Lecture 18: Pharmacological Interventions for Psychosis

Question 1

What is the definition of the term psychotic disorders?

Answer 1

the term “psychotic disorders” is used to describe a range of mental disorders that all involve symptoms of psychosis

includes: schizophrenia, schizoaffective disorder (manic depression), substance-induced psychotic disorder

Question 2

What is psychosis?

Answer 2

refers to mental disorders in which there is a loss of contact with reality, affecting a persons ability to think, feel, and act

Question 3

What is schizophrenia?

Answer 3

schizophrenia is a severe psychotic disorder that is diagnosed if a person has 2 or more symptoms for 6 months, from the core clusters: positive, negative, and cognitive symptoms

Question 4

What are positive symptoms of schizophrenia?

Answer 4

mental phenomena that are absent in healthy individuals (e.g., hallucinations and delusions)

Question 5

What are negative symptoms of schizophrenia?

Answer 5

loss or impairment of normal psychological function (e.g., loss of motivation and social withdrawal)

Question 6

What are cognitive symptoms of schizophrenia?

Answer 6

poor concentration, disorganized thinking, poor memory, etc.

Question 7

What are the gene and environment interactions in schizophrenia?

Answer 7

the risk of schizophrenia is highly influenced by genes

predisposing genetic factors interact with a wide range of environmental factors that can trigger neurochemical and structural changes leading to schizophrenia

most often manifests in early adulthood

Question 8

What are the three biochemical theories of schizophrenia?

Answer 8

dopamine hypothesis

glutamate hypothesis

serotonin (5-HT) hypothesis

Question 9

What is the dopamine hypothesis of schizophrenia?

Answer 9

symptoms of schizophrenia are due to the hyperactivity of the dopamine system

Question 10

What evidence is the dopamine hypothesis based on?

Answer 10

that drugs that increase synaptic dopamine (amphetamine, cocaine, cannabis) can cause delusions and hallucinations at high doses

drugs that block dopamine receptors are effective antipsychotics (First Generation Antipsychotics)

Question 11

Where are dopamine neurons located in the brain?

Answer 11

dopamine neurons are located in a few discrete brain regions

the largest population of dopamine neurons are located in the midbrain (ventral segmental area and substantial nigra)

Question 12

What is the mesocortical/mesolimbic system?

Answer 12

dopamine neurons located in the ventral tegmental area project to the striatum and the prefrontal cortex

mediate memory, learning, affect and thought organization

hyperactivity in this pathway contribute to psychotic symptoms

blocking dopamine transmission is effective at treating the positive symptoms of schizophrenia

Question 13

What are dopamine receptors?

Answer 13

dopamine receptors are G-protein coupled receptors

there are two classes of dopamine receptors: D1 and D2

Question 14

What are D1 receptors?

Answer 14

stimulate adenylate cyclase via Gs protein and subsequently activate cAMP-dependent protein kinases

although they are a target for antipsychotic drugs, they are unlikely to contribute to the therapeutic action of many anti-psychotics

Question 15

What are D2 receptors?

Answer 15

are coupled to Gi and inhibit the activity of adenylate cyclase

blocking D2 receptors is directly related to clinical anti-psychotic potency

Question 16

What is the nigrostriatal dopamine system?

Answer 16

dopamine neurons in the substantia nigra that project to the striatum

involved in movement initiation

inhibiting this pathway is involved in the production of extrapyramidal symptoms (movement disorders), including tardive dyskinesias (involuntary movements of the face and mouth) after long-term use of some antipsychotics

Question 17

What is the tuberoinfundibular dopamine system?

Answer 17

dopamine neurons in the arcuate nucleus that control hormone release in the pituitary

dopamine released here inhibits the secretion of prolactin and growth hormone

long-term use of some anti-psychotics is associated with hyperprolactinemia (increased prolactin release)

associated with amenorrhea, decreased libido, and infertility

Question 18

What is the glutamate hypothesis of schizophrenia?

Answer 18

symptoms of schizophrenia linked to deficiencies in glutamate signaling, particularly in the cortex

support comes from the effects of phencyclidine (PCP/Angel dust) and ketamine which are NMDA antagonists that produce hallucinations and paranoid delusions

current theory is that schizophrenia associated with hypofunctional NMDA receptors on GABA interneurons in the cerebral cortex; this hypofunction leads to overactivation of downstream glutamate signaling to the ventral tegmental area

Question 19

What is the serotonin hypothesis of schizophrenia?

Answer 19

symptoms of schizophrenia due to increased serotonin signaling

also based on inferential evidence: some 5HT agonists are hallucinogenic (e.g. LSD), 5HT antagonist improves positive symptoms of schizophrenia

current theory is that activation of 5HT-2A receptors in the prefrontal cortex cause hallucinations by enhancing excitation of glutamate neurons (activating the mesolimbic dopamine system)

5HT-2A antagonists block glutamate release in the cortex, thus reducing hallucinations and other positive symptoms

Question 20

What are first generation antipsychotics?

Answer 20

also known as typical antipsychotics

targets both classes of dopamine receptors (D1 and D2), but efficacy particularly relates to D2 receptor antagonism

e.g., Haloperidol, chlorpromazine

Question 21

What are second generation antipsychotics?

Answer 21

also known as atypical antipsychotics

most are antagonists at both 5HT receptors and D2 receptors

because they bind looser (lower affinity) to dopamine receptors than first generation antipsychotics they produce less dopamine related side effects (they have other side effects, though)

e.g., clozapine, risperidone

Question 22

What is the therapeutic margin of antipsychotic drugs?

Answer 22

between 60-80% occupation of D2 receptors is required to produce an antipsychotic effect for both typical and atypical antipsychotics

about 80% of D2 receptor occupancy results in side effects such as Parkinson-like side effects (called extra pyramidal symptoms and can include tardive dyskinesias which is involuntary movements of the face and jaw), elevated prolactin (hyperprolactinemia)

second generation (aka atypical) antipsychotics are associated with less dopamine-related side effects

Question 23

How is the mesolimbic/nigrostriatal pathway involved in the kinetic hypothesis for side effects of antipsychotics?

Answer 23

dopamine is released into synaptic cleft, where it binds to receptors on the post synaptic membrane

tight squeeze!

high degree of receptor rebinding

Question 24

How is the tuberoinfundibular pathway involved in the kinetic hypothesis for side effects of antipsychotics?

Answer 24

dopamine secreted into the blood stream and carried across the blood brain barrier via the hypophysial portal system to the pituitary gland

high degree of clearance, less receptor rebinding

Question 25

What are fast on, slow off compounds?

Answer 25

e.g. haloperidol

the fast on rate results in a high receptor binding potential at D2 in the striatum and pituitary

therefore high extrapyramidal side effects and increased prolactin release (hyperprolactinemia)

Question 26

What are fast on, fast off compounds?

Answer 26

e.g. chlorpromazine

the fast on rate leads to high extrapyramidal symptoms

fats off rates results in prolactin release staying normal

Question 27

What are slow on, fast off compounds?

Answer 27

e.g. clozapine

slow on rates resulting lower re-binding potential and low extrapyramidal symptoms

fast off rates result in prolactin release staying normal

Question 28

How does receptor occupancy contributing to therapeutic and side effects?

Answer 28

both first and second generation antipsychotics will have varying affinity for multiple other receptors (dopamine, serotonin, adrenergic, GABA, glutamate)

this can cause many problematic side effects

clozapine has unique affinity for dopamine D4 receptors (among others), and causes serious side effect called agranulocytosis (loss of white blood cells)

clozapine is no longer a first line therapy for schizophrenia

Question 29

What are the considerations of pharmacodynamic treatment to schizophrenia?

Answer 29

antipsychotic medications start to work within hours or days (i.e. dopamine receptor blockage reaches 65% quickly) but can take 4-6 weeks to reach their full effect

similar to depression, about 30% of people with schizophrenia are treatment resistant (i.e. do not respond to 2 or more trials with a first line antipsychotic)

about 50% or more people taking antipsychotic medication cannot tolerate the side effects so stope taking it

Question 30

What are the main side effects of first generation antipsychotics?

Answer 30

extrapyramidal symptoms
dyskinesias
prolactin release

Question 31

What are the main side effects of second generation antipsychotics?

Answer 31

cardiovascular effects
metabolic syndrome
diabetes
weight gain