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 Onset 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 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

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 serotonin-glutamate 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 Relation to 5HT therapeutic effect is unknown Resembles traditional antipsychotics 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 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

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 Half life 22hrs Considered a first-line treatment for schizophrenia 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 Well absorbed orally Peak plasma levels at 5 to 8 hours Elimination half-life 27-38 hours Overall effectiveness 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 Two or more daily doses needed Greater affinity for 5HT2 than D2 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