Pharmacology of Psychotic Disorders

Question 1

4 Main pathways of DA release

Mesolimbic: cell bodies in ______ and axons in the ___ system. Increased DA in this pathway → __ symptoms of psychosis

Mesocortical: cell bodies in __ and axons in __ areas. Reduce DA in this pathway → __ symptoms and cortical symptoms

Nigrostriatal: cell bodies in ___ and axons in the __ __

• Reduced DA in this pathway → __
• Increased DA in this pathway → __, __ and __

Tuberoinfundibular: cell bodies in __ and axons in the __ pituitary. Reduce DA in this pathway → __ release.

Answer 1

Mesolimbic: cell bodies in ventral tegmental area and axons in the limbic system. Increased DA in this pathway → positive symptoms of psychosis

Mesocortical: cell bodies in VTA and axons in cortical areas. Reduce DA in this pathway → negative symptoms and cortical symptoms

Nigrostriatal: cell bodies in substantia nigra and axons in the basal ganglia

• Reduced DA in this pathway → parkinsonism
• Increased DA in this pathway → chorea, dyskinesia and tics

Tuberoinfundibular: cell bodies in hypothalamus and axons in the anterior pituitary. Reduce DA in this pathway → prolactin release.

Question 2

Schizophrenia

Mesolimbic: increased activity → ___ symptoms

Mesocortical: decreased activity → __ and __ symptoms

Nigrostriatal and tuberoinfundibular: no change

Answer 2

Schizophrenia

Mesolimbic: increased activity → positive symptoms

Mesocortical: decreased activity → negative and cognitive symptoms

Nigrostriatal and tuberoinfundibular: no change

Question 3

Dopamine hypothesis of schizophrenia: postulates that hyperactivity of dopamine __ receptor neurotransmission in __ and __ brain regions contributes to ___ symptoms of schizophrenia, whereas __ and cognitive symptoms of the disorder can be attributed to __ of dopamine __

Answer 3

Dopamine hypothesis of schizophrenia: postulates that hyperactivity of dopamine D2 receptor neurotransmission in subcortical and limbic brain regions contributes to positive symptoms of schizophrenia, whereas negative and cognitive symptoms of the disorder can be attributed to hypofunctionality of dopamine D1

Question 4

First generation (typical): chlorpromazine (low potency), __ (high potency)

Second generation (atypical): __, __

Third generation: aripiprazole

__ (class of its own)

Answer 4

First generation (typical): chlorpromazine (low potency), haloperidol (high potency)

Second generation (atypical): olanzapine, risperidone

Third generation: aripiprazole

Clozapine (class of its own)

Question 5

first gen antipsychotics block ____ receptors in the ___ of the brain.

a key side effect is neuroleptic malignant syndrome. What are the key features and how to treat?

Answer 5

First Generation

MOA: Dopamine D2 Blocker in the subcortical area

Side Effects:

Muscarinic: cholinergic block– dry mouth, blurry vision, urinary retention, cognitive dysfunction

Histamine receptor block: sedation, appetite stimulation

Alpha-1-adrenergic block: postural hypotension

*Neuroleptic Malignant Syndrome: delirium + muscle rigidity; elevated CK, myoglobinuria, fever.

MEDICAL EMERGENCY!

Treat with aggressive cooling + dantrolene +/- bromocriptine

Extrapyramidal side effects: DA inhibits acetylcholine release in BG; therefore, blocking DA → increased acetylcholine → extrapyramidal side effects

Examples: tremor, slurred speech, akathisia, dystonia, anxiety, distress, paranoia and bradyphrenia

Treatment; anticholinergics (benztropine is most common)

Complications: increases risk of development irreversible tardive dyskinesia

*Neuroleptic Malignant Syndrome: delirium + muscle rigidity; elevated CK, myoglobinuria, fever.

MEDICAL EMERGENCY!

Treat with aggressive cooling + dantrolene +/- bromocriptine

Question 6

what is the MOA of second gen antipsychotics? why are they better at modulating negative symptoms of schizophrenia?

Answer 6

Second Generation

MOA: blocks dopamine DA receptor and serotonin 5HT2A receptor

Why block serotonin? Serotonin inhibits DA release from dopaminergic axons terminals. Therefore, serotonin blockers → increased DA release.

The degree of serotonin’s control varies from one DA pathway to another.

Mesolimbic: serotonin blockage is weak → overall reduced dopamine

Mesocortical: serotonin blockage is strong→ overall ­dopamine

Nigrostriatal: serotonin = dopamine blockade → no net effect

Tuberoinfundibular: serotonin = dopamine blockade → no net effect

Question 7

Note: read the pros and cons of each second gen antipsycotics

Question 8

MOA of third gen. Why don’t we use it more?

Answer 8

Third Generation (ex/ aripiprazole)

Definition: PARTIAL agonist of D2 and 5HT2A blocker

Mechanism: partial agonist of D2 → sable firing pattern of neurons (when DA is high → decreased, and when DA is low → increased)

Side effects: similar side effects as 2ng gen, but less metabolic syndrome and weight gain. Very low rates of tardive dyskinesia

its great but its so darn expensive

Question 9

T/F you can use depo right off the bat when managing schizophrenia

Answer 9

false.

Picking an Antipsychotic

Indications: schizophrenia, schizoaffective disorder, bipolar disorder, non-manic excited states, Tourette’s syndrome, non-psychiatric (hiccups, emesis)

Consider side effect profile

Formulation

Oral: all available in oral → ALWAYS try oral formulation FIRST

Depo: risperidone (q2wk); paliperidone (q4wk or q3mo); aripiprazole (q4wk).

Efficacy: all about the same except for clozapine (very potent)