More Antipsychotics Drug Information

Question 1

Where on the Agonist Spectrum do Drugs for Psychosis Lie?

Answer 1

1. Some have actions closer to a slient antagonsit and others have actions closer to a full agonist.
2. D2 agents with too much agonism may be psychotomimetic and not ideal for psychosis
   a. they can be useful for treating Parkinson’s Disease
3. D2 partial agonists hat are closer to the antagonist end of the spectrum are preferable for psychosis
   a. D2 antagonists are also preferable for treating psychosis
4. 5Ht2a antagonisits treat psychosis in conjunction:
   a. with D2 binding drugs
   b. without D2 binding drugs
5. 5HT1a agonism is a common property of many drugs used to treat psychosis, in particular many D2 partial agonists.

Question 2

5HT2a Actions

Answer 2

1. All are post-synaptic and excitatory.
2. The 5HT2a receptor locations that are important in the treatment of psychosis are:
   a. descending glutamatergic pyramidal neurons that directly innervate mesolimbic/mesostriatal dopamine neurons projecting to the emotional striatum.
   i. excessive activity here can lead to positive symptoms of psychosis.

   b. descending glutamatergic pyramidal neurons that indirectly innervate nigrostriatal dopamine neurons via a GABAergic interneuron in the subtantia nigra.
       i. excessive activity here can lead to reduction in dopamine release in the motor striatum and can cause side effects such as drug-induced parkinsonism.
   
   c. descending glutamatergic pyramidal neurons that indirectly innervate mseocortical dopamine neurons via a GABAergic interneuron in the ventral tegmental area.
       i. excessive activity here leads to a reduction in dopamine release in the prefrontal cortex which could lead to cognitive dysfunction and negative symptoms of emotional blunting and flat affect.

Question 3

5HT1a Actions

Answer 3

1. are inhibitory and located both presynaptically on serotonin neurons and postsynaptically on other neurons.
2. located on the descending glutamatergic pyramidal neurons that indirectly innervate nigrostriatal dopamine neurons via a GABAergic interneuron in the substantia nigra.
   a. Partial agonism of 5HT1a receptors reduces glutamatergic output in the substantia nigra
   i. this leads to reduce activity of the GABA interneuron and therefore to disinhibition of the nigrostriatal dopamine pathway.
   ii. the increased dopamine in the motor striatum can reduce motor effects caused by D2 antagonism/partial agonism because there is more dopamine to complete with the D2 binding agent
3. located in the descending glutamatergic pyramidal neurons that indirectly innervate the mesocortical dopamine neurons via a GABA ergic interneuron in the VTA.
   a. Partial agonism of 5HT1a reduces glutamatergic output in the VTA
   i. leading to reduced activity of the GABA interneuron and disinhibition of the mesocortical dopamine pathway.
   ii. the increased dopamine inthe prefrontal cortex can reduce cognitive, negative, and affective symptoms of psychosis.

Question 4

Alpha 1

Answer 4

1. causes seizures if stop taking suddenly

Question 5

5HT1a Actions

Answer 5

1. are inhibitory and located both presynaptically on serotonin neurons and postsynaptically on other neurons.
2. located on the descending glutamatergic pyramidal neurons that indirectly innervate nigrostriatal dopamine neurons via a GABAergic interneuron in the substantia nigra.
3. Partial agonism of 5HT1a receptors reduces glutamatergic output in the substantia nigra

Question 6

CATIE study )Clinical Antipsychotic Trials of Intervention Effectiveness (Jan 2001 to Dec 2004 ; 57 clinical sites in the USA).

Answer 6

1. published in 2005.
2. randomized to four different medications (zyprexa, trilafon, seroquel, risperdal_
3. Geodon was added after FDA approval
4. A lot of people could not tolerate the medications or they were not efficacious and there was a large discontinuation rate.
   a. discontinuation percentages: zyprexa 64%, trilafon 75 %, seroquel 82 %, risperdal 74%
5. Take aways from Phase 1 CATIE:
   a. High rates of discontinuation in all arms:
   i. no significant difference between trilafon and SGAs
   ii. Trilafon discontinued because of EPS
   iii. Zyprexa discontinued due to metabolic effectsb. Zyprexa had the lowest discontinuation rate
   i. high rates of weight gain, increased lipids and increased glucose

Phase 2 of CATIE:

1. random assignment of 1000 people
   a. Efficacy Pathway: Clozaril vs SGA; N=99b. Tolerability Pathway: another SGA (no clozapine): N=444
2. Take aways from Phase 2:
   a. CLozaril is more effective than the other SGAs
   i. Patients were less likely to discontinue clozaril because it was effective
   ii. zyprexa and risperdal were more effective than seroquel or geodon

NO Abilify or FGA in phase 2.

Question 7

CUtLASS (N=277)

Answer 7

1. Was a comparison between FGAs and SGAs.
2. Open-label randomized trials
   a. FGAs vs SGAs
   b. SGA vs Clozril
   c. participants were folks with schizophrenia psychosis who did not have an adequate response or had an adverse reaction to a previous medication
   d. monitored for one year
   e. blind assessments at 12, 26, and 56 weeks.
   f. outcome measures: QOL, symptom severity, adverse events, participant satisfaction, costs of care.
   g. drugs used: amisulpride (not approved in the USA); zyprexa, seroquel, risperdal.
3. Take aways:
   a. Patients taking FGAs showed a trend toward greater improvement on QOL and symptom severity.
   b. no clear patient preference between FGAs and SGAs.
   c. costs were similar.
   d. Clozaril was better than other SGAs in terms of symptoms improvement.

Question 8

PINES

Answer 8

1. clozapine
2. olanzapine
3. quetiapine
4. asenapine
5. zotepine

Question 9

Dones

Answer 9

1. risperidone
2. paliperidone
3. ziprasidone
4. iloperidone
5. lurasidone
6. lumateperone

Question 10

2 Pips and a Rip

Answer 10

1. aripiprazole
2. brexpiprazole
3. cariprazine