Antipsychotics

What is the central dopamine hypothesis?

What is the central dopamine hypothesis?

suggests that a dysregulated dopamine system contributes to positive, negative, and cognitive symptoms of the disease.

What are the systems and what type of symptoms do they cause?

• Hyperactive mesolimbic pathway → positive symptoms

• Hypoactive mesocortical pathway → negative symptoms

• Nigrostriatal pathway → neurological & motor symptoms

What is the mesolimbic pathway?

Dopamine is produced in the Vental Tegmental Area (VTA).

Mesolimbic pathway—transports dopamine from the VTA to the nucleus accumbens and amygdala. The nucleus accumbens is found in the ventral medial portion of the striatum and is believed to play a role in reward, desire, and motivation

The mesolimbic dopaminergic (ML-DA) system has been recognized for its central role in motivated behaviors, various types of reward, and, more recently, in cognitive processes.

Too much dopamine in in mesolimbic pathway = positive symptoms

What is the mesocortical pathway?

The mesocortical pathway transmits dopamine from the VTA to the prefrontal cortex.

VTA links to the Prefrontal Cortex (PFC).

This changes how you prioritise and plan**.**

one of the main dopamine pathways of the brain, the mesocortical pathway runs from the ventral tegmental area to the cerebral cortex. It forms extensive connections with the frontal lobes, and is thought to be important to a wide range of functions, such as motivation, emotion, and executive functions.

Drugs (e.g. cocaine) cause overstimulation and reliance on mesolimbic pathway

They act on VTA (which links to nucleus accumbens and PFC)

Too little dopamine in mesocortical pathway = negative pathway

What is the nigrostriatal pathway?

Most dopamine producing neurons are found in the VTA and Substantia Nigra

The Substantia Nigra forms the Nigrostriatal Pathway which is black due to (neuro)melanin (byproduct of dopamine synthesis)

Nigrostriatal pathway links substantia nigra to the basal ganglia with the caudate and putamen

The dorsal striatum consists of the caudate nucleus and the putamen. A white matter, nerve tract (the internal capsule) in the dorsal striatum separates the caudate nucleus and the putamen.

The main function of the nigrostriatal pathway is to influence voluntary movement through basal ganglia motor loops.

What illnesses are in nigrostriatal pathway?

In Parkinson’s the Substantia Nigra degenerates

Lewy Bodys form – abnormal aggregations of protein

This leads to the movement and initiation difficulties seen in Parkinson’s

Lose nigrostriatal pathway → lose upper/higher control of processing movement

What is the TUBEROINFUNDIBULAR pathway?

Hypothalamus to pituitary gland

• Increased levels of dopamine will cause decreased levels of prolactin

• Increased prolactin: amenorrhoea (increased prolactin decreases FSH), galactorrhoea

• ADR: hyperprolactinemia (as antipsychotics reduce levels of dopamine, it increases levels of prolactin causing lactation)

What are examples of 1st generation/ typical?

Chlorpromazine

Haloperidol

What is the MOA of typical antipsychotics?

dopamine receptor antagonist

High affinity for D2 receptors

Improves only +ve symptoms

What is the ADR of typical antipsychotics?

• Extrapyramidal symptoms and tardive dyskinesia e.g. restlessness, tremor, and stiffness due to the blockage of D2 receptors in nigrostriatal pathway

• Causes parkinsonism

• prolonged QT

• hyperprolactinemia

• weight gain

• Movement disorders

What are examples of 2nd generation/ atypical?

Olanzapine

Colzapine

Quetiapine

What is the MOA of atypical antipsychotics?

Serotonin/dopamine receptor antagonist

Higher affinity to 5-HT2A receptors than D2 receptors

What is the ADR of atypical antipsychotics?

Because they have lower D2 affinity, atypical antipsychotic drugs produce significantly fewer extrapyramidal symptoms and having a lower risk of tardive dyskinesia in vulnerable clinical populations at doses that produce comparable control of psychosis.

Antipsychotics block repolarisation of K+ channel in myocardium

Prolong QT interval (QTc)

Olanzapine- weight gain, metabolic syndrome, QT prolongation, movement disorders

Colzapine- weight gain, QT prolongation, sexual dysfunction

Quetiapine- weight gain, QT prolongation, movement disorders

Aripiprazole – Partial Dopamine Agonist

Aripiprazole binds to the D2 receptor with the same affinity as dopamine, but has a lower intrinsic efficacy, so the response it triggers is lower than dopamine but higher than an antagonist.

Aripiprazole might decrease activity in the mesolimbic pathway through partial D2 agonism, which would, in turn, reduce positive symptoms.

One postulated mechanism of action of aripiprazole in schizophrenia is the ability of the drug to increase dopaminergic activity from a subnormal level to normal activity in the mesocortical pathway. Partial D2 agonism might increase dopaminergic activity in the mesocortical pathway therefore reducing negative symptoms

•Aripiprazole is a partial agonist at D2 receptors.

•It may act as an antipsychotic by:

•Lowering dopaminergic neurotransmission in the mesolimbic pathway.

•Enhancing dopaminergic activity in the mesocortical pathway.

What is an example of an alkali metal?

Lithium carbonate

What is the MOA of lithium?

Supress dopaminergic + glutamatergic synaptic activity (pre + post cells) while also upregulating GABA synapti activity.