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

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Presentation on theme: "Schizophrenia Paul M. Moran Maverick Miller Leslie Radka Jennifer Schmid Michael Ball Cheryl Rosario."— Presentation transcript:

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

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

3 Background It is believed that Schizophrenia must be treated in a multifaceted treatment 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 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 Further developments in pharmacological treatments should increase functioning of patients in society by reducing side effects with more selective drugs

4 Etiology Schizophrenia is a misregulation of information in the brain 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 Many different NT pathways are hypothesized to be involved in the biological basis of the disorder Genetics may be an important role Genetics may be an important role The environment may trigger a possible genetic predisposition The environment may trigger a possible genetic predisposition

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

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

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

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

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

10 Role of Dopamine DA subtypes DA subtypes DA1 receptors DA1 receptors DA1, D1B DA1, D1B DA2 receptors DA2 receptors D2, D3 and D4 D2, D3 and D4 DA1 and DA2 exert opposite actions on intracellular mechanisms DA1 and DA2 exert opposite actions on intracellular mechanisms Traditional view of antipsychotics were that they antagonize D2 and D4 receptors 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 The problem with these drugs were that they caused Parkinson like symptoms, tardive dyskinesias and may worsen negative symptoms

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

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

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

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

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

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

17 Phenothiazines Widely used Widely used Least expensive Least expensive

18 Pharmacokinetics Absorbed unpredictably and erratically through the GI tract Absorbed unpredictably and erratically through the GI tract Dose decisions commonly made by trial and error Dose decisions commonly made by trial and error Oral is still most common Oral is still most common Rapid distributed once in bloodstream Rapid distributed once in bloodstream 24-48hr half life 24-48hr half life Slowly metabolized in liver Slowly metabolized in liver Bind extensively to tissue Bind extensively to tissue Causing slow elimination Causing slow elimination May be responsible for slow rate of reoccurrence of psychotic episodes May be responsible for slow rate of reoccurrence of psychotic episodes

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

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

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

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

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

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

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

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

27 Pharmacodynamics High binding affinity for DA, Seretonin1c, seretonin2, alpha1, muscaranic and histamine High binding affinity for DA, Seretonin1c, seretonin2, alpha1, muscaranic and histamine Low rate of binding to D2 receptors Low rate of binding to D2 receptors Blocks 5HT2 at higher levels Blocks 5HT2 at higher levels

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

29 Other Concerns Expensive Expensive Due to blood monitoring Due to blood monitoring

30 Risperidone Potent inhibitor of D2 and 5HT2 Potent inhibitor of D2 and 5HT2 Pharmacokinetics Pharmacokinetics Orally administered Orally administered Rate of metabolism varies Rate of metabolism varies 3hr half life 3hr half life Active metabolite 9-hydroxy-risperidone Active metabolite 9-hydroxy-risperidone Half life 22hrs Half life 22hrs Considered a first-line treatment for schizophrenia Considered a first-line treatment for schizophrenia High efficancy High efficancy Safe Safe Few detrimental effects on memory Few detrimental effects on memory Minimal extrapyramidal side effects Minimal extrapyramidal side effects Other side effects Other side effects Agitation, anxiety, insomnia, headache, nausea, extrpyramidal side effects (only at high doses) Agitation, anxiety, insomnia, headache, nausea, extrpyramidal side effects (only at high doses)

31 Olanzapine Structurally related to clozapine Structurally related to clozapine Blocks many receptors, but dopamine and serotonin interaction are thought to be responsible for therapeutic effect Blocks many receptors, but dopamine and serotonin interaction are thought to be responsible for therapeutic effect Pharmacokinetics Pharmacokinetics Well absorbed orally Well absorbed orally Peak plasma levels at 5 to 8 hours Peak plasma levels at 5 to 8 hours Elimination half-life hours Elimination half-life hours Overall effectiveness Overall effectiveness improvements in both positive and negative symptoms improvements in both positive and negative symptoms Studies seem to show better results with less severely impaired patients Studies seem to show better results with less severely impaired patients Also used in bipolar Also used in bipolar

32 Sertindole 5-HT2, D2, and alpha1-adrenoreceptors antagonist 5-HT2, D2, and alpha1-adrenoreceptors antagonist Treats both positive and negative symptoms Treats both positive and negative symptoms Minimal extrapyramidal side effects Minimal extrapyramidal side effects Reduced sedative effects due to no affinity for histamine receptors Reduced sedative effects due to no affinity for histamine receptors Half-life 60 hours to 95 hours Half-life 60 hours to 95 hours Can lead to severe cardiac arrythmias Can lead to severe cardiac arrythmias

33 Quetiapine (Seroquel) 5-HT2/D2 receptor antagonst 5-HT2/D2 receptor antagonst Half life 7hrs Half life 7hrs Two or more daily doses needed Two or more daily doses needed Greater affinity for 5HT2 than D2 Greater affinity for 5HT2 than D2 Separates the antipsychotic action from the extrapyramidal side effects Separates the antipsychotic action from the extrapyramidal side effects Reduces expression of glutamate receptor mRNA Reduces expression of glutamate receptor mRNA

34 Ziprasidone Similar in effect to Haloperidal Similar in effect to Haloperidal Weight gain is negliable Weight gain is negliable Inactive byproducts Inactive byproducts Poorly absorbed orally Poorly absorbed orally Unique actions on receptors Unique actions on receptors Blocks 5HT2 and D2 Blocks 5HT2 and D2 Agonist at 5HT1a Agonist at 5HT1a May cause an antidepresant function May cause an antidepresant function

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

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