Abstract
The a-typical effects of Olanzapine on body weight regulation.
Olanzapine (OLZ) is an a-typical antipsychotic used in the treatment of schizophrenia. The main side effect of OLZ is that it leads to severe weight gain and increased risk of developing diabetes. In this thesis we demonstrate that there is marked individual difference in the occurrence and severity of weight gain by OLZ. This difference seems to be related to individual differences within the sensitivity of the dopaminergic system. In our studies in humans and rats, we found several lines of (indirect) evidence for this. First, female rats were more sensitive to OLZ-induced weight gain than male rats, presumably due to OLZ’s antagonistic effect on the dopamine 2 receptor increasing circulating prolactin levels. Additionally, rats with a proactive coping style and high dopamine sensitivity were more prone to OLZ-induced weight gain compared to rats with reduced dopamine sensitivity. Furthermore, in a human study we observed that male volunteers with low basal thyroid stimulating hormone (TSH) levels prior to the start of the study were more susceptible to OLZ-induced weight gain. Since the secretion of TSH is –similar to prolactin- attenuated by dopamine, inhibition of the dopamine 2 receptor by OLZ may explain the increased circulating TSH levels observed at the end of the study. It is known from literature that patients gaining most weight due to OLZ treatment also show better improvement of schizophrenia symptoms. This suggests that low TSH levels prior to OLZ treatment may have a predictive value for the effectiveness of the OLZ treatment of schizophrenia. Furthermore, we also found that adjunctive Topiramate (TPM, an anticonvulsant) treatment was effective in inhibiting OLZ-induced weight gain, specifically in those subjects with a low TSH level. This implies that TPM may serve, in specific individual cases, as an effective therapy to prevent OLZ-induced weight gain.
Olanzapine (OLZ) is an a-typical antipsychotic used in the treatment of schizophrenia. The main side effect of OLZ is that it leads to severe weight gain and increased risk of developing diabetes. In this thesis we demonstrate that there is marked individual difference in the occurrence and severity of weight gain by OLZ. This difference seems to be related to individual differences within the sensitivity of the dopaminergic system. In our studies in humans and rats, we found several lines of (indirect) evidence for this. First, female rats were more sensitive to OLZ-induced weight gain than male rats, presumably due to OLZ’s antagonistic effect on the dopamine 2 receptor increasing circulating prolactin levels. Additionally, rats with a proactive coping style and high dopamine sensitivity were more prone to OLZ-induced weight gain compared to rats with reduced dopamine sensitivity. Furthermore, in a human study we observed that male volunteers with low basal thyroid stimulating hormone (TSH) levels prior to the start of the study were more susceptible to OLZ-induced weight gain. Since the secretion of TSH is –similar to prolactin- attenuated by dopamine, inhibition of the dopamine 2 receptor by OLZ may explain the increased circulating TSH levels observed at the end of the study. It is known from literature that patients gaining most weight due to OLZ treatment also show better improvement of schizophrenia symptoms. This suggests that low TSH levels prior to OLZ treatment may have a predictive value for the effectiveness of the OLZ treatment of schizophrenia. Furthermore, we also found that adjunctive Topiramate (TPM, an anticonvulsant) treatment was effective in inhibiting OLZ-induced weight gain, specifically in those subjects with a low TSH level. This implies that TPM may serve, in specific individual cases, as an effective therapy to prevent OLZ-induced weight gain.
| Translated title of the contribution | De a-typische effecten van olanzapine op gewichtsregulering: en de mogelijke tegenwerking van topiramaat |
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| Original language | English |
| Qualification | Doctor of Philosophy |
| Awarding Institution |
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| Supervisors/Advisors |
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| Award date | 6-Mar-2015 |
| Place of Publication | [S.l.] |
| Publisher | |
| Print ISBNs | 978-94-6259-546-0 |
| Publication status | Published - 2015 |