Antipsychotics

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).

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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**

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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**.

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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**.

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VTA links to the **Prefrontal Cortex** (PFC).

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

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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**.

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

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

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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**

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

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

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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.

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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**

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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.

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Antipsychotics **block repolarisation of K+ channel** in myocardium

**Prolong QT** interval (QTc)

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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.**

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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*

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•Aripiprazole is a partial agonist at D2 receptors.

•It may act as an antipsychotic by:

•**Lowering** dopaminergic **neurotransmission in the mesolimbic p**athway.

•**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.