25. Psychiatric Disorders and Psychopharmacology (HT) Flashcards

Question

Summarise the symptoms of depression.

Answer 1

* Unipolar depression * Bipolar depression -\> Features extreme mood swings from periods of mania to periods of depression

Answer 2

* Tricyclic antidepressants (TCA) * Monoamine oxidase inhibitors (MAOI) * Selective serotonin reuptake inhibitors (SSRI) * Selective serotonin and noradrenaline reuptake inhibitors (SNRI) * Atypical antidepressants * Lithium and other mood stabilisers * New antidepressant treatments (ketamine, psilocybin)

Answer 3

Non-selectively inhibit the reuptake of monoamines, such as 5-HT and noradrenaline.

Answer 4

Amitriptyline [IMPORTANT]

Answer 5

Treating neuropathic pain.

Answer 6

* Sedation (H1 receptors) * Dry mouth, constipation (m3 receptors) * Cardiotoxic * Toxic in overdose -\> This is dangerous in cases of deliberate overdose These effects occur largely because the tricyclic antidepressants are not selective for just the monoamines.

Answer 7

Inhibit the metabolism of monoamines, including 5-HT and noradrenaline.

Answer 8

* Isoniazid (no longer prescribed) [IMPORTANT] * Phenelzine [IMPORTANT] * Moclobemide (MAO A) * Selegiline (MAO B)

Answer 9

* MAO-A inhibition (e.g. moclobemide) leads to increases in noradrenaline and 5-HT, so it is better for use in treating depression * MAO-B inhibition (e.g. selegiline) leads to increases in dopamine, so it is better for use in treating Parkinson's

Answer 10

* Drug interactions -\> Inhibitors are often metabolised by cytochrome P450, which means that there may be reciprocal interactions with other drugs * Cheese reaction (tyramine accumulation) -\> Tyramine is found in various foods, such as cheese, and is also usually metabolised by MAO. If it is not metabolised, it leads to NA release, which can cause hypertension.

Answer 11

Selectively inhibit the reuptake of 5-HT.

Answer 12

* No, they are ineffective in certain patients. * Studies are looking at the biological differences between drug responders and non-responders to understand what could underlie this. * There have been some studies that suggest that SSRIs increase the risk of suicide, perhaps by increasing the motivation of the individual sufficiently to commit suicide. However, these studies have been largely dismissed.

Answer 13

Tricyclic antidepressant are not selective in their inhibition of reuptake of neurotransmitters, while SSRIs are. (CHECK IF THIS IS THE MAIN DIFFERENCE)

Answer 14

* Fluoxetine (Prozac) [IMPORTANT] * Paroxetine (Seroxat)

Answer 15

* Insomnia * GI disturbance * Sexual dysfunction * Withdrawal effects (emerging evidence) These can occur despite the SSRIs being selective.

Answer 16

Treating anxiety.

Answer 17

* It is used mostly in bipolar depression as a mood stabiliser (prophylactically) * It is thought to act by inhibiting the IP₃ pathway that may be overactive in bipolar disoder

Answer 18

* Narrow therapeutic index * Thirst, diarrhoea, tremor * Renal damage There is also poor compliance due to the side effects.

Answer 19

* Carbamazepine [IMPORTANT] * Valproate [IMPORTANT]

Answer 20

(Singh, 2013): * Studied ebselen, which is a lithium mimetic with fewer side effects thamn lithium * More recent small-scale clinical trials show that it has promise in treating the manic symptoms of bipolar

Answer 21

The idea that depression is due to a deficit in monoamine transmission (Schildkraut, 1965).

Answer 22

* Increased neurogenesis (neuron synthesis) is one form of neural plasticity induced by antidepressant treatment (Santarelli, 2003) * New theories suggest that depression may be linked to a failure in neural plasticity, which is increased by antidepressants. * Thus, this argues against the monoamine hypothesis of depression.

Answer 23

Venlafaxine [IMPORTANT]

Answer 24

Positive symptoms (acute): * Disordered thinking * Hallucinations * Persecutory ideas * Delusions Negative symptoms (chronic): * Social withdrawal * Poverty of speech * Cognitive deficits * Emotional blunting

Answer 25

* It is thought to be a developmental disorder, based on histological post-mortem findings * This is also supported by the prodromal state, which is the idea that schizophrenia is marked by other behavioural changes during childhood before it is diagnosed during adolescence/early adulthood * Thirdly, adverse early life events are a risk factor

Answer 26

Drugs used to relieve the symptoms of schizophrenia.

Answer 27

* Typical antipsychotic drugs (1st generation) * Atypical antipsychotic drugs (2nd generation)

Answer 28

* Typical antipsychotic drugs (1st generation) * Haloperidol [IMPORTANT] * Chlorpromazine [IMPORTANT] * Atypical antipsychotic drugs (2nd generation) * Clozapine [IMPORTANT] * Risperidone * Aripiprazole

Answer 29

They inhibit D2 dopamine receptors at synapses.

Answer 30

* Increased prolactinn secretion * Parkinsonian-like motor deficits * Increased weight gain * Tardive dyskinesia

Answer 31

* Involuntary movements of the face and upper limbs * This can be use to the use of dopamine antagonists, for example as antipsychotics in treatment of schizophrenia

Answer 32

(Seeman, 1976): * The potency of an antipsychotic drug is directly proportional to its affinity for dopamine receptors

Answer 33

The different antipsychotics have different pharmacological profiles and act on various other receptors, which may explain their different efficacies and side effects.

Answer 34

The idea that schizophrenia symptoms are due to a hyperactive DA system (Carlsson, 1963).

Answer 35

* Imaging studies are evidence for the dopamine hypothesis of schizophrenia * They show that there is increased dopamine signalling in the striatum in individuals with schizophrenia * (Laurelle, 1999) used a radioligand for D2 receptors, which loaded up the dopamine receptors in the brain. They then gave a dose of a dopamine-releasing drug (e.g. amphetamine), which causes the radioligand to be displaced from the receptor. This is a measure of dopamine release. Compared to control, the schizophrenics have much higher displacement (at least in the striatm), which is evidence for the greater dopamine signalling in schizophrenics.

Answer 36

The dopamine theory of schizophrenia is not the only theory. There are also alternative neurotransmitter theories (e.g. glutamate, GABA, 5-HT).

Answer 37

* Recreational drug use * 2.7 million adults use an illegal drug each year * 24% of 15 year-olds have tried drugs at least once * 294,000 heroin and crack users * 40% of prisoners have used heroin * Drug misuse damages health * Psychiatric disorder * Cardiovascular disease * Liver and lung damage * Overdose and drug poisoning * Families and communities * 1.2 million families affected by drug addiction * Alcohol misuse linked to ~50% of domestic violence and marital breakdown * Annual cost of drug addiction * Total cost to society £15.4bn (crime, loss of productivity, NHS) * A typical heroin user spends around £1,400 per month on drugs.

Answer 38

* Recreational drugs are psychotropic drugs with a diverse range of pharmacological targets * Some drugs used recreationally have important therapeutic uses (eg. pain relief from morphine) * Not all psychotropic drugs are used recreationally (eg. antidepressants and antipsychotics) * Prolonged use of many (but not all) recreational drugs leads to dependence and compulsive drug-seeking behaviour (drug addiction).

Answer 39

Drug addiction becomes problematic when: 1. It dominates lifestyle to damage quality of life 2. The habit causes harm to drug-user and society

Answer 40

(Nutt, 2010): * Blue shows the harm to user * Red shows the harm to others

Answer 41

The dependence liability is a good predictor of the harm caused by various drugs.

Answer 42

* Rate at which drugs reach the brain * How pleasurable the drug is (positive reinforcement)

Answer 43

* Positive reinforcement can be measured in animals by spontaneous self administration. * Pressing of lever results in drug administration via indwelling cannula. * If the drug has reinforcing properties then lever pressing increases.

Answer 44

A decrease in pharmacological effect on repeated administration of the drug.

Answer 45

A state in which drug-taking becomes compulsive, taking precedence over other needs.

Answer 46

Stopping drug intake results in unpleasant physical and psychological effects (negative reinforcement).

Answer 47

* Positive reinforcement (euphoria) * Negative reinforcement (avoidance of withdrawal) * Environment (behavioural conditioning) * Genes

Answer 48

These processes reflect compensatory neuroadaptive changes associated with continued presence of the drug.

Answer 49

* Examples * Morphine [IMPORTANT] * Heroin * Fentanyl * Molecular effects * µ opiate receptors are inhibitory (Gi ) * µ opiate receptors inhibit transmitter release & neuronal excitability * Behavioural effects * Intense euphoria * Strong sense of tranquillity * Drowsiness, slowed movement * High dependence liability linked to high mortality

Answer 50

* Acute morphine inhibits adenylate cyclase and reduces cAMP levels. * Over time, continued morphine use results in return of cAMP levels due to increased expression of adenylate cyclase. * Removal of morphine results in rebound increase in cAMP. The mechanism of tolerance in other drugs may be different to that in morphine.

Answer 51

* Yawning * Pupillary dilation * Hyperthermia * Sweating * Piloerection * Nausea and diarrhoea * High anxiety * Insomnia

Answer 52

* Precipitated by opiate antagonist (naloxone) * Relieved by opiate agonist (methadone)

Answer 53

* Many recreational drugs activate the mesolimbic dopamine pathway, which is a reward pathway * This means that drug use leads to aberrant positive reinforcement, leading to addiction

Answer 54

Mesolimbic pathway: * Ventral tegmental area (VTA) sends dopaminergic outputs to the nucleus accumbens (NA) (part of the striatum) * The dopamine binds to D2 (inhibitory) receptors, leading to reduced nucleus accumbens neuron firing, which is an indicator of reward * Thus, there is aberrant positive reinforcement that leads to addiction

Answer 55

* Morphine binds to inhibitory μ-opioid receptors on GABAergic neurons in the ventral tegmental area (VTA) * This leads to disinhibition of mesolimbic dopaminergic output from the VTA to the nucleus accumbens * Thus there is increased dopamine release in the nucleus accumbens, leading to decreased nucleus accumbens firing, which is a marker of reward

Answer 56

* Intra-VTA morphine increases lever pressing * Morphine increases DA cell firing in VTA and DA release in nucleus accumbens * DA antagonists block morphine-induced lever pressing

Answer 57

* Examples * Amphetamine * Cocaine * Mephedrone * Cathinone (Khat leaves) * Nicotine [IMPORTANT] * Molecular effects * They increase dopamine signalling: * Cocaine, mephedrone, cathinone -\> Inhibit dopamine reuptake * Amphetamines, nicotine -\> Increase dopamine release * Behavioural effects * Euphoria * Increased wakefulness * Reduced fatigue * Decreased appetite Methylxanthines are also psychostimulants, but we consider them seperately.

Answer 58

* Anorectic (fenfluramine - withdrawn) * ADHD (amphetamine, ritalin) * Substitution therapy (nicotine)

Answer 59

* Examples * Caffeine * Theophylline * Molecular effects * Increase overall dopamine signalling by either: * Inhibiting the degradation of cAMP downstream of D1 receptors * Block adenosine A_2A receptors, which usually counteract D2 receptor action * Behavioural effects * Increased wakefulness * Reduced fatigue * Decreased appetite * Weak reinforcing effects and not euphoric

Answer 60

(Volkow, 2004): * Cocaine addicts show fewer D2 receptors in the mesolimbic dopamine pathway -\> This may explain why look for drugs like cocaine to supplement this * Brain glucose metabolism is another marker of neuronal activity and it shows that in addicts there are deficits in: * Orbitofrontal cortex -\> May explain loss of awareness of drug habit * Cingulate gyrus -\> May explain loss of control of drug intake

Answer 61

(Hnasko, 2005): * Morphine was shown to still have a rewarding effect in dopamine deficient (tyrosine hydroxylase KO) mice. * This implies that dopamine is not required for the reward and addiction.

Answer 62

* LSD [IMPORTANT], Mescaline [IMPORTANT], Psilocybin -\> Agonists of 5-HT_2A receptors * MDMA -\> Stimulate 5-HT release * Cannabinoids [IMPORTANT] -\> CB₁ receptor agonists, leading to inhibition of NT release * Ketamine, Phencyclidine -\> Inhibit NMDA receptors

Answer 63

* Drugs that mimic the symptoms of psychosis, including delusions or delirium, as well as hallucinations. * They cause disturbances in perception and behaviour that cannot be classed as either sedative or stimulant. a.k.a. Hallucinogens

Answer 64

* Molecular mechanisms * Agonists of 5-HT_2Areceptors * Behavioural effects * Distorted perceptions * Hallucinations * Illogical thinking * Heightened sensory awareness * Not euphoric * Therapeutic uses * In the 1960s, some therapists used these as an aid to psychotherapy (e.g. low-doses of LSD helped other treatments be more effective) * Potential antidepressants

Answer 65

* Not because they are ineffective, but because governments have deemed them too dangerous and harmful * However, note how this contradicts the data from (Nutt, 2010), where many psychotomimetics drugs are some of the least dangerous drugs

Answer 66

(Madsen, 2019): * Carried out PET scanning in humans using a radioligand for the 5-HT_2A receptor * This showed that psilocybin binds to these receptors and that occupancy of the receptors by psilocybin is correlated to the intensity of hallucinations

Answer 67

(Cameron, 2021): * Showed that psychedelic drugs induce fast changes in the plasticity of neurons * This could be a potential mechanism for antidepressant action * The experiment involved two-photon imaging neurons in vivo, which showed that the rate of dendritic spine formation in a mouse cortex increased in the 24 hours after psychedelic drugs are administered

Answer 68

* Molecular mechanisms * Stimulates 5-HT release * Behavioural effects * Euphoria * Hallucinations * Feelings of intimacy, empathy * Bruxia, lockjaw * Hyperthermia * May increase the risk of 5-HT neurotoxicity * Therapeutic uses * In the 1960s, some therapists used these as an aid to psychotherapy and also in PTSD * No current clinical use

Answer 69

* Molecular mechanisms * Act on C₁ receptors * This leads to inhibition of neurotransmitter release * Behavioural effects * Feeling of well-being, disinhibition * Sharpening of senses * Amnesia, confusion * May produce dependence * Therapeutic uses * Nausea & vomiting (nabilone) * Neuropathic pain (Sativex) * Anticonvulsant

Answer 70

(Di Forti, 2015): * Showed that everyday or very frequent use of skunk was linked to an increased risk of having psychotic episodes

Answer 71

* Molecular mechanisms * Block NDMA (glutamate) channels * Behavioural effects * Stimulant/depressant * Hallucinations * Feelings of detachment * Staggering gait * Slurred speech * Therapeutic uses * General anaesthetic * Analgesia * Antidepressant

Answer 72

(Marcantoni, 2020): * This systematic review of the efficacy of IV ketamine for treating drug-resistant depression showed that it is an effective antidepressant * The mechanism of action as an antidepressant is uncertain. * Ketamine has recently been made available for prescription for depression.

Answer 73

* Molecular mechanisms * GABA_A potentiation * Inhibition of NMDA receptors * Inhibition of voltage-gated Ca²⁺ channels * Behavioural effects * CNS depressant * Therapeutic uses * N/A

Answer 74

Elevated expression of voltage-gated Ca²⁺ channels

Answer 75

* Metabolites are damaging * Thiamine deficiency (usually due to a poor diet)

Answer 76

* Molecular mechanisms * Facilitate the GABA_A receptor * Behavioural effects * Anxiolytic effects * Therapeutic uses * Anxiety * Insomnia

Answer 77

Altered expression of GABA_A receptor subunits.

Answer 78

New psychoactive substances that are designed to mimic drugs that are already banned, but are not yet illegal.

Answer 79

It is one of the psychoses. It is NOT a mood disorder.

Answer 80

The psychoses can be considered related to the late term "madness", although that term is not used anymore.

Answer 81

* Delusions (false beliefs) * Fully believed despite contrary evidence * Usually have personal signficance * Often are percusatory (e.g. someone is out to get me) * Hallucinations (sensations without an external stimulus) * Lack of insight (unaware of having schizophrenia)

Answer 82

* Positive -\> Delusions, hallucinations, thought disorder * Negative -\> Lack of drive, social interaction, speech

Answer 83

* Number and nature of psychotic symptoms (including ‘first rank symptoms’) * Positive and negative symptoms * Duration * Evidence for functional impairment * Lack of evidence for an ‘organic’ psychosis, mood disorder, autism There are two diagnostic systems: * ICD-11 (World Health Organisation) * DSM-5 (American Psychiatric Association)

Answer 84

* Cognitive impairment is frequently seen in patients with schizophrenia * The degree of impairment is a good predictor of the outcome, rather than just the severity of the symptoms at diagnosis * However, it is rarely used as a diagnostic criterion, since it is hard to measure, etc.

Answer 85

Around 7-70 years, although it is most commonly diagnosed in the 20s.

Answer 86

Equal sex ratio, but men get it earlier and more severely.

Answer 87

* 20% recover * 40% remit and relapse * 40% have chronic symptoms and impairment

Answer 88

* Increased mortality (x3) * This is due to both suicide (~10%) and natural causes, which can be explained by various mechanisms, including lifestyle choices and medication * Life expectancy reduced by \>15 years

Answer 89

* Antipsychotic drugs are D2 receptor blockers (e.g. chlorpromazine, haloperidol, clozapine) -\> Work in about 70% of patients, except clozapine which is more effective but limited by toxicity. Only treat positive symptoms. * CBT for delusions and hallucinations. * Nothing to treat the negative symptoms.

Answer 90

Genetic studies show heritability: * If both parents have schizophrenia, the risk is 40% * If an identical twin has schizophrenia, the risk is 48% Studies have led to the conclusion that schizophrenia is about 80% heritable.

Answer 91

* Adoption studies * Study the children of mothers with schizophrenia who were taken away from the mother by adoption * The children appear to retain the expected increased risk of illness * This supports the idea that schizophrenia is genetic, but does not control for pre- or perinatal environment * Family history * 90% of patients don’t have an affected parent * 60% have no family history at all * This may appear to dismiss the idea that schizophrenia is genetic, but in fact it can be explained by the idea that many genes of small effect underlie schizophrenia

Answer 92

* SNPs (single nucleotide polymorphisms) -\> Cumulatively explain majority of heritability, but individual SNP effects are tiny * CNVs (copy number variants) -\> Lengths of DNA deleted or duplicated. Very rare, but big effect size when present. * Rare variants. (SNVs, indels) -\> Role uncertain, probably minor.

Answer 93

The risk genes converge on several biological pathways: * Glutamate synapses and synaptic plasticity * Immune function (not certain what the importance of this is) * Calcium signalling * Epigenetic regulation The mutations tend to affect regulation of the gene, rather than the actual amino acid sequence of the protein.

Answer 94

* Ventricular enlargement (due to smaller brain) * Decreased brain volume and weight (-3%) * Larger basal ganglia (due to antipsychotics) Most changes in brain size are seen in first episode patients, but many are also seen in at risk individuals. There is essentially a shift towards a smaller mean brain volume, but there is still large overlap with normal patients so this cannot be used as a diagnostic. It is not progressive and there does not appear to be a correlation between brain size and severity of the symptoms.

Answer 95

* Hypofrontality (decreased frontal lobe activity) * Other features depending on symptoms: * Temporal lobe activation during auditory hallucinations * Increased hippocampal activation/blood flow during delusions

Answer 96

* It used to be thought that schizophrenia was caused by upbringing, but this has now been largely dismissed. * Current models are grounded in cognitive neuroscience (e.g. Delusion formation based on failure to integrate sensory perceptions with internal world, or failure to distinguish the two) * Such problems theorised to arise either from perceptual/attentional problems (‘bottom up’) or from cognitive impairments and prefrontal dysfunction (‘top down’) * ‘Aberrant salience’ theory (Kapur) links neuropsychology to dopamine hypothesis

Answer 97

* The dopamine hypothesis is the idea that excess dopamine underlies positive symptoms * PET and SPET show an excess in striatal dopamine: * Is a state not trait -\> Correlates with severity of psychotic symptoms * Begins during the prodrome * The greater the excess, the better the response to antipsychotic drugs * There is reciprocal regulation of striatal and cortical dopamine, so cognitive and negative symptoms may be due to insufficient cortical dopamine

Answer 98

Glutamate model -\> Schizophrenia is due to NDMA receptor hypofunction: * NMDA receptor antagonists induce psychosis; agonists can improve it (in patients and animal models) * Similarly, in schizophrenia, there may be genetic differences in NMDA receptor pathways or antibodies against NMDA receptors It is not certain whether these glutamate abnormalities precede the dopamine abnormalities, or whether they are seen in different cases of schizophrenia.

Answer 99

1. Nature of the neuropathology * Present at onset, if not earlier * Some of the histological changes appear prenatal in origin * Absence of gliosis or neurodegeneration 2. Risk factors are mostly pre- or peri- natal 3. ‘Pre-schizophrenic’ children impaired in motor, behavioural and intellectual functioning 4. Increased rate of minor physical anomalies in schizophrenia 5. Relevant models e.g. neonatal hippocampal lesions

Answer 100

(Ursini, 2018): * Described how placental biology (i.e. environmental risk factors) converge to determine whether the risk genes are expressed and play a role in predisposing to schizophrenia

Answer 101

* Prevalence of dementia rises from 5% to over 30% between the ages of 65 and 85 year old * Each year 150,000 people in UK develop cognitive impairment and memory loss; within 5 years half will have dementia * Alzheimer’s disease costs the country ~£17 billion per year, approximately 20% of the UK health budget * Parkinson’s: second most common neurodegenerative disease: 1% of population at 65; 5% at 85 * Number of people in UK over 60, now out number those under 16

Answer 102

* A term for the impaired ability to remember, think, or make decisions that interferes with doing everyday activities. * It is a collection of symptoms, not a disease in itself. * It usually occurs with age and is often caused by diseases such as Alzheimer's.

Answer 103

* Decreased ability to cope with oxidative stress * For example, Nrf2 is a protein that regulates genes that are crucial for metabolism of drugs/toxins and protection against oxidative stress. * The expression of Nrf2 falls with age. * Altered permeability of BBB: * Decreased secretion *towards* the brain * Decreased removal of toxic compounds *from* the brain * Increased mitochondrial mutations: * Reactive oxygen species (ROS) damage DNA and lead to mutations that decrease their function * Mitochondria mutations may, in part, cause ageing

Answer 104

Alzheimer's disease

Answer 105

* Progressive decline in memory * Factual memory * Short-term memory * Impaired word-finding * Visual and spatial disorientation * Alteration in personality * Agitation, irritability, aggression * Anxiety

Answer 106

Anatomical level: * Progressive cortical pathology with very consistent disease progression * It progresses from the entorhinal cortex progressing to hippocampus Cellular level: * Extracellular plaque formation * Intracellular neurofibrillary tangle formation

Answer 107

* Extracellular deposits of insoluble Aβ peptide * Activates astrocytes and microglia * Aβ peptide is a neurotoxin that requires tau protein for toxicity, meaning that cells lacking tau protein are resistant to toxicity

Answer 108

* Neurofibrillary tangles are made of microtubule associated protein tau (tau protein) * These tau proteins take on a paired helical filament structure and are hyperphosphorylated, as well as ubiquinated.

Answer 109

* No * The threshold hypothesis (Roth, 1986) suggests that all aspects of AD pathology are seen to a lesser extent in normal aged individuals and that AD symptoms occur when normal ageing passes a threshold * However, this has been largely dismissed, since "By the age of 85 virtually everyone will have some neurofibrillary tangles in their cerebral cortex and yet not everyone develops AD.” (Smith, 2002)

Answer 110

Temporal lobe (e.g. hippocampus, etc.) This can be detected by post-mortem histology or by CT scans that show progressive atrophy of the medial temporal lobe, which is correlated with cognitive decline. Spec mentions the "basal forebrain cholinergic systems"

Answer 111

Basal forebrain cholinergic systems

Answer 112

OPTIMA study found that: * The rate of medial temporal lobe thickness decline is up to 10 times greater in Alzheimer's * This suggests that Alzheimer's is a separate disease process and not just a normal part of ageing where AD happens once a threshold is reached

Answer 113

The tau tangles can start forming up to 50 years before diagnosis in the parahippocampal gyrus.

Answer 114

The Nun Study (1991-1993): * Studies 678 nuns who were isolated and had a shared environment and life-style * The nuns wrote a short hand-written autobiography aged ~22 * There was a correlation between the “idea density” and “grammatic complexity” of original autobiography in 93 nuns with cognitive ability and incidence of AD in 1995 “Our findings support a strong relationship between cognitive ability in early life, as indicated by linguistic ability, and cognitive function and Alzheimer's disease in late life."

Answer 115

Late Onset Alzheimer’s Disease (LOAD): * Late onset \>65 years * Vast majority of AD cases * Sporadic, with complex genetic susceptibility Early Onset Alzheimer’s Disease (EOAD): * Early onset \<65 years * More aggressive than LOAD * Accounts for \<1% of AD cases * Mendelian single gene cause They are clinically and neuropathologically extremely similar, meaning that EOAD can be studied to get a better understanding of LOAD.

Answer 116

Amyloid precursor protein (the precursor to Aβ): * Aβ peptide isolated from blood vessels of AD brain, then APP gene mapped to chromosome 21 * Some cases of EOAD linked to chromosome 21 * Now 25 mutations of APP characterised in AD

Answer 117

* APP is a membrane protein with uknonw function * It can be cleaved at various sites * If it is cleaved sequentially at two points by β-secretase and γ-secretase, it can form Aβ peptides * Aβ peptides, especially Aβ 42, are amyloidogenic and form the amyloid that is seen in Alzheimer's disease * The Aβ are usually cleared, but they accumulate in AD * Some early onset AD can be explained by: * Dominant mutations of APP gene * Near the cleavage sites * Increase production of Aβ peptide * Increase production of Aβ 42 peptide * Increase Aβ peptide fibrillisation * Gene dosage (duplications of the APP gene), which increase production of APP * γ-secretase mutations, which increase the formation of Aβ peptide * Early onset AD is rare compared to late onset, but these mutations tell us something about the pathogenesis of AD

Answer 118

Amyloid Cascade Hypothesis: * Aβ is involved in both early-onset (EOAD) and late-onset Alzheimer's disease (LOAD) * The mechanism by which the EOAD and LOAD lead to plaques and tangles is different, but the common factor is the build up of Aβ * EOAD may involve increased production of Aβ, while LOAD involves decreased clearance * Aβ42 forms into amyloid, which leads to a cascade of events * There is microglial and astrocyte activation, increased inflammation and then tau tangle formation within cells, leading to widespread neuronal loss and dementia However, this is just a theory and it has come under some criticism.

Answer 119

Aβ deposition as amyloid plaque leads to a cascade of events, including neurofibrillary tangles.

Answer 120

Removal of amyloid plaque should be a useful treatment for AD, since amyloid is the initiating event of the pathogenesis of AD.

Answer 121

* Active immunisation of patients with AD (via administration of Aβ42 and an adjuvant) leads to the production of antibodies * This leads to the removal of Aβ deposits from brain, but the degree of this is highly variable between patients * There was also no change in cognitive decline when the plaques were removed * This seems to argue against the amyloid cascade hypothesis -\> However, it can be explained by the idea that the amyloid initiates the intracellular tangle formation, which is self-sufficient once initiated, meaning that the amyloid removal has no effect.

Answer 122

EOAD is often caused by one dominant gene mutation (e.g. in APP), while LOAD involves multiple genes coming together, which individually might have tiny penetrance and are therefore difficult to find.

Answer 123

* ApoE -\> Involved in lipoprotein transport in blood * Having two ApoE4 alleles increases your risk of LOAD 4-fold compared to the most common ApoE homozygous phenotype * The mechanism for why this happens is unknown

Answer 124

* Slowness to move (bradykinesia) * Inability to move (akinesia) * Resting tremor * Postural instability

Answer 125

* Degeneration of midbrain dopaminergic neurons projecting from substantia nigra pars compacta to striatum * This degeneration is due to Lewy bodies, which are aggregations containing α-synuclein * Loss of dopamine in the striatum * Relentlessly progressive

Answer 126

α-synuclein (it is deposited, forming Lewy bodies)

Answer 127

α-synuclein mutations. These are most commonly duplications or triplications, which can be detected using fluorescent in situ hybridisation.

Answer 128

* Enormous metabolic demand -\> Predisposes to oxidative stress * Dopamine is a highly cytotoxic chemical

Answer 129

(Fearnley and Lees, 1991): * Compared controls and PD patients * Controls showed a linear loss of pigmented neurons in SNpc, with an average of 4.7% per decade. * PD patients showed exponential loss of pigmented neurons, with 45% loss in first decade. The pattern of loss within the brain was also different. * This shows that PD is not just a normal part of ageing, but a different disease process.

Answer 130

* Cognition is on a specturm, becoming more widely distributed with age * Between normality and dementia, there is a state of mild cognitive impairment, which can be considered as the prodrome of dementia

Answer 131

* Most types of cognition decline with age, including: * Working memory * Processing speed * Long-term memory * Reasoning * The only exception is semantic memory and crystallised intelligence.

Answer 132

No, different parts atrophy to different extents. The hippocampus in particular tends to atrophy significantly.

Answer 133

A chart developed to help record the functional deficiencies that patients with various brain lesions have.

Answer 134

It is preserved, but it might just take longer.

Answer 135

(Cabeza, 2002): * Studied participants performing a language task * Young participants showed high asymmetry between the hemispheres * Low-functioning older participants maintained this symmetry, but had low brain activity * High-functioning older participants did not show such great asymmetry but showed much higher activity in both hemispheres This can be explained by several theories: * Compensation -\> There is additional recruitment of neural activity to maintain performance * De-differentiation -\> There is loss of regional specificity * Scaffolding -\> There is a dynamic ongoing process of plasticity

Answer 136

* Cross-sectional studies tend to over-estimate the effects of ageing because younger participants are likely to be more familiar with technology used (e.g. tablets) * Longitudinal studies tend to under-estimate the effects of ageing because the participants get used to the method of assessing them and therefore do not appear to decline as much

Answer 137

1. Overactivity of relevant brain areas when performing a task (Smith, 2001) 2. Reductions in hemispheric asymmetry in functions such as language (Cabeza, 2002) 3. Shift from posterior to anterior brain activity (Davis, 2008)

Answer 138

* Late onset is typically sporadic * Early onset is typically familial (genetic)

Answer 139

* Alzheimer's disease -\> 60-80% * Fronto-temporal dementia -\> 5-20% * Vascular dementia -\> 5-15% * Lewy body disease -\> 2-8% * Creutzfeldt–Jakob disease (prion disease) -\> Rare

Answer 140

* Prevalence: 60-80% * Pathology: Amyloid plaques and tau tangles * Site/Features: Medial temporal lobe and parietal lobe -\> Then progresses to frontal areas

Answer 141

* Prevalence: 5-20% * Pathology: Several subtypes involving the aggregation of proteins such as tau, TDP43 or FUS * Site/Features: Frontal lobe (behavioural symptoms) or temporal lobe (semantic/aphasia symptoms)

Answer 142

* Prevalence: 5-15% * Pathology: Vascular pathology (e.g stroke) * Site/Features: Can be anywhere, Sudden changes, Step-wise progression

Answer 143

* Both show forgetfulness, impaired memory, confusion and degrees of paranoia. * Dementia shows a progressive gradual decline. * Delirium shows a fluctuating course, sudden onset, with short duration, and impaired attention and awareness.

Answer 144

* Prevalence: 2-8% * Pathology: Lewy bodies (also seen in Parkinson's disease) * Site/Features: Motor symptoms, Sleep disturbance (similar to in Parkinson's disease), Visual hallucinations, Fluctuating deficits

Answer 145

* Prevalence: Rare * Pathology: Prion protein deposition * Site/Features: ADD

Answer 146

A set of symptoms including memory loss, mood changes and problems with communicating and reasoning.

Answer 147

* Multiple cognitive deficits (including amnesia) * Functional impairment * Clear consciousness * Change from previous level * Long duration (\> 6 months)

Answer 148

* MMSE - Mini-mental state examination. Maximum score 30. MCI \< 27; AD \< 25 * ACE-R - Addenbrooke’s Cognitive Examination (revised): Includes MMSE, but more detail. Maximum score = 100, AD \< 88 * MOCA - Montreal Cognitive Assessment: Maximum score 30. HC = 25-29; MCI = 19-25; MD = 11-21

Answer 149

* Parkinson's disease * Stroke * Depression

Answer 150

* Dementia -\> Neurodegenerative, Vascular, etc. * Delirium -\> Metabolic disturbances (e.g. hypoxia, hypoglycaemia, etc.), etc. Both can be caused by toxins and infections.

Answer 151

When drug-seeking and use becomes compulsive despite negative consequences e.g. health risk physical and mental, inability to sustain normal social interactions, relationships or job, dissolution of family, child neglect

Answer 152

Yes, the American Society of Addiction Medicine 2011 defines it as: “A primary, chronic disease of brain reward, motivation, memory and related circuitry” characterized by the “inability to consistently abstain, impairment in behavioural control, craving, diminished recognition of significant problems with one’s behaviors and interpersonal relationships, and a dysfunctional emotional response”

Answer 153

GPCRs: * Opoids * Cannabinoids Ionotropic receptors: * Nicotine * Alcohol * Benzodiazepines Monoamine transporters: * Cocaine * Amphetamines

Answer 154

Their ability to increase dopamine transmission, especially in the nucleus accumbens (part of the striatum) via the mesolimbic (reward) pathway. Drugs that do not affect dopamine signalling are not addictive.

Answer 155

* The mesolimbic pathway features dopaminergic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NA) in the striatum * It is known as the reward pathway, but its role is more refined than that * (Hollerman & Schultz, 1998): * Found that there is an increase in dopamine firing when an animal receives an unexpected reward after an action/stimulus * Also found that there is a decrease in dopamine firing when an animal receives no reward after a action/stimulus (i.e. error) * However, this effect is lost once the animal learns to associate the correct action/stimulus with the reward * Instead, there is now dopamine firing after the conditioned stimulus, but not after the reward * This suggests there are two roles for the mesolimbic pathway: * Reward prediction error learning -\> Promotes learning about reward * Rewarding predictions or cues -\> Promotes reward-seeking behaviour

Answer 156

* Avoiding negative reinforcement? (i.e. Withdrawal avoidance) * Neuroplastic changes in synaptic strength throughout brain and gene expression * Maladaptive learning that leads to enhanced response to drug-seeking cues: cue-induced craving and drug-seeking habit * Impaired self-regulation (impaired cognitive control)

Answer 157

(Ungless, 2001) and (Saal, 2003): * Used the ratio of AMPA:NMDA receptors as an indicator of the strength of glutamatergic synapses between glutamate neurons and dopamine neurons of the mesolimbic pathway (i.e. the VTA neurons) * Found that there was long-term potentiation at these synapses upon long-term use of cocaine, amphetamines, morphine, nicotine and ethanol (Robinson & Kolb, 1997): * Found that drug sensitization is accompanied by visible changes to neuronal structure, namely changes in dendritic structure in the striatum

Answer 158

* There are changes in drug expression * These include up-regulation of growth/transcription/ chromatin/histone regulators e.g. BDNF, cFos, deltaFosB, CREB, epigenetic factors * These changes produce long-lasting changes in neuronal function that can last for several months

Answer 159

* Stimuli that are related to the drug taking environment, such that have acquired a behavioural salience (i.e. they have become conditioned stimuli). * For example, a lighter may be a drug-seeking cue for a smoker. * Environmental drug-associated cues drive craving and maintain drug-seeking habits.

Answer 160

* Initial acquisition of drug-seeking behaviour depends on dopamine in nucleus accumbens (ventral striatum), but dopamine antagonists in dorsal striatum not nucleus accumbens diminish cue-induced cocaine seeking (Vanderschuren, 2005) * Cue-elicited craving in human addicts activates dopamine release in dorsal striatum (Volkow, 2006)

Answer 161

Volkow showed that there was decreased prefrontal cortex activity in addicted individuals compared to non-addicted individuals and also suggested that executive control may be insufficient compared to the drive, reward and memory systems, such that there is impaired decision making.

Answer 162

3 main causes: * Drugs -\> Even just taking the drug once ("one more puff") will reinforce all of the circuit and reset the addiction * Drug-associated cues -\> Induce craving * Stress -\> Drives drug-seeking behaviour

Answer 163

Schizophrenia

Answer 164

Anti-cholinesterases may be used to increase cholinergic transmission.

25. Psychiatric Disorders and Psychopharmacology (HT) Flashcards

(211 cards)