Psychosis Flashcards
Positive Symptoms
Mental phenomena that are normally absent in healthy individuals
(Hallucinations and Delusions)
Negative Symptoms
Loss or impairment of normal physiological functions
(Loss of motivation and social withdrawal)
Cognitive Symptoms
Poor concentration, disorganized thinking, poor memory
What influences the development of schizophrenia
Highly influenced by genes
Environmental factors can also trigger neurochemical and structural changes leading to schizophrenia
Dopamine Hypothesis of Schizophrenia
Symptoms caused by hyperactivity of dopamine system
Inferential evidence of Dopamine hypothesis
Drugs that increase synaptic dopamine can cause delusions and hallucinations at high doses
Drugs that block dopamine receptors are effective antipsychotics
Where is the largest population of dopamine neurons located
Midbrain
Where are the Mesocortical and mesolimbic systems located
Ventral tegmental area (VTA)
Hyperactivity of the dopamine receptors in the VTA causes?
Contributes psychotic symptoms
Blocking dopamine transmission can treat what kind of symptoms
Positive symptoms of schizophrenia
What do the mesocortical and mesolimbic system mediate
Memory, learning, thought organization
What are D1 receptors, what are their effects
Gs coupled receptors
Increase AC, increase cAMP
Do not contribute to therapeutic effect of antipsychotic drugs
What are D2 receptors, what are their effects
Gi coupled receptors
Inhibits AC, decrease cAMP
Inhibiting an inhibitory GABAergic interneuron that is regulating Dopamine release through inhibition –> Thus, increases dopamine
Causes antipsychotic effects
Inhibition of D2 is related to antipsychotic effects, stops disinhibition of GABAergic interneurons and allows them to inhibit and regulate dopamine levels
Nigrostriatal System
This dopamine system contains dopamine neurons in the substantia nigra and project to the striatum
initiates movement
Inhibiting this pathway produces extrapyramidal symptoms (movement disorders)
Tardive dyskinesias
Involuntary movement of face and moth
Tuberoinfundibular System
This dopamine system contains dopamine neurons in the arcuate nucleus
Controls hormone release in the pituitary
Dopamine inhibits the secretion of prolactin and growth hormone
How does long term use of antipsychotics affect the Tuberoinfundibular System
Antipsychotics lower dopamine –> Nothing to inhibit prolactin release –> Hyperprolactinemia
Decreased libido, infertility, amenorrhea
Glutamate Hypothesis of Schizophrenia
Symptoms are caused by deficiencies in glutamate signaling
Evidence for Glutamate Hypothesis Hallucinogens
NMDA ( glutamate receptor) antagonists produce hallucinations
Theory behind mechanism of Glutamate Hypothesis
Associated with hypofunctional (decrease in function) NMDA receptors on GABA interneurons in the cerebral cortex.
Decreased function of GABA interneurons mean less inhibition of downstream glutamate receptors. These glutamates receptors will start to activate dopamine.
Summary: Overactivation of downstream glutamate signaling to the VTA
Serotonin Hypothesis of schizophrenia
Symptoms caused by an increase in serotonin signaling
Evidence for serotonin hypothesis
5HT agonists (5HT = Serotonin) are hallucinogenic
5HT antagonists improves positive symptoms of schizophrenia
Theory behind mechanism of Serotonin Hypothesis
5HT-2A receptors in the prefrontal cortex are activated enhancing the excitation of glutamate neurons activating mesolimbic dopamine systems
5HT-2A antagonists block glutamate release in the cortex, reduces hallucinations
First Generation Antipsychotics or _____
Typical Antipsychotics
Second Generation Antipsychotics or ___
Atypical Antipsychotics
What are First Generation Antipsychotics effects
Targets D1 and D2 dopamine receptors
Efficacy focuses on D2 receptor antagonism
What are Second Generation Antipsychotics effects
Antagonists for both D2 receptors (dopamine) and 5HT receptors (serotonin)
Lower affinity to dopamine receptors than first gen, produces less dopamine related side effects
Haloperidol
First Generation Antipsychotic
Fast on, Slow off
Chlorpromazine
First Generation Antipsychotic
Clozapine
Second Generation Antipsychotic
Also binds to D4 dopamine receptors, and causes agranulocytosis (loss of white blood cells)
Risperidone
Second Generation Antipsychotic
What is the Therapeutic Margin of Typical Antipsychotics
(Percentage and side effect)
60-80% of D2 receptors need to be occupied to produce antipsychotic effect
80% of D2 occupancy will lead to side effects like extra pyramidal symptoms (movement disorder) and hyperprolactinemia (elevated prolactin)
What is the Therapeutic Margin of Typical Antipsychotics
(Dose-Response Curve)
Has a narrow window between antipsychotic effects and neuroleptic threshold
Curves are both close to each other
What is the Therapeutic Margin of Atypical Antipsychotics
(Percentage and side effect)
Has a wide therapeutic window between antipsychotic effects and neuroleptic threshold
Curves are far apart from each other
What has more receptor rebinding mesolimbic/nigrostriatal pathway or tuberoinfundibular pathway
mesolimbic/nigrostriatal has a high degree of receptor rebinding due to dopamine being in a tight space when it lets go, nowhere for it to go so it rebinds to the receptor
In the tuberoinfundibular pathway blood flow will clear out dopamine
Kinetics of Haloperidol
Fast on, Slow off
High receptor binding potential
High extrapyramidal side effects and increased prolactin release
Kinetics of Chlopromazine
Fast on, Fast off
Fast on = high extrapyramidal effects (High affinity for binding at nigrostriatal and higher rebinding potential)
Fast off = normal prolactin release (Lets go of receptor and is cleared by blood)
Kinetics of Clozapine
Slow on, fast off
Slow on = low extrapyramidal effects (lower rebinding potential)
Fast off = normal prolactin release (Lets go of receptor and is cleared by blood)
What are the side effects of first generation antipsychotics
Extrapyramidal symptoms, dyskinesis, prolactin release
What are the side effects of second generation antipsychotics
Cardiovascular effects, metabolic syndrome, diabetes, weight gain
