Schizophrenia

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Schizophrenia Paul M. Moran Maverick Miller Leslie Radka Jennifer Schmid Michael Ball Cheryl Rosario 

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Background 1% Prevalence 10-15% take their own lives = Within first 10yrs of diagnosis 2 تزوزه) = Late teens to early 20’s Early treatments relied on Antipsychotics = There were however many adverse effects = Early 1990’s pharmacological breakthroughs allowed for a more functioning lifestyle in society 

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Background = It is believed that Schizophrenia must be treated in a multifaceted treatment ® While medication is the first line treatment counseling, social and family services should be provided for proper treatment of patients = Further developments in pharmacological treatments should increase functioning of patients in society by reducing side effects with more selective drugs 

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Etiology = Schizophrenia is a misregulation of iaicelaant-) (elem iameel=m ele) n = Many different NT pathways are hypothesized to be involved in the biological basis of the disorder ™ Genetics may be an important role = The environment may trigger a possible genetic predisposition 

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Etiology = Despite years of research there is no consensus on a single etiology for this disorder 

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Symptoms = Schizophrenia has been broken down into two sets of symptoms = Positive and Negative = Positive Symptoms = Hallucinations = Delusions = Disorganized Speech, Behavior and Movements = Increase in goal directed activity = |Illogical thoughts 

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Negative Symptoms = Blunted Affect = Impaired emotional responsiveness = Apathy = Loss of motivation and interest = Social withdrawal 

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Atypical vs Traditional = Traditional Antipsychotics only alleviate the positive symptoms = Atypical drugs however treat both the positive and negative symptoms = Lower extrapyrimidal effects = Act on 5HT2 as well as D2 ™ More expensive 

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Role of Dopamine = Original theory proposed that an over activation of DA led to schizophrenic symptoms = More recently it has been hypothesized that = Positive symptoms are caused by an over activation of specific DA pathways = Negative symptoms arise from and under activation of different DA pathways 

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Role of Dopamine DA subtypes = DA1 receptors ۶ 0۸1, 8 ™ DA2 receptors = D2, D3 and D4 ™ DA1 and DA2 exert opposite actions on intracellular mechanisms = Traditional view of antipsychotics were that they antagonize D2 and D4 receptors = The problem with these drugs were that they caused Parkinson like symptoms, tardive dyskinesias and may worsen negative symptoms 

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Atypical Antipsychotics There is no agreement on what biological actions define atypical antipsychotics These drugs are thought to block D2 receptors Have a possible effect on D1, 5HT2 or adrenergic receptor blockade Some are thought to effect D3 and D4 Problem with atypicals is that their action on D2 receptors also may cause side effects involving movement disorders 

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Serotonin Involvement = Observations of psychedelic drugs psilocybin and LSD ™ Cause a state similar to schizophrenia = These drugs are 5-HT agonist = 5-HT antagonism may have therapeutic efficacy 

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Serotonin Involvement Serotonin’s exact mechanisms of action are unclear Autopsy results show reduced 5HT2 receptors in the prefrontal cortex PET studies of living schizophrenics have not confirmed these findings Studies show a possibility of serotonin- glutamate interaction = Drug-induced serotonin blocking limits glutamate release 

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Glutamate Hypothesis = NMDA over activity leads to an excessive excitatory neurotransmission in the fontal cortex = This damages cortical neurons which causes degeneration 

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Summary of Theories = Overall = DA is considered to be involved with the positive symptoms = Glutamate is considered to be involved with the negative symptoms 

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Drug Classifications ™ Standard, classical, traditional = Phenothiazines are the prototypical agents ™ New generation or atypical «۶ Clozapine, risperidone, olanzapine, sertindole, quetiapine and ziprazadone = Advantages = Theputically effective without causing neuroplectic ‏تت‎ ‎™ Help relive negative symptoms and cognitive dysfunctions 

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Phenothiazines = Widely used = Least expensive 

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Pharmacokinetics Absorbed unpredictably and erratically through the GI tract = Dose decisions commonly made by trial and error Oral is still most common Rapid distributed once in bloodstream 24-480۳ ۱۵۱۲ 6 Slowly metabolized in liver Bind extensively to tissue = Causing slow elimination = May be responsible for slow rate of reoccurrence of psychotic episodes 

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Pharmacological Effects = Blocks D2 receptors ® Ach, 5HT, Histamine and NE receptors = Limbic system = Brain Stem = Basal Ganglia = Hypothalamus-Pituitary 

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Side Effects and Toxicity = High Potency Phenothiazapines = Fluphenazine, Trifluphenazine, Perphenazine = Cause less sedation = Fewer anticholergenic side effects = Less postural hypertension = More extrapyrimydal side effects = Low Potency Phenothiasapines = Chlorpromazine, Thioridazine = Used when sedation is desirable = Also when Anticholinergic side effects limit compliance = Often combined with benzodiazapines 

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Tolerance and Dependence = Rarely abused = No tolerance = No physical or psychological dependence = Stopping treatment can either result in relapse or withdrawal 

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۲۱۵۱006۲100۱ First therapeutic alternative to Phenothiasazines Similar effects of phenothiasazines Produces sedation Reduces initiative, anxiety and activity Well absorbed orally Slow rate of metabolism and excretion Acts on D2 receptors Few side effects Does produce Parkinson like effects 

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Atypical Antipsychotics = Molindone = Resembles 5HT = Relation to 5HT therapeutic effect is unknown = Resembles traditional antipsychotics = Mechanism of action, efficacy, side effects = Moderate sedation = Increased motor activity = Possibly euphoria 

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Loxapine = Similar in structure to atypicals = Actions differ little from traditional effects = Antipsychotic, antiametic and sedative properties = Causes abnormal motor movements = Good absorption, metabolism and ‏مماغعمعاء‎ 

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Clozapine = Used to treat treatment resistant schizophrenics = Clinically superior to traditional drugs = Relieves much of the negative symptoms = Lacks many extrapyramidal effects = Less of a cognitive inhibitor = Clozapine may cause a loss of white blood cells but it reduces suicide rates 

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Pharmacokinetics = Varied absorption rates among patients = Well absorbed orally = Metabolitic half life 9-30hrs = Peak plasma levels 1-4hrs = Metabolized by the liver into 2 active metabolites = Blood levels must be monitored to ensure proper dosing 

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Pharmacodynamics = High binding affinity for DA, Seretoninic, seretonin2, alphal, muscaranic and histamine = Low rate of binding to D2 receptors = Blocks 5HT2 at higher levels 

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Side Effects and Toxicity = Sedation = 40% of patients = Can affect compliance = Bed time dosing may help compliance = Weight gain = 80% of patients = Persistant = Reason not known = Withdrawal = Delusions, hallucinations, hostility, paranoid reaction, nausea, vomit, diarraheachachacha, headache, restlessness, agitation, confusion, sweating 

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Other Concerns = Expensive = Due to blood monitoring 

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Risperidone Potent inhibitor of D2 and 5HT2 ‏تزع ریات را‎ «۶ ‏عم کنم ص20 همم‎ le ‏ات یرال‎ atc 65 ‏ارات رولیت‎ عممل امع موا رورمل برا-9 عنازامط قاعم ملاعم 25 عاذ كاهلا * Considered a first-line treatment for schizophrenia ۱ 5 00 7 00 ‏ا‎ etal ate ence 211665 5۱06 0106۲ ا 0 2 0 effects (only at high doses) 

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Olanzapine Structurally related to clozapine Blocks many receptors, but dopamine and serotonin interaction are thought to be responsible for therapeutic effect Pharmacokinetics = Well absorbed orally ™ Peak plasma levels at 5 to 8 hours = Elimination half-life 27-38 hours ووه 616601۷60 0۷6۲۵۱۱ = improvements in both positive and negative symptoms لااعع ناعد 5و5ع| تاءأنلا 5غاناوع؟ )عنتءط للاهلاد مغ رعع؟5 5ع الاك " ‎impaired patients‏ Also used in bipolar 

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Sertindole 5-HT2, D2, and alphal-adrenoreceptors antagonist Treats both positive and negative symptoms Minimal extrapyramidal side effects Reduced sedative effects due to no affinity for histamine receptors Half-life 60 hours to 95 hours Can lead to severe cardiac arrythmias 

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Quetiapine (Seroquel) = 5-H12/D2 receptor antagonst = Half life 7hrs = Two or more daily doses needed = Greater affinity 101 5112 than D2 = Separates the antipsychotic action from the extrapyramidal side effects = Reduces expression of glutamate receptor MRNA 

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Ziprasidone = Similar in effect to Haloperidal = Weight gain is negliable = Inactive byproducts = Poorly absorbed orally = Unique actions on receptors = Blocks 5HT2 and D2 = Agonist at 5HT1la = May cause an antidepresant function 

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Amisulpride = Yet to be released = D2 and D3 ‏علا‎ blocked in limbic system but not in Basal Ganglia = Twice as selective for D3 than D2 Low doses blocks presynaptic receptors increasing DA = Higher doses it antagonizes DA ™ At these doses it has efficacy for negative symptoms = Low incidence of extrapyramidal side effects No affinity for 5HT which is unusual for Atypical 

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Schizophrenia Paul M. Moran Maverick Miller Leslie Radka Jennifer Schmid Michael Ball Cheryl Rosario Background   1% Prevalence 10-15% take their own lives   Onset   Within first 10yrs of diagnosis Late teens to early 20’s Early treatments relied on Antipsychotics   There were however many adverse effects Early 1990’s pharmacological breakthroughs allowed for a more functioning lifestyle in society Background  It is believed that Schizophrenia must be treated in a multifaceted treatment   While medication is the first line treatment counseling, social and family services should be provided for proper treatment of patients Further developments in pharmacological treatments should increase functioning of patients in society by reducing side effects with more selective drugs Etiology  Schizophrenia is a misregulation of information in the brain    Many different NT pathways are hypothesized to be involved in the biological basis of the disorder Genetics may be an important role The environment may trigger a possible genetic predisposition Etiology  Despite years of research there is no consensus on a single etiology for this disorder Symptoms  Schizophrenia has been broken down into two sets of symptoms   Positive and Negative Positive Symptoms      Hallucinations Delusions Disorganized Speech, Behavior and Movements Increase in goal directed activity Illogical thoughts Negative Symptoms      Blunted Affect Impaired emotional responsiveness Apathy Loss of motivation and interest Social withdrawal Atypical vs Traditional   Traditional Antipsychotics only alleviate the positive symptoms Atypical drugs however treat both the positive and negative symptoms    Lower extrapyrimidal effects Act on 5HT2 as well as D2 More expensive Role of Dopamine   Original theory proposed that an over activation of DA led to schizophrenic symptoms More recently it has been hypothesized that   Positive symptoms are caused by an over activation of specific DA pathways Negative symptoms arise from and under activation of different DA pathways Role of Dopamine  DA subtypes  DA1 receptors   DA2 receptors    DA1, D1B D2, D3 and D4 DA1 and DA2 exert opposite actions on intracellular mechanisms Traditional view of antipsychotics were that they antagonize D2 and D4 receptors  The problem with these drugs were that they caused Parkinson like symptoms, tardive dyskinesias and may worsen negative symptoms Atypical Antipsychotics      There is no agreement on what biological actions define atypical antipsychotics These drugs are thought to block D2 receptors Have a possible effect on D1, 5HT2 or adrenergic receptor blockade Some are thought to effect D3 and D4 Problem with atypicals is that their action on D2 receptors also may cause side effects involving movement disorders Serotonin Involvement  Observations of psychedelic drugs psilocybin and LSD    Cause a state similar to schizophrenia These drugs are 5-HT agonist 5-HT antagonism may have therapeutic efficacy Serotonin Involvement     Serotonin’s exact mechanisms of action are unclear Autopsy results show reduced 5HT2 receptors in the prefrontal cortex PET studies of living schizophrenics have not confirmed these findings Studies show a possibility of serotoninglutamate interaction  Drug-induced serotonin blocking limits glutamate release Glutamate Hypothesis   NMDA over activity leads to an excessive excitatory neurotransmission in the fontal cortex This damages cortical neurons which causes degeneration Summary of Theories  Overall   DA is considered to be involved with the positive symptoms Glutamate is considered to be involved with the negative symptoms Drug Classifications  Standard, classical, traditional   Phenothiazines are the prototypical agents New generation or atypical   Clozapine, risperidone, olanzapine, sertindole, quetiapine and ziprazadone Advantages   Theputically effective without causing neuroplectic syndrome Help relive negative symptoms and cognitive dysfunctions Phenothiazines   Widely used Least expensive Pharmacokinetics  Absorbed unpredictably and erratically through the GI tract       Dose decisions commonly made by trial and error Oral is still most common Rapid distributed once in bloodstream 24-48hr half life Slowly metabolized in liver Bind extensively to tissue  Causing slow elimination  May be responsible for slow rate of reoccurrence of psychotic episodes Pharmacological Effects       Blocks D2 receptors Ach, 5HT, Histamine and NE receptors Limbic system Brain Stem Basal Ganglia Hypothalamus-Pituitary Side Effects and Toxicity  High Potency Phenothiazapines       Fluphenazine, Trifluphenazine, Perphenazine Cause less sedation Fewer anticholergenic side effects Less postural hypertension More extrapyrimydal side effects Low Potency Phenothiasapines     Chlorpromazine, Thioridazine Used when sedation is desirable Also when Anticholinergic side effects limit compliance Often combined with benzodiazapines Tolerance and Dependence  Rarely abused    No tolerance No physical or psychological dependence Stopping treatment can either result in relapse or withdrawal Haloperidol          First therapeutic alternative to Phenothiasazines Similar effects of phenothiasazines Produces sedation Reduces initiative, anxiety and activity Well absorbed orally Slow rate of metabolism and excretion Acts on D2 receptors Few side effects Does produce Parkinson like effects Atypical Antipsychotics  Molindone  Resembles 5HT   Resembles traditional antipsychotics     Relation to 5HT therapeutic effect is unknown Mechanism of action, efficacy, side effects Moderate sedation Increased motor activity Possibly euphoria Loxapine      Similar in structure to atypicals Actions differ little from traditional effects Antipsychotic, antiametic and sedative properties Causes abnormal motor movements Good absorption, metabolism and excretion Clozapine       Used to treat treatment resistant schizophrenics Clinically superior to traditional drugs Relieves much of the negative symptoms Lacks many extrapyramidal effects Less of a cognitive inhibitor Clozapine may cause a loss of white blood cells but it reduces suicide rates Pharmacokinetics       Varied absorption rates among patients Well absorbed orally Metabolitic half life 9-30hrs Peak plasma levels 1-4hrs Metabolized by the liver into 2 active metabolites Blood levels must be monitored to ensure proper dosing Pharmacodynamics    High binding affinity for DA, Seretonin1c, seretonin2, alpha1, muscaranic and histamine Low rate of binding to D2 receptors Blocks 5HT2 at higher levels Side Effects and Toxicity  Sedation     Weight gain     40% of patients Can affect compliance Bed time dosing may help compliance 80% of patients Persistant Reason not known Withdrawal  Delusions, hallucinations, hostility, paranoid reaction, nausea, vomit, diarraheachachacha, headache, restlessness, agitation, confusion, sweating Other Concerns  Expensive  Due to blood monitoring Risperidone   Potent inhibitor of D2 and 5HT2 Pharmacokinetics     Orally administered Rate of metabolism varies 3hr half life Active metabolite 9-hydroxy-risperidone   Considered a first-line treatment for schizophrenia      Half life 22hrs High efficancy Safe Few detrimental effects on memory Minimal extrapyramidal side effects Other side effects  Agitation, anxiety, insomnia, headache, nausea, extrpyramidal side effects (only at high doses) Olanzapine    Structurally related to clozapine Blocks many receptors, but dopamine and serotonin interaction are thought to be responsible for therapeutic effect Pharmacokinetics     Overall effectiveness    Well absorbed orally Peak plasma levels at 5 to 8 hours Elimination half-life 27-38 hours improvements in both positive and negative symptoms Studies seem to show better results with less severely impaired patients Also used in bipolar Sertindole       5-HT2, D2, and alpha1-adrenoreceptors antagonist Treats both positive and negative symptoms Minimal extrapyramidal side effects Reduced sedative effects due to no affinity for histamine receptors Half-life 60 hours to 95 hours Can lead to severe cardiac arrythmias Quetiapine (Seroquel)   5-HT2/D2 receptor antagonst Half life 7hrs   Greater affinity for 5HT2 than D2   Two or more daily doses needed Separates the antipsychotic action from the extrapyramidal side effects Reduces expression of glutamate receptor mRNA Ziprasidone      Similar in effect to Haloperidal Weight gain is negliable Inactive byproducts Poorly absorbed orally Unique actions on receptors   Blocks 5HT2 and D2 Agonist at 5HT1a  May cause an antidepresant function Amisulpride      Yet to be released D2 and D3 subtypes blocked in limbic system but not in Basal Ganglia Twice as selective for D3 than D2 Low doses blocks presynaptic receptors increasing DA Higher doses it antagonizes DA    At these doses it has efficacy for negative symptoms Low incidence of extrapyramidal side effects No affinity for 5HT which is unusual for Atypical