The “classic” antipsychotic drugs fail to reduce negative and cognitive symptoms
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Question
The “classic” antipsychotic drugs fail to reduce negative and cognitive symptoms of schizophrenia. The newer atypical antipsychotic drugs can reduce all three categories of schizophrenic symptoms; positive, negative and cognitive. How do these atypical antipsychotics work? Using the “third generation” antipsychotic drug, Aripiprazole, as your atypical antipsychotic drug, explain how it works, according to the Carlson text. Consider that Aripiprazole is a partial agonist at dopamine receptors. Is that important information in understanding the mechanisms of how it works as an antipsychotic drug? Please review Figure 15.7 in your text and use that information in your Discussion answer. Please read the text material relevant to Figure 15.7 before you formulate your answer.
398 CHAPTER 15: Schizophrenia, Affective Disorders, and Anxiety Disorders The research findings presented in this subsection explain why the "classic" antipsychotic drugs fail to reduce negative and cognitive symptoms: One of the causes of these symptoms is decreased activation of dopamine receptors in the prefrontal cortex, and drugs that block dopamine receptors would, if anything make these symptoms worse. What is different about the newer atypical antipsy- chotic drugs that enables them to reduce all three categories of schizophrenic symptoms? Molecule of partial agonist Partial agonist displaces The atypical antipsychotic drugs seem to do the impossible: They increase dopaminergic activity in the prefrontal cortex and reduce it in the mesolimbic system. Let's examine the action of a so-called "third generation" antipsychotic drug, aripiprazole (Winans, 2003; Lieberman, 2004). Aripiprazole acts as a partial agonist at dopamine receptors. A partial agonist is a drug that has a very high affinity for a particular receptor but activates that receptor less than the normal ligand does. This means that in a patient with schizophrenia, aripiprazole serves as an antagonist in the mesolimbic system, where too much dopamine is pres ent, but serves as an agonist in regions such as the prefrontal cortex, where too little dopamine is present. Hence, this action appears to account for the abil ity of aripiprazole to reduce all three categories of schizophrenic symptoms (See Figure 15.7.) 1.0 1.0 1.0 1.0 1.0 0.5 0.5 1.0 0.5 0.5 Mean opening = 1.0 Mean opening = 0.6 Partial agonist binds with Low concentration of neurotransmitter 0.0 1.0 0.0 0.0 0.0 0.5 0.5 0.5 0.5 0.5 Mean opening = 0.2 Mean opening 0.5 FIGURE 15.7 Effects of a Partial Agonist. The diagram explains the differential effects of a partial agonist in regions of high and low concentrations of the normal ligand. Numbers beneath each receptor indicate the degree of opening of the ion channel: 1.0 fully open, 0.5 = partially open, 0.0 = fully closed. Partial agonists decrease the mean opening when the extracellular concentration of the neurotransmitter is high and increase it when the extracellular concentration of the neurotransmitter is low Schizophrenia is a puzzling and serious disorder, which has stimulated many ingenious hypotheses and much research. Some hypotheses have been proved wrong: others have not yet been adequately tested. Possibly, future research will find that all of these hypotheses (including the ones I have discussed) are incorrect or that one that I have not mentioned is correct. However, I am impressed with recent research, and I believe that we have real hope of finding the causes of schizophrenia in the near future. With the discovery of the causes we can hope for the discovery of methods of prevention and not just treatment partial agonist A drug that has a very high affinity for a particular receptor but activates that receptor less than the normal ligand does; serves as an agonist in regions of low normal ligand and as an antagonist in regions of high concentrations. concentration of theExplanation / Answer
The typical antipsychotics reduce the positive symptoms of schizophrenia such as delusions and hallucinations but fail to address the the negative symptoms such as social withdrawal and anhedonia. The third generation anti psychotics work differently from the typical antipsychotic as they reduce the negative symptoms of schizophrenia as well. aripiprazole is a partial agonist at dopamine receptors, this is important in understanding how antipsychotics work. Aripiprazole and other atypical antipsychotics work by selectively working at different brain areas in a specific manner, they increase the dopaminergic activity in the prefrontal cortex and reducing it in the mesolimbic system. This means that it works as an antagonist at the mesolimbic system by reducing the dopimne activity and as an agonist at the prefrontal cortex by increasing dopaminergic activity. So, aripiprazole, being a the partial agonist, acts as agonist in regions of low concentration of normal ligand and as antagonist in regions where there is high concentration.
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