Treatment of the Psychotic Disorders Schizophrenia Karl Kashfi

Treatment of the Psychotic Disorders: Schizophrenia Karl Kashfi

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

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?

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

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

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

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

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

History of Drug Discovery • 1950 s – 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!

Mechanism of Action • Inverse relationship found between doses of antipsychotics and their affinity for the dopamine D 2 receptors in the brain. • The observations of the 1950 s led to the Dopamine Hypothesis: – Excess dopamine leads to psychosis – Blockade of postsynaptic D 2 receptors should provide reversal of psychotic features of schizophrenia due to negative feedback reactions.

Other Hypotheses • If the dopamine hypothesis is true, then blockade of D 2 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

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 D 2 receptor sites • The dose requirements for 1 st generation antipsychotics follow a sigmoidal curve relative to efficacy. • Antipsychotic effects occur in presence of ~70% occupancy of the D 2 receptors.

Chlorpromazine

Side Effects! • Severe symptoms are associated with 1 st generation antipsychotics, known as Extrapyramidal 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.

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

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-orflight responses, motivation, etc. • They are projections from the limbic system • These include: – Mesolimbic pathway – Mesocortical pathway – Nigrostriatal pathway

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

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

Second generation Antipsychotics • Clozapine – introduced 1970 s • 1 st 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

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

2 nd generation antipsychotics • Other 2 nd 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

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!

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