Schizophrenia

1. Schizophrenia Gary Yin Cheung Chan, Ho, Ronald Chun Ho, Mary Salama, Matthew Yu December 4, 2013 PHM142 Fall 2013 Instructor: Dr. Jeffrey Henderson

2. What is it? • Mental disorder affecting the brain • Polygenic • Risk factors: • Genetic (heritable) • Environmental • Developmental

3. Epidemiology • Affects 24 million people worldwide • 1% worldwide • 1.4x more likely in males than females • Onset mainly occurring in: • Male – 20-28 • Female – 26-32 • 10% chance of suicide in lifetime

4. Symptoms • Positive – improvements with medication • Audio, visual, olfactory hallucinations, delusions • Negative – worsens with medication • lack of emotion, anhedonia, alogia, schizophasia

5. Diagnostic Criteria • Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) • 3 stage criteria • Characteristic symptoms • Positive or Negative symptoms • Two or more must be present for at least a month • Social/occupational dysfunction • Work, interpersonal skills, self care are lower than usual • Significant duration • Impairment for at least 6 months

6. Subtypes • Paranoid – auditory hallucinations and delusions about conspiracy and persecution • Disorganized – impaired thought process, speech and lack of emotion • Catatonic – immobile or random sharp movements • Residual – lower frequency and intensity of hallucinations and delusions • Undifferentiated – symptoms present but not sufficient for classification into a subtype

7. Dopamine Theory • Dopamine is a neurotransmitter, and it has been proposed that schizophrenia is caused by excess dopamine, this theory is supported by evidence that drugs which increase the concentration of dopamine or increase its activity are known to be related to schizophrenia onset. Dopamine receptors are found in different parts of the brain, where they have different functions.

8. Dopamine Pathway

9. Mesoblimibic and Nigrostriatal tract

10. Schizophrenia Treatments • First Generation Antipsychotics (FGAs) • Ex. Cholorpromazine • Mechanism: dopamine D2 receptor antagonists • Therapeutic window: 65-80% receptor occupancy • ST effects: extrapyrimidal side effects (EPS), neuroendocrine • LT effects: tardive dyskinesia (TD) • High fail rate

11. Schizophrenia Treatments • Second Generation Antipsychotics (SGAs) • Ex. Clozapine, quetiapine • Mechanism: serotonin-dopamine antagonism • Increase drug affinity for serotonin 5-HT2A receptor: dopamine D2 receptor • “fast-off D2” theory • Mechanism is still unclear

12. Clozapine • Effective for treatment-resistant individuals • Mechanism of action • D1/D2 antagonist • Hypothesized to increase dopamine concentrations in extracellular fluid of prefrontal cortex of the brain • Dopaminergic hypoactivity (lack of dopamine) causes negative symptoms • Clozapine relieves negative symptoms

13. Clozapine • Side effect: Drug-induced agranulocytosis • Agranulocytosis: decreased number of WBCs • Limited use • Require weekly blood tests • Pathogenesis • Unclear • Either immunological, genetic or toxic mechanisms

14. Effect of Serotonin in Schizophrenia Treatments • Serotonin is proposed to play a role in schizophrenia treatment. Clozapine has partial 5-HT1A agonist properties and other atypical antipsychotics share this feature, e.g. olanzapine, quetiapine, ziprasidone and bifuprenox. Evidence suggests that such activity could, through modulation of dopamine, decrease EPS liability while improving negative and cognitive symptoms. Clozapine and other atypicals demonstrate 5-HT2C blocking properties, and pursuit of its potential benefits is warranted based on evidence that 5-HT2C antagonists can increase dopamine in both the nucleus accumbens and the PFC, which are related to better outcomes1

15. Schizophrenia Treatments • Third Generation Antipsychotics • Ex. Aripriprazole • Mechanism: dopamine D2 receptor partial agonist + dopamine D2 receptor functional selectivity • High extracellular [dopamine] component • Low extracellular [dopamine] component

16. Schizophrenia Treatments • Other antipsychotic drugs • other serotonin receptors (5-HT1A, 5HT2C, 5-HT7) • Other dopamine receptors (D1, D3, D4) • Muscarinic cholinergic and histamine receptors • Glutamatergic interventions • α7-nicotinic agonists • New nomenclature system to accommodate novel drugs

17. Summary • Polygenic disorder affecting the brain • Genetics being the largest risk factor • Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria • Positive or negative symptoms for at least 1 month • Social/occupational dysfunction • impairment for at least 6 months • 5 subtypes: paranoid, disorganized, catatonic, residual, and undifferentiated • Dopamine has different receptors in four main areas that have different effects on the brain • There are three different classes of antipsychotics, first and second generation antipsychotics are dopamine antagonists, and third generation antipsychotic is a dopamine agonist • First Generation Antipsychotics – dopamine D2 receptor antagonist; many ST & LT side effects + high therapeutic fail rate • Second Generation Antipsychotics (ex. Clozapine) – targets serotonin 5-HT2A receptors in addition to dopamine D2 receptor; higher efficacy + fewer side effects • Clozapine is the most effective 2nd generation antipsychotic used to relieve negative symptoms of schizophrenia • Risk of Clozapine-induced agranulocytosis, therefore controlled use • Third Generation Antipsychotics – dopamine D2 receptor partial antagonist with functional selectivity • Other antipsychotic treatments – ligands targeting other serotonin/dopamine receptors, glutamatergic interventions, α7 nicotinic agonists

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