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Flashcards in lecture 33 Deck (28):

What are mental disorders?

- mental disorders have complex aetilogies that involve interactions among multiple genetic and non-genetic risk factors
- gender is related to risk in many cases:
- males have higher rates of attention deficit hyperactivity disorder, autism, and substance use disroders
- females have higher rates of major depressive disorder, most anxiety disorders, and eating disorders


What are the most significant mental disorders?

- schizophrenia
- bipolar affective disorder
- major depressive disorder
- panic disorder


What are further categories of bipolar affective and major depressive disorder?

- bipolar disorder
- cyclothymia (milder form)
- major (monopolar) depression
- dysthymia (milder form)


What is the definition of a major depressive episode?

A. Five (or more) of the following symptoms have been present during hte same 2-week period and represent a change from previous functioning; at least one of the symptoms is either 1) depressed mood or 2) loss of interest or pleasure

1. depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g. feels sad or empty) or observation made by others (e.g. appears tearful)
note: in children and adolescents, can be irritable mood

2. markedly diminished interest or pleasure in all, or almost all, activities

3. significant weight loss when not dieting or weight gain (>5% of body weight in a month), or decrease or increase in appetite nearly every day

4. insomnia or hypersomnia nearly every day

5. psychomotor agitation or retardation nearly every day

6. fatigue or loss of energy nearly every day

7. feelings of worthlessness or excessive or inappropriate/delusional guilt

8. diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others)

9. recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation


What is a major depressive episode?

- in major depressive disorder affective or mood symptoms include depressed mood and feelings of worthlessness or guilt, cognitive and somatic symptoms but also behavioural symptoms including social withdrawal and agitation


What is manic depression?

- manic episodes greatly elevated mood, creativity, profusion of thought and pressured speech
- may manifest as grandiosity and confidence or anxiety and aggression
- feeling of increased or limitless energy, including reduced need for sleep
- typically highly distractible, irritable, and exhibiting poor judgement
- extremem mania may include disordered (psychotic) thought


What is happening in the brain of people who are depressed?

- abnormally high blood flow abates with resolution of depression, regardless of the treatment (or lack of) associated with remission
- too high when depressed and too low when it goes away
- orbital and medial prefrontal cortex

manic depression
- can be found in people who are highly creative
- e.g. Robert Schumann's musical compositions and manic depressive episodes
- most prolific during periods of hypomania


Who is John Cade?

- a melbourne doctor (and UniMelb graduate) was conducting research in the 1940s on the effects of uric acid when accidentally discovered the mood stabilising effects of lithium on his guinea pigs
- lithium is an extremely effective drug that is still used to treat manic depression / depression


How has monopolar depression been treated?

- electroconvulsive therapy
-- still used today
-- still the most effective for SOME people's depression
- psychotherapy
- antidepressant drugs
-- tricyclics (not so common)
-- SSRIs NERIs (most commonly prescribed)
-- monoamine oxidase inhibitors


Where do drugs interact with neurons?

- drugs that affect the brain and behaviour (other than those affecting its growth or those having a degenerative or neurodegenerative effect) must directly or indirectly affect the excitability of neurons

- interactions with neurotransmission could occur at numerous places in the biochemical pathways related to neurotransmitter synthesis, storage, release, breakdown, re-uptake and postsynaptic receptor interaction


What is the "monoamine hypothesis" of mood disorder?

- point of action seems to be at noradrenaline and serotonin synapses

- tricyclics and reuptake inhibitors act where these chemicals are taken back up into axon terminal
- inhibition of reuptake prolongs neurotransmission - it's like you've released more

- fluoxetine (aka prozac) --> inhibitive action on reuptake allowing more serotonin to persist in synaptic cleft

- monoamine oxidase inhibitors prevent breakdown of serotonin/noradrenaline, second mechanism to maintain concentrations of neurotransmitter in synaptic cleft
- less frequently used

all of these seem to have the function of maintaining concentration of neurotransmitter in synapse


What are antidepressants?

MAO inhibitors
- MAO is the enzyme responsible for the destruction of all monoamines (noradrenaline, dopamine, and serotonin)

MA reuptake inhibitors
- monoamine reuptake (the other mechanism for limiting the action of monoamines at synapses) further supports the idea of impaired monoamine transmission underlying depression

- lithium salts are the third category of drugs used to treat depression, particularly manic depression
- their mode of action is not understood but may modulate phosphoinositol second messengers


What are the diffuse modulatory systems of the CNS?

- the consideration of the site of drug action often implcates the diffuse modulatory systems of the central nervous system
- these are:

1. a nucleus or cluster of nuclei with relatively few neurons (thousands rather than millions)

2. most of the nuclei are in the "central core" of the brain: the brainstem and basal forebrain

3. each neuron can influence many (maybe hundreds of thousands) of neurons elsewhere in the brain – this is called a highly divergent projection

4. the synapses made by these cells are typically "en passant"


What is the serotonergic system?

- cell bodies all in reticular core of brainstem
- raphe nuclei (midline)
- some project down to spinal cord
- some to cerebellum
- huge projection up to just about all areas of the cerebrum: huge target, 100 billion cells innervated by several 100 thousand cells


What is the noradrenaline system?

- main, small nucleus (locus coeruleus) (brainstem)
- few 100 thousand neurons projecting pretty much everywhere


What is the acetylcholine system?

- several nuclei - one in basal forebrain
- from reticular core region, massive projections everywhere


What is the dopaminergic system?

- doesn't project to spinal cord or cerebellum
- really concentrating on two targets: substantia nigra --> basal ganglia projection and VTA to prefrontal cortex projection
- still highly divergent


What do diffuse modulatory systems do?

- don't radically change function of the brain
- part of how the brain works to create subtle changes

- ionotropic neurotransmitter receptor/channel: rapid changes in neuronal excitability --> NOT the function of monoamines

- metabotropic neurotransmitter receptor: more subtle modulation of excitability
- typically bind and activate some biochemical process (typically enzymatic)
- e.g. serotonin binds one of its receptors
- activates via a G-protein cascade a particular enzyme
- that enzyme might do something to a channel, maybe not open it - maybe phosphorylate the channel to alter its dynamics e.g. it stays open longer once bound by its transmitter or activated for a shorter time

or maybe it via g-protin activates an enzyme that initiates a second messenger system to alter cell activity e.g. change the expression of ion channels - small changes on excitability

wide projections but subtle actions


What is schizophrenia?

- class of disorders which are characterised by problems of disorgnisation of thought

- prior to any psychotic episodes people with shizophrenia may exhibit prodromal signs, these may include:
- social withdrawal
- neglect of personal hygiene
- odd ideas and behaviour
- flattened affect and paucity of speech

- these signs are an absence of normal actions and are thus called negative symptoms

non-psychotic signs may include:
- certain tendencies to become overloaded with information
- difficulty in crowded rooms or when lots of people are talking
- easily distracted
- periods of great mental activity and creativity and excitement
- suspiciousness


What are the diagnostic criteria for schizophrenia?

A. characteristic symptoms: two (or more) of the following, each present for a significant portion of time during a 1-month period (or less if successfully treated):
1. delusions
2. hallucinations
3. disorganised speech (e.g. frequent derailment or incoherence)
4. grossly disorganised or catatonic behaviour
5. negative symptoms (i.e. affective flattening, alogia, or avolition)

note: only one criterion A symptom is required if delusions are bizarre or hallucinations consist of a voice keeping up a running commentary on the person's behaviour or thoughts, or two or more voices conversing with each other

B. social/occupational dysfunction: for a significant portion of the time since the onset of the disturbance, one or more major areas of functioning sucha s work, interpersonal relations, or self-care are markedly below the level achieved prior to the onset (or when the onset is in childhood or adolscence, failure to achieve expected level of interpersonal, academic, or occupational achievement)


What characterises acute psychotic episodes of schizophrenia?

- delusions of paranoia and grandiosity and spiritual or supernatural experiences, auditory hallucination, the feeling that they are being controlled by external forces and the misattribution of significance
- paranoia is often associated with psychotic illnesses, sometimes schizophrenia
- the emotional responses of people diagnosed with the Disorganised subtype of schizophrenia can often seem strange or inappropriate to the situation
- inappropriate facial responses may be common and behaviour is sometimes described as 'silly', such as inappropriate laughter
- complete lack of expressed emotion is sometimes seen, as is an apparent indifference, anhedonia (the lack of pleasure), and avolition (a lack of motivation)


What are examples of cognitive problems associated with schizophrenia?

- ruminating thoughts
- racing thoughts
- making up new words (neologisms)
- becoming incoherent or stringing unrelated words together (word salad)
- lack of insight (called anosognosia)
- frequent loose association of thoughts or speech

- directionless - lack goals, or the ability to set and achieve goals
- trouble with social cues: i.e. not being able to interpret body language, eye contact, voice tone, and gestures appropriately
- often not responding appropriately and thus coming off as cold, distant, or detached
- difficulty focusing attention and engaging in goal directed behaviour

- poor concentration/memory
- nonsensical logic

- thoughts, behaviour, and actions are not integrated


Is there a genetic component to schizophrenia?

- yes
- identical twins: 50/50 if your twin has it
- related to the extent to which you share genes with someone who has schizophrenia


What is the cause of schizophrenia?

- totally unknown
- idea that it occurs early in development but manifests later


What is a frequent anatomical correlate of schiziphrenia?

- enlarged ventricles
- not all
- interpretation difficult
- maybe loss of brain matter?
- no other evidence of neurodegenerative component


What is the efficacy of D2 receptor antagonists in the treatment of schizophrenia?

- it's treatment is associated with efficacy of antipsychotic drugs
- chlorpromazine one of the first, still commonly used
- efficacy highly related to their affinity for binding
- perhaps dopamine related function
- the fact that antagonist is effective suggests perphaps it is overstimulation of dopamine
- some people don't respond to this kind of treatment


What are problems with the dopamine hypothesis?

1. dopamine antagonists can be shown to bind to receptors a short time after administration, but relieve of symptoms takes several weeks (as with antidepressants)

2. PCP (angel dust) as a drug that causes psychotic states with similarities to schizophrenia (such as paranoid delusions and auditory hallucinations that control the person) but it acts on a subclass of glutamate receptors not dopamine receptors

3. some people with schizophrenia don't respond to D2 blockers, but to drugs that show broad monoamine antagonism


What is the link between glutamate and schizophrenic symptoms?

- PCP (angel dust), NMDA (glutamate receptor) antagonist, can cause florid psychotic behaviour in some people
- experimental reduction in glutamate receptors causes social withdrawal in mice

- we've underestimated complexity of cause of disease
- e.g. interactions of neurons, which neurons have which receptors etc
- mechanistically assume dopamine is causing excitibility
- maybe affecting neurogenesis?