Journal of Neurology, Neurosurgery, and Psychiatry 1986;49:1182-1190

Mood changes associated with "end-of-dosedeterioration" in Parkinson's disease: a controlledstudyR CANTELLO, M GILLI, A RICCIO, B BERGAMASCO*

From 1st and 3rd* Department ofNeurology, University School ofMedicine, Turin, Italy

SUMMARY Fluctuations of mood and psychic activation were assessed in relation to "mobile" and"immobile" periods in 18 patients with Parkinson's disease presenting typical "end-of-dose deterio-ration". Twelve subjects with chronic but active rheumatoid arthritis presenting increased physicaldisability due to severe morning joint stiffness with a repetitive pattern of mobile and immobileperiods acted as controls. The overall degree of disability and its fluctuations were close enough inthe two groups for fair comparison of changes in affective behaviour. Temporary immobility wasaccompanied by adverse changes of mood and activation, which were significantly more marked inthe Parkinson's disease group than in the controls, though to a lesser extent in those Parkinson'sdisease patients rated depressed even in their mobile periods. The possible correlation betweenmood changes and fluctuations of central dopaminergic function in the Parkinson's disease patientsis discussed.

Together with its clinical relevance to disability,1 -3one of the most interesting aspects of depression inParkinson's disease is the problem of its pathogeneticand pathophysiological mechanisms. There is nodefinite evidence for a "reactive" or for a "primary"genesis of Parkinson's disease depression. Obviouslyit could be conceived as a psychological reaction tolong-lasting motor impairment and yet it often pre-cedes the onset of motor impairment,3 and depressionis reportedly more common among Parkinsoniansthan among patients with other, equally severe,chronic diseases.4 This being so, some authors havebeen tempted to attribute Parkinson's disease depres-sion to the pathobiology of the disease itself.4-7Some have attributed a pathophysiological role inParkinson's disease mood disturbances to im-pairment of the mesocortical and mesolimbic dopa-minergic pathways.5 6 These structures, whichdegenerate in many Parkinson's disease patients,8 9have been shown to play a crucial role in the psycho-physiological reinforcement/reward processes 6which, in turn, are likely to be involved in the patho-physiology of "primary" or "endogenous" or "endo-

Address for reprint requests: Roberto Cantello MD, ClinicaNeurologica dell'Universiti, Via Cherasco 15, 10126 Torino, Italy.

Received 21 May 1985 and in revised form 9 December 1985.Accepted 15 December 1985

genomorphic"10 depression. Hence the suggestedcorrelation between Parkinson's disease depressionand impaired function of the mesocortical and meso-limbic dopamine systems.5 6 However, this fascina-ting hypothesis raises two more basic questions: canwe adduce further data to prove the reactive or pri-mary nature of Parkinson's disease depression? Andcan we establish any correlation between mood dis-turbances and central dopaminergic activity in Par-kinson's disease? The on-off phenomenon inParkinson's disease may provide relevant informa-tion. During motor swings the striatal dopaminergicfunction fluctuates "from one extreme to the other"'1

and it has been assumed that such changes occur-;nthe other dopamine systems as well.'' 12 Fluctuationsmay perhaps occur in non-motor aspects of Parkin-son's disease, if these aspects are dependent upon thefunctional integrity of dopamine systems. " 12 On thisassumption, the on-off paradigm was used to in-vestigate the possible relationship of cognitivefunction" 1' and nociception'2 to central dopami-nergic activity in Parkinson's disease. Brown etal"have also focused on the "affect-arousal state" ofswinging Parkinsonians, and found the "off"' periodto be accompanied by a definite worsening of this in-dex. The association between on-off motor changesand mood swings was then strikingly pointed out byHardie et al."4

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Table 1 Some characteristics of the patient and the control group

Diagnosis Males Females Hoehn and Yahr's Grade35

Mobile Immobile

Patients Idiopathic 10 8 I, IV and V: 0 pts I and II: 0 pts(n = 18) Parkinson's disease II: 10 pts III: 2 pts

III: 8 pts IV: 13 ptsV: 3 pts

Controls Rheumatoid arthritis 7 5 -(n = 12) (chronic, active)

Age (yr) Education Duration of Daily levodopa Mini-mental state(yr) illness (yr) dosage (mg)

Mobile ImmobilePatients Mean 64-4 11-2 7 2 780 28 2 28-0

SD 66 32 34 295 3-2 40Range 48-70

Controls Mean 66-2 12 1 8-7 - 28 4 28-6SD 76 41 49 - 28 34Range 44-74

In the present study, affective behaviour was sys-tematically investigated in a group of Parkinson's dis-ease subjects during motor fluctuations. Weattempted to identify mood swings and to define boththeir nature (reactive or primary) and their re-lationship to central dopaminergic function. For thispurpose we used a controlled experimental situation,in which the affective behaviour of swinging Parkin-son's disease patients was compared with that of agroup of controls with similarly fluctuating motordisability, unrelated to CNS alterations.

Patients and method

Patients Consenting patients with idiopathic Parkinson'sdisease were selected for the study from those periodicallyexamined at the Parkinson's disease Centre of the UniversityDepartment of Neurology. Great care was taken to excludesubjects with Parkinsonism due to atherosclerosis or othercauses. To this end, the subjects were admitted to the Neu-rological Department, where their complete case historieswere recorded and where they underwent physical and neu-rological examination, EEG and CT brain scanning. Pa-tients scoring above 4 on the Hachinski Ischemic Score15and/or below 24 on the Mini-mental state16 (during both the"immobile" and the "mobile" period) were also excluded, aswere patients with sudden capricious fluctuations in motorfunction ("yo-yo-ing").17 The 18 patients finally selected (ta-ble 1) showed "end-of-dose deterioration" (EDD),17 a situ-ation in which temporary brain dopaminergic deficiencyseems to be unquestionable.7 -19 All 18 patients had beentaking levodopa (associated with carbidopa or benserazide)since the beginning of their illness. Their motor fluctuationswere marked, but "immobile" periods never occurredabruptly, and the adverse influence on daily activities wasoften counterbalanced to some extent by adaptability.Controls In partial accordance with the criteria indicatedby Robins,4 we selected consenting nursing home patientssuffering from chronic but active rheumatoid arthritis, asbeing as nearly as possible comparable to swinging Parkin-son's disease patients. Twelve subjects carefully matched for

age, sex, years of schooling and duration of illness acted ascontrols (table 1). As is typical of the disease,20 all of themshowed marked fluctuations in physical disability, owing tosevere reversible morning articular stiffness, associated withtemporary pain exacerbation. Fluctuations in disability werefairly predictable and resembled those ofParkinson's diseasepatients in overall severity. No control had a family or per-sonal history of previous "endogenous" depression. Neu-rological examination, EEG and CT brain scanning showedno focal signs of organic brain damage. During both their"mobile" and "immobile" periods the score on the Mini-mental state16 was above 24 in all subjects. Two controlshad been taking psychotropic drugs, but these were stoppeda month prior to examination. Anti-inflammatories were theonly drugs allowed.Assessment of disability and of affective behaviour BothParkinson's disease patients and controls were rated on thescales described below by the same examiner (RC) on twooccasions: once during a period of "mobility" (defined as theperiod in which the patients achieved their lowest score onthe disability rating), and once during a period of "immo-bility" (the highest degree of disability resulting from EDDor from articular stiffness). This two-phase assessment wasrepeated I week later, with its sequence (mobile/immobile orimmobile/mobile) reversed for both groups. Each subjectwas then assessed four times (twice mobile and twice immo-bile). The mean values were calculated for each phase. Carewas taken to ensure that all the subjects were tested in iden-tical enviromental conditions. All the controls were exam-ined at 7 am (immobile period) and at 11 am (mobile period),which corresponded to the repetitive pattern of their articu-lar stiffness. After a prolonged clinical observation, whichenabled us to define the time pattern of their motorfluctuations, 12 out of the 18 Parkinson's disease patientswere examined once at 9.30 am (mobile period) and again at12 noon (immobile period preceding the next levodopadose). In the remaining six Parkinson's disease subjects themotor pattern was less regular.Disability The test used was the North Western UniversityDisability Scale (NUDS),21 which rates hygiene, eating,dressing, gait and speech on a 0-10 scale. The maximumscore was 50 points.

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Affective behaviour To obtain a reliable assessment of thebehavioural manifestations of depression we used an Italiantranslation of the Beck Depression Inventory (BDI).22 BDIhas often been used to study mood in Parkinson's diseasepatients' 2 23 24 and it was considered to provide a good in-dex at least for comparative purposes.24 As previouslydone,2 we gave a zero rating to items "N" (body image),"O" (work inhibition), "Q" (fatiguability) and "T" (somaticpreoccupation), as they would presumably be influenced bythe increase in physical disability typical of the immobileperiod rather than by real mood changes. Since the assess-ment was repeated over very short intervals of time, a zero

rating was given to item "S" (loss of weight). This shortenedversion of the BDI (sBDI) carried a maximum score of 47points. In addition, Parkinson's disease patients and con-trols were given an Italian translation of a shortened versionof the Mood and Behaviour Self-Rating Scale,25 which in-cluded items ranging over a 0-6 point scale of psychic activa-tion and euphoria-related emotional states. This scale isoften used for scoring the psychostimulant and euphorianteffects of amphetamines and methylphenidate,25 which areat least in part mediated via the mesocortical and meso-limbic dopamine pathways.26 In our view this Activationand Euphoria Scale (AES) (Appendix) provides not only a

very simple and basic self-assessment of psychic activation,but also a more thorough evaluation of the affective statethan the sBDI alone. The maximum score was 36 points.DSM III criteria In order to obtain a more comprehensivepsychiatric profile of Parkinson's disease patients and con-

trols, depressive behaviour was also evaluated and classified(in the mobile period) according to the diagnostic criteriacontained in the DSM III (Third Edition of the Diagnosticand Statistical Manual of the Mental Disorders of the Amer-ican Psychiatric Association).27Mini-mental State Cognitive performance was monitoredin both groups during the "mobile" and the "immobile"

Cantello, Gilli, Riccio, Bergamascoperiod by means of the Mini-mental State.'5 The maximumscore was 30 points.Statistics A high score on the NUDS, sBDI and AES de-noted more severe disability, more severely depressed moodand increased activation and euphoria respectively. Thesedata were analysed by means of the two-tailed WilcoxonSigned Rank test, which was used to determine levels ofsignificance of the mean differences, calculated withingroups, between immobile and mobile values for each scale.Moreover, mean immobile and mobile values and mean(immobile-mobile) differences for each scale were comparedin the two groups by means of the two-tailed WilcoxonRank Sum test. Within-group correlations were made bymeans of the two-tailed Spearman Rank correlation test.

Results

The numerical values are given in tables 2 and 3.As far as the test-retest reliability of the measures

adopted is concerned, the correlations (SpearmanRank correlation test) between the scores obtained inthe two immobile periods were the following: NUDS= 0 84 (controls) and 0-89 (Parkinson's disease pa-tients); sBDI = 0 81 (controls) and 0 83 (Parkinson'sdisease patients); AES = 0 86 (controls) and 0-84(Parkinson's disease patients). Between the two mo-

bile assessments the correlations were: NUDS = 0-87(controls) and 0 88 (Parkinson's disease patients);sBDI = 0 80 (controls) and 0 81 (Parkinson's diseasepatients); AES = 0 84 (controls) and 0 84 (Parkin-son's disease patients).Disability The disability assessment of Parkinson'sdisease patients and controls is represented in fig 1.Obviously, the NUDS items were differently affected

Table 2 Assessment of disability, affective behaviour and psychic activation in Parkinson 's disease patients during themobile(nm) and the immobile (i) period

Palients NUDS sBDI AES

in,m im i -n, mm i i -mr mm im i--mr

10 265 +165 8 105 +25 145 65 -82 185 345 +16 22 225 +05 6 5 -13 115 33 +21 5 95 95 0 10 75 -254 95 225 +13 9 12 +3 13 65 -655 85 265 + 18 195 195 0 6 -55 -056 175 36 + 185 155 16 +05 55 45 - I7 14 305 + 165 7 95 +25 135 75 -68 10 24 + 14 6 8-5 +2-5 14 8 -69 125 34 +21 5 85 14 +55 105 75 -310 13 305 +175 14 155 +1.5 85 6 -2511 8 345 +265 55 65 + 1 14 85 -5512 155 345 + 19 235 24 +05 6 45 -1-513 19 42-5 +23 5 19 19 5 +0 5 7-5 6-5 -114 13 29 +16 8 105 +25 125 9 -3515 105 30 + 195 4.5 5 +05 12 85 -3-516 12 305 + 185 25 4.5 +2 15 9.5 -5.517 16 34-5 + 18 5 9 13 5 +4-5 1 1 7 -418 16 36 +20 32 5 34-5 +2 6 4 -2Mean 1305 3163 + 18 58 1241 1419 + 177 103 677 -3-52SD 34 487 327 8 761 1.53 343 1-62 225

Numerical values. NUDS = North Western University Disability Scale. sBDI shortened Beck Depression Inventory. AES = Activationand Euphoria Scale. mi = mean individual value of the two assessments in the mobile period. i. = mean individual value of the twoassessments in the immobile period.

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Table 3 Assessment of disability, affective behaviour and psychic activation in controls during the mobile (m) and theimmobile (i) period. Numerical values. (For abbreviations see table 2)

Patients NUDS sBDI AES

nim i,. im-mm mm im im-m. mm im i.-MM1 165 415 +25 85 9 +05 8 75 -0.52 9 38 +29 14-5 15 +0 5 10.5 10 -0.53 10-5 40 +29-5 5 6 + 1 18 17 - 14 18 22-5 +4-5 2 2 5 +0-5 19 18 - 15 13-5 265 +13 1 2 +1 20 19 -16 14 295 +155 4 4 0 45 35 -17 85 27 +185 25 25 0 18 18 08 12 34-5 +22-5 12-5 13 5 + 1 10 9 -19 13 36 +23 175 18 +05 9 85 -0510 75 29 +215 6 6 0 45 35 -111 8 38 +30 7 8 +1 65 6 -0512 145 33-5 +19 8 8 0 14 12-5 -1-5Mean 12 08 33 +20 91 7-37 7-87 +0 5 11-83 11 04 -0 79SD 3-43 6-02 748 5 16 5 22 042 5-74 5 73 0 39

by the different kind of motor impairment seen in theParkinson's disease and the control subjects. How-ever, when the mean NUDS scores achieved in themobile period by Parkinson's disease patients andcontrols are compared, no significant differenceappears. Moreover, both Parkinson's disease patientsand controls show a highly significant (p < 0.01)mean increase in their overall disability (NUDS)scores during the immobile period. Finally, this in-crease in physical disability did not differ significantlybetween the two groups.Affective behaviour -Mean sBDI scores and theirchanges in Parkinson's disease subjects and in con-trols are shown in fig 2. The values are very scattered,owing to the presence of individuals with high or very

36 |

28'

NUDS0'rF1

Fig 1 Mean mobile (m) and immobile (T) scores on theNorth Western University Disability Scale (NUDS)21 in theParkinson (PD) and the Control (C) group. The difference(7-m) represents the mean increase in disability in theimmobile period, which is quite similar in both groups. Barsrepresent SD.

high depression scores. However, the two-tailed Wil-coxon Rank Sum test showed the mean mobile scoresin the Parkinson's disease group to be significantlyhigher than that of controls (p < 0-05). During theimmobile period there was an increase in the meansBDI score of both Parkinson's disease patients andcontrols. This increase, albeit slight, is significantwithin the Parkinson's disease group (p < 0-05), whilethe opposite is true for controls. Moreover, the abso-lute (immobile-mobile) mean value is significantlyhigher in Parkinson's disease subjects than in controls(p < 0-01).When individual subjects were observed during the

PD C PD C PD Cm i i-m

Fig 2 Mean mobile (m') and immobile (T) scores on theshortened Beck Depression Inventory (sBDI, see Methods)in the Parkinson (PD) and the Control (C) group. Thedifference (i-m) represents the mean increase in the sBDIscore during the immobile period, which is significantly higherin the PD group (p < 0 01). Bars represent SD.

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+18

+16

- 2

- 4

- 6

PD Cm

i-m

PD C

PD C

Fig 3 Mean mobile (m) and immobile (i) scores on theActivation and Euphoria Scale (AES) (Appendix) in theParkinson (PD) and the Control (C) group. The diference(i-m) represents the mean decrease in the AES score duringthe immobile period, which is significantly greater in the PDgroup (p < 0-001). Bars represent SD.

mobile period (tables 2 and 3), 7/18 (38 8%) of Par-kinson's disease patients and 3/12 (25%) of controlsscored above 10 points on the sBDI. According toSchwab etal,28 this fits the diagnosis of depression.Moreover, the seven Parkinson's disease patients sco-

ring highly on the sBDI met the DSM III criteria27for a "major depression". They had reportedly beenshowing signs and symptoms of depression for severalyears (mean + SD = 7 9 + 4 1); in three of them theonset of depression was described as nearly coincidingwith the onset of Parkinson's disease motor dis-turbances, while in the remaining four depression hadantedated the cardinal features of Parkinson's dis-

3

sBDI

2-

dPDnPD dCnC

-2-QAES i-m i-m

-4

-6

Fig 4 Comparison, within-groups, between "steadilydepressed" and "non-steadily depressed" subjects and theirchanges of the sBDI and AES scores during the immobileperiod (i-m values). "Steadily depressed" PD patients(dPD) show an increase in their sBDI and a decrease in theirAES scores significantly lower than those of "non-steadilydepressed" PD patients (nPD) (p < 005; p < 0 01). Thisphenomenon is not observed among "steadily depressed" and"non-steadily depressed" Controls (dC and nC respectively).Bars represent SD.

ease. On this basis, we rated these seven patients as

"steadily depressed" Parkinsonians (dPD). Theydiffered in affective behaviour during the immobileperiod from the remaining "non-steadily depressed"Parkinson's disease patients (nPD). Figure 4 showsthat the (immobile-mobile) mean value on the sBDIin dPD is significantly lower than the correspondingvalue in nPD (p < 0-05, Wilcoxon Rank Sum test).This difference was not observed between steadily de-pressed and non-steadily depressed controls, similarlydefined (fig4). (It must be emphasised that the threecontrols scoring highly on the sBDI in their mobileperiod met the DSM III diagnostic criteria27 for a

"dysthymic disorder").

Table 4 Parkinson's disease patients. Spearman rank correlation coefficientsfor the main variables

Duration of Levodopa NUDS sBDI AES Mini-mentalillness dosage state

(a) Mobile valuesAge 0-26 014 0-36 -0-08 0-11 -0-40Duration of illness 0.52* 0 56* 0-26 -0 34 -0-38Levodopa dosage 0.50* 0-13 0-11 -0-21NUDS 0 54* -0 57* -0 34sBDI -0 89t -0 44AES 0-36

(b) Immobile-mobile valuesAge 0-26 0-14 0 40 0-09 0-13 -0-38Duration of illness 0-52* 0-62* 0-15 -0-38 -0-23Levodopa dosage 0-64t 0-22 -009 -033NUDS -0-32 -0-34 -0-34sBDI 0 70t -0 37AES 040

*P < 0 05; tp < 0-01. For abbreviations see text.

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Table 5 Controls. Spearman rank correlation coefficientsfor the main variables

Duration of NUDS sBDI AES Mini-mentalillness state

(a) Mobile valuesAge 0 56 0-42 0-16 -0 34 -0 51Duration of illness 0-69* 0.70* -0-75* -0 10NUDS -0-23 0-30 -0-24sBDI -0-44 -0-36AES 0°54

(b) Immobile-mobile valuesAge 0-56 0-38 0-24 -0-41 -0 54Duration of illness 0-60* 0-62* -0-64* -0-24NUDS 0-44 -0-28 -0 16sBDI 0-10 -0 49AES 0-56

*p < 0-05. For abbreviations see text.

Mean AES values and their changes in Parkinson'sdisease patients and controls are shown in fig 3. Meanmobile AES values do not significantly differ in thetwo groups. By contrast, during the immobile periodthere is a decrease in the AES score that appears to bemuch greater in Parkinson's disease patients than incontrols (p < 0-001). The AES decrease during theimmobile period is significant both within the Parkin-son's disease and within the control group (p < 0-01and < 0-05 respectively). dPD patients show a smallerdecrease in their AES score during the immobileperiod than nPD patients (p < 0.01) (fig4). Thisdifference is absent in the control group (fig 4).Mini-mental state In both groups values obtainedduring the mobile period do not differ significantlyfrom the corresponding values in the immobileperiod.Correlations (tables 4 and 5). During both the mo-bile and the immobile period, a significant (p < 0-05)correlation was found in the control, but not in theParkinson's disease group, between sBDI/AES scoresand duration of illness.

In Parkinson's disease patients, but not in controls,there was a significant (p < 0.05) correlation betweenNUDS and sBDI/AES scores in the mobile period. Ifthe change in the measures during the immobileperiod is considered (immobile-mobile values), theincrease in the NUDS scores does not correlate withthat in the sBDI/AES scores among Parkinson's dis-ease patients. There is a tendency to such a cor-relation among controls, but it does not attainstatistical significance.sBDI and AES scores in the mobile period and

their changes in the immobile period show a strong(p < 0-01) correlation in the Parkinson's disease butnot in the control group.

Discussion

Several methodological problems had to be solved in

the course of our study of the affective changesattending end-of-dose deterioration in long-termlevodopa treated Parkinson's disease patients. Care-ful selection of Parkinson's disease subjects was essen-tial in order to exclude non-idiopathic cases: anyconclusion drawn from studies including (for in-stance) atherosclerotic or toxic Parkinsonism caseswould be misleading. The fluctuations in motor func-tion had to have all the characters typical of end-of-dose deterioration, as described by Marsden andParkes"7 for any proper assessment of affective be-haviour during a period of central dopaminergicdeficiency. We further had to exclude subjectspresenting with signs of intellectual impairment, asdetected by the Mini-mental state.'6 Consequently,the number of Parkinson's disease patients acceptablefor the study was fairly small. Selection of controlswas equally strict. Reliable and simple instrumentsfor assessing affective behaviour were required, sinceakinesia and other Parkinson's disease motor or sen-sory symtoms, exacerbated during end-of-dose deteri-oration, would distort several of the items belongingto the common scales used to rate depression. Al-though possible contamination of this kind could per-haps be tolerated in our experimental situation, whereequally disabled groups were compared, we tried tokeep it to a minimum by using the sBDI and the AES(see Method). The use of a control group consisting ofsubjects prone to intermittent physical disability (un-related to CNS alterations) allowed us to discriminatethe merely "reactive" depressive changes that mightaccompany "immobile" periods. Obviously, the in-creasing motor impairment and the general discom-fort typical of end-of-dose deterioration can beexpected to produce temporary adverse moodchanges, as a result of a "psychological reaction".This important factor cannot be taken into account ifnormal subjects are selected as controls. Depression iscommon among subjects suffering from chronic rheu-matic diseases, but is thought to be a "psychological

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reaction" to pain and gradually declining function.29This being so, we expected a comparative study ofaffective behaviour in Parkinson's disease and rheu-matoid arthritis patients to highlight the "neu-robiological" substrates of Parkinson's diseasedepression. Although the two groups were evaluatedon the Mini-mental state16 both in the mobile and theimmobile period (without finding any significantdifference), we did not make a comprehensive assess-ment of their intellectual function. In our preliminarystudy,2 concomitant evaluation of mood and cog-nitive performance proved to be difficult: patients un-duly burdened with questions and tests seemed to beless cooperative and reliable. Besides, Brown et al1stressed that adverse changes in mood and alertnesstended to trigger the functional cognitive impairmentwhich characterised a proportion of their "off" Par-kinson's disease patients. Thus, we thought it wasjustified to study mood and activation changes intheir own right; moreover, it seemed unlikely thatsubtle and inconstant cognitive changes could affectthe simple self-rating scales we used.Our results showed that the overall physical dis-

ability was similar in the Parkinson's disease and thecontrol group, both in the mobile and the immobileperiod. Thus, the most important condition for a cor-rect comparison was fulfilled. Thus, as far as groupresults are concerned, two main points arise:(1) In the mobile period signs and symptoms ofdepression were present both among Parkinson'sdisease patients and controls. However, they weresignificantly more common in the former group, afinding that confirms those of Robins.4 Assumingthat the adverse mood changes in the control groupwere an example of steady "psychological reaction"to chronic disability, the higher incidence of depres-sion in the Parkinson's disease group may indicatefurther depressive mechanisms, perhaps related to thepathobiology of Parkinson's disease. This is indirectlysupported by the different clinical features of depres-sion in the two groups, as evaluated on the DSM IIIcriteria.27(2) During the immobile period, that is during thetemporary increase in disability, a worsening of moodand, even more, of self-rated psychic activation wasfound both in the Parkinson's disease and in the con-trol groups. However, it was significantly greateramong Parkinson's disease patients. It must be re-membered that adverse changes in the "affect/arousalstate" were described by Brown etal 1 as an im-portant feature of the "off' period of their long-termlevodopa treated Parkinson's disease subjects. Thepresent study reliably confirms this finding thanks tothe use of a control group as disabled as the Parkin-son's disease group. If the depressive changes tempo-rarily observed among controls in the immobile

Cantello, Gilli, Riccio, Bergamasco

period were likely to be a transient "psychologicalreaction" to increased motor impairment, thesignificantly more severe mood alterations found inthe Parkinson's disease group further support theview that they were not only secondary to physicaldisability, but had a neurobiological substrate. Sincethe CNS change known to occur during end-of-dosedeterioration (that is, the immobile period of Parkin-son's disease patients) is hypofunction of dopaminesystems, there might be a link between central dopa-minergic deficiency and intermittent disturbances ofmood and activation in our Parkinson's diseasepatients. However, although primary or secondarychanges in non-dopaminergic neurotransmitter sys-tems during end-of-dose deterioration are not known,they cannot be ruled out a priori. Many of such sys-tems are involved in the pathobiology of Parkinson'sdisease (norepinephrinergic, serotonergic, GAB-Aergic and peptidergic neurons).9 30 Since a role ofthese structures in modulating affective behaviour isoften hypothesised or even proved,31 this aspect ofthe problem must not be overlooked.

If individual results are considered, it is evident thatthe reversible increase in disability typical of the im-mobile period was associated with a less severe wors-ening of mood and psychic activation in "steadilydepressed" than in "non-steadily depressed" Parkin-son's disease subjects, a finding that was not seenamong controls. There are two possible explanationsfor this phenomenon: (a) "steady depression" in ourParkinson's disease subjects was related to biologicalmechanisms largely independent of dopaminergic in-volvement; (b) in our "steadily depressed" Parkin-son's disease patients there was a permanent,structural derangement of dopamine pathways mod-ulating some aspects of affective behaviour so severeas to prevent any important functional fluctuation. Ifthis is true, the dissociation between motor swingsand mood features would imply that the latter wererelated to non-nigrostriatal dopamine function. Onlyinterpretation (b) is consistent with all our results.

In the Parkinson's disease patients, in contrast tothe controls, severity of depression did not correlatewith duration of illness, a finding which would indi-rectly support the "primary" genesis of their depres-sive symptoms. On the other hand, a correlation wasfound in the Parkinson's disease, but not in the con-trol group, between depression and disability duringthe mobile period. This finding might be an argumentin favour of a "reactive" genesis of mood alterationsin our Parkinson's disease patients. However, we werepreviously able to show that the presence of depres-sion may be a cause, rather than an effect, ofincreased disability in a Parkinson's disease popu-lation.2 In any case, no correlation was found in theParkinson's disease group between the change in dis-

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ability and the change in the depressive scores duringimmobility, whereas such a trend was revealed in thecontrols, although it was not statistically significant.

In no case did we observe very dramatic, cyclicalswings in mood of Parkinson's disease patients resem-bling those of the hypomanic-depressive illness andparalleling the "on" and the "of' periods. In everyinstance adverse mood changes in the Parkinson'sdisease group were accompanied by a significantworsening of self-rated psychic activation, as evalu-ated by the AES. In those subjects in whom mood didnot change, psychic activation did not change. Classi-cally, levodopa is thought to exert a general "arous-ing" influence on Parkinson's disease subjects, so thatlower levels of alertness, at least as subjectively appre-ciated, seem to be an obvious finding during end-of-dose deterioration, a condition associated with low orfalling plasma levodopa levels.17 -19 Besides, theclose parallelism of mood and activation features inour Parkinson's disease patients led us to speculatethat these two altered aspects of psychic function mayhave some common anatomophysiological im-pairment, related to CNS dopaminergic mechanisms.

Altered dopamine metabolism has been reported insubgroups of patients affected by retarded depression,even without Parkinson's disease.32 The effect of tri-cylic antidepressants, which can relieve Parkinson'sdisease depression,3 may be mediated by interactionwith dopaminergic neurotransmission.33 Moreover,Mayeux etal34 found homovanillic acid levels lowerin the CSF of Parkinson's disease patients with a"major depression" than in the others. Althoughthese authors did not comment on this feature of theirresults, it might suggest that a severe, widespread de-rangement of dopamine metabolism, resulting fromthe combined failure of nigro- and non-nigrostriataldopamine systems, may underlie or predispose to ma-jor depression in Parkinson's disease. However, thisinterpretation was later challenged by the authorsthemselves, who stressed the importance of abnormalserotonin metabolism in depressed Parkinsonians.

In our opinion, the interactions between the neu-rotransmitter and neuromodulator systems damagedin Parkinson's disease are too complex for depressionto be ascribed to one or other of the neural structures.In any case, our study does not provide conclusiveevidence to exclude the "reactive" process as a causalfactor of Parkinson's disease depression. However,the higher overall level of depression in the Parkin-son's disease group, their more adverse mood changesaccompanying increased disability and the pecu-liarities of affective behaviour within the group itselfshowed that a "reactive" model is not sufficient toexplain their depression. We are inclined to think thatbiological mechanisms were also at work, and thatcentral dopaminergic deficiency probably played apredisposing or contributory role.

Preliminary results of this study were presented at theFirst Meeting of the Italian Society of Neurosciences(Rome, 12-15 Dec, 1984).Work supported in part by Regione Piemonte,

grant No 17.

We thank Dr Masahiro Nomoto for his helpful crit-icism, Dr JPR Dick for editorial comment and ProfCD Marsden for having read the paper.

Appendix

ACTIVATION AND EUPHORIA SCALESelf-rating scale items (0-6 points).1. Feel active2. Feel alert3. Feel excited4. Feel talkative5. Feel close to people6. Feel confident.

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