behavioural therapy in COPD. ERJ Open Res. 2018;4:00094-2018. doi: 10.1183/23120541.00094-2018.
5. de Godoy DV, de Godoy RF. A randomized controlled trial of the effect of psychotherapy on anxiety and depression in chronic obstructive pulmonary disease. Arch Phys Med Rehabil. 2003;84(8):1154-1157.
6. Abernethy A, Currow D, Frith P, et al. Randomised, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea. BMJ. 2003;327(7414):523-528.
7. Janowiak P, Krajnik M, Podolec Z, et al. Dosimetrically administered nebulized morphine for breathlessness in very severe chronic obstructive pulmonary disease: a randomized, controlled trial. BMC Pulm Med. 2017;17:186.
8. Rocker G, Horton R, Currow D, et al. Palliation of dyspnoea in advanced COPD: revisiting a role for opioids. Thorax. 2009;64(10):910-915.
9. Pooler A, Beech R. Examining the relationship between anxiety and depression and exacerbations of COPD which result in hospital admission: a systematic review. Int J Chron Obstruct Pulmon Dis. 2014;9:315-330.
10. Carmen Valenza M, Valenza-Peña G, Torres-Sánchez I, et al. Effectiveness of controlled breathing techniques on anxiety and depression in hospitalized patients with COPD: a randomized clinical trial. Respir Care. 2014;59(2):209-215.
11. Pollok J, van Agteren J, Esterman A, et al. Psychological therapies for the treatment of depression in chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2019;3:CD012347. doi: 10.1002/14651858.CD012347.pub2.
12. Roberts N, Kidd L, Kirkwood K, et al. A systematic review of the content and delivery of education in pulmonary rehabilitation programmes. Respiratory Medicine. 2018;145:161-181.
13. Pumar M, Gray C, Walsh J, et al. Anxiety and depression-important psychological comorbidities of COPD. J Thorac Dis. 2014;6(11):1615-1631.
14. Alexopoulos G, Kiosses D, Sirey J, et al. Untangling therapeutic ingredients of a personalized intervention for patients with depression and severe COPD. Am J Geriatr Psychiatry. 2014;22(11):1316-1324.
15. Jackson D, Banerjee S, Sirey J, et al. Two interventions for patients with major depression and severe chronic obstructive pulmonary disease: impact on quality of life. Am J Geriatr Psychiatry. 2018;27(5):502-511.
CASE A passive wish to die
Ms. M, age 76, has a history of major depressive disorder, unspecified anxiety disorder, and severe chronic obstructive pulmonary disease (COPD), for which she requires supplemental oxygen. She is admitted to a psychiatric hospital after several months of increased dysphoria, rumination, anhedonia, and a passive wish to die. She also has a decreased appetite and has lost 10 lb, experiences frequent daily episodes of shortness of breath and associated racing thoughts, and has a rapid heart rate.
HISTORY Past medication trials
In addition to COPD, Ms. M’s medical history includes hypertension. Past psychotropic medication trials used to treat her depression and anxiety have included aripiprazole, 5 mg/d; duloxetine, 60 mg/d; fluoxetine, 40 mg/d; mirtazapine, 30 mg nightly; buspirone, 10 mg twice daily; and clonazepam, 0.5 mg twice daily. She has no history of psychotherapy, and because of her uncontrolled anxiety and depression, she has never completed a pulmonary rehabilitation program.
Her current medications include salmeterol, 50 mcg inhaled twice daily, for COPD; amlodipine, 10 mg/d, for hypertension; buspirone, 10 mg twice daily, for anxiety; and duloxetine, 60 mg/d, for depression.
EXAMINATION No evidence of dementia
On examination, Ms. M is alert and oriented to person, place, date, and situation. Overall, she has mild difficulty with attention and short-term recall, which appears to be due to poor effort; intact long-term memory; and is able to abstract appropriately. There is no evidence of dementia.
A mental status exam reveals a frail, elderly woman with fair-to-poor hygiene, cooperative behavior, slowed motor activity, slowed speech with low volume, low mood, and depressed affect with constricted range. Her thought process is linear, her thought content includes passive death wishes, and she does not have hallucinations.
Bitemporal electroconvulsive therapy (ECT), 1.0 ms pulse width at 1.5 times Ms. M’s seizure threshold 3 times weekly, is initiated to treat her depression, with seizure duration averaging 45 seconds for each session. She receives a total of 8 treatments over the course of admission. Buspirone, 10 mg twice daily, is stopped shortly after admission, but she continues to receive duloxetine, 60 mg/d. Ms. M continues to have shortness of breath, palpitations, fearful ruminations about the future, and difficulty falling asleep.
[polldaddy:10673878]
The authors’ observations
The treatment team explores other options, such as benzodiazepines, psychotherapy modalities, and mindfulness exercises, to treat Ms. M’s anxiety and comorbid COPD. Lorazepam, 0.5 mg twice daily, was chosen to treat her acute anxiety. Due to Ms. M’s need for supplemental oxygen, the treatment team attempted to mitigate the risk of using a benzodiazepine by limiting its use to the minimum effective dose. The teams also looked for alternative therapies.
Continue to: Evalution of anxiety...
Evaluation of anxiety and depression in a patient with COPD is complicated by a high degree of symptom overlap. Patients with COPD may experience anxiety symptoms such as shortness of breath, rapid heart rate, numbness/tingling, and racing thoughts, and/or depressive symptoms such as decreased energy, impaired sleep, and impaired concentration. It can therefore be difficult to discern if a symptom is attributable to the physical diagnosis, the psychiatric diagnosis, or a combination of both. Catastrophic thinking about mild physical symptoms is common in patients with COPD. This can lead to hyperventilation and hypocapnia (manifested by lightheadedness, dizziness, paresthesia, and altered consciousness), with a reciprocally escalating cascade of anxiety and somatic symptoms.1
First-line therapy for anxiety disorders with comorbid COPD is CBT and other nonpharmacologic interventions.2,3
Although there is little evidence that traditional pharmacologic treatments (eg, antidepressants, benzodiazepines) have a statistically significant effect on anxiety and depression in COPD, studies have found that they have some clinical benefit.3 Risks, however, limit the utility of certain agents. Sedative-hypnotics potentially decrease respiratory drive and, particularly in older patients, antidepressants’ sedating effects can increase the risk of falls3 leading to increased morbidity, hospitalization, and mortality.
TREATMENT Mindfulness techniques and meditation
Ms. M’s symptoms show no improvement with the addition of lorazepam, 0.5 mg twice daily. A clinician teaches Ms. M mindfulness techniques, and she begins a trial of daily, individual, guided meditation using a meditation app. Respiratory therapists also instruct her on controlled breathing techniques such as pursed-lips breathing, diaphragmatic breathing, and deep breathing. They also encourage Ms. M to participate in the daily exercise group while on the unit.
[polldaddy:10673881]
The authors’ observations
Research indicates that low doses of opioids are safe and effective for refractory breathlessness in patients with severe COPD(those with an arterial partial pressure of oxygen ≤55 mm Hg or arterial oxygen saturation ≤88%).6,7
Continue to: The current opioid crisis...
The current opioid crisis prompts additional caution in prescribing, especially when considering using short-acting, immediate-release opioids such as morphine, which have a greater potential for abuse and dependence.
Many patients with COPD in the end-of-life phase and in severe pain or discomfort due to the advanced stages of their illness receive opioids as part of palliative care. Patients with COPD whose medical care is predominantly palliative may benefit greatly from being prescribed opioids. Most patients with COPD who find relief from low-dose opioids usually have 6 to 12 months to live, and low-dose opioids may help them obtain the best possible quality of life.
Choosing opioids as a treatment involves the risk of physiologic dependence and opioid use disorder. For Ms. M, the potential benefits were thought to outweigh such risks.
OUTCOME Breathlessness improves, anxiety decreases
Ms. M’s lorazepam is discontinued, and immediate-release morphine is prescribed at a low dose of 1 mg/d on an as-needed basis for anxiety with good effect. Ms. M’s breathlessness improves, leading to an overall decrease in anxiety. She does not experience sedation, confusion, or adverse respiratory effects.
Ms. M’s anxiety and depression improve over the course of the hospitalization with this regimen. On hospital Day 25, she is discharged with a plan to continue duloxetine, 60 mg/d, ECT twice weekly, and low-dose morphine, 1 mg/d, as needed for anxiety. She is referred for pulmonary rehabilitation and CBT to maintain remission.
[polldaddy:10673882]
Continue to: The authors' observations
The authors’ observations
Ms. M’s case highlights several challenges associated with treating psychiatric illness in a patient with a chronic medical illness. The relationship between COPD, anxiety, and depression is complex, and is associated with reduced quality of life, increasing severity of pulmonary disease, increased dyspnea, a sense of loss and inability to cope, and decreased self-efficacy and adherence to treatment.9-11
Bottom Line
When traditional antidepressant and anxiolytic therapies have not sufficiently helped, consider low-dose, once-daily opioids to address refractory breathlessness in a patient with COPD with comorbid anxiety and depression. This treatment can lead patients to participate in rehabilitation therapies and improve their quality of life.
Related Resources
- Alexopoulos G, Kiosses D, Sirey J, et al. Untangling therapeutic ingredients of a personalized intervention for patients with depression and severe COPD. Am J Geriatr Psychiatry. 2014;22(11):1316-1324.
- Jackson D, Banerjee S, Sirey J, et al. Two interventions for patients with major depression and severe chronic obstructive pulmonary disease: impact on quality of life. Am J Geriatr Psychiatry. 2018;27(5):502-511.
Drug Brand Names
Amlodipine • Norvasc
Aripiprazole • Abilify
Buspirone • Buspar
Clonazepam • Klonopin
Duloxetine • Cymbalta
Fluoxetine • Prozac
Hydromorphone • Dilaudid
Levodopa • Sinemet
Lorazepam • Ativan
Mirtazapine • Remeron
Morphine • MS Contin
Naloxone • Narcan
Oxycodone • Oxycontin
Salmeterol • Serevent Diskus
CASE A passive wish to die
Ms. M, age 76, has a history of major depressive disorder, unspecified anxiety disorder, and severe chronic obstructive pulmonary disease (COPD), for which she requires supplemental oxygen. She is admitted to a psychiatric hospital after several months of increased dysphoria, rumination, anhedonia, and a passive wish to die. She also has a decreased appetite and has lost 10 lb, experiences frequent daily episodes of shortness of breath and associated racing thoughts, and has a rapid heart rate.
HISTORY Past medication trials
In addition to COPD, Ms. M’s medical history includes hypertension. Past psychotropic medication trials used to treat her depression and anxiety have included aripiprazole, 5 mg/d; duloxetine, 60 mg/d; fluoxetine, 40 mg/d; mirtazapine, 30 mg nightly; buspirone, 10 mg twice daily; and clonazepam, 0.5 mg twice daily. She has no history of psychotherapy, and because of her uncontrolled anxiety and depression, she has never completed a pulmonary rehabilitation program.
Her current medications include salmeterol, 50 mcg inhaled twice daily, for COPD; amlodipine, 10 mg/d, for hypertension; buspirone, 10 mg twice daily, for anxiety; and duloxetine, 60 mg/d, for depression.
EXAMINATION No evidence of dementia
On examination, Ms. M is alert and oriented to person, place, date, and situation. Overall, she has mild difficulty with attention and short-term recall, which appears to be due to poor effort; intact long-term memory; and is able to abstract appropriately. There is no evidence of dementia.
A mental status exam reveals a frail, elderly woman with fair-to-poor hygiene, cooperative behavior, slowed motor activity, slowed speech with low volume, low mood, and depressed affect with constricted range. Her thought process is linear, her thought content includes passive death wishes, and she does not have hallucinations.
Bitemporal electroconvulsive therapy (ECT), 1.0 ms pulse width at 1.5 times Ms. M’s seizure threshold 3 times weekly, is initiated to treat her depression, with seizure duration averaging 45 seconds for each session. She receives a total of 8 treatments over the course of admission. Buspirone, 10 mg twice daily, is stopped shortly after admission, but she continues to receive duloxetine, 60 mg/d. Ms. M continues to have shortness of breath, palpitations, fearful ruminations about the future, and difficulty falling asleep.
[polldaddy:10673878]
The authors’ observations
The treatment team explores other options, such as benzodiazepines, psychotherapy modalities, and mindfulness exercises, to treat Ms. M’s anxiety and comorbid COPD. Lorazepam, 0.5 mg twice daily, was chosen to treat her acute anxiety. Due to Ms. M’s need for supplemental oxygen, the treatment team attempted to mitigate the risk of using a benzodiazepine by limiting its use to the minimum effective dose. The teams also looked for alternative therapies.
Continue to: Evalution of anxiety...
Evaluation of anxiety and depression in a patient with COPD is complicated by a high degree of symptom overlap. Patients with COPD may experience anxiety symptoms such as shortness of breath, rapid heart rate, numbness/tingling, and racing thoughts, and/or depressive symptoms such as decreased energy, impaired sleep, and impaired concentration. It can therefore be difficult to discern if a symptom is attributable to the physical diagnosis, the psychiatric diagnosis, or a combination of both. Catastrophic thinking about mild physical symptoms is common in patients with COPD. This can lead to hyperventilation and hypocapnia (manifested by lightheadedness, dizziness, paresthesia, and altered consciousness), with a reciprocally escalating cascade of anxiety and somatic symptoms.1
First-line therapy for anxiety disorders with comorbid COPD is CBT and other nonpharmacologic interventions.2,3
Although there is little evidence that traditional pharmacologic treatments (eg, antidepressants, benzodiazepines) have a statistically significant effect on anxiety and depression in COPD, studies have found that they have some clinical benefit.3 Risks, however, limit the utility of certain agents. Sedative-hypnotics potentially decrease respiratory drive and, particularly in older patients, antidepressants’ sedating effects can increase the risk of falls3 leading to increased morbidity, hospitalization, and mortality.
TREATMENT Mindfulness techniques and meditation
Ms. M’s symptoms show no improvement with the addition of lorazepam, 0.5 mg twice daily. A clinician teaches Ms. M mindfulness techniques, and she begins a trial of daily, individual, guided meditation using a meditation app. Respiratory therapists also instruct her on controlled breathing techniques such as pursed-lips breathing, diaphragmatic breathing, and deep breathing. They also encourage Ms. M to participate in the daily exercise group while on the unit.
[polldaddy:10673881]
The authors’ observations
Research indicates that low doses of opioids are safe and effective for refractory breathlessness in patients with severe COPD(those with an arterial partial pressure of oxygen ≤55 mm Hg or arterial oxygen saturation ≤88%).6,7
Continue to: The current opioid crisis...
The current opioid crisis prompts additional caution in prescribing, especially when considering using short-acting, immediate-release opioids such as morphine, which have a greater potential for abuse and dependence.
Many patients with COPD in the end-of-life phase and in severe pain or discomfort due to the advanced stages of their illness receive opioids as part of palliative care. Patients with COPD whose medical care is predominantly palliative may benefit greatly from being prescribed opioids. Most patients with COPD who find relief from low-dose opioids usually have 6 to 12 months to live, and low-dose opioids may help them obtain the best possible quality of life.
Choosing opioids as a treatment involves the risk of physiologic dependence and opioid use disorder. For Ms. M, the potential benefits were thought to outweigh such risks.
OUTCOME Breathlessness improves, anxiety decreases
Ms. M’s lorazepam is discontinued, and immediate-release morphine is prescribed at a low dose of 1 mg/d on an as-needed basis for anxiety with good effect. Ms. M’s breathlessness improves, leading to an overall decrease in anxiety. She does not experience sedation, confusion, or adverse respiratory effects.
Ms. M’s anxiety and depression improve over the course of the hospitalization with this regimen. On hospital Day 25, she is discharged with a plan to continue duloxetine, 60 mg/d, ECT twice weekly, and low-dose morphine, 1 mg/d, as needed for anxiety. She is referred for pulmonary rehabilitation and CBT to maintain remission.
[polldaddy:10673882]
Continue to: The authors' observations
The authors’ observations
Ms. M’s case highlights several challenges associated with treating psychiatric illness in a patient with a chronic medical illness. The relationship between COPD, anxiety, and depression is complex, and is associated with reduced quality of life, increasing severity of pulmonary disease, increased dyspnea, a sense of loss and inability to cope, and decreased self-efficacy and adherence to treatment.9-11
Bottom Line
When traditional antidepressant and anxiolytic therapies have not sufficiently helped, consider low-dose, once-daily opioids to address refractory breathlessness in a patient with COPD with comorbid anxiety and depression. This treatment can lead patients to participate in rehabilitation therapies and improve their quality of life.
Related Resources
- Alexopoulos G, Kiosses D, Sirey J, et al. Untangling therapeutic ingredients of a personalized intervention for patients with depression and severe COPD. Am J Geriatr Psychiatry. 2014;22(11):1316-1324.
- Jackson D, Banerjee S, Sirey J, et al. Two interventions for patients with major depression and severe chronic obstructive pulmonary disease: impact on quality of life. Am J Geriatr Psychiatry. 2018;27(5):502-511.
Drug Brand Names
Amlodipine • Norvasc
Aripiprazole • Abilify
Buspirone • Buspar
Clonazepam • Klonopin
Duloxetine • Cymbalta
Fluoxetine • Prozac
Hydromorphone • Dilaudid
Levodopa • Sinemet
Lorazepam • Ativan
Mirtazapine • Remeron
Morphine • MS Contin
Naloxone • Narcan
Oxycodone • Oxycontin
Salmeterol • Serevent Diskus
1. Harnett D. The difficult-to-treat psychiatric patient with comorbid medical illness. In: Dewan M, Pies R, eds. The difficult-to-treat psychiatric patient. Washington, DC: American Psychiatric Association Publishing; 2001:325-357.
2. Panagioti M, Scott C, Blakemore A, et al. Overview of the prevalence, impact, and management of depression and anxiety in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2014;9:1289-1306.
3. Cafarella P, Effing T, Usmani ZA, et al. Treatments for anxiety and depression in patients with chronic obstructive pulmonary disease: a literature review. Respirology. 2012;17(4):627-638.
4. Heslop-Marshall K, Baker C, Carrick-Sen D, et al. Randomised controlled trial of cognitive behavioural therapy in COPD. ERJ Open Res. 2018;4:00094-2018. doi: 10.1183/23120541.00094-2018.
5. de Godoy DV, de Godoy RF. A randomized controlled trial of the effect of psychotherapy on anxiety and depression in chronic obstructive pulmonary disease. Arch Phys Med Rehabil. 2003;84(8):1154-1157.
6. Abernethy A, Currow D, Frith P, et al. Randomised, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea. BMJ. 2003;327(7414):523-528.
7. Janowiak P, Krajnik M, Podolec Z, et al. Dosimetrically administered nebulized morphine for breathlessness in very severe chronic obstructive pulmonary disease: a randomized, controlled trial. BMC Pulm Med. 2017;17:186.
8. Rocker G, Horton R, Currow D, et al. Palliation of dyspnoea in advanced COPD: revisiting a role for opioids. Thorax. 2009;64(10):910-915.
9. Pooler A, Beech R. Examining the relationship between anxiety and depression and exacerbations of COPD which result in hospital admission: a systematic review. Int J Chron Obstruct Pulmon Dis. 2014;9:315-330.
10. Carmen Valenza M, Valenza-Peña G, Torres-Sánchez I, et al. Effectiveness of controlled breathing techniques on anxiety and depression in hospitalized patients with COPD: a randomized clinical trial. Respir Care. 2014;59(2):209-215.
11. Pollok J, van Agteren J, Esterman A, et al. Psychological therapies for the treatment of depression in chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2019;3:CD012347. doi: 10.1002/14651858.CD012347.pub2.
12. Roberts N, Kidd L, Kirkwood K, et al. A systematic review of the content and delivery of education in pulmonary rehabilitation programmes. Respiratory Medicine. 2018;145:161-181.
13. Pumar M, Gray C, Walsh J, et al. Anxiety and depression-important psychological comorbidities of COPD. J Thorac Dis. 2014;6(11):1615-1631.
14. Alexopoulos G, Kiosses D, Sirey J, et al. Untangling therapeutic ingredients of a personalized intervention for patients with depression and severe COPD. Am J Geriatr Psychiatry. 2014;22(11):1316-1324.
15. Jackson D, Banerjee S, Sirey J, et al. Two interventions for patients with major depression and severe chronic obstructive pulmonary disease: impact on quality of life. Am J Geriatr Psychiatry. 2018;27(5):502-511.
1. Harnett D. The difficult-to-treat psychiatric patient with comorbid medical illness. In: Dewan M, Pies R, eds. The difficult-to-treat psychiatric patient. Washington, DC: American Psychiatric Association Publishing; 2001:325-357.
2. Panagioti M, Scott C, Blakemore A, et al. Overview of the prevalence, impact, and management of depression and anxiety in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2014;9:1289-1306.
3. Cafarella P, Effing T, Usmani ZA, et al. Treatments for anxiety and depression in patients with chronic obstructive pulmonary disease: a literature review. Respirology. 2012;17(4):627-638.
4. Heslop-Marshall K, Baker C, Carrick-Sen D, et al. Randomised controlled trial of cognitive behavioural therapy in COPD. ERJ Open Res. 2018;4:00094-2018. doi: 10.1183/23120541.00094-2018.
5. de Godoy DV, de Godoy RF. A randomized controlled trial of the effect of psychotherapy on anxiety and depression in chronic obstructive pulmonary disease. Arch Phys Med Rehabil. 2003;84(8):1154-1157.
6. Abernethy A, Currow D, Frith P, et al. Randomised, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea. BMJ. 2003;327(7414):523-528.
7. Janowiak P, Krajnik M, Podolec Z, et al. Dosimetrically administered nebulized morphine for breathlessness in very severe chronic obstructive pulmonary disease: a randomized, controlled trial. BMC Pulm Med. 2017;17:186.
8. Rocker G, Horton R, Currow D, et al. Palliation of dyspnoea in advanced COPD: revisiting a role for opioids. Thorax. 2009;64(10):910-915.
9. Pooler A, Beech R. Examining the relationship between anxiety and depression and exacerbations of COPD which result in hospital admission: a systematic review. Int J Chron Obstruct Pulmon Dis. 2014;9:315-330.
10. Carmen Valenza M, Valenza-Peña G, Torres-Sánchez I, et al. Effectiveness of controlled breathing techniques on anxiety and depression in hospitalized patients with COPD: a randomized clinical trial. Respir Care. 2014;59(2):209-215.
11. Pollok J, van Agteren J, Esterman A, et al. Psychological therapies for the treatment of depression in chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2019;3:CD012347. doi: 10.1002/14651858.CD012347.pub2.
12. Roberts N, Kidd L, Kirkwood K, et al. A systematic review of the content and delivery of education in pulmonary rehabilitation programmes. Respiratory Medicine. 2018;145:161-181.
13. Pumar M, Gray C, Walsh J, et al. Anxiety and depression-important psychological comorbidities of COPD. J Thorac Dis. 2014;6(11):1615-1631.
14. Alexopoulos G, Kiosses D, Sirey J, et al. Untangling therapeutic ingredients of a personalized intervention for patients with depression and severe COPD. Am J Geriatr Psychiatry. 2014;22(11):1316-1324.
15. Jackson D, Banerjee S, Sirey J, et al. Two interventions for patients with major depression and severe chronic obstructive pulmonary disease: impact on quality of life. Am J Geriatr Psychiatry. 2018;27(5):502-511.
