Lecture 12: Drugs used to treat Psychosis Flashcards
1
Q
What does Psychotic disorders mean?
A
The term used to describe a range of mental disorders that involve symptoms of psychosis
2
Q
What is Psychosis?
A
The mental disorders in which there is a loss of contact with reality, affecting a person’s ability to think, feel and act
3
Q
What are the three types of symptoms of Schizophrenia?
A
- Positive
- Negative
- Cognitive
4
Q
When is Schizophrenia diagnosed?
A
When a person has two or more symptoms for more than six months
5
Q
What are the positive symptoms of schizophrenia?
A
Mental phenomena that are absent in healthy individuals
•Hallucination
•Delusions
6
Q
What are the Negative symptoms of schizophrenia?
A
Loss or impairment of normal psychological functions
•Loss of social motivation
•Social withdrawal
7
Q
What are the Cognitive symptoms of schizophrenia?
A
- Poor concentration
- Disorganized thinking
- Poor memory
8
Q
What is the risk of Schizophrenia highly influenced by?
A
Genes
9
Q
When does Schizophrenia often manifest?
A
In early adulthood
10
Q
What neurotransmitters are thought to be associated with Schizophrenia?
A
- Dopamine
- Glutamate
- GABA
- Serotonin
11
Q
What is meant with the statement Schizophrenia is a biochemical Disorder?
A
People with schizophrenia have altered levels of neurotransmitters
12
Q
What are the three Biochemical Theories of Schizophrenia?
A
- Dopamine hypothesis
- Glutamate hypothesis
- Serotonin (5-HT) hypothesis
13
Q
What is the overarching theme to the Dopamine Hypothesis?
A
Symptoms of schizophrenia are due to the hyperactivity of the dopamine system
14
Q
What is the inferential evidence that support the Dopamine Hypothesis?
A
- Drugs that increase synaptic dopamine can cause delusions and hallucinations at high doses
- Drugs that block dopamine receptors are effective antipsychotics
15
Q
Where are Dopamine neurons located?
A
In a few discrete regions of the brain
16
Q
Where is the largest population of dopamine neurons located?
A
In the midbrain (ventral tegmental area and substantia nigra)
17
Q
What is the Mesocortical/Mesolimbic system?
A
Dopamine neurons located in the ventral tegmental area thar project to the striatum and prefrontal cortex
18
Q
What is the function of the Mesocortical/Mesolimbic system?
A
Mediate memory, learning, affect and thought organization
19
Q
What does hyperactivity in the Mesocortical/Mesolimbic pathway contribute to?
A
Psychotic symptoms
20
Q
What is blocking dopamine transmission in the Mesocortical/Mesolimbic pathway effective at?
A
Treating positive symptoms of schizophrenia
21
Q
What does the Mesocortical/Mesolimbic system start with?
A
Dopamine neurons in the ventral tegmental area
22
Q
What are dopamine neurons in the striatum important for?
A
Reward in behavior associated with drugs like cocaine
23
Q
What are dopamine neurons in the cortex important for?
A
Memory, learning and organization
24
Q
What does hyperactivity in the Ventral tegmental cortical tract do?
A
Drives the psychosis associated with schizophrenia
25
What kind of receptors are Dopamine receptors?
G-protein coupled receptors
26
What are the two types of Dopamine receptors?
```
D1 receptors (Gs)
D2 receptors (Gi)
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27
What G coupled receptor is D1 coupled to?
Gs
28
What G coupled receptor is D2 coupled to?
Gi
29
What do D1 Gs coupled receptors do?
Stimulate AC and activate cAMP dependant kinases
30
What do D2 Gi coupled receptors do?
Inhibit the activity of adenylate cyclase
31
The blocking of which Dopamine receptors is directly related to clinical antipsychotic potency?
D2 receptors
32
Which Dopamine receptors are blocked with anti-psychotics?
D2 receptors
33
What does antipsychotics blocking the activity of D2 do?
Stops D2 from inhibiting AC
34
What are the other Dopamine Pathways are not associated with psychosis?
* Nigrostriatal system
| * Tuberoinfundibular system
35
What is the Nigrostriatal system?
Dopamine neurons in the substantia nigra that project to the striatum
36
What is the Nigrostriatal system involved in?
Movement initiation
37
What is inhibiting Nigrostriatal system associated with?
Tardive Dyskinesias
38
What is Tardive Dyskinesias?
Involuntary movements of the face and body after long-term use of some antipsychotics that inhibit dopamine transmission
39
Which neurons degenerate in parkinson's disease?
The Nigrostriatal neurons
40
What is the Tuberoinfundibular system?
Dopamine neurons in the arcuate nucleus that control hormone release in the pituitary
41
What does Dopamine released in the Tuberoinfundibular System do?
Inhibits the secretion of prolactin and growth hormone
42
What is Hyperprolactinemia?
The long-term use of some antipsychotics that affect the dopamine pathways of the tuberoinfundibular system
43
Other than hyperprolactinemia, what does inhibiting the Dopamine in the Tuberoinfundibular pathway associated with?
Amenorrhea, decreased libido, infertility
44
What is the overall Glutamate hypothesis?
Symptoms of schizophrenia linked to deficiencies in glutamate signalling, particularly in the cortex
45
What is the support of the Glutamate Hypothesis for psychosis?
Phencyclidine (PCP/Angel dust) and Ketamine which are NMDA antagonists produce hallucination and paranoid delusions
46
What is the current theory of Glutamate and schizophrenia and NMDA receptors?
Schizophrenia is associated with hypofunctional NMDA receptors on GABA interneurons in the cerebral cortex
47
What does the hypofunction of GABA interneurons in the cerebral cortex cause?
This hypofunction leads to overactivation of downstream glutamate signalling to the VTA
48
What are Dopamine neurons under the control of?
Glutamate neurons that lie in the cortex that project to the VTA
49
What are Glutamate neurons under the control of?
GABA interneurons
50
What have scientists found in the brains of Schizophrenics in terms of glutamate receptors?
They have a hypofunctional glutamate receptor on the GABAergic interneurons
51
What does the NMDA receptor do?
Binds to glutamate and causes the NMDA channel to open and a flow a positively charged ions leads to depolarization of GABAergic neurons
52
What should depolarization of GABAergic neurons do?
Release GABA to bind to GABAergic receptors on the glutamate neuron
53
What kind of receptors are GABA receptors?
They are inhibitory
54
What does GABA binding to GABA receptors on Glutamate neurons do?
Shuts off the Glutamate neuron
55
What neurons activate dopamine neurons?
Glutamate neurons
56
What does shutting off the Glutamate neurons by GABA do?
Reduces the activity of dopamine release because glutamate usually activates Dopamine neurons
57
What do GABAergic neurons in the cortex do?
Inhibit dopamine neurons by inhibiting Glutamate neurons which activate dopamine neurons
58
What is wrong with the NMDA receptors on GABA neurons that glutamate is supposed to bind to and activate GABA neurons in order to inhibit glutamate neurons in people with Schizophrenia?
They don't work very well
59
What is a consequence of the NMDA receptors not working?
Glutamate released on the GABAergic neurons are no longer able to to activate GABA neurons and as a consequence GABA neurons can't release GABA in order to inhibit the Glutamine neurons. This causes glutamate to release onto Dopamine receptors and activate dopamine and create a hyperactivity of dopamine which causes psychosis
60
What overall does the Serotonin Hypothesis state?
That the symptoms of schizophrenia are due to increased serotonin signaling
61
What is the inferential evidence of the serotonin hypothesis?
5HT agonists are hallucinogenic. 5HT antagonists improve positive symptoms of schizophrenia
62
How is it hypothesized in the serotonin hypothesis that serotonin causes hallucinations?
5HT-2A receptors in the prefrontal cortex cause hallucinations by enhancing excitation of glutamate neurons which activate the mesolimbic dopamine system
63
What do 5HT-2A antagonists do?
Block glutamate release in the cortex, thus reducing hallucination and other positive symptoms
64
What is the difference between the Serotonin and Glutamate hypothesis?
The serotonin hypothesis states that the upstream control of glutamate neurons is serotonin and not hypofunction of the NMDA receptor GABA interneurons
65
What are the two major groups of antipsychotic drugs?
* First gen antipsychotics/Typical antipsychotics
| * Second gen antipsychotics/Atypical antipsychotics
66
What do First gen antipsychotics target?
Both classes of dopamine receptors (D1 and D2)
67
What does the efficacy of First gen antipsychotics relate to?
D2 receptor antagonism
68
What are the two first gen antipsychotics?
Haloperidol and chlorpromazine
69
What kind of drugs are second gen antipsychotics?
Antagonists
70
What receptors do second gen antipsychotics target?
They are antagonists at 5HT and D2 receptors
71
Why do second gen antipsychotics have less dopamine related side effects than first gen antipsychotics?
Because they bind with lower affinity to dopamine receptors
72
What are the second gen antipsychotics?
Clozapine and Risperidone
73
What dopamine relate side effects do second gen antipsychotics lack?
Tardive Dyskinesia and prolactin release
74
How much occupation of D2 receptors is required to produce an antipsychotic effect of typical and atypical antipsychotics?
60-80%
75
What does 80% D2 occupancy of antipsychotics do?
Results in side effects such as
•Parkinson-like side effects (extrapyramidal symptoms)
•Elevated prolactin (hyperprolactinemia) and
•Tardive dyskinesia
76
What is the Therapeutic window of the typical antipsychotics?
It has a very narrow therapeutic window
77
Why do Atypical antipsychotics have a wider therapeutic window?
Because they have a lower binding affinity to D2 receptors
78
What can the relationship between how well a drug binds and how well a drug dissociates to a ligand be expressed by?
The ratio of the association constant and the ratio of the dissociation constant aka the equilibrium constant (kd)
79
What does a Low Koff and a high Kon have in terms of the Kd and affinity?
This will cause a low Kd and a high affinity
80
How does Dopamine work in the mesolimbic-nigrostriatal pathway?
Dopamine is released into the synaptic cleft where it binds to receptors on the postsynaptic membrane
81
What are the characteristics of Dopamine binding in the mesolimbic/nigrostriatal pathway?
It is a tight squeeze and there is a high degree of receptor rebinding
82
How does Dopamine work in the Tuberoinfundibular pathway?
Dopamine is secreted into the bloodstream and carried across the BBB to the pituitary gland
83
What are the characteristics of Dopamine binding in the Tuberoinfundibular pathway?
There is a high degree of clearance and less receptor rebinding
84
What generation antipsychotic is Haliperidol?
A first generation
85
What are the characteristics of Haloperidol at the D2 receptor?
It binds very well to the D2 receptor and tends not to let go
86
What would the Kd of Haloperidol be?
It would have a high dissociation constant because it tends not to dissociate (Kon>Koff)
87
What are the effects of Haloperidol at the VTA/Substantia Nigra/Striatum versus the pituitary?
At the Striatum it will have a high rate of receptor binding potential and in the pituitary it will also have a high rate of receptor binding
88
Why does Haloperidol (first gen) have high extrapyramidal side effects?
Because it has high binding in the Striatum and in the Pituitary
89
What generation antipsychotic is Chlorpromazine?
First gen
90
What is the affinity for the receptor in Chlorpromazine?
It has high binding affinity for the receptor
91
What is the difference between Haloperidol and Chlorpromazine at the receptor?
Chlorpromazine and Haloperidol both bind quickly but Chlorpromazine unbinds a lot easier
91
What is the difference between Haloperidol and Chlorpromazine at the receptor?
Chlorpromazine and Haloperidol both bind quickly but Chlorpromazine unbinds a lot easier
92
What are the effects of Chlorpromazine at the VTA/Substantia Nigra/Striatum versus the pituitary?
Because Chlorpromazine unbinds very quickly in the striatum the tight space helps it to rebind better but in the pituitary blood flow doesn't allow it to rebind
93
What are the side effects of Chlorpromazine?
Because it still binds in the striatum it will still have high extrapyramidal effects but because it does not bind highly in the pituitary it doesn't really effect prolactin release
94
What kind of Antipsychotic is Clozapine?
A second gen antipsychotic
95
What is the kinetic profile of Clozapine?
It has a slow on and a fast off meaning that it is really slow to bind to the receptor and unbinds quickly. So it is less likely to occupy the receptors
96
What are the effects of Clozapine at the VTA/Substantia Nigra/Striatum versus the pituitary?
In the striatum even though it is a tight synaptic space the fact that it's not binding well in the first place means its less likely to occupy the receptors. And in the pituitary it is cleared in the pituitary quicker
97
What are the Side effects of Clozapine?
It tends to have lower extrapyramidal effects and less effects on prolactin release
98
Aside from their side effects in the striatum and pituitary what effects can antipsychotics have?
They can have affinity for other receptors like serotonin, adrenergic, GABA and glutamate receptors
99
What other receptor does Clozapine have an affinity for?
D4 receptors
100
What are the effects of Clozapine binding to D4 receptors?
Agranulocytosis (loss of WBCs) making an individual more susceptible to infection
101
Why is Clozapine not a first choice antipsychotics?
Because it binds to WBCs and makes an individual more susceptible to infection and death
102
What are the side effects of second gen antipsychotics?
* Cardiovascular effects
* Metabolic syndrome
* Diabetes
* Weight gain
