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Week 10 Flashcards

1
Q

What is schizophrenia

A

Schizophrenia ‘divided mind’
Severe psychiatric disorder
Distortion of thoughts and perception also mood
[cognitive impairment]
Affects ~1% population

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2
Q

Clinical features

A

Onset in adolescence or early adulthood
Males=females
Repeated episodes
Or chronic-> progressive decline
Chronic schizophrenics account for most of the patients in long stay psychiatric hospitals

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3
Q

Positive symptoms Type I

A

Presence of abnormal thoughts and behaviours
-delusions (often paranoid)
-hallucinations (auditory ie hearing voices)
-disorganised speech
-grossly disorganised or catatonic behaviour
-[thought disorder (“inserted” thoughts)]

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4
Q

Negative symptoms Type II

A

Absence of normal responses/behaviours
Reduced expression of emotion
Social withdrawal (avolition)
[cognitive impairment- not currently diagnostic]
Not just one illness, more a spectrum with subtypes
Eg paranoid schizophrenia; catatonic

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5
Q

Aetiology of schizophrenia

A

Strong but not invariable hereditary component
-suggest environment has an impact
Possible factors include:
-slow viral infection
-associated autoimmune process
-poor maternal nutrition
-developmental abnormality (arising from above?)
Genetic predisposition with environmental trigger

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6
Q

Dopamine hypothesis of schizophrenia

A

States that dopaminergic hyperactivity underlies schizophrenia
Evidence in support comes from the effects of a number of dopaminergic agents

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7
Q

Dopamine hypothesis of schizophrenia: evidence

A

Amphetamine abuse (dopamine releasing drug)
Can lead to toxic psychosis, manifesting:
-paranoid delusions
-either visual or auditory hallucinations
-compulsive behaviours
Ie type I like symptoms in non-schizophrenic
Exacerbates symptoms of schizophrenic (type I not type II)
Dopamine D2 receptor agonists-> type I like symptoms (eg apomorphine, bromocriptine)
-also exacerbates patient symptoms (type I not type II)
Too much L-dopa-> type I symptoms
-disappear when dose reduced

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8
Q

Chlorpromazine: the first antipsychotic

A

Originally developed as an antihistamine (Thorazine)
Attenuates positive symptoms without excessive sedation
Part of a group of related drugs termed typical or first generation neuroleptics

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9
Q

Typical neuroleptics: chemical classes

A

Neuroleptic= antischizophrenic= antipsychotic= major tranquilliser
Typical neuroleptics 3 main classes
Phenothiazines eg chlorpromazine, fluphenazine
Butyrophenones eg haloperidol, droperidol
Thioxanthines eg flupenthixol, clopenthixol

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10
Q

Typical neuroleptics: receptor antagonists

A

‘Dirty drugs’ especially phenothiazines
Block a variety of receptor sites
-dopamine (D1 and D2 receptor families)
-ACh (muscarinic)
-histamine H1
-noradrenaline
-5-HT
Antipsychotic activity through dopamine receptor block

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11
Q

Atypical (second generation) neuroleptics

A

Distinction from typical on the basis of:
-different pharmacological profile. Eg higher dopamine receptor selectivity
-fewer motor (extrapyramidal) side effects (EPS)
-more effective against negative symptoms
-more effective against treatment-resistant schizophrenia (TRS) (~30%)

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12
Q

Atypical neuroleptics

A

Sulpiride, amisulpride
-selective dopamine receptor antagonists D2/D3
Clozapine, olanzapine
-multi acting receptor targeted agents MARTAs. Les’s side effects
Risperidone, zotepine, sertindole
-serotonin-dopamine antagonists
Quetiapine:
-Novel type

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13
Q

Therapy with antipsychotic drugs

A

Effective treatment for ~70%
‘Treatment resistant’ group (particularly chronic sufferers)
Typical neuroleptics:
-control positive symptoms
-negative symptoms not so well treated
-side effects problematic
Atypical drugs better for negative symptoms (eg clozapine)
-side effect less marked (eg clozapine)
-some efficacy in TRS (eg clozapine)

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14
Q

Dopamine pathways and schizophrenia

A

Mesocortical pathway:
-hypofunction
—negative symptoms. Antagonists dont work as well
Mesolimbic pathway:
-hyperfunction
—positive symptoms. Antagonists help
Positive symptoms respond best to neuroleptics

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15
Q

Side effects of neuroleptic drugs: anti-emetic

A

Due to dopamine receptor block in the chemoreceptor trigger zone (CTZ)
H1 receptor block also important
Beneficial

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16
Q

Side effects of neuroleptic drugs: endocrine- increased prolactin release

A

Prolactin (hormone) released by pituitary gland
Release normally inhibited by dopamine
D2 receptor mediated
Neuroleptics block inhibition
-> breast swelling, pain, lactation

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17
Q

Dopamine pathways-motor side effects

A

Due to blockade of striatal dopamine receptors
Nigrostriatal pathway

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18
Q

Motor side effects of neuroleptic drugs

A

Due to blockade of dopamine receptor in the striatum
Dystonias
-involuntary movements (face, tongue, neck)
-Parkinsonism: tremor at rest, muscle rigidity, decease mobility
Developed relatively rapidly
Reversible

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19
Q

Tardive dyskinesia

A

Severely disabling motor disturbance
Involuntary movements of face/tongue, limbs and trunk
Slow developing (tardive), chronic treatment
Generally irreversible
Serious side effect
Not produced by all neuroleptics

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20
Q

Side effects of neuroleptic drugs: non-dopaminergic

A

Related to blockade of other receptor sites
Anti-muscarinic effects: dry mouth, constipation, visual disturbances etc
Postural hypotension due to alpha adrenoceptor block
Sedation due to histamine H1 receptors block

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21
Q

Side effects of atypical neuroleptics

A

Better side effect profiles
Mainly due to greater selectivity
Lower incidence of motor disturbances
Increased likelihood of compliance
Ie will continue to take the drugs

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22
Q

Not just D2 receptor block

A

Many neuroleptics block 5-HT2A with similar affinities as D2
MARTAs (clozapine, olanzapine): block D2, D4, 5-HT2A, ACh muscarinic
More effective for treatment of negative symptoms
(Risk of serious side effects with clozapine: agranulocytosis, myocarditis)

23
Q

Problems with the dopamine hypothesis

A

Neuroleptics take weeks to work therefore secondary effects important
Less effective on negative symptoms therefore too simplistic
Dysfunction of dopaminergic system may not be primary cause

24
Q

What is emotion

A

Aka “affect”
Combination of psychological and physiological responses to a stimulus
Normal= range
Individual and population
Disorder
Emotions can be positive or negative

25
Why have emotion
Communication Aids memory Evidence for importance? -motor cortex —expression -other species We don’t have high degree of localisation of emotion in the cortex -network of neurones across various structures that form circuits that underpin our emotional state
26
Linking the limbic system and emotion
Papez circuit 1930s ‘Emotion system’ -expression of emotion. ANS. -awareness Neocortex (awareness) <-> cingulate gyrus -> hippocampus -> hypothalamus (physiological expression) -> anterior thalamic nuclei—> cingulate gyrus
27
Papez circuit
Evidence: -lesions/tumours —anterior thalamus —spontaneous laughing/crying -neocortex —prefrontal cortex. Phineas gage case —orbitofrontal cortex and pleasure
28
Current view
Some elements of the Papez circuit not just involved in emotion -hippocampus —decrease volume in chronic depression Other parts of the brain involved: -amygdala- one in either temporal lobe -important in fear and negative emotions like aggression
29
Amygdala
Temporal lobe Medial surface Closely associated with hippocampus Corticomedial nuclei Central nuclei Basolateral nuclei
30
Role for the amygdala in emotion
Why do we think it is involved? -experimental lesions . Temporal lobectomy in monkeys -Kluver-Bucy syndrome -decreased fear. Range of behavioural abnormalities Human evidence: -urbach-weithe disease -“fearless” inability to recognise emotional facial expressions -TLE- temporal lobe epilepsy. Feeling dread or fear before, involves amygdala Stimulation (humans and animals): -produces a fear response Amygdala important for emotional memory
31
Why do you need emotional memory
Interpretation of sensory input Stimulus -sensory cortex - central nuclei: hypothalamus —ANS -central nuclei: PAG (periaqueductal grey)- freezing behaviour —behavioural response -cortex —emotional experience
32
Aggression
Many controlling factors -amygdala -hypothalamus Overlap between fear and aggression pathways
33
Role for amygdala in emotion
Clinical relevance of a dysfunctional amygdala -anxiety disorders -PTSD -depression -autism -aggression
34
Treating emotional disorders
Can we explain psychiatric disorders-> circuitry dysfunction? Manipulation of the circuitry -psychosurgery -surgery on brain impacts emotional state -eg frontal lobectomy: no effect on intelligence, reduced anxiety/agitation, other behaviours affected. Eg decision making -DBS and depression -drugs to manipulate circuits
35
Lateralisation
Right hemisphere so right amygdala specialised for recognising emotions in others Both hemispheres don’t work the same
36
Mental illness
Human behaviour Highly variable Within and between individuals Biological and cultural factors DSM-5 anxiety disorders -depression and bipolar -disorders of mood or affect Neurological bases -incompletely understood -inferred from mechanisms of useful drug therapies
37
Anxiety disorders
An inappropriate or excessive anticipatory manifestation of the fear response often to a stressor -defensive behaviours -autonomic reflexes -corticosteroid secretions -negative emotions
38
Types of anxiety disorder
Multiple types -general anxiety disorder -somatic and autonomic effects -restlessness/agitation, tachycardia, sweating, sleep disturbance Phobic anxiety Panic disorder DSM IV vs V classification Normal anxiety-> pathological anxiety -what is the relationship with psychological stress -neuroendocrine response Implications of multiple types: -psychopathology the same? -single treatment method
39
Hypothalamic-pituitary-adrenocortical HPA axis
Anxiety disorders: presence of stressor not necessary, HPA overactive in anxiety?. Negative feedback control not as accurate Stressor -> Hypothalamus(paraventricular nucleus)—Corticotropin releasing factor CRF->+anterior pituitary—adrenocorticotropic hormone ACTH—> +adrenal gland —>cortisol negative feedback - hypothalamus Cortex—>amygdala->+ hypothalamus. Cortex—> hippocampus—>-hypothalamus Neuroplasticity?
40
Treatment of anxiety disorders
Self help Psychological Neuroplasticity reversed?Pharmacological -prescribed -self medication: ethanol known anxiolytic reduce anxiety but has problems Diverse: common neurobiology about changing synaptic activity
41
Anxiolytic drugs B-adrenoceptor antagonists
Choice influenced by: nature of predominant symptoms, duration of treatment needed B-adrenoceptor antagonists: -reduced somatic symptoms -used for situational phobias
42
Anxiolytic drugs benzodiazepines
Short term use: -eg diazepam, nitrazepam, midazolam Useful effects: -reduction in anxiety -sleep inducing- hypnotic Mechanism: -GABAa receptor, binds to allosteric site, increase GABA affinity, increase Cl- -in prefrontal cortex, amygdala and other places Problems: -sedation -acute overdose-> profound sedation -> with alcohol, serious respiratory depression Long term use: -tolerance, ‘tissue tolerance’ -dependence. Withdrawal increased anxiety, tremor, seizure, insomnia, depression Therefore short term <4 weeks use
43
Anxiolytic drugs monoaminergic drugs
Buspirone Antidepressant drugs -eg serotonin selective re uptake inhibitors SSRI -link between anxiety and depression
44
Major depressive disorder
~20% experience during lifetime Symptoms -misery, despair, loss of motivation, appetite, suicidal thoughts Might not be one neurobiological process
45
The monoamine theory of depression
“Depression is due to hypo activity at monoaminergic (NA and 5-HT) synapses in brain” Evidence for: -ADs increase MA in brain rapidly Evidence against: -ADs take >1-3 weeks to work
46
Treatment of MDD
Psychotherapy -Neuroplasticity Antidepressant drug classes: Electroconvulsive therapy ECT
47
Antidepressant drug classes
Selective serotonin re uptake inhibitors SSRIs Tricyclic antidepressant TCAs Monoamine oxidase inhibitors MAOIs Newer antidepressants Drug choice? ~efficacy Side effect profiles vary -SSRI
48
Selective serotonin reuptake inhibitors SSRIs
Eg Fluoxetine (Prozac), paroxetine, sertraline, citalopram 5-HT increases all over body. Unwanted effects: -GI and nausea/vomiting -weight changes -suicidal thoughts . Prefrontal cortex thoughts (Serotonin syndrome)
49
Mechanism SSRIs
Inhibits reuptake of serotonin so increases intrasynaptic [MA]
50
Tricyclic antidepressants
Eg amitriptyline pain medication for neuropathic pain, but dose MDD is much higher Mechanism: -5-HT/NA reuptake inhibition Unwanted effects: -anti-muscarinic -sedative (H1 antagonism)
51
Newer drugs
Various uptake/receptor mediated effects for 5-HT, NA, dopamine Melatonin receptor agonism -agomelatine Better adverse effect profile -targeting in brain -but still delay to action
52
Do AD drugs work
~30% patients may not respond Trial and error required MDD not a single neurobiological entity Pharmacogenomics? Different neurobiological changes?
53
New theory- network hypothesis
MDD-> increase [CRF] and [cortisol] Negative feedback blunted Reversed by AD ?hyperactivity/sensitisation of the neuroendocrine stress response-> depression Stress—> anxiety—> depression Network hypothesis chronic stress-> changes Mechanism: -cortisol receptors on hippocampus —decrease glucocorticoid receptors and BDNF (neurotrophic factors) —decrease neurogenesis and Neuroplasticity (change synaptic structure and function) AD -> Increase MA-> increase neurogenesis-> restore neuronal network ?latency to clinical effect
54
Future developments
Link MA and neuroendocrine dysfunction Requires: -increased understanding of role of —Neuroplasticity and/or neurogenesis —BDNF Non pharmacological and pharmacological interventions

BAB (10 decks)

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