13 - Psychosis Flashcards
Define psychosis
Mental disorders in which there is a loss of contact with reality, affecting a persons ability to think, feel, act
eg schizophrenia, schizoaffective disorder, substance-induced psychotic disorder etc
What is schizophrenia?
A severe psychotic disorder that is diagnosed if a person has 2+ symptoms for 6 months from the core clusters:
- Positive symptoms
- negative symptoms
- Cognitive symptoms
What are positive symptoms (of schizophrenia)?
Mental phenomena that are absent in healthy individuals (hallucinations and delusions)
What are negative symptoms of schizophrenia?
Loss or impairment of normal psychological function
eg loss of motivation, social withdrawal
ie things that a normal person has that allows normal functioning
What are Cognitive symptoms of schizophrenia?
poor concentration, disorganized thinking, poor memory etc
The risk of schizophrenia is highly influenced by ____
The risk of schizophrenia is highly influenced by genes
What causes schizophrenia?
Ultimately it is not 100% clear but can say that schizophrenia results from the interaction between predisposing genetic factors and a variety of environmental factors that can trigger neurochemical and structural changes
“biology loads the gun, environment pulls the trigger)
What are a few known factors that can contribute to schizophrenia?
- Genes play a huge role (KCNH2, DTNBP1, NRG1, DISC1, RGS4…)
- environmental factors:
- Prenatal:
- infections (influenza during specific developmental window)
- perinatal
- hypoxia (difficult birth)
- Adolescence (weaker evidence)
- drug abuse
- stress/early life trauma
- Prenatal:
Schizophrenia most often manifests in _________
Schizophrenia most often manifests in early adulthood
What is the biochemical theory of schizophrenia?
Based on the knowledge that pts with schizophrenia have shown altered biochemical properties in the brain post-mortem; different levels of neurotransmitters, different levels of receptors, reduced number of neurons that release NTs
-alteration in the biochemistry of the brain (particularly GABA, Dopamine + serotonin, Glutamate) is thought to be linked to schizophrenia
What are the three main Biochemical Theories of Schizophrenia?
Three Theories:
- Dopamine Hypothesis
- Glutamate Hypothesis
- Serotonin (5-HT) Hypothesis
What is the Dopamine Hypothesis?
What is the evidence?
Symptoms of Schizophrenia are due to the hyperactivity of the dopamine system
Evidence:
- Inferential evidence
- 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)
The largest population of dopamine neurons are located in the ______-
The largest population of dopamine neurons are located in the midbrain (ventral tegmental area and substantial nigra)
What is the Mesocortical/mesolimbic system?
Pathway of dopamine neurons located in the ventral tegmental area:
- project to the striatum and the prefrontal cortex
- striatum = reward centre
- prefrontal cortex drives psychotic symptoms
Hyperactivity in the _____________ pathway contributes to psychotic symptoms
Hyperactivity in the Mesocortical/mesolimbic pathway contributes to psychotic symptoms
Blocking dopamine transmission is effective at treating the ______ symptoms of schizophrenia
Positive
What type of receptors are dopamine receptors? What are the two classes?
G-Protein coupled receptors
- D1 and D2
How is the mechanism of action of D1 receptors?
How do antipsychotics affect D1 receptors?
D1 receptors stimulate adenylate cyclase via Gs protein and subsequently activate cAMP-dependent protein kinases
- Although a target for antipsychotic drugs, they are unlikely to contribute to the therapeutic action of many antipsychotics.
What is the mechanism of action of D2 receptors?
How are D2 receptors related to antipsychotic activity?
D2 receptors are G-protein coupled receptors coupled to Gi and inhibit the activity of adenylate cyclase
- blocking D2 receptors is DIRECTLY RELATED to clinical antipsychotic potency
Drugs are not pathway-specific so we must consider other dopamine pathways that could be affected by dopamine inhibitors. What are two such pathways covered in lecture?
- Nigrostriatal system
- dopamine neurons in substantia nigra that project to the striatum
- movement initiation
- inhibition => tardive dyskinesias
- Tuberinfundibular system
- dopamine neurons in the arcuate nucleus that control hormone release in the pituitary
- dopamine here inhibits the secretion of prolactin and GH
- long-term use => hyperprolactinemia
- assoc. w/ amenorrhea, ↓ libido, infertility
- dopamine neurons in the arcuate nucleus that control hormone release in the pituitary
What is the Nigrostriatal system and why might inhibition of this pathway be a problem?
- dopamine neurons in substantia nigra that project to the striatum
- movement initiation
- inhibition => tardive dyskinesias
- involuntary movements of the face and body
What is the Tuberinfundibular system and why might inhibition of this pathway be a problem?
- dopamine neurons in the arcuate nucleus that control hormone release in the pituitary (anterior pituitary aka adenohypophysis)
- dopamine here inhibits the secretion of prolactin and GH
- long-term use => hyperprolactinemia
- increased prolactin release
- assoc. w/ amenorrhea, ↓ libido, infertility
What is the Glutamate hypothesis?
What is the support for this hypothesis?
Current Theory?
- Glutamate hypothesis: symptoms of schizophrenia linked to deficiencies in glutamate signaling particularly in the cortex.
- Support:
- comes from the effects of phencyclidine (PCP) and ketamine
- NMDA antagonists that produce hallucinations and paranoid delusions
- comes from the effects of phencyclidine (PCP) and ketamine
- Current theory:
- schizophrenia is assoc w/ hypofunctional NMDA receptors on GABA interneurons in the cerebral cortex
- hypofunction lead to overactivation of downstream glutamate signaling to the ventral tegmental area (VTA)
- schizophrenia is assoc w/ hypofunctional NMDA receptors on GABA interneurons in the cerebral cortex
What is the current theory stemming from the glutamate hypothesis?
Schizophrenia is associated with hypofunctional receptors on GABA interneurons in the cerebral cortex.
This hypofunction leads to overactivation of downstream glutamate signaling to the ventral tegmental area
- NMDA doesn’t work well in those with schizophrenia = increase release of glutamate = increase activity of dopamine
What is the serotonin hypothesis?
Evidence?
Hypothesis: symptoms of schizophrenia are due to increased serotonin signaling
- Evidence:
- Based on inferential evidence
- some 5HT agonists are hallucinogenic (eg LSD)
- 5HT antagonist improves positive symptoms of schizophrenia
- Post-mortem and in-vivo imaging
- Based on inferential evidence
What is the current theory based on the serotonin hypothesis?
activation of 5HT-2A (subtype of serotonin receptor) receptors in the prefrontal cortex cause hallucinations by enhancing excitation of glutamate neurons (activating mesolimbic dopamine system)
5HT-2A receptors block ________ in the cortex, thus reducing _________
5HT-2A receptors block glutamate release in the cortex, thus reducing hallucinations and other positive symptoms
- drugs that target 5HT-2A cause hallucinations
What are the two major groups of antipsychotics for treating the symptoms of schizophrenia?
- First generation antipsychotics or typical antipsychotics
- Targets both classes of dopamine receptors (D1 and D2) but efficacy particularly relates to D2 Receptor antagonism
- haloperidol, chlorpromazine
- Second Generation Antipsychotics or atypical antipsychotics
- Most are antagonists at both 5HT (serotonin) receptors and D2 receptors
- Lower affinity to dopamine receptors than 1st gen = less dopamine related side effects (have other side effects though)
- eg clozapine, risperidone
Which class of antipsychotics have fewer dopamine related side effects and why?
2nd Generation because they have a lower affinity (looser binding) for dopamine receptors
Between ________% occupation of D2 receptors is required to produce an antipsychotic effect for both typical (1st gen) and atypical (2nd gen) antipsychotics
Between 60-80% occupation of D2 receptors is required to produce an antipsychotic effect for both typical (1st gen) and atypical (2nd gen) antipsychotics
About 80% D2 occupancy results in side effects such as _________, __________ and _________
About 80% D2 occupancy results in side effects such as extra-pyramidal symptoms, hyperprolactinemia and tardive dyskinesia
- Extra-pyramidal symptoms = parkinson-like side effects
- Hyperprolactinemia = elevated prolactin
- Tardive dyskinesia = involuntary movements of face and jaw
What is the term for elevated prolactin?
Hyperprolactinemia
What is the term for parkinson-like side effects
Extra pyramidal symptoms
What is the term for involuntary movements of the face and jaw?
Tardive dyskinesia
At the mesolimbic/nigrostriatal pathway, dopamine is released into the _______ where it binds to receptors on the __________
What does this mean for the kinetic hypothesis for dopamine side effects?
- At the mesolimbic/nigrostriatal pathway, dopamine is released into the synaptic cleft where it binds to receptors on the post-synaptic membrane
What does this mean for the kinetic hypothesis for dopamine side effects?
- Tight squeeze between the pre-synaptic and post-synaptic membrane (in synaptic cleft)
- high degree of receptor rebinding because dopamine hangs around in the synaptic cleft
- Kinetic hypothesis is the relationship between how well a drug binds and dissociates
What is the Kd (equilibrium constant).
What does a low Kd mean?
Ratio of Kon and Koff
- Low Kd = high affinity
- low Koff and high Kon
Tuberinfudibular pathway: Dopamine is secreted into the _____ and carried across the blood brain barrier via the __________ to the _________
- What does this mean for the kinetic hypothesis for dopamine side effects?
Tuberinfudibular pathway: Dopamine is secreted into the blood stream and carried across the blood brain barrier via the hypophysial portal system to the pituitary gland
- What does this mean for the kinetic hypothesis for dopamine side effects?
- high degree of clearance (because released into blood) = less receptor rebinding
What type of side effects would be expected from a fast on, slow off drug?
What is an example of a drug of this type?
Fast on slow off = Low Kd = strong binding
- eg: haloperidol
- Fast on rate results in high receptor binding potential at D2 in both the striatum and pituitary
- high extrapyramidal side effects and increased prolactin release (hyperprolactinemia)
What type of side effects would you expect to see from haloperidol?
- 1st generation (typical) antipsychotic
- Fast on, slow off (high affinity/ strong binding)
- high binding potential at D2 in both the striatum and the pituitary
- LOTS of side effects
- Extrapyramidal
- hyperprolactinemia
What type of side effects would you expect to see from a Fast on fast off antipsychotic? What is an example of this kind of drug?
- Fast on Fast off = high binding high dissociation
- eg chlorpromazine
- Fast on = high extrapyramidal symptoms because even though it’s fast off, dopamine will linger in the cleft where it can rebind
- Fast off = normal prolactin release because high dissociation = cleared quickly from pituitary
What is the mechanism of action of chlorpromazine?
Chlorpromazine blocks post-synaptic D2 dopamine receptors.
It is considered that dopamine receptor blockade in the mesolimbic area accounts for the antipsychotic effect, whilst blockade in the nigrostriatal system produces the extrapyramidal effects associated with chlorpromazine use
What is the mechanism of action of haloperidol?
Haloperidol is a first-generation (typical antipsychotic) which exerts its antipsychotic action by blocking dopamine D2 receptors (ie D2 antagonist) in the brain. When 72% of dopamine receptors are blocked, this drug achieves its maximal effect. [6] Haloperidol is not selective for the D2 receptor
- side effects: high extrapyramidal and hyperprolactinemia
What type of side effects would you expect from a slow on fast off antipsychotic? example?
- Slow on = lower rebinding potential and low extrapyramidal symptoms
- fast off = normal prolactin release
- eg Clozapine
- Wider therapeutic index = better side-effect profile
What is the mechanism of action of clozapine?
The mechanism by which clozapine exerts its effects involves the blocking of 5-HT2A/5-HT2C serotonin receptors and the D1-4 dopamine receptors, with the highest affinity for the D4 dopamine receptor
- affinity for D4 causes serious side effect called agranulocytosis (loss of WBC’s)
What is the mechanism of action of risperidone?
According to the dopamine theory of schizophrenia, the mechanism of action of risperidone might involve a reduction of dopaminergic neurotransmission in the mesolimbic pathway. The higher the risperidone daily dose, the higher the risk of EPS (extrapyramidal symptoms)
Both first and second generation antipsychotics are not ________ and have affinity for multiple other receptors such as ______, ______, _______, ________, ________ etc
Both first and second generation antipsychotics are not receptor specific and have affinity for multiple other receptors such as dopamine, serotonin, adrenergic, GABA, glutamate etc
Closapine has a unique affinity for D4 receptors which leads to a serious side effect called _______
Closapine has a unique affinity for D4 receptors which leads to a serious side effect called agranulocytosis (loss of WBC’s)
-can be fatal
Antipsychotic meds start to work within hours or days (ie dopamine receptor blockade reaches ___% quickly) but can take ______ weeks to reach full effect
Antipsychotic meds start to work within hours or days (ie dopamine receptor blockade reaches 65% quickly) but can take 4-6 weeks to reach full effect
About __% of people with schizophrenia are treatment resistant
What does this mean?
About 30% of people with schizophrenia are treatment resistant
What does this mean?
- do not respond to 2 or more trials with a first line antipsychotic
What are three potential side effects of first generation antipsychotics?
- Extrapyramidal symptoms (EPS)
- Dyskinesias
- Prolactin release (hyperprolactinemia)
What are 4 potential side efffects of second generation antipsychotics?
- Cardiovascular effects
- Metabolic syndrome
- Diabetes
- Weight gain
