Monoamine oxidase (MAO) is the predominant enzyme implied in the catabolism of the monoamines dopamine, noradrenaline, and serotonin.1 Dopamine is a substrate for both isoforms of MAO: the extraneuronal MAO-B; and MAO-A which is found both extraneuronally and intraneuronally.2 Intraneuronal MAO-A is active for dopamine, noradrenaline, and serotonin, which have a paramount influence in the pathogenesis of depression. The combination of MAO-A and MAO-B inhibition results in a strong increase of both dopamine, noradrenaline, and serotonin. Depression is the most frequent psychopathological finding in Parkinson’s disease.

In this study we compared moclobemide monotherapy with combined therapy with moclobemide and selegeline, under tyramine restriction.

Ten patients with idiopathic Parkinson’s disease of two to 15 years in duration contributed to the study. The actions of moclobemide and selegeline were described in the informed consent. Inclusion criteria were Parkinson’s disease disability Hoehn and Yahr stages II-IV, major depression using DSM III.R criteria, mini mental state examination (MMSE) score of 21 or above, and self recorded “on-off” patient diaries. A cut-off point of 21 on MMSE score was used to allow study of patients with Parkinson’s disease without substantial cognitive impairment. All patients had been on optimal and stable dosage of antiparkinson medication during the previous three months.

The present major depression had a duration of three to 15 months. Antidepressant medical treatment had not been initiated in any of these 10 patients before entering this study.

Moclobemide (600 mg) with or without selegeline (10 mg) was administered during the six week study period. Regular antiparkinson medication was kept unchanged. Folstein’s mini mental state examination score, patients’ “on-off” diaries during five days, and the Hamilton depression rating scale (HDRS) for depression were assessed one week before and after six weeks of treatment; MMSE and HDRS were scored in the “on” state of motor response to levodopa. Patients were randomly assigned to moclobemide monotherapy or to the combination of moclobemide and selegeline. These two treatment groups are further referred to as the MO group and the MOSES group.

Bradykinesia and start hesitation improved in six patients, one patient in the MO group and all patients in the MOSES group. Bradykinesia deteriorated in one patient (MO group). Tremor increased in four patients, one in the MO group and three in the MOSES group.

There were no significant differences for the percentage “on” hours per day between the MO group and the MOSES group at entry and at the end of study. Waking hours spent “on” increased in the MO group with 1.8 hours, and in the MOSES group with 5.2 hours. This difference was not significant (P=0.671, two sample t test).

Baseline clinicians’ rating of depression (HDRS) was not different between the two groups. After six weeks, however, the improvement of depression in the MO group was significantly less than in the MOSES group (P=0.0029; two sample t test, figure).

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Intensity of depression before and after treatment with moclobemide or moclobemide and selegeline.

The main phenomenology of the depressive illness was a depressed mood with psychomotor retardation.

The scores of MMSE disclosed no differences in both groups at entry in the study. At the end of the study the score was unchanged in the MO group, and there was a slight but significant increase of MMSE score in the MOSES group (P=0.0479; two sample t test).

There was no increase in blood pressure. In both groups one patient reported symptomatic hypotension.

The therapeutic potential of selective inhibition of MAO B with selegeline in Parkinson’s disease has been documented for many years, with a clear capacity to postpone the need for levodopa in early Parkinson’s disease. The neuroprotective properties of selegeline are controversial or inconclusive.3

Selective MAO-A inhibition in Parkinson’s disease has not been examined in detail. Sieradzan et al 4 found a mild symptomatic effect of moclobemide in non-depressed patients with Parkinson’s disease. Takats et al 5 reported an antidepressant effect of moclobemide in depressed patients with Parkinson’s disease. Moclobemide lacks anticholinergic and hepatotoxic effects, and is even able to antagonise the cognitive impairment resulting from cholinergic blockade.6

The present study confirms the antidepressant effects of moclobemide in depressed patients with Parkinson’s disease. The combination of moclobemide and selegeline, however, did have a more pronounced efficacy on mood and cognitive performances. Increased concentrations of the monoamines by combined MAO inhibition is a plausible reason for the superior efficacy of moclobemide/selegeline treatment over monotherapy with moclobemide in depressed patients with Parkinson’s disease.

The effect of combined MAO inhibition on the MMSE scores was significant. The influence of MAO-A and MAO-B inhibition on cognitive functions is becoming of increasing importance in recent years. The cognitive improvement with moclobemide is parallel to, but independent from, the establishing of antidepressant effects.7 The number of patients in this study was too small to give robust answers in this respect.

Tyramine restriction during combined MAO inhibition is inconvenient. But if further studies confirm the additional efficacy of combined MAO-A and MAO-B inhibition, then this hindrance is justifiable.