CONTINUOUS APOMORPHINE INFUSION (CAI) AND NEUROPSYCHIATRIC DISORDERS IN PATIENTS WITH ADVANCED PARKINSON S DISEASE: A FOLLOW-UP OF TWO YEARS.

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1 Arch. Gerontol. Geriatr. Suppl. 9 (2004) /$ see front matter # 2004 Elsevier Ireland Ltd. All rights reserved CONTINUOUS APOMORPHINE INFUSION (CAI) AND NEUROPSYCHIATRIC DISORDERS IN PATIENTS WITH ADVANCED PARKINSON S DISEASE: A FOLLOW-UP OF TWO YEARS. L. MORGANTE a*, G. BASILE b, A. EPIFANIO a, E. SPINA c, A. ANTONINI d, F. STOCCHl e, E. DI ROSA a, G. MARTINO a, R. MARCONI f, P. LA SPINA a, V. NICITA-MAURO b and A.E. DI ROSA a a Department of Neuroscience, Psychiatry and Anesthesiology, b School and Division of Geriatric Medicine, c Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, University Polyclinic, Via Consolare Valeria 1, I Messina; d Department of Neurosciences, Clinical Institutes, Via Bignami, I Milano; e Neurological Institute IRCCS NEUROMED (IS), Via Atinense, 18, I Isernia; f Department of Neurology, Misericordia Hospital, Via Senese 161, I Grosseto, Italy *Corresponding author: Phone: +(39-090) ; Fax: +(39-090) ; morgante@unime.it SUMMARY This study was performed to assess whether patients with Parkinson s disease (PD) develop cognitive and psychiatric impairments more frequently during therapy with continuous subcutaneous apomorphine infusion (CAI) compared to the standard oral treatment. Thirty consecutive PD patients with severe motor fluctuations were included. Of them, 12 patients received the CAI treatment, while the remaining 18 continued the treatment with oral dopaminergic drugs. The two groups were evaluated with neuropsychological, psychiatric and motor tests at baseline and after two years. The off-awake daily duration and the levodopa dosage were significantly reduced in the patients infused with apomorphine. In comparison with the baseline evaluation, the neuropsychiatric assessment did not change in either of groups at the follow-up, except for a significant improvement of mood in the CAI treated group. Keywords: continuous apomorphine infusion, Parkinson s disease, neuropsychiatric impairments INTRODUCTION L-dopa still remains the most effective drug for controlling parkinsonian symptoms, but the development of severe long term motor complications (Poewe and Wenning, 1998) represents one of the most challenging problems facing the practicing neurologist. Despite the recent introduction of new dopamine-agonists and catechol-o-methyltransferase (COMT)-inhibitor drugs, as well as deep brain stimulation (DBS) of subthalamic nucleus, the treatment of the advanced phase of Parkinson s disease (PD) remains very difficult. CAI can improve sianificantly motor fluctuations in patients with advanced PD (Poewe et at.,

2 ; Stocchi et al., 1993). However, only few studies have investigated the occurrence of cognitive and psychiatric disorders in parkinsonian patients undergoing CAI. An uncontrolled study (Pietz et al., 1998) reported the development of cognitive and psychotic complications during follow-up. In a preliminary report (Di Rosa et al., 2003), we studied the impact of CAI in a group of fluctuating parkinsonian patients on cognitive and psychiatric assessment. In this preliminary report, after one year of follow-up, we did not observe any significant impairment in comparison with the baseline. The aim of this paper is to verify, if patients with PD develop cognitive and psychiatric complications during a prolonged period of CAI. PATIENTS AND METHODS Consecutive patients attending the Parkinson Unit at the Department of Neuroscience of University of Messina, with PD defined by the criteria of Gelb et al. (1999), and a history of severe motor complications were eligible for the study. The exclusion criteria were: (i) history of allergy to morphine and its derivatives, (ii) the presence of dopaminergic psychosis, (iii) the presence of orthostatic hypotension, (iv) the presence of pulmonary, liver and cardio-vascular diseases, (v) a score lower than 24 in the mini mental state examination (MMSE) (Folstein et al., 1975) and (vi) an age higher than 65 years. Thirty patients were included in the study, which was an open-labeled, blinded rater, parallel group trial. Twelve patients previously treated with oral L-dopa preparation and other antiparkinsonian drugs, agreed to receive the treatment with CAI, while the remaining 18 refused it and preferred to continue the standard oral dopaminergic therapy. Both groups were similar for demographic and clinical features (Table I), and were evaluated at baseline and after 6, 12, 18 and 24 months using abnormal involuntary movement scale (AIMS) (Guy, 1976), daily on-off diaries during the awake part for at least 1 week before the start of treatment and before each follow-up visit, and tests including: MMSE, brief psychiatric rating scale (BPRS) (Overall and Gurham, 1962) and Beck depression inventory (BDI) (Beck et al., 1961). Patients were weaned off dopaminergic treatment the evening before the admis -sion for initiation of CAI. They were pretreated with the anti-emetic domperidone (60 mg/day) for three days before performing an acute test with apomorphine bolus. Blood pressure and the electrocardiogram were monitored in the first 10 minutes following the first subcutaneous bolus injection (2 mg). The infusion was successively started with a dose of 2 mg/hour. Further increase of apomorphine dose and reintroduction of lower dose of L-dopa was required in the next davs to obtain optimum benefit. All patients were finally treated with 100

3 293 mg/day of CAI with variable dosage: 6-8 mg/hour. Patients who refused the infusion maintained their previous treatment with oral dopaminergic drugs and the dosage was changed in relation to clinical condition, if necessary. The within and between -group differences were analyzed using the analysis of covariance (ANCOVA). Table I DEMOGRAPHIC AND CLINICAL FEATURES OF THE TWO GROUPS (mean ± SD) Number of patients Age (years) Illness duration (months) Hoehn/Yahr stage (1967) L-DOPA dosage (mg/day) Baseline Endpoint Apomorphine dosage (mg/day) CAI ± ± ± ± ± 125* 100 L-DOPA ± ± ± ± ± 285* *p < 0.01, for the differences between end point and baseline RESULTS At the final follow -up of 2 years, two patients dropped out in the CAI group (the first died after 18 months, because of complication of hip fracture, the second patient dropped out because the infusion site nodule became infected) and one patient in the other group (pneumonia). Ten patients concluded the study in the CAI group and 17 in the group treated with oral dopaminergic drugs. The results are summarized in Table II. Compared with pre-infusion, L-dopa intake, L-dopa dosage was significantly reduced of 52 % (p < 0.001) in infused patients and unchanged in the control group. The off-awake duration was significantly reduced of 38 % (p < 0.001) and the AIMS improved significantly of 40 % (p < 0.001) compared with the baseline in the infused group, while they did not change significantly in the control group. The neuropsychiatric assessment did not change significantly in either of the groups, in comparison to the the baseline, except for a significant improvement (p < 0.01) of BDI in the apomorphine group. Only one patient showed nausea in the first five days of treatment in the apomorphine group. This adverse effect disappeared increasing the dose of dornperidone. All infused patients developed small, itchy nodules at injection sites. Dilution of apomorphine to 5 mg/ml and application of steroid ointment minimized this complication

4 294 Table II COMPARISON OF VARIOUS PARAMTERES OF THE TWO GROUPS (mean ± SD) Apomorphine L-DOPA BPRS Total Baseline 28.0 ± ± 7.6 Endpoint 26.5 ± ± 7.1 BDI Baseline End-point 22.0 ± ± ± 2.6* 21 ± 2.8 AIMS Baseline Endpoint 7.7 ± ± 0.6** 7.7 ± ± 1.6 Off-awake daily duration (hours) Baseline 5.0 ± ± 1.8 Endpoint 2.0 ± 0.5** 6.7 ± 1.8 MMSE Baseline 27.6 ± ± 2.0 Endpoint 27.4 ± ± 2.0 *p < 0.001, **p < 0.01, for the differences between end point and baseline CONCLUSIONS CAI is a highly effective treatment and allows a marked reduction of levodopa dosage, daily off-time and dyskinesias in patients with advanced PD. The results of our study sho w that CAI may be an effective and well tolerated agent in treating severe fluctuating parkinsonian patients, thus confirming previous observations from clinical open trials (Poewe et al., 1993; Pollak et al., 1989; Stocchi et al., 1993). In fact, in comparison with baseline, CAI (100 mg/day) is effective in reducing significantly the levodopa dosage and off-awake daily duration as assessed by the daily on-off diaries. Furthemore, CAI improves significantly the AIMS score, while the neuropsychiatric assessment does not change signi - ficantly in either of the groups. These findings are similar to those reported for DBS (Limousin et al., 1998). In the CAI group, adverse effects were mild and generally transitory. All patients, who received CAI, developed minor local skin reactions but none of these forced the treatment to be stopped, except for 1 patient who dropped out because in the infusion site nodule became infected. Concerning the neuropsychiatric assessment, our results

5 295 show that the treatment does not modify significantly MMSE and BPRS scores in either of the groups, while BDI score shows that mood is significantly improved in CAI-treated patients at one and two years of follow-up. On the contrary, it is known that DBS induces depression within six months postoperatively (Berney et al., 2002). The improvement of mood in our patients could be related with a previous report referring that apomorphine may induce hypomaniac euphoric state (Giovannoni et al., 2000). In conclusion, these results confirm that CAI is very efficient in the management of motor complications in PD, and does not produce cognitive and psychiatric impairments in the period of two years, in comparison with PD patients treated with traditional oral dopaminergic therapy. To obtain more reliable evidences, much larger randomized, controlled trials are needed to assess the longer-term effects of CAI on cognitive and psychiatric state. The excellent effect on motor complications, the good safety and the absence of neuropsychiatric impairment in brief-middle period suggest that this therapeutic strategy should be tried before invasive procedures such as DBS are considered. REFERENCES Beck, A.T., Ward, C.N., Mendelson, M., Mock, J.F. and Erbanga, J.K. (1961): An inventory for measuring depression. Arch. Gen. Psychiatry, 4, Berney, A., Vingerhoets, F., Perrin, A., Guex, P., Villermure, J.G., Burkhard, P.R., Benkelfat, C. and Ghika, J. (2002): Effect on mood of subthalamic DBS for Parkinson s disease: a consecutive series of 24 patients. Neurology, 59, Di Rosa, A.E., Epifanio, A., Antonini, A., Stocchi, F., Martino, G., Di Blasi, L., Tetto, A., Basile, G., Imbesi, D., La Spina, P., Di Raimondo, G. and Morgante, L. (2003): Continuous apomorphine infusion and neuropsychiatric disorders: a controlled study in patients with advanced Parkinson s disease. Neurol. Sci., 24, Folstein, M.F., Folstein, S.E. and McHugh, P.R. (1975): Mini-Mental State. A practical method for grading the cognitive state of patients for the clinician. J. Psychiatr. Res., 12, Gelb, D.J., Olivier, E. and Gilman, S. (1999): Diagnostic criteria for Parkinson s disease. Arch. Neurol., 56, Giovannoni, G., O Sullivan, J.D., Tarner, K., Manson, A.J. and Lees, A.J. (2000): Hedonistic homeostatic dysregulation in patients with Parkinson s disease on dopamine replacement therapies. J. Neurol. Neurosurg. Psychiatry, 68, Guy, W. (1976): Abnormal involuntary movement scale. In: US Department of Health, Education and Welfare: Assessment Manual for Psychopharmacology. Washington, DC, pp.: Hoehn, M.M. and Yahr, M.D. (1967): Parkinsonism: onset, progression and mortality. Neurology, 17, Limousin, P., Krack, P., Pollak, P., Benazzous, A., Ardouin, C., Hoffman, D. and Benabid, A.L. (1998): Electrical stimulation of the subthalamic nucleus in advanced Parkinson s disease. New Engl. J. Med., 339, Overall, J.E. and Gurham., D.R. (1962): The brief psychiatric rating scale. Psychol. Rep., 10,

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