A mysterious case of mania

The authors’ observations

Our first step was to clarify Mrs. P’s diagnosis. In reviewing differential diagnoses, we considered:

• serotonin syndrome
• benzodiazepine withdrawal syndrome
• antidepressant-induced mania
• adrenergic toxicity
• malignant hyperthermia
• heat stroke
• infectious causes.

Our index of suspicion for serotonin syndrome was low because Mrs. P didn’t meet criteria required for diagnosis. Relevant signs and symptoms included confusion, elevated mood (major) and agitation, nervousness, insomnia, and low blood pressure (minor).

Based on concerns about medication interactions, we discontinued sertraline and desipramine. According to the patient’s sister, Mrs. P’s manic symptoms markedly responded to PRN doses of lorazepam. We prescribed lorazepam, 1 mg every 6 hours, and observed Mrs. P for signs and symptoms of benzodiazepine withdrawal.

HISTORY: OTC drug use

According to Mrs. P’s mother, after her daughter abruptly discontinued methadone, she began to have very strong headaches, which she treated with Excedrin or Excedrin Sinus. The mother said that 4 days before Mrs. P came to the ED, she found her daughter holding 4 tablets of Excedrin and an empty bottle. Unfortunately her mother was unable to say what type of Excedrin it was. When the treatment team asks Mrs. P how many pills she usually takes, she says she doesn’t know but usually until the pain stops.

The authors’ observations

Management of secondary mania should focus on treating the underlying condition (Algorithm). Neurology categorizes mania into 3 categories:²

• confusional-delirious states
• manic symptoms associated with focal or multifocal cerebral lesions
• affective disorders (manic-depressive and depressive psychoses).

Medical workup ruled out common secondary causes of psychosis. Collaborative information from relatives revealed no family history of mental illness.

Patients with hearing loss and deafness have been shown to be at increased risk for psychotic disorders compared with the general population. Severe sensory deficits early in Mrs. P’s life may have influenced the orderly development of neural connections in her sensory cortex and association areas.³ Mrs. P was deaf for the first 45 years of life. It could be hypothesized that her sensory deficits significantly influenced her ability to reality test. After receiving a cochlear implant, Mrs. P rapidly went from no auditory stimulation to marked improvement. This stressor might precipitate psychotic symptoms. However, her presentation seemed to be characterized more by manic symptoms or an agitated delirium. It also did not fit temporally with her presentation.

We begin to suspect that Mrs. P’s mania is substance-induced. Excedrin, an over-the-counter medication, contains aspirin and caffeine. Excedrin Sinus also contains phenylephrine. Amphetamines, caffeine, ephedrine, pseudoephedrine, and phenylpropanolamine have all been linked to manic-like psychotic episodes.

Concerns about the illicit conversion of pseudoephedrine into methamphetamine obliged pharmaceutical companies in the United States to switch product formulations to phenylephrine in 2005,⁴ although some “behind-the-counter” medications may contain pseudoephedrine. Phenylephrine is a relatively selective α1 agonist with weak α2 adrenoceptor agonist activity and low β agonist activity. It is very similar to pseudo-ephedrine, which is known to be implicated in the development of manic symptoms.^5,6

Pseudoephedrine can raise CK levels and cause rhabdomyolysis.^7,8 Mrs. P’s CK level was 176 (normal range 36 to 176 U/L) 4 days after her initial presentation, and she had a moderate amount of myoglobin in her urine. Her creatinine was normal. The patient was taking excessive amounts of caffeine and—if she was using Excedrin Sinus—pseudoephedrine or phenylephrine. We were unable to determine whether her Excedrin contained pseudoephedrine or phenylephrine. In addition, she was going through opioid withdrawal and reported problems with her sleep. There was also a question of Mrs. P’s unknown methadone use combined with its decreased clearance secondary to medication interactions.

While previously hospitalized for overdose, Mrs. P tested positive for propoxyphene. Excessive use of propoxyphene also can cause numerous adverse reactions. Some of that could have explained why Mrs. P’s presentation includes nervousness, CNS stimulation, excitement, insomnia, and restlessness.⁵

Based on multiple factors, we believe Mrs. P meets DSM-IV-TR criteria for substance-induced mood disorder (Table 2).⁹ This diagnosis is supported by Mrs. P’s history of complex polypharmacy, excessive caffeine use, sleep deprivation, and possible opioid withdrawal.

Algorithm: Managing substance-induced manic disorder

CK: creatine kinase; CRP: C-reactive protein; CT: computed tomography; EEG: electroencephalogram; HIV: human immunodeficiency virus; MRI: magnetic resonance imaging; VDRL: venereal disease research laboratoryTable 2

DSM-IV-TR criteria for substance-induced mood disorder*