Lecture 18- Mental disease II

Question 1

What do the brains of a depressed/ non-depressed and after winning lottery person look like?

Answer 1

-imaged using PET (glucose uptake) -shows that depression is a real physiological issue

Question 2

What are the neuroanatomical changes in depression?

Answer 2

-glucose metabolism is altered, reduced in depressed patients -altered CBF, increased in the amygdala -reduction in is sgACC gray matter volume (particular in bipolar disorder) -different activation in response to positive and negative stimuli, in depressed people reduced response to positive stimuli particularly in the ventral striatum (bilaterally), this is also true of nucleus accumbens

Question 3

What are the neurobiological changes in depression?

Answer 3

1.Alterations to 5-HT (serotonin) signalling 2. Alterations to the HPA (hypothalamo-pituitary axis) =the main axis regulating the stress response 3. Brain Derived Neurotrophic Factor and downstream signalling (growth factors ) 4. Inflammatory cytokines 5. Epigenetics (the ability of the environment to modulate certain genes)

Question 4

What are the alterations to serotonin signalling in depression?

Answer 4

•A deficiency in serotonergic activity increases vulnerability to major depression. •Drugs that enhance serotonergic neurotransmission can be effective in treating depression. •Abnormalities in serotonergic activity could occur at several levels of the serotonin signalling pathway. –11 different receptors (serotonin), some excitatory , some inhibitory (pre and post synaptic, autoreceptors).

Question 5

What are the specific alterations in serotonergic signalling in depression?

Answer 5

1. decrease in serotonin receptors= less serotonin binding to its receptors 2.decrease in tryptophan hydroxylase= less serotonin being synthesized
2. increase in transporter expression and activity= less serotonin binding to to its receptors
3. increase in monoamine oxidases= breakdown of serotonin
   - all of these are possible disruption that can cause depression all of which lead to less serotonin in the synaptic cleft

Question 6

What is acute stress?

Answer 6

-the fight or flight response, enhances immune system, memory, energy replenishment and cardiovascular function

Question 7

What is chronic stress?

Answer 7

-suppresses immune system and memory, promotes bone mineral loss, muscle waning, metabolic syndrome

Question 8

What is the HPA axis?

Answer 8

• hypothalamus-pituitary-adrenal axis
• this controls the stress response
• leads to release of cortisol and adrenaline
• if happens too much= get chronic stress
• too much cortisol is neurotoxic and inflammatory

Question 9

What is the difference in intracellular signal transduction in depressed patients?

Answer 9

• altered protein activity
• postreceptor adaptations: signal transduction and gene expression -the mechanism in depression
• alteration in calcium signaling
• disruption of CREB (bad as it transcribes BDNF and other growth factors)

Question 10

What is the mechanism of altered protein activity- inflammation in depression?

Answer 10

-increase in stress= increase in cortisol= increase in inflammatory cytokines= increase in reactive oxygen species (ROS)= activity of protein kinases -glutathione a possible new drug that could reduce the reactive oxygen species

Question 11

What are epigenetics?

Answer 11

•Potentially heritable information that is not encoded by DNA sequence variation, but can change how the DNA is interpreted. •These mechanisms represent inducible and potentially reversible phenomena that can be modified by environmental factors. •These effects may mediate gene-environment interactions -two main components of the epigenetic code: DNA methylation and histone modification

Question 12

What are the 4 classes of anti-depressants?

Answer 12

1.Monoamine oxidase inhibitors 2.Tri-cyclic antidepressants 3.Selective serotonin re-uptake inhibitors 4.Atypical anti-depressants

Question 13

What are the monoamine oxidase inhibitors?

Answer 13

• inhibit monoamine oxidase A & B, increasing NA, 5HT, in pre-synaptic terminals
• inhibits serotonin breakdown -they don’t break down so released again

Question 14

What are the tri-cyclic antidepressants?

Answer 14

-block re-uptake of NA, 5HT into nerve terminal -block the reuptake so there is more in the synaptic

Question 15

What are the Selective serotonin re-uptake inhibitors?

Answer 15

-increase the extracellular serotonin by inhibiting its reuptake into the pre-synaptic cell, increasing the level of serotonin in the synaptic cleft available to bind to the post-synaptic receptor. Pure SSRIs weak affinity for the noradrenaline and dopamine transporter. -similar but are selective to serotonin

Question 16

What are some atypical anti-depressants?

Answer 16

Prescribed when TCA or SSRI have not worked. Inhibit uptake of NA, 5-HT and DA

Question 17

What is the Porsolt test for antidepressants?

Answer 17

• Behavioural despair/immobility by forced swimming
• a rat, when forced to swim in a stituation from which there is no escape, will, after an initial period of vigorous activity, eventually cease to move altogether making only those movements necessary to keep its head above water….”
• if not depressed= fight to stay afloat for longer

Question 18

What is the efficacy of current anti-depressants?

Answer 18

•Different treatments for different patients •Lag period ~ 4 weeks -May represent time required to desensitize inhibitory 5-HT1A pre- synaptic receptors -May represent time required to increase neurotrophic factors such as BDNF

Question 19

What is electroconvulsive therapy? (ECT)

Answer 19

•Electrical stimulation via electrodes on the head •A general anaesthetic is given first, and then a small electric current is passed between two electrodes placed on the scalp •Effective in depression (at least as good as AD drugs), not psychosis •Quicker efficacy (~ 2 weeks) • Memory loss, confusion • Neurotransmitter mechanisms unknown •Transcranial magnetic stimulation (TMS) – uses electromagnetic induction to induce weak electric currents using a rapidly changing magnetic field -these are used only if antidepressants don’t work

Question 20

What is Deep Brain Stimulation? (DBS)

Answer 20

-Functional neurosurgical procedure -Continuous application of high frequency electrical pulses to an implanted stimulating electrode -Motor disorders: Parkinson’s disease, generalised dystonia, and essential tremor -Neuropsychiatric and other diseases: obsessive compulsive disorder, depression, Tourette’s syndrome, addiction, epilepsy and pain -only if nothing else works -it does seem to be very effective

Question 21

What is the Psychological treatment?

Answer 21

•Cognitive Behaviour Therapy – goal orientated, problem solving •Interpersonal therapy – building interpersonal skills. Interpersonal factors may contribute to psychological problems. •Family therapy – ensure support from the family •Psychodynamic psychotherapy – depth psychology to reveal unconcious content of a persons psyche

Question 22

What is the treatment for Bipolar Depression?

Answer 22

•Lithium: •Dr. John Cade University of Melbourne – lithium as a mood stabilizer •drug of choice in acute manic illness/prophylaxis • narrow therapeutic index- • effective conc 0.5 -1 mM, toxic effects > 1.5 mM (can be very effective in 0.5-1mm, gets toxic above 1.5 mM) • ␣therefore need to monitor plasma levels -Mechanism? • Unclear: effects observed on monoamine release, intracellular signaling and transcription factors.

Question 23

What are the side effects of lithium?

Answer 23

• nausea • tremor •decreased thyroid function •polyuria - decrease in concentrating ability in collecting tubule

Question 24

What is the summary of depression?

Answer 24

• Society burden – 1 in 5 suffer from depression • Symptoms – persistent low mood and lack of interest in pleasurable activity – more than 2 weeks • Causes: gene x environment – genetic polymorphism + significant stress -disruption of: • Neurobiology – HPA axis - disruption to serotonergic signalling - increased cortisol - increased inflammation - intracellular signaling - epigenetic regulation

Question 25

Summary of treatment for depression?

Answer 25

• Antidepressants: MOA inhibitors, tricyclic antidepressants, SSRIs and atypical antidepressants. Increase serotonin and NA. - Electroconvulsive therapy: Electrical stimulation via electrodes on the head - Deep brain stimulation: Continuous application of high frequency electrical pulses to an implanted stimulating electrode - Bipolar depression: lithium

Question 26

What are the neuroanatomical anomalies in schizophrenia?

Answer 26

-Enlarged ventricles, reduced hippocampal and cortical volumes, reduced amygdala volume -but still cannot say if has schizophrenia just by MRI or PET •In twin studies when only one twin had schizophrenia, the ventricles were always enlarged •Suggest loss of grey and or white matter

Question 27

What is the dorsolateral prefrontal cortex?

Answer 27

-serves as the highest cortical area responsible for motor planning, organisation, intellectual function and behaviour. It is the last area of the human brain to fully develop.

Question 28

Is there neuronal loss in schizophrenia?

Answer 28

• Mapped grey matter loss (schizo relative to controls) • Parietal first (visuospatial and associative thinking) • Progressed over 5 y to involve sensorimotor and prefrontal cortex • Not due to medication • A particular type of fast onset schizophrenia -patients with fast onset of schizophrenia -lot of neuronal loss

Question 29

What is the neural activity in schizophrenic brains?

Answer 29

-PET analysis of schizophrenic, contrasting brain between halucinating and non-halucinating states -Highlighted regions are active during hallucinations -Left bias (language?)

Question 30

What was the fMRI like in schizophreniacs during hallucinations?

Answer 30

•fMRI of schizophrenic during auditory hallucinations •Superior temporal lobe (primary auditory cortex) is active (during the hallucination) •The “voice” sounds real

Question 31

What are the three hypotheses about the neurobiology of schizophrenia?

Answer 31

1. Signal transduction hypothesis=Dopamine hypothesis or Serotonin hypothesis 2.Molecular-genetic hypothesis 3.Neural network hypothesis

Question 32

What is the signal transduction hypothesis about?

Answer 32

– basic alterations in neurotransmitter signalling induces schizophrenia-like psychopathology

Question 33

What is the dopamine hypothesis about?

Answer 33

-Excessive activity of dopaminergic neurotransmission – not necessarily a surplus of dopamine itself BUT altered dopamine receptor subtypes. -Drugs that decrease dopaminergic activity are antipsychotic – All typical antipsychotic drugs are D2 receptor antagonists -Drugs that increase dopaminergic activity are psychotomimetic -Dopamine-releasing drugs worsen symptoms in schizophrenia patients

Question 34

What is the serotonin hypothesis about?

Answer 34

•Overactive serotonin system •Post-mortem studies show alterations in central serotonergic activity in schizophrenic patients •Drugs that activate 5-HT2A receptors are psychotomimetic • Role of 5-HT2A/1A and 2C receptors in modulating dopaminergic tone. •Dopamine common pathway. -hallucinations etc= due to dopamine

Question 35

What are some other neurotransmitter systems that are altered in schizophrenia?

Answer 35

•adrenergic receptors – cognitive functioning, agonists used to treat cognitive symptoms. •Acetylcholine - motor function, attention, learning and memory, cholinesterase inhibitors AD. •Muscarinic acetylcholine receptors – M1 receptor, cognitive symptoms, clozapine acts on M1. (in dorsolateral prefrontal cortex= decreased there) subgroup of schiz. patients have the deficit, maybe different symptoms?) •Nicotinic acetylcholine receptors – schizophrenia sufferers smoke more (self medicating ?), improves cognition, ease some side effects. •Glutamatergic system – PCP and ketamine (N-methyl-D-aspartate glutamate receptor antagonist) produce psychotic symptoms, negative symptoms and cognitive dysfunction. - NMDAR, glycine transporter inhibitors, metabotropic glutamate receptors (mGluR). hallucination= positive symptom= gain of sth -negative symptom= when sth is reduced, missing

Question 36

What is the molecular genetic hypothesis?

Answer 36

– strong effects of susceptability genes underlies the pathophysiology of schizophrenia. - COMT (catecholomethytransferase) - DISC1 (disrupted in schizophrenia 1) - BDNF (Brain derived neurotrophic factor) •Design drugs to target these genes and their downstream intracellular pathways. •Individualized treatment strategies.

Question 37

What is the neural network hypothesis?

Answer 37

– schizophrenia results from the strong effects of altered neuronal integration. •Schizophrenia is a neurodevelopmental disorder associated with abnormal connectivity resulting from defects in synaptic prunning and migration of neurons. •Two-hit hypothesis •Early detection

Question 38

What are the types of antipsychotic medication for schizophrenia?

Answer 38

1. Typical 2. Atypical

Question 39

What are the typical antipsychotic medication?

Answer 39

-D2 antagonists, -Typical (1950) • Chlorpromazine (Thorazine) •Haldol (Haloperidol) •Prolixin (Fluphenazine) •Flupentixol (Fluanxol) •Loxapine (Loxapac) -Treat positive symptoms of schizophrenia -deinstitutionalization of worlds mentally ill

Question 40

What are the atypical antipsychotic medication?

Answer 40

-Atypical 1971 -the next generation =also 5-HT2 antagonist -Weak D2 antagonists, potent 5-HT2 antagonists •Clozaril (Clozapine) •Risperdal (Risperidone) •Geodon (Ziprasidone) •Seroquel (Quetiapine) •Zyprexa (Olanzapine) •Abilify (Aripiprazole) -Lack of extra pyramidal side effects Superior for treatment resistant Sz and suicidaility. BUT other side-effects

Question 41

What are the typical drugs and their side effects?

Answer 41

– Chlorpromazine, haloperidol – Potent dopamine D2 antagonists – Have little effect on negative and cognitive symptoms – Extrapyramidal symptoms (EPS), drowsy

Question 42

What are the atypical drugs and their side effects?

Answer 42

–Clozapine, olanzapine, quetiapine, aripiprazole –Weak D2 antagonists, potent 5-HT2 antagonists –Are superior in terms of effectiveness –Seizures, agranulocytosis, weight gain and diabetes

Question 43

What are some questions about the antipsychotic medication?

Answer 43

• Differences in symptom reduction? • Common mechanism: D2 antagonists? • Differences in side effect profile? • Effective only in proportion of patients • new drugs in trials or development ? Acteylcholine, mGluR -antipsychotics= only good for some patients -2/3 of patients go off the drugs= ineffective or can’t handle the side effects

Question 44

What are atypical psychotics in molecular genetic hypothesis?

Answer 44

• Clozapine increases BDNF expression in human serum samples • Risperidone and olanzapine increase COMT expression in the rat frontal cortex, haloperidol and clozapine had no effect. (so if polymorphism in the COMT gene then these drugs to beused) • Risperidone and olanzapine increase DISC-1 expression in the frontal cortex and hippocampus of mice, while haloperidol has no effect. (again if polymorphism= then target) • Screen patients for genetic polymorphisms • Tailor treatment strategies to the individual. -it is really expensive so cannot do on everyone

Question 45

What is the neural network hypothesis preventative treatment? (hypothesis= that schizophrenia is a developmental disease)

Answer 45

•Prodromal phase – 12-18 months prior to first psychotic episode (at risk patients) •Cognitive behavioural therapy (CBT) – strategies to change thinking patterns •CBT used in prodromal phase as preventative •CBT and low dose antipsychotic mediation can prevent conversion to schizophrenia

Question 46

What is the psychological treatment for schizophrenia?

Answer 46

-Psychological treatment -CBT -Family therapy -Case managing (psychologist / social worker) - behavioural and social skills training - accommodation - employment (60% are unemployed)

Question 47

What is schizophrenia summary?

Answer 47

•Breakdown in thinking, perceptions and emotions • Symptoms – Positive: hallucinations, delusions – Negative: flat affect, avolition – Cognitive impairment •Cause unknown – Genes and environment – Neurochemical imbalance: dopamine is common pathway Antipsychotic medications – Target the dopamine system – Modulate genetic disturbances • CBT • Case management