CVD risk (PF3010)
Insufficient D(1) receptor signalling in the prefrontal results in cognitive deficits. Possible treatment of negative and cognitive symptoms with D1 agonist
Positive symptoms due to overactivity of D2 receptors in mesolimbic pathway. Antipsychotics act as D2 receptor antagonists
PET scans can show over- or under-activity of dopamine in certain parts of the brain.
Diabetes risk (PF3009) and cancer risk (PT2448)
Schizophrenia

Schizophrenia

Diagnosis

Diagnosis

One of:

Hallucinations

Delusions

Thought Disorder

Or two of:

Catatonia

Negative Symptoms

Consistent Change in Personal Behaviour

Earlier Diagnosis Improves Outcome

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Diagnosis – earlier you see the GP the better. Bonn scale shows good evidence for prodromal diagnosis.

Prodromal Diagnosis

Bonn Scale (BSABS)

Diminished Affectivity

Disturbed Contact

Cognitive, Personal or Self-Disorder

Perplexity and Cenethesias

Prognosis

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 Natural causes in over 50%·     Non-natural causes:o  Most common in males was suicideo  Most common in females was CVDo  Suicide was particularly high in the first year after diagnosis in young patients

Reduced Life Expectancy

Suicide in males

CVD in females

Brain Imaging

PF4015: PET Scans

PET images contain more or less intense colour to provide information about chemical activity within certain organs and tissues.

Treatment

Treatment

First Generation Antipsychotics

Chemistry: Chlorpromazine developed from phenothiazine compounds

Side Effects

Mainly associated with movement disorders - decreased nigrostriatal dopamine activity

Hyperprolactinemia, sedation, weight gain. muscarinic and alpha adrenergic - decreased tuberoinfundibular dopamine activity

Second Generation Antipsychotics

Pharmaceutics: Risperdal Consta® Depot IM Injection

Reduced incidence of EPSE's

Third Generation Antipyschotic?

Aripirazole

Partial D2 agonist

5HT2A antagonist

Partial 5HT1A agonist

Reduced incidence of hyperprolactinemia and EPSE's

CBT or Family Interventions

Future Treatment

Novel targets - drugs targeting glutamatergic, cholinegeric and nicotinic receptors and signalling proteins such as PDE and AKT. Theoretically rationale but no proof.

Target risk genes - DISC-1, neuregulin and RGS proteins

Natalizumab

No treatment to alleviate negative and cognitive symptoms

Pathophysiology

Pathophysiology

Dopamine Hypothesis

D2 Receptors

D1 Receptors

Dihydrexidine is a selective D1 agonist
that has shown positive results in clinical trials where there was significant increase in bilateral prefrontal cortical perfusion after infusion of the drug

Serotonin Hypothesis

5HT1A receptors have been shown to be increased in the frontal cortex, hippocampus, and thalamus in schizophrenia - causing decreased dopaminergic activity

Glutamate Hypothesis

Etiology

Etiology

Stress-Vulnerability

Neurodevelopmental

Slight defects of the head, hair, eyes, mouth, feet and hands

Ventricular enlargement

Genetics

Not due to a single gene mutation

About 33% chance of both identical
twins developing the disease, compared to 7%
chance in non-identical twins

Combination of environmental factors and genetics

Transmitter Abnormality

Risk Factors:

Prenatal and Perinatal Complications

Social Deprivation

Urban Living

Ethnicity

Cannabis Use

Re-hospitilisations, psychosocial functioning, alcohol abuse and relapse more common among cannabis abusers

Immigrants

r

Immigrants and their second generation offspring showed rates of schizophrenia up to 10 times higher than those of the general population

Symptoms

Symptoms

Cognitive

Decreased processing speed

Decreased episodic memory

Poor executive function

Positive

Hallucinations

Delusions

Confused thoughts/Difficulty concerntrating

Disorganised or unpredictable behaviour

Negative

r

Negative symptoms can often appear years before first psychotic episode - known as prodromal period

Social withdrawal

Deterioration in appearance and hygeine

Anhedonia

Loss of motivation

Misconception

r

Symptoms – does not cause split personality or violence. Violence is usually linked to drug or alcohol misuse.Infamous serial killers who were diagnosed as having a psychotic illness were also drug and alcohol abusers - Jeffrey Dahmer, Daniel Gonzales (drug fuelled killing spree - 'Freddy Krueger Killer'), Richard Chase ('Vampire of Sacramento')

Pharmacoeconomic Effects

Pharmacoeconomic Effects

Cost of €460.6 million in Ireland in 2006

Medication

Psychiatric Therapy

Co-morbidities and hospital admissions

High incidence of physical and social disability

Patients require care services
on daily basis - family member, friend or care worker

Majority of patients are unable to work and require social welfare