James Greene Schizo Flashcards
Explain how antipsychotics cause extra-pyramidal symptoms
Dopamine facilitates movement by enhancing the direct pathway of the basal ganglia, inhibiting the indirect pathway and inhibiting the cholinergic interneurons of the striatum. When active, these cholinergic interneurons inhibit the direct pathway and excite the indirect pathway, having a net effect of inhibiting facilitated movement.
The net effect of dopaminergic transmission in the nigrostriatal pathway is therefore excitation of the ventrolateral thalamus which excited the corticospinal tract which controls the lower motor neurons to skeletal muscle, therefore allowing for normal, facilitated movement.
Therefore D2 blockade from antipsychotics results in loss of excitation of direct pathway, loss of inhibition of the indirect pathway, and now unopposed action of cholinergic interneurons which further compound direct pathway inhibition and indirect pathway excitation.
The net effect is inhibition of the ventro-lateral thalamus, loss of excitation of the corticospinal descending tracts and loss of the “net inhibitory” effect of this tract on the lower motor neurons extra-pyrimidial effects.
Explain the benefits of Atypical antipsychotics
1. Reduced D2 Affinity + Transient Receptor Occupancy
Atypical antipsychotics have a lower affinity for D2 receptors compared to typical antipsychotics, combined with transient receptor occupancy. This allows them to block D2 receptors in the mesolimbic pathway effectively, reducing positive symptoms such as hallucinations and delusions.
However, their weaker and transient binding reduces the risk of prolonged dopamine suppression in other pathways, preventing secondary negative symptoms (e.g., emotional blunting) and minimizing the risk of motor side effects.
2. Activity at 5-HT Receptors
Atypical antipsychotics also target serotonin receptors, particularly 5-HT2A and 5-HT1A receptors, which play key roles in improving negative symptoms:
5-HT2A antagonism disinhibits dopamine neurons, leading to increased dopamine release in the mesocortical pathway, which is typically hypofunctional in schizophrenia. This helps alleviate negative symptoms such as social withdrawal and reduced emotional expression.
5-HT1A agonism directly promotes dopamine release, further supporting dopamine activity in the mesocortical pathway.
The net effect of this serotonin modulation is a rebalancing of dopamine levels across pathways, addressing both positive and negative symptoms of schizophrenia.
3. Reduced Extrapyramidal Symptoms (EPS)
The combination of reduced D2 receptor affinity and serotonin receptor activity also benefits the nigrostriatal pathway.
Lower D2 affinity minimizes dopamine blockade in this pathway, while 5-HT2A antagonism facilitates dopamine release.
This increased dopaminergic transmission in the nigrostriatal pathway significantly reduces the risk of EPS, such as rigidity, tremors, and other motor disturbances, which are more common with typical antipsychotics.
Explain why typical antipsychotics are good for positive symptoms but bad for negative symptoms
Effectiveness for Positive Symptoms:
Typical antipsychotics have a high affinity for D2 receptors, binding strongly and dissociating slowly. In the mesolimbic pathway, this intense dopamine blockade reduces positive symptoms such as delusions and hallucinations by limiting overactive dopaminergic transmission.
Negative Impact on Negative Symptoms:
The excessive D2 receptor blockade can worsen negative symptoms through two mechanisms:
(i) In the mesolimbic pathway, suppression of the reward system reduces motivation, pleasure, and emotional engagement, leading to secondary negative symptoms like apathy and anhedonia.
(II) In the already hypofunctional mesocortical pathway, further dopamine reduction exacerbates preexisting deficits, worsening symptoms such as social withdrawal and diminished cognitive function.
Extrapyramidal Symptoms (EPS):
Typical antipsychotics also block D2 receptors in the nigrostriatal pathway, which is critical for motor control. This leads to motor side effects such as rigidity, tremors, bradykinesia, akathisia, and dystonia. These symptoms arise because dopamine activity is necessary to balance motor pathways, and its suppression disrupts this balance.
Lack of Serotonin Receptor Modulation:
Unlike atypical antipsychotics, typical drugs have minimal activity at 5-HT2A and 5-HT1A receptors. This absence of serotonin modulation means typical antipsychotics lack the ability to offset dopamine blockade, which could otherwise mitigate both negative symptoms and EPS.
List 3 extra-pyramidal conditions and indicate how antipsychotics causes each.
All are related to D2 blockade in the nigro-striatal pathway
- Acute Dystonia
-D2 blockade leads to disinhibition of the cholinergic interneurons of the striatum which results in downstream net inhibition of the thalamus causing muscle spasms. - Parkinsonism
-D2 blockade causes loss of excitation of the direct pathway, excitation of the indirect pathway and increased activity of cholinergic interneurons, further compounding the above effects. This leads to net inhibition of the thalamus. - Tardive Dyskinesia
-Chronic blockade of D2 receptors causes upregulation of D2 receptors which results in excessive dopaminergic stimulation causing abnormal motor movement.
List the 4 dopamine pathways
- Nigrostriata
-From substatia nigra pars
compacta to striatum - Mesolimbic
-From ventral tegmental area to nucleus accumbens, amygdala and hippocampus - Mesocortical
-From Ventral tegmental area to pre frontal cortex - Tuberohypophyseal
-from hypothalamus to median eminence/pituitary
Define psychosis
Psychosis is a syndrome associated with dysregulation in neurotransmitters in the brain, particularly dopamine and serotonin. Frontal, temporal and mesostriatal brain circuits are primarily affected.
Psychosis typically causes hallucinations, delusions and disorganised thoughts.
It can be caused by primary “functional” psychotic disorders or be caused secondary to organic causes such as substance use or other medical aetiologies.
List 4 drugs that can cause psychosis
- Antihistamines
- Anti cholinergic
- Corticosteroids
- Dextrometorphan (cough suppressant)
- Isoniazid (TB)
Define delusion
A delusion is a fixed, false belief that is held with conviction despite irrefutable evidence against it.
It is a mis-interpretation of the external reality and is not in-keeping with the perons’s cultural or societal norms
Define neurosis and state 3 ways in which it differs from psychosis
Neurosis is a mental condition that is not caused by organic disease, involving symptoms of stress (depression, anxiety, obsessive behaviour, hypochondria) but not a radical loss of touch with reality.
- Neurosis does not cause loss of touch with reality
- It does not involve hallucinations or delusions
- Those with neurosis typically maintain social interactions/ can function in day to day life
List the 5 primary psychotic disorders and the time frame needed for diagnosis
- Brief psychotic disorder >1 day but < 1 month
- Schizoaffective disorder > 2 weeks
- Delusional disorder > 1 month
- Schizophreniform 1-6 months
- Schizophrenia > 1 month
Explain why regular blood monitoring is needed for patients on clozapine
Clozapine is an atypical antipsychotic that can cause neutropenia and more severe agranulocytosis. This means the patients immune system is wiped leaving the patient open to potentially life threatening infection.
Mandatory monitoring:
-White cell count weekly for 18 weeks
-Two weekly until 1 year
-Monthly thereafter
What is meant by neuroleptic malignant syndrome
NMS is caused by dopamine antagonism
Altered mental status
Hyperthermia
Tachycardia
Autonomic dysfunction (BP fluctuations)
Muscle rigidity
