Therapeutic Mechanism of Antipsychotic Drug Treatment in Schizophrenics Still Remain a Mystery…
by Bikem Sonmezler
For schizophrenia treatment, antipsychotic drugs have been the primary and fundamental treatment for half a century but what is interesting is that we still don’t know the exact mechanism taking place in the presence of these drugs…
In the paper “Antipsychotic drug mechanisms: links between therapeutic effects, metabolic side effects and the insulin signaling pathway” Girgis et al. hypothesized that the therapeutic antipsychotic and negative metabolic effects of antipsychotic drugs were related and by using this link they hoped to understand the causations of schizophrenia in a better way. In order to do this, they first looked at the effectiveness of the antipsychotics used and their metabolic side effects. Furthermore, they reviewed the abnormalities in insulin metabolism, interactions between the dopamine and NMDA systems in the patients with schizophrenia.
In the paper, they talked about various topics but in this blog I am going to specifically focus on the “the relationship between the comparative effectiveness and metabolic disturbances of antipsychotic drugs”
First, let’s talk about the different kinds of antipsychotics: FGAs and SGAs. The full name of FGA and SGA are first generation antipsychotics and second generation psychotics, respectively. Both have different characteristics that make them unique from one another.
FGAs are known for their high affinity and sustained D2 receptor (dopamine receptor) blockade. On the other hand, SGAs have low affinity for D2 receptors and known for the most effective antipsychotic treatment. But here is the catch.. They are also the ones that cause the most metabolic side effects. Some of these metabolic side effects, for example, are hyperglycemia, hyperlipidemia, obesity, insulin resistance and sometimes frank diabetes mellitus. Therefore, what one can interfere from this is that SGAs might be useful to possibly understand the the mechanisms taking place in the patients with schizophrenia.
There is also evidence that points out that the patients with schizophrenia are more likely to develop diabetes mellitus indicating the involvement of the glucose metabolism. But this complicates the understanding of how the antipsychotics contribute the effects on the metabolic syndrome because it is not clear whether the anomalies in the glucose metabolism present from the very beginning or whether they develop over time. But one thing is clear: Using SGAs increase the risk of developing diabetes mellitus.
In the paper they said that the most effective SGAs have the greatest metabolic side effects but also they put a great emphasis on the fact that this relationship is not as simple as it looks. If it was, we would have already figured out everything that is to know about schizophrenia! On the other hand, we can use this relationship to examine the hypothesis that Girgis et. al proposed. The table below shows the comparison between the drugs on effectiveness and metabolic disturbances.
So what do we exactly mean by SGAs cause the most metabolic side orders? SGAs are associated with many metabolic syndrome disturbances. They are associated with increased blood glucose levels, glycosylated hemoglobin and insulin, insulin resistance, diabetes mellitus and a very significant weight gain, sometimes even more than twenty pounds! They are also linked with increased cholesterol, low density lipoprotein, triglyceride levels. It is no surprise that the drugs that are the most effective (clozapine and olanzapine) are also more likely to develop these side effects in the schizophrenics..