Parkinson’s disease is known to be a rare predisposing factor for mania—possibly related to potential manicogenic properties of dopaminergic medications5—but this would not explain new-onset mania in the context of uremia in a patient whose carbidopa/levodopa dose had been stable for several years. It is possible that Ms. Z’s refusal of dialysis could have led to build-up of carbidopa/levodopa in her blood, thereby contributing to mania; however, when she began feeling irritable, she refused several of her medications, including carbidopa/levodopa. Therefore, it is unlikely that carbidopa/levodopa accumulated to toxic levels.
We carefully evaluated Ms. Z’s complete medication list to determine if other drugs could be contributing factors. She has been taking escitalopram for anxiety for several years. Although Ms. Z had no personal or family history of bipolar disorder and no past hypomania or agitation associated with this medication, we discontinue escitalopram in case it was contributing to her manic symptoms. Ms. Z also receives amlodipine, 5 mg/d for hypertension; atorvastatin, 20 mg/d, for hyperlipidemia; pantoprazole, 40 mg/d, for acid reflux; metoprolol, 100 mg/d, for hypertension; aspirin, 81 mg/d, for cardioprotection; and fish oil, 2000 mg/d, for cardioprotection. We do not feel that any of these medications significantly contribute to her current state.
TREATMENT: Restarting dialysis
We start Ms. Z on olanzapine, 5 mg/d, for manic symptoms 1 day after admission, and resume dialysis treatments 1 day later. Because of concerns that olanzapine could worsen her myelodysplasia, we switch to aripiprazole, titrating up to 30 mg/d, 4 days later. After 2 dialysis treatments, her manic symptoms begin to resolve.
The authors’ observations
A number of factors suggest that uremia likely is causing Ms. Z’s manic symptoms. Her symptoms suddenly developed shortly after her first missed dialysis treatment, but gradually resolved after re-initiating dialysis. It is possible that antipsychotics relieved her manic symptoms, but this does not detract from the factors that make a causal relationship between uremia and mania likely.
Manic symptoms have been reported to be precipitated by a variety of medical problems, including metabolic disturbances, infections such as human immunodeficiency virus brain infection, neurologic disorders, brain neoplasms, or traumatic brain injuries (Table 2).6,7 End-stage renal disease frequently is associated with psychiatric manifestations—including depression, psychosis, delirium, and dementia—but mania is not a typical presentation. It is possible that this condition occurs more often but is not recognized.
Table 2
Common causes of secondary mania
| Metabolic/endocrine disturbances (hyperthyroidism, hyperadrenalism) |
| Infections (HIV) |
| Neurologic disorders (cerebrovascular accident, multiple sclerosis, Parkinson’s disease, epilepsy, Huntington’s disease) |
| Brain neoplasms |
| Traumatic brain injuries |
| Medications (anabolic steroids, antidepressants, corticosteroids, dextromethorphan, dopamine agonists, hypericum, isoniazid, stimulants, ephedrine, zidovudine) |
| Substance abuse (cocaine, amphetamines) |
| HIV: human immunodeficiency virus |
| Source: References 6,7 |
Kidney disease and psychotropics
We considered the effect of dialysis on psychotropics when selecting pharmacotherapy for Ms. Z’s manic symptoms. Haloperidol is not renally cleared so no dosage adjustment is necessary;8 however, this potent dopamine D2-blocker could have worsened Ms. Z’s parkinsonism. Lithium is contraindicated in acute renal failure. Valproic acid clearance is reduced in renal failure, but because it is cleared by hemodialysis, dosage adjustment is not recommended for dialysis patients.8 However, Ms. Z’s myelodysplasia is a contraindication for valproic acid as well as carbamazepine. With atypical antipsychotics as our primary options, we noted that olanzapine, quetiapine, or aripiprazole do not require dosage adjustments for dialysis patients.8,9 Of these, we eventually chose aripiprazole because we felt that it was least likely to exacerbate Ms. Z’s myelodysplasia.10
How uremia might cause mania
The pathophysiology of uremia-induced mania remains speculative. Possible factors include:
- Chronic renal failure can cause an elevation in plasma free tryptophan, a serotonin (5-HT) precursor.11 Postmortem examination of brains of patients who died in uremic coma show elevated 5-HT.12 Moreover, cerebrospinal fluid of patients with chronic renal failure has shown increased 5-hydroxyindoleacetic acid, the major 5-HT metabolite.13 Increased 5-HT could cause mania in some uremic patients, similar to how serotonergic medications can precipitate mania in some patients.
- Circulating ß-endorphin levels are increased in renal failure.14 ß-endorphins increase animal locomotor activity, which is the basis of an animal model of mania.15,16 Therefore, uremia-induced mania could be partly related to elevated ß-endorphin levels.
This case demonstrates that mania could be a psychiatric manifestation of end-stage renal disease. Clinicians should be aware of this possibility, and further study should examine underlying pathophysiologic changes in uremia and other secondary causes of mania that might lead to such a mood state.