Treatment of the Psychotic Disorders: Schizophrenia

1. Treatment of the Psychotic Disorders: Schizophrenia Karl Kashfi

2. What is schizophrenia? • A mental illness among the world’s top ten causes of long-term disability • Develops between the ages of 16 and 30 • Cause is unknown, but various theories have been proposed in regards to a biological cause • In addition to biological causes, studies indicate a multitude of genetic and environmental factors

3. Epidemiology and Prevalence • Affects 1% of the population at any one time! • Gender-based variations in prevalence of schizophrenia (men>women?) • Cross-cultural variations in prevalence and the nature of the illness?

4. Symptoms • The trademark of schizophrenia is an impairment in the perception of reality, though there are many other symptoms. • Three broad types of symptoms: • Psychotic (positive) symptoms • Delusions and hallucinations • Negative symptoms • Diminution of basic emotional and behavioral processes • Cognitive impairment • Decline in concentration and thinking

6. Etiology and Risk factors • Genetic factors • Higher rates of illness among relatives of a patient than in general population • Environmental factors • Prenatal/obstetric complications • Brain abnormalities • Poverty and low social class (two reasons) • Urban residents, migrants, and minorities

7. Onset, Course, and Prognosis • Onset of schizophrenia: age 16-30 (usually earlier in men than in women) • Onset lasts 5 years • Prodrome • Cognitive impairment • Psychosis/hospitalization • Psychosis is episodic over time; negative symptoms are more stable • No cure; less than average life-expectancy

8. Review: Neurotransmitters • Neurotransmitters are the chemical messengers of the nervous system • They relay electrical signals from one neuron to the next in a series of steps: • Calcium influx • Exocytosis from presynaptic neuron • Diffusion across synapse • Fusion with postsynaptic neuron and generation of impulse • Neurotransmitters can be excitatory or inhibitory

10. Important neurotransmitters • Biogenic amines – play a role in emotional behavior • Dopamine • Catecholamine (like epinephrine, norepinephrine) • Synthesized from amino acid tyrosine • Can be inhibitory or excitatory (depends on receptor) • “Feeling good” neurotransmitter • Seritonin (5-HT) • Indolamine • Synthesized from amino acid tryptophan • Sleep, appetite, mood

12. History of Drug Discovery • 1950s – Chlorpromazine found to induce neurolepsy in animals and reduce psychosis in psychotic patients. • These compounds were found to increase metabolism of dopamine (less dopamine) • Conclusion #1: Good antipsychotic! • Conclusion #2: If less dopamine means less psychosis, then high dopamine must mean more psychosis!

13. Mechanism of Action • Inverse relationship found between doses of antipsychotics and their affinity for the dopamine D2 receptors in the brain. • The observations of the 1950s led to the Dopamine Hypothesis: • Excess dopamine leads to psychosis • Blockade of postsynaptic D2 receptors should provide reversal of psychotic features of schizophrenia due to negative feedback reactions.

14. Other Hypotheses • If the dopamine hypothesis is true, then blockade of D2 receptors by antipsychotics should provide immediate reversal of psychosis, BUT this doesn’t happen. • A majority of patients require 2-4 weeks for a response • Some never even improve appreciably after prolonged use of antipsychotics. • WHY? • Depolarization Inactivation Hypothesis • Multiple gene action delay

15. First Generation Antipsychotics • The discovery of chlorpromazine set the stage for the era of the first-generation antipsychotics • Not everyone, however, responded equally: • 1/3 of patients improved completely, 1/3 partially, and 1/3 showed little recovery • Drug potency inversely related to affinity for the D2 receptor sites • The dose requirements for 1st generation antipsychotics follow a sigmoidal curve relative to efficacy. • Antipsychotic effects occur in presence of ~70% occupancy of the D2 receptors.

16. Chlorpromazine

18. Side Effects! • Severe symptoms are associated with 1st generation antipsychotics, known asExtrapyramidal Symptoms: • Dystonias • Akathisia • Pseudo-Parkinsonian symptoms • Unfortunately, therapeutic doses tend to be quite close to those which cause EPS • Other side effects include prolactin increase and tardive dyskinesia.

19. More Problems • Another problem with 1st generation antipsychotics: They suppress positive (psychotic) symptoms of schizophrenia, but the negative symptoms remain! • WHY? Because of NON-SPECIFICITY in dopamine receptor blockade.

20. Dopaminergic Neural Pathways • Several neural pathways which utilize dopamine are located in the midbrain of the brainstem, and they mediate such things as emotion, fight-or-flight responses, motivation, etc. • They are projections from the limbic system • These include: • Mesolimbic pathway • Mesocortical pathway • Nigrostriatal pathway

24. “Motivational salience” • Mesolimbic dopamine pathways are involved in motivational and reward-associated stimuli • What is the relationship between these pathways and the symptoms of schizophrenia? • “Motivational salience” theory

25. Dopaminergic Neural Pathways • Blockage by antipsychotics of dopamine receptors in mesolimbic pathway – reduction of positive (psychotic) symptoms • However, antipsychotics also non-specifically block the mesocortical and striatal pathways, leading to EPS and prolonging of negative symptoms.

26. Second generation Antipsychotics • Clozapine – introduced 1970s • 1st of the second generation antipsychotics • Second generation antipsychotics = “atypical” antipsychotics • “Atypical” because EPS is absent! • Other beneficial properties include reduction of negative symptoms • This is because serotonin receptors are blocked as well as dopamine receptors

27. Clozapine – Side Effects • Clozapine – “Gold standard” in treating schizophrenia • Has been shown to reduce aggression, substance abuse, and treat other mood-related disorders • Unfortunately, though very potent, its primary problem is agranulocytosis.

28. 2nd generation antipsychotics • Other 2nd generation antipsychotics exist, which work by the same mechanism as clozapine: • Risperidone • Olanzipine • Quetiapine • Ziprasidone • Unfortunately, these also come with side effects, which vary with the medication: • Metabolic disorders (glucose) • Weight gain • Increased prolactin release

30. Prognosis of treated patients • The success of outcome is a function of the promptness of treatment following onset • Cognitive function is a relevant parameter in prognosis • Overall, life expectancy is still shortened when compared to the general population due to side effects, stigma, and decreased quality of life. • Anosognosia!

33. What does the future hold? • Potentiation techniques • D-cycloserine • New receptor targets (NMDA receptor) • New neurotransmitter systems • Dopamine-glutamate • Dopamine-acetylcholine • Pharmacogenomics