Question Answer **In the 21st century, how do we deal with madness? We still confine people (psychiatric wards) but largely we use drugs and psychotherapy to try deal with it in a therapeutic realm rather than locking them up. If you want to change behaviour you must change the brain… **Recall the ways to do this Surgery, Electricity (TMS), Drugs, PsychoTherapy, Potentially stem cells in the future. **We have lots of disorders such as schizophrenia, bipolar disorder, delusional disorder, dementia, delirium etc which are all labelled under the general term __________? psychosis. **Define psychosis An altered mental state caused by dysregulation in information processing within the brain. (So all disorder in previous slide share this definition) *What are the 3 types of symptomology for psychosis ? 1) Positive, 2) Negative, 3) Cognitive **Name the four positive symptoms for psychosis Perception (hallucinations), Reasoning (delusions, suspicions), Language (disordered speech), Motor (Dyskinesia, tics). **Name the three negative symptoms for psychosis Social fixation (asocial, aggression), executive function (avolition, planning), emotion (blunted affect, apathy, anhedonia). **Name the two cognitive symptoms for psychosis Attention (+/- concentration), memory (impaired memory) Psychosis cna be a feature of functional psychotic disorders, organic brain disorders, acute psychological stress, or it can be *drug-induced*. **What kind of drugs might cause psychosis? * Psychostimulants (puts you at risk of acute psychotic episode) * Parkinsons Disease drugs that target dopamine if it cases too much dopamine in both non PD and PD patients. *Why can Schizophrenia be a fatal disorder? Because of its increased suicide risk **Describe the Dopamine theory (1970s) for Schizophrenia. Its the idea that Schizophrenia happens because you have too much Dopamine in your brain. So they gave drugs that block DA receptors, and observed reduced symptoms to support the theory. **What is the synthesis for Dopamine? What are the names for the Dopamine receptors? What is the clearance for Dopamine? Derived from Tyrosine –> DOPA –> Dopamine. Receptors are D1, D5 (metabotropic -Gs) and D2, D3, D4 (metabotropic – Gi, g(K+). Clearance is via pre-synaptic dopamine transporter (DAT) AND monoamine oxidase (MAO-B) What are the three key things to NOTE about DA? (diagram) MAO-B metabolism, DAT (DA transporter), D2 (Gi) autoreceptor. **We have 4 Principle Dopamine Tracts. **What are they? Nigrostriatal, Mesolimbic, Mesocortical, Tuberoinfundibular (hormone control) **There are three suggested causes/aetiology of Schizophrenia (three things going on at neurotransmitter level). What are they? Dopamine Theory (1970s), Serotonin Hyperfunction and NMDA Hyperfunction. We will focus on 5 drugs for psychosis. **What are the names for the two Classic/Traditional Anti-psychotic drugs? **How to both help to facilitate therapy? Chlorpromazine and Haloperidol. . They both calm the patient down (settles emotions, decreases suspicions, decreases agitation and motor activity) so can do CBT. **What is the mode of action for Chlorpromazine and Haloperidol (Traditionals)? **What is the mechanism of action for Chlorpromazine and Haloperidol (Traditionals)? decrease positive symptoms. primarily an antagonist for the D2 receptor. **Chlorpromazine and Haloperidol (Traditionals) anti-psychosis drugs can cause hormonal changes. Why? Because hormonal function relies on DA so by blocking DA receptors in the Tuberoinfundibular pathway this can lead to hormonal disruption **Because hormonal function relies on DA so by blocking DA receptors in the Tuberoinfundibular pathway this can lead to hormonal disruption and cause ….? cause 1) prolactin release dishinhibition (*lactation and *breast enlargement in men/women) 2) decreased Gonadotropic release (*sexual side effects and *infertility). There are LOTS of side effects with the Classic/Traditional anti-psychotics Chlorpromazine and Haloperidol. Keep this in mind! (take home message) … **What is the key point about the distribution for Chlorpromazine? It is highly bound to plasma albumin (85%+) so reduced amount of drug available to distribute to tissues. **What is the key point about the elimination of Chlorpromazine? There is a protracted elimination period because of its long half life so it can be weeks before you get it out of your system. As part of the clearance of Chlorpromazine there is a protracted elimination period because of its long half life so it can be weeks before you get it out of your system. **Why might this be a good thing? And why might it be a bad thing? GOOD: if you forget to take or intentionally stop taking, will still be an effect. BAD: for compliance issues as they may think they don't need to take if they feel fine without it. **What is the main difference between Chlorpromazine and Haloperidol? Haloperidol is much more potent so need less of it to get the same effect. e.g. 100mg chlor and only 2mg halop. **What are the three Atypical Anti-Psychotic drugs? Clozapine, Risperidone, Aripiprazole **What is the mode of action for Clozapine? **What is the MOA for Clozapine? **Must memorise subtypes!** Decrease in positive AND NEGATIVE symptoms (big benefit!). MOA is that it is a weak D1, D2, D4 antagonist, stronger 5-HT1C, 5-HT2 antagonist. (so antagonist for BOTH DA and Serotonin!) **What are the two side effects of Clozapine that tie into compliance issues? * Weight gains of 5 to 10+ kg. * Agranulocytosis = destruction of white blood cells so can cause toxic so need weekly WBC monitoring (draw blood weekly) which is expensive and inconvenient. **What is the main difference between Clozapine and Risperidol? Risperidol has no risk of granulolcytosis (destruction of WBC). so HIGE benefit! **What is the mode of action for Risperidol? **What is the MOA for Risperidol? Decreases positive AND NEGATIVE symptoms. Weak D2 antagonist, strong 5-HT2 antagonist **What are the three key differences that the drug Aripiprazole (Abilify) holds compared to all the other anti-psychosis drugs? 1) it is contraindicated in elderly dementia (can't be used). 2) has suicide risk 3) is heavily marketed compared to others **What is the mode of action for Abilify? **What is the MOA for Abilify? Decrease in positive AND NEGATIVE symptoms. MOA is its a partial agonist (stabilising-type strategy) for D2 and 5-HT1A receptors, 5-HT2 receptor antagonism. **Anti-psychotics typically have a wide therapeutic window so fatal overdose is no common. However, CYP450 metabolism and protein binding means that there is a potential for ….? drug-drug interactions which is a concern. **There is often a problem with the compliance of anti-psychotic drugs. **Why? (list the first three reasons) 1)When you go off drug you're fine due to lipid stores & long half lives so patients don't think need drug. 2)Dillusional-think govt is trying to kill them with drugs. 3)Cycle of compliance -relapse so psychotic symptoms stop you from going back to doctor **There is often a problem with the compliance of anti-psychotic drugs. **Why? (list the other three reasons) 4) Post-psychotic boredom (you do not like being dull and experiencing) and depression 5) Inefficacy of drug for some people 6) Side effects, cost and inconvenience (blood drawn) **What are anti-psychotic drugs often referred to as? major tranquilizers (as they calm people down to level society has deemed acceptable. **Compare and contrast benefits and how they differ for all the anti-psychosis drugs learnt about** .. We have got these main drugs (and many others)…. so do we really need to develop more? **Why or why not? Yes because there are still issues with all the current drugs. Drug use is ineffective in some patients AND other patients 1) cannot tolerate side effects, 2) continue to experience pos. and/or neg/ symptoms, 3) experience persistent cogn. symptoms.