CASE: First-episode mania
Mrs. P, age 47, is brought to the emergency department (ED) because her family is concerned about her behavioral changes over the last week. Her husband reports that Mrs. P has become hyper-religious and talkative. She has been perseverating on numbers and dates and incessantly calling people. Mrs. P reports increased energy and decreased need for sleep. On examination, she has pressured speech. She has no psychiatric history; however, for the past year, she has been taking sertraline, 100 mg/d, and desipramine, 25 mg/d, which her primary care physician prescribed for unknown reasons.
Mrs. P has struggled with chronic back pain for years, but an MRI of her spine is negative. Her family strongly believes that for the past 3 years Mrs. P has been receiving too many medications from her pain management specialist. Six weeks before her current presentation, she was receiving methadone, 40 mg/d, hydrocodone, at least 20 mg/d, and tramadol, 400 mg/d in divided doses. She also was taking an unknown dose of at least 1 benzodiazepine.
Mrs. P’s husband notes she stopped taking methadone abruptly approximately 5 weeks ago. However, about 3 weeks ago, Mrs. P accidentally overdosed on opioids and was hospitalized for several days. Urine drug screen at the time was positive for acetaminophen, salicylate, propoxyphene, opiate, benzodiazepine, and tricyclic antidepressant.
Mrs. P’s medical history includes auditory nerve loss from birth; her mother had German measles (rubella). Mrs. P never learned American Sign Language. She underwent cochlear implant surgery 1 year ago and now has only mild difficulties speaking.
The authors’ observations
Manic symptoms are common in patients with comorbid medical disorders and present a diagnostic challenge. Obtaining an accurate history from the patient may be difficult. Such evaluations often require extensive investigation and collection of data from multiple sources, including:
- medical records
- family members
- patient observation.
Mrs. P’s history is marked by contradicting data from these sources. For example, her family says she stopped taking “pain medications” 5 weeks ago, but 2 weeks later her urine drug screen showed opioids.
Both illicit drugs and prescribed medications can precipitate manic symptoms. From medical records and drug testing, it was evident that Mrs. P had a history of medication abuse/overdose/misuse.
Mania also has been associated with substance withdrawal. Mrs. P allegedly stopped taking methadone 4 weeks before the onset of manic symptoms. Methadone is a synthetic opioid with a pharmacokinetic and pharmacodynamic profile that presents clinical challenges, including:
- large interindividual variability in methadone pharmacokinetics
- lack of reliable equianalgesic conversion ratio to and from other opioids
- potential for multiple drug interactions and complex pharmacodynamics.
An opioid’s half-life determines the onset and duration of withdrawal syndrome symptoms.1 Methadone metabolism is predominantly mediated by CYP3A4, CYP2B6, CYP2D6, and to some extent by CYP2C19.1 We performed genetic testing to help evaluate how Mrs. P metabolized medications. Mrs. P had a normal genotype for CYP2D6, which meant that she should process opioids at a normal rate; however, she was heterozygous for CYP2C19*2 polymorphism, so it is possible that methadone stayed in her system longer than average.
Evidence documenting methadone drug interactions is limited (Table 1).1 Mrs. P was taking sertraline and desipramine; both have potent effects via 2D6 inhibition that could increase plasma methadone concentration. Other evidence indicates that benzodiazepines and methadone may have synergistic interactions that could increase opioid sedation or respiratory depression.1
Table 1
Is a drug interaction with methadone causing Mrs. P’s mania?
| Medication class/agent | Effect on methadone level | Effect on methadone metabolism | Additional effects of interaction |
|---|---|---|---|
| Selective serotonin reuptake inhibitors | |||
| Fluvoxamine | Increase | Inhibition | Opioid toxicity |
| Fluoxetine | Increase | Inhibition | Torsades de pointes |
| Paroxetine | Increase | Inhibition | Decreased hepatic metabolism |
| Sertraline* | Increase | Autoinduction | Torsades de pointes |
| Citalopram | — | — | Torsades de pointes |
| Tricyclic antidepressants | |||
| Desipramine* | — | Inhibition | Increased desipramine levels/inhibition of desipramine metabolism |
| Amitriptyline | Increase methadone clearance | — | Torsades de pointes/prolonged QT interval |
| Anti-inflammatory drugs | |||
| NSAIDs* | — | — | Enhanced analgesia/opioid-sparing effect |
| Aspirin* | — | — | Paradoxical activation of platelet receptors |
| Benzodiazepines | |||
| Alprazolam | — | — | CNS depression/sedation/overdose |
| Diazepam* | — | Inhibition | Additive depressant effects |
| Opioid agonists | |||
| Dextromethorphan | — | Inhibition (not significant) | Increased side effects, especially sleepiness and drowsiness |
| Tramadol* | — | — | Well tolerated |
| Nicotine | Decrease | Can increase smoking rate | |
| *Medications taken by Mrs. P | |||
| NSAIDs: nonsteroidal anti-inflammatory drugs | |||
| Source: Reference 1 | |||
EVALUATION: Few clues
In our ED, Mrs. P’s urine drug abuse screen is positive for salicylate and benzodiazepine only. Findings from physical examination, vital signs, ECG, and chest radiography are within normal limits. Internal medicine consultation is unremarkable. Mrs. P’s laboratory investigation is notable for an elevated white blood cell count, but this normalizes over a week.
Mrs. P shows no evidence of infection and is normoglycemic. B12 and folate are within normal limits. Serum electrolytes, liver function testing, sensitive thyroid stimulating hormone, and C-reactive protein are within normal limits. Urinalysis is negative except for a small amount of hemoglobin. Her creatine kinase (CK) is in the upper normal range. Human immunodeficiency virus (HIV) and syphilis testing is negative. Ceruloplasmin level also is normal. Heavy metal screen is negative. Head MRI and CT from previous hospitalizations were unremarkable.