Week 10 Flashcards
What is schizophrenia
Schizophrenia ‘divided mind’
Severe psychiatric disorder
Distortion of thoughts and perception also mood
[cognitive impairment]
Affects ~1% population
Clinical features
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
Positive symptoms Type I
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)]
Negative symptoms Type II
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
Aetiology of schizophrenia
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
Dopamine hypothesis of schizophrenia
States that dopaminergic hyperactivity underlies schizophrenia
Evidence in support comes from the effects of a number of dopaminergic agents
Dopamine hypothesis of schizophrenia: evidence
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
Chlorpromazine: the first antipsychotic
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
Typical neuroleptics: chemical classes
Neuroleptic= antischizophrenic= antipsychotic= major tranquilliser
Typical neuroleptics 3 main classes
Phenothiazines eg chlorpromazine, fluphenazine
Butyrophenones eg haloperidol, droperidol
Thioxanthines eg flupenthixol, clopenthixol
Typical neuroleptics: receptor antagonists
‘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
Atypical (second generation) neuroleptics
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%)
Atypical neuroleptics
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
Therapy with antipsychotic drugs
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)
Dopamine pathways and schizophrenia
Mesocortical pathway:
-hypofunction
—negative symptoms. Antagonists dont work as well
Mesolimbic pathway:
-hyperfunction
—positive symptoms. Antagonists help
Positive symptoms respond best to neuroleptics
Side effects of neuroleptic drugs: anti-emetic
Due to dopamine receptor block in the chemoreceptor trigger zone (CTZ)
H1 receptor block also important
Beneficial
Side effects of neuroleptic drugs: endocrine- increased prolactin release
Prolactin (hormone) released by pituitary gland
Release normally inhibited by dopamine
D2 receptor mediated
Neuroleptics block inhibition
-> breast swelling, pain, lactation
Dopamine pathways-motor side effects
Due to blockade of striatal dopamine receptors
Nigrostriatal pathway
Motor side effects of neuroleptic drugs
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
Tardive dyskinesia
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
Side effects of neuroleptic drugs: non-dopaminergic
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
Side effects of atypical neuroleptics
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
Not just D2 receptor block
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)
Problems with the dopamine hypothesis
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
What is emotion
Aka “affect”
Combination of psychological and physiological responses to a stimulus
Normal= range
Individual and population
Disorder
Emotions can be positive or negative
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
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
Papez circuit
Evidence:
-lesions/tumours
—anterior thalamus
—spontaneous laughing/crying
-neocortex
—prefrontal cortex. Phineas gage case
—orbitofrontal cortex and pleasure
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
Amygdala
Temporal lobe
Medial surface
Closely associated with hippocampus
Corticomedial nuclei
Central nuclei
Basolateral nuclei
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
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
Aggression
Many controlling factors
-amygdala
-hypothalamus
Overlap between fear and aggression pathways
Role for amygdala in emotion
Clinical relevance of a dysfunctional amygdala
-anxiety disorders
-PTSD
-depression
-autism
-aggression
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
Lateralisation
Right hemisphere so right amygdala specialised for recognising emotions in others
Both hemispheres don’t work the same
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
Anxiety disorders
An inappropriate or excessive anticipatory manifestation of the fear response often to a stressor
-defensive behaviours
-autonomic reflexes
-corticosteroid secretions
-negative emotions
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
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?
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
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
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
Anxiolytic drugs monoaminergic drugs
Buspirone
Antidepressant drugs
-eg serotonin selective re uptake inhibitors SSRI
-link between anxiety and depression
Major depressive disorder
~20% experience during lifetime
Symptoms
-misery, despair, loss of motivation, appetite, suicidal thoughts
Might not be one neurobiological process
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
Treatment of MDD
Psychotherapy
-Neuroplasticity
Antidepressant drug classes:
Electroconvulsive therapy ECT
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<TCA<MAOI
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)
Mechanism SSRIs
Inhibits reuptake of serotonin so increases intrasynaptic [MA]
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)
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
Do AD drugs work
~30% patients may not respond
Trial and error required
MDD not a single neurobiological entity
Pharmacogenomics? Different neurobiological changes?
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
Future developments
Link MA and neuroendocrine dysfunction
Requires:
-increased understanding of role of
—Neuroplasticity and/or neurogenesis
—BDNF
Non pharmacological and pharmacological interventions
