Lecture 18: Pharmacological Interventions for Psychosis Flashcards
What is the definition of the term psychotic disorders?
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
What is psychosis?
refers to mental disorders in which there is a loss of contact with reality, affecting a persons ability to think, feel, and act
What is schizophrenia?
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
What are positive symptoms of schizophrenia?
mental phenomena that are absent in healthy individuals (e.g., hallucinations and delusions)
What are negative symptoms of schizophrenia?
loss or impairment of normal psychological function (e.g., loss of motivation and social withdrawal)
What are cognitive symptoms of schizophrenia?
poor concentration, disorganized thinking, poor memory, etc.
What are the gene and environment interactions in schizophrenia?
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
What are the three biochemical theories of schizophrenia?
dopamine hypothesis
glutamate hypothesis
serotonin (5-HT) hypothesis
What is the dopamine hypothesis of schizophrenia?
symptoms of schizophrenia are due to the hyperactivity of the dopamine system
What evidence is the dopamine hypothesis based on?
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)
Where are dopamine neurons located in the brain?
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)
What is the mesocortical/mesolimbic system?
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
What are dopamine receptors?
dopamine receptors are G-protein coupled receptors
there are two classes of dopamine receptors: D1 and D2
What are D1 receptors?
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
What are D2 receptors?
are coupled to Gi and inhibit the activity of adenylate cyclase
blocking D2 receptors is directly related to clinical anti-psychotic potency
What is the nigrostriatal dopamine system?
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
What is the tuberoinfundibular dopamine system?
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
What is the glutamate hypothesis of schizophrenia?
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
What is the serotonin hypothesis of schizophrenia?
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
What are first generation antipsychotics?
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
What are second generation antipsychotics?
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
What is the therapeutic margin of antipsychotic drugs?
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
How is the mesolimbic/nigrostriatal pathway involved in the kinetic hypothesis for side effects of antipsychotics?
dopamine is released into synaptic cleft, where it binds to receptors on the post synaptic membrane
tight squeeze!
high degree of receptor rebinding
How is the tuberoinfundibular pathway involved in the kinetic hypothesis for side effects of antipsychotics?
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
What are fast on, slow off compounds?
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)
What are fast on, fast off compounds?
e.g. chlorpromazine
the fast on rate leads to high extrapyramidal symptoms
fats off rates results in prolactin release staying normal
What are slow on, fast off compounds?
e.g. clozapine
slow on rates resulting lower re-binding potential and low extrapyramidal symptoms
fast off rates result in prolactin release staying normal
How does receptor occupancy contributing to therapeutic and side effects?
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
What are the considerations of pharmacodynamic treatment to schizophrenia?
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
What are the main side effects of first generation antipsychotics?
extrapyramidal symptoms
dyskinesias
prolactin release
What are the main side effects of second generation antipsychotics?
cardiovascular effects
metabolic syndrome
diabetes
weight gain
