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PBL SEM 3 > 8 - schizophrenia and its neurobiology > Flashcards

8 - schizophrenia and its neurobiology Flashcards

1
Q

what is the ICD-10 definition of schizophrenia?

A

“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”

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2
Q

what is schizophrenia accompanied by?

A

high levels of social dysfunction, inability to maintain employment, depression, and suicide

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3
Q

what are the main 3 symptom domains?

A
  • positive symptoms (psychosis)
  • negative (deficit) symptoms
  • cognitive impairments
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4
Q

what are the positive symptoms?

A

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)
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5
Q

another name for thought disorder?

A

derailment or knights move thinking

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6
Q

what is word salad?

A

thought disorder — incoherent speech — can become completely incoherent and speak gibberish

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7
Q

describe negative (deficit) symptoms

A
  • 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

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8
Q

describe cognitive impairments

A
  • particularly memory (esp working memory) and executive functions (learning, planning, mental flexibility and impulse control)
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9
Q

what is a delusion?

A

a fixed, false belief, unshakeable by superior evidence to the contrary, and out of keeping with a person’s cultural norms

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10
Q

what are examples of delusions and which are often seen in schizophrenia?

A

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)
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11
Q

what is a reference delusion?

A

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

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12
Q

what is a persecution delusion?

A

believe others are out to kill/harm them

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13
Q

what is a control delusion?

A

believe their thoughts/feelings/impulses/behaviour are under the control of other people or an external force

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14
Q

what is a nihilistic delusion?

A

believe they no longer exist, a part of their body is missing, or the world itself has ceased to exist

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15
Q

what is a guilt delusion?

A

belief of being guilty or worthy of punishment

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16
Q

what delusions are not uncommon, esp in the elderly?

A

nihilistic and guilt

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17
Q

in what type of delusion does someone belief they have a disease or some abnormality in their body?

A

hypochondriacal or somatic

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18
Q

what is a hallucination?

A

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

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19
Q

what are hallucinations characteristically in schizophrenia?

A

auditory

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20
Q

how is schizophrenia diagnosed?

A

at least 1 first rank symptoms for at least 1 month or at least 2 second rank symptoms for at least 1 month

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21
Q

what are the first rank symptoms?

A
  1. 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)
  2. delusions of control, influence or passivity, clearly referred to body or limb movements or specific thoughts, actions or sensations
  3. auditory hallucinations giving a running commentary or discussing the patient between themselves, hallucinatory voices from parts of the body
  4. persistent delusions that are completely impossible
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22
Q

what are 2nd rank symptoms?

A
  1. other persistent hallucinations in any modality
  2. thought disorder (neologisms, loosening or breaks in the train of thought resulting in incoherent or irrelevant speech)
  3. 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)
  4. negative symptoms, not due to depression or medications
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23
Q

what is another name for the SNc?

A

A9 group of cells

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24
Q

describe the nigrostriatal pathway

A

from SNc (in midbrain) to the caudate nucleus and putamen (striatum)

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25
Q

what are the 2 subdivisions of the nigrostriatal pathway?

A
  • 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)

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26
Q

describe the mesolimbic pathway

A

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

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27
Q

another name from ventral tegmental area (VTA?

A

A10 nucleus of cell bodies

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28
Q

what projects from the A10 (VTA)?

A

mesolimbic and mesocortical pathways

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29
Q

describe the mesocortical pathway

A

VTA to frontal cortex, including dorsolateral prefrontal cortex (DLPFC)

  • cognitive function, motivation and emotional response
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30
Q

describe the tuberoinfundibular pathway

A

a short projection from the tuberal region (of hypothalamus) to median eminence (infundibular region at top of pituitary stalk)

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31
Q

what is the normal acton of DA in the tuberoinfundibular pathway?

A

to inhibit the release of prolactin from the anterior pituitary

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32
Q

what pathway does each number refer to?

A

1 = nigrostriatal
2 = mesolimbic
3 = mesocortical
4 = tuberoinfundibular

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33
Q

what are the 3 functional divisions of the striatum?

A
  • 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
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34
Q

which subdividision of the striatum receives strong input from DLPFC?

A

associative

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35
Q

the SNc runs to what divisions of the striatum in the nigrostriatal pathway?

A

associative and sensorimotor

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36
Q

what are the caudate and putamen separated by?

A

internal capsule

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37
Q

what does the ventral striatum contain?

A

nucleus accumbens

38
Q

what pathway projects to the ventral striatum from the midbrain?

A

mesolimbic (from VTA)

39
Q

where is the greatest conc of D1 and D2 receptors found?

A

striatum

40
Q

what are the DA receptor subtypes?

A

D1 RECEPTOR FAMILY
- D1 (true)
- D5

D2 RECEPTOR FAMILY
- D2 (true) — long and short
- D3
- D4

41
Q

what DA receptors are found in all 3 functional striatum subdivisions?

A

true D1 and true D2

42
Q

long vs short true D2 receptors

A

long = postsynaptic

short = presynaptic

43
Q

what is D3 predominantly?

A

limbic

44
Q

D2-like receptors in the frontal cortex are mainly what?

A

D4

45
Q

all known antipsychotic drugs have their antipsychotic efficacy by blocking what?

A

the postsynaptic true D2 receptor

46
Q

in addition to the post-synaptic D1 to 5 receptors, ________ on the terminals in the midbrain regulate _______

A
  • presynaptic D2 short and D3 autoreceptors
  • dopamine release and synthesis
47
Q

where are D5 receptors found?

A

hippocampus and hypothalamus

48
Q

where are D3 receptors mainly found?

A

ventral striatum and associative striatum

mainly limbic

49
Q

what are the 2 principle DA abnormalities in schizophrenia?

A
  1. excessive DA release in striatum during acute psychotic episodes
  2. inadequate DA in frontal cortex (more constant)
50
Q

what is excessive DA release in striatum in acute psychotic episodes correlated with?

A
  • positively correlated with positive symptoms
  • more DA = higher severity of psychosis
  • correlated with good treatment response to antipsychotic drugs
51
Q

what is inadequate DA in frontal cortex associated with?

A

deficits in cognitive function eg. working memory

the less dopamine in the frontal cortex = worse cognitive impairment

52
Q

what is DA dysregulation in schizophrenia thought to be secondary to?

A

a more proximal abnormality, probably in GABA-Glu interaction (specifically hypofunction of the NMDA Glu receptor)

53
Q

untreated schizophrenics show an increase in synaptic DA conc in what part of the striatum? what part is unaffected overall?

A
  • associative
  • ventral striatum DA unaffected overall
54
Q

patients with a low dopamine in what area have the worst negative symptoms?

A

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

55
Q

what is “at risk mental state” - ARMS?

A

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

56
Q

in ARMS, 18F-DOPA uptake is correlated with what?

A
  • positively correlated with severity of symptoms
  • negatively correlated with cognitive function
57
Q

DA function in ARMS?

A
  • elevated at baseline in the ARMS subjects who developed schizophrenia
  • DA function not elevated at baseline in non-transition group
58
Q

what does 18F-DOPA uptake provide an index of?

A

presynaptic DA function in striatum

59
Q

where was the elevated DA function seen in the ARMS subjects who developed schizophrenia?

A

in associative, not limbic or sensorimotor subdivisions

60
Q

what causes psychosis?

A

an increase in DA synthesis and release in the nigrostriatal pathway

61
Q

what is DA like in mesolimbic pathway in schizophrenia?

A

normal

the significant increase is in the associate subdivision

62
Q

what glu receptors are there?

A

NMDA, AMPA, kainate, mGluR1-8 (metatropic)

63
Q

what does NDMAR hypofunction lead to?

A
  • 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

64
Q

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)

A

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)

65
Q

explain the Glu-DA interaction hypothesis

A
  1. neurodevelopmentally hypofunctional NMDA receptor-mediated synapse with GABA interneurones
  2. GABA release is low and doesnt adequately suppress cortico-brainstem glutamate outflow
  3. excessive direct glutamate stimulation of SNc DA neuron cell bodies leads to increased DA in associative striatum and sensorimotor striatum
  4. excessive glutamate indirectly (via GABA interneuron) inhibits mesolimbic and mesocortical DA neuron cell bodies in VTA
  5. decreased cortical DA release
66
Q

glu pathway from DLPFC is mainly to where? effect?

A

mainly to cell bodies of associative branch of nigrostriatal pathway

therefore excessive DA release is mainly in associative striatum

67
Q

psychosis is strongly associated with overactivity of ____ DA function (synthesis and synaptic release) in ____ pathway, particularly _____ division

A
  • presynaptic DA function
  • nigrostriatal pathway
  • associative divison
68
Q

what is cognitive impairment associated with?

A

decreased DA release in PFC (in particular the DLPFC)

69
Q

negative symptoms are less well explained by DA, but some evidence they may be worse if DA release is deceased in ______?

A

ventral striatum ie. mesolimbic pathway

70
Q

how do all known antipsychotic drugs reduce positive symptoms?

A

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)

71
Q

what is the threshold for antipsychotic efficacy?

A

> 65% D2 receptor occupancy in the associative striatum

72
Q

what are the adverse effects of D2 blockage at termination of nigrostriatal motor pathway in sensorimotor striatum?

A

parkinsonism and other extrapyramidal side effects (EPSE)

73
Q

what are the adverse effects of D2 blockage at termination of mesocortical pathway in DLPFC?

A

may exacerbate low DA, leading to deterioration in cognitive function

74
Q

what are the adverse effects of D2 blockage at top of pituitary stalk (tuberoinfundibular pathway)?

A

hyperprolactinaemia secondary to antipsychotics

75
Q

why are patients’ serum prolactin levels routinely measured via blood tests when taking antipsychotics?

A

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

76
Q

what can hyperprolactinaemia cause?

A
  • sexual dysfunction
  • breath pathology
  • reproductive dysfunction
  • hypogonadism
  • acne and hirsutism (excessive growth of coarse black here like in males)
77
Q

DA, prolactin and FSH?

A

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

78
Q

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

A

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

79
Q

whcih drugs have a particularly high D2 receptor affinity and are particularly prone to giving the adverse effects associated with unwanted D2 receptor blockade?

A

haloperidol and risperidone

80
Q

______, _____ and _____ have quite a high histamine H1 affinity and this makes them ______

A

clozapine, olazapine and quetiapine

sedative

81
Q

which have quite a high affinity at the muscarinic receptor, giving them antimuscarinic side effects?

A

olanzapine and clozapine

82
Q

haloperidol and risperidone have quite high affinity where?

A

one or both of the noradrenergic receptors

83
Q

where else do many of the drugs have a high affinity?

A

at the 5-HT2A or 2C receptors

84
Q

what are the M1 antagonism ‘anti cholinergic’ side effects

A
  • dry mouth
  • sore throat
  • blurred near vision
  • tachycardia
  • urinary retention
  • abuse potential
  • acute confusion in overdose
85
Q

what are the a-adrenergic antagonism side effects?

A
  • orthostatic hypontesion and reflex tachycardia
  • small pupils
86
Q

cardio toxicity side effects causes

A
  • delayed conduction
  • M1 antagonism and a-adrenergic antagonism
87
Q

sedation side effects causes

A

H1 antagonism and a adrenergic antagonism

88
Q

weight gain causes

A

most evidence for H1, 5-HT2A/C, ACh M3 adrenergic a1,a2 antagonism

effects on leptins

more receptors blocked = more weight gain

89
Q

summarise the major side effects of antipsychotics

A
90
Q

where is DA elevated?

A

presynaptic neurons in nigrostriatal pathway

PBL SEM 3 (49 decks)

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