Case 8 - neurobiology of schizophrenia Flashcards
what does the ICD 10 define schizophrenia as
a severe and enduring mental disorder, with fundamental and characteristic distortions of thinking and perception, and affects that are inappropriate or blunted. clear consciousness and intellectual capacity are usually maintained although cognitive deficits may evolve in the course of time
what are the positive symptoms
delusions
hallucinations
thought disorder
what are the negative symptoms
flat or blunted affect and emotion
poverty of speech
inability to experience pleasure
lack of desire to form relationships
lack of motivation
what are delusions
a fixed false belief, unshakeable by superior evidence to the contrary and out of keeping with a persons cultural norms
examples of delusions
Examples:
reference
Persecution
Control
Bizarre and impossible
Grandiosity (mania in bipolar disorder)
Hypochondriacal or somatic (various, often depression)
Nihilistic (usually psychotic depression)
Guilt (usually psychotic depression)
what is hallucination
a perception, internally generated in the absence of external stimulus
in any sense modality examples
In any sensory modality:
hearing (auditory)
Vision (visual)
Taste (gustatory)
Smell (olfactory)
Somatosensory (tactile)
Kinaesthetic (body position), temperature, pressure
In schizophrenia, hallucinations are characteristically auditory
ICD 10 diagnostic criteria
At least 1 first-rank symptoms (for at least 1 month):
Thought echo, thought insertion or withdrawal, or thought broadcasting
Delusions of control, influence or passivity, clearly referred to body or limb movements or specific thoughts, actions or sensations
Auditory hallucinations giving a running commentary or discussing the patient between themselves, hallucinatory voice from parts of the body
Persistent delusions that are completely impossible
OR at least 2 second-rank symptoms (at least 1 month):
Other persistent hallucinations in any modality
Thought disorder (neologisms, loosening or breaks in the train of thought resulting in incoherent or irrelevant speech)
Catatonic behaviour (posturing, waxy flexibility, mutism, stupor, catatonic excitement)
Negative symptoms, not due to depression or medications
classification of DA receptors
what are the four dopamine pathways
nigrostrital pathway
mesolimbic pathway
mesocortical pathway
tuberoinfundibulnar pathway
what is the nigrostrital pathway
substantia nigra (A9) —> caudate and putamen
1. SNc —> sensorimotor (dorsal) striatum - motor (involuntary) control. PD 2. SNc —> associative (mild) striatum - cognition, emotion, volition. PD
what is the mesolimbic pathway
ventral tegmental (A10) area in midbrain to limbic regions associated with reward, motivation, affect and memory
Include ventral striatum (nucleus accumbens) amygdala, hippocampus and medial prefrontal cortex
what is the mesocortical pathway
VTA to frontal cortex, including dorsolateral prefrontal cortex (DLPFC)
Cognitive function, motivation and emotional response
what is the tuberoinfundibulnar pathway
puberal region to median eminence
DA acts to inhibit prolactin release from pituitary
what are the 3 functional divisions of the striatum
sensorimotor
Associative: learning, habituation, memory, attention, motivation, emotion and volition. Strong input from DLPFC
Limbic: ventral striatum: reward
what are the DA abnormalities in schizophrenia
Excessive DA release in striatum during acute psychotic episodes
- positively correlated with positive symptoms
- correlated with good treatment response to antipsychotic drugs
Inadequate DA in frontal cortex
- associated with deficits in cognitive function e.g working memory
is DA dysregulation thought to be a primary abnormality
DA dysregulation is not thought to be a primary abnormality. Secondary to a more proximal abnormality, probably in GABA-glutamate interaction.
where is the excessive dopamine release in the striatum
increased synaptic DA concentration is associative striatum in untreated schizophrenic patients
VST DA unaffected overall. But associated with severity of negative symptoms in patients with decreased VST DA
Low dopamine in the mesolimbic pathway may contribute to negative symptoms
when does increased DA develop
DA function elevated on average in people at high risk of developing schizophrenia, though none has yet done so
This elevation approached that seen I patients with established schizophrenia
18F-DOPA uptake is correlated positively with severity of symptoms and negatively with cognitive function
DA abnormalities in ARMS II (case group study)
DA function elevated at baseline in the ARMS subjects who developed schizophrenia
Elevated DA function in associative, not limbic or sensorimotor subdivision
DA function NOT elevated at baseline in non-transition group
within the psychotic transition group: significant positive relationship between DA function and CAARMS and PANSS
No relationship in the non-transition group
pooled data from the 2 studies
associative dopamine raised substantially
Sensorimotor dopamine raised slightly
Ventral/limbic dopamine is normal
The associative and sensorimotor are both the nigrostriatal pathway
what was the result found:
DA synthesis is increased in the nigrostriatal pathway and NOT the mesolimbic pathway as predicted for decades
what are the challenges of the current concept of schizphernia
biomarker for conversion to schizophrenia: PET expensive and 18f-DOPA uptake is unlikely to provide enough specificity and selectivity to play a significant role in treatment decision in UHR patients
How to selectively reduce firing of the nigrostriatal pathway, especially the associative branch? Perhaps not fully antipsychotic but may reduce conversion from ARMS (at risk mental state) and reduce relapse in patients with schizophrenia
What is dysregulating associative striatum DA function? Most likely explanation is abnormal DLPFC function, possibly secondary to abnormal glutamate NMDA receptors affecting GABA and glutamate function
schizophrenia and glutamate relationship
glutamate is the most abundant excitatory neurotransmitter in the CNS
Receptors: NMDA, AMPA, kainate, mGluR1-8
NMDA receptor hypofunction is a model for positive and negative and cognitive symptoms of schizophrenia
Decreases NMDA receptor function:
Glu excitotoxicity leads to impaired neuronal development leads to disease progression
DA dysregulation via Glu-DA interactions
Glu-DA interaction hypothesis
Neurodevelopmentally hypo functional NMDA receptor-mediated synapse with GABA interneurones
GABA release is low and doesn’t adequately suppress cortico-brainstem glutamate outflow
Excessive direct glutamate stimulation of SNc DA Nerone cell bodies leads to increase DA in AST and SMST
Excessive glutamate indirectly (via GABA interneurone) inhibits the mesolimbic and mesocortical DA neurone cell bodies in VTA
Decrease cortical DA release
DA abnormalities summary
psychosis is strongly associated with overactivity of presynaptic DA function (synthesis and synaptic release) in nigrostrital pathway, particularly associative division
opposite of PD
What would we like? To selectively attenuate this pre-synaptically
What do we have? The ability to block the action of the excess DA post synaptically at D2 receptors
cognitive impairment is associated with decrease DA release in PFC
Negative symptoms less well explained by DA, but some evidence they may be worse if DA release is decreased in ventral striatum (i.e mesolyombic pathway)
what is the mechanism of antipsychotic efficacy
all known antipsychotic drugs reduce positive symptoms by blocking true D2 receptors in the associate striatum i.e they are D2 receptor antagonists
Many also block the D3 and D4 receptor and the 5HT2A receptors, but that doesn’t reduce antipsychotic symptoms
what is the threshold of D2R receptor occupancy
antipsychotics are (true) D2 receptor antagonists
Threshold for antipsychotic efficacy >65% D2 receptor occupancy in the associate striatum
antipsychotic efficacy summary
all current antipsychotics are true D2 receptor antagonists
For antipsychotic efficacy, a drug must block more than 65% of D2 receptors in the associative striatum for an adequate proportion of the time
This threshold is the same for all antipsychotics, but the doses needed to achieve it vary widely between drugs
Occupancy >65% does not need to be continuous. Some APs (e.g clozapine and quetiapine) only achieve this intermittently. The optimum duration is not yet known
Other receptor occupancy is unnecessary for efficacy
D2 antagonism adverse effects in nigrostrital pathway: efficacy
antipsychotic efficacy mediated by D2 antagonism in nigrostrital associative pathway
adverse effects in mesolimbic pathway (VST)
excessive D2 blockade leads to worsening of negative symptoms
adverse effects in nigrostrital motor pathway (SMST)
Parkinsonism and other extrapyramidal side effects (EPSE)
adverse effects in mesocortical pathway (DLPFC)
May exacerbate low DA, leading to deterioration in cognitive function
adverse effets in the tuberoinfundibulnar pathway
hyperprolatinaemia secondary to antipsychotics
hyperprolactinamyia
Sexual dysfunction:
diminished libido
Decreased arousal
Orgasmic dysfunction
Breast pathology:
galactorrhoea
Breast enlargement
Slight increased risk of breast cancer
Reproductive dysfunction:
anovulation
Oligomenorrhoea
Amenorrhoea
Subfetility
False pregnancy tests
Hyopgonadism:
decreased bone mineral density
Hip fracture
Miscellaneous:
acne and hirsutism
receptor binding affinities
the further up the line the colour goes that means it has higher binding efficacy
what receptor binding makes them sedative
H1 (histamine)
what are the receptor mediated adverse effects
antipsychotic side effects summary
unwanted high levels of D2 receptor antagonism:
Motor nigrostriatal branch —> Parkinsonism and EPSE
Mesolimbic pathway —> worsening negative symptoms
Mesocortical pathway —> worsening cognitive function
Tuberoinfundibulnar pathway —> raised prolactin
unwanted other receptor antagonism —> a range of side effects including anticholinergic, postural hypotension, cardiotoxicity, sedation and weight gain (know the mechanisms behind these)
It is important that Pharma companies develop antipsychotics with better tolerability and efficacy
diagnosis criteria screenshot
