Methylphenidate hydrochloride improves cognitive function in patients with advanced cancer and hypoactive delirium: a prospective clinical study

Abstract

Objective: To investigate the clinical improvement observed in patients with advanced cancer and hypoactive delirium after the administration of methylphenidate hydrochloride.

Methods: Fourteen patients with advanced cancer and hypoactive delirium were seen between March 1999 and August 2000 at the Palliative Care Day Hospital and the inpatient Tertiary Palliative Care Unit of Montreal General Hospital, Montreal. They were chosen for inclusion in a prospective clinical study on the basis of (1) cognitive failure documented by the Mini-Mental State Examination (MMSE), (2) sleep-wake pattern disturbances, (3) psychomotor retardation, (4) absence of delusions or hallucinations, and (5) absence of an underlying cause to explain the delirium. All patients were treated with methylphenidate, and changes in their cognitive function were measured using the MMSE.

Results: All 14 patients showed improvement in their cognitive function as documented by the MMSE. The median pretreatment MMSE score (maximum score 30) was 21 (mean 20.9, standard deviation [SD] 4.9), which improved to a median of 27 (mean 24.9, SD 4.7) after the first dose of methylphenidate (p < 0.001, matched, paired Wilcoxon signed rank test). One patient died before reaching a stable dose of methylphenidate. In the other 13 patients, the median MMSE score further improved to 28 (mean 27.8, SD 2.4) (p = 0.02 compared with the median MMSE score documented 1 hour after the first dose of methylphenidate). All patients showed an improvement in psychomotor activities.

Conclusions: Hypoactive delirium that cannot be explained by an underlying cause (metabolic or drug-induced) in patients with advanced cancer appears to be a specific syndrome that could be improved by the administration of methylphenidate.

Fig. 1: Examples of changes over time induced by hypoactive delirium and treatment with methylphenidate in the drawing and writing abilities of patients with advanced cancer.

Fig. 2: Proposed modifications produced by methylphenidate in hypoactive delirium. We hypothesize that specific central nuclei [*] of the brain are affected in these patients. One consequence of this is the development of impaired phasic–tonic firing in the mesolimbic–nucleus accumbens–anterior cingulate–prefrontal circuitry. The clinical picture reflects this dysfunction. Methylphenidate, through its effect particularly on hippocampal neurons, fosters phasic dopamine (DA) spikes, promoting recovery of the phasic–tonic balance in the circuitry. It does this by its ability to block dopamine uptake, particularly in the extrasynaptic space.

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