- Psychosis is characterized by....................
A distorted or nonexistent sense of reality
Postitive symptom clusters of schizophrenia
Hyperdopaminergic
- Suspiciousness
- Delusions
- Hallucinations
- Conceptual disorganization
Negative symptom clusters of schizophrenia
Hypodopaminergic
- Affective flattening
- Alogia
- Anhedonia
- Avolition
Cognitive symptom clusters of schizophrenia
Impaired attention
Impaired working memory
Impaired executive function
How does neuronal migration contribute to the pathogenesis of schizophrenia
Affects positioning of neurons for local signaling. Abnormal positioning affects signaling
How does synaptogensis contribute to the pathogenesis of schizophrenia
Ability to form synapses is critical for normal neurodevelopment
How does synaptic DA availability contribute to the pathogenesis of schizophrenia
Expression of enzymes that metabolize DA (catechol-O-methyltransferase) can reduce DA availability
How does glutamate and DA neurotransmission contribute to the pathogenesis of schizophrenia
Proper coordination of communication mediated by Glu and DA neurons is critical for normal neurodevelopment
How does neuronal signaling contribute to the pathogenesis of schizophrenia
Higher number of loss of function mutations of SETD1A* gene compared to healthy people
What are effects of expression of loss function mutations of SETD1A gene?
Loss of function leads to development of neurons with fewer than normal spines needed to relay signals compared to the normal neurons
Fewer spines leads to dysfunctional neurons causing loss of cognitive function
Describe role of mesocortical dopamine pathways
Mesocortical Pathway: Cognitive and executive function
Reduced firing of dopaminergic neurons in this pathway leads to which symptom cluster of schizophrenia
Negative symptoms (hypodopaminergic)
Glutamate hypothesis states that increased glutamate activity may contribute to the increased DA release in mesolimbic pathway
True
Which dysfunctions associated with schizophrenia are related to defects in mesolimbic pathway?
Mesolimbic pathway: Regulation of emotional behavior
POSITIVE symptoms: hyperdopaminergic
Haloperidol, fluphenazine, trifluperazine, and thiothixene are associated with higher rates of extra-pyramidal side effects (EPSs), akathisia, hyperprolactinemia and have fewer side effects associated with M1, H1, and α1 effects
True
D2 receptor antagonism by antipsychotic drugs in which DA pathway reduces positive symptoms?
Mesolimbic pathway
D2 receptor antagonism by antipsychotic drugs which DA pathway can result in EPS?
Nigrostriatal pathway
D2 receptor antagonism by typical antipsychotics which DA pathway can increase prolactin levels?
Tuberoinfundibular pathway
D2 receptor antagonism by typical antipsychotics which DA pathway can cause or worsen negative and cognitive symptoms
Mesocortial pathway
Treating a patient with schizophrenia with a dopamine antagonist can successfully treat their positive symptoms by reducing dopamine signaling in the mesolimbic pathway. However, these agents can worsen the negative and cognitive symptoms. Explain why
Because D2 antagonism blocks D2 receptors throughout the brain worsening cognitive symptoms (mesocortical pathway), cause EPS (nigrostriatal), and increase prolactin (tuberoinfundibular)
US Boxed Warning for chlorpromazine is for which adverse effect this drug?
INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
One adverse effect of chlorpromazine is aspiration of vomit. What is the mechanism underlying this adverse effects?
Because chlorpromazine suppresses the cough reflex
Clozapine is an agonist at alpha-adrenergic, histamine H1, cholinergic, and other dopaminergic and serotonergic receptors
False- Antagonist
Why clozapine is available only through a restricted program under a Risk Evaluation Mitigation Strategy (REMS)?
Because of severe risk of neutropenia
Why clozapine should be used with caution in patients with decreased gastrointestinal motility, urinary retention, BPH, xerostomia, or visual problems?
Because it may cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention)
Atypical antipsychotics have been associated with development of hyperglycemia; in some cases, may be extreme and associated with ketoacidosis, hyperosmolar coma, or death.
True
Which antipsychotic agents have higher rates of EPSs, akathisia, hyperprolactinemia
1. Haloperidol
2. Fluphenazine
3. Trifluperazine
4. Thiothixene
Which antipsychotics are 5HT2A and D2 antagonists?
- Asenapine
- Clozapine
- Iloperidone
- Lurasidone
- Olanzapine
- Paliperidone
- Quetiapine/ XR
- Risperidone
- Ziprasidone
Antipsychotic agents are in pregnancy class B or C
True
Actions of antipsychotics agents on which receptors lead to extrapyramidal symptoms?
DA antagonist inhibit receptors in the nigrostriatal pathway leading to excess Ach release leading to the EPS
List the 4 movement disorders that constitute the extrapyramidal side effects of antipsychotics.
- Pseudo parkinsonism
- Acute dystonic reactions
- Akathisia
- Tardive dyskinesia
How does DA regulate Ach release in nigrostriatal pathway? How do antipsychotics change this DA- mediated regulation of Ach release? What are the consequences of altered Ach release in nigrostriatal pathway
- Inhibitory influence on DA neurons in the nigrostriatal pathway(regulate movements) leads to normal Ach release and normal motor activity
- Antipsychotic DA antagonists inhibit the inhibitory influence of DA on Ach leading to excess Ach release increasing EPS
Mania has two poles or extremes, high mood and low mood. A person with mania can experience extreme changes in mood, from high mood (also known as a manic or hypomanic episode) to low mood (also known as a depressive episode).
False- Bipolar disorder
List anticonvulsants and second-generation antipsychotics used in alternative or adjunctive treatments for bipolar disorder
1. Lamotrigine
2. CBZ
List second-generation antipsychotics used in alternative or adjunctive treatments for bipolar disorder
1. Aripiprazole
2. Quetiapine
Inhibition of which enzyme involved in transcriptional regulation results in mood stabilizing effects of Li
GSK-3
How do thiazides and osmotic diuretics affect renal excretion of Li?
- Thiazides: Cause REDUCTIONS in Li+ clearance that result in toxic levels
- Osmotic diuretics: INCREASE renal excretion of Li+
The most common adverse effects of lithium is fine postural hand tremor. How would you minimize it?
- Avoid caffeine and other agents that increase tremor amplitude
- Try a dose reduction
What will you do avoid adverse effects of lithium such as incoordination, ataxia, or slurred speech?
- Dose at bedtime
Which adverse effect of lithium is magnified by concurrent use of antipsychotic drugs?
- Significant weight gain
Describe the mechanism underlying reduced EPSE produced by SGA:
Increasing DA in the nigrostriatal areas
Describe the mechanism underlying reduced negative symptoms produced by SGA:
Improving DA in the prefrontal cortex
Describe the mechanism underlying reduced deptressionproduced by SGA:
Increasing DA in the ventromedial prefrontal cortex
Chlorpromazine use can lead to hypotension. Identify receptors for each of these side effects.
a1-adrenergic antagonism
Which adverse effects are common for chlorpromazine and clozapine?
- Hypotension
- Central and peripheral anticholinergic effects
Which agent has high α1 adrenergic affinity
Chlorpromazine
Which antipsychotics are first-generation medium- and high-potency D2 antagonists?
- Haloperidol
- Fluphenazine
- Chlorpromazine
- Thioridazine
Which antipsychotics are D2 partial agonists
- Aripiprazole
- Brexpiprazole
- Cariprazine
Which antipsychotic agents have a greater risk of causing hypotension
- Chlorpromazine
- Clozapine
- Loxapine
- Thioridazine
- Quetiapine
- Ziprasidone
Which antipsychotic agents have a greater risk of QT interval prolongation; torsade de pointes
- Thiordiazine
- Ziprasidone
Which two enzymes in inositol recycling pathway does Li affect? How do these effects lead to improvement in bipolar disorder?
- IPP
- IMPase
- This leads to reduced IP3 and reduced PKC and Ca2+ signaling, resulting in reduced activity of hyperactive circuits involved in producing mania
Inhibition of which enzyme involved in transcriptional regulation results in mood stabilizing effects of valproate?
- HDACs
Inhibition of which enzyme leads to lithium-induced nephrogenic diabetes insipidus? How can be treated?
- GSK-3
- Amiloride
NSAIDs and ACEi lead to lithium retention? T/F
True