6.1 Antipsychotic drugs

Question 1

What are the 3 main dopaminergic pathways and their origin + projections + function?

Answer 1

1) NIgrostriatal
- origin: SNc
- projections: striatum
- function: control and regulation of movement

2) Mesolimbic
- origin: ventral tegmental area
- projections: Nucleus accumbens, frontal cortex, limbic cortex, olfactory tubercle
- function: Emotion, sensing the environment, reward pathways

3) Tubero-infundibular:
- origin: hypothalamic arcuate nucleus (short neurones)
- projections: Medial eminence of hypothalamus, pituitary gland
- function: Regulation of hormonal secretion

Question 2

Dopamine is synthesised from ____________ in the presynaptic knob
• Packaged into neurotransmitter vesicles by the ____________________ uptake protein as a free molecule (protected from breakdown enzymes)
• Released into the synaptic cleft and binds to dopamine receptors (D1/D2 families)
• After dopamine serves its functions, it is deactivated by reuptake systems into the nerve endings (via VMAT-1) and into adjacent astrocytes for breakdown

Answer 2

L-tyrosine ;

vesicular monoamine transporter (VMAT-2);

Question 3

______________ gene: involved in synaptic development and plasticity, and effects on NMDA receptor (glutamate) expression
o Transgenic mice expressing the gene shows schizophrenic-like phenotype

Answer 3

Neuregulin-1

Question 4

The pathogenesis of schizophrenia is linked to dopamine and glutamate and their relationship with GABAergic striatal neurones:
• GABAergic striatal neurones project to the _______ (serves as sensory gate) → ____________ glutamate/ __________ dopamine disables the gate → uninhibited sensory input to cerebral cortex → overinterpretation of external environment

Answer 4

thalamus;

too little; too much;

Question 5

Dopamine: Normally exerts inhibitory effects on GABAergic striatal neurones
1. Excessive dopaminergic transmission in _________________:
• Causes positive symptoms (mediated via ______________ → mainly found on the presynaptic neurone)
• Dopamine agonists (e.g. bromocriptine) and amphetamines can induce various psychotic reactions
• Typical anti-schizophrenic drugs are dopamine receptor antagonists → strong correlation with D2 blocking activity

2. Deficient dopaminergic transmission in _________________:
   • Causes negative symptoms (mediated via _______________)

Answer 5

mesolimbic and striatum;

D2 receptors;

prefrontal region;

D1 receptors

Question 6

Glutamate: Normally exerts excitatory effects on ________________:

1. Reduced glutamate concentration/receptor density:
   • Observed in post-mortem schizophrenic brains
   • NMDA receptor antagonists (e.g. phencyclidine, ketamine) produce psychotic symptoms

Answer 6

GABAergic striatal neurones

Question 7

What are the atypical anti psychotic drugs?

Answer 7

Risperidone, Quetiapine, Olazapine, Clozapine, Aripiprazole

Question 8

What are the typical anti psychotic drugs>

Answer 8

1) Phenothiazines
- Group 1: Chlorpromazine
- Group 2: Pericyazine
- Group 3: Fluphenazine, Trifluperazine

2) Thioxanthines
- flupenthixol
- zuclopenthixol

3) others
- haloperidol
- pimozide
- sulpride

Question 9

Which receptors do atypical antipsychotics have strong relative affinities at?

Answer 9

α-adrenoceptors, H1 receptors and 5-HT2A receptors

Question 10

Antipsychotics also exert an anti-emetic effect by blocking ______________ receptors in the chemoreceptor trigger zone (CTZ):
• Phenothiazine (neuroleptic) is effective at controlling nausea and vomiting caused by _________________ and _____________
• Histamine receptor blockade helps to control motion sickness
• Newer atypical antipsychotics target 5-HT receptors to control nausea and vomiting

Answer 10

dopamine or histamine;

Question 11

Extrapyramidal side effects (more common with typical antipsychotics)

Acute dystonia: involuntary movements (e.g. muscle spasms, protruding tongue, fixed upward gaze, neck spasm) + _______________ (e.g. bradykinesia)
• Occurs in first few weeks (then decline with ongoing therapy)
• Reversible on ____________ (but risk of schizophrenia relapse) or use of _________________

Tardive dyskinesias: involuntary movements often involving the face and tongue (limb and trunk may be affected)
• Occur late in treatment (~20% of patients after several months or years) → may be related to proliferation of presynaptic D2 receptors or glutamate excitotoxic striatal neurodegeneration
• Aggravated by drug withdrawal or anticholinergics
• Improved by increasing dose (causes vicious cycle)

Answer 11

Parkinsonian features

drug withdrawal;

anticholinergics;

Question 12

What are the endocrine side effects more common with atypical antipsychotics?

Answer 12

Blockade of D2 receptors in tuberoinfundibular system:

• Increased serum prolactin concentrations → breast swelling (in men and women) and sometimes lactation (in women)

Question 13

What are the adrenergic side effects more common with atypical antipsychotics?

Answer 13

Blockade of α-adrenoceptors → orthostatic hypotension

Question 14

What are the metabolic side effects more common with atypical antipsychotics?

Answer 14

Blockade of 5-HT receptors → weight gain

Question 15

What are the muscarinic side effects more common with atypical antipsychotics?

Answer 15

Blockade of cholinergic muscarinic receptors → typical peripheral anti-muscarinic side effects (e.g. blurry vision, increased IOP, dry mouth, constipation, urinary retention)

Question 16

What is the side effect that occurs with both typical and atypical antipsychotics which is the most life threatening adverse effect?

Answer 16

Neuroleptic malignant syndrome (NMS): Deranged dopaminergic function → precise physiology unknown • Most life-threatening adverse effect of antipsychotic use (20% mortality if not treated immediately)
• Presents with hyperthermia, muscle rigidity, autonomic instability, fluctuating unconsciousness
• Appears from a few days to weeks after beginning treatment

Question 17

Huntington’s disease (HD):
movement disorder affecting the bas al ganglia (increased _________ concentration in putamen; deficient _____________ –> reduced inhibition on nigrostriatal
system –> dopaminergic hyperactivity
• Hyperkinetic disorder (associated with excessive abnormal movements) –> movements are______________ (affecting different muscle groups in face, trunk,
• Hereditary disorder (onset during adult life) + associated with progressive dementia
• May be controlled to some extent using antipsychotics (by blockade of dopamine
receptors in the nigrostriatal pathway)

Answer 17

DA;

GABA and ACh;

involuntary, irregular , jerky