Psychotic disorders and antipsychotics

Question 1

Sx of schizophrenia

Answer 1

• Positive (adding things to sensation that aren’t there): hallucinations, delusions
• Negative (removing things from sensation that should be present): flat affect, abolition (lack of motivation), alogia (poverty of speech/thought), disinterest, social withdrawal, adhedonia

Question 2

Diagnostic features of schizophrenia

Answer 2

• Total duration of Sx of at least 6 mo, including prodromal, active and residual phases
• Active phase of at least one mo characterized by at least two of the following: delusions, hallucinations, disorganized speech/behavior, negative symptoms
• Subtypes of schizophrenia no longer in DSM

Question 3

Differential Dx of schizophrenia

Answer 3

• Brief psychotic d/o: Sx of schizophrenia but lasts less than 1 mo w/ full return to normal level of functioning
• Schizophreniform d/o: Sx of schizophrenia that lasts more than 1 mo but less than 6
• Schizoaffective d/o: uninterrupted illness in which there is either a major depressive d/o, manic episode, or mixed episode w/ Sx similar to schizophrenia. There must also be delusions or hallucinations for at least 2 weeks in the absence of prominent mood symptoms
• Other types of psychotic d/o: one due to medical condition, substance-induced, mood d/o w/ psychotic features

Question 4

Overview of circuits involved in psychosis/schizophrenia

Answer 4

• Positive Sx: mesolimbic (overactivation)
• Delusions and hallucinations
• Negative Sx: mesocortical/prefrontal cortex (PFC, underactivation)
• Flat affect, abolition (lack of motivation), alogia (poverty of speech/thought), disinterest, social withdrawal, adhedonia
• Affective Sx associated w/ ventromedial PFC
• Aggressive Sx associated w/ orbitofrontal cortex
• Cognitive Sx associated w/ dorsolateral PFC

Question 5

DA pathways of the brain

Answer 5

• Nigrostriatal DA pathway: projects from substantia nigra to basal ganglia and striatum (i.e. direct and indirect). Controls motor function and movement
• Mesolimbic DA pathway: projects from midbrain VTA to nucleus accumbens (NA)
• Responsible for pleasurable sensations/euphoria, delusions, and hallucinations (is affected in schizophrenia: + Sx)
• Mesocortical DA pathway: projects from VTA to areas of the PFC
• Responsible for cognition (dorsolateral PFC) and affect (ventromedial PFC), is affected in schizophrenia (- Sx)
• Tuberoinfundibular DA pathway: projects from hypothalamus to anterior pituitary to control prolactin secretion

Question 6

Antipsychotics

Answer 6

• Drugs that reduce psychotic Sx in a variety of conditions
• A neuroleptic is a subtype of antipsychotic that produces a high incidence of extrapyramidal side effects (EPS)
• Atypical antipsychotics (now used) have antipsychotic effect w/o EPS

Question 7

Typical antipsychotics

Answer 7

• Are D2 (DA receptor) antagonists, w/ some ability to block the a1 adrenergic receptor (causing cardiovascular side effects like hypotension and drowsiness)
• Compares to atypical antipsychotics, these stay bound to the receptors for a longer period of time and will block some other receptors along w/ the D2 receptors
• Typical antipsychotics produce EPS b/c they affect all of the DA pathways (even the ones that do not have altered activity from schizophrenia: nigrostriatal and tuberoinfundibular)

Question 8

Atypical antipsychotics

Answer 8

• There are multiple differences btwn atypical and typical antipsychotics
• Atypical antipsychotics not only block the D2 receptor but they also block 5HT2 receptors
• 5HT2 acts to reduce DA release in the DA pathways (esp the nigrostriatal and mesocortical), thus blocking the 5HT2 receptors will increase the DA released in these pathways and reduce the EPS caused by D2 antagonism
• This mechanism is mostly effecting the nigrostriatal/mesocortical pathways
• Other major differences: there is more rapid dissociation from the D2 receptors w/ atypical, and there is less binding to other receptor types

Question 9

Mechanism of action of typical antipsychotics

Answer 9

• Presynaptic D2 autoreceptors will inhibit the release of DA, thus blocking these receptors increases the release of DA
• Postsynaptic D2 receptors induce inhibitory potentials in the postsynaptic cell when activated
• The overall affect of D2 blockers is the balance btwn this DA release disinhibition and the blocking affect of the postsynaptic D2 receptors
• Overall, there is decreased activity in the mesolimbic DA pathway w/ typical antipsychotics (reduces positive Sx)
• There is little effect on the mesocortical pathway (does not reduce negative Sx, could potentially worsen them by reducing DA activity)
• There is a decreased activity in the nigrostriatal pathway (results in EPS) and tuberoinfundibular pathway (increased prolactin secretion)

Question 10

Typical antipsychotics on the nigrostriatal pathway

Answer 10

• Blocking the D2 postsynaptic receptor prevents DA from binding and decreases the functioning of the nigrostriatal pathway
• This causes motor side effects EPS (extrapyramidal symptoms): akinesia, hypotension, drowsiness
• The long term effects include tardive dyskinesia (hyperkinetic facial and tongue movements), due to up-regulation of the D2 receptors

Question 11

Serotonin affect of the atypical antipsychotics

Answer 11

• Serotonin inhibits DA release, therefore 5HT2A antagonists will stimulate DA release (via 2 mechanisms)
• This is either done by blocking the 5HT2A postsynaptic receptors on DA neurons (thus activating them) or by blocking 5HT2A receptors on GABA interneurons, which will inhibit them and allow the DA neurons to be activated

Question 12

5HT2A antagonistic effect on DA pathways

Answer 12

• There is no difference in the mesolimbic pathway for atypical antipsychotics compared to typical (i.e. they both reduce the mesolimbic DA pathway by blocking D2 to reduce positive Sx)
• For atypical antipsychotics, the blockade of 5HT2A receptors and the resultant DA release increases the activity of DA in the mesocortical pathway
• This results in the improvement of negative Sx of affect and cognition

Question 13

5HT2A antagonism in nigrostriatal pathway

Answer 13

• The action of 5HT2A antagonism on the nigrostriatal pathway reverses the effect of D2 antagonism
• Increasing DA release in the nigrostriatal pathway will restore the normal activity despite the D2 antagonism from the drug
• Therefore atypical antipsychotics cause little to no EPS or tardive dyskinesia

Question 14

Overall affect of atypical antipsychotics

Answer 14

• There is a decrease in DA activity (D2 postsynaptic antagonism) in the mesolimbic pathway: reduces positive Sx
• There is an increase in DA activity (mostly 5HT2A antagonism, some D2 presynaptic antagonism) in the mesocortical pathway: reduces negative Sx
• There is no change in nigrostriatal pathway (5HT2A and D2 antagonism balance): no EPS or tardive dyskinesia
• No change in tuberoinfundibular pathway (same reason as nigrostriatal): no change in prolactin secretion