8 - schizophrenia and its neurobiology Flashcards
what is the ICD-10 definition of schizophrenia?
“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 intellectually capacity are usually maintained, although cognitive deficits may evolve in the course of time”
what is schizophrenia accompanied by?
high levels of social dysfunction, inability to maintain employment, depression, and suicide
what are the main 3 symptom domains?
- positive symptoms (psychosis)
- negative (deficit) symptoms
- cognitive impairments
what are the positive symptoms?
PSYCHOSIS
presence of experiences that are additional to what a person is usually like
- delusions (= abnormal beliefs)
- hallucinations (= abnormal sensory experiences — mainly auditory)
- thought disorder (loosening of associations between thoughts - difficult to follow in talking — incoherent speech)
another name for thought disorder?
derailment or knights move thinking
what is word salad?
thought disorder — incoherent speech — can become completely incoherent and speak gibberish
describe negative (deficit) symptoms
- flat or blunted affect (moods) and emotion
- poverty of speech (alogia)
- inability to experience pleasure (anhedonia)
- lack of desire to form relationships (asociality)
- lack of motivation (avolition)
-ve symptoms disproportionately contribute to the functional impairment and poor psychosocial outcomes
describe cognitive impairments
- particularly memory (esp working memory) and executive functions (learning, planning, mental flexibility and impulse control)
what is a delusion?
a fixed, false belief, unshakeable by superior evidence to the contrary, and out of keeping with a person’s cultural norms
what are examples of delusions and which are often seen in schizophrenia?
often seen in schz:
- 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 a reference delusion?
believe that everyday events or coincidences have a strong personal significance and refer to them
eg. believe people on street are following and talking about them
what is a persecution delusion?
believe others are out to kill/harm them
what is a control delusion?
believe their thoughts/feelings/impulses/behaviour are under the control of other people or an external force
what is a nihilistic delusion?
believe they no longer exist, a part of their body is missing, or the world itself has ceased to exist
what is a guilt delusion?
belief of being guilty or worthy of punishment
what delusions are not uncommon, esp in the elderly?
nihilistic and guilt
in what type of delusion does someone belief they have a disease or some abnormality in their body?
hypochondriacal or somatic
what is a hallucination?
a perception, internally generated, in the absence of an external stimulus
in any sensory modality:
- hearing (auditory)
- vision (visual)
- taste (gustatory)
- smell (olfactory)
- somatosensory (tactile)
- kinaesthetic (body position), temperature, pressure
what are hallucinations characteristically in schizophrenia?
auditory
how is schizophrenia diagnosed?
at least 1 first rank symptoms for at least 1 month or at least 2 second rank symptoms for at least 1 month
what are the first rank symptoms?
- thought echo (hearing thoughts as an auditory hallucination), thought insertion (not all your thoughts are your own and some have been put there by some other agency), thought withdrawal (some thoughts are being taken out of your head by an external agency), thought broadcasting (thoughts no longer private and can be known/read/heard by others, sometimes over a great distance)
- 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 voices from parts of the body
- persistent delusions that are completely impossible
what are 2nd rank symptoms?
- 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 (behaviour intended to mislead or impress), waxy flexibility (decreased response to stimuli and a tendency to remain in an immobile posture), mutism, stupor, catatonic excitement)
- negative symptoms, not due to depression or medications
what is another name for the SNc?
A9 group of cells
describe the nigrostriatal pathway
from SNc (in midbrain) to the caudate nucleus and putamen (striatum)
what are the 2 subdivisions of the nigrostriatal pathway?
- sensorimotor subdivision — involved in involuntary motor control
- associative subdivision — involved in associative functions, which include learning, habituation, memory, attention, motivation, emotion, and volition
(degeneration in PD occurs in both divisions)
describe the mesolimbic pathway
ventral tegmental area (midbrain) to limbic regions associated with reward, motivation, affect and memory
areas include ventral striatum (nucleus acumbens), amygdala, hippocampus and medial prefrontal cortex
another name from ventral tegmental area (VTA?
A10 nucleus of cell bodies
what projects from the A10 (VTA)?
mesolimbic and mesocortical pathways
describe the mesocortical pathway
VTA to frontal cortex, including dorsolateral prefrontal cortex (DLPFC)
- cognitive function, motivation and emotional response
describe the tuberoinfundibular pathway
a short projection from the tuberal region (of hypothalamus) to median eminence (infundibular region at top of pituitary stalk)
what is the normal acton of DA in the tuberoinfundibular pathway?
to inhibit the release of prolactin from the anterior pituitary
what pathway does each number refer to?
1 = nigrostriatal
2 = mesolimbic
3 = mesocortical
4 = tuberoinfundibular
what are the 3 functional divisions of the striatum?
- sensorimotor — straddles the DORSAL parts of caudate and putamen. function is involuntary motor control
- associative — learning, habituation, motivation, memory, attention, emotion and volition
- limbic — ventral striatum. reward
which subdividision of the striatum receives strong input from DLPFC?
associative
the SNc runs to what divisions of the striatum in the nigrostriatal pathway?
associative and sensorimotor
what are the caudate and putamen separated by?
internal capsule
what does the ventral striatum contain?
nucleus accumbens
what pathway projects to the ventral striatum from the midbrain?
mesolimbic (from VTA)
where is the greatest conc of D1 and D2 receptors found?
striatum
what are the DA receptor subtypes?
D1 RECEPTOR FAMILY
- D1 (true)
- D5
D2 RECEPTOR FAMILY
- D2 (true) — long and short
- D3
- D4
what DA receptors are found in all 3 functional striatum subdivisions?
true D1 and true D2
long vs short true D2 receptors
long = postsynaptic
short = presynaptic
what is D3 predominantly?
limbic
D2-like receptors in the frontal cortex are mainly what?
D4
all known antipsychotic drugs have their antipsychotic efficacy by blocking what?
the postsynaptic true D2 receptor
in addition to the post-synaptic D1 to 5 receptors, ________ on the terminals in the midbrain regulate _______
- presynaptic D2 short and D3 autoreceptors
- dopamine release and synthesis
where are D5 receptors found?
hippocampus and hypothalamus
where are D3 receptors mainly found?
ventral striatum and associative striatum
mainly limbic
what are the 2 principle DA abnormalities in schizophrenia?
- excessive DA release in striatum during acute psychotic episodes
- inadequate DA in frontal cortex (more constant)
what is excessive DA release in striatum in acute psychotic episodes correlated with?
- positively correlated with positive symptoms
- more DA = higher severity of psychosis
- correlated with good treatment response to antipsychotic drugs
what is inadequate DA in frontal cortex associated with?
deficits in cognitive function eg. working memory
the less dopamine in the frontal cortex = worse cognitive impairment
what is DA dysregulation in schizophrenia thought to be secondary to?
a more proximal abnormality, probably in GABA-Glu interaction (specifically hypofunction of the NMDA Glu receptor)
untreated schizophrenics show an increase in synaptic DA conc in what part of the striatum? what part is unaffected overall?
- associative
- ventral striatum DA unaffected overall
patients with a low dopamine in what area have the worst negative symptoms?
ventral striatum
therefore there is a theory that the cause of -ve symptoms may be due to a decrease in DA in the mesolimbic pathway
what is “at risk mental state” - ARMS?
the clinical presentation of those considered at high risk of developing psychosis or schizophrenia
eg. odd, mild symptoms
- 20-30% transition to schizophrenia in next few years
in ARMS, 18F-DOPA uptake is correlated with what?
- positively correlated with severity of symptoms
- negatively correlated with cognitive function
DA function in ARMS?
- elevated at baseline in the ARMS subjects who developed schizophrenia
- DA function not elevated at baseline in non-transition group
what does 18F-DOPA uptake provide an index of?
presynaptic DA function in striatum
where was the elevated DA function seen in the ARMS subjects who developed schizophrenia?
in associative, not limbic or sensorimotor subdivisions
what causes psychosis?
an increase in DA synthesis and release in the nigrostriatal pathway
what is DA like in mesolimbic pathway in schizophrenia?
normal
the significant increase is in the associate subdivision
what glu receptors are there?
NMDA, AMPA, kainate, mGluR1-8 (metatropic)
what does NDMAR hypofunction lead to?
- Glu neurons release excess Glu at their terminals
- overstimulation of neuronal systems where `glu neurons synapse onto (inc DA system) and dysregulates them and causes long-term damage and disease progressing through glu excitotoxicity
—> glu excitotoxicity —> impaired neuronal development —> disease progression
—> DA dysregualtion by glu-DA interactions
As neurodevelopment proceeds the NMDA receptor hypofunction manifests as a range of _____ and _____ deficits, and contributes to ______ symptoms. It also has the knock- on effect of dysregulating the dopamine system to cause _____ synthesis and release in the _______ pathway (which causes _______ symptoms) and ______ dopamine release in the prefrontal cortex (which causes the deficits of working memory and other executive functions)
As neurodevelopment proceeds the NMDA receptor hypofunction manifests as a range of sensory and cognitive deficits, and contributes to negative symptoms. It also has the knock- on effect of dysregulating the dopamine system to cause excessive synthesis and release in the nigrostriatal pathway (which causes positive symptoms) and inadequate dopamine release in the prefrontal cortex (which causes the deficits of working memory and other executive functions)
explain the Glu-DA interaction hypothesis
- neurodevelopmentally hypofunctional NMDA receptor-mediated synapse with GABA interneurones
- GABA release is low and doesnt adequately suppress cortico-brainstem glutamate outflow
- excessive direct glutamate stimulation of SNc DA neuron cell bodies leads to increased DA in associative striatum and sensorimotor striatum
- excessive glutamate indirectly (via GABA interneuron) inhibits mesolimbic and mesocortical DA neuron cell bodies in VTA
- decreased cortical DA release
glu pathway from DLPFC is mainly to where? effect?
mainly to cell bodies of associative branch of nigrostriatal pathway
therefore excessive DA release is mainly in associative striatum
psychosis is strongly associated with overactivity of ____ DA function (synthesis and synaptic release) in ____ pathway, particularly _____ division
- presynaptic DA function
- nigrostriatal pathway
- associative divison
what is cognitive impairment associated with?
decreased DA release in PFC (in particular the DLPFC)
negative symptoms are less well explained by DA, but some evidence they may be worse if DA release is deceased in ______?
ventral striatum ie. mesolimbic pathway
how do all known antipsychotic drugs reduce positive symptoms?
by blocking true D2 receptors in the associative striatum (ie. they are D2 receptor antagonists)
(many also block the D3 and D4 receptor, and 5-HT2A receptors, but that doesn’t reduce antipsychotic symptoms)
what is the threshold for antipsychotic efficacy?
> 65% D2 receptor occupancy in the associative striatum
what are the adverse effects of D2 blockage at termination of nigrostriatal motor pathway in sensorimotor striatum?
parkinsonism and other extrapyramidal side effects (EPSE)
what are the adverse effects of D2 blockage at termination of mesocortical pathway in DLPFC?
may exacerbate low DA, leading to deterioration in cognitive function
what are the adverse effects of D2 blockage at top of pituitary stalk (tuberoinfundibular pathway)?
hyperprolactinaemia secondary to antipsychotics
why are patients’ serum prolactin levels routinely measured via blood tests when taking antipsychotics?
Most of the adverse effects of D2 blockade are clinically obvious fairly quickly. The exception is hyperprolactinaemia. People often can have raised serum prolactin without side effects becoming clinically apparent for some time, therefore they’re measured routinely
what can hyperprolactinaemia cause?
- sexual dysfunction
- breath pathology
- reproductive dysfunction
- hypogonadism
- acne and hirsutism (excessive growth of coarse black here like in males)
DA, prolactin and FSH?
DA is inversely proportional to prolactin
— decrease in DA —> increase in prolactin
prolactin is inversely proportional to FSH
— increase in prolactin —> decrease in FSH
this leads to reproductive dysfunction
Hyperprolactinaemia is usually _________, and the usual management is to _____ the dose of the antipsychotic if possible (though that’s not always possible), change to an antipsychotic with a lower risk of hyperprolactinaemia such as ____ or ______. Or to add in a small dose of _____ to the existing antipsychotic, as _____ actually ____ prolactin levels
Hyperprolactinaemia is usually dose-dependent, and the usual management is to reduce the dose of the antipsychotic if possible (though that’s not always possible), change to an antipsychotic with a lower risk of hyperprolactinaemia such as quetiapine or aripiprazole. Or to add in a small dose of aripiprazole to the existing antipsychotic, as aripiprazole actually lowers prolactin levels
whcih drugs have a particularly high D2 receptor affinity and are particularly prone to giving the adverse effects associated with unwanted D2 receptor blockade?
haloperidol and risperidone
______, _____ and _____ have quite a high histamine H1 affinity and this makes them ______
clozapine, olazapine and quetiapine
sedative
which have quite a high affinity at the muscarinic receptor, giving them antimuscarinic side effects?
olanzapine and clozapine
haloperidol and risperidone have quite high affinity where?
one or both of the noradrenergic receptors
where else do many of the drugs have a high affinity?
at the 5-HT2A or 2C receptors
what are the M1 antagonism ‘anti cholinergic’ side effects
- dry mouth
- sore throat
- blurred near vision
- tachycardia
- urinary retention
- abuse potential
- acute confusion in overdose
what are the a-adrenergic antagonism side effects?
- orthostatic hypontesion and reflex tachycardia
- small pupils
cardio toxicity side effects causes
- delayed conduction
- M1 antagonism and a-adrenergic antagonism
sedation side effects causes
H1 antagonism and a adrenergic antagonism
weight gain causes
most evidence for H1, 5-HT2A/C, ACh M3 adrenergic a1,a2 antagonism
effects on leptins
more receptors blocked = more weight gain
summarise the major side effects of antipsychotics
where is DA elevated?
presynaptic neurons in nigrostriatal pathway
