A 61-year-old with bipolar disorder and cognitive impairment: Dementia or polypharmacy?

DIFFERENTIAL DIAGNOSIS

1. On the basis of this information, which is the most likely cause of this patient’s cogitive impairment?

• Dementia with Lewy bodies
• Early-onset Alzheimer disease
• Stroke with vascular cognitive impairment
• Lithium neurotoxicity

Lithium neurotoxicity is the most likely cause of this patient’s symptoms, given the temporal relationship between the adjusting of his lithium dose and the onset of his symptoms. Lithium therapy causes subtle cognitive deficits. Its dosing in older patients requires careful monitoring because of age-related alterations in its pharmacology and its various drug interactions; both mechanisms played a role in precipitating lithium toxicity in this patient.

Although his lithium levels are in the broadly accepted therapeutic range, there is much debate about the best maintenance level for patients with bipolar disorder. A level in the range of 1 to 1.2 mmol/L may be best in acute mania, while a lower level of around 0.8 mmol/L is preferred in the depressive phase. Once the patient’s mood has stabilized, the best maintenance level may be in the range of 0.2 to 0.6 mmol/L.

Dementia with Lewy bodies, although suggested by the patient’s cognitive impairment, history of parkinsonian symptoms, and somnolence, is an unlikely cause because his motor symptoms resolved after the aripiprazole was discontinued, his somnolence improved after the dose of lithium was reduced, and his alertness did not fluctuate thereafter as would be expected in dementia with Lewy bodies.

Alzheimer disease usually manifests as gradually progressive cognitive deficits involving memory impairment with one or more of the following: aphasia, apraxia, agnosia, and disturbance in executive functioning. In contrast, this patient’s memory loss was fairly abrupt and not slowly progressive.

Stroke is also unlikely, as he has no history of stroke or focal neurologic deficits. Although a magnetic resonance scan of the brain showed some evidence of small-vessel ischemic changes, it showed no cortical infarcts.

MECHANISMS OF LITHIUM NEUROTOXICITY

2. What are the possible mechanisms of lithium neurotoxicity in this patient?

• The increased dose of lithium
• The interaction of nonsteroidal anti-inflammatory drugs (NSAIDs) and lithium
• The interaction of the other psychotropic medications with lithium
• All of the above
• None of the above

All of the above could be contributing.

Although lithium is thought to cause side effects in as many as 60% of patients of any age who take it, the rate of serious adverse effects is reportedly higher in older patients than in younger patients.¹

That said, cognitive deficits are common in bipolar disorder irrespective of lithium use.

COGNITIVE IMPAIRMENT IN BIPOLAR DISORDER

3. If cognitive impairment in bipolar disorder is common, when does it occur?

• Only in the remission phase
• Only in the manic phase
• Only in the depression phase
• In all phases of the disease

Cognitive impairment occurs in all phases of bipolar disorder. Neuropsychological testing of bipolar patients in remission uncovers subtle, persistent cognitive impairment in executive function and in visuospatial memory without mood symptoms.^3–5 Impaired executive functioning, predominantly frontal lobe dysfunction, interferes with one’s ability to initiate, plan, perform, and successfully complete a task and challenges one’s ability to function effectively in society and to comply with medical advice and instructions on taking medications.

RECOMMENDATIONS

4. What should we recommend to this patient?

• Decrease the current dose of lithium
• Stop all medications
• Undergo detailed neuropsychological testing
• Follow up with a psychiatrist, if needed

The patient’s lithium level was within the therapeutic range and his bipolar symptoms were well controlled. In older patients, however, the optimal serum level of lithium is often unclear, making it advisable to reduce the dose when an adverse effect is suspected.

His other medications should be reviewed. Gabapentin is not indicated for use as a mood stabilizer, and his divalproex dose (250 mg) is well below the usual therapeutic dose of 1,000 to 2,000 mg/day.⁶ The gabapentin could be discontinued, and the divalproex could be increased to a therapeutic dose.

NSAIDs can increase serum lithium levels, diminish renal lithium clearance, and possibly induce lithium toxicity, but the effect varies considerably among drugs and individuals.⁷ We would advise this patient to stop taking naproxen and switch to acetaminophen (Tylenol) for his arthritis pain, and we would inform him of the risk of lithium toxicity with continuous use of NSAIDs.

We would also recommend additional neuropsychological testing. The patient noticed subtle difficulties in his cognitive abilities that were not apparent on the MMSE. While the MMSE is an acceptable cognitive test, it is often not sensitive enough to detect milder forms of cognitive impairment, especially in well-educated patients at the usual cut-point of 24. A comprehensive neuropsychological examination is a more sensitive measure of cognition, involving the detailed testing of various cognitive domains. It can reveal a pattern of cognitive impairment that helps to differentiate between normal and mood disorders and also can detect subtle executive dysfunction.

However, detailed neuropsychological testing is time-consuming and may not be obtained rapidly enough to help in making clinical decisions quickly. In this patient’s case, immediate collaboration and follow-up with the patient’s psychiatrist would be the most expeditious way to reassess the patient’s medication regimen.