Platelet cytochrome c-oxidase activity in patients with acute schizophrenia in the course of their treatment with risperidone

doi:10.4236/health.2011.31003

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Vol.3, No.1, 13-19 (2011) Health

doi:10.4236/health.2011.31003

Platelet cytochrome c-oxidase activity in patients with

acute schizophrenia in the course of their treatment with

risperidone

Gulnur Sh. Burbaeva1, Irina S. Boksha1, Marina S. Turishcheva1, Olga K. Savushkina1,

Alan G. Beniashvili2, Georgiy E. Rupchev2, Margarit a A. M orozova2

1Laboratory of Neurochemistry, Mental Health Research Centre, Russian Academy of Medical Sciences, Moscow, Russia;

*Corresponding Author: [email protected]

2Laboratory of Psychopharmacology at the Clinical Department Mental Health Research Centre, Russian Academy of Medical Sci-

ences, Moscow, Russia; [email protected]

Received 5 October 2011; revised 15 October 2011; accepted 19 October 2011

ABSTRACT

Objectives: Testing a hypothesis, that platelet

cytochrome c-oxidase (COX) activities in pa-

tients with paranoid schizophrenia, acute epi-

sode, may be li nked to d ynamics of their cl in ical

patterns and quality of cognitive functioning

under antipsychotic treatment. Methods: Psy-

chopathological (PANSS, NSA-16) and cognitive

assessments; platelet COX enzymatic activity

determination, post-hoc nonparametric statis-

tical analysis. Results: Psychopathological and

cognitive assessments were done and blood

was sampled in p atients before (at baseline) and

af ter treatment with risperidone. Following regu-

larities were found after the treatment of pa-

tients: Significant elevation of COX, w herein the

higher was COX at baseline, the more prom inent

was dec rease in PANSSneg and NSA rates; sig-

nificant negative correlation between COX and

executive time in cognitive tests. When the pa-

tient group was divided by median of COX at

baseline into two subgroups (greater or equal

median, and <m edian), signi ficantly larger amount

of patients with PANSSpos decrease by >20% was

assigned to the fir st subgr oup; signi ficantly larger

amount of patients with PANSSneg by <20% was

assigned to the second group. Conclusions:

Therapy with risperidone seems to be more ef-

fective for patients with higher COX activity at

baseline, but this fact requires further study.

Keywords: Schizophrenia; Risperidone;

Biochemical Markers; Acute Phase Treatment;

Atypical Antipsychotics

1. INTRODUCTION

Many evidences have been obtained for energy me-

tabolism impairment in brain of patients with mental

disorders [1-6]. The decrease in rates of glucose oxida-

tion and oxygen consumption in some brain areas of

demented patients with Alzheimer’s disease [1,2] or

schizophrenia [4,7] has been demonstrated by MRT and

PET methods. Significant decrease in cytochrome c-

oxidase activity (COX—the complex IV of mitochon-

drial respiratory chain) has been observed in several

autopsied brain structures obtained from patients with

schizophrenia as compared with control [4,8]. This fact

suggests for defect of oxidation phosphorylation in

brain of patients with s chizophr enia , puta tively resulting

in energy metabolism impairment [9].

Blood platelets are often used for biochemical model-

ing of processes occurring in nervous tissue, wherein

platelet mitochondria possess the complete respiratory

electron transport chain, including all its enzymatic

complexes, sufficiently active for in vitro biochemical

studies with clinical aims [10,12,13]. Attempts have

been made to evaluate platelet COX activity in mental

disorders, such as dementia (due to Alzheimer ’s disease),

and mild cognitive impairment (MCI) [14-16], cognitive

decline in Parkinson disease [17], and schizophrenia.

Platelet COX activity in the groups with dementia and

MCI was found lower than that in controls, wherein the

patients with MCI “occupied” positions between the

control group and demented patients [14-16]. Taken to-

gether this data has enabled to put forward an assump-

tion on probable diagnostic validity of COX as a biolog-

ical marker of Alzheimer’s disease [14]. Another group

of investigators explored the diagnostic aspect of platelet

respiratory chain activity and found elevation of respira-

tory complex I activity in patients with schizophrenia,

G. S. Burbaeva et al. / Health 3 (2011) 13-19

whereas no difference was found in COX activity be-

tween the samples from patients with schizophrenia and

controls [13].

In the present study we tested a hypothesis, which

assumed that platelet COX activities in patients with

acute schizophrenia might be linked to the dynamics

of their clinical patterns and quality of their cognitive

functioning under the antipsychotic treatment. The

study included following tasks: comparative estima-

tion of COX activity in patients with schizophrenia

and in control group; estimation of COX activity

changes under antipsychotic treatment; evaluation of

links between COX and clinical and neurocognitive

assessments before treatment course (“at baseline”)

and after the treatment. Besides, on the basis of the

tasks solved, we attempted to evaluate a possibility of

COX usage for prognosis of antipsychotic treatment

efficacy.

2. MATERIALS AND METHODS

2.1. Subjects and Methods of the Study

After receiving approval for the study from the Ethics

Committee of MHRC RAMS, 27 patients (men, 20-56

years old; median 33 years, 25%-, and 75%-quartiles are

25 and 44 years, respectively) with acute schizophrenia,

paranoid type (DSM-IV 295.30), have been included

into the study and assigned to the antipsychotic treat-

ment with risperidone (4-6 mg per day).

Psychopathological assessments by PANSS, negative

symptom scale NSA-16, and neurocognitive assessments

(battery of neurocognitive tests evaluating various as-

pects of memory, attention, executive functioning) were

regarded at baseline and after treatment course with ris-

peridone for 2 months, blood was sampled at the same

time ranges for COX activity assay.

Neurocognitive assessment tests:

1) Working memory: Wechsler memory scale, subtest

V: series A; series B; sum A and B.

2) Associative memory: Wechsler memory scale, sub-

test VII;

3) Psychomotor speed: WAIS test, subtest VII: Sym-

bol coding.

4) Verbal memory: Text No1 reconstruction, and Text

No2 reconstruction.

5) Visua l-spatial memory: Benton visual in tention test

(BVRT), Fifth Educati on .

6) Attention: Schulte tables and Bourdon test (pen-

cil-and-paper test), Continues attention task (CAT),

(Computerised testing).

7) Executive functions: Tower of London (TOL dx);

Computerised Wisconsin Card Sort Task Version 4

(WCST).

The control group consisted of 25 volunteers (men,

17-43 years old; median 25 years, 25%- and 75%-quartiles

are 20, and 27 years, respectively)—healthy persons with

no history of mental or ne urologica l disorders.

There was found significant age difference between

the patient and control groups (p < 0.00033), however,

no influences of age on COX activity in controls or pa-

tients were found (Spearmen R < 0.22, p > 0.32), there-

fore we admitted this control group.

Isolation of platelets and extraction method for COX

activity determination .

Each blood sample was processed in 2 hours after

sampling. Blood plasma prepared from 10 ml of venous

blood taken with citrate buffer containing dextrose, pH

5.7 (1:5, v/v), by centrifugation at 1000 rpm for 10 min

at room temperature (Beckman J-6 centrifuge), was

carefully collected for following centrifugation at 10,000

rpm for 20 min at 5˚C (Beckman J-21 centrifuge , JA20.1

rotor). The supernatant was removed, and the pellet was

washed with the citrate buffer by centrifugation, super-

natant removed, and the pellet re-suspended in 62.5 mM

Tris -HCl buffer, pH 6.8, then frozen in liquid nitrogen

and stored at –70˚C prior the analysis of COX activity.

Just before the measurement the sample was defrosted,

and n-dodec yl-be ta-D-maltoside was added to its final

concentration of 1%, then incubated for 10 min at 4˚C,

centrifuged (10 min 10,000 g at 4˚C), and COX activity

was measured in supernatant.

COX enzymatic activity was determined by kinetic

method using spectrophotometer (λ = 550 nm) [18,19].

Specific activity of COX was calculated (U/mg), taken

the total protein measured by Lowry et al. [20].

Internal s t andard

Platelet sample collection accumulated in th e Laboratory

of Neurochemistry RAMS includes the samples from

healthy volunteers used for the internal standard prepara-

tion. Protein extracts prepared from these samples ac-

cording with the described above procedure are used as

the internal standard (a gauge) in comparative COX es-

timations in each experiment.

2.2. St atistica l Analysis

Clinical data, demography, and biochemical data of

the patients co mposed a da tabase. Nonpar ametric statistics

(Spearmen correlations, Wilcoxon Matched Pairs Test,

Mann-Whitney U-test, Chi-square distribution with Yates

correction factor using Statistica 6.0 software) was em-

ployed for assessment of changes in the target parame-

ters and links between them.

3. RESULTS

1) Comparison of COX baseline activity in group of

G. S. Burbaeva et al. / Health 3 (2011) 13-19

Table 1. Result of statistical COX activity data processing in patient group (before the treatment course) and in controls by

Mann-Whitney U-Test.

Rank Sum Rank Sum U Z

Patients with schizophrenia

Controls

p-level

COX 462 916 84 –4.642 27 25 0.000001

patients with schizophrenia (before the beginning of

treatment course with risperidone) and in control group.

Comparison of COX baseline activity in group of pa-

tients with schizophrenia and in control group (by

Mann-Whitney U-test) has revealed, that platelet COX

activity is significantly d ecreased in the patient group (p

= 0.000001, Table 1).

The distributions of observation numbers of various

COX activities in the control group and in the group of

patients before the treatment course are shown in the

Figures 1(a) and (b). Comparison of these diagrams

demonstrates, that the number of lower COX activity

observations is higher in the patient group than in the

control group.

2) COX comparison in patient group before and after

treatment course.

Comparison of COX activity before and after the

treatment course by non-parametric statistics (Wilcoxon

Matched Pairs Test) has demonstrated its significant

change (Table 2), wherein the increase in COX activity

was observed in 20 patients, and its decrease was ob-

served in 7 patients. Although COX has increased in

most patients after the treatment course, the patient

group has been found significantly different still from

the control group (p = 0.00015).

The increase in COX activity after the treatment

course is illustrated with the figur e showing diagrams of

COX activity distribution in the patient group (COX

activity vs. observations’ number) before and after the

treatment course (diagrams b and c, respectively). It is

obviously from the comparison of the diagrams that the

number of patients with higher COX activities increases

after the treatment course.

3) Search for links between COX activity and altera-

tions in clinical and cognition assessments under the

treatment course with risperidone.

Since the decreased COX activity has been found in

patients with schizophrenia in comparison with controls,

we have supposed this parameter has to be reflecting the

severity of psychosis and cognitive dysfunction in the

patients. Search for links between COX activity and

these assessments has provided no direct support for this

hypothesis, however, baseline COX activity has proved

to have prognostic value due to its link with PANSSneg

magnitude of alteration under the treatment course (R =

0.45, p < 0.02): the higher was baseline COX activity,

the more prominent was the decrease in deficit rates.

Similar link was found with magnitude of NSA de-

crease after the treatment course (R = 0.48, p < 0.05).

The patients with decreasing COX activity after the

treatment course (N = 7) displayed negative significant

correlations between COX activity and PANSS total and

PANSS psychopathological scores at baselines (R =

–0.85, p < 0.01, R = –0.82, p < 0.02, respectively), i.e.,

the higher is COX at baseline, the less is psychotic

symptoms’ score.

The Figure 1(b) shows, that most patients demon-

strate COX baseline activities near the median in the

group (60 U/mg), however, prominent deviations from

median value are seen as well. Hence, the group of

patients was divided into two subgroups by COX base-

line activity “

≥

median” (subgroup 1) and “<median”

(subgroup 2) (no significant difference in age between

them).

Significantly higher number of patients with decreasing

PANSS positive by 20% and more has been detected in

the subgroup 1, and the subgroup 2 contained signify-

cantly higher number of patients with PANSS negative

score decreasin g by less than 20% after the treatment (Χ2

= 9.53, Yates corrected = 7.6, p < 0,01, and Χ2 = 6.52,

Yates corrected = 4.53, p < 0.025, respectively). These

findings mean, that patients with higher COX baseline

activities demonstrate more prominent reduction of psy-

chotic symptoms than those with lower COX baseline

activities.

Patients with COX baseline activity

≥

median (sub-

group 1) have demonstrated also significant improvement

in results of neurocognitive testing: Psychomotor speed

(Symbol coding), Total Executive Time of TOL, Middle

Total Executive Time of TOL, and Psychomotor Speed.

No significant changes in results of clinical assessments

were found in patients with COX baseline activity < me-

dian (subgroup 2), however, a significant improvement was

observ ed in results of neurocognitive testing (Working

memory a nd Verbal m emory reconstruction).

The negative significant correlation was found in the

total patient group between COX activity and time spent

Table 2. Result of comparison of COX activity in the patient

group before (at baseline) and after the treatment course by

Wilcoxon Matched Pairs Test.

Valid

N T Z p-level

COX baseline & COX after

the treatment 27 65.500 2.414 0.016

G. S. Burbaeva et al. / Health 3 (2011) 13-19

(a)

(b)

(c)

Figure 1. Observation numbers plotted versus various COX activities

(U/mg) in control group (a), in patient group before treatment course (b),

and in the patient group after the treatment course with risperidone (c).

for planning tests after the treatment course (R = –0.44,

p < 0.03). This link means that the higher is COX activi-

ty, the easier patient fulfills these tests after the treatment.

4. CONCLUSIONS

Platelet COX activity is significantly decreased in the

studied group of patients with schizophrenia at baseline

(before the antipsychotic treatment course) in comparison

with control grou p.

Significantly higher number of patients with signifi-

cantly better dynamics of clinical parameters is revealed

in the subgroup of patients with COX baseline activities

G. S. Burbaeva et al. / Health 3 (2011) 13-19

≥ median. This is fairly for psychotic symptoms (more

than 20% reduction of PANSS total score), and for men-

tal deficit (significant reduction of NSA scores). Some

results of neurocognitive tests have improved after the

treatment therewith.

One would suppose, that the COX baseline levels ≥

median in acute st at e of pa tients with schizophrenia coul d

be a sign of favorable dynamics of psychotic e pi s ode , a n d,

possibly, positive response to antipsychotic treatment,

although note, that the last statement requires an addi-

tional study.

5. DISCUSSION

In the present work, activity of enzymatic complex IV

(cytochrome c-oxidase, COX) determined in platelet

fraction enriched with mitochondrial membranes has

proved to be sufficient for quantitative comparative stu-

dies in all inspected subjects. The platelet COX activity

has been found therewith significantly decreased in the

group of patients with paranoid schizophrenia (DSM

-IV-TR 295.3), in comparison with control group. Re-

view of Dr. Kato [21] pointed out some inconsistency in

results obtained by different researchers, who studied

enzymatic activity of mitochondrial electron transport

chain and expression levels of genes encoding its com-

plexes in schizophrenia on various populations and var-

ious tissues from patients. Recent data is not uniform as

well [13,22]. So, significantly increased activity and

gene expression of complex I (NADH: ubiquinone oxi-

doreductase) in blood of patients with schizophrenia has

been reported [13], whereas decreas ed NDUFV2 exp res-

sion levels have been detected in other study on patients

with schizophrenia from Caucasian population [22].

The data indicating that the activity of complex I is

higher in patients than in controls has enabled the au-

thors [13] to propose complex I as diagnostic peripheral

marker for sc hizophrenia . As for COX, the authors st ated

the absence of significant differences in its activity be-

tween patients and controls, but the experimental data on

individual COX activity was not published making im-

possible a comparison between these results and data of

the present work. However, one could suppose from our

data, that “normalizing” platelet enzymatic activities by

COX (proposed by Ben-Shachar and Klein) would result

in overestimations of these activities in patients with

schizophrenia.

Some disagreement in data on influence of neurolep-

tics on the activity of respiratory complexes is seen in

literature as well, as noted earlier by Kato [ 21]. The pa-

per of Ben-Shachar and Klein [13] reports on higher

activity of complex I in patients treated w ith neurolep tics

versu s u ntreated patients. Other research groups reported

on inhib itio n of complex I activity with neuroleptics

(more prominent with typical, such as haloperidol, chlor-

promazine, less prominent with atypical, such as rispe-

ridone), whereas COX activity was either not influenced,

or affected. These results were obtained in vitro [23], in

model experiments with animals [24], and on mononuc-

lears in peripheral blood of patients with schizophrenia

[25].

In the present study, significant elevation of COX ac-

tivity was observed in the most patients after treatment

course with risperidone, possibly it is associated with

improvement of thei r cli nical stat e. So, our spe cial attention

was paid to the treatment efficiency (clinical response)

evaluation in the patients. In our previous study, when

searching for biochemical predictor of pharmacological

therapy efficiency we have taken the decrease in PANSS

total for positive treatment effect [26]. In the present

work, we additionally regard PANSS positive, PANSS

negative, PANSS psychopathological, NSA, and neuro-

cognitive tests.

The initially higher COX activity has been found to

account for favorable prognosis in respect to whole clin-

ical dynamics’ pattern, especially to psychotic symptoms.

This may be an indication, that higher level of energy

metabolism is a good “background” for improvement in

mental state of patients with schizophrenia, and, vice

versa, lower level—a b ad one. The initially higher COX

activities (≥ median in total group) are associated with

favorable prognosis for improvement of cognitive test

results (WAIS subtest 7). Taking into account that this

sub-test is the most complex by the number of intellec-

tual functions included and is associated with various

properties of attention, perception, visual- motor coor-

dination, rate of new skills’ formation, and ability of

visual-motor stimuli integration [27], the successful im-

provement in the results of this test can be considered as

a sign of cognitive function enhancement.

We recognize that the design of the present study does

not allow unambiguous stating, that favorable clinical

dynamics is associated with the therapy employed only,

but we surely do admit this, taking into account numer-

ous risperidone studies supporting its high antipsychotic

activity [28]. Hence, one can admit, that the found link

between the baseline COX activity and positi ve res pon s e

to the treatment of patients in acute state is not casual:

possibly, these patients have yet a “potential” to restore,

whereas the patients with low COX level possibly need

in additional therapy supporting energy metabolism.

Thus, the measurement of single parameter, such as

platelet COX activity, related to platelet mitochondrial

respiratory chain could have some prognostic value for

prediction of individual efficacy of medication with ris-

peridone in patients with schizophrenia (although, ob-

viously, inspection of larger groups of patients is neces-

G. S. Burbaeva et al. / Health 3 (2011) 13-19

sary for accomplishment individual prognosis, and an

additional study is needed on dependence of COX activ-

ity on various factors).

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