Introduction
It was first proposed in 1972 that mood level is controlled, at least in part, by a dynamic balance between central cholinergic and adrenergic systems (Janowsky et al., Reference Janowsky, El-Yousef, Davis and Sekerke1972). Hypocholinergic states are associated with mania and hypoadrenergic states with depression. In support of this hypothesis there is considerable clinical and preclinical evidence that cholinergic agonists and cholinomimetic agents can cause dysphoria along with physiologic changes typical of depression (Bymaster and Felder, Reference Bymaster and Felder2002). Furthermore, clinical experience and product datasheets indicate that depression is a known, albeit uncommon, adverse effect of cholinesterase inhibitors. There is also some preliminary evidence that these agents may have therapeutic benefit in mania (Burt et al., Reference Burt, Sachs and Demopulos1999), although a prospective controlled trial of donepezil for this indication (Evins et al., Reference Evins, Demopulos, Nierenberg, Culhane, Eisner and Sachs2008) was negative.
In apparent contradiction of the above, however, there have been occasional case reports of a rare association of donepezil with mania or hypomania (Benazzi, Reference Benazzi1998; Reference Benazzi1999; Rao, Reference Rao2008). There have been no reports of a similar association with either rivastigmine or galantamine. Of the seven cases reported, all had a previous history of major functional or organic psychiatric disorders (three had bipolar I disorder) in addition to cognitive decline.
The cholinergic system interacts with a variety of other transmitters or neuromodulators, including dopamine, serotonin, gamma-aminobutyric acid, opioid peptides, substance P and angiotensin II (Cummings, Reference Cummings2000). Alterations of serotonergic systems, in particular, are associated with mood disorders. Although there is in-vitro evidence that donepezil can alter brain extracellular serotonin concentrations (Shearman et al., Reference Shearman2006), it is uncertain whether these effects are clinically important.
We here present a further case of hypomania apparently precipitated by donepezil, in this instance without any history of antecedent major functional psychiatric disorder. Further, in this case, bipolar mood fluctuations persisted for some time after cessation of donepezil.
The patient gave written informed consent to publication in this Journal.
Case summary
A 76-year-old widow of Maori racial descent was diagnosed by another psychiatrist with mild subcortical ischemic vascular dementia in late 2008. There was no history of major mood disorder although she had some minor, transient depressive symptoms (briefly treated with fluoxetine by her general practitioner) prior to and following the death of her husband several months earlier. Her family psychiatric history was negative.
At presentation her only medication with potential impact on the central nervous system was metoprolol 47.5 mg daily. Donepezil 5 mg daily, increasing to 10 mg daily, was introduced. Although this was an off-label prescription, the patient was keen for a trial of this medication. She was referred back to her general practitioner.
Within a few weeks of commencing the larger dose of donepezil she developed an apparent hypomanic illness characterized by mild elation, increased confidence, overspending, overactivity and overtalkativeness, reduced sleep, irritability, tactlessness and poor judgment. There were no psychotic features. Clinical features suggestive of delirium (abrupt increase in confusional symptoms and functional impairment, fluctuating attentional deficit, perplexity, perceptual disturbance) were absent. After several months, donepezil was stopped by the general practitioner. It was unclear if there had been any positive yield in terms of cognitive functioning. The patient then quickly switched to a severe, non-psychotic depressive state. Her main symptoms at that time were pervasive low mood and anhedonia, anergia and low volition, pessimistic thinking, loss of confidence, poor concentration and loss of will to live without active suicidality. She was prescribed citalopram 10 mg daily by her general practitioner.
Two weeks after antidepressant initiation she was assessed by the second author and referred for inpatient treatment under the care of the first author, at which point her mood switched once more to mild hypomania with similar symptom profile to that described above. Citalopram was stopped on admission. Hypomania persisted for two months, treated with valproate and olanzapine. In the latter stage of her admission some mixed-mood features emerged, i.e. intermittent frustration and dysphoria related to her slow progress. She was not re-challenged with a cholinesterase inhibitor. After some adjustment difficulties relating to her dementia-related disability, her mood eventually stabilized and she has since remained well for two years, living in supported accommodation, although her cognition has continued to decline.
Discussion
It is possible that this patient had a latent bipolar diathesis which was unmasked by the combination of small-vessel cerebrovasular disease and donepezil treatment. The central cholinergic system changes induced by donepezil may have produced secondary alteration of noradrenergic, dopaminergic or other neurochemical systems, initially producing hypomania. Complex perturbations of neurotransmitter and neuromodulator networks may have persisted following cessation of donepezil, accounting for her ongoing mood instability.
Conflict of interest
None.
Description of authors' roles
B. Copeland carried out the literature review and C. Collins wrote the paper; both were involved in the later stages of the patient's treatment. M. Croucher assisted with revision of the paper.
