Psychiatric Annals

Case Report 

Mania with Psychosis Induced by Low-Dose Trazodone

Ibrahim Alfurayh, MD; Hind Aboheimed, PharmD; Adriana Carvalhal, MD

Abstract

A 67-year-old woman presented to the emergency department (ED) with erratic behavior, including irritable mood, agitation, and aggression to the degree that required restraint, after having been charged with assaulting a police officer. She had a history of hypertension, hyperlipidemia, chronic low back pain, osteoarthritis, and chronic hypokalemia. The patient had been taking 150 mg/day of amitriptyline for back pain for the past 2 years, which had been prescribed by her primary care physician. Her other medications (also prescribed by her primary care physician) included 2.5 mg/day of bisoprolol, 360 mg/day of diltiazem, 40 mg/day of pantoprazole, 20 mg/day of pravastatin, and 8 mmol/day of potassium chloride.

It was difficult to obtain a history from the patient, but collateral history from her family members revealed progressively erratic behavior over the 2 weeks prior to her presentation to the ED. The behavior began after starting a new medication, trazodone (100 mg/day), which had been prescribed by her primary care physician for insomnia. Since then, she had gradually become irritable, hyperactive, talkative with a clear flight of ideas, and disinhibited. She had been spending large amounts of money on unnecessary things, consumed alcohol excessively in the last 5 to 6 days (which was unusual for her), and had not slept at all for the last 3 days prior to the ED but showed no signs of fatigue. The patient also had delusions that Jesus was sending her messages through a wristwatch, and she believed she had a special power to end world poverty.

There was no report of a perceived stressor preceding the current episode. The patient had no associated medical comorbidities such as coronary heart disease, obstructive airway disease, or endocrine abnormalities. The patient had no history of head injury, migraines, central nervous system infection, or significant medical or psychiatric illness, including mood or psychotic disorder. Her family history for psychiatric disorders was unremarkable as well.

The patient was admitted to the hospital, and the trazodone and amitriptyline were discontinued. A Clinical Institute Withdrawal Assessment (CIWA) protocol was initiated to rule out alcohol withdrawal, and the following tests were performed: complete blood count (CBC) with differentials, liver and renal function, bilirubin, lactate, albumin, thyroid function, random glucose and hemoglobin A1c, vitamin B12, and C-reactive protein tests, all of which were within normal ranges. Blood and urine cultures were negative. A urine toxicology screen was positive for tricyclic antidepressants (ie, amitriptyline). Her blood alcohol level was elevated in the ED but responded well to CIWA and was normal on the third day after admission; urea and electrolyte levels showed low potassium (the lowest was 2.8 mmol/L), so intravenous potassium was initiated and her levels slowly returned to normal range. She did not have vomiting or diarrhea and was not taking any diuretics before her admission. The cause of her chronic hypokalemia was difficult to determine. Furthermore, a head computed tomography scan excluded acute ischemic or hemorrhagic lesions but revealed mild frontal lobe parenchymal volume loss.

The patient's mania with psychosis had not improved by day 4, so psychiatry was consulted. She was assessed and diagnosed as having a secondary manic episode with psychosis due to either a medication change (starting trazodone and potentially her amitriptyline) or organic causes. Intramuscular haloperidol and olanzapine were initiated to control her agitation. After little improvement, neurology was consulted to rule out any neurological causes of her condition, including encephalitis. An electroencephalogram and magnetic resonance imaging were performed but results were normal.

Although rare, paraneoplastic syndromes were considered as part of the differential diagnosis at that time because they can affect the central nervous system and lead…

A 67-year-old woman presented to the emergency department (ED) with erratic behavior, including irritable mood, agitation, and aggression to the degree that required restraint, after having been charged with assaulting a police officer. She had a history of hypertension, hyperlipidemia, chronic low back pain, osteoarthritis, and chronic hypokalemia. The patient had been taking 150 mg/day of amitriptyline for back pain for the past 2 years, which had been prescribed by her primary care physician. Her other medications (also prescribed by her primary care physician) included 2.5 mg/day of bisoprolol, 360 mg/day of diltiazem, 40 mg/day of pantoprazole, 20 mg/day of pravastatin, and 8 mmol/day of potassium chloride.

It was difficult to obtain a history from the patient, but collateral history from her family members revealed progressively erratic behavior over the 2 weeks prior to her presentation to the ED. The behavior began after starting a new medication, trazodone (100 mg/day), which had been prescribed by her primary care physician for insomnia. Since then, she had gradually become irritable, hyperactive, talkative with a clear flight of ideas, and disinhibited. She had been spending large amounts of money on unnecessary things, consumed alcohol excessively in the last 5 to 6 days (which was unusual for her), and had not slept at all for the last 3 days prior to the ED but showed no signs of fatigue. The patient also had delusions that Jesus was sending her messages through a wristwatch, and she believed she had a special power to end world poverty.

There was no report of a perceived stressor preceding the current episode. The patient had no associated medical comorbidities such as coronary heart disease, obstructive airway disease, or endocrine abnormalities. The patient had no history of head injury, migraines, central nervous system infection, or significant medical or psychiatric illness, including mood or psychotic disorder. Her family history for psychiatric disorders was unremarkable as well.

Management

The patient was admitted to the hospital, and the trazodone and amitriptyline were discontinued. A Clinical Institute Withdrawal Assessment (CIWA) protocol was initiated to rule out alcohol withdrawal, and the following tests were performed: complete blood count (CBC) with differentials, liver and renal function, bilirubin, lactate, albumin, thyroid function, random glucose and hemoglobin A1c, vitamin B12, and C-reactive protein tests, all of which were within normal ranges. Blood and urine cultures were negative. A urine toxicology screen was positive for tricyclic antidepressants (ie, amitriptyline). Her blood alcohol level was elevated in the ED but responded well to CIWA and was normal on the third day after admission; urea and electrolyte levels showed low potassium (the lowest was 2.8 mmol/L), so intravenous potassium was initiated and her levels slowly returned to normal range. She did not have vomiting or diarrhea and was not taking any diuretics before her admission. The cause of her chronic hypokalemia was difficult to determine. Furthermore, a head computed tomography scan excluded acute ischemic or hemorrhagic lesions but revealed mild frontal lobe parenchymal volume loss.

The patient's mania with psychosis had not improved by day 4, so psychiatry was consulted. She was assessed and diagnosed as having a secondary manic episode with psychosis due to either a medication change (starting trazodone and potentially her amitriptyline) or organic causes. Intramuscular haloperidol and olanzapine were initiated to control her agitation. After little improvement, neurology was consulted to rule out any neurological causes of her condition, including encephalitis. An electroencephalogram and magnetic resonance imaging were performed but results were normal.

Although rare, paraneoplastic syndromes were considered as part of the differential diagnosis at that time because they can affect the central nervous system and lead to similar mood symptoms and/or psychosis. Paraneoplastic testing was performed, and it included CBC with differential, comprehensive metabolic panel, urinalysis, ectopic hormone levels (parathyroid hormone-related protein, adrenocorticotropic hormone, and alcohol dehydrogenases), cerebrospinal fluid analysis (CSF), and assay of paraneoplastic antibodies in blood and CSF to rule out any organic causes that might present with similar presentation such as paraneoplastic encephalitis. All results showed normal levels.

Her manic episodes had improved significantly by day 10, and upon discharge she was alert and oriented with no sign of confusion or behavioral changes. She was educated about her new medications and encouraged to try sleep hygiene tips for her insomnia. She was seen in the clinic as an outpatient 6 weeks after discharge and remained stable without any signs or symptoms of relapse.

Discussion

This case illustrates the problem of off-label prescription of trazodone for insomnia, as there is no strong scientific evidence for its efficacy. Use of trazodone for insomnia is the most common off-label use of an antidepressant.1 One of the influences that may lead physicians to prescribe off-label medication is the absence of a medication for treating the desired condition.2 Interestingly, the lack of physician knowledge of the drug-approved indication is the primary factor for inappropriate prescribing.3

Current guidelines strongly recommend cognitive-behavioral therapy for insomnia as an initial treatment for primary and comorbid insomnia, and numerous medications approved for insomnia have been developed (Table 1).4 In this case, the physician prescribed trazodone as a first-line treatment despite the absence of evidence for its use. Inefficacious antidepressant use creates unnecessary costs and puts patients at risk of experiencing burdensome but preventable adverse effects.1

Commonly Used Medications for Insomnia in Older Adults

Table 1.

Commonly Used Medications for Insomnia in Older Adults

Trazodone is a triazolopyridine derivative approved for treating depression. It is a multifunctional drug depending on the dose; low doses of 25 to 150 mg will antagonize serotonin type 2 receptors, alpha-1 adrenergic receptors, and histamine H1, which will inhibit the arousal stimuli that act on these receptors, hence inducing and maintaining sleep. At higher doses (150–600 mg), trazodone causes an antidepressant effect by acting as a serotonin antagonist-reuptake inhibitor and blocking serotonin transporters.5 The patient in this case was taking 100 mg once daily, which is considered a low dose and subtherapeutic to treat depression. Some literature suggests there is a low risk for switching to mania with sleep-promoting antidepressants like trazodone and mirtazapine, especially with doses subtherapeutic for depression (<150 mg/day for trazodone).6 The case presented here contradicts those findings, as our patient was using a low dose of trazodone but still developed manic symptoms.6 This can be explained by the concomitant use of amitriptyline, as tricyclic antidepressants are a well-known risk factor for induced hypomania/mania in a dose-related manner.7

Moreover, trazodone carries risks and adverse effects that differ from the commonly used insomnia medications, including but not limited to QT prolongation, priapism, neuroleptic malignant syndrome, switching to mania/hypomania, and psychosis.8 Increased subcortical serotonin function is postulated to be involved in the pathophysiology of the psychosis that occurred in the case presented in this article.9 In addition, auditory and visual hallucinations induced by trazodone have been reported.10,11 Other general side effects include drowsiness, dizziness, tiredness, blurred vision, changes in weight, headache, muscle ache, dry mouth, and a rare side effect of seeing visual trails of images after eye movements.8

Moreover, it has been suggested that factors such as age, female gender, and comorbid conditions such as medical or psychiatric illness would increase the probability of adverse drug events.4 The patient described in this case was age 67 years, which rendered her more prone to adverse drug reactions, as older age is frequently accompanied by polypharmacy, comorbidity, and frailty, with decreased pharmacokinetics and pharmacodynamics.12 In similar cases, low-dose trazodone has been associated with induced to mania and hypomania in patients older than age 60 years; this could be related to their decreased elimination rates and hence higher plasma concentrations as compared to younger patients.6

Conclusion

This case emphasizes the importance of considering the level of evidence supporting the risk-benefit ratio when prescribing trazodone off-label, especially with its known adverse effects. It highlights the need for more evidence on the risks and benefits of off-label trazodone use and presents other medication options with strong evidence for efficacy for insomnia.

References

  1. Wong J, Motulsky A, Abrahamowicz M, Eguale T, Buckeridge DL, Tamblyn R. Off-label indications for antidepressants in primary care: descriptive study of prescriptions from an indication based electronic prescribing system. BMJ. 2017;356:j603. doi:10.1136/bmj.j603 [CrossRef] PMID:28228380
  2. US Food and Drug Administration. Understanding unapproved use of approved drugs “off label.” https://www.fda.gov/ForPatients/Other/OffLabel/default.htm. Accessed November 4, 2019.
  3. Eguale T, Buckeridge DL, Verma A, et al. Association of off-label drug use and adverse drug events in an adult population. JAMA Intern Med. 2016;176(1):55–63. doi:10.1001/jamainternmed.2015.6058 [CrossRef] PMID:26523731
  4. Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American academy of sleep medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2):307–349. doi:10.5664/jcsm.6470 [CrossRef] PMID:27998379
  5. Stahl SM. Mechanism of action of trazodone: a multifunctional drug. CNS Spectr.2009;14(10):536–546. doi:10.1017/S1092852900024020 [CrossRef] PMID:20095366
  6. Wichniak A, Jarkiewicz M, Okruszek L, Wierzbicka A, Holka-Pokorska J, Rybakowski JK. Low risk for switch to mania during treatment with sleep promoting antidepressants. Pharmacopsychiatry. 2015;48(3):83–88. doi:10.1055/s-0034-1396802 [CrossRef] PMID:25599460
  7. Koszewska I, Rybakowski JK. Antidepressant-induced mood conversions in bipolar disorder: a retrospective study of tricyclic versus non-tricyclic antidepressant drugs. Neuropsychobiology.2009;59(1):12–16. doi:10.1159/000202824 [CrossRef] PMID:19221443
  8. Khouzam HR. A review of trazodone use in psychiatric and medical conditions. Postgrad Med. 2017;129(1):140–148. doi:10.1080/00325481.2017.1249265 [CrossRef] PMID:27744763
  9. Breier A. Serotonin, schizophrenia and antipsychotic drug action. Schizophr Res. 1995;14(3):187–202. doi:10.1016/0920-9964(94)00043-8 [CrossRef] PMID:7539288
  10. Shiotsuki I, Terao T, Ishii N, Hatano K. Auditory hallucinations induced by trazodone. Case Reports. 2014;2014:bcr2014203865. doi:10.1136/bcr-2014-203865 [CrossRef]
  11. Santos G, Moreira AM. Distressing visual hallucinations after treatment with trazodone. Case Rep Psychiatry. 2017;2017:6136914. doi:10.1155/2017/6136914 [CrossRef] PMID:28702268
  12. Davies EA, O'Mahony MS. Adverse drug reactions in special populations—the elderly. Br J Clin Pharmacol.2015;80(4):796–807. doi:10.1111/bcp.12596 [CrossRef] PMID:25619317
  13. Bain KT. Management of chronic insomnia in elderly persons. Am J Geriatr Pharmacother.2006;4(2):168–192. doi:10.1016/j.amjopharm.2006.06.006 [CrossRef] PMID:16860264
  14. Gooneratne NS, Vitiello MV. Sleep in older adults: normative changes, sleep disorders, and treatment options. Clin Geriatr Med. 2014;30:591–627. doi:10.1016/j.cger.2014.04.007 [CrossRef]. PMID:25037297
  15. Schroeck JL, Ford J, Conway EL, et al. Review of safety and efficacy of sleep medicines in older adults. Clin Ther. 2016;38(11):2340–2372. doi:10.1016/j.clinthera.2016.09.010 [CrossRef] PMID:27751669
  16. Ramakrishnan K, Scheid DC. Treatment options for insomnia. Am Fam Physician.2007;76(4):517–526. https://www.aafp.org/afp/2007/0815/p517.pdf PMID:17853625

Commonly Used Medications for Insomnia in Older Adults

Drug Dose (mg) Adverse effects FDA approved
Nonbenzodiazepine receptor agonists


  Eszopiclone13,14,16 1 Headache, unpleasant taste, somnolence, dyspepsia, dry mouth, dizziness Yes
  Zolpidem13,14,16 2–5 Headache, dizziness, drowsiness, nausea, vomiting, antero-grade amnesia, hallucinations, delirium, unusual nighttime behaviors Yes
  Zaleplon13,14,16 5–10 Headache, nausea, dizziness, somnolence, rhinitis, asthenia, abdominal pain Yes

Benzodiazepines


  Estazolam13,14,16 0.5 Daytime drowsiness, dizziness, lightheadedness, dementia, fall risk, hip fractures Yes
  Temazepam13,14,16 7.5–15 Drowsiness, dizziness, dementia, fall risk-hip fractures, mobility problems Yes
  Triazolam13,14,16 0.125–0.25 Rebound insomnia, anterograde amnesia, psychological dependence, anxiety Yes
  Flurazepam13,14,16 15 Residual daytime sedation, confusion, dizziness, impaired motor coordination, fall risk, motor vehicle accidents Yes

Melatonin receptor agonist


  Ramelteon13,16 8 Headache, somnolence, nasopharyngitis Yes

Orexinant agonist


  Suvorexant14,16 5–20 Somnolence, fatigue, headache, dry mouth, residual daytime sedation, sleep paralysis, fall risk Yes

Antidepressants


  Trazodone13,16 25–100 Residual daytime sedation, orthostasis, headache, nausea, vomiting, xerostomia No
  Mirtazapine14,16 7.5–30 Residual daytime sedation, anticholinergic effects, weight gain No

Over-the-counter


  Diphenhydramine15,16 12.5–50 Residual daytime sedation, anticholinergic effects No
  Herbal valerian15 300–600 Drowsiness, headache, depression No
  Melatonin15 1–2 Residual daytime sedation No
Authors

Ibrahim Alfurayh, MD, is a Psychiatry Fellow, King Saud University. Hind Aboheimed, PharmD, is a Pharmacist, King Saud University. Adriana Carvalhal, MD, is a Psychiatry Consultant, Queen's University.

Address correspondence to Hind Aboheimed, PharmD, King Saud University, 7612 Hittin, Riyadh 3490-13518, Saudi Arabia; email: Hendabo@gmail.com.

Disclosure: The authors have no relevant financial relationships to disclose.

10.3928/00485713-20191104-01

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