Antipsychotics

What is Schizophrenia?

Mental disorder involved thinking, feeling and behaviour. Starts between ages of 15 to 35. Affects 1 in 100 people during their lifetime

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What are the causes of Schizophrenia (6)?

Genes, subtle brain damage at birth, viral infections during pregnancy, childhood abuse, street drugs (ecstasy, LSD, amphetamines, crack as triggers, cannabis), stressful events/family tensions make it worse

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Describe the pathology of Schizophrenia

Grey matter loss in brains of teenagers with early onset Schizophrenia. Large loss in temporal and frontal brain regions that control memory/hearing/motor functions/attention. Bilateral increase in ventricular volume (displacement of corpus callosum)

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Which of the main causes increases the risk for developing Schizophrenia?

Genetics (e.g. from grandparents, parents etc.)

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What are the positive symptoms of Schizophrenia (4)?

Hallucinations, delusions, difficulty thinking, feeling controlled (symptoms become prominent with age and time)

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What are the negative symptoms of Schizophrenia (5)?

Apathy, affective blunting, poverty of thought/speech, social withdrawal, self-neglect - see lecture slide

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Which chemicals are involved in Schizophrenia?

Dopamine, glutamate, serotonin, GABA (based on receptor profile of antipsychotics)

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What are the three major pathways of dopamine in the brain?

Mesolimbic pathway - sensory stimuli/movement (VTA to NA, positive symptoms). Mesocortical pathway - cognitive/reward/emotional behaviour (VTA to cortex). Turbero-infundibular system - (hypothalmic-pituitary endocrine)

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What is the fourth pathway of dopamine in the brain?

Nifrostriatal (Substantia nigra to striatum)

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Which dopamine pathways in Schizophrenia are overactive?

Mesolimbic pathway

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Which dopamine pathways in Schizophrenia are underactive?

Mesocortical pathway and tubero-infundibular system (reduced neuronal control of hypothalmic - pituitary endocrine system)

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Outline the origin of the dopamine theory of Schizophrenia

Chlopromazine used as an antihistamine but also had effect on mental state. Chlopromazine used for patients with Schizophrenia. Approved by FDA due to already being on the market. 50 million people treated with chlorpromazine for psychotic disorder.

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What was the proposed dopamine theory of Schizophrenia?

Schizophrenia is the result of excessive/uncontrolled dopaminergic activity in specific pathways of the brain

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Describe features of the dopamine theory of Schizophrenia (4)

Stronger + relationship between antipsychotic activity of drugs/potency as D2 antagonists. Higher occupation of striatal D2 receptors by dopamine during episodes of active Schizophrenia. Amphetamines (chronic) produce Schizophrenia-like psychoses

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Super-sensitivity of which chemical occurs in Schizophrenia and other psychoses?

Dopamine (D2 high affinity states are increased) - see graphs

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What is the indirect evidence for the dopamine theory of Schizophrenia?

Amphetamine (symptoms identical to + symptoms of Schizophrenia). D2 agonists (apomorphine/bromocriptine). DA antagonists (chlorpromazine/haloperidol/reserpine) control positive symptoms. + relationship antipsychotic activity/potency of D2 antagonists

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What are the issues with atypical antipsychotics like clozapine?

Hight antipsychotic activity but relatively low affinity for D2 receptor. Lack of extra pyramidal symptoms and lack of effect on prolactin secretion

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Which chemical is the most toxic substance produced in the brain?

Glutamate

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Describe the mesolimbic pathway for glutamate

Glutamate switches off dopamine pathway (normal). Opposite occurs for those with Schizophrenia (action on GABA interneurones, disinhibition, increased DA activity in limbic system)

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Describe the mesocortical pathway for glutamate

Glutamate stimulates neurones, excites pathway (less glutamate for those with Schizophrenia, reduction in activity - decrease DA release in cortex, negative symptoms)

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Outline the glutamate theory of Schizophrenia

No main nucleus, 50% synapse in brain. Increase DA (mesocorticol decrease) decreased glutamate. Phencyclidine (angel dust) and ketamine (anaesthetic) blocks NMDA receptors- causes Schizophrenic symptoms, Schizophrenics more sensitive to Phencyclidine

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Based on the dopamine hypothesis of Schizophrenia, what is the current treatment for Schizophrenia?

Typical neuroleptics and atypical neuroleptics (antipsychotics)

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Give examples of typical neuroleptics

Phenothiazines (chlorpromazine, fluphenazine, thioridazine). Thioxanthines (flupentixol, clopenthixol). Butyrphenones (haloperidol)

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Give examples of atypical neuroleptics

Dibenzodiazepines (clozapine). Diphenylbutylpiperizines (pimozide). Benzamides (sulpiride, remoxipride)

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What is the function of D2 antagonists?

Inhibit alpha muscarinic and histamine receptors to varying degrees (typical neuroleptics)

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What are the side effects of typical neuroleptics?

Extra-pyramidal motor symptoms (EPS) - akathisia, akinesia, dyskinesia, dystonia. Increase prolactin secretion (stimulate tubero-infundibular pathway). Risk of tardive dyskinseia

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What is akathisia?

Feeling of inner restlessness. Compelling need to be in constant motion. Rocking whilst standing or sitting. Lifting feet (marching on spot). Crossing/uncrossing legs while sitting. Unable to sit or keep still

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What is akinesia?

Absence, loss, impairment of power of voluntary movement

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What is dyskinesia?

Abnormal involuntary movement e.g. tic, spasm etc.

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What is dystonia?

Involuntary tightening and twisting of limb. Painful. Seen in patients with Parkinson's disease

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What is tardive dyskinesia?

Repetitive involuntary purposeless movements e.g. rapid eye blinking, movement of arms/legs. Incidence increases with dose/duration of drugs treatment. Removing treatment doesn't always stop it. Symptoms may/may not disappear over time

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What are the limitations of typical neuroleptics (low potency) ?

Chlorpromazine - sedative, anti-histamine, anti-muscarinic, anti-adrenergic (alpha 1), prolactinaemia (rise in prolactin), cognitive impairment

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What are the limitations of typical neuroleptics (high potency) ?

Flupenthixol, fluphenazine, haloperiodol - no antihistimatic (not sedative), effect on basal ganglia, extra-pyramidal side effects (Parkinson's) - lower dose, tardive dyskinesea esp in older people. Cognitive impairment

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Describe the pharmacology of atypical neuroleptics

D2 and 5HT2A antagonists, D2/D3 antagonists, use of clozapine

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What are the side effects of atypical neuroleptics?

Few EPS - akathisia, akinesia etc. Hyperprolactinaemia. Risk of tardive dyskinesia. Doesn't impair cognition. Weight gain (clozapine/olanzapine). Insulin resistance triggering diabetes

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Describe features of 2nd generation antipsychotics

More expensive. Balance cost with effect. Hospitalisation, social services, family problems

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Describe features of dopamine as a new treatment for Schizophrenia

D1 receptor agonists (effect on cognition). D3/D4 antagonists or partial agonists or positive/negative allosteric modulators (PAMs, NAMs)

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Describe features of glutamate as a new treatment for Schizophrenia

NMDA receptor positive allosteric modulators. Reuptake inhibitors. Metabotropic GLU receptor agonists. AMPA/kainate agonsists. AMPkines (AMPA modulators)

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Describe features of NE, COMT and ACH as a new treatments for Schizophrenia

Alpha 1 agonists/antagonists, COMT inhibitors. ACh - alpha 7 nicotinic receptor agonists (cognition), alpha 4/beta 2 nicotinic agonists, allosteric modulators

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Antipsychotics

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