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Vol. 39, No. 3, 2013 July September Original Paper Antipsychotic Drugs And Salivary Leptin Levels In Wistar Rats
RISTINA DUMITRESCU , CATALINA PISOSCHI , A. CAMEN
1Department of Pharmacology, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova 2Department of Biochemistry, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova 3Department of Oral and Maxillo-Facial Surgery, Faculty of Dentistry, University of Medicine and ABSTRACT: Purpose. Mental dissorders such as psychosis, agitation, mania, dementia and bipolar disorder are treated with variable doses of antipsychotics. However, these drugs are often associated with metabolic side effects (weight gain), endocrine disruptions, diabetes mellitus and cardiovascular diseases.Unfortunately, a single reliable predictor of weight gain has not been found, but a relation is to be mentioned between the levels of circulating leptin, administration of antipsychotics and weight increase. The aim of this study was to assess the effects of exposure to antipsychotics from both generations on the salivary leptin levels. Material and Methods. Salivary leptin was determined by the ELISA technique, on three groups of male Wistar rats treated with haloperidole, haloperidole decanoate and aripiprazole for 4 weeks.Results. The present study evidences a significant statistical difference between the values of salivary leptin prior to and after the drug treatment with the first generation agents. Aripiprazole produced no changes. Conclusions. The treatment with haloperidole and haloperidole decanoate induces an increase in salivary leptin levels. KEYWORDS antipsychotics, rats, salivary leptin, weight gain
The purpose of this study was to evidence
Introduction
changes of salivary leptin levels during
Since the introduction of chlorpromazine in
the early 1950s, a large number of antipsychotics (neuroleptics) have been
Material and Methods
discovered. In recent years the so-called atypical
The study was done according with Directive
neuroleptic drugs have also become available.
[1]. The increasing use of atypical (second
generation) antipsychotics has led to a greater
Commitee from The University of Medicine and
appreciation of not only the benefits of these
drugs, but also of the spectrum of toxicity that
21 adult male Wistar rats were divided into
three groups of seven (weight 225-240 g, age
Typical drugs still play an important role in
70-80 days). For the 28 days period of the
the treatment of psychotic disorders and offer a
experiment, their weight was recorded a jeun,
valid alternative to atypicals where atypicals are
between 9.00 and 10.00 am for an adequate
poorly tolerated. The essential difference
dosing of the substances. All medications were
between the two groups is the size of the
therapeutic index in relation to extrapyramidal
However, most second-generation - haloperidole (animals labeled from H1 to H7);
antipsychotics, and to a lesser degree first-
- haloperidole decanoate (animals labeled from
generation antipsychotics, can produce adverse
effects (such as substantial drug-induced weight
- aripiprazole (animals labeled from A1 to A7);
gain) that are a major factor in promoting poor
Each animal had a unique record file and
adherence to, and even discontinuation of,
antipsychotic treatment on the one hand, and
increasing the risk of metabolic syndrome and
cardiovascular disease on the other [5-8].
technique, applied in humans, for collecting the
These adverse effects could be explained by
gingival crevicular fluid, as adapted for saliva
a possible impact of antipsychotic drugs on
collecting [9], for 30 sec, saliva was collected on
peptide hormonal regulators of metabolic
filter paper strips introduced in the oral cavity of
control – leptin, ghrelin and adiponectin.
the animal. Collecting was done prior to
Maria Bogdan et al. - Antipsychotic Drugs and Salivary Leptin Levels in Winstar Rats
beginning of drug administration, as well as 24
Discussion
hours after the last administration. The absorbed
liquid was dilluted in 100μl phosphate-buffered
possible, prevention, of major adverse effects of
saline (PBS), the obtained samples being frozen
antipsychotics and some other drugs used to
treat mental illness is a topic of much debate,
because a wide range of side effects may be
encountered, especially the metabolic syndrome.
Sandwich technique for biological assays of
In 2001, Groschl identified salivary leptine in
rodents, according to the indications of the
healthy patients and the molecular form in
manufacturer. The results were expressed in
which it is excreted in the saliva [10].
ng/ml. Statistical analysis of the obtained results
was based on average value±SD (standard
circulating leptin during the administration of
deviation) and the Mann-Withney U-test, the
antipsychotic drugs, when increased values were
correlations for p<0.05 being considered
observed [11], and other investigations have
shown correlations between the values of seric leptin and the weight increase in patients
suffering from schizophrenia, subjected to
Salivary leptin levels prior to the initiation of
the treatment ranged between 0,1-0,4 ng/ml
antipsychotics [12, 13]. Also under study, beside
leptin, were other hormones present in the serum
haloperidole; 0,21ng/ml for haloperidole
(ghrelin, adiponectin, resistin), known as
impacting the energetical balance through
aripiprazole). In the end of the treatment,
salivary leptin registered values between 0,2-
Salivary leptin was determined in different
0,9ng/ml (0,54ng/ml) for the group treated with
pathological situations, sometimes representing
haloperidole, 0,2-0,6ng/ml (0,38ng/ml) for the
a better alternative than determination of the
one treated with haloperidole decanoate, and
circulating leptin, because the method of leptin
0,1ng/ml -0,2ng/ml for aripiprazole group,
collecting and determination in blood (plasma or
serum) is quite difficult for the investigator and uncomfortable for the pacient, the risk of failure
Table 1. Salivary Leptin levels (ng/ml)
being quite high. But, saliva collecting from
both humans and laboratory animals is much
simpler, noninvasive, the results obtained being
The levels of salivary leptin were measured
over a 24 hr interval, the circadian rhythm being
thus established, a correlation being also stated
As to the animal weight, the average value
between the leptin levels from saliva and plasma
was of 229,85g in the group treated with
haloperidole, comparatively with the initial
The results of the present study, which
average values of 232,00g; 228,35g, in the group
applied the antipshychotic treatment to rats,
treated with haloperidole decanoate, versus an
evidence a significant statistical difference
between the values of salivary leptin prior to and
230,57ng/ml for aripiprazole group versus the
after the drug treatment with neuroleptics, in
initial average values of 232,71ng/ml. (Table 2)
haloperidole (p=0.032), and haloperidole decanoate groups (p=0.045), but not for the
Table 2. Weight values (g)
aripiprazole group (p=1.000). As to the differences between the three groups, they are
not statistically significant for haloperidole-
haloperidole decanoate (p=0.236), only for
aripiprazole-haloperidole (p=0.02) and for
Haloperidole 231,14±3,42 228,35±2,57 aripiprazole-haloperidole decanoate (p=0.005).
As for the animals’ body weight, the values
registered no statistically significant differences for haloperidole group, but significant differences were observed for aripiprazole
Vol. 39, No. 3, 2013 July September
(p<0.05), and haloperidole decanoate (p<0.05)
6. Coccurello R., Moles Anna, Potential mechanisms
groups, prior to and after the treatment.
of atypical antipsychotic-induced metabolic
derangement: clues for understanding obesity and novel drug design, Pharmacology & Therapeutics
treatment (4 weeks), the literature mentioning an
interval of 3-20 weeks of antipsychotic drugs
7. Boyda H.N., Tse L., Procyshyn R.M., Honer W.G.,
Barr A.M., Preclinical models of antipsychotic
modifications in the body weight of human
drug-induced metabolic side effects, Trends in Pharmachological Sciences 2010; 31:484-497.
subjects [2], the results support the idea that
8. Reynolds Gp., Kirk Sl., Metabolic side effects of
some antipsychotics modifie salivary leptin
antipsychotic drug treatment - pharmacological
mechanisms, Pharmacology&Therapeutics 2010; 125:169-179.
9. Offenbacher S., Odle Bm., et all, The use of
Conclusions
prostaglandin E2 levels as a predictor of
The conducted experiment showed that, of
periodontal attachment loss, J. Periodontal Res
the three antipsychotic drugs that we studied,
typical (haloperidole and haloperidole decanoate
10. Gröschl M, Rauh M, Wagner R, Neuhuber W,
– retard formulation) and atypical (aripiprazole),
Identification of leptin in human saliva, J Clin
the salivary leptin levels were modified during
the administration of the two neuroleptics
11. Iqbal Mm, Rahman A, Husain Z, Mahmud Sz,
belonging to the first generation, higher values
Ryan Wg , Feldman Jm, Clozapine: A Clinical Review of Adverse Effects and Management, Ann
Determinations of salivary leptin should be
continued on larger experimental groups and
12. Gorobets Ln (2008) Contribution of leptin to the
over longer periods of time, for evidencing the
formation of neuroleptic obesity in patients with
possible body weight modifications in the
schizophrenia during antipsychotic therapy, Bull Exp Biol Med., 146(3):348-50.
13. [entissi O, Epelbaum J, Olié Jp, Poirier Mf., Leptin
and Ghrelin Levels in Patients With Schizophrenia
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Corresponding author: Maria Bogdan, University Assistant, PhD, Department of Pharmacology, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 2-4 Petru Rares Street, 200349 Craiova, Romania, e-mail: bogdan.maria81@yahoo.com
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