Pyschosis (Midterm II)

Question 1

psychotic disorders

Answer 1

• range of mental disorders that all involved symptoms of psychosis
• includes schizophrenia, schizoaffective disorder, substance-induced psychotic disorder, etc

Question 2

psychosis

Answer 2

mental disorders in which there’s a loss of contact with reality, affecting a person’s ability to think, feel and act

Question 3

schizophrenia

Answer 3

-sever psychotic disorder diagnosed if a person has 2+ symptoms for at least 6 months, from the core clusters (positive, negative and cognitive symptoms)

Question 4

positive symptoms (schizophrenia)

Answer 4

mental phenomena that are absent in healthy individuals
-primarily hallucinations (visual or auditory imaginings of things that don’t exist) and delusions (false understandings or expectations of how the world works (ex believing the devil can communicate with you through your radio)

Question 5

negative symptoms (schizophrenia)

Answer 5

loss or impairment of normal psychological function; generally pertain to mood and affect (ex loss of motivation, social withdrawal, depression, etc)

Question 6

cognitive symptoms (schizophrenia)

Answer 6

poor concentration, inability to focus, disorganized thinking, poor memory, etc

Question 7

schizophrenia: gene-environment interactions

Answer 7

• the risk of schizophrenia is highly influenced by genes
• predisposing genetic factors interact with a wide range of environmental factors (infection, hypoxia, drug abuse, stress, etc) that can trigger neurochemical and structural changes leading to schizophrenia
• people who have those genetic variants are more likely to develop schizophrenia, but it’s just an increased risk, not a one-to-one thing
• individuals aren’t born with it and it most often manifests in early adulthood, which indicates that a combo of genes and precipitating environmental stimuli are involved

Question 8

biochemical theory of schizophrenia

Answer 8

• schizophrenia is a biochemical brain disease, cause by disruption of brain biochemistry from altered neurotransmission
• patients have been seen to have increased DA and 5HT in the brain, as well as reduction of some GABA signaling; drugs that increase levels of DA and 5HT produce schizophrenic-like symptoms

Question 9

NT classes

Answer 9

AAs (Glu, GABA, etc): important for maintaining fundamental brain activity
-ubiquitous; cells that contain these NT as well as cells that express their receptors are expressed abundantly throughout the brain
Monoamines (DA, 5hT, NE): all share a similar structure and play more of a modulatory role in the brain
-receptors for these NTs are expressed widely thr/out the brain, including in the limbic system (wide projections), but cells that express the NTs themselves are located in very discrete regions
peptides (somatostatin, substance P, opioid peptides, etc)
Others: Purines (ATP), gasotransmitters (NO), Ach

Question 10

DA hypothesis of schizophrenia

Answer 10

• symptoms due to hyperactive DA in the mesolimbic pathway
• psychotic symptoms can be developed by drugs that increase synaptic DA (amphs, cocaine, cannabis) in non-schizophrenics if given in sufficiently high doses
• pyshcotic symptoms can be decreased with drugs that block DA receptors
• positive symptoms are mediated by the mesocortical and mesolimbic pathways
• side effects of drugs used to treat psychosis have to do with non specific DA receptor interactions in the nigrostriatal and tuberoinfundibular systems

Question 11

Glutamate hypothesis of schizophrenia

Answer 11

• proposes symptoms of schizophrenia are linked to deficiencies in Glu signaling due to NMDA receptor hypofunction, particularly in the cortex (the disorder is associated with lower than normal release of Glu, as well as fewer receptors in the hippocampus and cortex)
• PCP (phenylcyclidine), a potent NMDAR inhibitor, can induce a syndrome that mimics not only the positive but also the negative symptoms of schizophrenia
• NMDAR co-agonists such as glycine may improve symptoms of schizophrenia

Question 12

serotonin hypothesis of schizophrenia

Answer 12

• suggests symptoms or schizophrenia are due to altered 5HT signialing and cortical 5HT2AR hyperfunction
• based on observation that hallucinogens such as lysergic diethylaminde (LSD) are potent 5HT2AR agonists and that 5HT antagonists (which encompasses many 2nd gen antipsychs) improve positive symptoms
• activation of 5HT2AR in PFC enhances excitation of Glu neurons, causing hallucinations (antagonists therefore block Glu release, reducing hallucinations and other positive symptoms)

Question 13

schizophrenia and the mesocortical / mesolimbic pathway

Answer 13

• the largest pop of DA neurons are in the midbrain (VTA and substantia nigra); the mesocortocal/mesolimbic tracts send DA from the VTA to the striatum and PFC to mediate mem, learning, affect, though organization
• disturbances in these paths contribute to psychotic symptoms and blocking DA transmission is effective for treating positive symptoms

Question 14

schizophrenia and the nigrostriatal system

Answer 14

• involved the DA neurons in the substantia nigra (the same ones that degenerate in PD) that project to the striatum
• these are involved in movement initiation and long term inhibition (with antipsychotic drugs that non-selectively inhibit DA transmission) leads to tardive dyskinesias (involuntary mvmts of the face and body, a side effect that resembles PD)

Question 15

schizophrenia and tuberoinfundibular system

Answer 15

• another DA pathway, the inhibition of which produces some of the side effects associated with non-selective antipsychotics
• involves DA neurons in the arcuate nucleus (a very small pop in the hypothalamus that butt onto the pituitary gland (release of DA here regulates hormone release))
• DA release here inhibits the secretion of prolactin and growth hormone, so sometime long term use of some anti-psychotics is associated with hyperprolactinemia (increased prolactin release leading to amenorrhea, decreases libido, and infertility)

Question 16

DA receptors

Answer 16

-GPCRs; two classes
D1: Gs coupled, stimulate adenylate cyclase and activate cAMP-dependent protein kinases; although they are targetted by many antipsychotics (due to unspecificity), they’re unlikely to contribute to therapeutic action
D2: Gi coupled, inhibiting adenylate cyclase, coupling with numerous other effector systems; blocking D2 receptors is directly related to clinical anti=psychotic potency and is thus the driving force for clinical activity

Question 17

limitations to the biochemical theories of schizophrenia

Answer 17

• no theory adequately explains all symptoms
• antipsychotics take several weeks of continuous exposure to work, despite the fact that their biochemical activity, D2 antagonist, occurs immediately
• psychostimulants like amphetamine increase DA at all doses, but generally only cause psychosis after prolonged use at high doses
• schizophrenic symptoms can be induced by either blocking Glu signaling with an NDMA antagonist OR by stimulating Glu release with a 5HT agonist

Question 18

the two major groups of antipsychotics

Answer 18

first gen/typical: target both D1 and D2 receptors, but efficacy (antipsychotic effects) relate mostly to D2 antagonism examples: haloperidol, chlorpromazine
2nd gen/atypical:
most have affinity for 5HT receptors in addition to D2
-bind looser to DA receptors than the 1st gens and therefore have less DA related side effects
-also generally better at treating negative symptoms
examples: clozapine, risperidone

Question 19

antipsychotics and therapeutic margin

Answer 19

• antipsychotic effects for both typical and atypicals require 60-80% occupation of D2 receptors
• problematically, it’s also around 80% D2 occupancy that we see parkinson like, extra pyramidal symptoms (DA-mediated motor effects), hyperprolactinemia (elevated prolactin) and tardive dyskinesia (involuntary mvmts of face/jaw)
• the 2nd gens have a greater therapeutic margin than the 1sts

Question 20

kinetic hypothesis for antipsychotic side effects

Answer 20

• in the mesolimbic/nigrostriatal pathway, DA is released into the synaptic cleft, where it binds to receptors on the post synaptic membrane; this is a tight squeeze, and even if the compounds dissociate rapidly, proximity allows for a high degree of receptor rebinding
• in the tuberoinfundibular pathway, DA is secreted into the blood stream and carried across the BBB via the hypophysial portal system to the pituitary gland; there is a high degree of clearance and less receptor rebinding
• the kinetic hypothesis accounts for different drugs side effects by considering receptor affinity as well as likelihood of rebinding

Question 21

haloperidol

Answer 21

• a fast on/slow off typical (1st gen) antipsychotic
• it’s quick to bind and has high rebinding potential at D2 receptors in the striatum and pituitary, leading to extrapyramidal motor side effects
• it also binds tightly to receptors; being slow to release means being carried away from the pituitary by blood flow is also less likely and the prolonged binding leads to increased prolactin release (hyperprolactinemia)

Question 22

chlorpomazine

Answer 22

• a fast on/fast off typical (1st gen) antipsychotic
• it binds quickly, but dissociates quickly too; this has little effect in the striatum as it will just rebind D2 due to the synaptic squeeze, leading to high extrapyramidal symptoms, but the quick dissociation means that it can easily be washed away from the pituitary after binding, leaving prolactin levels normal

Question 23

clozapine

Answer 23

• a slow on/fast off atypical (2nd gen) antipsychotic
• slow on rates mean that after binding, there is more time for them to diffuse out of the synapse in the striatum or be broken down as opposed to rebinding D2 receptors
• the fast off rates also mean the drug is washed away from the pituitary by blood flow, leaving prolactin levels normal too
• clozapine also has a unique affinity for D4 receptors though that causes a serious side effect called agranulocytosis (loss of white blood cells which an be deadly for some patients)

Question 24

considerations for pharmacodynamic treatments of schizophrenia

Answer 24

• antipsychotics start to work within hours or days (rapidly reaching ~65% D2 receptor blockade) but can take 4-6 weeks to reach a full effect, suggesting LT adaptation
• also ~30% of schizophrenics are treatment resistant (don’t respond to 2+ trials with first line antipsychs)
• ~50% stop taking antipsychotics bc they can’t tolerate the side effects (extrapyramidal symptoms, dyskinesias and hyperprolactinemia for 1st gens; CV effects, metabolic syndrome, diabetes and weight gain for 2nd gens)
• maintaining plasma levels is also tricky as many drugs, env chemical and foods (cig smoke, grapefruit, etc) will alter them by inhibiting or inducing the liver enzymes involved in its metabolism
• short half lives require continuous drug adherence to see therapeutic effects -some have active metabolites (clozapine -> norclozapine (has sim affinity for D2 and 5HT2A), risperidone->paliperidone (also an antipsych))