Lecture 17- Mental disease I

Question 1

What is the burden of mental disease?

Answer 1

-in terms of years of life lost it is not only 6.8% so not as much -in terms of years lived with disability it is a substantial burden around 20% and increase with age

Question 2

What is the largest health burden?

Answer 2

-brain and mind disorder pose the largest health, economic and social capital burden to Australia of any disease group -this arises because these disorders are chronic and disabling

Question 3

How many people suffer from depression?

Answer 3

-affects approximately 20% of the population at any one time -WHO predicts depression will be the second leading cause of disability by 2020 -~2200 Australians take their own lives every year.

Question 4

Is depression more common in one sex?

Answer 4

-More common in women

Question 5

How many people suffer of Schizophrenia?

Answer 5

Affects ~ 1% of population

Question 6

What is the difference in prevalence of schizophrenia in males vs females?

Answer 6

1.4:1 in males: females -more common in males

Question 7

When is the onset of schizophrenia?

Answer 7

-Early onset: 16 – 25 yrs (males) 25-30 (females)

Question 8

Is schizophrenia curable?

Answer 8

-Life-long illness, no cure – No preventative treatment ‒ Current antipsychotic treatments manage symptoms (but have side effects)

Question 9

What are courses and outcomes of schizophrenia?

Answer 9

Heterogeneous illness ‒ Course and outcome vary ‒ Many possible combinations of symptoms ‒ Different aetiologies? ‒ Single disorder? -maybe a mix of several

Question 10

Are there famous people with schizophrenia?

Answer 10

There are relatively few famous people with schizophrenia because of young age of onset – People this age are too young to be famous – Schizophrenia is very disabling

Question 11

What are the types of depression?

Answer 11

•Major depression – a depressed mood that lasts for at least 2 weeks •Psychotic depression – a depressed mood which includes symptoms of psychosis •Dysthymia – a less severe depressed mood that lasts for years •Mixed depression and anxiety – a combination of symptoms of depression and anxiety •Bipolar disorder (formerly known as manic depressive illness) – involves periods of feeling low (depressed) and high (manic). Silver linnings playbook.

Question 12

What is the definition

Answer 12

-Depression – DSM-IV Diagnostic and Statistical Manual (DSM) For the last 2 weeks have you had: -1. Depressed mood -2. Loss of interest or pleasure -If you answered ‘YES’ to either of these questions, complete the symptom checklist below: -1. Depressed mood most of the day -2. Less interest or pleasure in all activities -3. Weight loss or gain (when not dieting) -4. Sleeping difficulties -5. Slowed or fastened movements -6. Tiredness or loss of energy -7. Feeling worthless -8. Difficulty concentrating -9. Thoughts of death

Question 13

What is Schizophrenia?

Answer 13

• Mental illness characterised by a breakdown of thought processes, perceptions and emotional responsiveness •Greek origin ‘split’ and ‘mind’, but NOT split personality •Symptom categories –Positive symptoms: ‘add’ to a person’s personality –Negative symptoms: take away from a person’s personality –Cognitive impairment

Question 14

What are the positive symptoms of Schizophrenia? (1)

Answer 14

• Hallucinations – Patient hears, sees, smells, tastes or feels something that is not there – Brain registers information as if it is real – Voice keeping up a running commentary on the person’s behaviour or thoughts – Two or more voices conversing with each other

Question 15

What are the positive symptoms of Schizophrenia? (2) and (3)

Answer 15

2. Delusions – A mistaken personal belief – Often bizarre – Usually of persecution, being watched, guilt, grandeur or religious – Hidden messages 3.•Disorganised speech – Speech that is disconnected and illogical, frequent derailment

Question 16

What are the negative symptoms of Schizophrenia?

Answer 16

•Slowness to move, think, react •Avolition - lack of motivation • Lack of insight •Alogia or poor speech •Social withdrawal • Blunted affect - reduced ability to express emotion •Inappropriate responses - e.g. laughing at something distressing •Cognitive impairment –deficits in memory, general intelligence, verbal fluency, processing speed

Question 17

What are the Schizophrenia subtypes?

Answer 17

•1.Paranoid Type – Preoccupation with one or more delusions or frequent auditory hallucinations •2.Disorganised Type – All of the following are prominent: disorganised speech, disorganised behaviour, flat or inappropriate affect •3.Catatonic Type – Motoric immobility as evidenced by catalepsy (including waxy flexibility) or stupor – Excessive motor activity (that is apparently purposeless and not influenced by external stimuli) – Peculiarities of voluntary movement as evidenced by posturing, stereotyped movements, prominent mannerisms, or prominent grimacing •4.Undifferentiated Type – The criteria are not met for the Paranoid, Disorganised or Catatonic Type •5.Residual Type – Absence of prominent delusions, hallucinations, disorganised speech, and grossly disorganised or catatonic behaviour –6.There is continuing evidence of the disturbance, present in an attenuated form (e.g., odd beliefs, unusual perceptual experiences)

Question 18

What is the definition of Schizophrenia?

Answer 18

Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) • Characteristic symptoms (active-phase): 2 or more of the following, each present for a significant portion of time during a 1-month period. At least one of these should include 1-3: 1. Delusions 2. Hallucinations 3. Disorganised speech 4. Grossly abnormal psychomotor behaviour, such as catatonia 5. Negative symptoms • Social/occupational dysfunction: 1 or more major areas of functioning (e.g. work, interpersonal relations, self-care) are markedly below the level achieved prior to the onset. • Duration: Continuous signs of disturbance for >6 months. Must include >1 month of active-phase symptoms and may include periods of prodromal or residual symptoms. – Prodromal periods: only negative symptoms or 2+ active-phase symptoms present in an attenuated form (e.g. odd beliefs, unusual perceptual experiences).

Question 19

What is the causes of mental illness?

Answer 19

•No single mechanism • Genetics ‒ Increases with proportion of shared genetics ‒ Familyhistory • Environment ‒ Neurodevelopment, psychological and social processes • Neurobiology-Neurotransmitters, molecular changes, neuroanatomical anomalies

Question 20

What are the genes involved in depression?

Answer 20

• Monoamine dysfunction • Serotonin transporter (5-HT-T) •Serotonin 2A receptor •Tyrosine hyrdoxylase (dopamine synthesis) •Tryptophan hydroxylase 1 (serotonin synthesis) •Catechol-o-methyltransferase (COMT) (dopamine catabolism) •Neurotrophic factors (like growth factors of the brain) • BDNF -genes associated with monoamine dysfunction

Question 21

Genes vs environment in schizophrenia?

Answer 21

-Twin studies have revealed a strong genetic component (but not 100%) -48% chance if a twin, the more related the higher the chance of getting it -Genainquadruplets- all developed schizophrenia between 22-24 y of age

Question 22

What are the genes involved in schizophrenia?

Answer 22

•Multitude of genes have been implicated in development of schizophrenia: molecular genetics, preclinical studies •Meta-analysis produced a list of 16 genes -(– APOE – COMT – DAO – DRD1, DRD2, DRD4 –DTNBP1 –GABRB2 –GRIN2B- HP - IL1B - MTHFR - PLXNA2 - SLC6A4 -TP53 - TPH1) -mostly to do with dopamine receptors -if have polymorphism in two or more= higher chance of having the illness -•Gene-gene interactions •Gene-environment interactions

Question 23

What is the neurodevelopmental influence in mental illness?

Answer 23

•Mental illness is hypothesized to be due to disorders in neural development • Proliferation • Migration • Axon targeting • Synapse formation •Environmental factors interact with genes in utero or during childhood when brain is still developing •Prenatal influenza, obstetric complications, winter birth, malnutrition, stress, vitamin D deficiency (winter birth= higher chance of schizophrenia= mayb edue to vit D deficiency)

Question 24

What are the later environmental in schizophrenia?

Answer 24

– childhood social difficulties – childhood infections influenza epidemic ␣ schizophrenia – puberty onset (Cycling hormone levels) low estrogen= higher symptoms higher hospitalizations postpartum menstruation – stress: Stress hormones (glucocorticoids) may alter neurodevelopment – illicit drug use Psychostimulants (MDMA /‘ecstacy’ (increase serotonin) amphetamine /‘speed’ (increase dopamine) Hallucinogens (LSD/ ‘acid’, psilocybin/ ‘magic mushrooms’ (serotonin) Marijuana ‘cannabinoid psychosis’

Question 25

What are some other factors involved in schizophrenia?

Answer 25

– Immigrant status: migrant>native born – Urban>rural (more likely in the city) – Male vs female -menopause= second peak of onset for women (due to estrogen level falls)

Question 26

What are the sex differences in schizophrenia?

Answer 26

Gender-different age trends in the severity of psychosis (Lewine et al 1997; Hafner 2003). 1. Men develop severe first episodes at a young age, women milder cases on average. 2. Later in life, severity of first episodes decrease in men but increase in post-menopausal women. • Females who show an earlier onset of functional estrogen secretion with puberty generally show a later onset of schizophrenia. • Estrogen / testosterone. -high levels of estrogen= preventing the onset of schizophrenia???

Question 27

What are the sex differences in depression?

Answer 27

prevalence • incidence Higher in females than in males beginning at mid-puberty and persisting through adult life. -Differences in stress response -Social status of women – less freedom than men? -Biological – hormones interacting estrogen / cortisol -strogen amplifies the cortisol release= explains the bias??

Question 28

What is the two hit hypothesis?

Answer 28

• first get a developmental disruption in the developing brain= creates a more vulnerable brain (first= in development =causes the brain to be vulnerable)
• then late environmental disruptions act on the vulnerable brain and here we go
• Neuropsychiatric illness is caused by at least two developmental “insults” .

Question 29

What is the first hit in the two hit hypothesis?

Answer 29

‒ Prenatal: influenza, malnutrition, stress, vitamin D deficiency ‒ Early postnatal: obstetric complications, head injury, infections

Question 30

What is the second hit in the two hit hypothesis?

Answer 30

– Stress, puberty, substance abuse, head injury

Question 31

What are animal models good for in Psychiatry?

Answer 31

• Provide a way to test new therapeutic treatments • Very difficult: “depressed mouse” or “schizophrenic mouse”doesn’t exist • Use a range of behavioural tests to model various symptoms of the disease

Question 32

What are the behavioural models that are used?

Answer 32

1.Sensorimotor gating – startle reflex :Prepulse inhibition (their startle response is not inhibited upon cue) 2.Motor activity: Open-field behaviour, locomotor activity monitors, turning behaviour 3.Stereotyped behaviour – repetitive: Yawning, grooming 4.Learning and memory: radial arm maze, Y-maze 5.. Anxiety: Elevated plus-maze 6.Depression: Porsolt swim test

Question 33

How did they model the two hit hypothesis in animals?

Answer 33

BDNF = brain derived neurotrophic factor Polymorphism in BDNF gene associated with schizophrenia

Question 34

What was the hypothesis?

Answer 34

We hypothesize that: ␣ the combined effect of two “hits” during development will cause behavioural deficits ␣ one “hit” alone is not sufficient to cause significant alterations to behaviour. ␣ The combined effect of two “hits” during development will alter the neurobiology of the brain.

Question 35

What were the methods?

Answer 35

Groups:

• Non deprived, placebo treated (control)
• Non deprived, cannabis treated (one hit)
• Maternally deprived, placebo treated (one hit)
• Maternally deprived, cannabis treated (two hits) -both males and females!

Question 36

What were the results of experiment 1- sucrose preference test?

Answer 36

-Males two-hit animals drink an equal amount of sugar water compared to normal water indicating anhedonic behaviour (inability to experience pleasure)

Question 37

What were the results of experiment 2 Y maze?

Answer 37

-group 2- BDNF and stress hormone -Short term spatial memory is disrupted in male two-hit animals

Question 38

Can we recover spatial memory deficits?

Answer 38

•Environmental Enrichment •Physical, social, and mental activity may protect memory -yes we can! -when environmental enrichment= reverse the effect

Question 39

What were the results: experiment 3 locomotor activity?

Answer 39

• control and MK-801 treated NMDA receptor antagonist Causes hallucinations
• WT mice show a heightened response to MK-801 following castration. BDNF hets show a heightened response to MK-801 Castration abolishes this effect.
• when testosterone gone= increase in wild, and reverse in the het sham

Question 40

What are the conclusions of the experiment?

Answer 40

• Male two-hit animals show anhedonic behaviour (inability to experience pleasure). •Male two-hit animals show cognitive deficits. •Male two-hit animals show an altered response to pyschostimulant MK-801. •Future Directions •Now that we have a model of anxiety /depression, cognitive deficits and altered hyperlocomotion we can: •1. Study the neurobiology of the brain •2. Test certain drugs using this model (estrogen-based).

Question 41

What is another thing they found?

Answer 41

-Estrogen improves cognition via regulation of Parvalbumin-positive GABAergic interneurons.