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 (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 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!

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.

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

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 1 st generation antipsychotics follow a sigmoidal curve relative to efficacy. Antipsychotic effects occur in presence of ~70% occupancy of the D2 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-or- flight 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 reward- associated 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 non- specifically block the mesocortical and striatal pathways, leading to EPS and prolonging of negative symptoms.

Second generation Antipsychotics Clozapine – introduced 1970s 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 mood- related 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